research about aids

CDC provides national leadership for HIV prevention research, including the development and evaluation of HIV biomedical and behavioral interventions to prevent HIV transmission and reduce HIV disease progression in the United States and internationally. CDC’s research efforts also include identifying those scientifically proven, cost-effective, and scalable interventions and prevention strategies to be implemented as part of a high-impact prevention approach for maximal impact on the HIV epidemic.

The AIDS epidemic, although first recognized only 20 years ago, has had a profound impact in communities throughout the United States.

The Serostatus Approach to Fighting the HIV Epidemic: Prevention Strategies for Infected Individuals R. S. Janssen, D. R. Holtgrave, and K. M. De Cock led the writing of this commentary. R. O. Valdiserri, M. Shepherd, and H. D. Gayle contributed ideas and helped with writing and reviewing the manuscript.

CDC has provided funding to HIV partners to help implement programs that will help curb the increase of HIV infections. These programs facilitated with our partners and grantees are critical in the goal of eliminating HIV infection in the United States.

CDC has researched several HIV prevention interventions that have proven effective in helping to prevent HIV infection in certain populations and communities.

CDC has worked with key cities to create effective policies and programs to curb the tide of HIV infections in those cities. These cities have higher rates of HIV due to a number of factors therefore making them key locations for studies.

The Medical Monitoring Project (MMP) is a surveillance system designed to learn more about the experiences and needs of people who are living with HIV. It is supported by several government agencies and conducted by state and local health departments along with the Centers for Disease Control and Prevention.

• Assessment of 2010 CDC-funded Health Department HIV Testing Spending and Outcomes pdf icon [PDF – 359 KB]
• HIV Testing Trends in the United States, 2000-2011 pdf icon [PDF – 1 MB]
• HIV Testing at CDC-Funded Sites, United States, Puerto Rico, and the U.S. Virgin Islands, 2010 pdf icon [PDF – 691 KB]
• HIV Prevention Funding Allocations at CDC-Funded State and Local Health Departments, 2010 pdf icon [PDF – 792 KB]

Cost-effectiveness of HIV Prevention

• The cost-effectiveness of HIV prevention efforts has long been a criterion in setting program priorities. The basic principle is straightforward: choose those options that provide the greatest outcome for the least cost.
• The fact sheet Projecting Possible Future Courses of the HIV Epidemic in the United States pdf icon compares the cost-effectiveness of three different prevention investment scenarios.

The HIV/AIDS Prevention Research Synthesis (PRS) Project identifies evidence-based HIV behavioral interventions (EBIs) listed in the Compendium of Evidence-Based HIV Behavioral Interventions to help HIV prevention planners and providers in the United States choose the interventions most appropriate for their communities.

• On January 1, 2012, CDC began a new 5-year HIV prevention funding cycle with health departments, awarding $339 million annually.
• The STD/HIV National Network of Prevention Training Centers provides training for health departments and CBOs on the HIV prevention interventions.
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Nih…turning discovery into health ®.

On June 5, 1981, federal health officials reported the first cases of a new and fatal disease. Since then, acquired immunodeficiency syndrome, or AIDS, has become one of the deadliest pandemics in history. Today, more than a million people in the United States are living with HIV/AIDS.

In the late 1980s, the no effective therapies were available. But in 1989, NIH researchers made several major discoveries about how the human immunodeficiency virus (HIV) destroys the body’s immune system and ultimately leads to full-blown AIDS.

In 1996, NIH-funded scientists discovered a new class of drugs, known as protease inhibitors. When used in combination with other AIDS drugs, these medicines attack HIV in several ways at once, extending the lives of HIV-infected people.

The discovery and development of new drugs have turned HIV infection from a death sentence into a chronic disease for those who have access to, and can tolerate, these powerful medicines.

Today, in the United States, there is less than a 1% chance that a child will become infected by his or her HIV-infected mother if she is taking anti-HIV medicines.

NIH continues a vigorous HIV/AIDS research program to study the basic biology of HIV and related complications, as well as to develop and test new drugs and prevention approaches.

Imagine the Future… 

• New medicines and prevention stem the spread of HIV/AIDS in the developing world. 
• The ultimate defeat of HIV/AIDS is a toolkit of HIV prevention interventions, including safe, effective, and widely available vaccines, microbicides, and behavioral interventions.

Next: Influenza »

This page last reviewed on October 7, 2015

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HIV/AIDS: Current Updates on the Disease, Treatment and Prevention

Praveen kumar gupta.

Department of Biotechnology, R.V College of Engineering, Bangalore, 560059 India

Apoorva Saxena

CCR5-delta 32 homozygous stem cell transplantation for HIV-infected individuals is being treated as a milestone in the global AIDS epidemic. Since 2008, when the second Berlin patient was cured from HIV after undergoing transplantation from a donor with delta-32 mutation, scientists are aiming for a long-term cure for the wider population. In 2019, a London patient became the second person to be free of HIV and came off the antiretroviral drugs completely. CCR5 gene is now being treated as a viable target for HIV treatment. It can be used in the treatment of HIV either through administration of drugs that bind to CCR5 and stop the receptor from working or through gene therapy to alter the CCR5 gene using CRISPR/Cas9 and prevent protein production. This review article aims to identify the obstacles and the need to overcome them in order to bridge the gap between current research and future potential cures for HIV.

Introduction

Human immunodeficiency virus or HIV is the cause of HIV infection that leads to the autoimmune disorder acquired immune deficiency syndrome (AIDS) [ 1 ] (Fig.  1 ). The major cause of spreading of HIV is through unprotected sex, during pregnancy from mother to foetus, through contaminated hypodermic needles and infected blood transfusions [ 1 ]. In the year 2016, an estimated 37 million people were living with HIV and 1 million deaths were reported. HIV/AIDS is a pandemic condition—an epidemic of diseases that spreads across large areas like multiple continents or even worldwide [ 1 ]. The first time AIDS was recognized was in the year 1981 by the United States Center for Disease Control and Prevention (CDC). Since the reported case of an individual who had successfully undergone a stem cell transplant from a person who showed a homozygous CCR5-delta 32 mutation, after receiving extensive high dose chemotherapy, there has been a greater interest in finding a potential cure.

Human Immunodeficiency Virus [ 5 ]

HIV is a type of retrovirus that adversely infects the immune system of a human, mainly targeting the CD4 + T-helper cells, accessory cells and the macrophages [ 2 ]. When it gains entry into the target cell, the viral genomic RNA undergoes a process of the reverse transcription with the help of reverse transcriptase enzyme and forms double stranded DNA (ds-DNA). This ds-DNA then gets integrated into the target cellular DNA with the help of enzyme integrase and other host co-factors [ 3 ]. The virus now can either become dormant or conceal itself and the target cell detection by the host immune system or it can get transcribed into new viral RNA and proteins that are released from the cell and begin the cycle again. HIV can be characterized into 2 major classes—HIV-1 and HIV-2. HIV-1, which is more virulent, infective and the major cause of HIV in humans, was discovered first and was initially referred to as HTLV-III or LAV [ 4 ] (Fig.  2 ). HIV-2 is less infective and far fewer people exposed to it are infected.

Structure of HIV-1 [ 8 ]

The crucial factor in gaining entry into target cell is through binding of HIV to the CD4 receptor present on the T-helper cells and to one of the chemokine receptors- either CCR5 or CXCR4 [ 6 , 7 ]. Binding to the co-receptor depends on the virus’s tropism which is the ability to bind to a specific receptor. Naturally, there are two types of tropic strains—R5 that bind to CCR5 and X4 which bind to CXCR4. Dual tropic strains are capable of binding to both. Of these two co-receptors, CCR5 is the prime receptor for virus’s entry into the target cell. R5-tropic strains prevail during early stages of infection, whereas the X4-tropic strains emerge later with disease progression. The envelope-like glycoprotein structure of HIV-1 is paramount in ensuring the viral entry into a target host cell [ 7 ]. This glycoprotein has 2 protein subunits: the gp41 (transmembrane) subunit and gp120 (external) subunit, which mimics a chemokine [ 6 , 7 ]. It does not manifest the unique structure of the chemokine but somehow manages to bind to both the co-receptors [ 6 ]. It forms a heterotrimeric complex wherein the gp120 subunit binds to the CD4 protein and specific co-receptor present on the target cell [ 6 ]. When this complex is formed, it triggers the release of a peptide which facilitates cell–cell fusion, that causes the viral membrane to fuse with the target cell membrane [ 6 ]. Binding to CD4 alone is not sufficient as it can result in gp120 shedding. So, it has to bind to the specific co-receptor for the fusion to proceed. The V1–V2 region of gp120 is recognized by the co-receptor, that influences which co-receptor will bind to the protein and is determined by degree of N-linked glycosylation and peptide composition. The highly variable V3 loop is the one that determines co-receptor specificity. The binding of gp120 glycoprotein to the CCR5 co-receptor is determined by two essential factors—the tyrosine-sulphated amino terminus of CCR5 receptor and following which there must be reciprocal action between the transmembrane domains of CCR5 and gp120 protein, i.e., inter-communication and synergy.

Antiretroviral Therapy

The usage of a combination of three or more antiretroviral drugs for suppression of the HIV infection is called antiretroviral therapy. Using multiple drugs in combination to increase the effectivity on various viral targets is called highly active antiretroviral therapy (HAART). It helps in maintaining the immune system to function, preventing HIV from developing resistance and other infections that potentially lead to death. The five classes of drugs used in combination to treat HIV infection are: entry inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors.

Zidovudine/ZVD (also called azidothymidine) is an extensively used antiretroviral medication [ 9 ]. It is a thymidine analogue and is dosed twice daily in combination with other antiretrovirals. Its function is to particularly inhibit the reverse transcriptase enzyme which is necessary for the production of ds-DNA.

Cellular enzymes are used in converting AZT into the 5′-triphosphate form. Research studies suggest that the termination of forming ds-DNA chains is a crucial factor that leads to an inhibitory effect.

Studies have also shown that at very high dosage of this drug, its triphosphate form may inhibit the DNA polymerase enzyme which is used for cell division by the uninfected cells and mitochondria for replication. It may lead to toxic but reversible effects on certain skeletal and the cardiac muscles, causing the condition of myositis [ 10 ]. However, zidovudine also shows greater affinity for the reverse transcriptase enzyme, which is around 100-fold. This selectivity has been proven by the cell's ability to quickly repair its DNA strands if broken by AZT during its formation, whereas the HIV virus will lack this ability (Fig.  3 ).

Structure of zidovudine [ 11 ]

Zidovudine is commonly used in combination with nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, HIV integrase strand transfer inhibitor and protease inhibitor [ 9 ]. The combination of lamivudine and zidovudine is not recommended for non-pregnant HIV-infected adults and adolescents due to greater toxicity but is used as an alternative, though not a preferred one, in antiretroviral-naive pregnant women as an initial treatment [ 9 ]. However, for paediatric patients (neonates, infants and children of age 12 or less), zidovudine with lamivudine/emtricitabine is a preferred option. For adolescents greater than the age of 12, it is an alternative [ 9 ].

Zidovudine Administration and Pharmacokinetics

Administration and dosage.

It is usually administered orally or by continuous IV infusion, although not rapid infusion and IM injection [ 9 ] (Tables ​ (Tables1, 1 , ​ ,2). 2 ). The dosage for paediatric patients and adult patients depends on their body weight (Tables ​ (Tables3, 3 , ​ ,4 4 ).

Oral administration [ 9 ]

IV administration [ 9 ]

Dosage for paediatric patients [ 9 ]

Dosage for adult patients [ 9 ]

Administration

Zidovudine: 1 mg/kg every 4 h [ 9 ].

Pharmacokinetics

Pharmacokinetics gives a detailed view of the fate of drugs in the human system. It includes various components like absorption, distribution, excretion or elimination and metabolism (Tables ​ (Tables5, 5 , ​ ,6, 6 , ​ ,7). 7 ). The stability of such retroviral drugs should also be taken into account for both oral and parenteral dosage forms (Table ​ (Table8 8 ).

Absorption [ 9 ]

Distribution [ 9 ]

Elimination process [ 9 ]

Stability of antiretrovirals [ 9 ]

Contraindications [ 9 ]

• Zidovudine has a history of life-threatening hypersensitivity reactions like Stevens–Johnson syndrome and anaphylaxis to the drug or maybe due to some ingredient in the formulation.
• Lamivudine/zidovudine: hypersensitivity history.
• Abacavir/zidovudine/lamivudine: history of hypersensitivity to abacavir, zidovudine or lamivudine; hepatic impairments may be mild or severe.

CCR5 Gene Structure

C–C chemokine receptor type 5 (also called CCR5 or CD195) is a receptor for chemokines present on the white blood cells. The CCR5 gene in humans is located on the short arm (p) at position 21 on chromosome number 3 (Fig.  4 ). It is mainly expressed cells like T-cells, macrophages, microglia, dendritic cells and eosinophils and is found within a cluster of genes coding for some other receptors like XCR1, CCBP2, etc. [ 12 , 13 ]. The gene has two promoters, three exons and two introns. Pu or PR2, the upstream promoter, has a 1.9 kb region, 57 bp in length and precedes the exon 1 [ 12 ]. Exon 1, which is the start of the coding region, is followed by the first intron, 501 bp in length. The second exon 2 is intron-less. It is found as exon 2a, 235 bp in length, and exon 2b, 54 bp in length. Pd or PR1, the second promoter, accommodates the intron 1 and exon 2 regions [ 12 ]. A 1.9 kb length intron is located between exon 2 and exon 3. Exon 3 is also intron-less and consists of the full ORF of the CCR5 gene, 11 bp of the 5′ untranslated regions and the complete 3′ untranslated regions [ 12 ].

Location of CCR5 gene on chromosome 21 [ 14 ]

These two promoters are devoid of the consensus TATA and CCAAT sequences, although the Pd promoter has a non-consensus TATA sequence and have an unusually high content of pyrimidine in them [ 12 ]. The upstream Pu promoter was found to be weaker than the downstream Pd promoter which had exhibited up to fivefold greater activity. But these results were established as erroneous [ 13 ]. With the help of RT-PCR technique, it was later identified that the Pu promoter was used in stimulated T-cells and the Pd promoter was used in unstimulated primary T-cells [ 13 ]. The error resulted due to the use of transformed T-cells affecting the overall expression of CCR5 protein via the Pu promoter [ 13 ]. Results also showed that transcription of the CCR5 gene when controlled by the Pu promoter containing exon 1 resulted in CCR5A or B and when controlled by the Pd promoter resulted in truncated isoforms [ 13 ].

CCR5 Gene Expression Regulation

The expression of CCR5 gene is regulated at three levels: 1. genetic factors, 2. factors involved in activation, signalling and trafficking of the receptor which includes desensitization, internalization and recycling and 3. environmental triggers [ 13 ].

CCR5 receptor is part of the G-protein coupled receptor family, which binds to its ligand and releases αi and βγ G-protein subunits. This results in a mediated effector response. Such responses stimulate the release of phospholipase Cβ and adenylyl cyclase. This in turn facilitates the release of intracellular calcium and form inositol triphosphate [ 13 ]. This leads to activation of phosphorylation of the CCR5 receptor which occurs at the serine and C-terminal residues via protein kinase C and G-protein coupled receptor kinases [ 13 ]. The regulatory proteins, β-arrestin 1 and 2, bind to the activated serine and the conserved DRY motif in the intracellular loop [ 13 ]. The β-arrestin proteins have functions like desensitizing the receptor to further stimulation and participating in endocytosis. The CCR5 expression level is controlled by the rates of recycling and endocytosis [ 13 ]. In the endocytosis process, β-arrestin protein facilitates the binding process between clathrin-coated pits and the phosphorylated receptor. Infection and entry of HIV into cells do not require CCR5 signalling, but the chemokine-induced endocytosis decreases the available receptor for HIV entry. This is the process of chemokine-mediated anti-HIV activity [ 13 ].

Environmental factors affecting CCR5 expression are infectious pathogenic agents like Mycobacterium tuberculosis , which increases the CCR5 expression. Studies have shown that CCR5 expression is considerably increased in all leukocyte subset cells during tuberculosis and dual infection with HIV [ 13 ]. However, the level of CCR5 expression on CD4 + T-cells was not increased. Conversely, it was also shown that HIV affects the level of expression of CCR5, due to a correlation with HIV disease progression. Individuals with end stage HIV were shown to have the highest percentages of CCR5 expressing CD4 + T-cells [ 13 ].

The regulation of CCR5 is complex. The introns as well as sequences in the 5′ UTR and 3′ UTR affect CCR5 gene regulation [ 13 ]. Therefore, mutations in these regions should be considered critical in the regulation process.

CCR5-Delta 32 Mutation

The discovery of CCR5-delta 32 mutation in the CCR5 gene in 1996 which exhibited some protection against HIV was a ground breaking one. Studies showed that the CD4 + T-cells when expressing this mutation prevented HIV envelope fusion [ 12 ] (Fig.  5 ). The mutant allele has a length of 215 in comparison to the wild type which contains 352 amino acid residues [ 13 ]. This mutation basically results due to the deletion of 32 base pairs from the position of nucleotides starting from 794 till 825, a frameshift mutation, and seven new amino acids are incorporated between amino acid 174 and stop codon at amino acid 182 [ 13 ] (Fig.  6 ). This mutation affects the region of second extracellular loop where the resultant protein lacked the last three transmembrane domains and also some regions necessary for G-protein interaction and signal transduction.

Comparison of HIV infecting cell with CCR5 and without CCR5 [ 15 ]

Difference between wild type CCR5 and CCR5-delta 32 [ 16 ]

This mutation is majorly restricted to people of European descent. The gene frequencies are found to be around 10% and shows a decline from north to south latitude. A 2–5% gene frequency in Europe, the Middle East and parts of the Indian subcontinent was observed in more than 3000 individuals. The highest frequency, at 20.93%, was discovered in the Ashkenazi Jewish population. The mutant allele is absent in Black populations excluding the African American group who may have acquired the mutation through genetic admixture [ 13 ].

The origin of the delta-32 mutant allele has been dated back to the year 275–1875, which increased over a period of time as a result of selective pressure, mainly the Black plague. However, historical data have shown that Black plague may not in fact be the cause [ 13 ]. The distribution of the delta-32 mutant allele in a north to south gradient does not correlate to the casualties of the plague and instead follows a south to the north gradient. The Black plague has shown the greatest casualties in areas like the Mediterranean region and China, with lowest allele frequencies of the mutation [ 13 ].

Studies suggested that delta-32 arose without a selective event. Tandem repeats found in the coding region of the CCR5 gene could cause unequal homologous recombination, which results in the delta-32 allele. The origins of the delta-32 mutation, however, remain a mystery [ 13 ].

The hype about the delta-32 mutation comes from its ability to protect homozygous individuals from HIV. The protective effect of the delta-32 mutation is a result of eliminating the expression of CCR5 protein on the cell surface, which prevents HIV’s entry into the cell. In the year 1997, however, studies showed that some of them having the homozygous delta-32 mutation were HIV-infected [ 13 ]. Further studies revealed the HIV virus was of the X4 type, which led to very rapid CD4 + T cell decline. Hence, this mutation is limited in its function and does not protect against viral strains which utilize other receptors or show dual-tropism [ 13 ].

In contrast, however, the delta-32 protein product which is localized to the endoplasmic reticulum is an important factor. It is shown to exert a trans-dominant negative effect on the wild-type CCR5 protein, which inhibits its transport to the cell surface. Further analysis in vitro showed the reduction of surface expression of wild type CCR5 and CXCR4 through dimerization by this mutant protein product [ 13 ]. This confers an inhibition to R5, X4 and R5X4 HIV infections [ 13 ]. Homozygous delta-32 individuals with this mutant protein were shown to have suppressed CXCR4 surface protein expression and decreased susceptibility to X4 infection. Experimental proofs also suggested that delta-32 heterozygous individuals with HIV infection do not stably express the mutant protein, are devoid of the molecular mechanism of complete protection and only maybe partially protected [ 13 ].

Stem Cell Transplantation

Stem cells are undifferentiated cells that can differentiate into specialized cells and can also undergo mitosis to produce more stem cells. There are mainly two classes—embryonic stem cells (ECS) and adult stem cells. Stem cells are also taken from the umbilical cord blood just after birth. These act as a repair mechanism for the body, such as skin, blood or intestinal tissues. Adult stem cells are majorly used in medical therapies like bone marrow transplantation. Bone marrow is the spongy tissue present inside the bones which serves as a rich source of adult stem cells. Long-term control of HIV is possible with CCR5-delta 32 stem cell transplantation [ 13 ].

Allogeneic transplantation of stem cells with this mutation in patients with HIV infection and malignancy has been considered as an option since the late 1990s (Fig.  7 ). Human leukocyte antigen (HLA) is a critical factor to be considered during the process of transplantation. The HLA should be a proper match; otherwise, it would lead to rejection by the recipient’s immune system. The limited availability of HLA-matched unrelated donors has made it even more difficult. Only about 1% of Caucasians possess this CCR5 null allele [ 13 ].

Allogeneic hematopoietic stem cell transplant [ 17 ]

Gene Therapy

Zinc finger nuclease technology is a popular tool which can be used for targeting specific DNA sequences in the genome. It falls in the class of restriction enzymes and is artificially made by fusing a zinc finger DNA-binding domain and DNA-cleavage domain. This technique is also engineered to eliminate the CCR5 expression over CD4 + T-cells, and the modified cells have shown to have a half-life of 48 weeks [ 13 ]. But it has its own issues. It is difficult to ensure that the desired repair mechanism is one which is used to repair the double stranded break (DBS) [ 13 ]. It is also challenging to scale it upwards and is an expensive technique.

A breakthrough technique, the CRISPR/Cas9 gene-editing system, is also used to eliminate the CCR5 receptor on the blood stem cells which can give rise to differentiated blood cells that are devoid of this receptor [ 18 ] (Fig.  8 ). These gene-edited stem cells can be established into an HIV-infected patient through bone marrow transplantation and give rise to an HIV-resistant immune system [ 18 ]. This technique, however, can also go sideways which leads to unwanted results that can cause ethical issues to rise. As seen in the highly controversial case of the Chinese scientist, He Jiankui, who with the help of this technology deleted the CCR5 gene in the twins, Lulu and Nana, introduced some unintended mutations in their genetic codes. There is still a lot of research needed to make this technology bioethically a safe tool.

CRISPR/Cas9 gene editing [ 19 ]

Researchers have also engineered a molecule called the chimeric antigen receptor (CAR) and introduced a gene for that molecule into blood-forming stem cells [ 18 ]. This molecule has two receptors that will recognize the antigen (HIV) and direct the immune cells to locate and kill the HIV-infected cells [ 18 ]. When transplanted into mice, which would have the CAR-carrying blood stem cells, it would result in reduced levels of HIV by inducing the immune cells to fight effectively against the virus [ 18 ]. An 80% to 95% drop in viral load was observed in the mice [ 18 ]. It was concluded that gene therapy could be a feasible option for treatment in HIV-positive humans.

Immunological Approaches

Studies have shown that vaccine can contribute effectively in viral clearance such as the Rhesus CMV vaccine vector [ 18 ]. A vaccine vector is a kind of vaccine which consists of chemically weakened viruses that are transported in the body to generate an immune response. The genes used in these vaccines are antigen coding surface proteins from that particular pathogen.

SAV001-H is the first and only preventive HIV vaccine which uses killed HIV-1 virus [ 18 ]. It is unique from other vaccines, as it uses genetically engineered whole virus genome, eliminating its pathogenicity and inactivating its virulence through irradiation and chemical treatments, finally approaching to the first “whole-killed virus”-based HIV vaccine [ 18 ]. The results of Phase 1 clinical trial, which were completed in the year 2013, were found to have serious and adverse effects in the 33 participants [ 18 ]. There was also a surprising boost in the antibody production against p24 and gp120. The HIV viral core is mostly made up of the structural protein, p24, which is called the capsid. A crucial factor in the diagnosis of primary HIV-infected individuals is the p24 antigen assay. High levels of p24 are found in the blood serum during the period between infection and seroconversion. The antibody production is found to increase as much as 64-fold [ 18 ]. The antibody production against gp120, which is a glycoprotein, necessary for attachment to a cell receptor and allow HIV entry, is found to increase up to eight-fold [ 18 ].

Another promising vaccine called the Kang's vaccine also uses the “whole-killed HIV-1,” which is similar to vaccines developed for rabies, polio and influenza [ 18 ]. However, HIV-1 is genetically engineered in such vaccines and raises questions about safety and possibility of large quantity production.

Researchers have also tested an immunogen called eOD-GT8 60mer, a protein nanoparticle, which is designed to mimic a crucial part of the HIV envelope protein which will bind to and activate the B cells to produce plasma cells that secrete antibodies needed to fight HIV [ 18 ]. This nanoparticle was developed in the Schief laboratory and tested in mouse models engineered by the Nemazee laboratory [ 18 ]. The researchers showed that immunization with eOD-GT8 60mer produced antibody progenitors with some of the characters crucial to recognize and block the HIV infection, proposing that it could be a promising first step in a series of immunizations against HIV [ 18 ]. The vaccine appears to work well in mouse models. The researchers are now investigating other immunogens that could work in coexistence with eOD-GT8 60mer [ 18 ].

Case Studies

The berlin patient [ 20 ].

The strongest proof available in favour of a HIV cure stems from the case of Timothy Brown who is popularly known as the Berlin patient (Fig.  9 ). He is considered the first person ever to be cured of HIV. The victory was predicated on doctors taking advantage of nature’s own experiment—the genetic mutation of CCR5 gene that produces a protein co-receptor present on the surface of CD4 + T-cells that HIV uses to gain entry. He was attending university in Berlin when was diagnosed HIV positive. His initial treatment include ART, and he was taking low doses of zidovudine and protease inhibitors. He continued to live a normal life for the next 10 years. But one day, he was again feeling extremely exhausted and the doctor had diagnosed it to be anaemia. He had received red blood cell transfusion for nearly a week and was then sent to an oncologist, Dr Huetter, when the previous doctor was unable to resolve the situation. The oncologist performed a painful bone marrow biopsy and after further diagnosis he was informed that he had acute myeloid leukaemia (AML).

Timothy Ray Brown a.k.a. “The Berlin patient” [ 21 ]

He then started receiving treatment at one of the Berlin University hospitals and had to receive four rounds of chemotherapy treatment. During the third round of chemotherapy, he had gotten a fatally dangerous infection and was immediately put into an induced coma. His blood sample was collected and sent to a stem cell donor bank with the German Red Cross to find matches in case he needed transplantation. Luckily, he had 267 matches which sparked an idea to locate donors with a homozygous CCR5 delta-32 mutation on CD4 + T-cells who are almost immune to HIV infection. A donor was found at the 61st attempt and had agreed to donate when necessary (Fig.  10 ).

Adam Castillejo a.k.a “The London patient” [ 23 ]

However, Timothy Brown had been reluctant and had said no to transplantation as the success rate was only 50–50. But at the end of 2006, leukaemia had rebounded and he desperately needed transplantation to survive. He received the stem cell transplant on February 6, 2007 and stopped taking his antiretroviral medication. Nearly 3 months after he underwent transplantation, HIV was no longer found in his body and he had thrived until the end of the year.

Unfortunately, life had other plans for him. After coming back from a trip to the USA, he was diagnosed with pneumonia and the leukaemia was back. The doctors decided to treat him with a second transplantation from the same donor in February 2008. The recovery was a tough one. He was almost paralyzed and went nearly blind. He had, however, eventually learnt to walk again and fully recovered 6 years later. He was continuously tested for HIV with extensive and precise tests. It was finally good news for him! Since 2010, when he decided to go public, he had interviewed for various magazines: POZ Magazine , New York Magazine and Science Magazine among others and decided to devote his life in supporting research for cures against HIV. In July 2012, he started the Timothy Ray Brown Foundation under World AIDS Institute and has worked with many scientists, organizations, research laboratories and universities to work on cures such as vaccination against HIV.

The London Patient [ 22 ]

The London patient may be the second person with HIV to no longer have the virus. In March 2019, in a report published in journal Nature , a group of investigators had announced the cure of a second HIV-positive patient. His success story depicts that CCR5 is a viable target for HIV research and treatment.

The London patient, who had chosen to remain anonymous, came out in public on March 9 th 2020. Adam Castillejo grew up in Caracas, Venezuela, and later shifted to London with his mother, as his parents were divorced. He was first diagnosed with HIV in 2003 and had started taking drugs to control the HIV infection in 2012. He had taken antiretroviral therapy for years before being diagnosed with an advanced form of blood cancer called Hodgkin’s lymphoma. Again, as in the case of the Berlin patient, the cancer was resistant to standard chemotherapy, so his doctors had advised more intensive chemotherapy along with bone marrow stem cell transplant. In 2016, he had agreed to transplantation and received it from a healthy donor who carried the CCR5 mutation. So, when his immune system regrew, it lacked the protein and was impervious to HIV. His virologist, Dr Ravindra Gupta, from the University of Cambridge, thinks it is a cure because a year had passed and they had carried out a few more tests for the viral load. In Adam Castillejo’s own words, “I don’t want people to think, “Oh, you’ve been chosen.” No, it just happened. I was in the right place, probably at the time right time, when it happened.” Adam Castillejo wants to be the “ambassador of hope” for people with this illness.

Although the scientists describe this case as a long-term remission, experts are calling it a potential cure. Such transplants are, however, dangerous and can be fatal. They are also an impractical approach to cure the millions already infected. These are highly risky procedures and can lead to serious complications. There still has to be a lot of research done to extend this type of treatment to a wider population infected with HIV.

A comparative study of the two patients reveals that their cases were in fact quite similar (Table ​ (Table9 9 ).

Summary of the two cases—the Berlin patient and the London patient [ 24 ]

Lifestyle Practices to Prevent HIV Infection

Prevention is better than cure. And with HIV infections, one should practice prevention with utmost care and sincerity. An HIV diagnosis could turn one’s life upside down. So, it’s better to lead a healthy lifestyle by making the correct choices.

Measures for Protection Against HIV Infection

HIV is majorly spread through unprotected vaginal or anal sex. Choose less risky behaviour and be cautious. Not taking medicines to prevent or treat HIV is equally responsible for HIV infection. The number of sexual partners should be limited. One should get tested for sexually transmitted diseases and also know the sexual partner’s status. One can talk about pre-exposure prophylaxis to their respective healthcare provider. It is a preventive option for people who are not infected yet but are exposed to high risks of being HIV positive. HIV is also spread through intravenous injections and blood transfusions. Use of sterile equipment in such cases is a necessity.

Pre-exposure Prophylaxis

This is a preventive method of taking pills by people who are not HIV positive yet but who are at a high risk of getting infected and spreading it to others. A pill, named Truvada, contains two medicinal components, emtricitabine and tenofovir, that are used in combination with other drugs to treat HIV [ 25 ]. These medicines work on keeping the virus from creating a permanent infection.

Post-exposure Prophylaxis

Post-exposure prophylaxis (PEP) is a short course of HIV medicines taken soon after a possible exposure to HIV [ 25 ]. Every hour counts. For the treatment to be effective, the course should begin within 72 h after exposure to HIV; otherwise, it will not have any effect [ 25 ]. This treatment should be used only in cases of emergency. A person prescribed with PEP will need to take the medicines for 28 days at a stretch and then visit their respective healthcare provider for further tests [ 25 ]. Even if taken correctly, it may not be 100% effective. The sooner the medication is started, the better.

Healthy Practices to Follow When Living with HIV

A healthy, well-balanced and nutritious diet can help a person lead a better life by preventing health related issues like malnutrition and stopping the progression from HIV to AIDS. A well-balance diet is rich in whole grains, fresh fruits and vegetables, protein, low fat dairy products and multivitamins like zinc and B12. It also constitutes what should be cut down—fried foods, processed foods and sugary drinks. Smoking should be stopped when diagnosed with HIV. According to CDC, in the USA, the rate of adults with HIV, smoking is two to three times higher in adults infected with HIV than the nearly 18% of uninfected adults who smoke. Researchers at the Syracuse University analysed the data from 212 adults infected with HIV and found that the ones who smoked reported having more symptoms like dizziness and coughing.

Putting a stop to illegal drug use is equally necessary. People should seek treatment for addiction to illegal drugs like heroin, cocaine and methamphetamines. Sharing of needles for drugs can leave one exposed to other infections like hepatitis which might lead to a faster progression from HIV to AIDS. A recent study from the University of Pennsylvania School of Medicine showed a dramatic increase in the ability of HIV to attack healthy cells when methamphetamine is present in the bloodstream. This indicates that illegal drugs are also aiding in the HIV infection.

Being physically fit through a good work-out three to six times a week can help improve a person’s mood, perspective and overall quality of life. A good amount of moderate exercise can help fight HIV symptoms of nerve pain, loss of appetite and reduce the risks of other chronic diseases like heart disease, diabetes and osteoporosis. Taking the prescribed medication on time is known as adherence. This is vital to help reduce the risk of HIV becoming drug resistant and helps the immune system function for a longer time.

Nowadays, with the help of Internet of Things or IoT, patient’s health can be monitored 24/7. The quality of care provided can be increased many-folds with the help of monitoring devices enabled with current technology [ 26 ]. Concept of E-Health and M-Health is currently trending. E-Health makes use of electronic and communication processes with improved cyber security [ 26 ]. Some of the E-Health devices include GPS tracking, pedometer and electronic health records [ 26 ]. M-Health systems provide doctors with the complete medical history of the patient, so the treatment becomes easier and does not delay in case of emergencies. It makes use of mobile phones and other communication systems to help the patients with information about preventive health care services and collects data in real time as well [ 26 ]. The other important applications include chronic disease management, monitoring of diseases and tracking of epidemic outbreaks [ 26 ].

Genomic Diversity and Clinical Implications

Despite billions of dollars being invested, there is currently no HIV vaccine available that can either prevent the disease or treat those who suffer from it. An AIDS patient harbours 100 million genetically distinct variants of HIV [ 27 ]. This high diversity of HIV-1 is due to high replication rates, errors in reverse transcriptase and recombination events that mainly occur during the viral replication process. Reverse transcriptase enzyme has approximately a rate of 10 –4 nucleotide substitutions per replication cycle. Deletions, insertions and duplications are major contributing factors to the genetic variation of the virus [ 27 ]. Genetic recombination also plays an important role in creating genetic diversity. Template switches between two copies of RNA strands occur regularly during reverse transcription [ 27 ]. This generates a lot of mutations with the help of inter- and intra-molecular jumps. These mutations can either be drug resistant or inhibit the viral replication capacity.

HIV-1 can be classified into four main groups: M, N, O and the recently identified P. The M group is further identified into 4 subtypes (A to J). Studies have shown that there is a worldwide spread of non-B subtype viruses, and with the introduction of antiretroviral drugs, more research has to be conducted regarding the responsiveness of the drug resistance in non-B subtypes [ 27 ]. Different types of HIV-1 resistance are observed in different subtypes at varied levels. For example, subtypes B and G have shown to develop resistance against nelfinavir [ 27 ]. Research is also being done in the role of polymorphisms for development of drug resistance, to assess the genotypes before and after the therapy to be able to establish any association between the two [ 27 ].

Variation of Disease Progression Rate

There are 3 phases of the progression of HIV-1 infection- primary infection, chronic asymptomatic phase of infection and finally, AIDS. In the asymptomatic phase, neither signs nor symptoms of the disease are present, and this phase lasts an average of about 10 years. They can be divided as typical progressors, rapid progressors, slow progressors and long-term progressors. Rapid ones (10–20%) develop AIDS within 5 years of infection [ 28 ]. Slow progressors (5–15%) remain free of AIDS 15 years after infection [ 28 ]. Long-term progressors that constitute 1% show no signs and symptoms [ 28 ]. Factors like host genetic make-up, immune responses, co-infection and viral genetics and adaptation are attribute to this huge variation in disease progression [ 28 ]. But there is no solid evidence as such.

Some individuals known as elite controllers are able to manage the viral replication for longer durations, others are shown to rapidly lose CD4 + T-cells after seroconversion in the absence of cART (combination antiretroviral therapy). Scientists have conducted research studies that has led to the conclusion that rapid progression before administration of cART stops the recovery of CD4 + T-cells once the suppressive response to HIV-1 through cART is achieved. These findings have implications in public health policy making, clinical outcomes and science research. Ideally, cART should be initiated as soon the patient is diagnosed with HIV-1 irrespective of the CD4 + T-cell count. However, in clinical settings where cART is not widely available, these results would support strategies that may help in promoting frequent testing to reduce the proportion of patients initiating cART at low CD4 + T-cell counts. For those testing early, frequent CD4 + T-cell count should be monitored close to the time of HIV diagnoses to establish the rapid progressors phenotype in order to avoid unnecessary CD4 + T-cell count decay among rapid progressors. Finally, interpretation of the immunopathological basis of rapid progression can help improve individual clinical outcomes and limit its impact in the global HIV-1 pandemic.

Development of Drug Resistance as a Major Barrier to Treat HIV

HIV-1 has a high mutation rate. An estimated 10 10 virions per day can be produced in untreated patients that may result in variants called quasispecies. The complexity is also increased due to high recombination rate whenever more than one variant infects the same cell. All these are contributing factors that help in invading the host’s immune system and fostering drug resistance. Salvage therapy is also useful in cases when more than one regimen failed or a single regimen failed for a patient. It can be used to suppress the virus levels below the detection level and should have high genetic barrier to resistance to prevent rebound [ 29 ]. Clinicians need to focus on patient’s adherence as well as access to antiretrovirals (ARVs), drug interactions, tolerability, genotypic and phenotypic resistance testing, cross-resistance, genetic barrier and potency of ARVs [ 29 ].

Overcoming Obstacles and Future Prospects

At present, the reason for not being able to achieve a complete cure with the help of ART, in spite of achievement of undetectable viral load, is due to the presence of dormant virus or HIV latency. In a method call shock and kill, immune stimulants shock the latent virus from hidden reservoirs and then attempt to kill reactivated HIV [ 18 ]. An enzyme has been identified which is called histone deacetylase (HDAC) which is responsible for the sustained latency. Some studies show promise but are yet to be confirmed by clinical trials. Flushing these latent CD4 HIV-infected cells from their reservoirs with these HDAC-inhibitors into the blood circulation makes them susceptible to ART. Vorinostat and panobinostat are two such promising drugs [ 18 ].

Histone deacetylase inhibitors seem to have a broad spectrum of epigenetic activities. Vorinostat (also called Zolinza) is a U.S. Food and Drug Administration approved medicine, which has been used for the treatment of cutaneous T-cell lymphoma (CTCL) [ 18 ]. They help in flushing the virus from the reservoirs into the circulation. The dose is 400 mg. Other drugs on the pipeline are Protein kinase C agonist bryostatin-1 and GS-9620—TLR7 agonist [ 18 ].

Romidepsin (also called Istodax) is another HDAC inhibitor drug, which induces HIV-1 transcription to form plasma HIV-1 RNA that can be easily detected with standard assays [ 18 ]. This gives a possibility of reversing the HIV-1 latency in vivo without hindering T cell mediated immune response [ 18 ]. These findings will help the researchers with future clinical trials aiming to eliminate the HIV-1 reservoirs.

Research for curing HIV is at an infant stage but a promising one. Scientists are working on two broad types of HIV cures—a functional cure and a sterilising one.

The approach of the functional cure is to reduce the virus levels in the body to an undetectable stage, where the patient no longer needs to be on HIV medication or has no risk of progression to AIDS nor transferring the virus to others. Unlike the functional cure, however, a sterilising cure aims to get rid of HIV from the body completely by eliminating cells from latent reservoirs. It has proved to be an extremely challenging task for scientists, who believe it may be unachievable in the majority of them living with HIV. However, some findings by researchers at the University of Pittsburgh could lead to a foundation for an HIV vaccine. Clinical trials are in the works.

Abivax, a French company, is developing a drug that binds to some specific sequence of the viral RNA and inhibits its replication. During clinical trials, it has shown that this may have the potential to become a functional cure. The key is that it can target the reservoir of HIV viruses that hide inactive within our cells. It can target the reservoirs where HIV viruses act as inactive, within the infected cells. The result of phase IIa trial was quite promising. Fifteen patients were given the drug in combination with ART, and it was observed after 28 days of treatment that eight patients showed a 25% to almost 50% reduction of their HIV reservoirs compared to those only taking ART. The company is planning a phase IIb clinical trial to confirm the effects of the drug in the long term.

Research and development in HIV and its cure have come a long way since the disease was discovered in the 1980s. ART was a major milestone that has changed the lives of millions for good, but the next ambitious goal is to find an HIV cure before the year 2020. There are several approaches to an HIV cure ranging from shock and kill therapy, immunotherapy, vaccine development to gene editing using zinc finger nucleases and the CRISPR/Cas9 system, but finding the best possible solution is a challenge. One of the biggest challenges around any HIV treatment is the ability of the virus to rapidly mutate and develop resistance. Many of the new approaches do not provide any valuable insights as to whether the virus has the potential to become resistant. As of now, none of these functional cures have reached late-stage clinical trials, and the aim of finding an HIV cure until 2020 seems far-fetched. However, 2020 will likely be marked as an important milestone as the first late-stage trials will be executed. If successful, it could bring the approval of the first functional HIV cure in ten years.

There are two gene therapies undergoing human trials—one is to destroy the CCR5 receptor of the immune cells of people infected with HIV and the other therapy includes the CRISPR technology which is still under early trials. This mutation does not necessarily protect the person against all types of HIV. It was found that in one of the patients who had received the bone marrow treatment, it was found to have the CXCR4-tropic form. It uses a different type of receptor to enter and infect the cells. It was, however, not known whether this virus was acquired after the treatment or if some patients do contract a small amount of CXCR4-tropic virus that starts to multiply when other types are not present.

HIV research continues on many fronts that could provide the same results and only some of which rely on the CCR5 delta 32 mutation, which should be explored extensively. There are many strategies which are in the early stages of development. Scientific process can be slow but if done correctly, advances can be made to find a scalable, cost-effective cure for everyone.

Acknowledgments

The authors listed in this paper wish to express their appreciation to the RSST trust Bangalore for their continuous support and encouragement.

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All authors have contributed equally with their valuable comments which made the manuscript to this form.

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The authors declare that they have no conflict of interest.

All the authors listed hereby confirmed that in the above research, there were no human participants and/or animals involved in any kind of determination, evaluation or research studies.

There is also final confirmation given by all the listed authors for the submission of manuscript in its actual state. The authors listed above also confirm that the above-mentioned manuscript is in its original state and the manuscript is neither submitted anywhere nor in the submission process in any other journals. In addition, all the authors have solely contributed their original work in the preparation of this manuscript. If the copying or similarity have been found, then in all situations the listed authors are solely responsible.

Significance Statement

This article aims to increase awareness among the society about the current scenario of HIV/AIDS. The scientists are working on 2 types of cures—functional and sterilizing. The path to finding a cure is a promising one as late-phase trials begin in 2020.

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Contributor Information

Praveen Kumar Gupta, Email: ni.ude.ecvr@atpugkneevarp .

Apoorva Saxena, Email: [email protected] .

Volume 27, Number 6—June 2021

Perspective

Reflections on 40 years of aids.

Cite This Article

June 2021 marks the 40th anniversary of the first description of AIDS. On the 30th anniversary, we defined priorities as improving use of existing interventions, clarifying optimal use of HIV testing and antiretroviral therapy for prevention and treatment, continuing research, and ensuring sustainability of the response. Despite scientific and programmatic progress, the end of AIDS is not in sight. Other major epidemics over the past decade have included Ebola, arbovirus infections, and coronavirus disease (COVID-19). A benchmark against which to compare other global interventions is the HIV/AIDS response in terms of funding, coordination, and solidarity. Lessons from Ebola and HIV/AIDS are pertinent to the COVID-19 response. The fifth decade of AIDS will have to position HIV/AIDS in the context of enhanced preparedness and capacity to respond to other potential pandemics and transnational health threats.

“When the history of AIDS and the global response is written, our most precious contribution may well be that, at a time of plague, we did not flee, we did not hide, we did not separate ourselves.”

—Jonathan Mann, Founding Director of Project SIDA and the World Health Organization Global Programme on AIDS, 1998

Forty years ago, on June 5, 1981, the Centers for Disease Control’s Morbidity and Mortality Weekly Report described 5 cases of Pneumocystis pneumonia in gay men ( 1 ). That report heralded the HIV/AIDS pandemic, which has resulted in over 75 million HIV infections and 32 million deaths. In 2011, we reviewed 30 years of AIDS and commented that the HIV/AIDS response would be a benchmark against which responses to other health threats would be compared ( 2 ). After 40 years of AIDS, we present our personal reflections on scientific and global health evolution over the fourth decade of AIDS in a world that has recently suffered other major epidemics. We focus on biomedical advances because these have had the greatest effect on HIV transmission and disease; advances in structural and behavioral interventions are reviewed in the CDC Compendium of Evidence-Based Interventions and Best Practices for HIV Prevention ( 3 ).

After the initial MMWR report was published, it took 2–3 years for the cause of AIDS, the novel retrovirus designated HIV, to be identified ( 4 , 5 ), and many more years to uncover its simian origin ( 6 ). Because of the asymptomatic spread of HIV, the long incubation period before disease, and transmission through sex and blood, millions of persons around the world, including several hundred thousand in the United States, were infected by the time the first AIDS cases were reported. The epidemiology and natural history of HIV infection, combining elements of acute and chronic diseases, ensured a diverse and long-lasting pandemic.

The history of HIV/AIDS and the struggle to contain it have seen the best and worst of human nature. Frequent examples of discrimination and exclusion are contrasted by leadership, illustrated by community activists ( 7 ), Jonathan Mann molding the first global response ( 8 ), Kofi Annan rallying the United Nations behind the search for a global fund ( 9 ), and President George W. Bush committing United States generosity to a war on HIV/AIDS of uncertain duration ( 10 ). Despite continued instances of injustice, the story has overall been a positive one, providing lessons for how to respond to other epidemic and pandemic threats.

Evolving Epidemiology

The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates that in 2019, 38 million persons worldwide were living with HIV, 1.7 million became newly infected, and 690,000 died with HIV disease ( 11 ). Compared with 2010 estimates, overall HIV incidence in 2019 decreased by 23% and mortality by 37%. However, age stratification shows that new infections have decreased by 52% among children but by only 13% among adults. With reduced mortality rates yet continued HIV incidence and population growth, the overall number of persons living with HIV was 24% greater in 2019 than in 2010.

Global summaries hide regional differences. The epicenter of the pandemic remains in East and southern Africa, which account for 54% of all HIV-infected persons and 43% of incident HIV infections and deaths ( 11 ). High prevalence of HIV-infected persons with unsuppressed viremia predicts high incidence and maintenance of community infection, an observation that applies to regions and countries, as well as specific populations such as men who have sex with men (MSM).

The next greatest HIV burden is in the Asia and Pacific region, where the population is vastly greater than that of East and southern Africa but there are 3.5 times fewer HIV-infected persons ( 11 ). Despite overall prevention progress, HIV incidence has not declined equally everywhere; little success has been seen in eastern Europe, the Middle East, and Central Asia.

Ever clearer is the global burden of HIV in key populations: MSM, transgender persons, people who inject drugs, sex workers and their clients, and incarcerated persons. In 2019, an estimated 62% of all new HIV infections were in members of those key populations ( 11 ). In 7 of the 8 UNAIDS regions, key populations accounted for 60%–99% of incident HIV infections; only in East and southern Africa, where the proportion was 28%, were new infections predominant in general populations ( 11 ).

Among high-income nations, the most heavily affected country is still the United States. In 2018, a total of 37,881 HIV infections were newly reported, with regional differences ( 12 ). In the South, the rate of new infections was more than twice that for the Midwest, where the rate was the lowest. Major disparities by race/ethnicity persist; the rate among Black/African American persons is 2 times that among Hispanic and 8 times that among White persons. Also associated with higher rates are factors indicating social deprivation and poverty, even allowing for racial and ethnic disparities. Among new HIV infections, 70% resulted from male-to-male sex. A cause for concern is potential overlap between the HIV/AIDS and opioid epidemics through increased drug injection and needle sharing, which has resulted in explosive HIV outbreaks ( 13 ).

Evolving Science and Program

In our 2011 commentary ( 2 ), we considered the following as priorities: improving use of existing interventions, defining how best to use HIV testing and antiretroviral therapy (ART) for prevention as well as treatment, continuing the quest for new knowledge and interventions, and ensuring sustainability of the global response. By and large, progress has been made on all fronts.

After the CAPRISA 004 trial of precoital and postcoital use of tenofovir gel was published in 2010 ( 14 ), the Ring ( 15 ) and Aspire ( 16 ) studies (randomized, placebo-controlled trials in South Africa) examined the protective efficacy of a self-inserted vaginal ring impregnated with slow-release dapivirine, a nonnucleoside reverse transcription inhibitor. The overall efficacy rates for reducing HIV incidence were 31% (Ring) and 27% (Aspire); many questions about overall efficacy, adherence, and differences by age remained. This collective experience provided proof of concept for woman-controlled prevention but did not provide the definitive public health solution to high HIV incidence among young women in Africa.

Four pivotal randomized trials ( 17 – 20 ) of oral preexposure prophylaxis (PrEP) with Truvada (combination of tenofovir and emtricitabine) were pivotal for international licensing of the compound. The relevant trials studied MSM, transgender women having sex with men, and at-risk heterosexual persons. A review of evidence considered another 9 studies, some of tenofovir alone, in different populations including people who inject drugs ( 21 ). The pivotal trials showed reduced HIV incidence (44%–86%) with Truvada use. However, a consistent observation has been a strong association between efficacy and adherence; PrEP is effective, but the drugs need to be taken.

Subsequent research focused on differential tissue penetration of drugs to relevant anatomic sites in men and women and on modes of drug delivery. HIV Prevention Trials Network (HPTN) studies compared the prevention efficacy of the long-acting injectable drug cabotegravir with Truvada in men and transgender women who have sex with men (study 083 [ 22 ]) and in heterosexual women (study 084 [ 23 ]). Interim results showed that cabotegravir, delivered every 8 weeks by injection, was associated with 66% lower incidence than oral Truvada in study 083 and 89% less in study 084. The long half-life of cabotegravir enables intermittent dosing, but waning drug levels over time may become subtherapeutic, thus requiring additional interventions to prevent infection and preclude development of drug resistance.

In its 2016 guidelines, the World Health Organization (WHO) recommended public health use of PrEP, as have other national and international regulatory or advisory bodies. However, the enthusiasm engendered by PreP science needs to be tempered by consideration of cost, need for rigorous adherence, rising rates of other sexually transmitted infections and thus need for continued condom use, and contraception for women. Long-acting injectables could be a major advance, but accessibility and logistics for their delivery need to be considered.

Mathematical modeling and ecologic studies suggested that greatly increased delivery of ART could reduce HIV transmission at the community level. The definitive study showing that ART provided prevention benefits was the landmark HPTN 052 study ( 24 ), published in interim form in 2011. This trial among discordant couples found a 96% reduction in HIV transmission among those who started ART early versus those for whom it was deferred. Combined with an influential modeling study ( 25 ) that suggested that regular HIV testing and immediate use of ART could suppress and perhaps ultimately eliminate HIV transmission, the results of HPTN 052 led to studies in East and southern Africa of the so-called test and treat intervention ( 26 – 29 ). These studies were community randomized evaluations of widespread HIV testing and immediate ART compared with standard care; the primary endpoint was HIV incidence. These large, expensive implementation science studies yielded rich information but did not lead to local HIV elimination. Of the 4 studies, 2 showed no significant incidence reduction and the other 2 showed 20%–30% reduction.

One of the reasons for the unexpectedly modest differences in HIV incidence between intervention and control communities in the test and treat study was changing global practice with regard to when to start ART. In 2015, results of the START ( 30 ) and TEMPRANO ( 31 ) trials showed unequivocally that immediate ART, irrespective of CD4+ lymphocyte count, resulted in reduced HIV-associated disease and death, ending more than 2 decades of argument about when to start treatment. WHO rapidly changed global recommendations to immediately start ART, one result of which was erosion of differences between intervention and control communities in the test and treat trials.

Although test and treat did not reduce HIV incidence to the extent hoped for, the accumulated evidence supports the notion of early, universal ART for extending the lives of HIV-positive persons as well as reducing the prevalence of unsuppressed viremia, the driver of HIV transmission. Large observational studies ( 32 ) showed that persons with suppressed viremia do not transmit the virus sexually, leading to the slogan “U = U”—undetectable equals untransmittable. This experience provides a much more compelling argument for active HIV case finding through increased HIV testing and partner notification, to enhance individual and public health through early treatment.

Although none of the approaches described provides a unique solution, the combination of widespread HIV testing, early ART for those infected, and PrEP for those at risk offers opportunity for substantially limiting the epidemic. Such approaches have been associated with reductions in new HIV infections among MSM in London, UK ( 33 ), and in New South Wales, Australia ( 34 ). In the United States, these advances—testing, case finding including through partner notification, universal treatment, PrEP, and rapid molecular investigation of clusters for service provision—have been incorporated into a revised national strategy for HIV elimination ( 35 ).

Progress toward an HIV vaccine remains discouraging. The only report of protective efficacy, published in 2009, has been the RV-144 study in Thailand ( 36 ), which investigated use of a recombinant canarypox vector vaccine (ALVAC-HIV) delivered in 4 monthly priming injections followed by a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E) given in 2 additional injections. Reported efficacy was 26%–31%, but statistical and technical interpretation of these results was controversial ( 37 ). In 2016, the HVTN 702 study was launched in South Africa and used the same product as in the Thailand trial but modified for the dominant subtype C. After interim analysis, the study was halted for futility in early 2020 ( 38 ). Other efficacy studies of vaccines based on so-called mosaic immunogens from diverse HIV subtypes are in progress.

There has been great interest in broadly neutralizing antibodies to HIV, which some infected persons produce naturally and which might protect against a wide variety of strains. Two international trials of infusions with a broadly neutralizing antibody, VRC01, every 8 weeks showed relative protection against sensitive strains but no significantly reduced HIV incidence overall ( 39 ).

In 2014, UNAIDS launched its 90:90:90 initiative, aiming for 90% of persons with HIV infection to be diagnosed, 90% of those with an HIV diagnosis to receive ART, and 90% of those receiving treatment to show viral suppression by 2020. Globally, the respective proportions in 2019 were 81%, 82%, and 88%, so that an estimated 59% of persons living with HIV were showing viral suppression. Initially, 90:90:90 (with a goal of these numbers being 95s by 2030) was an advocacy proposal rather than an evidence-based initiative, but these targets have become adopted as policy promising “epidemic control,” itself a concept requiring precise definition ( 40 ).

ART scale-up, increased male circumcision, and prevention of mother-to-child transmission have all contributed to encouraging advances in the most heavily affected regions of Africa ( 11 , 41 , 42 ). Successful program implementation and declines in new HIV infections and deaths, combined with scientific progress, have led to a certain complacency that “AIDS is over.” Former US Secretary of State Hillary Clinton and staff promoted the idea that current tools could abruptly halt the epidemic. We largely agree with the 2018 judgment of the International AIDS Society–Lancet Commission on AIDS: “The HIV/AIDS community made a serious error by pursuing ‘the end of AIDS’ message” ( 43 ). Key populations, hiding in obscurity as well as in plain sight, will probably remain as reservoirs, even with highly performing programs. Experience in East and southern Africa has highlighted the challenge of adequate service provision to youth and men. Stigma and discrimination remain barriers in many parts of the world, and lack of an HIV cure (a priority research area) and vaccine remain scientific obstacles ( 44 ).

Evolving Global Health

The HIV/AIDS pandemic has evolved in parallel with other global health events that necessarily influence how HIV/AIDS is perceived and prioritized. In a 2012 paper, author K.D.C. suggested that global health trends could best be analyzed through the lenses of development, public health, and health security ( 45 ). The fourth decade of AIDS started in the aftermath of the global financial crisis and the influenza (H1N1) pandemic and is finishing amid the coronavirus disease (COVID-19) pandemic. Although substantial progress has been made toward reducing maternal deaths, improving child survival rates, and scaling up programs for HIV/AIDS, malaria, and tuberculosis, the past decade has seen major disease outbreaks and a consequent focus on health security. Because of its sociodemographic effects, AIDS was portrayed as a security issue in United Nations discussions early in this century. With massive scale-up of treatment and prevention, HIV/AIDS is now perceived as another public health priority rather than a security emergency.

In 2014, Ebola was reported in Guinea, Liberia, and Sierra Leone, far west of previously recognized outbreaks. The epidemic lasted until mid-2016 and ultimately resulted in 28,646 reported cases and 11,323 deaths ( 46 ). Infections were exported to 3 other countries in Africa, several countries in Europe, and the United States. This health crisis resulted in widespread fear of possible global spread, unparalleled global mobilization of emergency health assistance including use of armed forces of the different high-income countries, and political involvement at the highest levels of governments and the United Nations. Subsequent outbreaks of Ebola have occurred in Uganda and the Democratic Republic of the Congo (DRC), including a large epidemic in conflict-ridden eastern DRC in 2018–2020 that resulted in 3,481 reported cases and 2,299 deaths ( 47 ). Underemphasized aspects of these Ebola epidemics were that cases over the past 6 years represent more than 90% of all cases reported cumulatively since recognition of Ebola in 1976; that vast geographic distances were involved; and that these outbreaks were largely urban, sometimes involving capital and other major cities. Ebola epidemiology has changed from that of an exotic, remote infection in Africa to one capable of causing extensive urban outbreaks threatening global health ( 48 ). Also of note was that field research conducted during the outbreaks under the most difficult conditions showed efficacy of a vaccine and therapeutics, both now considered the standard of care for Ebola ( 49 , 50 ).

Over the past decade, arboviral epidemic activity has been diverse. The epidemics of yellow fever in Angola and the DRC in 2015–2016 were the world’s largest over the past 30 years. A total of 965 cases and 400 deaths were reported, but true numbers were far greater. Over 30 million persons were vaccinated, and shortage of yellow fever vaccine required healthcare providers to resort to the untested practice of fractionating vaccine doses ( 51 ). Huge epidemics of chikungunya and dengue occurred internationally; virus was transmitted to areas previously considered at low risk, such as Europe ( 52 ). In 2015, the Zika epidemic raised global concern when infection with this virus was shown to be associated with microcephaly in infants and with Guillain-Barré syndrome and to be sexually transmissible. The outbreak resulted in at least 3,700 cases of birth defects in the Americas ( 53 ).

In 2005, after the outbreak of severe acute respiratory syndrome (SARS), WHO revised its International Health Regulations ( 54 ). A key change was authority to declare a Public Health Emergency of International Concern, a health emergency that could result in international spread or required coordinated action. WHO has implemented this authority only 6 times, 5 of them during the fourth decade of AIDS: for polio (2014), Ebola (2014 and 2019), Zika (2015), and COVID-19 (2019).

Related to health security are the interrelated challenges of global warming, demographic change, and migration. Climate change affects social and environmental determinants of health, such as access to clean air, water, shelter, and arable lands, but also exerts direct health effects. The United Nations High Commissioner for Refugees characterized 2010–2019 as “a decade of displacement,” during which 100 million persons were forced to flee their homes, many because of conflict such as that in the Middle East. During 2014–2020, some 20,000 migrants crossing the Mediterranean Sea to Europe drowned, and another 12,000 or more were unaccounted for.

Broad themes that have dominated global health discourse include the transition from the era of the Millennium Development Goals (MDGs; 2000–2015) to that of the broader Sustainable Development Goals (SDGs; 2015–2030) ( 55 ) and the issue of universal health coverage. Other disease-specific programs require continued support, such as the unfinished efforts to eradicate polio and Guinea worm disease. The MDGs had 3 specific health goals relating to child survival; maternal health; and HIV/AIDS, tuberculosis, and malaria. Only 1 of the 17 SDGs is devoted to health, SDG3, which has 13 targets and 28 indicators. Specifically, SDG3 calls for: “By 2030, end the epidemics of AIDS, tuberculosis, malaria and neglected tropical diseases and combat hepatitis, water-borne diseases and other communicable diseases.” Another target and WHO priority is provision of universal health coverage, global access to decent healthcare, and protection against penury from out-of-pocket health expenditures. HIV/AIDS exists in a crowded and complex global health space.

Preparing for the Fifth Decade of AIDS

As the world emerged from the financial crisis a decade ago, there was concern that HIV/AIDS funding might be constrained. Development assistance for health reached $40.6 billion in 2019, an increase of 15% over the amount in 2010 ( 56 ). Approximately half of this assistance goes to HIV/AIDS, especially for treatment, and to newborn, maternal, and child health. Thus, although health security has eclipsed health development and global public health in this fourth decade of AIDS, financial commitments have been largely maintained.

The overall annual spending on HIV/AIDS by low- and middle-income countries is ≈$20.2 billion, of which ≈$9.5 billion represents donor funding. UNAIDS consistently communicates that to meet SDG targets, overall spending on HIV/AIDS needs to increase by ≈40%. Nonetheless, this HIV-specific spending is privileged compared with funding for other high-impact diseases in low-income settings, such as malaria and tuberculosis. AIDS is no longer among the 10 leading causes of death globally and is now widely viewed as a medically manageable disease. HIV/AIDS prioritization and funding may be justified by the youthful groups affected and its lifelong nature, but this view may be increasingly challenged. Expecting the United States to pay indefinitely for most of the world’s HIV/AIDS response is unrealistic. The end of the SDG era in 2030 will probably come with reappraisal of global commitments, including those for global health funding, disease-specific focus, and maintenance of single-disease organizations such as UNAIDS. Over the coming years, HIV/AIDS programs need to show good fiscal management and epidemiologic results, and affected countries need to shoulder an increased share of their disease burdens.

Lessons from HIV/AIDS and Other Epidemics

The most dramatic epidemics in recent time (COVID-19 [ 57 ], Ebola, and HIV/AIDS) involve quite different biological agents and challenges yet also raise common themes and questions. Especially needed are global responses to challenges that transcend national borders. Pathogen emergence is enhanced by globalization, but globalized systems are needed to address an interconnected worldwide emergency. The slogan “no one is safe until everyone is safe” has been heard in relation to COVID-19, but it was said years ago about HIV. And global health needs global funding.

Individual leaders and organizations have performed valiant work on COVID-19, yet countries have isolated themselves in all senses, resulting in global fragmentation. Major powers look inward yet are reluctant to cede space, and the influence of multilateral agencies is limited. WHO was heavily criticized after the Ebola epidemic in West Africa but is constrained by restricted authority, inadequate funding, and unrealistic expectations from member states. Repeated calls for WHO reform are unclear about what is really wanted.

Honesty is required concerning preparedness and surveillance. The Ebola epidemic in West Africa became as severe as it did because the 3 affected countries had been neglected for years and had no functioning surveillance and public health infrastructure. We cannot say that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was completely unexpected; the literature on pandemic threats is voluminous. SARS in 2002–2003 was severe but not widespread; the 2009 influenza (H1N1) pandemic was widespread but not severe. It is hubristic to assume that pathogen severity and spread would always segregate, yet we were not prepared. Preparedness metrics can give false reassurance, witnessed by the lamentable response to COVID-19 in the United States in 2020. “Never again” was the mood after the Ebola epidemic in West Africa, but preparedness just seems too hard and costly. Perhaps true preparedness exists only in the military, where personnel train continuously for wars they hope will never happen.

As a result of technologic advances such as whole-genome sequencing, scientific progress on COVID-19 has been breathtakingly rapid compared with early laboratory research on HIV. We hope to not see a replay of the early history of ART, with scientific advances relating to COVID-19, and specifically vaccines, not being rapidly or equitably accessible everywhere. “Vaccine nationalism” is a new term raising the specter of lower risk groups in high-income countries receiving vaccine before, for example, frontline healthcare workers in low-income settings. Healthcare workers have been disproportionately affected by Ebola and COVID-19, highlighting the need for much greater investment in infection prevention and control in healthcare settings worldwide. Attention and innovation are required to ensure maintenance of HIV and other essential public health services amid other outbreaks such as COVID-19.

Although initially slow, the HIV/AIDS response over the years has been a beacon in global health for respect for individuals and their rights and for health equity. More reflection is required with regard to what the responses to HIV and Ebola have taught us and how they might be relevant to COVID-19 and other future epidemics.

Conclusions

Although great need remains, the past decade has seen scientific and programmatic successes with regard to the HIV/AIDS priorities we defined after 30 years of AIDS. Existing interventions have been scaled up, and new tools such as PrEP and long-lasting drug preparations have been introduced. The roles of HIV testing and ART for treatment and prevention have been clarified, and the need for immediate ART for all HIV-infected persons has been proven. The global HIV/AIDS response has been sustained, financing has been maintained, and the world has kept focus on the SDGs. Mann’s judgment that “we did not separate ourselves” remains justified. We must also accept that political promises of “the end of AIDS” were hyperbole that current epidemiology does not support.

The COVID-19 pandemic has exploited the fault lines of global systems and existing inequalities in a way that HIV did early on. Regrettably, the solidarity that HIV/AIDS engendered has not yet been carried over. In retrospect, the recent epidemics of Ebola in West Africa and DRC were preparation for the COVID-19 pandemic, but follow-through was lacking. The fifth decade of AIDS will take us to the SDG target date and reassessment of global health and development priorities. HIV/AIDS may not be central to global health discourse as it was earlier, but it will remain a yardstick by which to judge commitment and efforts, including, and especially in relation to, health security.

On February 7, 2021, the Ministry of Health of DRC reported a laboratory-confirmed case of Ebola in North Kivu Province, the most heavily affected province during the 2018–2020 outbreak in eastern Congo. The case-patient experienced symptom onset on January 25, 2021, and died in Butembo, a city of ≈1 million persons, on February 4, 2021. She was reportedly linked epidemiologically to an Ebola survivor, and genetic sequencing reportedly showed phylogenetic association with the earlier outbreak rather than a new spillover event. As of February 8, 2021, a total of 118 contacts were being investigated ( https://www.who.int/emergencies/diseases/ebola/ebola-2021-north-kivu , https://www.who.int/csr/don/10-february-2021-ebola-drc/en ).

Separately, on February 14, 2021, the Ministry of Health of the Republic of Guinea reported an outbreak of Ebola in the subprefecture of Gouécké, Nzérékoré Region, the first report of Ebola in Guinea since the 2014–2016 epidemic. The index case-patient, a nurse, experienced symptoms on January 18, 2021, and died on January 28, 2021. A total of 6 secondary Ebola cases were reported, 1 in a traditional practitioner who cared for the index case-patient and 5 in family members attending her subsequent funeral. Of the 7 case-patients, 5 died. As of February 15, 2021, a total of 192 contacts were being investigated, including in the capital city, Conakry ( https://www.who.int/emergencies/diseases/ebola/ebola-2021-nzerekore-guinea , https://www.who.int/csr/don/17-february-2021-ebola-gin/en ).

Dr. De Cock retired from CDC in December 2020. He had previously served as founding director of Projet RETRO-CI, Abidjan, Côte d’Ivoire; director of the CDC Division of HIV/AIDS Prevention, Surveillance and Epidemiology; director of the WHO Department of HIV/AIDS; founding director of the CDC Center for Global Health; and director, CDC Kenya.

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DOI: 10.3201/eid2706.210284

Original Publication Date: April 29, 2021

Table of Contents – Volume 27, Number 6—June 2021

Please use the form below to submit correspondence to the authors or contact them at the following address:

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Global HIV & AIDS statistics — Fact sheet

Global HIV statistics

• 39 million [33.1 million–45.7 million] people globally were living with HIV in 2022.
• 1.3 million [1 million–1.7 million] people became newly infected with HIV in 2022.
• 630 000 [480 000–880 000] people died from AIDS-related illnesses in 2022.
• 29.8 million people were accessing antiretroviral therapy in 2022.
• 85.6 million [64.8 million–113.0 million] people have become infected with HIV and 40.4 million [32.9 million–51.3 million] people have died from AIDS-related illnesses since the start of the epidemic.

People living with HIV

• 37.5 million [31.8 million–43.6 million] adults (15 years or older).
• 1.5 million [1.2 million–2.1 million] children (0–14 years).
• 53% of all people living with HIV were women and girls.
• 86% [73– >98%] of all people living with HIV knew their HIV status in 2022.

People living with HIV accessing antiretroviral therapy

• 77% [65–90%] of adults aged 15 years and older had access to treatment; however, just 57% [44–78%] of children aged 0–14 years had access.
• 82% [69–95%] of women aged 15 years and older had access to treatment; however, just 72% [60–84%] of men aged 15 years and older had access.
• 82% [64–98%] of pregnant women living with HIV had access to antiretroviral medicines to prevent transmission of HIV to their child in 2022.
• 9.2 million people living with HIV did not have access to antiretroviral treatment in 2022.

New HIV infections

• In 2022, 1.3 million [1 million–1.7 million] people were newly infected with HIV, compared to 3.2 million [2.5 million–4.3 million] people in 1995.
• Women and girls accounted for 46% of all new infections in 2022.
• Since 2010, new HIV infections have declined by 38%, from 2.1 million [1.6 million–2.8 million] to 1.3 million [1 million–1.7 million] in 2022.
• Since 2010, new HIV infections among children have declined by 58%, from 310 000 [210 000–490 000] in 2010 to 130 000 [90 000–210 000] in 2022.

AIDS-related deaths

• AIDS-related deaths have been reduced by 69% since the peak in 2004 and by 51% since 2010.
• In 2022, around 630 000 [480 000–880 000] people died from AIDS-related illnesses worldwide, compared to 2.0 million [1.5 million–2.8 million] people in 2004 and 1.3 million [970 000–1.8 million] people in 2010.
• AIDS-related mortality has declined by 55% among women and girls and by 47% among men and boys since 2010.

Women and girls

• Globally 46% of all new HIV infections were among women and girls in 2022.
• In sub-Saharan Africa, adolescent girls and young women accounted for more than 77% of new infections among young people aged 15-24 years in 2022.
• In sub-Saharan Africa adolescent girls and young women (aged 15-24 years) in were more than three times as likely to acquire HIV than their male peers in 2022. 
• Every week, 4000 adolescent girls and young women aged 15–24 years became infected with HIV globally in 2022. 3100 of these infections occurred in sub-Saharan Africa.
• Only about 42% of districts with high HIV incidence in sub-Saharan Africa had dedicated HIV prevention programmes for adolescent girls and young women in 2021.
• 2.5% among sex workers
• 7.5% among gay men and other men who have sex with men
• 5.0% among people who inject drugs
• 10.3% among transgender persons
• 1.4% among people in prisons.

Testing and treatment targets (95–95–95)

• In 2022, 86% [73– >98%] of all people living with HIV knew their HIV status. Among people who knew their status, 89% [75– >98%] were accessing treatment. And among people accessing treatment, 93% [79– >98%] were virally suppressed.
• Among all people living with HIV, 86% [73– >98%] knew their status, 76% [65–89%] were accessing treatment and 71% [60–83%] were virally suppressed in 2022.
• Five countries— Botswana, Eswatini, Rwanda, the United Republic of Tanzania, and Zimbabwe had achieved the 95-95-95 targets by 2022.
• A total of US$ 20.8 billion (constant 2019 US$) was available for HIV programmes in low- and middle-income countries in 2022––2.6% less than in 2021 and well short of the US$ 29.3 billion needed by 2025.
• Around 60% of resources available in 2022 were sourced domestically, compared with around 50% in 2010.
• The reduction in resources available for HIV in 2022 is due to declines in both international and domestic funding. The US$ 8.3 billion of external HIV funding in 2022 was 3% lower than in 2021. At the same time, domestic funding is diminishing.
• Bilateral funding from the United States Government constituted 58% of all international assistance for HIV, while disbursements from the Global Fund to Fight AIDS, Tuberculosis and Malaria accounted for about 29%. Other international donors contributed the remainder, but that share has diminished considerably, from approximately US$ 3 billion in 2010 to US$ 1.2 billion in 2022, a 61% decrease.
• In 2022, there was an estimated 90% funding gap for HIV prevention programmes among people from key populations, compared with the funding needed by 2025.

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Progress in the HIV epidemic: Identifying goals and measuring success

* E-mail: [email protected]

Affiliation Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America

• Jeb Jones, 
• Patrick S. Sullivan, 
• James W. Curran

Published: January 18, 2019

• https://doi.org/10.1371/journal.pmed.1002729
• Reader Comments

Substantial progress has been made towards the goal of ending the HIV/AIDS epidemic due to advancements in both prevention and treatment of HIV. However, major challenges still remain. We describe basic principles of epidemic control in the context of HIV and identify a number of attainable goals in terms of control and elimination of HIV in specific populations and risk groups, given currently available HIV prevention and treatment methods. Currently available HIV prevention methods make it a feasible goal to eliminate HIV transmission attributable to mother-to-child transmission and blood transfusions. Reductions in transmission attributable to sexual behavior and injection drug use are feasible, but elimination of these modes of transmission will require further advancements in behavioral and biomedical HIV prevention. With regard to HIV-related mortality, we argue that elimination of death due to HIV-related causes is a feasible goal. HIV-related deaths should be treated as sentinel events triggering epidemiological investigation into the breakdowns in the HIV care continuum that led to them. We briefly discuss additional considerations that will affect the success of HIV prevention programs.

Citation: Jones J, Sullivan PS, Curran JW (2019) Progress in the HIV epidemic: Identifying goals and measuring success. PLoS Med 16(1): e1002729. https://doi.org/10.1371/journal.pmed.1002729

Copyright: © 2019 Jones et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: An earlier version of this paper was commissioned by UNAIDS for a meeting convened in October 2017. JJ received compensation for producing the earlier version of the paper. UNAIDS reviewed and provided feedback on earlier drafts of the paper; however, final editorial decisions were made by coauthors.

Competing interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PSS reports research funding from NIH, research grants and personal fees from Centers for Disease Control and Prevention, research fees from Gilead Sciences, and research fees from MAC AIDS Fund.

Abbreviations: ARV, antiretroviral; MSM, men who have sex with men; PLWH, persons living with HIV; PrEP, pre-exposure prophylaxis; UNAIDS, Joint United Nations Programme on HIV/AIDS; VMMC, voluntary medical male circumcision

Provenance: Not commissioned; externally peer reviewed

Introduction

The United Nations has declared a goal of ending the AIDS epidemic by 2030 [ 1 ], an aspiration echoed by many individual countries. To achieve this goal, targets have been set for each step in the HIV diagnosis and care continuum. Specifically, besides primary prevention targets for voluntary medical male circumcision (VMMC) [ 2 , 3 ], pre-exposure prophylaxis (PrEP) [ 4 , 5 ], use of condoms [ 6 ], harm reduction [ 7 ], and opioid substitution treatment [ 8 ], the 90-90-90 goals aim for 90% of individuals infected with HIV to be aware of their status, 90% of those diagnosed to initiate antiretroviral (ARV) treatment, and 90% of those on ARVs to have viral loads suppressed below levels of detection, by 2020 [ 9 , 10 ]. These aspirational goals are laudable and, to the degree that they can be achieved, will have a meaningful impact on HIV incidence as well as mortality globally. However, the heterogeneity of the HIV epidemic globally raises challenges in terms of measuring success along the way. In a recently published article, Peter Ghys and colleagues have proposed six different metrics to measure transitions in different aspects (e.g., incidence, mortality) of the HIV epidemic [ 11 ].

Differing definitions of what it means for the epidemic to be “over” or “under control” can lead to confusion among stakeholders and the public. It is crucial to define quantifiable goals that will be clearly understood and can be used to measure progress toward vanquishing HIV/AIDS as a major public health problem. This will bring focus and provide benchmarks to measure success of HIV prevention and care programs globally. The purpose of this paper is to review concepts of epidemic control and apply them to the case of HIV. We identify aspirational but feasible goals for control and elimination of HIV transmission and HIV-related mortality. Finally, we will briefly discuss additional challenges and considerations that play an important role in controlling the HIV epidemic.

Epidemiological principles

Disease occurrence is typically measured in terms of incidence (all new cases of a disease during a given period of time) and prevalence (all existing cases of disease at a given point in time). Incidence and prevalence represent measures that we aspire to accurately count or estimate to characterize a certain disease at the population level. However, there are practical considerations, particularly with respect to HIV, that make estimating these measures difficult.

HIV incidence is difficult to measure because HIV infections are initially asymptomatic or cause minimal nonspecific symptoms. Therefore, most newly infected persons do not immediately seek HIV testing and are often diagnosed many months or years after infection. In addition, HIV infection is associated with a window period of one to three months, during which antibody tests cannot detect infection, meaning that early infection may be missed, even when people with very recent HIV infections are tested for antibodies to HIV. Because of these challenges, new infections are frequently measured in terms of new HIV diagnoses. Although this is a pragmatic approach, reporting diagnoses instead of incidence can be problematic in terms of understanding prevailing disease dynamics. For example, increases in diagnoses might be due to more effective HIV testing campaigns that identify previously undiagnosed individuals. The proportion of new diagnoses that occur among individuals with CD4 cell counts <350 (i.e., late-stage diagnosis) highlight the fact that many new diagnoses are not new cases of HIV. For example, a 2015 Dutch study found that 28% of men who have sex with men (MSM) had a CD4 count <350 at the time of diagnosis [ 12 ]. Similarly, the proportion of late-stage diagnoses in a 2013 South African study was 34% [ 13 ]. It is a goal to reduce the time between HIV infection and HIV diagnosis in order for persons to access ARV treatment and to reduce incident infections. As an alternative to using new HIV diagnoses as a proxy for HIV incidence, statistical modeling methods can be used to obtain estimates of HIV incidence in general and within specific populations [ 14 , 15 ].

In the absence of curative therapy, HIV is a lifelong infection. Thus, prevalence measures alone cannot provide a meaningful indication of changes in the epidemic in the short or near term; changes in prevalence must be interpreted in the context of HIV incidence, treatment outcomes, and mortality. Reducing HIV transmission and incidence requires identifying and counselling persons with HIV infection and providing lifelong ARV treatment in order to decrease the probability of transmission of the virus and reduce HIV-associated mortality, in addition to increasing coverage of primary HIV prevention methods among those at risk of infection. Programmatically, these are costly endeavors; estimates suggest that the cost of mounting a comprehensive AIDS response will be US$26–$36 billion annually [ 1 , 10 , 16 ].

Standard measures of epidemic control include control, elimination, eradication, and extinction ( Box 1 ) [ 17 , 18 ]. These measures represent increasing levels of success with respect to ending disease incidence. The language surrounding epidemic control can be confusing, because the terms describing each level of control have common and imprecise meanings in colloquial language. In this paper, we use the words control, elimination, eradication, and extinction only in accord with their technical definitions.

Box 1. Relationship between incidence, prevalence, and duration of disease under steady state

Prevalence = Incidence * Average duration of disease

This equation demonstrates that reductions in prevalence can be achieved by reducing incidence of a disease or the average duration of a disease. Conversely, increases in incidence or duration will increase prevalence. This is why public health successes, such as increasing coverage of ARV therapy, which increases the average duration of HIV infection by extending the life span, leads to increases in HIV prevalence.

Measures of disease control

Control : reduction of disease incidence, prevalence, or mortality in a geographically defined area to a locally acceptable level via effective interventions.

Elimination : complete cessation of incidence in a geographically defined area. Because the disease-causing agent persists, elimination requires ongoing intervention to be maintained.

Eradication : complete removal of the disease-causing agent from the natural environment. The disease-causing agent might persist in controlled laboratory environments. Prevention interventions are no longer needed.

Extinction : complete removal of the disease-causing agent from all natural and laboratory environments.

Formulating goals for controlling the HIV epidemic

HIV has unique characteristics that affect the interpretation and utility of standard measures of epidemic control. Any measurable goals that are put forward in terms of reducing incidence of HIV must take into account the biological and sociological characteristics of the epidemic. Because eradication requires that a disease-causing agent is entirely removed from the natural environment on a global scale, eradication of HIV will not be an attainable goal until a vaccine and cure are developed and uniformly utilized. Table 1 presents aspirational epidemic control goals in terms of HIV transmission and HIV mortality that are attainable using current prevention methods. Control of the HIV epidemic includes both primary prevention of HIV among those at risk of infection and treatment of persons living with HIV (PLWH) to prevent HIV-related mortality and reduce the risk of onward transmission. Although these are distinct processes, there are some overlapping approaches that contribute to both.

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https://doi.org/10.1371/journal.pmed.1002729.t001

HIV transmission

Elimination achieved within a given geographic region by mode of transmission is defined as a reduction of incidence to zero. Unlike with eradication, the disease-causing agent continues to persist in the population, and prevention efforts are necessary to ensure that elimination persists. Elimination of incident infections could thus theoretically be achieved even as HIV prevalence persists, using existing prevention methods like treatment as prevention [ 19 ], PrEP [ 4 , 5 ], condoms [ 6 ], VMMC [ 2 , 3 ], harm reduction [ 7 ], and opioid substitution programs [ 8 ], but only if these interventions are universally and continually utilized over time. Thus, goals related to transmission differ by risk populations.

The aspirational goal of elimination of transmission is more feasible for transmission attributable to blood transfusions and mother-to-child transmission because prevention methods are currently available that are very effective [ 20 , 21 ], and because these modes of transmission largely occur within medical settings, in which interventions can be scaled up universally. HIV infections caused by blood transfusions can be eliminated by testing all donated blood. Mother-to-child transmission can be eliminated by HIV testing all pregnant women, by providing lifelong ARV therapy to mothers who are diagnosed, by providing appropriate prophylaxis at the time of birth, and by following the breastfeeding guidelines established by the World Health Organization [ 22 ]. Transmission events due to these causes should be investigated to understand where the breakdown in systems to identify mothers living with HIV and systems to protect infants occurred, so that necessary systems and policies can be put in place to ensure universal coverage of these prevention methods. Of note, new HIV infections among children had reduced 35% to 180,000 in 2017 compared to 270,000 in 2010 [ 23 ].

HIV transmission due to sexual behavior and injection drug use can be controlled, but elimination is not currently realistic in that the number of transmissions is considerably higher and the structural opportunities for intervention (such as in the context of perinatal care) do not exist. A realistic goal will therefore be epidemic control (e.g., to reduce HIV incidence to locally acceptable low levels, which should be defined clearly and represent considerable improvement over the status quo). Many prevention tools, both old and new, are available to reduce the transmission of HIV due to these risk behaviors. The effectiveness of ARV therapy [ 19 ] and PrEP [ 4 , 24 ]—in addition to condom use [ 25 , 26 ], needle and syringe exchange programs [ 27 ], and VMMC [ 2 , 3 ]—in reducing the risk of HIV transmission following strong adherence by HIV + and HIV − individuals, respectively, demonstrates that existing methods have the potential to greatly reduce HIV transmission. Delivering these tools in combinations and in appropriate service settings, monitoring the uptake in target populations, and monitoring for inequities in uptake will be important to maximize impact. Current ARV-based prevention strategies require substantial levels of adherence for prevention efficacy; these tools can be improved by considering long-acting formulations or shorter, on-demand approaches. A safe and effective vaccine and curative therapy, neither of which are currently available, would change the HIV prevention and treatment landscape. These types of future advancements in biomedical and behavioral prevention research are needed to achieve a goal of elimination of sexual and injection drug use transmission.

HIV mortality

Given current treatment options, elimination of HIV mortality should be an aspirational yet feasible goal. Combination ARV therapy with substantial adherence has been shown to be effective in reducing viral loads and extending the life span of PLWH [ 28 ]. Expanding testing programs to identify all PLWH followed by treatment initiation and adherence support for those persons who are diagnosed could lead to the elimination of mortality due to AIDS-related complications. Deaths from HIV-related causes should be treated as sentinel events, instigating a public health investigation to understand the factors leading to treatment failure. In 2017 there were approximately 940,000 AIDS-related deaths globally [ 23 ]. Appropriate resources will need to be made available to investigate the complex, multilevel failures that likely contribute to HIV-related mortality, including limited healthcare access, poverty, substance use, and mental health problems.

Current progress in controlling the HIV epidemic

Since the 90-90-90 targets were announced in 2014, substantial progress has been made. Compiling country-level data from around the world, the Joint United Nations Programme on HIV/AIDS (UNAIDS) has summarized progress through the end of 2017 [ 29 ]. Although progress—in some countries, substantial progress—has been made, a number of gaps and challenges remain. It is beyond the scope of this paper to fully review global progress, but there are some conspicuous trends. Gains in epidemic control have been notably slower among men and young people, highlighting that existing interventions and programs are not equally effective across demographic groups. This is evident in the faster declines in mortality from AIDS-related causes among women compared with men since 2000. This suggests that additional work will be necessary to increase uptake of HIV testing and treatment among groups that lag behind in the current environment. Additional marginal gains towards the 90-90-90 targets will require engaging these harder-to-reach groups.

There have also been consistent increases in HIV infections and AIDS-related deaths in Eastern Europe and Central Asia since 2000. This is in contrast to generally stable or declining rates of HIV infections and AIDS-related deaths in other regions globally. This suggests additional dynamics that need to be understood and managed in Eastern Europe and Central Asia, in order to halt the growing epidemic in this region.

Varying definitions of control: Defining feasibility

Control of the HIV epidemic should be measured at the local, national, and global levels. To achieve control of the HIV epidemic will mean identifying local goals that result in forward progress but are achievable for a given epidemiological context, as well as identifying and implementing the means to achieve those goals. In the 2016 Prevention Gap Report, UNAIDS identified a target of fewer than 500,000 new HIV infections globally by 2020 [ 30 ]. To achieve this goal, the report recommends implementing the Fast-Track strategy, including achieving the 90-90-90 targets in combination with primary prevention programs. Substantial progress will be required to achieve the 90-90-90 targets globally by 2020, and, under this aspirational goal, a substantial proportion, that is 27% of PLWH, will continue to have unsuppressed viral loads (i.e., if the goals are met, about 73% of PLWH will have a suppressed viral load [90% * 90% * 90% = 73%]).

Beyond identifying methods most appropriate to measure successes and identify challenges in HIV prevention, defining epidemic control also requires identifying aspirational yet feasible goals for a given geographical region and epidemiological context. Because control is achieved within a specific geographic region, the local dynamics and epidemic characteristics must be considered in order to identify appropriate goals. Thus, although benchmarks such as the 90-90-90 goals are helpful in planning at a global level, the target epidemiologic measures of incidence, prevalence, transmission rate, or mortality might need to be different depending on local epidemic characteristics. Goals must be identified in terms of what is aspirational, feasible, and measurable at the local, national, and global levels.

Additional considerations

Any discussion of epidemic control must acknowledge the sociocultural context in which HIV exists. It will be difficult, if not impossible, to achieve control of the HIV epidemic without addressing other factors that contribute to the epidemic, such as stigma and criminalization associated with HIV infection and the need for ancillary health services.

Stigma associated with HIV infection and HIV risk behaviors continues to pose a challenge to public health programs designed to reduce HIV incidence [ 31 ]. Stigma can reduce the likelihood that an individual is aware of their status and seeking treatment or effective prevention tools owing to fear of testing and disclosure. Joseph Amon and colleagues [ 32 ] have described the importance of measuring stigma in addition to other disease-specific indicators (e.g., HIV incidence, AIDS-related mortality) in order to track changes in the epidemic over time.

HIV prevention and treatment programs exist within larger healthcare and economic systems and PLWH, and those at risk of HIV seroconversion, have health needs beyond HIV treatment and prevention services. Mental health services, drug treatment programs, and programs ensuring continuity of care for incarcerated populations are all necessary components of a holistic approach to HIV prevention. Furthermore, these issues serve as a reminder that the populations of PLWH without a diagnosis and those at high risk of HIV infection are very heterogeneous, and there are additional challenges that can be barriers to reaching them. As programs approach the 90-90-90 goals, continued progress might be increasingly challenging because certain key populations have not been reached in individual settings, or different strategies might be required to make further progress.

Conclusions

In this paper, we have reviewed concepts related to epidemiological control in the context of the biology and epidemiology of HIV infection and considered sociobehavioral factors that contribute to the HIV epidemic. Substantial progress has been made in the past 35 years with regard to HIV prevention, treatment, and surveillance methods; however, significant challenges remain. The global commitment to ending the HIV epidemic, exemplified through the United Nations’ Political Declaration On HIV and AIDS [ 1 ], indicates a high degree of motivation from countries around the world to reduce morbidity and mortality due to HIV/AIDS. Existing strategies to measure and evaluate progress of HIV prevention interventions should be examined, and additional new measures should be considered in order to most effectively characterize current and future progress in stemming the epidemic. Targets related to controlling HIV incidence and AIDS-related mortality should reflect realistic capabilities of currently available interventions.

In addition to reliable data to track progress in controlling the HIV epidemic, continued research, including implementation science, will be needed to further our understanding of the most effective HIV prevention interventions and how to most effectively deploy these interventions. As outlined above, we identified elimination of HIV transmission due to mother-to-child transmission and blood transfusions as currently attainable. In order to meet this goal, however, resources will need to be allocated appropriately to ensure that appropriate interventions are broadly available, and studies will need to be conducted to understand barriers to implementation when those interventions are underutilized or ineffective. A holistic approach including surveillance, appropriate measures to track epidemic transition, and implementation science is key to continued progress in meeting global targets for control of the HIV epidemic.

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NIH Ending the HIV Epidemic Projects Bridge Gaps Between HIV Research and Public Health Practice (VIDEO)

The National Institutes of Health recently issued $26M in  awards  to HIV research institutions in its fifth year supporting implementation science under the  Ending the HIV Epidemic in the U.S.  (EHE)  initiative. These awards are the latest investments in a program that is rapidly and rigorously generating evidence to inform the unified domestic HIV response by agencies in the Department of Health and Human Services. 

The EHE initiative aims to achieve a 90% reduction in the number of new HIV infections in the United States by 2030. Since the initiative was announced in 2019, NIH has contributed by supporting implementation science projects through its network of  Centers for AIDS Research (CFAR)  and the National Institute of Mental Health (NIMH)  AIDS Research Centers (ARC) .

CFARs are co-funded by 11 NIH institutes and centers (ICs), including the National Institute of Allergy and Infectious Diseases (NIAID). NIH ICs provide scientific stewardship to participating institutions in collaboration with the  Fogarty International Center  and the  NIH Office of AIDS Research , which coordinates the NIH HIV research program across the agency. CFAR and ARC-affiliated investigators conduct research in jurisdictions that are disproportionately affected by HIV, and many of the CFAR and ARC member institutions are based in these communities.

Dr. Jeanne Marrazzo, director of the National Institute of Allergy and Infectious Diseases, describes the Ending the HIV Epidemic in the U.S. (EHE) initiative, which seeks to combat the HIV epidemic by supporting implementation science. See below:

Read how the Harvard CFAR, which is based in the high-priority jurisdiction of Suffolk County, has launched an EHE Steering Committee to support local and national EHE efforts .

A global epidemic and the leading cause of death in some countries.

By Max Roser and Hannah Ritchie

This page was first published in November 2014 and last revised in December 2023.

Infection with HIV (human immunodeficiency virus) can lead to AIDS (acquired immunodeficiency syndrome). AIDS results in a gradual and persistent decline and failure of the immune system, resulting in a heightened risk of life-threatening infection and cancers .

In the majority of cases, HIV is a sexually transmitted infection. However, HIV can also be transmitted from mother to child, during pregnancy or childbirth, or through breastfeeding. Non-sexual transmission can also occur by sharing injection equipment such as needles.

Other research and writing on HIV/AIDS on Our World in Data:

Antiretroviral therapy has saved millions of lives from AIDS and could save more

See all interactive charts on HIV/AIDS ↓

HIV/AIDS is one of the world's most fatal infectious disease

Almost 1 million people die from hiv/aids each year; in some countries, it's the leading cause of death.

HIV/AIDS is one of the world's most fatal infectious diseases – particularly across Sub-Saharan Africa, where the disease has had a massive impact on health outcomes and life expectancy in recent decades.

The Global Burden of Disease is a major global study on the causes of death and disease published in the medical journal The Lancet . 1 These estimates of the annual number of deaths by cause are shown here. This chart shows the global total but can be explored for any country or region using the "Change country" button.

According to the Global Burden of Disease study, nearly a million people die yearly from HIV/AIDS. To put this into context: this is just over 50% higher than the number of deaths from malaria . It's one of the largest killers globally, but for some countries – particularly across Sub-Saharan Africa, it's the leading cause of death.

The global distribution of deaths from HIV/AIDS

In some countries, hiv/aids is the cause of a quarter of all deaths.

Globally, around 1.5% of deaths are caused by HIV/AIDS.

This share is high but masks the wide variations in the toll of HIV/AIDS worldwide. In some countries, this share was much higher.

On this interactive map, we see the share of deaths that resulted from HIV/AIDS across the world. Across most regions, the share was low: across Europe, for example, it accounted for less than 0.1% of deaths.

However, the share is very high across some countries – focused primarily in Southern Sub-Saharan Africa.

Death rates are high across Sub-Saharan Africa

The significant health burden of HIV/AIDS across Sub-Saharan Africa is also reflected in death rates. Death rates measure the number of deaths from HIV/AIDS per 100,000 individuals in a country or region.

In the interactive map, we see the distribution of death rates worldwide. Most countries have a rate of less than 10 deaths per 100,000 – often much lower, below 5 per 100,000. Across Europe, the death rate is less than one per 100,000.

Across Sub-Saharan Africa, the rates are much higher. Some countries in the South of the region have rates greater than 100 per 100,000.

Death rates are highest for younger adults and children under five years old

Which population groups are most at risk from HIV/AIDS?

In the chart, we show death rates by age group. Here we see that the most at-risk group is younger adults (15 to 49-year-olds). Since HIV is primarily a sexually transmitted infection, where unsafe sex is a primary risk factor, this is what we would expect.

But we also see that death rates are higher for children under five; that’s because HIV can be transmitted from mother to child if the mother is infected.

Is the world making progress in its fight against HIV/AIDS?

How have cases and deaths changed over time.

The 1990s saw a substantial increase in people infected with HIV and dying of AIDS.

In the second half of that decade, over 3 million people were infected with HIV yearly. Since then, the number of new infections began to decline, and it's now below 2 million, the lowest number of new infections since 1990.

As for mortality, AIDS-related deaths increased throughout the 1990s and peaked in the mid-2000s, with nearly 2 million annual deaths. Since then, the annual number of deaths from AIDS has declined and since halved. 2016 was the first year since the peak in which fewer than 1 million people died from AIDS.

The chart also shows the continuing increase in the number of people living with HIV. The growth rate has slowed compared to the 1990s, but the absolute number is at the highest ever.

Global deaths from HIV/AIDS halved within a decade

The world has made significant progress against HIV/AIDS. Global deaths from AIDS have halved over the past decade.

In the visualization, we see the global number of deaths from HIV/AIDS in recent decades – this is shown by age group. In the mid-2000s, global deaths peaked at almost 2 million per year.

Driven mainly by the development and availability of antiretroviral therapy (ART), global deaths have more than halved since then.

You can explore this change for any country or region using the "Edit countries" button on the interactive chart.

HIV/AIDS once accounted for a large share of deaths in some countries, but rates are now falling

Global progress on HIV/AIDS has been driven by significant improvements in the countries most affected by the epidemic.

Today, the share of deaths remains high: more than 1 in 5 deaths in some countries are caused by HIV/AIDS. But in the past, this share was even higher.

In the visualization, we see the change in the share of deaths from HIV/AIDS over time. From the 1990s through to the early 2000s, it was the cause of more than 1 in 3 deaths in several countries and even more than half of annual deaths in the late 1990s in Zimbabwe.

Over the past decade, this share has fallen as antiretroviral treatment has become more widely available.

HIV/AIDS has had a significant impact on life expectancy across Sub-Saharan Africa

The health and mortality burden of HIV/AIDS across Sub-Saharan Africa has been considerable. We see this impact on health reflected in trends in life expectancy . In the visualization, we show changes in life expectancy across select countries in Sub-Saharan Africa for which HIV/AIDS has had the most significant toll.

We see a dramatic drop in life expectancy starting around 1990, coinciding with the rise of HIV. In Botswana, life expectancy fell by a decade; in Eswatini, it fell by two decades. Since the early 2000s — as progress has been made in tackling HIV — we see that life expectancy has been rising again.

In some countries, life expectancy is higher than before the epidemic began.

The prevalence of HIV/AIDS

Prevalence in the total population, share of the population with hiv.

You can explore the total number of people living with HIV/AIDS worldwide here .

Number of new infections each year

Prevalence by gender, is hiv/aids more common in men or women.

There are differences in the prevalence of HIV and death rates from AIDS between men and women. The chart shows the share of women in populations living with HIV.

As we see, HIV prevalence tends to be higher in women across Sub-Saharan Africa, although higher in males across most other regions. The trend in AIDS-related deaths shows the opposite: more men tend to die from AIDS every year than women. The reasons for differences in prevalence and death rates are complex; however, across Sub-Saharan Africa, women tend to be infected with HIV earlier than men and survive longer (explaining both the higher prevalence and lower annual AIDS deaths in women). Several gender inequality and social norm issues result in a higher prevalence of HIV in females across many countries; women are at greater risk when they have a limited role in sexual decision-making and protection, lower rates of sexual education, and higher rates of transactional sex 2 .

Prevalence in children

Share of children infected with hiv, children living with hiv.

When children are infected with HIV, transmission has typically occurred from the mother either during pregnancy or childbirth or through breastfeeding. This is called mother-to-child-transmission, or MTCT. This map shows the total number of children aged 14 and under living with HIV. Globally the number of children living with HIV peaked in 2005 at approximately 2.6 million.

New HIV infections in children

The map shows the total number of children newly infected with HIV yearly. Globally — with similar trends at national levels — the number of new infections in children peaked around the early 2000s (with over 500,000 new infections per year globally), followed by a rapid decline over the last decade.

Children orphaned from AIDS

Some children have lost either one or both parents to AIDS. This does not necessarily imply that children orphaned by AIDS have HIV themselves (although, in some cases, HIV has been transmitted from mother to child). The chart shows the number of children (aged 17 and under) orphaned from AIDS deaths.

Tuberculosis among people living with HIV

Tuberculosis (TB) is the leading HIV-associated opportunistic infection in low- and middle-income countries, and it is a leading cause of death globally among people living with HIV. Death due to tuberculosis remains high among people living with HIV. However, the number of deaths is decreasing. Most of the global mortality due to TB among those with HIV is from cases in Sub-Saharan Africa.

The charts here show the number of TB patients who tested positive for HIV, the number receiving antiretroviral therapy, and the number of TB-related deaths among those living with HIV.

What can be done to prevent HIV/AIDS?

Antiretroviral therapy.

A couple of decades ago, the chances of surviving more than ten years with HIV were slim. Today, thanks to antiretroviral therapy (ART), people with HIV/AIDS can expect to live long lives.

ART is a long-term medical treatment for HIV/AIDS. It works by suppressing the virus from multiplying in the body. This keeps the infection under control and helps to prevent the disease from progressing. ART is essential in progressing against HIV/AIDS because it saves lives, allows people with HIV to live longer, and prevents new HIV infections. Read more in our article:

38 million people had HIV/AIDS in 2020. A couple of decades ago, the chances of surviving more than ten years with HIV were slim. Today, thanks to antiretroviral therapy (ART), people with HIV/AIDS can expect to live long lives. How many lives has ART saved?

Prevention of mother-to-child transmission (PMTCT)

Given that most AIDS cases in children are due to the virus transmission from mother to child during pregnancy, stopping mother-to-child transmission is critical to preventing children from getting infected with HIV.

The chances of an HIV-positive mother transmitting the virus to a child are between 15% and 45%. Effective prevention of mother-to-child transmission (PMTCT) services can reduce the chances of transmission to newborns down to 5%. 3

PMTCT services include preventative measures such as antiviral therapy for mothers and newborns, correct breastfeeding practices, and early child testing for HIV infection.

This visualization shows the number of child infections averted by ART coverage in mothers.

You can explore the number of new HIV infections prevented by PMTCT as a result of antiretroviral therapy across the world here .

Coverage of ART in pregnant women

This map shows the share of pregnant women infected with HIV who receive antiretroviral therapy – a vital intervention to prevent the transmission from mother to child.

Unsafe sex is a leading risk factor for death in Sub-Saharan Africa

Share of people practicing safe sex.

The majority of HIV infections are transmitted through sexual activity.

Sexual transmission can be prevented through condom use (both in heterosexual and homosexual relationships). In the charts here, we see the prevalence of condom use, particularly in cases of “high-risk sex”, which is defined by this data’s source as non-marital, non-cohabiting sexual partner.

Education on HIV/AIDS

Funding to support efforts against hiv/aids, funding needs to meet hiv targets, comparisons of unaids and ihme estimates.

Several sources publish estimates on HIV and AIDS. Two of the most established sources, presented on this page, are UNAIDS and the Institute of Health Metrics and Evaluation (IHME). The charts below show a comparison of these two sources' estimates.

Prevalence of HIV

Incidence/new cases of hiv, interactive charts on hiv / aids.

The latest study can be found at the website of the Lancet here: TheLancet.com/GBD

The 2017 study was published in the following publication: "Roth, G. A., Abate, D., Abate, K. H., Abay, S. M., Abbafati, C., Abbasi, N., ... & Abdollahpour, I. (2018). Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet , 392(10159), 1736-1788". It is online here .

Greig, A., Peacock, D., Jewkes, R., & Msimang, S. (2008). Gender and AIDS: time to act.  AIDS (London, England) ,  22 (Suppl 2), S35. Available online .

World Health Organization (WHO)  'Mother-to-child transmission of HIV'  [accessed November 2019]

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‘It’s the greatest living experiment’: Pitt Men’s Study marks 40 years of AIDS research

PITTSBURGH — In a Pittsburgh hospital in the early 1980s, Charles Rinaldo saw a young, previously healthy gay man critically ill with a virus usually only seen in weakened immune systems.

Around the same time, Jeffrey Toth was hearing terms like “the gay cancer” and “gay related immune deficiency” — and watching players in his gay softball league get mysteriously ill.

“People were dying and we didn’t know why,” said Marc C. E. Wagner. “I knew it was a devastating condition, even early on.”

Through gay bars and picnics, word began to spread about a study at the University of Pittsburgh investigating the disease, and on April 1, 1984, the study officially began recruiting its first participants.

Forty years later, the Pitt Men’s Study is one of the longest-running studies on HIV and AIDS in the country. About 2,000 men have participated since the beginning, coming every six months to give blood samples and answer questionnaires, building a scientific goldmine in the process.

“It’s the greatest living experiment,” said Wagner, an AIDS researcher at Pitt and one of the original study participants. “As one of my mentors, who is no longer with us, once told me, ‘You start in ignorance and you grow in knowledge, and that’s the basis of science.’”

Overall, 1,811 people have participated in the Pitt Men’s Study over the last 40 years, with 438 still-active participants — 201 of those who joined in 1985 or before. Of those who have ever participated in the study, 539 have died from AIDS or other causes.

In 1978, Rinaldo came to Pittsburgh, fresh from completing postdoctoral studies at Massachusetts General Hospital in Boston. His focus was an “opportunistic virus” called cytomegalovirus that attacked people with weakened immune systems, such as organ transplant recipients. Pittsburgh was growing as a transplant center by 1981, boosted by the arrival of transplant pioneer Thomas Starzl.

That same year, Rinaldo remembers seeing a “perplexing case” of a critically ill gay man in his mid-20s with CMV and Pneumocystis pneumonia, another opportunistic virus. Unlike most of the patients that Rinaldo saw with CMV, he had no previous health problems and had not received an organ transplant. Though the disease didn’t have a name yet, the man is now recognized as Pittsburgh’s first known AIDS patient, and later died of the disease.

Shortly afterward, Rinaldo met David Lyter, a Pitt medical student who had recently come out as gay. Lyter had seen the new disease affecting the gay community and approached Rinaldo about putting together a study to investigate it. With no official funding, and with Lyter doing most of the recruiting, they put together a pilot study of about 70 gay men.

At the same time, the country was starting to recognize the virus as well. In June of 1981, the U.S. Centers for Disease Control reported on a cluster of five cases in Los Angeles — all gay men with no known contact with each other, sick with Pneumocystis pneumonia and CMV infections. In September 1982, the CDC used the term AIDS, or acquired immune deficiency syndrome, for the first time. A few months later, the National Institutes of Health put out a request for research proposals for a large study of the new disease.

The study was looking to include one research site in a city that didn’t have as high of an incidence of AIDS as major population centers such as L.A. or New York City. “They thought maybe there was a different cause,” said Rinaldo. “That was one of the hypotheses at the time.”

Rinaldo was decades younger than most of the academic heavyweights vying for funding. But with the support of leaders at the university, he applied.

In the summer of 1983, he received a grant for $4.2 million — which equates to more than $13 million in 2024 — over four years. The study, called the Multicenter AIDS Cohort Study, also included sites in San Francisco, Los Angeles, Baltimore and Chicago, and all except San Francisco are still involved today.

“We were to define the natural history of what was just then being called AIDS,” said Rinaldo. “We did not know the virus that was the cause of this. Part of our intent was to help discover what was causing this mysterious disease.”

But first, Rinaldo needed to find more than 1,000 gay men to come to Pittsburgh to participate in the study — at a time of great fear of the virus and stigma toward homosexuality.

Building the study

“I’m a straight male scientist, never having dealt with the LGBTQ community,” he said. “This is Pittsburgh; it wasn’t San Francisco. That community was not as prominent and accepted as it was in some of the larger cities at the time.”

With Lyter’s help, he enlisted the Tavern Guild — a group of gay bar and bathhouse owners — to spread the word. They recruited at gay bars, putting up posters and handing out napkins with the study’s name and address. Sometimes they took blood specimens right in the bars, using an office or coat check room. Many bars at the time had switched to using plastic utensils, unsure how the virus could spread.

The study also hired Tony Silvestre, a prominent gay leader from Philadelphia, to lead recruiting. An instrumental part of the history of the Pitt Men’s Study, Silvestre died in 2022.

The recruitment was effective, in part because some viewed it as their chance to do something positive about a terrible situation.

Toth heard about the study from a former boss. “HIV was affecting the community — nobody knew what it was, but it was quite scary back then,” he said. “We were younger back then, and we saw some older people just getting very sick. We thought, ‘Oh, we have to do something. It may affect us eventually.’ And it did.”

Because of the fear at the time, the study took immense precautions on secrecy. The clinic was in the Oakland neighborhood of Pittsburgh, not in a university building. Participants were identified only by an ID number; information about their names was kept in a different office in a different building.

Even outside of the building, employees of the study practiced strict confidentiality.

“If you were walking down the street and saw someone and you knew they were part of the study, you just walked right past them,” said Bill Buchanan, who worked for the study from 1988 until he retired in 2022. “Unless you talked to me first, it would be like I never saw you in my life. You have to play that game.”

Even the door to the clinic didn’t fully identify what was going on. “There were no signs on the door that said Pitt Men’s Study. It just said PMS Clinic,” said Buchanan. “Once in a blue moon, you’d get a woman that came in. When she found out that wasn’t what PMS meant, she’d get a little upset.”

At first, visits to the clinic would involve taking all sorts of specimens — blood, saliva, feces, semen — and questionnaires about sexual practices.

“Back then, we took everything,” said Rinaldo. “We didn’t know what we were looking for.”

Evolving testing

In 1985, the FDA approved a test to determine whether antibodies for the virus that caused AIDS were present in a blood test.

All these men who had submitted blood samples could now find out — if they chose to — whether or not they had the virus now known as HIV.

The researchers carefully developed a protocol for how they would let the participants know: They would tell them in person, whether they were positive or negative.

Wagner remembers going in for his session. Though he had no symptoms, he was told that his blood did have the antibodies. Sometime in between his first and second visit to the study, he contracted HIV.

“It was devastating,” he said. “Back then, there were literally no medications. All you were hearing was that it was a death sentence — that in some course of time that you didn’t know yet, you would die.”

In Pittsburgh, about 22% of the participants had antibodies indicating HIV. In some of the other sites in the study, that figure was closer to 50%.

Testing for HIV and AIDS improved further with viral load testing, which not only showed antibodies but also the presence of the virus itself.

One of the Pitt Men’s Study’s most important findings was research on viral loads in the mid-1990s, showing that people who had higher levels of the virus in their blood were much more likely to develop AIDS than people who had lower levels.

“Common sense would dictate it, but we were the first to actually prove it,” said Rinaldo. “To this day, it’s one of the most cited papers in the field.”

Forging community

With so many gay men — both with AIDS and without — regularly visiting the Pitt Men’s Study office, it started to become a de facto clearinghouse of information. Pittsburgh’s gay infrastructure wasn’t as developed as in cities with larger populations, such as San Francisco, and people weren’t sure where else to turn.

“Ultimately, people would turn to the study for all kinds of help — medical help, legal help, I’ve been evicted from my apartment,” said Buchanan. “We were a study, we didn’t have those kinds of resources, and that was the impetus behind creating the Pittsburgh AIDS Task Force.”

The study frequently referred those with AIDS to Jerry Rabinowitz, who was killed in the Squirrel Hill synagogue shooting in 2018. Rabinowitz was one of the first doctors in Pittsburgh willing to treat AIDS patients.

Contributing to the study’s legacy are the larger AIDS services that developed from it. Education programs that stemmed from the study likely prevented many more AIDS cases, said Buchanan.

The study also created a community advisory board that continues to this day, and for years the study led the way locally in commemorating World AIDS Day in Pittsburgh.

Growing understanding — and options

As the AIDS epidemic continued, understanding of the virus grew, as did treatments. In 1987, the FDA approved the first AIDS drug, called AZT. The drug prolonged the lives of some AIDS patients but had serious side effects for some, such as nausea, liver problems and headaches.

For Wagner, the side effects of AZT were unbearable. In what he believed was a choice between quality of life and quantity of life, he stopped taking it.

By 1993, HIV was the leading cause of death among Americans aged 25 to 44. But new and better drugs were on the way. In the mid-1990s, the FDA approved combination therapies that were more effective, but required taking many pills per day. By the late 1990s, those medications were further improved and consolidated into fewer pills.

With medication, Wagner’s viral load is now so low that it is considered undetectable. “I’ve outlived so many of my relatives. If you would have told me at the beginning of this journey that I would still be here and they would be gone, I never would have believed this to be possible. The study gave back to me so much understanding of my own body, peace of mind of knowing what’s going on.”

In some ways, the study has transformed into research on aging with HIV and AIDS, and the effect that the virus has on the body.

With such a large bank of data — and 40 years of specimens in freezers — there are unlimited opportunities for research. Rinaldo is involved in one study that has taken modern understanding of microbiomes and applied it to decades-old stool samples of HIV-positive men, showing differences in the bacteria of those who developed AIDS. Other studies are looking at how HIV affects men who become infected today versus in the early 1980s.

“Forty years later, the specimens that the men gave us are extremely relevant,” said Rinaldo. “I tell my students and postdocs, every time you go into the freezer and take out these specimens, just remember how we got these. Even with all the fancy technology we use now, there’s no way at all we could do all this without these men.”

And to those involved, the study has meant more than just science. For 40 years, they have come to a nondescript building, sharing not just their blood but also friendship, sorrow and camaraderie.

“It’s one of the most dedicated groups of people that I’ve ever seen. Some of the best people in the world walk through that door,” said Buchanan. “I came to love them as friends. Even though I’m retired, there’s a number of them who said, ‘I need your home number, I need to stay in touch.’ Some of them showed up at my mother’s funeral last month.”

Part of the close kinship, of course, comes from tragedy. Toth, one of the original participants and a current data manager for the study, still has a photo from his gay softball team in the early 1980s. “The majority of the team is gone,” he said, “and most of them, sadly, is because of AIDS.”

Later this year, the study will hold events to honor the participants and mark 40 years.

“I don’t call this a celebration: I call this a commemoration,” said Rinaldo. “We won’t be celebrating until we don’t have to do this anymore — until we cure this infection or have a vaccine. We want to keep this going until the study is no longer needed.”

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PACHA Members Discuss HIV Research Highlights from CROI 2024 By HIV.gov

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Each year, the Conference on Retroviruses and Opportunistic Infections (CROI) features an array of exciting new developments in HIV research that can help support the health and well-being of people across the globe. Before the start of the 80 th full council meeting of the Presidential Advisory Council on HIV/AIDS (PACHA) in Houston, TX, HIV.gov had the opportunity to speak with PACHA members Patrick Sullivan, DrPH, MPH, Professor of Epidemiology at Emory University’s Rollins School of Public Health, and Jeff Taylor, Executive Director of the HIV and Aging Research Project, who both attended CROI 2024, about what they presented and what stood out to them at this year’s conference. Watch their conversation Exit Disclaimer :

Mentorship and HIV and Aging Research

Mr. Taylor noted that this year was the first time a formal mentorship program for advocates was launched at the conference, with seasoned mentors paired with new Community Educator Scholars to support and engage them to ensure they got the most out of CROI. He also reflected on the range of research presented at CROI related to HIV and aging. He noted that there continue to be findings presented via abstracts and presentations from the NIH-supported  REPRIEVE trial , a global study that demonstrated that a statin, a cholesterol-lowering medication, may offset the high risk of cardiovascular disease in people with HIV by more than a third, potentially preventing one in five major cardiovascular events (e.g., heart attacks, strokes, or surgery to open a blocked artery) or premature deaths in this population. As he noted,  new clinical guidelines were recently published based on those findings, helping clinicians better support the health of those ages 40-75. ( View HIV.gov’s CROI 2024 conversation with Dr. Carl Dieffenbach about new REPRIEVE trial findings .)

The Further Promise of PrEP

Dr. Sullivan discussed new evidence from a study he and his colleagues at Emory University conducted Exit Disclaimer showing that, over the past decade, U.S. states with high PrEP coverage among those who need it experienced steeper declines in new HIV diagnoses rates than states with low PrEP coverage. Their analysis showed that from 2012 to 2021, states with the lowest levels of PrEP coverage saw an annual increase in new HIV diagnoses, while all other states saw an annual decrease in HIV diagnoses, with the largest decreases among states with the highest levels of PrEP coverage. In other words, he emphasized, while we’ve known for decades that PrEP works to prevent HIV at the individual level, we now know that when we remove barriers to PrEP access and take PrEP to scale, we can see an impact on the population level as well. He further noted that other studies presented at CROI 2024 about all stages in the PrEP cascade—awareness, access, uptake, and adherence—show that we have the tools to get us to that high level of PrEP coverage and better knowledge of how to deploy them.

Catch Up on Other CROI HIV Research Updates

Mr. Taylor also shared an important observation about the opening session with the HIV.gov team as we were working on this blog. He noted, “There was ongoing discussion at CROI regarding stigma as an obstacle to ending the epidemic. Ugandan activist Frank Mugisha, Sexual Minorities Uganda (SMUG), highlighted the chilling impact of new laws criminalizing LGBTQ individuals during the conference's opening plenary. He added that these laws hinder access to HIV care and threaten progress against HIV and that discriminatory policies can cripple the fight against HIV.”

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s social media channels and with recaps here on the blog available by using the CROI topic tag .

More than 3,600 HIV and infectious disease researchers from 73 countries gathered in Denver and virtually from March 3-6 this year for CROI, an annual scientific meeting on the latest research that can help accelerate global progress in the response to HIV and other infectious diseases, including STIs and viral hepatitis. Over 1,000 summaries of original research were presented. Visit the conference website Exit Disclaimer for more information. Session webcasts and more information will be published there for public access in 30 days.

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David E. Barmes Global Health Lecture 2024 | Global HIV/AIDS Response: Then, Now, Future

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NIDCR and the NIH Fogarty International Center (FIC) present the David E. Barmes Global Health Lecture 2024 : Global HIV/AIDS Response: Then, Now, Future. The keynote speaker is Ambassador John Nkengasong , Ph.D., U.S. Global AIDS Coordinator and Special Representative for Global Health Diplomacy, overseeing the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR).

NIH Director Monica Bertagnolli, M.D., and the directors of NIDCR and FIC will also give remarks.

For more information, visit FIC’s Barmes 2024 webpage .

John N. Nkengasong, Ph.D. Ambassador-at-Large U.S. Global AIDS Coordinator Special Representative for Global Health Diplomacy U.S. Department of State

About Ambassador Nkengasong

Dr. John N. Nkengasong is an Ambassador-at-Large and serves as the U.S. Department of State’s U.S. Global AIDS Coordinator and Special Representative for Global Health Diplomacy. In this role, he oversees the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR). Previously, Dr. Nkengasong served as the first director of the Africa Centres for Disease Control and Prevention. As Africa CDC director, he led the COVID-19 response in Africa and helped secure 400 million doses of COVID-19 vaccines at the height of vaccine scarcity. He’s served as acting deputy principal director of the Center for Global Health, as well as the Division of Global HIV and TB’s chief of the International Laboratory Branch at the U.S. Centers for Disease Control and Prevention. Dr. Nkengasong’s contributions to global health have been recognized by the Bill and Melinda Gates Foundation and Time Magazine, among others. Last year, he was invited to join the National Academy of Medicine and he became the first laureate of the Virchow Prize for Global Health. Dr. Nkengasong has been knighted by the governments of Sénégal, Côte d’Ivoire, and Cameroon.

• About the Barmes Global Health Lecture: The David E. Barmes Global Health Lecture series honors the late David Edward Barmes, special expert for international health at NIDCR. Prior to joining NIDCR, Dr. Barmes, a public health dentist and epidemiologist by training, served in senior management positions related to oral health, health promotion, and non-communicable diseases at the World Health Organization in Geneva. The lecture series was established by the NIDCR and Fogarty in 2001 to honor his lifelong dedication to research aimed at improving health for people in low-income countries.
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The pioneer of America’s embattled global HIV program recalls the hope after years of despair

FILE - John Nkengasong, head of the U.S. President’s Emergency Plan for AIDS Relief, or PEPFAR, poses for a portrait on Aug. 29, 2023, in Washington. Nkengasong spoke to The Associated Press about his experience, at a period when challenges by anti-abortion groups and House Republican have made the future of PEPFAR uncertain. (AP Photo/Mark Schiefelbein, File)

FILE - John Nkengasong, head of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR), speaks during an interview on Aug. 29, 2023, in Washington. Nkengasong spoke to The Associated Press about his experience, at a period when challenges by anti-abortion groups and House Republican have made the future of PEPFAR uncertain. (AP Photo/Mark Schiefelbein, File)

FILE - Ambassador-at-Large John Nkengasong, new head of the Bureau of Global Health Security and Diplomacy at the State Department, speaks during the launch of the new bureau, Aug. 1, 2023, at the State Department in Washington. Nkengasong spoke to The Associated Press about his experience, at a period when challenges by anti-abortion groups and House Republican have made the future of PEPFAR, the U.S. President’s Emergency Relief Plan for AIDS Relief, uncertain. (AP Photo/Jacquelyn Martin, File)

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WASHINGTON (AP) — Through his office window at what was then one of Africa’s few modern clinics dealing with HIV and AIDS, the man who now oversees the United States’ threatened global AIDS effort used to hear the sound of taxis pulling up throughout the day.

If he turned his head to look out the window, Dr. John Nkengasong said, he knew what he would see: another desperate family carrying a dying loved one — a man or woman already lapsing into a coma, a stick-thin child — and hoping to find help.

It was before the Bush administration started the U.S. President’s Emergency Relief Plan for AIDS Relief, known as PEPFAR , in 2004. There was almost no affordable effective treatment anywhere between South Africa and the Sahara, no rapid HIV tests or high-quality government labs, and few beds for AIDS patients.

Nkengasong has spent decades working in Africa on HIV and AIDS, a career intertwined with the U.S. program that since its introduction 20 years ago has transformed care in some of the hardest-hit countries and saved an estimated 25 million lives. He spoke to The Associated Press during a battle over funding in Congress that imperils the AIDS program’s future.

Opponents say the HIV/AIDS funding could be indirectly supporting abortion abroad, although the Biden administration and PEPFAR’s defenders say there is no evidence that it does. After a handful of conservative lawmakers threatened for months to block the funding unless restrictions were attached, a compromise was struck in late March that extends the funding for a year.

But advocates of the program warn that without the full five-year renewal, its future remains in doubt as the political debate over abortion and reproductive rights only becomes more combative.

Before PEPFAR, in most cases, Nkengasong’s infectious disease clinic in Abidjan, in the Ivory Coast, could offer the families no care. In their loved ones’ last hours, the families who came there often were left to crouch outside, in the parking lot.

They would surround “a skeleton of a human being, with a tinge of flesh over their bodies,” Nkengasong recalled. “They held their loved ones, giving them the best comfort they could.”

Soon enough, the sound of wailing would rise through his windows. The cries signaled another death to HIV/AIDS, one of millions in Africa by the mid-2000s.

The scene would be repeated “nearly hour by hour,” Nkengasong said. Sometimes he would get up and close the curtains, blocking out the misery of an epidemic he could not then stem.

Two decades later, Nkengasong says, his trips to the region from his offices in Washington bring joyous meetings with men, women and children whose lives were saved through PEPFAR, credited as the biggest government effort ever against a single disease.

In all, the U.S. program has spent more than $110 billion on HIV care and treatment, local medical systems and social programs aimed at stemming infection. The U.S. says it has saved 25 million lives in sub-Saharan Africa and other vulnerable regions, including those of 5.5 million children.

‘A THRIVING INDUSTRY OF COFFINS’

Nkengasong, who was born in Cameroon and did his graduate studies in Belgium, worked in Africa in the 1990s, when the AIDS epidemic was raging all but unchecked.

It made for a “thriving industry of coffins,” he said. Visiting cities in Uganda, Rwanda, Kenya and elsewhere for his work on infectious diseases, he would travel streets lined by handmade coffins of all sizes.

Beds of infectious-disease clinics were full of “adults lying there looking like babies, because of what HIV had done. That ugly face,” Nkengasong recalled.

With early retroviral medication averaging $10,000 per patient per year, only 50,000 HIV-infected people in sub-Saharan Africa were estimated to be receiving effective treatment in the mid-to-late 1990s. That was out of what the World Health Organization said was 10 million people there living with HIV and AIDS.

THE ‘AHA’ MOMENT

One day in spring 2002, as he was in his lab conducting tests, a large American delegation suddenly arrived at the clinic in Abidjan.

Health Secretary Tommy Thompson and other leading U.S. health officials crowded into the facility, along with representatives of businesses and members of faith-based organizations.

“I remember opening the door and the first person who walked through was Dr. Fauci,” Nkengasong recounted. Anthony Fauci, a leading HIV researcher, was then a top official at the U.S. National Institutes of Health and a leader in Nkengasong’s field of HIV and AIDS work. “And he said, ‘John, good to see you again.’ And I was so excited.”

Unbeknownst to Nkengasong and his colleagues, national security adviser Condoleeza Rice and other officials privately had been making the case to President George W. Bush that the global HIV epidemic was where the U.S. could make a huge difference.

For the Bush administration, the epidemic presented an opportunity to do good at a time when the U.S. was waging war in Afghanistan and later Iraq as well after the Sept. 11, 2001 attacks.

Nine months after the Americans showed up in his lab, “we’re watching news on CNN, it was the State of the Union address,” Nkengasong recalled. “And President Bush announced the start of PEPFAR.”

That night, the president pledged an initial $15 billion over the next five years to tackle the AIDS epidemic around the world.

Nkengasong called it the “aha moment” for himself and others fighting AIDS in the most vulnerable region of the world.

Two decades later, AIDS deaths globally have fallen nearly 70% from their peak in 2004. Sub-Saharan Africa is still the most vulnerable region and home to two-thirds of the people living with HIV. But the PEPFAR program and others have strengthened health care systems to deal with infectious diseases, made treatment available to millions, and expanded support for the most at-risk populations, including women.

On a trip back to Abidjan, Nkengasong met a healthy 17-year-old girl, one of millions spared from infection at birth thanks to medical treatment that prevented HIV transmission from their infected mothers.

This past summer, he visited a clinic in Namibia where HIV-infected mothers had delivered “super healthy” babies thanks to treatment that saved them from infection.

“I grabbed some of the babies and looked at them,” he said. Holding them, he wondered what would have happened to them without proper care.

“And they just give you that smile,” he said.

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• Published: 01 July 2003

HIV and AIDS: 20 years of science

• Anthony S Fauci 1  

Nature Medicine volume  9 ,  pages 839–843 ( 2003 ) Cite this article

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From the identification of HIV as the agent that causes AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research in the past 20 years have been formidable. Some of the other important areas of accomplishment include the development of blood tests for HIV and increased knowledge of the molecular virology, epidemiology and pathogenesis of this virus.

The pandemic of HIV infection, the cause of AIDS, is clearly the defining medical and public health issue of our generation and ranks among the greatest infectious disease scourges in history 1 . Since the world first became aware of AIDS in the summer of 1981 (refs. 2 , 3 ), the disease has spread in successive waves in various regions around the globe. By 2003, HIV had infected a cumulative total of more than 60 million people, over a third of whom subsequently died 4 . Unfortunately, the catastrophic potential of the AIDS pandemic has not yet been fully realized. HIV and AIDS continue to exact an enormous toll throughout the world, notably in sub-Saharan Africa, and their incidence is accelerating in some countries and regions, including China, India and parts of eastern Europe and central Asia 4 .

Commensurate with the magnitude of the HIV and AIDS problem has been the extraordinary scientific effort to delineate the etiology, molecular virology, natural history, epidemiology and pathogenesis of disease caused by HIV (reviewed in refs. 5 – 8 ). These areas have paved the way for the development of effective therapies and tools of prevention that have provided enormous benefits to individuals and communities in resource-rich countries and increasingly also in resource-poor countries.

As we look back on the 20 years since the identification in 1983 of HIV as the etiological agent of AIDS 9 , 10 , it is appropriate to reflect on some of the many accomplishments in AIDS science, as well as the numerous challenges that remain. Thousands of investigators in diverse disciplines have contributed to an effort that has resulted in an extraordinary, but still incomplete, mosaic of understanding with regard to HIV and AIDS. The collective output of the HIV and AIDS research community has been prodigious: more than 125,000 papers related to HIV and AIDS are catalogued in the PubMed database of the National Library of Medicine.

Although it would be impossible to describe all of the important scientific contributions in HIV and AIDS research within the context of a brief commentary, I have attempted to highlight in broad strokes some of the main areas of accomplishment in the fight against HIV and AIDS without attempting to be all-inclusive. Other authors in this focus will discuss these and additional topics in greater detail.

A new disease

In the summer of 1981, clinicians in New York and California observed among young, previously healthy, homosexual men an unusual clustering of cases of rare diseases, notably Kaposi sarcoma and opportunistic infections such as Pneumocystis carinii pneumonia, as well as cases of unexplained, persistent lymphadenopathy 2 , 3 . It soon became evident that these individuals had a common immunological deficit in cell-mediated immunity, resulting predominantly from a significant diminution of circulating CD4 + T cells 11 , 12 . Early suggestions that AIDS resulted from behavior specific to gay men were largely dismissed when the syndrome was observed in distinctly different groups in the United States.

After several false leads, many investigators concluded that the clustering of AIDS cases and their occurrence in diverse risk groups could be explained only if AIDS were caused by an infectious microorganism transmitted by intimate contact, for example through sexual activity or blood 13 . As with many emerging infectious diseases, the initial and most powerful tool to illuminate the etiology of the disease was classic epidemiology. Initial observations regarding the immunopathogenesis of AIDS, together with a growing understanding of human and animal retroviruses, suggested that the disease might have a retroviral etiology 9 , 10 . Two retroviruses, human T-lymphotrophic virus (HTLV)-I and HTLV-II, which had been recently recognized at that time, were the only viruses known to preferentially infect CD4 + T cells. The transmission pattern of HTLV was similar to that seen among individuals with AIDS; in addition, HTLV-I and related retroviruses were known to cause varying degrees of immune deficiency in humans and animals 14 . Thus, the search for a new retrovirus was undertaken in earnest.

In 1983, experimental data indicating an association between a retrovirus and AIDS were published by a research team in France led by Luc Montagnier 15 . In 1984, the French group and researchers at the US National Institutes of Health, led by Robert C. Gallo, published seminal papers that established, with virological and epidemiological evidence, that the virus now known as HIV was the cause of AIDS 9 , 10 . The virus was also isolated independently by Jay Levy in California from both individuals affected with AIDS and asymptomatic individuals from groups at high risk for AIDS 16 .

As is very often the case in science, the identification of HIV drew heavily on many previous advances, in particular the discovery in the 1970s of the reverse transcriptase enzyme used in the replication cycle of retroviruses 17 and the cytokine interleukin-2, which is required for the robust growth of cultured T cells essential to the propagation of large quantities of HIV in the laboratory 18 .

Molecular virology and epidemiology

The identification of HIV led to intense activity in the field of molecular virology that continues to the present time. Three structural and six regulatory genes, which together encode at least 15 viral proteins, were identified and their relationship to the complex mechanisms of HIV replication soon unfolded 7 . These findings were crucial to an understanding of the replication cycle of HIV and its relationship to the pathogenic mechanisms of HIV disease. In addition, they provided an avenue to identify important targets for the development of effective antiretroviral drugs.

The study of the molecular virology of HIV also opened the door to the study of the molecular epidemiology of HIV 19 . The science of molecular epidemiology was essential in defining the evolving heterogeneity of HIV throughout the world, including the presence of circulating recombinant forms of the virus 20 and the origin of HIV in the human species. With regard to the latter, the zoonotic nature of HIV was established by the close phylogenetic relationship between HIV-2, first identified in West African individuals in 1986 (ref. 21 ), and the simian immunodeficiency virus in sooty mangabeys. In 1999, it was shown that HIV-1 had probably originated from the Pan troglodytes troglodytes species of chimpanzees, in which the virus coevolved over centuries 22 . Because chimpanzees are killed for food in parts of sub-Saharan Africa, the species jump probably occurred by accident.

A blood test for HIV

The next critical advance after the identification of HIV was the development of a sensitive and specific test for antibodies to HIV that could be used for diagnosing individuals (with confirmation by immunoblot analysis) and for large-scale screening 23 . This fundamental scientific advance had immediate and profound implications for public health. With an ELISA to detect antibodies to HIV, the blood supplies in the United States and other developed countries were screened for HIV and rendered extremely safe by 1985 (ref. 24 ), thereby preventing millions of potential transfusion-related infections. HIV antibody tests have subsequently been used in numerous epidemiological and natural history studies to clarify the global scope and evolution of the epidemic 25 . Only with the availability of this simple screening was the real and potential scope of the AIDS pandemic fully appreciated.

Before the ELISA for HIV, clinicians were generally seeing individuals who were in the late stages of disease and had a life expectancy measured in months 26 . The availability of the blood test allowed investigators to readily identify asymptomatic individuals infected with HIV, to describe more accurately the true clinical course of HIV disease, and to follow the natural history of the disease prospectively in individuals for whom a time of seroconversion could be determined.

HIV pathogenesis

The pathogenesis of HIV disease, from a virological and immunological standpoint, has been studied intensively and defined progressively over the past 20 years 6 , 8 . The pathogenic mechanisms of HIV disease are extremely complex and multifactorial 27 ( Fig. 1 ). Even before HIV was identified, it was recognized that an apparent paradox existed whereby the immune system was aberrantly activated at the same time that the individual was experiencing immune deficiency 5 . This was later shown to be due to a combination of the aberrant secretion of various cytokines, many of which could upregulate virus expression, and the intensive cell signaling induced by the viral envelope 28 . Depletion of CD4 + T cells was recognized as a hallmark of disease early on 11 , 12 , even before the classic demonstration in 1984 that the CD4 molecule was the primary receptor for the virus on a subset of T cells and monocytes 29 , 30 . In addition, much evidence suggested that other factors were necessary for HIV fusion and entry, but these putative 'coreceptors' remained elusive for several years 31 .

HIV (pink) enters the body and binds to Langerhans or dendritic cells (orange), which carry the virus to CD4 + T cells. Infected CD4 + T cells home to lymphoid tissue, where the infection is established. Virus replication accelerates, and massive viremia leads to the wide dissemination of virus throughout the body's lymphoid tissue. An HIV-specific immune response occurs and virus is trapped on the follicular dendritic cells of germinal centers in the lymphoid tissue. At this point, chronic, persistent infection is established despite an immunological response to the virus. Immune activation is an important driver of HIV replication and is mediated by the secretion of various cytokines and by aberrant cell signaling caused by interaction of the viral envelope with cellular receptors. Because there is usually only partial immunological control of virus replication, continual and accelerated production of virus ensues. This is associated with a rapid turnover of CD4 + T cells. Ultimately, lymphocyte depletion occurs, along with destruction of the architecture of lymphoid tissue. Adapted with permission from ref. 6 .

In the mid-1990s, a number of diverse areas of investigation elucidated the roles of the chemokine receptors CXCR4 and CCR5 in the efficient binding and entry of two different strains of HIV-1 called X4 and R5, respectively 6 , 31 . Indeed, RANTES, MIP-1α and MIP-1β, the ligands for CCR5, were shown to potently inhibit the binding of virus to its target cell. This recognition that HIV could use different coreceptors also helped to explain the occurrence of syncytial (CXCR4-using) and nonsyncytial (CCR5-using) variants of HIV 6 . The importance of the CCR5 coreceptor in the pathogenesis of HIV infection was proven by the finding that cells from individuals homozygous for a deletion of 32 base pairs in the CCR5 gene could not be infected in vitro with R5 viruses and that such individuals, who comprise about 1% of white populations, are extremely resistant to HIV infection even when repetitively exposed to virus 32 .

Studies of lymphoid tissue in individuals infected with HIV revealed the disseminated nature of HIV infection and the fact that lymphoid tissue is indeed the chief target and reservoir of HIV infection 33 , 34 . In addition, it became clear that HIV continually replicates at varying degrees in lymphoid tissue despite the fact that the individual might appear to be clinically well. Although the clinical course varied widely among individuals, the inexorably progressive nature of disease in most individuals became clear.

An important advance in HIV research has been the development of highly sensitive techniques for the precise quantification of small amounts of nucleic acids 35 . The measurement of serum or plasma levels of HIV RNA is now an essential component of the monitoring of individuals with HIV infection and, together with CD4 + T cell counts, guides therapeutic decisions 36 . Assays such as RT-PCR and the bDNA technique for directly detecting HIV RNA have helped to clarify the direct relationship between amounts of virus and rates of disease progression, rates of viral turnover, the relationship between immune system activation and viral replication, and responsiveness to therapy 6 .

The ability to measure plasma viremia precisely led to the classic viral dynamics studies of Ho and Shaw in 1995, which characterized the enormous turnover of virus in HIV disease and the delicate balance bet-ween virus production and T cell dynamics 37 , 38 . These studies led to a cascade of insights into HIV pathogenesis, among them an appreciation of the direct relationship between virus replication and disease progression and the association of a given viral set point in an untreated individual with the prognosis for disease progression 39 . The latter observation has been essential in the design of therapeutic strategies and has guided clinicians in decisions regarding the initiation and modification of therapeutic regimens 36 .

The finding of latent reservoirs of HIV, particularly in the resting subset of CD4 + T cells, has had a sobering effect on hopes of eradicating HIV in individuals whose viral load is rendered 'undetectable' by antiretroviral therapy 40 . Indeed, simple but defining studies have shown that even in individuals in whom plasma viremia is driven by antiretroviral therapy to levels of less than 50 copies of RNA per ml ('undetectable') for up to 3 years, the viral reservoir persists and the virus rebounds from this reservoir within weeks of discontinuing therapy 41 .

Studies of the immune response to HIV have been both productive and frustrating. Clearly, individuals in whom HIV infection has been established cannot eliminate the virus from their bodies 40 , 41 . Despite this consistent observation, individuals infected with HIV also show several elements of HIV-specific immunity. Neutralizing antibodies, potent HIV-specific CD8 + cytotoxic T cell responses and HIV-specific CD4 + T cells are present in many individuals infected with HIV at various stages of disease 6 . Unfortunately, CD8 + cytotoxic T cells select for escape mutants, and the most effective neutralizing antibodies are directed at cryptic epitopes against which it is difficult to induce antibodies. Although CD4 + T cells capable of undergoing lymphocyte blast transformation to HIV antigens are more likely to be seen in individuals in the early stages of disease, the induction of such responses has minimal, if any, effect on disease progression 6 .

Thus, the initial hope that the identification of HIV-specific elements of the immune system in HIV-infected individuals would lead to better therapies and vaccines has been replaced by the realization that we have yet to identify a clear correlate of protective immunity against HIV infection 42 . Understanding the correlates of immune protection and their potential role in vaccine development remains one of the greatest challenges in HIV and AIDS research.

Therapy for HIV infection

Second to the identification of HIV as the causative agent for AIDS, the most impressive scientific advances have occurred in the development of effective antiretroviral drugs for treating individuals infected with HIV. The spectrum of drug discovery for HIV centers on an appreciation of vulnerable targets in the replication cycle of the virus ( Fig. 2 ). The first effective drug against HIV was the reverse transcriptase inhibitor azidovudine (zidovudine), or AZT 43 . It was identified by a screening process using large numbers of compounds that had been already produced for other purposes. AZT was originally developed as an anticancer drug but did not prove effective in that capacity. It was licensed instead as the first antiretroviral drug in 1987.

The replication cycle of HIV and targets for antiretroviral therapy.

Subsequently, more sophisticated science in the form of targeted drug design has been the rule as drugs have been developed to target specific vulnerable points in the virus replication cycle, providing a cogent example of the importance of the basic research endeavors in viral biology and the translational approaches in drug development 44 . The prototype of this approach was the expression, purification and crystallization of the HIV protease enzyme to facilitate the tailored design of protease inhibitors—a class of antiretroviral drug that was first approved by the US Food and Drug Administration (FDA) in 1995 (ref. 45 ).

The newest class of drug, fusion inhibitors, represents another example of successful targeted drug development led by basic science discovery 44 . These compounds block the fusion of the viral envelope to the cell membrane, and became available with the FDA approval of enfuvirtide (Fuzeon) in 2003 (ref. 46 ). New and improved drugs in all three classes (reverse transcriptase inhibitors, protease inhibitors, and fusion and entry inhibitors) are being actively pursued along with drugs against alternative targets such as the viral integrase 44 . Currently, there are 20 FDA-approved drugs or combinations of drugs for HIV ( Table 1 ). The availability of these therapeutics and their use in combinations of three or more drugs have transformed the treatment of individuals infected with HIV such that morbidity and mortality owing to HIV disease have sharply declined in developed nations where such drugs are readily available 25 .

HIV vaccinology

The progression of HIV disease in the setting of vigorous anti-HIV responses remains a central paradox in the pathogenesis of HIV infection 6 , 8 . Elements of both the humoral and cell-mediated immune responses against HIV have been implicated in the partial control of viral replication. Even after 20 years of HIV and AIDS science, however, our lack of understanding of the correlates of protective immunity in HIV infection continues to hamper the rational development of HIV vaccines 47 . With 14,000 individuals worldwide becoming infected with HIV every day 4 , a vaccine that prevents HIV infection or at least slows the progression of disease in individuals who become infected is badly needed.

Despite the lack of a clear understanding of the correlates of protective immunity in HIV infection and other formidable obstacles, significant progress toward an HIV vaccine has been made 47 . At the time of writing, numerous promising HIV vaccine candidates are in various stages of preclinical and clinical development. But it is still not clear at this point how successful, if at all, we will be in the development of a vaccine that truly protects against HIV infection. Candidate vaccines in nonhuman primate models generally have not been able to protect against infection, but they have shown protection (at least for a time) against disease progression in primates that become infected despite having been vaccinated 47 . The superinfection of already-infected individuals whose current virus had been under excellent immunological control is a troubling observation 48 . Clearly, the development of a safe and effective vaccine for HIV is one of the most formidable challenges for research in infectious diseases.

The scientific accomplishments in the field of HIV research over the past 20 years reflect an extraordinary odyssey of discovery. Indeed, these accomplishments represent a model of what can be accomplished when the world's scientific community is galvanized in a common goal of pitting its best minds and substantial resources against a historic public health challenge. This Nature Medicine special issue will take up in detail these and other crucial accomplishments in the scientific response to HIV and AIDS.

Unfortunately, the HIV pandemic still rages throughout the world, particularly in resource-poor countries such as those in sub-Saharan Africa, the Caribbean and parts of Asia. This fact should energize the scientific and public health communities to continue the quest for scientific discovery and, simultaneously, to ensure that the fruits of scientific discovery are adequately applied to those most in need.

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I thank G. Folkers for help with preparing the manuscript and H.C. Lane for critically reading the manuscript.

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