neuropsychiatric presentation of hiv

Neuropsychiatric manifestations of HIV infection and AIDS

Affiliation.

• 1 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA 19104, USA. [email protected]
• PMID: 16049567
• PMCID: PMC1160559

Abstract in English, French

As the life expectancy of people living with HIV infection has increased (through recent advances in antiretroviral therapy), clinicians have been more likely to encounter neuropsychiatric manifestations of the disease. Some patients present with cognitive deficits due to an HIV-triggered neurotoxic cascade in the central nervous system. However, more patients present with a depressive spectrum disorder during the course of their illness, the underlying pathogenesis of which is not as well understood. This category of psychiatric disorders presents diagnostic challenges because of the many neurovegetative confounding factors that are present in association with HIV illness. As quality of life becomes a more central consideration in the management of this chronic illness, better awareness of these neuropsychiatric manifestations is paramount. This article reviews these clinical issues and the available psychopharmacologic treatment options.

Comme l'espérance de vie des personnes vivant avec le VIH a augmenté (grâce aux progrès récents de la thérapie aux antirétroviraux), les cliniciens sont maintenant plus susceptibles de faire face à des manifestations neuropsychiatriques de la maladie. Certains patients se présentent avec des déficits de la cognition attribuables à une cascade neurotoxique déclenchée par le VIH dans le système nerveux central. Plus de patients se présentent toutefois avec un trouble du spectre dépressif pendant leur maladie, dont on ne comprend pas aussi bien la pathogénèse sous-jacente. Cette catégorie de troubles psychiatriques pose des défis diagnostiques en raison des nombreux facteurs confusionnels neurovégétatifs associés à l'infection par le VIH. Comme la qualité de vie devient un facteur plus central dans la prise en charge de cette maladie chronique, il est primordial d'être plus conscient de ses manifestations neuropsychiatriques. Dans cet article, les auteurs passent en revue ces enjeux cliniques et les traitements psychopharmacologiques possibles.

Publication types

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Research Support, U.S. Gov't, P.H.S.
• Acquired Immunodeficiency Syndrome / psychology*
• Antidepressive Agents / therapeutic use
• Antipsychotic Agents / therapeutic use
• Brain / physiopathology*
• Central Nervous System Stimulants / therapeutic use
• Cognition Disorders / diagnosis
• Cognition Disorders / etiology
• Cognition Disorders / physiopathology
• HIV Infections / psychology*
• Mental Disorders* / drug therapy
• Mental Disorders* / etiology
• Mental Disorders* / physiopathology
• Neuropsychological Tests
• Selective Serotonin Reuptake Inhibitors / therapeutic use
• Antidepressive Agents
• Antipsychotic Agents
• Central Nervous System Stimulants
• Serotonin Uptake Inhibitors

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HIV and AIDS in Older Adults: Neuropsychiatric Changes

• Geriatric Disorders (JA Cheong, Section Editors)
• Published: 09 July 2022
• Volume 24 , pages 463–468, ( 2022 )

Cite this article

• Paroma Mitra   ORCID: orcid.org/0000-0003-1947-3564 1 , 2 ,
• Ankit Jain 3 &
• Katherine Kim 1 , 2  

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Purpose of Review

Patients diagnosed with HIV can now survive well into their old age. Aging with HIV is not only associated with comorbid medical illnesses but also with neuropsychiatric conditions that can range from cognitive changes to severe behavioral manifestations. This paper reviews mood, anxiety, and cognitive changes in older patients with HIV, as well as some of the treatment challenges in this population.

Recent Findings

Most recent findings show that untreated HIV illness over a long period of time may further worsen both preexisting neuropsychiatric illness and may cause new onset behavioral and cognitive symptoms. HIV induces immune phenotypic changes that have been compared to accelerated aging Low CD 4 counts and high viral counts are indicative of poor prognosis.

Evaluation for potential HIV infections may be overlooked in older adults and require screening. Older adults experience accelerated CD4 cell loss. Older adults endorsing new onset mood or cognitive changes must be screened for HIV infection. New onset neurobehavioral symptoms should be carefully screened for and treated simultaneously in patients with HIV infection.

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Mitra, P., Jain, A. & Kim, K. HIV and AIDS in Older Adults: Neuropsychiatric Changes. Curr Psychiatry Rep 24 , 463–468 (2022). https://doi.org/10.1007/s11920-022-01354-z

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• Case Reports

February 2011

CASE REPORT: Neurocognitive Presentation of HIV: HIV-associated Progressive Encephalopathy

A case report and review of the literature explores hiv presenting as a syndrome complex with cognitive, motor, and behavioral features..

Eva Pilcher, MD and Michael J. Schneck, MD

Acute HIV infection often involves neurological symptoms in which patients present with an encephalopathic syndrome with no clear history that might otherwise raise a high index of suspicion for HIV. These patients, during the initial infectious phase, may not have yet underwent seroconversion and so routine HIV antibody testing may not be positive leading to a lost opportunity for treatment as anti-retroviral therapy is most effective in this acute phase of HIV infection. The phenomenon has been previously well-described but remains an under-recognized and under-appreciated presentation of HIV infection.

Case Report A 60-year-old man was admitted to the Loyola University Medical Center in November 2009 because of headache, neck pain, and fever. One week before admission, the patient went on a ship cruise to Puerto Rico. On the first day of the trip, he became ill with development of a headache accompanied by fever and chills. He was evaluated by the cruise physician and prescribed azithromycin. He was also advised to take ibuprofen. The patient continued this treatment for five days without improvement; his fever continued, the headache worsened, and he developed neck pain. He became progressively fatigued, weak, and also developed mild confusion. He returned from the cruise and was brought to our emergency department by concerned family members.

The patient lived at home with his family in another state and was an owner of several restaurants. He had traveled to Chicago two weeks prior to join his family on the aforementioned cruise, and was planning on returning home after the vacation. The patient's admission medical history included borderline hypertension, and admission medications were only acetaminophen. He provided no history of alcohol, tobacco, or illicit drug use. He denied any nausea, vomiting, vision changes, focal neurological symptoms, or loss of consciousness.

On initial examination the patient appeared in mild distress due to the headache. The axillary temperature was 37.1°C. The pulse was regular at 89 beats per minute, the blood pressure was 137/81mm Hg, and the respiratory rate was 20 breaths per minute.

The general examination showed no abnormalities. On neurological examination, however, he was inattentive and distractible; he had difficulty following two-step commands and recalled 2/3 words at five minutes. His speech was fluent.

The cranial-nerve examination was normal. He had some difficulty cooperating with the motor examination due to neck pain, but strength and coordination were otherwise normal. He was not able to stand with both eyes closed, but his gait otherwise appeared to be steady. The sensory and reflex examinations were also normal. The Brudzinski sign was negative, but the Kerning sign was positive.

Laboratory investigations included a normal complete blood count and a complete metabolic panel. The C-reactive protein was elevated at 2.8, and the sedimentation rate was increased at 58. A chest radiograph was also normal except for an old clavicular fracture. Magnetic resonance imaging of the brain, with special attention given to the temporal area, with and without gadolinium contrast, did not reveal any abnormalities. An electroencephalogram showed diffused slowing consistent with encephalopathy but no epileptiform activity. A lumbar puncture demonstrated mild lymphocytic pleocytosis: white blood cell count was 40 with 81 lymphocytes and elevated CSF protein at 63.

Because of the altered mental status and abnormal CSF findings, the possibility of viral encephalitis led to initiation of acyclovir 1000mg twice a day at admission. The HSV CSF titer drawn at admission was 3.01, and the patient was continued on acyclovir for a total of six days, until the HSHV PCR results came back negative. Multiple additional CSF studies were obtained, including West Nile Virus IgM, Varicella Zoster Virus, Cytomegalovirus, fungal cultures, CSF cultures, and Acid Fast Bacilli; these all returned negative.

Additional serum studies were sent for HIV 1 and 2 antibodies, influenza A and B, respiratory syncytial virus assay, blood cultures, Epstein Barr Virus and mononucleosis screen. All of these tests were also negative. A CT of the chest and thorax was obtained to investigate for any infectious or neoplastic process and was also normal.

Throughout the hospitalization, the patient continued to complain of neck pain that later developed into a back and shoulder discomfort, especially on the right side. It was thought that the discomfort might be attributable to muscle spasm, so a trial of cyclobenzaprine, and then low dose diazepam, was attempted without providing relief to the patient. Due to the continued significant pain in the neck, back, and shoulder, an MRI of the cervical spine and brachial plexus was obtained. The images from the initial MRI were suboptimal and the study was repeated again with sedation. The repeat study revealed no cervical spine or brachial plexus etiologies, but demonstrated a bursal surface tear of the right anterior supraspinatus tendon. Orthopedic consultants recommended conservative therapy and the patient was started on a flexor patch and a steroid taper for the rotator cuff injury.

Ultimately, the patient's family arrived from out of state and he was discharged with plan to travel back home and follow up with his primary care physician. It was not until two weeks after discharge that the HIV viral load returned at over 500,000 and the patient's primary physician was subsequently contacted, and retroviral therapy was initiated. Of note, neither the patient nor the family had ever provided a history of HIV risk factors.

Discussion Human immunodeficiency virus (HIV) has infected approximately 33 million individuals worldwide, and the virus is rapidly becoming a world pandemic. Initial presentation of an acute infection often involves neurological symptoms. These individuals present with an encephalopathic syndrome, but no prior suspicion for HIV diagnosis and insufficient HIV antibodies to produce a positive HIV enzyme immunoassay. They present at a crucial time: at initial phase of the infection, and prior to seroconversion, when antiretroviral therapy has been shown to be most effective in reducing mortality and morbidity. HIV infection of the CNS is especially problematic; it causes a barrier to management and eradication of the virus because of the incomplete impermeability to antiretroviral drugs, resulting in sub-therapeutic levels within the CNS. As a result, while the HIV infection goes undiagnosed, the CNS ends up being a reservoir for the virus, providing a safe environment where the virus can replicate and mutate. Early treatment with antiretroviral therapy targets the virus before it has the advantage of sequestration in the CNS. Considering the crucial importance of prompt and accurate diagnosis of an acute HIV infection, it is troublesome that guidelines for management of acute HIV aseptic meningitis are limited to case reports. The need for increased awareness of neurological presentation of acute HIV infection is evident.

On admission to the hospital, our patient was thought to have an acute change in mental status accompanied by headache, neck pain and fever along with CSF lymphocytosis and elevated CSF protein. In this patient, the absence of clinical and laboratory evidence of electrolyte or organ function abnormalities ruled out metabolic or toxicologic etiologies. Instead, given the abnormal cerecerebrospinal fluid findings, the focus was redirected at infectious causes of meningitis and encephalitis. While the patient was treated with an antiviral agent (acyclovir) because of appropriate concerns of HSV encephalitis, retroviral therapies were not initiated early in the course of therapy. All other tests for viral, bacterial, and fungal pathogens were negative, and symptomatic treatment was ineffective except for a transient improvement in headache that may have been related to the administration of pain medications. It was not until after discharge that the HIV viral load was found to be significantly elevated; previously obtained HIV antibody testing was negative. As such, a missed opportunity for early intervention in HIV infection resulted.

In this context, the diagnostic evaluation was disappointingly inconclusive as to the etiology; it was not until after the patient had been discharged that an HIV viral load of over 500,000 was discovered. While the patient did not disclose any risk factors for HIV infection, his presentation was consistent with acute encephalitis likely due to a recent HIV infection. Unfortunately, it is often difficult to identify patients with primary HIV infection when they fail to disclose risk factors for acquiring the virus and there are no clinical findings indicative of immunosuppression. The presentation is depressingly common. Similarly, in other reports, patients with an underlying diagnosis of primary HIV infection were not initially identified, which resulted in a delay of diagnosis.

Successful identification of a primary HIV infection is fundamental; it offers the patient the opportunity to receive potent antiretroviral therapy prior to the time of virus seroconversion, when one can favorably affect the prognosis of the disease.

Neurological symptoms can occur before HIV diagnosis is suspected, before there are sufficient HIV antibodies to produce a positive HIV enzyme immunoassay. Neurological features of an acute HIV virus infection include aseptic meningitis, meningoencephalitis and encephalitis that can occur in up to 17 percent of patients. These individuals present with fever, headache, stiff neck, photophobia, CSF with mild lymphocytic pleocytosis and slightly elevated protein, but normal glucose. Approximately 40-90 percent of patients with an acute HIV infection present with physical symptoms similar to influenza or mononucleosis. Primary HIV infection is characterized by fever, lethargy, and headache and generalized flu-like symptoms. The HIV virus does not directly invade nerve cells, but rather causes inflammation. It is this persistent infection and inflammation that results in breakdown of the blood-brain barrier, neuronal and axonal injury, neurotoxicity, and clinical symptom such as confusion, forgetfulness, headache and even changes in behavior and cognition.

Unfortunately the management of acute HIV aseptic meningitis is limited to case reports. Our case is consistent with other reports in the literature. One case report described a patient that presented with mild confusion and was not able to follow commands. Another case described a patient that had been well until 13 days prior to presentation, at which time he began having bi-frontal headaches, low-grade fever and began experiencing changes in behavior. Interestingly, another very similar report described a 31 year-old male, which presented with one week of confusion and fever after having returned from a trip to the Caribbean; this patient's provisional diagnosis was viral encephalitis, based on lymphocytic fluid obtained via a lumbar puncture and he was treated with intravenous acyclovir.

It is evident that accurate diagnosis of HIV infection is crucial at time of acute onset. In acute presentation, when suspicion is high, the need for thorough history-taking cannot be forgotten. But patients can fail to disclose risk factors for HIV infection; hence, proper testing is crucial. It is important to remember that a viral load can detect the virus a few days after HIV infection, while a standard HIV antibody test can remain negative for months after the HIV infection.

While starting acyclovir in patients with a clinical picture of meningoencephalitis until an HSV PCR returns negative is an accepted clinical practice, a parallel approach is not considered for acute HIV infection. We suggest therefore, in cases of meningoencephalitis of unclear etiology, where the HIV antibodies are negative and the HIV viral load has been sent but remains pending, it may be reasonable to initiate a short course of retroviral drugs until return of the HIV viral load assay results. Thus, with awareness of the neurological presentations of an acute HIV infection, diligent history taking, proper laboratory testing, and rapid initiation of therapy, failure to identify primary infection can be minimized and crucial delays in antiretroviral therapy can be eliminated.

The author(s) declare that they have no competing interests. An attempt was made to contact the patient, but this unsuccessful. However we have taken adequate steps to keep his identity safe and in no way have we revealed any personal information about the patient in the case report.

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Neuropsychiatric Aspects of HIV

Mar 17, 2013

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Neuropsychiatric Aspects of HIV. University of Hawaii James Dilley, MD and Emily Leavitt, LCSW. Prevalence of MH Disorders among People with HIV/AIDS n = 1489. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”. Depression in HIV.

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Neuropsychiatric Aspects of HIV University of Hawaii James Dilley, MD and Emily Leavitt, LCSW

Prevalence of MH Disorders among People with HIV/AIDSn = 1489 Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”

Depression in HIV • Most common dx in outpt settings • Concern re: diagnosis in medically ill • Emphasize cognitive/affective vs. neurovegatative signs/sxs • Assoc with CD4, soc support and  phys limitations and HIV sx • Excellent pharmacologic response • Give benefit of the doubt

Pharmacotherapy of Depression in HIV

Depression & Testosterone • 50% of men with Sx HIV/AIDS have deficiency and sx of hypogonadism: • Fatigue • Decreased libido • Decreased appetite • Decreased mood

Screening Tests • Total Serum Testosterone: <300-400ng/dl • Serum Free testosterone: <5-7 pcg/ml • Tx: depot IM injections q ii wks (100-200mg IM; max 400 mg/wk) • Patch (5-10mg; 1-2 times daily) • Gel (25-100 mg to skin daily) • Can see mood improvement

HIV produces at diff rates in CNS vs. plsma Diff phen/genotypes: esp later in disease All ARV’s not = in treating CNS cx May result in peripheral success (pVL) but central failure CNS: HIV’s Most Important Sanctuary Site

HIV Neuropathogenesis Early and continuous seeding Importance of Blood Brain Barrier

HAD: A Diagnosisof Exclusion • HIV antibody positive • No other treatable disorder known to be associated with mental status changes (e.g., no other CNS OI’s, trauma, metabolic disorders, etc.

Diagnosis Requires (continued): • “Clinical findings of disabling cognitive and /or motor dysfunction interfering with occupation or activities of daily living” • Neuropsychological testing often needed, especially in early cases-- • (1 SD below age/education adjusted norms on 2/8 tests) AND • Either impairment in lower ext or fine motor skills or selfreported depression interfering with function

Pseudo-Dementia • Depression in “dementia’s clothing” • Index of suspicion high if: • unremitting and detailed c/o memory pblms • “I don’t know” responses to cog questions: communicates distress/emphasizes disability • Behavior often incongruent w/level of complaint • In early stages of HIV disease • Frequently has past hx of psychiatric pblms

Cognitive Functions A. Memory Short-term vs. delayed B. Concentration, Calculation and Constructional Ability C. Personality Change: alteration or accentuation of pre-morbid traits D. Language E. Judgement “Reasonable plans”

Early Manifestations of HAD • Cognitive Memory Loss (names, historical details, etc.) Impaired Concentration (difficulty reading, loses track of conversation) Mental slowing (“not as quick,” less verbal) Confusion (time, especially)

Early Manifestations of HAD (continued) • Behavioral Apathy, withdrawal, “depression” Agitation, hallucination • Motor Unsteady gait Bilateral leg weakness Tremor Loss of fine motor coordination

Late Manifestations • Cognitive global dementia in all spheres confusion and distractability slow verbal responsiveness • Behavioral vacant stare disinhibition and restlessness organic psychosis

Late Manifestations (cont.) • Motor general slowing truncal ataxia weakness: legs > arms pyramidal tract signs: spasticity, hyperreflexia

Effect of HAART • Significant changes in the epidemiology of CNS disorders since HAART • In Sx illness • Studies are more consistent with subcortical dementia • In asx illness, NP findings are inconsistent • > Length of battery>NP deficits • Significance clinically is unclear

Pathological Findings in CNS of AIDS Patients at Autopsy N = 1597 1984-1987 (No therapy) 1988-1994 (monotherapy) 1995-1996 (dual comb. therapy) 1997-2000 (triple comb. therapy) Vago L., et al. AIDS 2002, 16:1925-28

Risk Factors for Cognitive Impairment in HIVCase Control: 90 HIV- ; 88 ASX; 94 SXCI = Scores of 2SD below the means of the control on 2 or more standard neuropsychological tests

HAART N 69 CD 4 254 UVL 42% NPI 22% Non-HAART 61 342 20% p<0.01 54% p<0.0001 HAART Use & NP FunctionN = 130; Avg Age = 41; 42% NW; 82% AIDS Ferrando et al., AIDS, 1998, 12F 65-70 NOTE: IMP =  25D in the impaired direction of age-matched population-based norms HAART=  NRTI + Ritanavir, Indinavir or Nelfinavir

Median HIV RNA levels for brain (for all available brain regions) and peripheral tissues stratified by neurologic status: non-demented, mild, and moderate/severe McClernon D.R, et al. Neurology 2001, 57:1396-1401

P  CSF < 200 >200 No No No Yes* No Yes No Yes* No No CSF  NP Status < 200 >200 Yes No Yes No Yes No Yes No Yes No Correlation of Plasma VL to CSF VL Brew (Aus) Ellis (US) MacArthur (US) Dore (US) DiStephano (Italy) ___________________________ * Correlation exists in ASX state

Favorable CNS Characteristics of ARVs • % protein binding ( = better) • lipid solubility ( = better) • molecular weight ( = better) • inhibitory concentration ( = better)

Medical Rx of HAD 1. Aggressive ARV: neuroprotective 2. Use combinations of 3, 4 or more Should include: • AZT, D4T, 3TC, Abac-NRTI • Nevirapine, Efavirenz-NNRTI • Indinavir - PI (best BBB penetrance)

Factors Influencing Efficacy of ARV Rx: • Stage of HIV disease • Degree of CNS replication/resistance • Integrity of BBB • Specific treatment strategy/ARV choice

Some NeuroprotectiveDisappointments Nimodipene  interaction with CAH Peptide T block gp-120 *Memantine NMDA antagonist/showing efficacy for ADV *Deprenyl Anti-oxidant/anti-poptotic Lexipafant PAF antagonist *some benefits

Case History - “JC” ID: 42 y/o GWM architect admitted for agitation, irritability, decreased sleep, and grandiose delusions. Brought in by lover of 7 yrs. HPI Two mos intermittent confusion/ hypomania (rapid speech, disorganized thinking over last 3 days; focus on spiritual issues. Felt friends were trying to harm him, stated he had been cured of AIDS; claimed he was a millionaire. PMH HIV infected x 10 years; current CD4 count = 70. No OI’s. No previous psych hx.

Case History - “JC” (cont.) MS: Alert, mildly agitated, unable to sit still. Speech: mildly pressured, loud, but interruptable. Thought process: overly inclusive, loose assns. Content: grandiose, “richest family in California,” had “cured himself of AIDS.” Some paranoia. Cognitive: 0 x 2. Memory: Imm = 4/4; 2/4 @ 5 mins. 3/4 with prompts. Attention: Serial 7’s = mult. Errors; WORLD backwards, “d-l-o-w.” Abstraction: Some concreteness. Construction: OK Insight: none Judgement: impaired

Case History - “JC” (cont.) Diff Dx: Axis 1: Delirium due to HIV disease (293.0). Dementia due to HIV disease (294.1) R/O BAD R/O Toxic Psychosis Axis II: Deferred Axis III: AIDS

Hospital Course LAB: MRI: Extensive cortical atrophy. LP: unremarkable Rx: Trilafon 2mg p.o. BID and 4 mg @ HS Valproic acid 250mg p.o. BID and 500 mg @ HS Ativan 0.5 mg p.o. BID and prn agitation

Psychotropic Medication Use NOTE: Use among Af-Am was significantly lower than White or Hispanic. Vitiello et al. AJPsych 2003, 160:547-54 from “HIV Cost and Services Utilization Study—1996”

Psychopharmacology in HIV Disease Consider geriatric dosing - “start low and go slow” Look for low-anticholinergic meds ConsiderPay special attention to Ritonavir (NORVIR - strong CYP3A4 inhibitor) Overall, anti-HIV meds are not problematic

Pharmacotherapy of Anxiety Disorders 1. “Reactive” Anxiety -Lorazepam 0.5 mg B/TID Max: 4 mg q 4 hrs 2. Panic Disorders with or without Agoraphobia Paroxetine (Paxil) 10-40 mg/D Lorazepam for breakthrough 3. GAD - Paroxetine;Buspirone (Buspar) 5-10 mg BID - 20 mg TID Note: Buspirone is the “does not” drug: cause tolerance, physical dependence or a withdrawal syndrome, have abuse potential (hypnotic, muscle relaxant activity), work right away

Ritonavir (Norvir)(Potent inhibitor of CP450, esp. 2D6 and 3A4) 1. AdjustAnti-depressants SSRI’s - initially  by 1/2 TCA’s - initially  by 1/2 to 1/3 Nefazodone and St. John’s Wort 2. Avoid Benzodiazepines Anti-psychotics Clonazepam (Klonopin) Clozapine Alprazolam (Xanax) Pimozide Diazepam (Valium) Flurazepam (Dalmane) Triazolam (Halcion) Zolpidem (Ambien) 2. Allow Temazepam (Restoril) Oxazepam (Serax) Lorazepam (Ativan) Bupropion (Wellbutrin)

Methadone • Ritonavir and Nevirapine (and likely Efavirenz) has been shown to lead to significant withdrawal symptoms in stable methadone users • Should follow serum meth levels before & after initiation; may need to increase by 25-30%

Other Pharm Issues • Sildenafil levels may be significantly raised by Ritonavir, Saquinavir and Indinavir--potentially serious CV effects (DNE 25mg) • Fatal case reports have been filed suggesting Ritonavir in combination with methamphetamine and Ecstasy (MDMA) was the cause of death • St. John’s Wort: may decrease PI’s

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Neuropsychiatric Aspects of HIV Infection

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (513K), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References .

Selected References

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• Atkinson JH, Jr, Grant I, Kennedy CJ, Richman DD, Spector SA, McCutchan JA. Prevalence of psychiatric disorders among men infected with human immunodeficiency virus. A controlled study. Arch Gen Psychiatry. 1988 Sep; 45 (9):859–864. [ PubMed ] [ Google Scholar ]
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