HIV: A Primary Care Update

Educational Objectives

The goal of this program is to improve screening for and management of HIV infection and sexually transmitted dis­ease in HIV-infected individuals. After hearing and assimilating this program, the clinician will be better able to:

1.   Incorporate routine HIV screening into health care maintenance.

2.   Describe current and newer methods for reducing HIV transmission.

3.   Counsel patients about when to start HIV treatment.

4.   Review screening options for syphilis.

5.   Select the best treatments of gonorrhea.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and plan­ning committee reported nothing to disclose.

Acknowledgements

Dr. Gandhi spoke in San Francisco, CA, on May 8, 2009 at the 30th Annual Advances in Infectious Disease: New Di­rections for Primary Care, presented by the University of California, San Francisco, School of Medicine. Dr. Bolan was recorded in San Francisco at The Medical Management of HIV/AIDS, presented December 11-13, 2008, by the University of California, San Francisco, School of Medicine, and San Francisco General Hospital. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Case-based Approach to HIV

Monica Gandhi, MD, MPH, Assistant Professor of Medicine, Divisions of HIV/AIDS and Infectious Diseases, University of California, San Francisco, School of Medicine

Introduction: according to 2007 data, 33.2 million people infected with HIV; 25 million deaths since start of docu­mentation; two-thirds of infections worldwide in sub-Saharan Africa; rates in women equal to those in men (higher in women in some areas of sub-Saharan Africa)

Case presentation: white woman 58 yr of age with 4 to 5 yr of cognitive decline (believed secondary to profound de­pression after bouts of unemployment and homelessness); positive history of non-Hodgkin lymphoma 8 yr ago (cancer treated, but patient never recovered from stress); presented to psychiatric unit on multiple psychiatric med­ications; no tobacco smoking and little use of alcohol or drugs; 3 male sex partners in last 20 yr; examination  —no­table hypoxemia; flat affect; somnolent; able to follow 1-step commands, but not 2-step commands; appeared dazed; diffuse widespread reticulonodular pattern seen on chest x-ray; white matter changes seen on computed to­mography (CT) of head; diagnosis  —  bronchial Pneumocystis infection; HIV antibody positive; CD4 cell count, 46/mm³; viral load nearly 500,000 copies/mL; HIV encephalopathy (preventable with earlier diagnosis); 25% of US population unaware of their HIV infection

Centers for Disease Control and Prevention (CDC) screening guidelines: from 2006; routine HIV screening should be performed in all health care settings in patients 13 to 64 yr of age; written consent requirements vary by state (in California, written consent not required [patient must be informed verbally]); routine screening recom­mended in pregnancy; repeat screening during third trimester in communities where rates of HIV in pregnant women elevated; rapid testing during labor if no HIV documented

Testing in primary care: incorporate HIV screening into health care maintenance; every patient should have ³1 test documented in chart; repeat testing per patient’s request (possibly during preconception counseling), if patient presents with new risk factor (eg, sexually transmitted infection [STI]), and when determined appropriate by health care provider; certified rapid HIV antibody tests available; enzyme-linked immunosorbent assay (ELISA) highly sensitive, but specificity poor (false-positive rate, 4%; positive results require Western blot confirmation)

Male circumcision: evidence from multiple large randomized controlled clinical trials (mostly in Africa) found male circumcision most effective method of preventing heterosexual transmission of HIV (except for condoms; due to ethics, condoms never studied in randomized controlled clinical trials); level of protection conferred, »60%; re­sulted in some behavioral disinhibition (eg, less condom use reported); meta-analysis showed efficacy of circumci­sion uncertain in men who have sex with men; effect on women  —  some early data suggest women more likely to contract HIV from circumcised men, but reanalysis of data found participating couples had sex early after circum­cision (ie, before glans developed protective keratin layer); data under analysis

HIV vaccine: treatment and prevention  —  in 2007, for every one person newly treated with antiretroviral therapy, 2.5 people newly infected; analysis found treatment more effective than prevention, leading to idea that vaccine with 50% efficacy given to 30% of target population could avert one-third of infections worldwide; vaccines containing live or whole inactive components unsafe; earlier trials found monomeric gp120 VaxGen vaccine ineffective; vac­cine by Merck  —  designed to affect cytotoxic T cell responses and neutralize antibodies; placed in adenovirus vec­tor; tested in large trial (Step study); trial stopped early because vaccine appeared to have no efficacy and some subgroups appeared more susceptible to HIV infection; in subsets of patients who already had high adenovirus an­tibodies, risk for HIV transmission increased with hazard ratio of 2.3 (may be due to massive T cell activation); in vaccine group, risk higher in uncircumcised men

Microbicide: biologic or chemical substance that substantially reduces transmission of HIV; applied topically in va­gina or rectum; usually in gel or cream form; rings that release microbicide slowly over time after placement in cer­vix presently under development; current microbicides must be applied 1 to 2 hr before intercourse; many products in development; models show potential to avert many infections; failures  —  nonoxynol-9 may lead to increased transmission, due to nonspecific membrane disruption; anionic polymers (eg, Carraguard gel [seaweed derivative], cellulose sulfate) that disrupt HIV entry into T cells shown to have no efficacy; PRO 2000  —  synthetic polyanionic polymer; blocks HIV attachment to cell; study looked at use of PRO 2000, pH buffer gel, placebo gel, and no gel; number of HIV transmissions per 100 person-years similar between buffer gel, placebo gel, and no gel; PRO 2000 arm showed 30% reduction (hazard ratio compared to no gel, 0.70); currently undergoing studies

Treatment as prevention: studies of serodiscordant couples in Uganda found higher plasma viral loads increase like­lihood of transmission of HIV to partner; mathematic models suggest universal testing and immediate treatment could eliminate HIV in next 20 yr (controversial)

Life expectancy: studies show improved outcomes under care of physician comfortable and experienced with HIV management; since 1996 (advent of highly active antiretroviral therapy [HAART]), life expectancy improved, but less than that of noninfected individuals; risk for death after HIV seroconversion, compared to mortality of general population  —death rate same for first 5 yr, but excess mortality with HIV in long term; analysis found »33% of deaths AIDS-related, 66% “non-HIV-related” (eg, cardiovascular death, non-AIDS-related cancers [eg, lung, colon, liver]), with some liver-related deaths and deaths due to renal causes; non-HIV-related deaths thought to be due to chronic inflammation

When to treat HIV infection: untreated HIV infection  —follow CD4 cell count and HIV viral load; CD4 cell count dips down during acute infection, then increases, followed by decline over time; HIV viral load spikes (high risk for transmission), then decreases to viral load set point (prognostically significant), and eventually increases over time; start antiretroviral therapy when CD4 cell count ³350 cells/mm³; guidelines  —  consider treatment if CD4 cell count ³350 cells/mm³ (if <350 cells/mm³, treat); treat patients with history of AIDS or HIV-related illness (eg, peripheral neuropathy, chronic fever, lymphadenopathy); reasons to defer treatment  —  avoidance of drug-related toxicity or treatment fatigue; preservation of future drug options; delaying drug resistance; conflicting data about deferral or initiation of therapy at CD4 cell count of 500 cells/mm³ 

Treatment interruptions: Strategies for Management of AntiRetroviral Therapies (SMART) study saw treatment in­terruptions associated with increased mortality, increased serious HIV events, and increased complications (eg, car­diovascular, hepatic and renal events, strokes); associated with 1.5-fold greater risk for severe non-HIV-related complications; treatment interruptions no longer considered advisable

Classes of HIV medications: CCR5 receptor antagonist (maraviroc [Selzentry]); nonnucleoside reverse transcriptase inhibitors (NNRTIs); nucleoside reverse transcriptase inhibitors (NRTIs); nucleotide reverse transcriptase inhibi­tors; HIV integrase inhibitor (raltegravir [Isentress]); protease inhibitors

Which medication to start in therapy-naive patients: 2 NRTIs and 1 NNRTI; 2 NRTIs and 1 protease inhibitor (boosted with ritonavir); once-daily pill  —  available since 2006; comprised of 2 NRTIs (tenofovir and emtric­itabine) and 1 NNRTI (efavirenz [Sustiva])

Side effects of NRTIs: lactic acidosis and hepatic steatosis (more common with older NRTIs, eg, didanosine [ddI], atavudine [d4T]); body fat changes; abacavir (Ziagen)  —hypersensitivity reaction (eg, rash, fever) in 5% to 8% of patients (lower in blacks and patients positive for HLA-B5701 genetic polymorphism); screen for HLA-B5701; some data about increased risk for myocardial infarction associated with ddI and abacavir; d4T  —  peripheral neu­ropathy; pancreatitis; combination of efavirenz, emtricitabine, and tenofovir (Atripla) or tenofovir (Viread) alone  —  commonly used; renal problems (eg, proximal tubular dysfunction, microalbuminuria, glucosuria, phosphate spill­ing); azidothymidine (AZT)  —  not used as often; pancytopenia

Side effects of NNRTIs: nevirapine (Viramune)  —  rash and liver problems (worse in women); patients with higher CD4 cell counts at higher risk for hepatotoxicity; in women, nevirapine never started if CD4 cell count >250/mm³ (400 in men); efavirenz  —  commonly used; teratogenic; women of child-bearing age on Atripla or Sustiva must be counseled on contraception; must be discontinued during pregnancy; some central nervous system (CNS) effects (eg, dizziness, nightmares); etravirine  —  rash; hepatotoxicity

Side effects of protease inhibitors: drug interactions with statins  —  use mnemonic for remembering which ones safe “pravastatin’s your pal”; “fluvastatin’s your friend”; “atorvastatin’s (at lower doses) your amigo”; simvastatin and lovastatin contraindicated with protease inhibitors; toxicities include lipid and body fat changes, blood glucose elevations, liver problems, increased risk of bleeding in hemophiliacs; indinavir can lead to kidney stones; combi­nation of lopinavir and ritonavir (Kaletra) associated with gastrointestinal (GI) intolerance; nelfinavir not boosted with ritonavir (less potent; not used as often); amprenavir and fosamprenavir (Lexiva) carry sulfa moiety; atazana­vir (Reyataz)  —  contraindicated in combination with proton pump inhibitors (H₂-blockers acceptable); must be taken with food; benign indirect elevation in bilirubin (also occurs with indinavir); newer agents  —  some case re­ports of intracranial hemorrhage with tipranavir; darunavir must be taken with food and has liver warning; ritonavir never used alone

Side effects of other agents: enfuvirtide  —  antiretroviral injectable; injection site reactions; raltegravir increased cre­atine phosphokinase, nausea, and vomiting; maraviroc associated with abdominal pain and postural hypotension

Perceptions of childbearing for HIV-positive women: survey found 14% believe HIV-positive women should have children (even less than those with schizophrenia or Down syndrome); survey of 700 HIV-positive women found 27% felt HIV-positive women should be strongly urged against having children, and nearly 60% felt societal pres­sure to forgo having children (worse in south than in other regions); HIV-positive women less likely to feel they should not have children if being treated by nurse practitioner or physician assistant, compared to medical doctor; 50% of women asked by providers whether they desire pregnancy

Perinatal transmission: rate in United States, <1%; if HIV untreated, »25% chance of transmission to baby during pregnancy (mostly in intrapartum phase); additional 10% risk associated with breastfeeding; interventions (ie, anti­retroviral therapy during pregnancy) reduce rate to <1%; viral load of mother determines risk for transmission to baby; recommendations  —  mothers on medications should remain on them, but avoid contraindicated drugs (eg, efavirenz); mothers not on therapy who do not need therapy, should start combination therapy (ie, HAART) during second trimester; at time of delivery, if viral load >1000 copies/mL, perform cesarean delivery (if <1000 cop­ies/mL, vaginal delivery equally safe); mothers who did not receive treatment before labor and mothers on combi­nation antiretroviral therapy should get intravenous (IV) AZT during delivery; infant should be treated with AZT for 6 wk after birth; breastfeeding not recommended

STD Management in HIV-infected Individuals

Gail Bolan, MD, Assistant Clinical Professor of Medicine, University of California, San Francisco, School of Medicine, and Chief of STD Control Branch, California State Department of Public Health, Richmond

Screening for syphilis: newer treponemal tests  —  enzyme immunoassay (EIA) and chemiluminescence assay (CLIA); highly automated and inexpensive; approved by Food and Drug Administration for clinical use; little data about sensitivity and specificity available; due to persistence of syphilis in patients with history of syphilis, difficult to distinguish new infections from old infections; studies  —  1) of nearly 30,000 specimens, only 2.6% found posi­tive on EIA; 51% of those confirmed by rapid plasma reagin (RPR), and tested with second treponemal test (trepo­nema pallidum particle agglutination assay [TPPA; 75% of those not confirmed); EIA-positive, RPR-negative, and TPPA-negative cases reported as unconfirmed EIA tests unlikely to be syphilis (in high-risk patients, repeat testing in 1 mo); 2) of »100,000 specimens, 6% found positive on EIA; 44% (of second-generation specimens) confirmed by RPR (may consider treatment of latent syphilis in patients with negative RPR; controversial); 17% negative on TPPA (ie, 2000 cases confirmed with TPPA); difficult to distinguish between old untreated cases, old treated cases, early cases, and false-positives

California testing guidelines: acceptable to withhold treatment for patients with positive EIA results without confir­matory TPPA (in high-risk patients, repeat testing in 1 mo); follow algorithm (ie, if starting with EIA, insist on quantitative RPR [if negative, perform TPPA]); patients with positive EIA confirmed by TPPA and negative RPR  —  evaluate for early chancres, and ask about history of syphilis and previous treatment; if no evidence of symptoms and past treatment, make individualized decision about whether to treat; if treating, repeat RPR testing 1 wk after treatment; reasonable to wait 1 mo to confirm positive EIA results

Multiplex polymerase chain reaction (PCR) test: can differentiate between herpes, syphilis, and chancre; widely used internationally; may be available in California; specific and sensitive results within 1 to 2 days

Treatment of gonorrhea: ceftriaxone; fluoroquinolones no longer recommended; cefixime more costly than cefpo­doxime; therapeutic ratio of ceftriaxone superior to those of cefpodoxime and cefixime; cephalosporin-resistant cases emerging in Asia; efficacy of cefpodoxime for pharyngeal coverage, 74%; ceftriaxone best option for pharyn­geal disease; spectinomycin no longer manufactured; for cephalosporin-allergic patients, CDC recommends desen­sitization; azithromycin  —  2 g efficacious against gonorrhea; may not be available within 2 yr due to resistance; use on limited basis (ie, only in patients allergic to ceftriaxone)

HIV and uveitis: treat with 14-day course of IV penicillin; follow serum RPR every 3 mo and cerebrospinal fluid (CSF) white blood cell count; study found serum RPR predictive of CSF parameters; follow serum VDRL test or RPR titers every 3 mo to make sure titers remain constant or slowly decrease; consider multiple lumbar punctures at 2 yr if titers do not decrease by 4-fold

Suggested Reading

Antiretroviral Therapy Cohort Collaboration: Life expectancy of individuals on combination antiretroviral therapy in high-in­come countries: a collaborative analysis of 14 cohort studies. Lancet 372:293, 2008; Branson BM et al: Centers for Disease Con­trol and Prevention (CDC). Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep 55:1, 2006; D:A:D Study Group et al: Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 371:1417, 2008; Marra CM et al: Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clini­cal abnormalities after treatment of neurosyphilis. Clin Infect Dis 47:893, 2008; Mâsse BR et al: Using mathematical modeling to bridge phase 3 microbicide trials with public health decision making. J Acquir Immune Defic Syndr 50:434, 2009; Moran JS et al: Drugs of choice for the treatment of uncomplicated gonococcal infections. Clin Infect Dis 20:S47, 1995; Quinn TC et al: Vi­ral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 342:921, 2000; Sachdev DD et al: The differential binding and activity of PRO 2000 against diverse HIV-1 envelopes. J Acquir Immune Defic Syndr 51:125, 2009; Strategies for Management of Antiretroviral Therapy (SMART) Study Group et al: CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 355:2283, 2006; Tobian AA et al: Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 360:1298, 2009.