Advances In Managing Hiv And Aids

From The Medical Management of HIV/AIDS course, sponsored by the University of California,
San Francisco, School of Medicine

Educational Objectives

The goal of this program is to improve prevention and management of human immunodeficiency virus (HIV) infec­tion and AIDS. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the benefits associated with early initiation of antiretroviral therapy.

2.   Implement evidence-based guidelines for initiating treatment in patients with HIV and AIDS-related complica­tions.

3.   Detail the treatment options for treatment-naive and treatment-experienced patients with HIV infection.

4.   Identify patients at increased risk of transmitting HIV and initiate interventions that decrease that risk.

5.   Summarize the progress and remaining challenges related to the global AIDS epidemic.

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.

Acknowledgments

Drs. Havlir and Ammann were recorded at The Medical Management of HIV/AIDS, presented by the University of Califor­nia, San Francisco, School of Medicine, and held December 12-13, 2008, in San Francisco. The Audio-Digest Foundation thanks the speakers and the UCSF School of Medicine for their cooperation in the production of this program.

Latest Top Stories in HIV Medicine

Diane V. Havlir, MD, Professor of Medicine, University of California, San Francisco, School of Medicine, and Chief, Division of HIV/AIDS, San Francisco General Hospital, San Francisco

Initiating antiretroviral therapy (ART): obstacles to early initiation  —  drug toxicity; complicated regimens; sim­pler regimens now available; newer drugs less toxic; recent studies support early initiation of ART; benefits  —  prevents complications associated with human immunodeficiency virus (HIV) infection (eg, Pneumocystis jiroveci [formerly, Pneumocystis carinii] pneumonia [PCP], cryptococcal meningitis, dementia); data suggest that ongoing HIV replication increases risk for liver, cardiac, and renal disease and that ART decreases risk; ART reduces risk for AIDS-associated malignancies (eg, primary brain lymphoma, central nervous system lymphoma) and may pro­tect against other malignancies as well; proposed mechanism  —  ongoing HIV replication causes immune activation and, in effect, premature aging; ART decreases immune activation; more benefits  —  Strategies for Management of Anti-Retroviral Therapy (SMART) study showed association between deferred ART and increased risk for oppor­tunistic diseases and death among treatment-naive patients; guidelines  —ART recommended for asymptomatic pa­tients with CD4 cell counts <350 cells/mL (previous version specified 250 cells/mL as cutoff); for asymptomatic patients with CD4 cell counts >350 cells/mL, treatment decisions individualized; considerations include high viral load, rapid decline of CD4 cell count, high risk for cardiovascular (CV) disease, active infection with hepatitis B or C virus, or HIV-associated nephropathy

ART and opportunistic infections (OIs): study compared early (£48 hr after diagnosis of OI) with delayed (6-12 wk after diagnosis of OI) ART; patients with tuberculosis (TB) excluded; categorical end points  —  death or disease progression; virologic suppression and absence of disease progression; no disease progression but absence of viro­logic suppression; participants  —282 patients; 70% of patients had CD4 cell counts <50 cells/mL; 90% of patients treatment naive; most had PCP; other infections included cryptococcal meningitis (»10%) and severe bacterial in­fections (14%); results  —  delayed treatment associated with 50% reduction in time to death or AIDS-related ill­ness; clinical practice  —  early initiation of ART for patients with PCP or severe bacterial infection (but caution required for patients with cryptococcal meningitis); all patients with OIs require close follow-up, regardless of tim­ing of ART; ongoing studies looking at timing of ART in patients with TB

Atazanavir dosing: package insert includes updated regimens for treatment-naive and treatment-experienced pa­tients; higher target concentrations required for successful treatment of experienced patients; nevirapine (NVP)  —  avoid coadministration with atazanavir or boosted atazanavir (atazanavir levels decrease; NVP levels may become dangerously high); efavirenz  —  avoid coadministration with atazanavir or boosted atazanavir in ART-experienced patients; coadministration acceptable in treatment-naive patients, but increase dose of atazanavir from 300 mg to 400 mg (to 100 mg efavirenz); taking efavirenz on empty stomach enhances absorption; H₂-blockers  —  400 mg ata­zanavir acceptable for treatment-naive patients unable to tolerate ritonavir; atazanavir taken 2 hr before and ³10 hr after H₂ blocker; maximum single dose of H₂ blocker, 20 mg (not to exceed 40 mg/day); note  —  patients with end-stage renal disease undergoing hemodialysis attain lower levels of atazanavir

Abacavir: risk for CV disease  —  large cohort study showed long-term treatment with abacavir or didanosine (DDI) associated with increased risk; subsequent analysis showed abacavir associated with 2- to 4-fold increased risk for minor events, major events, and myocardial infarction (MI), regardless of duration of use; proposed mechanism  —  abacavir and DDI associated with increased levels of inflammatory markers; conflicting data  —  confounding fac­tors (eg, comorbid conditions) and sampling artifacts problematic in observational studies; review of manufac­turer’s database did not reveal similar association; recent study showed no changes in levels of biomarkers with abacavir; efficacy  —  ongoing randomized clinical trial comparing efavirenz to boosted atazanavir plus nucleoside reverse transcriptase inhibitor (NRTI) backbone (abacavir plus lamivudine [3TC] or tenofovir plus emtricitabine [FTC]); among patients with high viral loads (>100,000 copies of HIV RNA), abacavir associated with poorer out­comes and higher rate of virologic failure, compared to tenofovir; however, review of manufacturer’s database did not reveal similar association; guidelines  —  International AIDS Society (IAS) continues to list abacavir/3TC as front-line NRTI backbone when initiating therapy, but specifies caveats; Department of Health and Human Services (DHHS) no longer recommends abacavir/3TC as front-line NRTI backbone; clinical practice  —treat reversible CV risk factors; acceptable to continue abacavir in responsive patients without high risk for CV disease; consider switching to alternative therapy if patient has multiple irreversible risk factors for CV disease; for treatment-naive patients, consider alternative option (eg, tenofovir/FTC), but acceptable to use abacavir if indicated

Newer drugs as first-line therapies: important for treatment-resistant patients; now being considered as first-line therapy; boosted darunavir  —  shown to be noninferior to boosted lopinavir/ritonavir (Kaletra) at 48 and 96 wk (may even have advantage at 96 wk) in treatment-naive patients; listed as option for treatment for treatment-naive patients; raltegravir (vs efavirenz)  —   rate of viral suppression similar at 48 wk, but achieves viral suppression faster; associated with significantly greater CD4 cell count; does not increase lipid levels (efavirenz associated with elevated levels of low-density lipoprotein [LDL], high-density lipoprotein [HDL], total cholesterol, and triglycer­ides; similar ratio of total to HDL cholesterol)

CCR5 inhibitors: maraviroc  —  noninferior to efavirenz for treatment-naive patients when viral load <400 RNA cop­ies/mL, but inferior when viral load <50 copies/mL; effective for treatment-naive patients with only CCR5 variant of HIV; Trofile assay  —  enhanced-sensitivity assay detects low levels (0.3% of viral population) of X4 variant; CCR5 inhibitors contraindicated for patients infected with X4 variant; previous data reanalyzed, excluding patients who should not have received CCR5 inhibitor (based on X4 levels); maraviroc noninferior to efavirenz when pa­tients appropriately selected; similar reanalysis of data from studies of another CCR5 inhibitor (vicriviroc)

Drug-resistant variants: new technologies available for detecting resistant viruses occurring at low frequency (ie, “minority drug resistance”); some data suggest that presence of minority drug resistance increases risk for virologic failure among treatment-naive patients, but conflicting data exist; clinical application remains unclear

Heterosexual transmission rates: rate often quoted as 1 per 1000 sexual contacts, but global epidemic implies higher rate of transmission; factors that increase transmission rates  —  acute infection; high viral load; AIDS; ac­tive sexually transmitted infection (STI); susceptible partner uncircumcised or has STI; risk increases substantially when multiple risk factors present

Global epidemic: by 2007, >3 million people treated with ART, but challenges persist; challenges  —  high mortality rate; drug resistance especially problematic in resource-poor settings (eg, technology for monitoring resistance un­available); 33% to 66% of patients do not fully respond to NRTI backbone agents, partly due to long-term failure of inadequate therapy; inadequate treatment ultimately leads to variants with “pan-NRTI” resistance

International HIV Update

Arthur Ammann, MD, Clinical Professor of Pediatrics, University of California, San Francisco, School of Medicine, and President, Global Strategies for HIV Prevention, San Rafael, CA

Introduction: progress made in relation to global epidemic; »14,000 AIDS-related deaths in United States in 2006 (in 2005, »41,000 deaths caused by influenza virus); early diagnosis and treatment important

Prevention: proven effective; sexual transmission  —behavioral interventions (eg, abstinence, monogamy, using con­doms, circumcision) effective; intravenous drug use  —needle exchange programs effective; blood transfusions  —safe in United States, but still problematic in resource-poor countries; »100,000 new infections occur worldwide each year as result of insufficient blood screening or poor qualitycontrol; accidental inoculation  —  postexposure prophylaxis effective, but unavailable in many resource-poor settings; pregnancy  —  ART effective at reducing transmission to child, but only 20% of HIV-infected pregnant women worldwide receive ART; breastfeeding  —  formula-feeding often unsafe in developing countries; ART during breastfeeding significantly decreases transmis­sion to child; universal treatment  —  very important for slowing global epidemic

Incidence: United States  —  incidence peaked in 1980s at »150,000 new infections per year; global  —  recently esti­mated at 2.5 million new infections per year; mother-to-child transmission  —  results in <100 infections per year in United States, but huge problem in developing world (»1800 infants infected daily); progress  —  evidence that epi­demic has slowed in Zambia; programs in Uganda have had significant impact, but incidence may rise as advocacy loosens; rates of new infections have decreased in China, India, Brazil, Thailand, Angola, Kenya, Mozambique, Ni­geria, Zambia, and Zimbabwe

Challenges: downside of economic development  —  remote regions have very low prevalence; development brings HIV into previously unaffected communities; developers and corporations may have role in education and preven­tion; warfare  —  rape (common in some war-torn regions) is mode of intentional transmission of HIV (ie, “planting viral landmines”); huge need for postexposure prophylaxis

Progress: rapid diagnostic tests  —  availability has revolutionized ability to screen individuals in resource-poor coun­tries; tests cost $1.80 to $2.00; knowing HIV status focuses education and identifies individuals for treatment; improved access to ART  —  initially expensive; activism and advocacy resulted in decreased cost (eg, through in­creased availability of generics) to <$250/yr for combination ART; generic cotrimoxazole (available for ³15 yr) costs only $6/yr for daily dosing, and has had significant impact on global epidemic

Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS): specifies situations in which coun­tries may violate intellectual property laws; compulsory license  — enables competent government authority to li­cense use of patented invention (enabling, eg, manufacture of patented drug in-country); parallel importation  —  country may import patented and generic versions of drug; impact  — millions of people in resource-poor coun­tries have benefitted

Treatment guidelines: slowly adopted in resource-poor countries, and difficult to change once adopted (often incor­porated as law); 2003 guidelines by World Health Organization (WHO) suggested initiating treatment in patients with advanced disease (economic decision, based on limited resources for treatment); early treatment associated with greater efficacy, lower mortality rate, and greater overall benefit; new guidelines by International AIDS Society  —  treat symptomatic patients; consider CD4 cell or lymphocyte counts, when available; individualize treat­ment

Mother-to-child transmission: in 1994, azidothymidine (AZT) shown to reduce transmission by 60%; in 1999, sin­gle doses of NVP (to mother and infant) shown to reduce infection of breast-fed babies by 50%; goal  —  decrease global rates of perinatal transmission to <2%; encouraging results  —  combination therapy with NVP initiated early in pregnancy, and single-dose NVP for infants, reduces transmission rates to levels seen in United States; cautions  —  single-drug therapy may lead to viral resistance; incomplete therapy results in reduced efficacy; impor­tant to apply strategies shown effective in other settings; rationale for expanding treatment  —  individuals should re­ceive equivalent treatment, regardless of sex or pregnancy status; most antiretroviral agents safe for use during pregnancy; earlier treatment (eg, patients with high CD4 cell counts and minimal symptoms) associated with lower viral loads and decreased mortality; combination therapy reduces risk of developing resistance; postexposure pro­phylaxis effective and should be expanded to include breastfeeding babies

Male circumcision: background  —  risk for cervical cancer (caused by human papillomavirus) low in some popula­tions and may be related to practice of male circumcision; HIV  —  two large studies stopped early because of evi­dence that circumcision reduces rate of contracting HIV (by 53% [in Kenya] and 48% [in Uganda]; longer follow-up suggests even greater reductions); no direct benefit seen among women; unknown whether circumcision de­creases transmission rates among men who have sex with men (MSM); if HIV-infected circumcised men increase sexual activity and/or decrease use of condoms, overall transmission rate may not decrease  

Cotrimoxazole: used to prevent AIDS-related OIs since 1980s; low cost important in resource-poor settings; previ­ously, concern that use might lead to development of resistant malaria, but studies showed that daily prophylactic treatment with cotrimoxazole resulted in decreased incidence of malaria among individuals infected with or sus­ceptible to HIV and malaria; prophylactic treatment of adults and children with HIV associated with dramatic de­creases in mortality rates (eg, 28% vs 42% in placebo group in study of HIV-infected children in Zambia); beneficial even when ART unavailable

Vaccine: important challenge for scientific community; more research necessary to identify targets for effective vac­cine

Suggested Reading

Arrive E, Dabis F: Prophylactic antiretroviral regimens for prevention of mother-to-child transmission of HIV in resource-limited settings. Curr Opin HIV AIDS 3:161, 2008; Burman W et al: Episodic antiretroviral therapy increases HIV trans­mission risk compared with continuous therapy: results of a randomized controlled trial. J Acquir Immune Defic Syndr 49:142, 2008; Cohen MS et al: Prevention of the sexual transmission of HIV-1: preparing for success. J Int AIDS Soc 11:4, 2008; D:A:D Study Group: 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; Hammer SM et al: Anti­retroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 300:555, 2008; Kuhn L et al: Breastfeeding and AIDS in the developing world. Curr Opin Pediatr 21:83, 2009; Martin­son NA et al: Women exposed to single-dose nevirapine in successive pregnancies: effectiveness and nonnucleoside reverse transcriptase inhibitor resistance. AIDS 27:809, 2009; Metzner KJ et al: Minority quasispecies of drug-resistant HIV-1 that lead to early therapy failure in treatment-naive and –adherent patients. Clin Infect Dis 48:239, 2009; Ortiz R et al: Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1–infected patients at week 48. AIDS 22:1389, 2008; Powers KA et al: Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis. Lancet Infect Dis 8:553, 2008; Saag M et al: A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis 199:1638, 2009; Sax PE: Report from the 2008 Joint ICAAC/IDSA meeting: more data on abacavir/3TC. AIDS Clin Care 20:104, 2008; Strategies for Management of Anti­retroviral Therapy (SMART) Study Group: Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 197:1133, 2008; Zolopa A et al: Early antiret­roviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter random­ized strategy trial. PLoS ONE 4:e5575, 2009.