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This update examines and summarizes the most recent data on prevention, testing, and treatment of HIV infection for the general internist. Our aims were: (1) to describe the most recent data on HIV prevention; (2) to discuss the recommendations and emerging evidence for routine HIV screening, particularly in community-based settings; (3) to interpret the most recent data on initiation and selection of antiretroviral therapy; and (4) to facilitate the application of these findings to the clinical practice of the generalist.
We performed a PUBMED search of from March 2008 through April 2010, using the Medial Subject Heading (MeSH) term “HIV,” limited to English language articles focusing on human subjects. Additionally, the authors each reviewed studies published between March 2008 and April 2010 in the major internal medicine and HIV journals. We also performed targeted searches using the search terms “HIV prevention” and “HIV testing.” Articles were included after review by consensus among a group of experts, all practicing HIV clinicians and researchers, if they met the following criteria: (1) offered novel findings in HIV prevention, HIV testing, or initiation of antiretroviral therapy; and (2) had the potential for direct clinical relevance to the practicing generalist. We narrowed down our selection by group consensus with the goal of presenting the eight to ten most relevant papers published since March 2008.
In HIV-1 infected populations, the seroprevalence of HSV ranges from 60-90%1, and studies suggest that HSV may increase HIV transmission. In coinfected cells, HSV proteins bind HIV and promote transcription2–5. HSV reactivation is associated with increased HIV levels in blood and the genital tract,6–9 and rates of sexual HIV transmission are markedly higher from persons with genital ulcers.10 Additionally, several randomized clinical trials (RCTs) demonstrate that anti-HSV therapy decreases plasma HIV levels.6,11–14
This study is an RCT designed to evaluate the effect of daily acyclovir therapy on HIV transmission.15 The investigators enrolled HIV serodiscordant heterosexual couples from seven sites in southern Africa and seven sites in eastern Africa. For each couple, the HIV-infected partner was seropositive for HSV, had CD4 cell count ≥250 cells/mm3, no AIDS-related conditions, no current antiretroviral therapy, and no persistent genital ulcers. The HIV-negative partner was eligible whether HSV-negative or positive. The intervention group received acyclovir 400 mg twice daily, and the control group received an identical-appearing placebo. The primary outcome was HIV incidence. HIV sequencing was used to classify the transmission as ‘linked’ or ‘unlinked.’
There were 3,360 discordant couples included in the final analysis. In 68% of couples, the woman was HIV-infected. The median CD4 count was 462 cells/mm3. Sixty-eight percent of HIV-negative partners had HSV-2. There were 132 new HIV infections, corresponding to an incidence of 2.7 per 100 person-years (95% CI: 2.3 to 3.2). Eighty-four linked transmissions were included in the analysis, 41 in the acyclovir group and 43 in the placebo group (HR 0.92; 95% CI: 0.60–1.41).
The Bottom Line: Suppressive doses of acyclovir given for up to 2 years did not reduce HIV transmission, despite significantly decreased HIV viremia and symptomatic genital ulcers.
The World Health Organization (WHO) recommends male circumcision as a male HIV prevention strategy16 on the basis of several recent RCTs that reduced HIV transmission from females to their male partners17–19.
This study enrolled 922 HIV-infected uncircumcised men aged 15–49 years of age who were randomized to receive either immediate circumcision or circumcision delayed for 24 months20. One hundred sixty HIV-negative female partners were also enrolled. The primary outcome was the rate of acquisition of HIV among female partners, including all couples with at least one follow-up visit for the female partner. Seventeen of 92 (18%) women in the intervention group and 8 of 67 (12%) in the control group had incident HIV infection during the study period. Over 24 months, the cumulative probability of HIV infection was 21.7% (95% CI: 12.7–33.4) for women in the intervention group and 13.4% (95% CI: 6.7–25.8) for those in the control group. In a Cox proportional hazards regression analysis, the adjusted hazard ration (HR) was 1.49 (95% CI: 0.62–3.57; p=0.368). There were no significant differences in HIV incidence by participant characteristics or by women’s self-reported risk behaviors.
The Bottom Line: The trial was stopped early because of ineffectiveness: male circumcision of HIV-infected men did not reduce transmission of HIV to female partners of HIV-infected men in this study over a 24-month period.
More than half of all adults living with HIV/AIDS in sub-Saharan Africa are women.21 Most strides that have been made in HIV prevention (condoms, circumcision) depend largely on male cooperation. Topical microbicides offer the possibility of initiation by women. Cellulose sulfate is an entry inhibitor with in-vitro activity against HIV and demonstrated safety and tolerability. This was a randomized, double-blind, placebo-controlled trial22 of cellulose sulfate gel for prevention of HIV.
Women who were 18 or older, had a negative HIV-antibody test and reported three or more acts of vaginal intercourse/week and three or more different partners in the previous 3 months were recruited from five sites in Africa and India. The intervention group received 6% cellulose sulfate gel and controls an identical placebo (the pH of the compounds were different). The primary outcome was incident HIV infection.
Among 1,398 women, at the prespecified interim analysis point, there were 24 new HIV infections in the cellulose sulfate group and 11 among those receiving placebo (HR: 2.23, 95% CI: 1.05–5.03, p=0.02), prompting early termination of the trial. While this suggested increased risk of HIV transmission among women using cellulose sulfate, the interim analysis did not include an additional six incident cases that had not been entered in the database. Analysis including these cases yielded HR: 1.61 (95 CI: 0.86–3.01, p=0.13). An additional pre-planned analysis censoring data from participants who interrupted cellulose or placebo use (most often due to pregnancy) yielded a HR 2.02 (95% CI 0.97–4.18, p=0.05).
In summary, there was a higher incidence of HIV in the cellulose sulfate group: however, this did not reach significance in the primary effectiveness analysis. It was noted by the investigators that there were non-differential pregnancy rates in the two groups. Given the contraceptive profile of cellulose sulfate, non-adherence might have been a factor in the observed results.
The Bottom Line: Cellulose sulfate is not effective in the prevention of vaginal HIV transmission.
This was a multicenter community-based, randomized double-blind, placebo-controlled trial in Thailand to evaluate the efficacy of vaccines to prevent HIV.23 The vaccine protocol consisted of a primer of a recombinant canarypox vector vaccine (ALVAC-HIV) (four injections) and two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). A total of 16,402 HIV-uninfected persons aged 18–30 years were enrolled. HIV testing was performed at baseline, 24 weeks, 26 weeks, and every 6 months for 3 years of follow-up. The primary outcomes were HIV infection and early HIV viremia.
There were 132 new HIV infections, 56 in the vaccine group and 76 in the placebo group over a total of 52,985 person-years of follow-up in the intention-to-treat analysis. This result translated to an observed efficacy of 26.4% (95% CI: -4.0–47.9, p=0.08). A modified intention-to-treat analysis excluded seven persons found to be HIV-infected at baseline. In this group, there were 125 new HIV infections, 51 in the vaccine group and 74 in the placebo group over 52,985 person-years of follow-up, corresponding to an observed vaccine efficacy of 31.2% (95% CI: 1.1–52.1, p=0.04). A per-protocol additional analysis included only those who received all scheduled vaccinations in the series, maintained eligibility in the study, and had not acquired HIV by the fourth vaccination. Among this group, there were 86 new HIV infections, 36 in the vaccine group and 50 in the placebo group in 36,720 person-years of follow-up corresponding to an observed vaccine efficacy of 26.2% (95% CI: -13.3–51.9, p=0.16).
The Bottom Line: While the intention to treat analysis demonstrated only a trend towards efficacy, after excluding those with HIV at baseline, there was a significant reduction in HIV incidence in the vaccination group. Future studies must address the immune mechanisms involved as well as whether vaccine efficacy varies over time and in certain populations.
Implementing expanded HIV testing in primary care requires an understanding of the context into which broad testing will be introduced. Bokhour and colleagues conducted focus groups with patients (N=28) and health-care providers (N=13) from primary care clinics at two US Veterans Administration facilities to better understand issues in the expansion of HIV testing.24 Patients in the four focus groups were HIV-negative men aged 35–88 years, predominantly low income, with a range of educational backgrounds. The two provider focus groups consisted of men (N=6) and women (N=7), and included physicians, nurse practitioners, and a registered nurse.
Semi-structured group interviews led to several recurrent themes. Both patients and health-care providers felt that HIV testing should be routine. Many felt that routine testing could reduce stigma. Concerns were expressed about special written consent forms and the anxieties that they may cause. Though “normalizing” the HIV testing was a consistent theme, results showed that patients wanted to be aware that HIV testing was being done and that it should be explicitly offered, with the option to decline. They also pointed out the need for clear and prompt communication of results.
The Bottom Line: Veteran patients are likely to accept routine testing, but attention to issues of stigma and clear communication about results are important for both patients and providers. To help with patient-centered discussions, the authors developed “Six R’s” for routine testing: (1) Raise the topic; (2) Reassure the patient that the offer is routine; (3) provide Rationale for the test; (4) Respond to questions; (5) Request the test; and (6) tell the patient when and how they will get Results.
The Centers for Disease Control and Prevention (CDC) HIV testing guidelines include emergency departments (EDs) as target locations for expanded routine HIV testing.25 This research study surveyed ED providers before and 6 months after institution of an ED-based HIV testing program to understand attitudes toward testing and how they might change with experience.26
One hundred eight providers (43% nurses, 29% resident physicians, 17% attending physicians, 7% nursing assistants, and 4% physician assistants) completed both pre- and post-surveys. Before starting the HIV testing intervention in the ED, many providers identified barriers to HIV testing such as inadequate resources (70%), inadequate time (51%), and concerns about assuring follow-up (50%). After experience with the intervention, two of these barriers were more frequently reported than at baseline: inadequate time (62%) and follow-up care (59%). In multivariate modeling, female providers, providers who felt they had sufficient time to test, and providers reporting sufficient legal understanding of testing issues were more likely to favor HIV testing in the ED. While most providers favored HIV testing in general (86%), fewer supported doing it in the ED (56%), and still fewer expressed willingness to offer it themselves (37%).
The Bottom Line: For HIV testing in the ED to be substantially adopted, provider perceptions about barriers must be addressed, including concerns about inadequate time and legal ramifications of testing.
Federally qualified community health centers (CHC) are a crucial part of the health-care delivery system for predominantly underserved populations. In late 2006 the National Association of Community Health Centers supported the expansion of point-of-care HIV testing programs across North Carolina, South Carolina, and Mississippi. Myers and colleagues conducted a before-and-after analysis of data from six CHCs who adopted routine rapid HIV screening.27 Efforts included redesign of patient flow, written protocol development, clinic in-service trainings, on-site technical assistance, follow-up support, and dissemination of patient educational materials.
During the year prior to program rollout, approximately 3% (N=3,078) of patients seen for care were tested for HIV. During the 13 months after rollout, 16,148 were offered testing, and 10,769 (66%) accepted. Thirty-nine persons tested positive on rapid test results, of whom 20 were confirmed HIV-positive and 17 were new HIV diagnoses. Rates of infection were lower than expected by the investigators, but still higher than thresholds disseminated by the CDC for identifying health-care settings eligible for routine testing. Twelve of the 17 newly diagnosed patients were successfully linked to HIV care. Patients who were white were significantly less likely than African-Americans or Latinos to be HIV tested, as were the oldest patients (those aged 55–64 years). While false positives occurred at rates to be expected for the rapid tests, staff were not fully prepared for false positives, and had to develop procedures for understanding and communicating the inherent uncertainty of the initial, preliminary rapid test results.
The Bottom Line: Routine point of care testing markedly increased screening rates in community health centers.
When to start antiretroviral therapy (ART) has been an ongoing controversy.29,30 The decision regarding when to start therapy has to balance anticipated benefits with potential side effects, impact on quality of life, and risk of therapeutic burnout and virologic resistance. Potential benefits of starting early include: modulation of the inflammatory response, lowering of the viral set point, higher rates of immune reconstitution, and use of treatment as prevention.31,32
Kitahata, writing for the NA-ACCORD investigators, investigated the effects of starting therapy at different levels of CD4 counts33. The NA-ACCORD group consists of 22 clinical cohorts in North America. They identified antiretroviral naïve patients who began therapy at CD4 counts greater than 500 cells/mm3, at CD4 counts between 350 and 500 cells/mm3, and patients who chose to defer therapy between 1996 and 2006. The main outcome was survival comparing earlier therapy (at either greater than 500 cells/mm3 or between 350 and 500 cells/mm3) with deferred therapy. At both levels, deferred treatment was associated with increased death rates [500 cells/mm3: RR 1.94; 95% CI, 1.37 to 2.79, 350–500 cells/mm3: RR: 1.69; 95% confidence interval (CI), 1.26 to 2.26].
Evidence supporting starting ART above 350 cells/mm3 was also recently released by the ART-Cohort Collaboration.34 They found an increased hazard of death (HR 1.28, 95% CI 1.04–1.57) for starting ART in the 250–350 cells/mm3 CD4 count range versus 350–450 cells/mm3. It should be noted that patients with a history of injection drug use were excluded from this study, which may account for the lower hazard ratio. The ART-CC study did not observe a benefit of starting above 450 cells/mm3, and it is unclear why there is a discrepancy at this higher range. Even larger differences were seen for comparisons with lower CD4 counts at time of treatment initiation.
Because both of these studies are based on observational cohort data, the potential for unmeasured confounders exists. ART initiation is no doubt strongly associated with health status, physician expectations, and patient health seeking behaviors. Both studies adjusted for or excluded patients with a history of injection drug use as a major potential confounder. The NA-ACCORD investigators performed a sensitivity analysis that found a large confounder effect would be needed to reduce or negate their findings. However, an effect of this magnitude was uncovered by the Women’s Health Initiative trial of hormone replacement therapy in primary prevention of coronary heart disease compared to prior observational cohort studies.35 An RCT of ART, the Strategic Timing of AntiRetroviral Treatment (START) trial, is underway and may help to establish the validity of the guidelines.
The Bottom Line: Antiretroviral therapy should be initiated once the CD4 declines below 500 cells/mm3 and may be beneficial at CD4 counts above 500 cell/mm3.
The studies presented both favor earlier treatment in the 350–500 cells/mm3 range and possibly above. The combined data have led to a change in DHHS Guidelines28:
Dr. Sullivan was a Robert Wood Johnson Physician Faculty Scholar during the conduct of this study.
This update was presented at the meeting of the Society of General Internal Medicine on April 30, 2010.
Conflict of Interest Dr. Cofrancesco has been a consultant for Gilead Sciences. No other disclosures.