Kimberly A. Powers

Rethinking the heterosexual infectivity of HIV-1: a systematic review and meta-analysis

Studies of cumulative HIV incidence suggest that cofactors such as genital ulcer disease, HIV disease stage, and male circumcision influence HIV transmission; however, the heterosexual infectivity of HIV-1 is commonly cited as a fixed value (approximately 0.001, or one transmission per 1000 contacts). We sought to estimate transmission cofactor effects on the heterosexual infectivity of HIV-1 and to quantify the extent to which study methods have affected infectivity estimates. We undertook a systematic search (up to April 27, 2008) of PubMed, Web of Science, and relevant bibliographies to identify articles estimating the heterosexual infectivity of HIV-1. We used meta-regression and stratified random-effects meta-analysis to assess differences in infectivity associated with cofactors and study methods. Infectivity estimates were very heterogeneous, ranging from zero transmissions after more than 100 penile-vaginal contacts in some serodiscordant couples to one transmission for every 3.1 episodes of heterosexual anal intercourse. Estimates were only weakly associated with study methods. Infectivity differences, expressed as number of transmissions per 1000 contacts, were 8.1 (95 % CI 0.4-15.8) when comparing uncircumcised to circumcised susceptible men, 6.0 (3.3-8.8) comparing susceptible individuals with and without genital ulcer disease, 1.9 (0.9-2.8) comparing late-stage to mid-stage index cases, and 2.5 (0.2-4.9) comparing early-stage to mid-stage index cases. A single value for the heterosexual infectivity of HIV-1 fails to reflect the variation associated with important cofactors. The commonly cited value of 0.001 was estimated among stable couples with low prevalences of high-risk cofactors, and represents a lower bound. Cofactor effects are important to include in epidemic models, policy considerations, and prevention messages.

Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection

Objectives:This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection. Design:A prospective cohort study was embedded within a cross-sectional study of HIV screening in a Lilongwe, Malawi STD clinic. Methods:Blood samples from HIV antibody negative or indeterminate volunteers were used to detect HIV RNA in plasma using a pooling strategy. Blood and seminal plasma HIV-1 RNA concentrations were measured over 16 weeks. Results:Sixteen men with acute HIV infection and 25 men with chronic HIV infection were studied. Blood viral load in subjects with acute HIV infection was highest about 17 days after infection (mean ± SE, 6.9 ± 0.5 log10 copies/ml), while semen viral load peaked about 30 days after infection (4.5 ± 0.4 log10 copies/ml). Semen viral load declined by 1.7 log10 to a nadir by week 10 of HIV infection. Semen and blood viral loads were more stable in chronically infected subjects over 16 weeks. Higher semen levels of HIV RNA were noted in subjects with low CD4 cell counts. Conclusions:These results provide a biological explanation for reported increases in HIV transmission during the very early (acute) and late stages of infection. Recognizing temporal differences in HIV shedding in the genital tract is important in the development of effective HIV prevention strategies.

The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study

BACKGROUND HIV transmission risk is higher during acute and early HIV infection than it is during chronic infection, but the contribution of early infection to the spread of HIV is controversial. We estimated the contribution of early infection to HIV incidence in Lilongwe, Malawi, and predict the future effect of hypothetical prevention interventions targeted at early infection only, chronic infection only, or both stages. METHODS We developed a deterministic mathematical model describing heterosexual HIV transmission, informed by detailed behavioural and viral-load data collected in Lilongwe. We included sexual contact within and outside of steady pairs and divided the infectious period into intervals to allow for changes in transmissibility by infection stage. We used a Bayesian melding approach to fit the model to HIV prevalence data collected between 1987 and 2005 at Lilongwe antenatal clinics. We assessed interventions that reduced the per-contact transmission probability to 0.00003 in people receiving them, and varied the proportion of individuals receiving the intervention in each stage. FINDINGS We estimated that 38.4% (95% credible interval 18.6-52.3) of HIV transmissions in Lilongwe are attributable to sexual contact with individuals with early infection. Interventions targeted at only early infection substantially reduced HIV prevalence, but did not lead to elimination, even with 100% coverage. Interventions targeted at only chronic infections also reduced HIV prevalence, but coverage levels of 95-99% were needed for the elimination of HIV. In scenarios with less than 95% coverage of interventions targeted at chronic infections, additional interventions reaching 25-75% of individuals with early infection reduced HIV prevalence substantially. INTERPRETATION Our results suggest that early infection plays an important part in HIV transmission in this sub-Saharan African setting. Without near-complete coverage, interventions during chronic infection will probably have incomplete effectiveness unless complemented by strategies targeting individuals with early HIV infection. FUNDING National Institutes of Health, University of North Carolina Center for AIDS Research.

Antiretroviral treatment of HIV-1 prevents transmission of HIV-1: where do we go from here?

Antiretroviral drugs that inhibit viral replication were expected to reduce transmission of HIV by lowering the concentration of HIV in the genital tract. In 11 of 13 observational studies, antiretroviral therapy (ART) provided to an HIV-infected index case led to greatly reduced transmission of HIV to a sexual partner. In the HPTN 052 randomised controlled trial, ART used in combination with condoms and counselling reduced HIV transmission by 96·4%. Evidence is growing that wider, earlier initiation of ART could reduce population-level incidence of HIV. However, the full benefits of this strategy will probably need universal access to very early ART and excellent adherence to treatment. Challenges to this approach are substantial. First, not all HIV-infected individuals can be located, especially people with acute and early infection who are most contagious. Second, the ability of ART to prevent HIV transmission in men who have sex with men (MSM) and people who use intravenous drugs has not been shown. Indeed, the stable or increased incidence of HIV in MSM in some communities where widespread use of ART has been established emphasises the concern that not enough is known about treatment as prevention for this crucial population. Third, although US guidelines call for immediate use of ART, such guidelines have not been embraced worldwide. Some experts do not believe that immediate or early ART is justified by present evidence, or that health-care infrastructure for this approach is sufficient. These concerns are very difficult to resolve. Ongoing community-based prospective trials of early ART are likely to help to establish the population-level benefit of ART, and-if successful-to galvanise treatment as prevention.

The year-long effect of HIV-positive test results on pregnancy intentions, contraceptive use, and pregnancy incidence among Malawian women.

Objectives:To estimate the effect of receiving HIV-positive test results on intentions to have future children and on contraceptive use and to assess the association between pregnancy intentions and pregnancy incidence among HIV-positive women in Malawi. Methods:Women of unknown HIV status completed a questionnaire about pregnancy intentions and contraceptive use and then received HIV voluntary counseling and testing (VCT). Women who were HIV-positive and not pregnant were enrolled and followed for 1 year while receiving HIV care and access to family planning (FP) services. Results:Before receiving their HIV test results, 33% of women reported a desire to have future children; this declined to 15% 1 week later (P < 0.0001) and remained constant throughout follow-up. Contraceptive use increased from 38% before HIV testing to 52% 1 week later (P < 0.0001) and then decreased to 46% by 12 months. The pregnancy incidence among women not reporting a desire to have future children after VCT was less than half of the incidence among women reporting this desire. Conclusions:With knowledge of their HIV-positive status, women were less likely to desire future pregnancies. Pregnancy incidence was lower among women not desiring future children. Integration of VCT, FP, and HIV care could prevent mother-to-child HIV transmission.

Role of acute and early HIV infection in the sexual transmission of HIV.

Purpose of reviewAcute HIV infection (AHI), the earliest period after HIV acquisition, is only a few weeks in duration. In this brief period, the concentration of HIV in blood and genital secretions is extremely high, increasing the probability of HIV transmission. Although a substantial role of AHI in the sexual transmission of HIV is biologically plausible, the significance of AHI in the epidemiological spread of HIV remains uncertain. Recent findingsAHI is diagnosed by detecting viral RNA or antigen in the blood of persons who are HIV seronegative. Depending on the setting, persons with AHI represent between 1 and 10% of persons with newly diagnosed HIV infection. The high concentration of virus during AHI leads to increased infectiousness, possibly as much as 26 times greater than during chronic infection. In mathematical models, the estimated proportion of transmission attributed to AHI has varied considerably, depending on model structure, model parameters, and the population. Key determinants include the stage of the HIV epidemic and the sexual risk profile of the population. SummaryDespite its brief duration, AHI plays a disproportionate role in the sexual transmission of HIV infection. Detection of persons with AHI may provide an important opportunity for transmission prevention.

Antiviral agents and HIV prevention: controversies, conflicts, and consensus

Antiviral agents can be used to prevent HIV transmission before exposure as preexposure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups - including intravenous drug users and MSM - has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation.

Rapid real-time detection of acute HIV infection in patients in Africa.

BACKGROUND We conducted a prospective study to evaluate methods of detecting clients with sexually transmitted diseases (STDs) who were acutely coinfected with human immunodeficiency virus (HIV) in Lilongwe, Malawi. METHODS After informed consent was obtained, all clients with acute STDs were offered voluntary HIV counseling and testing by 2 rapid antibody tests. Samples from rapid test-negative or -discordant subjects were pooled (50 : 5 : 1) and tested for HIV RNA. Western blots were performed on all rapid test-discordant specimens with detectable HIV RNA. A subset of specimens received p24 antigen testing with standard and/or ultrasensitive methods. Patients with possible acute HIV infection were followed to confirm seroconversion. RESULTS A total of 1450 clients (34% female and 66% male) agreed to testing, of whom 588 (40.55%) had established HIV infection and 21 (1.45%) had acute infection. Discordant rapid antibody tests identified 7 of 21 (33.3% sensitivity), standard p24 antigen identified 12 of 16 (75% sensitivity), and ultrasensitive p24 antigen identified 15 of 17 (88% sensitivity) acute cases. By definition, the sensitivity of the RNA assay was 100%. CONCLUSIONS Real-time pooled RNA testing for the detection of acute HIV infection is feasible in resource-limited settings. However, parallel rapid testing and p24 antigen testing are technologically simpler and together may detect approximately 90% of acute cases.

HIV treatment as prevention: Debate and commentary-will early infection compromise treatment-as-prevention strategies?

Universal HIV testing and immediate antiretroviral therapy for infected individuals has been proposed as a way of reducing the transmission of HIV and thereby bringing the HIV epidemic under control. It is unclear whether transmission during early HIV infection—before individuals are likely to have been diagnosed with HIV and started on antiretroviral therapy—will compromise the effectiveness of treatment as prevention. This article presents two opposing viewpoints by Powers, Miller, and Cohen, and Williams and Dye, followed by a commentary by Fraser.

Improved detection of acute HIV-1 infection in sub-Saharan Africa: development of a risk score algorithm.

Objective:Individuals with acute (preseroconversion) HIV infection (AHI) are important in the spread of HIV. The identification of AHI requires the detection of viral proteins or nucleic acids with techniques that are often unaffordable for routine use. To facilitate the efficient use of these tests, we sought to develop a risk score algorithm for identifying likely AHI cases and targeting the tests towards those individuals. Design:A cross-sectional study of 1448 adults attending a sexually transmitted infections (STI) clinic in Malawi. Methods:Using logistic regression, we identified risk behaviors, symptoms, HIV rapid test results, and STI syndromes that were predictive of AHI. We assigned a model-based score to each predictor and calculated a risk score for each participant. Results:Twenty-one participants (1.45%) had AHI, 588 had established HIV infection, and 839 were HIV-negative. AHI was strongly associated with discordant rapid HIV tests and genital ulcer disease (GUD). The algorithm also included diarrhea, more than one sexual partner in 2 months, body ache, and fever. Corresponding predictor scores were 1 for fever, body ache, and more than one partner; 2 for diarrhea and GUD; and 4 for discordant rapid tests. A risk score of 2 or greater was 95.2% sensitive and 60.5% specific in detecting AHI. Conclusion:Using this algorithm, we could identify 95% of AHI cases by performing nucleic acid or protein tests in only 40% of patients. Risk score algorithms could enable rapid, reliable AHI detection in resource-limited settings.