https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(97)02190-9.pdf

Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1

Background: Many mathematical models have investigated the impact of expanding access to antiretroviral therapy (ART) on new HIV infections. Comparing results and conclusions across models is challenging because models have addressed slightly different questions and have reported different outcome metrics. This study compares the predictions of several mathematical models simulating the same ART intervention programmes to determine the extent to which models agree about the epidemiological impact of expanded ART. Methods and Findings: Twelve independent mathematical models evaluated a set of standardised ART intervention scenarios in South Africa and reported a common set of outputs. Intervention scenarios systematically varied the CD4 count threshold for treatment eligibility, access to treatment, and programme retention. For a scenario in which 80% of HIV-infected individuals start treatment on average 1 y after their CD4 count drops below 350 cells/ml and 85% remain on treatment after 3 y, the models projected that HIV incidence would be 35% to 54% lower 8 y after the introduction of ART, compared to a counterfactual scenario in which there is no ART. More variation existed in the estimated long-term (38 y) reductions in incidence. The impact of optimistic interventions including immediate ART initiation varied widely across models, maintaining substantial uncertainty about the theoretical prospect for elimination of HIV from the population using ART alone over the next four decades. The number of person-years of ART per infection averted over 8 y ranged between 5.8 and 18.7. Considering the actual scale-up of ART in South Africa, seven models estimated that current HIV incidence is 17% to 32% lower than it would have been in the absence of ART. Differences between model assumptions about CD4 decline and HIV transmissibility over the course of infection explained only a modest amount of the variation in model results. Conclusions: Mathematical models evaluating the impact of ART vary substantially in structure, complexity, and parameter choices, but all suggest that ART, at high levels of access and with high adherence, has the potential to substantially reduce new HIV infections. There was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up, but more variation in longer term projections and in the efficiency with which treatment can reduce new infections. Differences between model predictions could not be explained by differences in model structure or parameterization that were hypothesized to affect intervention impact. Please see later in the article for the Editors’ Summary.

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HIV treatment as prevention: Systematic comparison of mathematical models of the potential impact of antiretroviral therapy on HIV incidence in South Africa

Objective: To develop a model to predict transmission of HIV-1 from men to women. Design: HIV-1 in seminal plasma, and endocervical CCR5 receptors were correlated with epidemiological studies of HIV-1 transmission to develop a probabilistic model. Settings: Semen samples were collected from patient subjects in Seattle Washington, Chapel Hill, North Carolina, and St. Gallen, Switzerland. Endocervical biopsy specimens were obtained from women in Chicago, Illinois. Participants: Eighty-six men (not receiving antireroviral therapy) in whom CD4 cell count and semen volume were available, and 24 women in whom the number of endocervical CCR5 receptors were determined. Main outcome measures: Prediction of transmission of HIV-1 from men to women per episode of vaginal intercourse based on the absolute burden of HIV (volume 3 HIV RNA copies/ml seminal plasma). Results: The model suggests efficient heterosexual transmission of HIV-1 when semen viral burden is high. When semen contains 100 000 copies of non-syncytium-inducing (NSI) HIV RNA the probability of HIV-1 transmission is 1 per 100 episodes of intercourse; conversely, with 1000 copies NSI HIV RNA in semen, transmission probability is 3 per 10 000 episodes of intercourse. Conclusions: This model links biological and epidemiological data related to heterosexual HIV-1 transmission. The model can be used to estimate transmission of HIV from men with high semen viral burden from inflammation, or reduced burden after antiretroviral therapy. The results offer a biological explanation for the magnitude of the HIV epidemic in places where earlier studies have shown men have high semen viral burden, such as in sub-Saharan Africa. The model can be used to develop and test HIV-1 prevention strategies.

Viral burden in genital secretions determines male-to-female sexual transmission of HIV-1: a probabilistic empiric model.

Both qualitative and quantitative virologic measurements were compared between blood and genital compartments for 128 men infected with human immunodeficiency virus type 1 (HIV-1) to address several controversial issues concerning HIV-1 shedding in semen and to obtain further information about the distribution of virus between these two compartments. Evidence for viral compartmentalization was suggested by earlier studies that noted the poor correlation between blood and seminal virus load, phenotype, and genotype. Further support for this viral compartmentalization was based on the following observations between semen and blood: lack of association between culturability of virus in semen and viral RNA level in blood, discordant distribution of viral phenotypes, discordant viral RNA levels, a weak correlation between viral RNA level in semen and CD4 cell count in blood, differences in the biologic variability of viral RNA levels, and differences in the virus load response to antiretroviral therapy.

Association between Culturable Human Immunodeficiency Virus Type 1 (HIV-1) in Semen and HIV-1 RNA Levels in Semen and Blood: Evidence for Compartmentalization of HIV-1 between Semen and Blood

Objective: The amount of HIV in semen likely influences infectiousness. Antiretroviral therapy decreases HIV-RNA in semen, but data on HIV concentrations in semen in a large cohort of men with suppressed HIV-RNA in blood is unavailable. Methods: Male patients with a treatment-induced reduction of HIV-RNA load in plasma below 400 copies/ml were asked to donate a semen and blood sample. Blood and seminal plasma were tested for the presence of HIV-RNA by the NucliSens method (detection limit 400 copies/ml). Seminal cell samples from 67 patients were further analysed for the presence of HIV-DNA using a nested DNA-polymerase chain reaction. Results of RNA and DNA testing in semen were compared with 55 HIV-positive antiretroviral therapy-naive men. Results: A total of 114 patients participated in the study. Seminal plasma HIV-RNA was detectable in only two patients [1.8%, 95% confidence ratio (CI), 0-4.2%] compared with a detection frequency of 67% in untreated controls [Odds ratio (OR), 0.01; 95% CI, 0-0.03]. Detection of cell-associated HIV-DNA in semen was significantly less frequent (16 versus 38%) in patients receiving suppressive therapy compared with untreated controls (OR, 0.32; 95% Cl, 0.12-0.80). Conclusion: In patients with treatment-induced suppression of blood viral load the likelihood of having detectable HIV in semen is very low (< 4%). In addition, seminal shedding of cell-free and cell-associated HIV is significantly lower than in an untreated population of HlV-infected asymptomatic men. On a population basis, this effect of therapy may help to reduce sexual transmission of HIV. However, individual patients may still be infected as evidenced by continued shedding of cells harbouring the HIV provirus.

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Potent antiretroviral treatment of HIV-infection results in suppression of the seminal shedding of HIV

HIV-1 infection continues to spread worldwide, primarily through sexual intercourse. Because semen is a major vehicle for transmission of HIV-1, we evaluated the effects of reverse transcriptase inhibitor therapy on the amount of HIV-1 in semen. The semen and blood of 11 HIV-1-infected men (i.e. treatment group) were collected before the initiation of reverse transcriptase inhibitor therapy and then 8 to 18 weeks after initiation of therapy. The semen and blood of another 11 HIV-1-infected men (i.e., longitudinal group), who were not on or had no change in antiretroviral therapy for at least 2 months before study entry, were collected at approximately 2-week intervals for 10 to 26 weeks. In the treatment group, 82% of the seminal plasma HIV-1 RNA levels decreased from baseline after 8 to 18 weeks of therapy (median reduction of 1.01 log10, p = 0.01), and 100% of the blood plasma RNA levels decreased from baseline over the same period (median reduction of 0.92 log10, p = 0.003). Five of these patients were followed for at least 52 weeks and had a median seminal plasma HIV-1 RNA level of 0.66 log10 below baseline at 1 year. All subjects in the treatment group with positive cultures at baseline (50%) had negative cultures or a lower infectious units per ejaculate at the 8- to 18-week follow-up examinations. The HIV-1 RNA levels in blood and semen of the longitudinal group did not change significantly over 10 to 26 weeks. Initiation of reverse transcriptase inhibitor therapy effectively reduces shedding of HIV-1 in semen and may therefore reduce the spread of infection within populations.

Susan Zhou

Papers

Effects of reverse transcriptase inhibitor therapy on the HIV-1 viral burden in semen.