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Quantifying the reduction in sexual transmission of HIV-1 among MSM by early initiation of ART: A mathematical model.

ABSTRACT: BACKGROUND:We analyzed the effect of time to initiation of antiretroviral therapy (ART) after diagnosis on the probability of HIV-1 transmission events (HIV-TE) in naïve HIV-1-infected men having sex with men (MSM). SETTING:Mathematical model. METHODS:We used discrete event simulation modeling to estimate the probability of HIV-TE in the first 8 weeks after ART initiation; we varied ART initiation from D0 to D28 after simulated "diagnosis". The model inputs used sexual behavior parameters from the MSM population of the START trial, and transmission rates per-sex act and HIV-1 RNA from recent meta-analyses. HIV-1 RNA decay curves were modeled from the databases of Single (efavirenz [EFV] v dolutegravir [DTG]), Spring-2 (raltegravir [RAL] v DTG), and Flamingo (darunavir/ritonavir [DRVr] v DTG) trials. RESULTS:We found that the number of HIV-TE per index patient in the first 8 weeks after ART initiation increased linearly for same-day ART to initiation on day 28. Small but statistically significant advantages of integrase strand transfer inhibitors (INSTI) over EFV and DRVr were found. CONCLUSIONS:Rapid, if not same-day initiation of INSTI-based ART to newly diagnosed HIV-infected MSM has the potential for substantial public health benefits related to decreases in HIV-TE.

SUBMITTER: Berenguer J

PROVIDER: S-EPMC7371210 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Quantifying the reduction in sexual transmission of HIV-1 among MSM by early initiation of ART: A mathematical model.

Berenguer Juan J Parrondo Javier J Landovitz Raphael J RJ

PloS one 20200720 7

<h4>Background</h4>We analyzed the effect of time to initiation of antiretroviral therapy (ART) after diagnosis on the probability of HIV-1 transmission events (HIV-TE) in naïve HIV-1-infected men having sex with men (MSM).<h4>Setting</h4>Mathematical model.<h4>Methods</h4>We used discrete event simulation modeling to estimate the probability of HIV-TE in the first 8 weeks after ART initiation; we varied ART initiation from D0 to D28 after simulated "diagnosis". The model inputs used sexual beha ...[more]

PMID: 32687492

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Project description:Transmission of multiple founder variants has been associated with faster HIV disease progression. Many studies have attempted to determine the number of founder variants, mainly by analysis of sequence diversity and/or tree topology from acutely HIV-infected individuals. We hypothesized that adding sequence data collected from source partners might improve resolution and characterization of transmission events. Blood plasma samples were collected from both the source and recipient in thirty epidemiologically- and phylogenetically linked transmission pairs. All were men who have sex with men, sampled on average 70 days (range 11-170) after the recipient's estimated date of infection. Next generation sequencing (454 FLX, Roche) of HIV-1 env (C2-V3) was performed for all samples. Inspection of sequence alignments, highlighter plots, phylogenetic tree topologies and sequence diversity were used to determine the multiplicity of founder viruses with and without the inclusion of source data. Using only recipient sequence data, we were able to resolve multiplicity in twenty-six of the thirty transmission pairs (87 percent). Among them, five presented with a high viral diversity at baseline (>0.10 subst/site), consistent with multiple founders. By incorporating sequence data collected from the source partner, we were able to characterize all thirty transmission pairs. Overall, sixteen transmission events (53.3 percent) involved multiple founders. Results obtained by combining sequence data from recipient and source were congruent for nineteen of the twenty-six (73 percent) cases where conclusions were made using only recipient sequence data. The multiplicity of founders was associated with significantly higher HIV RNA levels (P = 0.04). To further evaluate the transmission bottleneck, we focused on single founder transmissions (fourteen of the thirty), and identified four recipients (28.6 percent) that had founder variants that were inferred to arise from minority viral populations in the source. These source clades ranged from 1.0 to 5.4 percent of the sampled population. Incorporating sequence data from the source increased of the ability to determine the multiplicity of founder variants, reduced misclassification, and allowed us to infer the transmission of minority variants.

Project description:BackgroundIt is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.Methods and findingsColorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.ConclusionsWe report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

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Quantifying the reduction in sexual transmission of HIV-1 among MSM by early initiation of ART: A mathematical model.

Publications

Quantifying the reduction in sexual transmission of HIV-1 among MSM by early initiation of ART: A mathematical model.

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