MTN-015

Primary Objective

• Compare HIV disease progression twelve months post seroconversion among participants assigned to an active agent compared to placebo/control participants

Study Summary
MTN-015 was a multi-site, prospective, observational cohort study of women following HIV-1 seroconversion in microbicide trials of ARV-based microbicides or oral pre-exposure prophylaxis (PrEP). MTN-015 was designed to capture extensive prospective data on the clinical progression of HIV disease, virologic and immunologic responses following initiation of ART, and HIV-1 drug resistance profile among ART recipients at the time of virologic failure. This study also described post-seroconversion changes in participant sexual behaviors and partnership status. 499 participants were enrolled into the study from four parent protocols. The status of MTN-015 participants enrolled from the parent studies is as follows:

• HPTN 035 protocol cohort completed follow-up on 31 May 2013
• MTN-003 protocol cohort completed follow-up on 30 June 2014
• MTN-020 protocol cohort completed follow-up on 30 June 2019
• MTN-025 protocol cohort completed follow-up on 30 June 2019

As of the date of this report, a total of six papers have been published from this study. Secondary manuscripts development is ongoing.

Primary Results
MTN-015/HPTN-035 cohort results were presented at the 2010 International Microbicides Conference held on May 22-25, 2010, in Pittsburgh, PA. The primary manuscript was published online in HIV Clinical Trials on July 28, 2016. Of 194 HIV-infected women in HPTN 035, 186 were eligible to enroll in MTN-015 and 100 (72%) were enrolled. The median time from HIV detection to enrollment in MTN-015 was 18.2 months (range 5.0–45.7). There was a delay in enrollment that occurred because of the implementation timeline of MTN-015 during HPTN 035.  Due to the enrollment timeframe, the analysis of HIV disease progression 12 months after seroconversion could not be performed for the HPTN 035 subset. The median follow-up time was 48 months from enrollment. The median age at enrollment was 27 years (range 20–45). The majority (n=82) were enrolled prior to initiating antiretroviral therapy (ART). In ART-naïve participants, the median CD4+ was 405 cells/mm³ (interquartile range [IQR] 273, 657) and median plasma HIV-1 RNA was 3.9 log10 copies/ml (IQR 3.3, 4.6). ART was initiated prior to or during the trial in 68/100 (68%) participants. Combination ART regimens (≥3 medications) were used in 54/68 participants and were most commonly non-nucleoside reverse transcriptase (NNRTI)-based regimens. HIV genotypic resistance test results were available for 85/100 participants: 84 were infected with clade C virus. Several resistance-associated polymorphisms were identified including F77F/L, V90I/V, E138E/A, and V179A/D/T in reverse transcriptase and M46I/L in protease. However, none were associated with reductions in susceptibility to ART.

MTN-015/VOICE cohort results were presented at HIV Research for Prevention (HIV R4P) 2016 meeting held on October 17-21, 2016, in Chicago, IL. The primary manuscript was published in PLoS One on June 28, 2017. Of 312 women that were HIV-infected during VOICE, 229 (73%) were enrolled in MTN-015 and 224/229 had subsequent follow-up visits and were include in the analysist. Median age at enrollment was 24 years; the majority (93%) were from South Africa and majority (94%) had clade C virus. No significant differences for HIV RNA at steady state or the trajectory at 12 months were observed for each active study arm (oral or vaginal tenofovir-based regimen) as compared to placebo.  With a median follow-up of 31 months, no significant differences were observed for time to CD4 count ≤ 350 cells/mm³, or the composite endpoint of CD4 cells ≤ 350 cells/mm³, ART initiation, or death for each active arm compared to placebo. In conclusion, no clinically significantly impact was shown following use of tenofovir-based for HIV prevention on subsequent HIV disease parameters in HIV-infected women from the VOICE trial.

MTN-015/ASPIRE cohort results were presented at 2017 Conference on Retroviruses and Opportunistic Infections (CROI) meeting held on February 13-16, 2017, in Seattle, WA. The primary manuscript was published online in Clinical Infectious Diseases on October 22, 2018. Of 168 participants with incident HIV-1 infection in ASPIRE, 158 had at least one post-seroconversion assessment and were included in the analysis. Among the 158 participants (dapivirine ring, n= 65, placebo ring, n= 93), no significant differences between participants in the dapivirine and placebo arms were observed in CD4+ cell counts or plasma HIV-1 RNA over the first year after infection (prior to ART). During follow-up, 100/158 (63%) participants initiated NNRTI-containing ART (dapivirine: 39/65; placebo: 61/93); the median time to HIV-1 RNA <200 copies/ml was approximately 90 days for both dapivirine and placebo ring recipients (log-rank p=0.40).  Among 81 participants with at least 6 months of post-ART follow-up, 19 (24%) experienced virologic failure (dapivirine: 6/32, 19%; placebo: 13/39, 27%, p=0.42). A total of 121 women enrolled into MTN-015 study. In conclusion, acquisition of HIV-1 infection during dapivirine or placebo treatment in ASPIRE did not lead to differences in HIV-1 disease progression. After initiation of NNRTI-containing ART, a similar time to virologic suppression and risk of virologic failure was observed in dapivirine and placebo participants. These results provide reassurance that NNRTI-based ART regimens are effective among women who acquired HIV-1 while receiving the dapivirine vaginal ring.

MTN-015/HOPE cohort results were summarized in the MTN-015 summary reports by International Partnership for Microbicides (IPM). Nineteen 19 participants who used the DVR in HOPE were enrolled and 18 completed the study early. Demographic characteristics and key baseline characteristics (including mean and median HIV-1 ribonucleic acid [RNA] concentration and cluster of differentiation [CD]4+ T-cell counts) were generally similar between the groups who used the DVR and a placebo ring. Viruses encoding non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations were observed at seroconversion in four participants who used the DVR. Considering participants who received at least 6 months of ARV treatment (ie, had the opportunity for an optimal ARV response), 15 participants achieved HIV-1 RNA < 200 copies/mL. Of the participants with no NNRTI mutations at seroconversion and who were on ARV treatment, two participants had virologic failure. Overall, data from MTN-015 demonstrate no differences in HIV-1 disease progression and ARV treatment response between participants who used the DVR in and ASPIRE and HOPE, compared to those who used a placebo ring.