Deep sequencing analysis of M184V/I mutation at the switch and at the time of virological failure of boosted protease inhibitor plus lamivudine or boosted protease inhibitor maintenance strategy (substudy of the ANRS-MOBIDIP trial).

BACKGROUND: The ANRS12286/MOBIDIP trial showed that boosted protease inhibitor (bPI) plus lamivudine dual therapy was superior to bPI monotherapy as maintenance treatment in subjects with a history of M184V mutation. OBJECTIVES: We aimed to deep analyse the detection of M184V/I variants at time of switch and at the time of virological failure (VF). METHODS: Ultra-deep sequencing (UDS) was performed on proviral HIV-DNA at inclusion among 265 patients enrolled in the ANRS 12026/MOBIDIP trial, and on plasma from 31 patients experiencing VF. The proportion of M184V/I variants was described and the association between the M184V/I mutation at 1% of threshold and VF was explored with logistic regression models. RESULTS: M184V and I mutations were detected in HIV-DNA for 173/252 (69%) and 31/252 (12%) of participants, respectively. Longer duration of first-line treatment, higher plasma viral load at first-line treatment failure and higher baseline HIV-DNA load were associated with the archived M184V. M184I mutation was always associated with a STOP codon, suggesting defective virus. The 48 week estimated probability of remaining free from VF was comparable with or without the M184V/I mutation for dual therapy. At failure, M184V and major PI mutations were detected in 1/17 and 5/15 patients in the bPI arm and in 2/2 and 0/3 in the bPI+lamivudine arm, respectively. CONCLUSIONS: Using UDS evidenced that archiving of M184V in HIV-DNA is heterogeneous despite past historical M184V in 96% of cases. The antiviral efficacy of lamivudine-based dual therapy regimens is mainly due to the residual lamivudine activity.

Getting pregnant in HIV clinical trials: women's choice and safety needs. The experience from the ANRS12169-2LADY and ANRS12286-MOBIDIP trials.

INTRODUCTION: Pregnancy is an exclusion criteria in most clinical trials involving antiretroviral therapy (ART) and modern contraception methods are systematically proposed to women of childbearing age. Nevertheless pregnancies are often observed. Reproductive choices during clinical trials should be understood to adapt interventions to the level of risk for mother and baby safety. Our goal was to describe the reproductive behavior and pregnancy outcomes among HIV-infected women on second-line antiretroviral treatment enrolled in two clinical trials and to compare them with those of HIV-positive women in non-research settings. METHODS: The number and outcomes of pregnancies were recorded among 281 non menopausal women enrolled in the ANRS 12169-2LADY and ANRS 12286-MOBIDIP clinical trials in Cameroon, Senegal and Burkina Faso. All participants had agreed to use a least one contraceptive method (barrier or non-barrier) which was provided for free during the study. Data were collected through revision of pregnancy notification forms and by data extraction from the study database, regularly updated and checked during the study. RESULTS: Sixty-six women had 84 pregnancies between January 2010 and July 2015 resulting in a pregnancy rate of 8.0 per 100 women-years (WY) (95% CI 6.5-9.9) which is similar to the ones observed in cohort studies in Sub-Saharan Africa (varying from 2.5 to 9.4 pregnancies per 100 WY). Among 60 live births, 10 (16.6%) were born prematurely and 9 (15%) had a low birth weight. Sixteen miscarriages/stillbirths occurred (19.5%). This percentage is comparable to the one expected in the seronegative population which is reassuring for HIV-positive women considering pregnancy on ART. Only one minor birth defect was diagnosed. In univariate and multivariate analysis, miscarriages/stillbirths were not associated either with age, nadir of CD4 count, duration of ART, CD4 count, or viral load at the beginning of pregnancy. CONCLUSION: HIV-positive women participating in clinical trials conducted in Sub-Saharan Africa tend to get pregnant as often as seropositive women who received medical care in non-research settings. It is therefore essential to adopt a pragmatic approach by re-evaluating the relevance of the criteria for exclusion of pregnant women according to the risk associated with exposure and to seek more effective and innovating contraceptive strategies when using potentially teratogenic molecules.