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Background: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates., Methods: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography-mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the 150-850 ng/ml efficacy-tolerance thresholds. Safety data and newborn HIV status were recorded. A mother's virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery., Results: 103 pregnant women were included, mostly from sub-Saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported., Conclusions: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required.

Background: Little is known in HIV-2 infection about the kinetics of disappearance of raltegravir (RAL)-resistant virus after RAL withdrawal., Methods: RAL was interrupted in four highly antiretroviral-experienced HIV-2-infected patients exhibiting a virological failure when receiving RAL. Integrase gene was sequenced from plasma samples collected at the time of RAL failure and at further time points following RAL withdrawal., Results: At the time of RAL withdrawal, virus exhibited different integrase resistance pathways: G140S/Q148R, E92Q/N155H, T97A/N155H and T97A/Y143C. In patient 1, the G140S/Q148R double-mutant was still detected at month (M)7 and at M11 after stopping RAL, but was no longer detected at M15. Regarding patient 2, the double-mutant E92Q/N155H was still present at M2 and M8 after stopping RAL, and was no longer detected at M12. In patient 3, RAL-resistant virus with T97A/N155H mutations were still present 1 month after stopping RAL, and were no longer detected at M14. Regarding patient 4, the mutant T97A/Y143C was still detected at M1 and M3 following RAL withdrawal. At M18 after RAL stop, integrase genotypic pattern evolved to T97A/Y143G., Conclusions: Persistence of HIV-2 RAL-resistant mutants was observed in all the key genetic RAL resistance pathways. These findings have clinical implications especially in HIV-2-infected patients for whom therapeutic arsenal is limited compared to HIV-1, since the persistence of resistant mutants might compromise the possible efficacy of upcoming second-generation integrase inhibitors., (© 2011 International Medical Press)

Objective: Previous studies have described the presence of the L74V reverse transcriptase (RT) mutation in highly experienced individuals as a risk factor for reduced response to tenofovir and selection of the K65R mutation. This study examined whether, in the context of a first-line abacavir/lamivudine highly active antiretroviral therapy (HAART) regimen, K65R might occur as a minority population where L74V was detected at virological failure., Methods: Four previously ART-naive individuals undergoing virological failure were selected, all receiving abacavir and lamivudine with either protease inhibitors or efavirenz and with virus displaying L74V and M184V or M184V alone following transient L74V emergence. Clonal analyses from plasma viral RNA were performed on samples taken at baseline and after virological failure. Clones were screened for the presence of K65R by real time K65R-selective PCR (K65R-sPCR). RT genes from clones displaying K65R were sequenced., Results: At baseline, all clones were wild type at codon 65 by K65R-sPCR, except in one patient in which one of 720 clones exhibited K65R. At failure with M184V and L74V present by bulk sequencing, this K65R was retained in one of 855 clones assessed. One additional patient (M 184V alone by bulk sequencing) displayed K65R in one of 466 failure clones. Virological failure samples from the remaining two patients were wild type at codon 65 in all of 524 and 270 clones, respectively., Conclusions: Minority species harbouring K65R are uncommon and occur at very low population densities in patients experiencing virological failure on first-line abacavir/lamivudine-containing HAART.

In HIV-2 infection, many studies have reported a high frequency of selection of the Q151M mutation, but its impact on phenotypic susceptibility of HIV-2 isolates remains unclear. Four HIV-2 infected patients from the French ANRS HIV-2 cohort, with evidence of Q151M mutation in both plasma and available peripheral blood mononuclear cells (PBMCs) co-cultivated supernatants, were selected. In vitro phenotypic susceptibilities to different nucleoside reverse transcriptase inhibitors (NRTIs) were determined using a PBMC assay. In HIV-2 isolates, the Q151M mutation alone impacts only the phenotypic susceptibility to stavudine and abacavir. A decrease in susceptibility to all NRTIs was observed when Q151M was selected with V111I, a mutation of unknown impact on HIV-1 resistance. Clinical relevance of these phenotypic susceptibility results needs to be evaluated in HIV-2 treated patients.

Objective: Stavudine-based antiretroviral combinations are less effective in zidovudine-experienced patients than in naive subjects and recently, mutations have been described to be associated to the use of both stavudine and zidovudine. In the ALTIS 2 trial, it was shown that a combination of stavudine and lamivudine is less effective in zidovudine-experienced patients than in naive patients. We conducted a retrospective genotypic and phenotypic resistance study (expressed as stavudine phenotypic index, calculated by dividing the inhibitory concentrations 50% [IC50] by the mean value of the sensitive viruses) to evaluate the factors associated with decrease in plasma HIV-1 RNA., Design: Associations with continuous variables were studied using non-parametric Spearman correlation coefficients. Associations with categorical variables were studied using non-parametric Mann-Whitney tests. Multivariate stepwise regression analyses were used to determine independent prognostic factors of the virological response., Results: At baseline, most of the subjects harboured zidovudine-associated mutations in plasma and peripheral blood mononuclear cells. Zidovudine and stavudine IC50 and IC50 were strongly associated with response. It appears that a cut-off of stavudine phenotypic index of 1.8-fold of IC50, much lower than the usually used value, could be clinically significant for response to stavudine. In the multivariate analysis, the stepwise model with the higher multiple correlation coefficient (R2 = 0.742) included the presence of a 215 Y/F mutation, the number of previously used nucleoside analogues and a resistant stavudine phenotype., Conclusion: These results argue for a phenotypic and genotypic cross resistance between stavudine and zidovudine. Modest increases of IC50 and IC50 for stavudine had an important impact on the virological response during the trial and plead for a new definition of the threshold value for stavudine phenotypic index.