Population sequencing was performed for persons identified with persistent low-level viremia in 2 clinical trials. Persistent low-level viremia (defined as plasma HIV-1 RNA level >50 and <1000 copies/mL in at least 2 determinations over a 24-week period, after at least 24 weeks of antiretroviral therapy) was observed in 65 (5.6%) of 1158 patients at risk. New resistance mutations were detected during persistent low-level viremia in 37% of the 54 evaluable cases. The most common mutations were M184I/V (14 cases), K103N (9), and M230L (3). Detection of new mutations was associated with higher HIV-1 RNA levels during persistent low-level viremia.
Objectives To evaluate the risk of virologic failure conferred by suboptimal adherence to non-nucleoside reverse transcriptase inhibitors (NNRTI) and minority NNRTI resistance mutations. Design Pooled analysis of the risk of virologic failure conferred by minority NNRTI resistance mutations and NNRTI adherence from three studies of treatment-naïve individuals initiating an NNRTI-based regimen. Methods Participants from each study were categorized into both adherence quartiles (Q1–Q4) and four strata: ≥95%, 80–94%, 60–79%, and <60%. Weighted Cox proportional hazard models were used to estimate the risk of virologic failure. Results The majority of participants (N=768) had high measured adherence, but those in the lowest adherence quartile had the highest proportion of participants with virologic failure and the risk of virologic failure increased step-wise with adherence below 95%. Detection of minority NNRTI drug resistance mutations increased the proportion of participants with virologic failure across adherence quartiles (Cochran-Mantel-Haenszel P<0.001) and adherence strata (Cochran-Mantel-Haenszel P<0.001; <60% adherence, HR 1.7 [1.1–2.7], P=0.02; 60–79% adherence, HR 1.2 [0.5–3.2], P=0.67; 80–94% adherence, HR 2.5 [0.98–6.3], P=0.06; ≥95% adherence, HR 3.6 [2.3–5.6], P<0.001). On multivariate analysis, the effect of minority variants was also most prominent at higher levels of medication adherence. Conclusions The presence of minority NNRTI resistance mutations and NNRTI adherence were found to be independent predictors of virologic failure, but also modify each other’s effects on virologic failure. In addition to the focus on medication adherence counseling, ultrasensitive HIV-1 drug resistance assays could play a role in optimizing the success rates of first-line antiretroviral therapy.
Objectives To evaluate the relationship between incomplete antiretroviral therapy (ART) adherence and levels of residual HIV-1 viremia. Design Medication adherence and residual viremia <50 copies/mL were quantified in participants of a cohort of homeless and marginally housed individuals with HIV/AIDS. Methods Participants had at least 6 months of virologic suppression <50 copies/mL and were in the adherence monitoring cohort with monthly unannounced pill counts. Residual viremia was measured by the single-copy assay. Results The median average ART adherence over the prior 1 and 2 months were 94% [IQR 79%–100%] and 93% [IQR 82%–98%], respectively. Average ART adherence over the past 2 months was significantly associated with levels of residual HIV viremia (Spearman r = −0.25, P=0.04). One-third of participants with 100% ART adherence over the past 2 months had detectable residual viremia. On multivariate regression analysis, ART adherence over the past 2 months, but not duration of virologic suppression, CD4+ T cell count, or ART regimen, was significantly associated with levels of residual HIV viremia. Detectable residual viremia was associated with virologic failure (>50 copies/mL) on univariate Cox proportional hazard analysis (HR 2.08, P=0.02). However, on multivariate analysis, only ART adherence was associated with risk of virologic failure. Conclusions Incomplete ART adherence is associated with higher levels of residual HIV-1 viremia, but detectable residual viremia can be present despite 100% measured ART adherence.
Objectives To evaluate the effects of gender and initial antiretroviral regimen on decay of HIV RNA and virologic outcome. Methods We conducted a viral dynamics sub-study of A5142, a trial comparing lopinavir/ritonavir+efavirenz (LPV/EFV) versus LPV+2 NRTI (LPV) versus EFV+2 NRTI (EFV) in ARV-naive subjects. HIV RNA was measured at days 2, 10, and 14 in the sub-study and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the sub-study with bi-exponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV RNA change was assessed as a predictor of virologic failure (HIV RNA above 50/200 copies/mL) at weeks 24–96 using logistic regression. Results 68 subjects were enrolled in the sub-study (median HIV RNA 4.9 log10 copies/mL). Median rates of phase-1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) day−1. Phase-1 decay was significantly faster for EFV than LPV (P=0.023); other comparisons were not significant (P>0.11). Viral decay did not differ by gender (P=0.10). Week 1 HIV RNA change, calculated in 571 participants of A5142, was greater for the EFV (median - 1.47 log10 copies/ml) than either the LPV/EFV or LPV groups (−1.21 and −1.16 log10 copies/ml, respectively; P<0.001). Week 1 HIV RNA change was associated with virologic failure above 50 copies/mL at weeks 24 and 48 (P≤0.018), but not above 200 copies/mL or at week 96. Conclusions Phase-1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV RNA change predicted virologic outcome to week 48, but not at week 96.
BackgroundThe contribution of HIV-exposure to childhood mortality in a setting with widespread antiretroviral treatment (ART) availability has not been determined.MethodsFrom January 2012 to March 2013, mothers were enrolled within 48 h of delivery at 5 government postpartum wards in Botswana. Participants were followed by phone 1–3 monthly for 24 months. Risk factors for 24-month survival were assessed by Cox proportional hazards modeling.ResultsThree thousand mothers (1499 HIV-infected) and their 3033 children (1515 HIV-exposed) were enrolled. During pregnancy 58 % received three-drug ART, 23 % received zidovudine alone, 11 % received no antiretrovirals (8 % unknown); 2.1 % of children were HIV-infected by 24 months. Vital status at 24 months was known for 3018 (99.5 %) children; 106 (3.5 %) died including 12 (38 %) HIV-infected, 70 (4.7 %) HIV-exposed uninfected, and 24 (1.6 %) HIV-unexposed. Risk factors for mortality were child HIV-infection (aHR 22.6, 95 % CI 10.7, 47.5 %), child HIV-exposure (aHR 2.7, 95 % CI 1.7, 4.5) and maternal death (aHR 8.9, 95 % CI 2.1, 37.1). Replacement feeding predicted mortality when modeled separately from HIV-exposure (aHR 2.3, 95 % CI 1.5, 3.6), but colinearity with HIV-exposure status precluded investigation of its independent effect. Applied at the population level (26 % maternal HIV prevalence), an estimated 52 % of child mortality occurs among HIV-exposed or HIV-infected children.ConclusionsIn a programmatic setting with high maternal HIV prevalence and widespread maternal and child ART availability, HIV-exposed and HIV-infected children still account for most deaths at 24 months. Lack of breastfeeding was a likely contributor to excess mortality among HIV-exposed children.
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