Ultra-deep sequencing identified a significantly larger proportion of HIV-infected, treatment-naive persons as harboring drug-resistant viral variants. Among participants who initiated treatment with the NNRTI strategy, the risk of VF was significantly greater for participants who had low- and high-prevalence NNRTI-resistant variants.

Context Evidence regarding the impact of minority, or low frequency, HIV-1 drug-resistant variants on the effectiveness of first-line antiretroviral treatment (ART) is conflicting. Objective To evaluate the association of pre-existing HIV-1 minority drug-resistant variants with risk of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. Data Sources We searched published and unpublished studies in MEDLINE (1966 through December, 2010), EMBASE (1974 through December, 2010), conference abstracts, and article references. Authors of all studies were contacted for detailed laboratory, ART, and adherence data. Study Selection and Data Abstraction Studies involving ART-naive participants initiating NNRTI-based regimens were included. Participants were included if all drugs in their ART regimen were fully active by standard HIV population sequencing. Cox proportional hazard models using pooled patient-level data were used to estimate the risk of virologic failure based on a Prentice weighted case-cohort analysis stratified by study. Data Synthesis Individual data from 10 studies and 985 participants were available for the primary analysis. Minority HIV-1 drug resistance mutations were associated with an increased risk of virologic failure (HR 2.3 [95% CI, 1.7–3.3], P<0.001) after controlling for medication adherence, ethnicity, baseline CD4 cell count and plasma HIV-1 RNA levels. The increased risk of virologic failure was most strongly associated with minority variants resistant to NNRTIs (HR 2.6 [95% CI, 1.9–3.5], P<0.001). Among participants from the cohort studies, 35% of those with detectable minority variants experienced virologic failure as compared to 15% of those without minority variants. The presence of minority variants was associated with 2.5–3 times the risk of virologic failure at either ≥95% or <95% overall medication adherence. A dose-dependent increased risk of virologic failure was found in participants with a higher proportion or quantity of drug-resistant variants. Conclusion In this pooled analysis, minority HIV-1 resistance mutations, particularly involving NNRTI-resistance, were significantly associated with a dose-dependent increased risk of virologic failure with first-line ART.

Naturally occurring mutations in HIV-1-infected patients have important implications for therapy and the outcome of clinical studies. However, little is known about the prevalence of mutations that confer resistance to HIV-1 protease inhibitors in isolates derived from patients naive for such inhibitors. In the first clinical application of high-density oligonucleotide array sequencing, the sequences of 167 viral isolates from 102 patients have been determined. The DNA sequence of USA HIV-1 clade B proteases was found to be extremely variable and 47.5% of the 99 amino acid positions varied. This level of amino acid diversity is greater than that previously known for all worldwide HIV-1 clades combined (40%). Many of the amino acid changes that are known to contribute to drug resistance occurred as natural polymorphisms in isolates from patients who had never received protease inhibitors.

Background. The pilot phase IIb VIKING study suggested that dolutegravir (DTG), a human immunodeficiency virus (HIV) integrase inhibitor (INI), would be efficacious in INI-resistant patients at the 50 mg twice daily (BID) dose.Methods. VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg BID while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued. The primary efficacy endpoints were the mean change from baseline in plasma HIV-1 RNA at day 8 and the proportion of subjects with HIV-1 RNA <50 c/mL at week 24.Results. Mean change in HIV-1 RNA at day 8 was −1.43 log10 c/mL, and 69% of subjects achieved <50 c/mL at week 24. Multivariate analyses demonstrated a strong association between baseline DTG susceptibility and response. Response was most reduced in subjects with Q148 + ≥2 resistance-associated mutations. DTG 50 mg BID had a low (3%) discontinuation rate due to adverse events, similar to INI-naive subjects receiving DTG 50 mg once daily.Conclusions. DTG 50 mg BID–based therapy was effective in this highly treatment-experienced population with INI-resistant virus.Clinical Trials Registration.  (NCT01328041) and (112574).

Penicilliosis incidence correlates with the HIV/AIDS epidemic in Viet nam. The number of cases increases during rainy months. Injection drug use, shorter history, absence of fever or skin lesions, respiratory difficulty, higher lymphocyte count, and lower platelet count predict poor in-hospital outcome.