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Objectives: The main objective of this analysis was to evaluate the impact of pre‐existing drug resistance by next‐generation sequencing (NGS) on the risk of treatment failure (TF) of first‐line regimens in participants enrolled in the START study. Methods: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre‐existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first‐line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). Results: Baseline NGS data were available for 1380 antiretroviral therapy (ART)‐naïve participants enrolled over 2009–2013. First‐line ART included a non‐nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0–2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01–2.74; p = 0.05) and 2.32 (95% confidence interval 1.32–4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI‐based regimen. Conclusions: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI‐based regimens. [ABSTRACT FROM AUTHOR]

Introduction: For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side effects, past intolerance, and administration inability contribute to the need for novel drug classes in this population.Areas Covered: Herein, we review the pharmacology, clinical efficacy, and safety profile of fostemsavir, a first in its class attachment inhibitor recently FDA approved for use.Expert Opinion: Fostemsavir is a well-tolerated oral medication with relatively few drug-drug interactions. Clinical trial data demonstrates virologic and notable immunologic response in conjunction with optimal background therapy in HTE persons living with HIV. Fostemsavir exhibits no cross-resistance with other ARV classes and thus is an important advancement for patients harboring drug-resistant HIV. Further study will be needed to determine outstanding clinical questions such as the role of drug resistance testing and fostemsavir use outside of the HTE population. [ABSTRACT FROM AUTHOR]

Objective: Determine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF). Methods: 29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs (Stanford DRMs with an algorithm value ≥15, include low-, intermediate and high-level resistance) by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels. Results: DS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×104 c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency (26 NNRTI, 12 NRTI and 2 PI) and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1–4% and 24 (60%) at levels of 5–19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS. Conclusions: DS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects. [ABSTRACT FROM AUTHOR]

Low-frequency HIV variants possessing resistance mutations against non-nucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes. [ABSTRACT FROM AUTHOR]

Background: There are few data on the prevalence of WHO transmitted drug resistance mutations (TDRs) that could affect treatment responses to first line antiretroviral therapy (ART) in Hunan Province, China. Objective: Determine the prevalence of WHO NRTI/NNRTI/PI TDRs in ART-naïve subjects in Hunan Province by deep sequencing. Methods: ART-naïve subjects diagnosed in Hunan between 2010–2011 were evaluated by deep sequencing for low-frequency HIV variants possessing WHO TDRs to 1% levels. Mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility. Results: Deep sequencing was performed on samples from 90 ART-naïve subjects; 83.3% were AE subtype. All subjects had advanced disease (average CD4 count 134 cells/mm3). Overall 25.6%(23/90) of subjects had HIV with major WHO NRTI/NNRTI TDRs by deep sequencing at a variant frequency level ≥1%; 16.7%(15/90) had NRTI TDR and 12.2%(11/90) had a major NNRTI TDR. The majority of NRTI/NNRTI mutations were identified at variant levels <5%. Mutations were analyzed by HIVdb.stanford.edu and 7.8% of subjects had variants with high-level nevirapine resistance; 4.4% had high-level NRTI resistance. Deep sequencing identified 24(27.6%) subjects with variants possessing either a PI TDR or hivdb.stanford.edu PI mutation (algorithm value≥15). 17(19.5%) had PI TDRs at levels >1%. Conclusions: ART-naïve subjects from Hunan Province China infected predominantly with subtype AE frequently possessed HIV variants with WHO NRTI/NNRTI TDRs by deep sequencing that would affect the first line ART used in the region. Specific mutations conferring nevirapine high-level resistance were identified in 7.8% of subjects. The majority of TDRs detected were at variant levels <5% likely due to subjects having advanced chronic disease at the time of testing. PI TDRs were identified frequently, but were found in isolation and at low variant frequency. As PI/r use is infrequent in Hunan, the existence of PI mutations likely represent AE subtype natural polymorphism at low variant level frequency. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated the association between risk behaviors and antiretroviral resistance in HIV-positive patients receiving opioid agonist treatment. Researchers evaluated 59 subjects from opioid treatment and outpatient programs. They found that 14% reported unprotected sex, 7% reported sharing needles or works, and 60% had positive urine toxicology for illicit drug use. They concluded that improved prevention and treatment programs for patients were needed.

Background: It is unknown whether HIV-positive patients experiencing virologic failure (VF) on boosted-PI (PI/r) regimens without drug resistant mutations (DRM) by standard genotyping harbor low-level PI resistant variants. CASTLE compared the efficacy of atazanavir/ritonavir (ATV/r) with lopinavir/ritonavir (LPV/r), each in combination with TVD in ARV-naïve subjects. Objective: To determine if VF on an initial PI/r-based regimen possess low-level resistant variants that may affect a subsequent PI-containing regimen. Methods/Results: Patients experiencing VF on a Tenofovir/Emtricitabine+PI/r regimen were evaluated by ultra deep sequencing (UDS) for mutations classified/weighted by Stanford HIVdb. Samples were evaluated for variants to 0.4% levels. 36 VF subjects were evaluated by UDS; 24 had UDS for PI and RT DRMs. Of these 24, 19 (79.2%) had any DRM by UDS. The most common UDS-detected DRM were NRTI in 18 subjects: M184V/I (11), TAMs(7) & K65R(4); PI DRMs were detected in 9 subjects: M46I/V(5), F53L(2), I50V(1), D30N(1), and N88S(1). The remaining 12 subjects, all with VLs<10,000, had protease gene UDS, and 4 had low-level PI DRMs: F53L(2), L76V(1), I54S(1), G73S(1). Overall, 3/36(8.3%) subjects had DRMs identified with Stanford-HIVdb weights > 12 for ATV or LPV: N88S (at 0.43% level-mutational load 1,828) in 1 subject on ATV; I50V (0.44%-mutational load 110) and L76V (0.52%-mutational load 20) in 1 subject each, both on LPV. All VF samples remained phenotypically susceptible to the treatment PI/r. Conclusion: Among persons experiencing VF without PI DRMs with standard genotyping on an initial PI/r regimen, lowlevel variants possessing major PI DRMs were present in a minority of cases, occurred in isolation, and did not result in phenotypic resistance. NRTI DRMs were detected in a high proportion of subjects. These data suggest that PIs may remain effective in subjects experiencing VF on a PI/r-based regimen when PI DRMs are not detected by standard or UDS genotyping. [ABSTRACT FROM AUTHOR]

The article discusses a systematic review and pooled analysis of the link between preexisting drug-resistant human immunodeficiency (HIV)-1 minority variants and the risk of nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral virologic failure. The risk of virologic failure was estimated using Cox proportional hazard models. There was a significant link between low-frequency HIV-1 drug resistance mutations and a higher risk of virologic failure with first-line antiretroviral treatment (ART) based on the analysis. It was found that race or ethnicity was a significant predictor of virologic failure.

The article presents medical research that reveals directly administered antiretroviral therapy (DAART) for HIV-positive drug abusers does not have an effect on antiretroviral drug resistance. This is a randomized, controlled, and community-based clinical trial of DAART compared with self-administered HIV therapy (SAT). Outcome measures include number of new drug resistance mutations, total genotypic sensitivity score, and future drug options.

Presents a study of HIV drug resistance and risk behavior among HIV injection drug users in care to determine the number of needle-sharing events involved. Proportion of sharing partners exposed to drug-resistant HIV; Strategies to reduce injection drug use risk behaviors among patients in clinical care; Diagnosis of HIV.

Background. The prevalence of drug resistance among persons with newly acquired human immunodeficiency virus (HIV) infection is well documented. However, it is unclear to what extent these mutations persist in chronically infected, treatment-naive patients. Methods. Prevalence of and factors associated with genotypic drug resistance were analyzed retrospectively in a subset of 491 chronically HIV-infected, antiretroviral-naive patients enrolled at 25 cities in the Terry Beirn Community Programs for Clinical Research on Acquired Immune Deficiency Syndrome (AIDS) Flexible Initial Retrovirus Suppressive Therapies trial during 1999-2001. Resistance was defined on the basis of the International AIDS Society 2003 definition, as well as the presence of additional mutations at codons 215 (C/D/E/S) and 69 (A/N/S) in the poi gene. Prevalence of mutations was estimated by use of techniques for stratified random samples. Logistic regression models were used to determine factors associated with resistance. Results. Among the 491 chronically HIV-infected patients (mean CD4 cell count, 269 cells/mm3; 31% of patients had a prior AIDS diagnosis), 57 (11.6%) had &ges;1 resistance mutation, resulting in an estimated prevalence for the cohort of 10.8% (95% confidence interval [CI], 9.5%-12.1%). The prevalence was 8.8% if the 1181 mutation was excluded. By drug class, the estimated prevalence of mutations conferring resistance to nucleoside reverse-transcriptase inhibitors was 7.8%, and the prevalence was 3.0% for nonnucleoside reverse-transcriptase inhibitors and 0.7% for protease inhibitors. In a multiple logistic regression analysis, non-Hispanic white subjects were twice as likely than African American subjects to have resistance (odds ratio [OR], 2.1; 95% CI, 1.1-4.1; P = .03), and there was a 40% increase per year in prevalence of mutations by later year of enrollment (OR, 1.4; 95% CI, 1.0-2.1; P = .05). Conclusions. These results demonstrate the persistence of drug resistance mutations in chronically HIV-infected patients and an increasing prevalence of resistance over time, and they support genotyping of virus at baseline for chronically HIV-infected patients. [ABSTRACT FROM AUTHOR]

Acquired resistance to antiretroviral agents is an established sequela of HIV pharmacotherapy. Viral mutations can confer reduced susceptibility to antiretroviral medications, resulting in virologic and clinical failure in more than half of treated patients. Cross-resistance that can develop within each drug class leads to the progressive loss of future therapeutic options for individual patients. Although protease inhibitors (PIs) are a potent class of antiretrovirals, resistance can still develop rapidly, and multiple-PI resistance has become a serious, growing clinical problem. Development of rational treatment strategies that recognize specific patterns of cross-resistance among PIs are needed to help clinicians choose the most appropriate PI. Rational sequencing of PI use should be based on genotypic and phenotypic resistance testing. Maintaining higher drug plasma levels or using specific PI combinations may also diminish PI cross-resistance. New agents that are less likely to induce or be susceptible to cross-resistance will be of value in HIV treatment. This article reviews the acquisition of resistance to currently available PIs, discussing the drug-specific mutational patterns and evidence of clinical cross-resistance. The resistance profiles of two newer PIs, atazanavir and tipranavir, are also presented. [ABSTRACT FROM AUTHOR]

An abstract of the article "Use of New Technologies to Detect and Understand HIV Drug Resistance," by Michael J. Kozal is presented.