In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).

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Twice-daily maraviroc was not noninferior to efavirenz at <50 copies/mL in the primary analysis. However, 15% of patients would have been ineligible for inclusion by a more sensitive screening assay. Their retrospective exclusion resulted in similar response rates in both arms Trial registration. ClinicalTrials.gov identifier: (NCT00098293) .

High-throughput sequencing platforms provide an approach for detecting rare HIV-1 variants and documenting more fully quasispecies diversity. We applied this technology to the V3 loop-coding region of env in samples collected from 4 chronically HIV-infected subjects in whom CCR5 antagonist (vicriviroc [VVC]) therapy failed. Between 25,000–140,000 amplified sequences were obtained per sample. Profound baseline V3 loop sequence heterogeneity existed; predicted CXCR4-using populations were identified in a largely CCR5-using population. The V3 loop forms associated with subsequent virologic failure, either through CXCR4 use or the emergence of high-level VVC resistance, were present as minor variants at 0.8–2.8% of baseline samples. Extreme, rapid shifts in population frequencies toward these forms occurred, and deep sequencing provided a detailed view of the rapid evolutionary impact of VVC selection. Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists.

BackgroundHIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant viral variants harbouring one or two substitutions in the viral protease. To combat PI resistance development, two approaches have been developed. The first is to increase the level of PI in the plasma of the patient, and the second is to develop novel PI with high potency against the known PI-resistant HIV protease variants. Both approaches share the requirement for a considerable increase in the number of protease mutations to lead to clinical resistance, thereby increasing the genetic barrier. We investigated whether HIV could yet again find a way to become less susceptible to these novel inhibitors.Methods and FindingsWe have performed in vitro selection experiments using a novel PI with an increased genetic barrier (RO033-4649) and demonstrated selection of three viruses 4- to 8-fold resistant to all PI compared to wild type. These PI-resistant viruses did not have a single substitution in the viral protease. Full genomic sequencing revealed the presence of NC/p1 cleavage site substitutions in the viral Gag polyprotein (K436E and/or I437T/V) in all three resistant viruses. These changes, when introduced in a reference strain, conferred PI resistance. The mechanism leading to PI resistance is enhancement of the processing efficiency of the altered substrate by wild-type protease. Analysis of genotypic and phenotypic resistance profiles of 28,000 clinical isolates demonstrated the presence of these NC/p1 cleavage site mutations in some clinical samples (codon 431 substitutions in 13%, codon 436 substitutions in 8%, and codon 437 substitutions in 10%). Moreover, these cleavage site substitutions were highly significantly associated with reduced susceptibility to PI in clinical isolates lacking primary protease mutations. Furthermore, we used data from a clinical trial (NARVAL, ANRS 088) to demonstrate that these NC/p1 cleavage site changes are associated with virological failure during PI therapy.ConclusionsHIV can use an alternative mechanism to become resistant to PI by changing the substrate instead of the protease. Further studies are required to determine to what extent cleavage site mutations may explain virological failure during PI therapy.

In HIV-1-infected, treatment-experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment-experienced patients is warranted.

Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.The human immunodeficiency virus type 1 (HIV-1) envelope third variable loop (V3) is the major structural element of gp120 that determines coreceptor recognition and specificity (9,15,16). Vicriviroc (VCV; Schering-Plough) and maraviroc (Selzentry; Pfizer) are allosteric noncompetitive antagonists that bind to similar sites on CCR5 and antagonize the gp120-CCR5 interaction (19). To date, data on resistance to these agents have come largely from in vitro selection studies. Phenotypically, resistance manifests as a plateau in the maximum achievable suppression of viral replication (19). This plateau, referred to as the percent maximal inhibition, correlates with viral adaptation to the use of the inhibitor-bound form of CCR5 for entry (13,21). Genotypically, VCV resistance has been associated with a variety of amino-acid-changing mutations throughout the envelope gene (env) that most often involve V3 but whose effect on drug susceptibility depends on the env backbone into which they are introduced (5). In vitro data suggest that resistance to the closely related CCR5 antagonist AD101 does not confer a significant loss of viral fitness (1, 8). In vivo resistance to the CCR5 antagonists remains poorly defined.To study the emergence of VCV resistance in vivo, we monitored subjects enrolled in ACTG 5211, a 48-week study of VCV in 118 HIV-1-infected, treatment-experienced subjects (3). Among the 90 subjects receiving VCV, we studied all 29 who experienced protocol-defined virologic failure. We amplified full-length HIV-1 env from plasma samples collected during the period from study entry through week 48. These env sequences were used to generate pseudovirions for examining VCV susceptibility and coreceptor usage in the PhenoSense entry susceptibility and Trofile assays (Monogram Biosciences), respectively (20,22). In 28 of 29 subjects analyzed, no evidence of decreased VCV susceptibility was observed (data not shown). Samples from the remaining subject demonstrated increasing VCV resistance over 28 weeks (Fig. 1). This subject, randomly assigned to receive 10 mg of VCV daily, experienced protocol-defined virologic failure at week 16 but continued VCV treatment through week 28 (see Fig. S1 in the supplemental material). Samples from 13 of the 29 subjects showed the emergence...

The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.