Recommendations for the follow-up of study participants with breakthrough HIV infections during HIV/AIDS biomedical prevention studies.

CAPRISA_2013.Objective: To facilitate collection of cumulative data on longitudinal HIV disease outcomes during HIV prevention studies by developing recommendations for follow-up of the relatively few study participants with breakthrough infections. Design: We formed a working group to compare and contrast the various approaches taken in recent HIV prevention trials, to summarize the advantages and disadvantages associated with each, and to explore the feasibility of developing protocols for the long-term follow-up of seroconverters. Methods: We reviewed study designs, objectives, and assessments in 15 interventional studies that followed HIV seroconverters. Protocol team members joined discussions of the various approaches and developed recommendations. Results: Most HIV prevention clinical trials share a core set of objectives, including the description/comparison of virological, immunological, and clinical course of HIV, and sometimes a comparison of preseroconversion and postseroconversion behavior. Long-term follow-up of seroconverters can be conducted in separate studies if the transition from parent protocol is effectively managed. Conclusion: We recommend the development of harmonized seroconverter protocols. Although specific research questions in the postseroconversion period may differ depending on prevention modality, harmonizing key evaluations would create an opportunity to ask overarching questions that inform the prevention field with respect to design and implementation of future combination prevention studies. Follow-up immediately postseroconversion should be conducted in the parent protocol before roll over into a follow-up protocol. Development of specimen repositories with ample volumes for future assays, standardized definitions of infection, diagnosis and seroconversion dates, and harmonization of study objectives and sample collections at key time points are important

Virologic Response, Early HIV-1 Decay, and Maraviroc Pharmacokinetics With the Nucleos(t)ide-Free Regimen of MaravIroc Plus Darunavir/Ritonavir in a Pilot Study

To address the need for nucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens, we explored the virologic and pharmacokinetic characteristics of maraviroc plus ritonavir-boosted darunavir in a single-arm, open-label, 96-week study

SHIV-162P3 Infection of Rhesus Macaques Given Maraviroc Gel Vaginally Does Not Involve Resistant Viruses

Maraviroc (MVC) gels are effective at protecting rhesus macaques from vaginal SHIV transmission, but breakthrough infections can occur. To determine the effects of a vaginal MVC gel on infecting SHIV populations in a macaque model, we analyzed plasma samples from three rhesus macaques that received a MVC vaginal gel (day 0) but became infected after high-dose SHIV-162P3 vaginal challenge. Two infected macaques that received a placebo gel served as controls. The infecting SHIV-162P3 stock had an overall mean genetic distance of 0.294±0.027%; limited entropy changes were noted across the envelope (gp160). No envelope mutations were observed consistently in viruses isolated from infected macaques at days 14–21, the time of first detectable viremia, nor selected at later time points, days 42–70. No statistically significant differences in MVC susceptibilities were observed between the SHIV inoculum (50% inhibitory concentration [IC50] 1.87 nM) and virus isolated from the three MVC-treated macaques (MVC IC50 1.18 nM, 1.69 nM, and 1.53 nM, respectively). Highlighter plot analyses suggested that infection was established in each MVC-treated animal by one founder virus genotype. The expected Poisson distribution of pairwise Hamming Distance frequency counts was observed and a phylogenetic analysis did not identify infections with distinct lineages from the challenge stock. These data suggest that breakthrough infections most likely result from incomplete viral inhibition and not the selection of MVC-resistant variants

Quantitative Deep Sequencing Reveals Dynamic HIV-1 Escape and Large Population Shifts during CCR5 Antagonist Therapy In Vivo

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

Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study

Background. There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)–containing ART

Leveraging Novel Integrated Single-Cell Analyses to Define HIV-1 Latency Reversal

While suppressive antiretroviral therapy can effectively limit HIV-1 replication and evolution, it leaves behind a residual pool of integrated viral genomes that persist in a state of reversible nonproductive infection, referred to as the HIV-1 reservoir. HIV-1 infection models were established to investigate HIV-1 latency and its reversal; recent work began to probe the dynamics of HIV-1 latency reversal at single-cell resolution. Signals that establish HIV-1 latency and govern its reactivation are complex and may not be completely resolved at the cellular and regulatory levels by the aggregated measurements of bulk cellular-sequencing methods. High-throughput single-cell technologies that characterize and quantify changes to the epigenome, transcriptome, and proteome continue to rapidly evolve. Combinations of single-cell techniques, in conjunction with novel computational approaches to analyze these data, were developed and provide an opportunity to improve the resolution of the heterogeneity that may exist in HIV-1 reactivation. In this review, we summarize the published single-cell HIV-1 transcriptomic work and explore how cutting-edge advances in single-cell techniques and integrative data-analysis tools may be leveraged to define the mechanisms that control the reversal of HIV-1 latency

Barriers to a cure for HIV in women.

IntroductionDistinct biological factors exist that affect the natural history of HIV and the host immune response between women and men. These differences must be addressed to permit the optimal design of effective HIV eradication strategies for much of the HIV-positive population.Methods and resultsHere, we review the literature on sex-based differences in HIV pathogenesis and natural history in tissues and anatomic compartments, HIV latency and transcriptional activity, and host immunity including the role of sex hormones. We then outline the potential effects of these differences on HIV persistence, and on the safety and efficacy of HIV eradication and curative interventions. Finally, we discuss the next steps necessary to elucidate these factors to achieve a cure for HIV, taking in account the complex ethical issues and the regulatory landscape in the hopes of stimulating further research and awareness in these areas.ConclusionsTargeted enrollment of women in clinical trials and careful sex-based analysis will be crucial to gain further insights into sex-based differences in HIV persistence and to design sex-specific approaches to HIV eradication, if required