Docking Analysis and Resistance Evaluation of Clinically Relevant Mutations Associated with the HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine, Efavirenz and Etravirine

n/

Recommendations on data sharing in HIV drug resistance research

• Human immunodeficiency virus (HIV) drug resistance has implications for antiretroviral treatment strategies and for containing the HIV pandemic because the development of HIV drug resistance leads to the requirement for antiretroviral drugs that may be less effective, less well-tolerated, and more expensive than those used in first-line regimens.  • HIV drug resistance studies are designed to determine which HIV mutations are selected by antiretroviral drugs and, in turn, how these mutations affect antiretroviral drug susceptibility and response to future antiretroviral treatment regimens.  • Such studies collectively form a vital knowledge base essential for monitoring global HIV drug resistance trends, interpreting HIV genotypic tests, and updating HIV treatment guidelines.  • Although HIV drug resistance data are collected in many studies, such data are often not publicly shared, prompting the need to recommend best practices to encourage and standardize HIV drug resistance data sharing.  • In contrast to other viruses, sharing HIV sequences from phylogenetic studies of transmission dynamics requires additional precautions as HIV transmission is criminalized in many countries and regions.  • Our recommendations are designed to ensure that the data that contribute to HIV drug resistance knowledge will be available without undue hardship to those publishing HIV drug resistance studies and without risk to people living with HIV

Temporal trends of population viral suppression in the context of Universal Test and Treat: the ANRS 12249 TasP trial in rural South Africa

Introduction: The universal test-and-treat (UTT) strategy aims to maximize population viral suppression (PVS), that is, the proportion of all people living with HIV (PLHIV) on antiretroviral treatment (ART) and virally suppressed, with the goal of reducing HIV transmission at the population level. This article explores the extent to which temporal changes in PVS explain the observed lack of association between universal treatment and cumulative HIV incidence seen in the ANRS 12249 TasP trial conducted in rural South Africa. Methods: The TasP cluster-randomized trial (2012 to 2016) implemented six-monthly repeat home-based HIV counselling and testing (RHBCT) and referral of PLHIV to local HIV clinics in 2 9 11 clusters opened sequentially. ART was initiated according to national guidelines in control clusters and regardless of CD4 count in intervention clusters. We measured residency status, HIV status, and HIV care status for each participant on a daily basis. PVS was computed per cluster among all resident PLHIV (≥16, including those not in care) at cluster opening and daily thereafter. We used a mixed linear model to explore time patterns in PVS, adjusting for sociodemographic changes at the cluster level. Results: 8563 PLHIV were followed. During the course of the trial, PVS increased significantly in both arms (23.5% to 46.2% in intervention, +22.8, p < 0.001; 26.0% to 44.6% in control, +18.6, p < 0.001). That increase was similar in both arms (p = 0.514). In the final adjusted model, PVS increase was most associated with increased RHBCT and the implementation of local trial clinics (measured by time since cluster opening). Contextual changes (measured by calendar time) also contributed slightly. The effect of universal ART (trial arm) was positive but limited. Conclusions: PVS was improved significantly but similarly in both trial arms, explaining partly the null effect observed in terms of cumulative HIV incidence between arms. The PVS gains due to changes in ART-initiation guidelines alone are relatively small compared to gains obtained by strategies to maximize testing and linkage to care. The achievement of the 90-90-90 targets will not be met if the operational and implementational challenges limiting access to care and treatment, often context-specific, are not properly addressed. Clinical trial number: NCT01509508 (clinicalTrials.gov)/DOH-27-0512-3974 (South African National Clinical Trials Register)

Risk Factors for Selection of the L74I Reverse Transcriptase Mutation in Human Immunodeficiency Virus Type 1-Infected Patients

We analyzed 3,475 human immunodeficiency virus sequences and 241 therapeutic histories. The L74I mutation was carried by 7% of viruses. L74I was strongly associated with T215F, K70R, and V75M/S/T/A mutations and increased with the number of thymidine analog mutations. It seemed to be linked to the use of abacavir or efavirenz

Interruption of Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Therapy for 2 Months Has No Effect on Levels of Human Immunodeficiency Virus Type 1 in Plasma of Patients Harboring Viruses with Mutations Associated with Resistance to NNRTIs

A 2-month interruption of only nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients carrying mutations associated with resistance to NNRTIs was followed by no change in either viral load or CD4 cell counts. These data suggest that these compounds have lost all of their in vivo antiviral activity in such cases

State of the Antiretroviral Therapy in Human Immunodeficiency Virus Drug Resistance: Surveillance and Regional Gaps

This article is the second of a two-part review aiming to identify gaps in the knowledge and management of human immunodeficiency virus type 1 drug resistance (HIVDR) from global and regional perspectives. Here, we examine the policy and programmatic gaps in HIVDR surveillance, the affected populations and settings, and implications for clinical practice. The expert authorship of this review convened to identify gaps in HIVDR surveillance, with a particular focus on specific regional variations within and between Europe and Asia, to highlight directions for research and implementation. Further, evidence was gathered from a review of published studies, guidelines, and current practices. This review found that despite recent progress in the development, harmonization, and implementation of guidelines on HIVDR reporting and surveillance, programmatic, and policy gaps reflect the regional variability in HIV epidemics, clinical practice, and resources. The need for representative surveillance was identified as a key gap that has the potential to inform management policies. Monitoring must keep up with the evolution of transmission routes to adapt appropriately, and this will be further impacted by migration from areas with increasing levels of resistance. Analysis of the latest clinical data, regional practice, policy, and guidelines has identified a number of gaps in HIVDR population monitoring and surveillance. More efforts are needed to align surveillance platforms with harm reduction and patient education, particularly in vulnerable subgroups. Addressing these gaps will facilitate research into and progress in the management of HIV across a wide range of health-care settings.status: publishe

State of the Antiretroviral Therapy in Human Immunodeficiency Virus Drug Resistance: Surveillance and Regional Gaps

This article is the second of a two-part review aiming to identify gaps in the knowledge and management of human immunodeficiency virus type 1 drug resistance (HIVDR) from global and regional perspectives. Here, we examine the policy and programmatic gaps in HIVDR surveillance, the affected populations and settings, and implications for clinical practice. The expert authorship of this review convened to identify gaps in HIVDR surveillance, with a particular focus on specific regional variations within and between Europe and Asia, to highlight directions for research and implementation. Further, evidence was gathered from a review of published studies, guidelines, and current practices. This review found that despite recent progress in the development, harmonization, and implementation of guidelines on HIVDR reporting and surveillance, programmatic, and policy gaps reflect the regional variability in HIV epidemics, clinical practice, and resources. The need for representative surveillance was identified as a key gap that has the -potential to inform management policies. Monitoring must keep up with the evolution of transmission routes to adapt appropriately, and this will be further impacted by migration from areas with increasing levels of resistance. Analysis of the latest clinical data, regional practice, policy, and guidelines has identified a number of gaps in HIVDR population monitoring and surveillance. More efforts are needed to align surveillance platforms with harm reduction and patient education, particularly in vulnerable subgroups. Addressing these gaps will facilitate research into and progress in the management of HIV across a wide range of health-care settings

State of the Antiretroviral Therapy in Human Immunodeficiency Virus Drug Resistance: Science and Technology Knowledge Gap

Resistance to antiretroviral therapy (ART) threatens the efficacy of human immunodeficiency virus type 1 (HIV-1) treatment. We present a review of knowledge gaps in the science and technologies of acquired HIV-1 drug resistance (HIVDR) in an effort to facilitate research, scientific exchange, and progress in clinical management. The expert authorship of this review convened to identify data gaps that exist in the field of HIVDR and discuss their clinical implications. A subsequent literature review of trials and current practices was carried out to provide supporting evidence. Several gaps were identified across HIVDR science and technology. A summary of the major gaps is presented, with an expert discussion of their implications within the context of the wider field. Crucial to optimizing the use of ART will be improved understanding of protease inhibitors and, in particular, integrase strand transfer inhibitors (INSTI) in the context of HIVDR. Limited experience with INSTI represents an important knowledge gap in HIV resistance science. Utilizing such knowledge in a clinical setting relies on accurate testing and analysis of resistance-associated mutations. As next-generation sequencing becomes more widely available, a gap in the interpretation of data is the lack of a defined, clinically relevant threshold of minority variants. Further research will provide evidence on where such thresholds lie and how they can be most effectively applied. Expert discussion identified a series of gaps in our knowledge of HIVDR. Addressing prefsuch gaps through further research and characterization will facilitate the optimal use of ART therapies and technologies.status: publishe