Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel.

Importance: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice. Objective: Based on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection. Evidence Review: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered. Findings: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor-containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential. Conclusions and Relevance: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1.

OBJECTIVES: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. DESIGN: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600 mg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). METHODS: Virologic response rates (HIV-1 RNA <40 copies/ml, Snapshot analysis) and CD4+ T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4+ T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). RESULTS: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4+ T-cell count increases were comparable across subgroups. Participants with baseline CD4+ T-cell counts less than 20 cells/µl had a mean increase of 240 cells/µl. In the safety population, more participants with baseline CD4+ T-cell counts less than 20 vs. at least 200 cells/µl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. CONCLUSION: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.

Changes in weight and BMI with first-line doravirine-based therapy.

OBJECTIVE: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz. DESIGN: Post-hoc analysis of pooled data from three randomized controlled trials. METHODS: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined. RESULTS: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not. CONCLUSION: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.

Primary Care Guidance for Persons With Human Immunodeficiency Virus: 2020 Update by the HIV Medicine Association of the Infectious Diseases Society of America.

Advances in antiretroviral therapy (ART) have made it possible for persons with human immunodeficiency virus (HIV) to live a near expected life span, without progressing to AIDS or transmitting HIV to sexual partners or infants. There is, therefore, increasing emphasis on maintaining health throughout the life span. To receive optimal medical care and achieve desired outcomes, persons with HIV must be consistently engaged in care and able to access uninterrupted treatment, including ART. Comprehensive evidence-based HIV primary care guidance is, therefore, more important than ever. Creating a patient-centered, stigma-free care environment is essential for care engagement. Barriers to care must be decreased at the societal, health system, clinic, and individual levels. As the population ages and noncommunicable diseases arise, providing comprehensive healthcare for persons with HIV becomes increasingly complex, including management of multiple comorbidities and the associated challenges of polypharmacy, while not neglecting HIV-related health concerns. Clinicians must address issues specific to persons of childbearing potential, including care during preconception and pregnancy, and to children, adolescents, and transgender and gender-diverse individuals. This guidance from an expert panel of the HIV Medicine Association of the Infectious Diseases Society of America updates previous 2013 primary care guidelines.

Safety and efficacy of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results of the phase 3 BRIGHTE study.

BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel.

Importance: Data on the use of antiretroviral drugs, including new drugs and formulations, for the treatment and prevention of HIV infection continue to guide optimal practices. Objective: To evaluate new data and incorporate them into current recommendations for initiating HIV therapy, monitoring individuals starting on therapy, changing regimens, preventing HIV infection for those at risk, and special considerations for older people with HIV. Evidence Review: New evidence was collected since the previous International Antiviral (formerly AIDS) Society-USA recommendations in 2018, including data published or presented at peer-reviewed scientific conferences through August 22, 2020. A volunteer panel of 15 experts in HIV research and patient care considered these data and updated previous recommendations. Findings: From 5316 citations about antiretroviral drugs identified, 549 were included to form the evidence basis for these recommendations. Antiretroviral therapy is recommended as soon as possible for all individuals with HIV who have detectable viremia. Most patients can start with a 3-drug regimen or now a 2-drug regimen, which includes an integrase strand transfer inhibitor. Effective options are available for patients who may be pregnant, those who have specific clinical conditions, such as kidney, liver, or cardiovascular disease, those who have opportunistic diseases, or those who have health care access issues. Recommended for the first time, a long-acting antiretroviral regimen injected once every 4 weeks for treatment or every 8 weeks pending approval by regulatory bodies and availability. For individuals at risk for HIV, preexposure prophylaxis with an oral regimen is recommended or, pending approval by regulatory bodies and availability, with a long-acting injection given every 8 weeks. Monitoring before and during therapy for effectiveness and safety is recommended. Switching therapy for virological failure is relatively rare at this time, and the recommendations for switching therapies for convenience and for other reasons are included. With the survival benefits provided by therapy, recommendations are made for older individuals with HIV. The current coronavirus disease 2019 pandemic poses particular challenges for HIV research, care, and efforts to end the HIV epidemic. Conclusion and Relevance: Advances in HIV prevention and management with antiretroviral drugs continue to improve clinical care and outcomes among individuals at risk for and with HIV.

Core Elements of a National COVID-19 Strategy: Lessons Learned from the US National HIV/AIDS Strategy.

COVID-19 has caused devastating health consequences and social inequities globally and in the United States. Unfortunately, the US has not developed a comprehensive National COVID-19 Strategy. In this editorial, we briefly review lessons about the development, structure, implementation and evaluation of the National HIV/AIDS Strategy (NHAS) for the US, and use these lessons to inform an initial proposal for a timely, dynamic, evidence-based, participatory, comprehensive and impactful National COVID-19 Strategy. Without such a strategy, the national response to the COVID-19 pandemic will remain uneven across jurisdictions and less than optimally impactful on disease-related mortality, short- and long-term morbidity, and health and social inequities.

Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial.

BACKGROUND: Tenofovir alafenamide shows high antiviral efficacy and improved renal and bone safety compared with tenofovir disoproxil fumarate when used for HIV treatment. Here, we report primary results from a blinded phase 3 study evaluating the efficacy and safety of pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir alafenamide versus emtricitabine and tenofovir disoproxil fumarate for HIV prevention. METHODS: This study is an ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial done at 94 community, public health, and hospital-associated clinics located in regions of Europe and North America, where there is a high incidence of HIV or prevalence of people living with HIV, or both. We enrolled adult cisgender men who have sex with men and transgender women who have sex with men, both with a high risk of acquiring HIV on the basis of their self-reported sexual behaviour in the past 12 weeks or their recent history (within 24 weeks of enrolment) of bacterial sexually transmitted infections. Participants with current or previous use of PrEP with emtricitabine and tenofovir disoproxil fumarate were not excluded. We used a computer-generated random allocation sequence to randomly assign (1:1) participants to receive either emtricitabine (200 mg) and tenofovir alafenamide (25 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir alafenamide group), or emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg) tablets daily, with matched placebo tablets (emtricitabine and tenofovir disoproxil fumarate group). As such, all participants were given two tablets. The trial sponsor, investigators, participants, and the study staff who provided the study drugs, assessed the outcomes, and collected the data were masked to group assignment. The primary efficacy outcome was incident HIV infection, which was assessed when all participants had completed 48 weeks of follow-up and half of all participants had completed 96 weeks of follow-up. This full analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug and had at least one post-baseline HIV test. Non-inferiority of emtricitabine and tenofovir alafenamide to emtricitabine and tenofovir disoproxil fumarate was established if the upper bound of the 95·003% CI of the HIV incidence rate ratio (IRR) was less than the prespecified non-inferiority margin of 1·62. We prespecified six secondary bone mineral density and renal biomarker safety endpoints to evaluate using the safety analysis set. This analysis set included all randomly assigned participants who had received at least one dose of the assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02842086, and is no longer recruiting. FINDINGS: Between Sept 13, 2016, and June 30, 2017, 5387 (92%) of 5857 participants were randomly assigned and received emtricitabine and tenofovir alafenamide (n=2694) or emtricitabine and tenofovir disoproxil fumarate (n=2693). At the time of the primary efficacy analysis (ie, when all participants had completed 48 weeks and 50% had completed 96 weeks) emtricitabine and tenofovir alafenamide was non-inferior to emtricitabine and tenofovir disoproxil fumarate for HIV prevention, as the upper limit of the 95% CI of the IRR, was less than the prespecified non-inferiority margin of 1·62 (IRR 0·47 [95% CI 0·19-1·15]). After 8756 person-years of follow-up, 22 participants were diagnosed with HIV, seven participants in the emtricitabine and tenofovir alafenamide group (0·16 infections per 100 person-years [95% CI 0·06-0·33]), and 15 participants in the emtricitabine and tenofovir disoproxil fumarate group (0·34 infections per 100 person-years [0·19-0·56]). Both regimens were well tolerated, with a low number of participants reporting adverse events that led to discontinuation of the study drug (36 [1%] of 2694 participants in the emtricitabine and tenofovir alafenamide group vs 49 [2%] of 2693 participants in the emtricitabine and tenofovir disoproxil fumarate group). Emtricitabine and tenofovir alafenamide was superior to emtricitabine and tenofovir disoproxil fumarate in all six prespecified bone mineral density and renal biomarker safety endpoints. INTERPRETATION: Daily emtricitabine and tenofovir alafenamide shows non-inferior efficacy to daily emtricitabine and tenofovir disoproxil fumarate for HIV prevention, and the number of adverse events for both regimens was low. Emtricitabine and tenofovir alafenamide had more favourable effects on bone mineral density and biomarkers of renal safety than emtricitabine and tenofovir disoproxil fumarate. FUNDING: Gilead Sciences.

Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir-containing regimens for initial treatment of HIV-1 infection: week 144 results from two randomised, double-blind, multicentre, phase 3, non-inferiority trials.

BACKGROUND: In the primary week-48 analyses of two phase 3 studies, coformulated bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to a dolutegravir-containing regimen in treatment-naive people with HIV. We report week-144 efficacy and safety results from these studies. METHODS: We did two double-blind, active-controlled studies (now in open-label extension phase). Study 1 randomly assigned (1:1) HLA-B*5701-negative adults without hepatitis B virus co-infection to receive coformulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg, or coformulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg once daily. Study 2 randomly assigned (1:1) adults to bictegravir, emtricitabine, and tenofovir alafenamide, or dolutegravir 50 mg given with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg. We previously reported non-inferiority at the primary endpoint. Here, we report the week-144 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 144, by US Food and Drug Administration Snapshot algorithm, analysed in the same manner. These studies were registered with ClinicalTrials.gov, NCT02607930 and NCT02607956. FINDINGS: 629 participants were randomly assigned and treated in study 1 (314 to bictegravir, emtricitabine, and tenofovir alafenamide, and 315 to dolutegravir, abacavir, and lamivudine) and 645 in study 2 (327 to bictegravir, emtricitabine, and tenofovir alafenamide, 325 to dolutegravir, emtricitabine, tenofovir alafenamide). At week 144, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to both dolutegravir-containing regimens for efficacy. In study 1, 256 (82%) of 314 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 265 (84%) of 315 in the dolutegravir, abacavir, and lamivudine group (difference -2·6%, 95% CI -8·5 to 3·4). In study 2, 262 (82%) of 320 participants had plasma HIV-1 RNA less than 50 copies per mL in the bictegravir, emtricitabine, and tenofovir alafenamide group and 273 (84%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (difference -1·9%, -7·8 to 3·9). In both studies, no participant had treatment-emergent resistance to study drugs up to week 144. All treatment regimens were well tolerated with additional exposure. Adverse events that led to study drug discontinuation were reported for no participants in the bictegravir, emtricitabine, and tenofovir alafenamide group versus five (2%) of 315 in the dolutegravir, abacavir, and lamivudine group (study 1), and six (2%) of 320 in the bictegravir, emtricitabine, and tenofovir alafenamide versus six (2%) of 325 in the dolutegravir, emtricitabine, and tenofovir alafenamide group (study 2). In study 1, statistically significant differences were observed in median changes from baseline in fasting total cholesterol (14 mg/dL vs 10 mg/dL; p=0·034), direct LDL (21 mg/dL vs 14 mg/dL; p=0·004), and total cholesterol to HDL ratio (-0·1 vs -0·3; p=0·007) at week 144; no differences were observed between groups in study 2. Weight gain was seen across all treatment groups in both studies, with no differences in median changes from baseline in weight at week 144 for either study. INTERPRETATION: These long-term data support the use of bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people with HIV, with no emergent resistance. FUNDING: Gilead Sciences.

Differential Plasma Protein Regulation and Statin Effects in Human Immunodeficiency Virus (HIV)-Infected and Non-HIV-Infected Patients Utilizing a Proteomics Approach.

BACKGROUND: People with human immunodeficiency virus (PWH) demonstrate increased atherosclerotic cardiovascular disease (ASCVD). Statins are being studied to prevent ASCVD in human immunodeficiency virus (HIV), but little is known regarding the effects of statins on a broad range of inflammatory and cardiovascular proteins in this population. METHODS: We used a highly specific discovery proteomic approach (Protein Extension Assay), to determine statin effects on over 350 plasma proteins in relevant ASCVD pathways among HIV and non-HIV groups. Responses to pitavastatin calcium were assessed in 89 PWH in the INTREPID trial and 46 non-HIV participants with features of central adiposity and insulin resistance. History of cardiovascular disease was exclusionary for both studies. RESULTS: Among participants with HIV, PCOLCE (enzymatic cleavage of type I procollagen) significantly increased after pitavastatin therapy and PLA2G7 (systemic marker of arterial inflammation) decreased. Among participants without HIV, integrin subunit alpha M (integrin adhesive function) and defensin alpha-1 (neutrophil function) increased after pitavastatin therapy and PLA2G7 decreased. At baseline, comparing participants with and without HIV, differentially expressed proteins included proteins involved in platelet and endothelial function and immune activation. CONCLUSIONS: Pitavastatin affected proteins important to platelet and endothelial function and immune activation, and effects differed to a degree within PWH and participants without HIV.

Fostemsavir in Adults with Multidrug-Resistant HIV-1 Infection.

BACKGROUND: Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS: In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS: A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.).

Once-daily Doravirine for Initial Treatment of Adults Living With Human Immunodeficiency Virus-1: An Integrated Safety Analysis.

BACKGROUND: A prespecified integrated safety analysis was conducted for 3 doravirine (DOR) double-blind trials (Phase IIb: P007 [NCT01632345]; Phase III: DRIVE-FORWARD [NCT02275780] and DRIVE-AHEAD [NCT02403674]). METHODS: DOR (100 mg) arms from these trials were compared with darunavir plus ritonavir (DRV+r) in DRIVE-FORWARD and efavirenz (EFV) in P007 and DRIVE-AHEAD. Background therapies were emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in P007; abacavir/lamivudine (ABC/3TC) or FTC/TDF in DRIVE-FORWARD; and 3TC/TDF for DOR and FTC/TDF for EFV in DRIVE-AHEAD. The primary endpoint was the proportion of participants discontinuing due to adverse events (AEs) through Week 48. RESULTS: Discontinuation rates due to AEs were similar for participants on DOR and DRV+r (2.5% vs 3.1%, respectively) and lower for those on DOR than for those on EFV (2.5% vs 6.6%, respectively). Rates of drug-related AEs for DOR, DRV+r, and EFV were 30.9%, 32.1%, and 61.4%, respectively. In an analysis of DOR versus EFV, the treatment difference for discontinuations due to AEs was -3.4%, favoring DOR (95% confidence interval -6.2 to -0.8; P = .012). Fewer participants experienced neuropsychiatric AEs on DOR than on EFV (25.0% vs 55.9%, respectively), and fewer experienced diarrhea on DOR than on DRV+r (12.4% vs 22.5%, respectively). Changes from baseline in most lipid parameters also favored DOR. CONCLUSIONS: At Week 48, DOR at 100 mg had a favorable safety profile compared with EFV or DRV+r and a favorable tolerability profile compared with EFV. CLINICAL TRIALS REGISTRATION: NCT01632345; NCT02275780 and NCT02403674.

The first 90: the gateway to prevention and care: opening slowly, but not for all.

PURPOSE OF REVIEW: Knowledge of HIV status is the gateway to HIV treatment and prevention, and optimizing this pillar is essential to bend the curve of the HIV epidemic toward zero new infections. This review will discuss the epidemiology of serostatus awareness, including disparities among key populations, and explore interventions and societal barriers. RECENT FINDINGS: Rates of serostatus awareness have improved overall; however, progress is lagging in many regions, nations and populations, with substantial disparities seen among key populations. These populations and their partners now contribute the majority of new infections, fueling the epidemic. Data support a variety of interventions that have demonstrated effectiveness in increasing new diagnoses, particularly among underserved populations. Structural and societal barriers such as stigma, discriminatory laws and policies, and social determinants of health disproportionately affect key populations, and these must be addressed to achieve equity and end the epidemic. SUMMARY: According to United Nations Programme on HIV/AIDS (UNAIDS), the pace of progress toward epidemic control has slowed. Achieving substantial increases in serostatus awareness to meet 2020 and 2030 UNAIDS goals will require attacking complex societal barriers while bringing evidence-based interventions to scale in each nation and key population. A robust advocacy effort is now needed as political will and funding wane.

Doravirine dose selection and 96-week safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1 infection in a Phase IIb trial.

BACKGROUND: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). METHODS: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive once-daily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). RESULTS: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). CONCLUSIONS: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.

Bictegravir combined with emtricitabine and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection: week 96 results from a randomised, double-blind, multicentre, phase 3, non-inferiority trial.

BACKGROUND: Bictegravir co-formulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination is recommended for treatment of HIV-1-infection and might be better tolerated than other integrase inhibitor-based single-tablet regimens, but long-term outcomes data are not available. We assessed the efficacy, safety and tolerability of bictegravir, emtricitabine, and tenofovir alafenamide compared with co-formulated dolutegravir, abacavir, and lamivudine at week 96. METHODS: This ongoing, randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial was done at 122 outpatient centres in nine countries. We enrolled adults (aged ≥18 years) living with HIV who were treatment naive and HLA-B*5701 negative, did not have hepatitis B virus infection, and had an estimated glomerular filtration rate of at least 50 mL/min. We randomly assigned participants (1:1) to receive co-formulated bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg (the bictegravir group) or co-formulated dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (the dolutegravir group), each with matching placebo, once daily for 144 weeks. Treatment allocation was masked to all participants and investigators. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. We previously reported the primary endpoint. Here, we report the week 96 secondary outcome of proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 96 by US Food and Drug Administration snapshot algorithm, with a prespecified non-inferiority margin of -12%. This study was registered with ClinicalTrials.gov, number NCT02607930. FINDINGS: Between Nov 13, 2015, and July 14, 2016, we screened 739 participants, of whom 108 were excluded and 631 enrolled and randomly assigned to bictegravir, emtricitabine, and tenofovir alafenamide (n=316) or dolutegravir, abacavir, and lamivudine (n=315). Two participants in the bictegravir group did not receive at least one dose of their assigned drug and were excluded from analyses. At week 96, bictegravir, emtricitabine, and tenofovir alafenamide was non-inferior to dolutegravir, abacavir, and lamivudine, with 276 (88%) of 314 participants in the bictegravir group versus 283 (90%) of 315 participants in the dolutegravir group achieving HIV-1 RNA less than 50 copies per mL (difference -1·9%; 95% CI -6·9 to 3·1). The most common adverse events were nausea (36 [11%] of 314 for the bictegravir group vs 76 [24%] of 315 for the dolutegravir group), diarrhoea (48 [15%] vs 50 [16%]), and headache (41 [13%] vs 51 [16%]). 36 (11%) participants in the bictegravir group versus 39 (12%) participants in the dolutegravir group had a serious adverse event. Two individuals died in the bictegravir group (recreational drug overdose and suicide, neither of which was treatment related) and none died in the dolutegravir group. No participants discontinued because of adverse events in the bictegravir group compared with five (2%) of 315 in the dolutegravir group. Study drug-related adverse events were reported for 89 (28%) participants in the bictegravir group and 127 (40%) in the dolutegravir group. INTERPRETATION: These week 96 data support bictegravir, emtricitabine, and tenofovir alafenamide as a safe, well tolerated, and durable treatment for people living with HIV-1 with no emergent resistance. FUNDING: Gilead Sciences, Inc.

Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.

BACKGROUND: People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. METHODS: In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. FINDINGS: The mean age was 49.5 ±â€¯8.0 (mean ±â€¯SD), LDL-C 155 ±â€¯25 mg/dl and CD4 count 620 ±â€¯243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = -6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = -4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = -4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r = 0.43, P < 0.0001) and change in Lp-PLA2 (r = 0.29, P < 0.0001). INTERPRETATION: Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. FUND: This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].