Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study.

Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12.

Prediction of differential Gag versus Env responses to a mosaic HIV-1 vaccine regimen by HLA class I alleles.

class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of polymorphism on response to HIV vaccination may inform vaccine design. We sought associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed.

Mosaic HIV-1 vaccine regimen in southern African women (Imbokodo/HVTN 705/HPX2008): a randomised, double-blind, placebo-controlled, phase 2b trial.

Background: HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain.

Immunogenicity of 2 therapeutic mosaic HIV-1 vaccine strategies in individuals with HIV-1 on antiretroviral therapy.

Mosaic HIV-1 vaccines have been shown to elicit robust humoral and cellular immune responses in people living with HIV-1 (PLWH), that had started antiretroviral therapy (ART) during acute infection. We evaluated the safety and immunogenicity of 2 mosaic vaccine regimens in virologically suppressed individuals that had initiated ART during the chronic phase of infection, exemplifying the majority of PLWH. In this double-blind, placebo-controlled phase 1 trial (IPCAVD013/HTX1002) 25 ART-suppressed PLWH were randomized to receive Ad26.

HIV Diagnostics and Vaccines: It Takes Two to Tango.

Current serologic tests for HIV screening and confirmation of infection present challenges to the adoption of HIV vaccines. The detection of vaccine-induced HIV-1 antibodies in the absence of HIV-1 infection, referred to as vaccine-induced seropositivity/seroreactivity, confounds the interpretation of test results, causing misclassification of HIV-1 status with potential affiliated stigmatization. For HIV vaccines to be widely adopted with high community confidence and uptake, tests are needed that are agnostic to the vaccination status of tested individuals (ie, positive only for true HIV-1 infection).

Towards Novel HIV-1 Serodiagnostic Tests without Vaccine-Induced Seroreactivity.

Vaccine-induced seroreactivity/positivity (VISR/P) poses a significant and common challenge to HIV vaccine implementation, as up to 95% of vaccine recipients may be misclassified as having HIV infection by current HIV screening and confirmatory serological assays. We investigated whether internal HIV proteins could be used to overcome VISR and discovered a set of 4 antigens (gp41 endodomain, p31 integrase, p17 matrix protein, and Nef) that are recognized by antibodies produced in individuals with HIV infection but not in vaccinated individuals. When evaluated in a multiplex double-antigen bridging ELISA, this antigen combination had specificities of 98.

Poststudy Point-of-Care Oral Fluid Testing in Human Immunodeficiency Virus-1 Vaccinees.

Background: Experimental human immunodeficiency virus (HIV)-1 vaccines frequently elicit antibodies against HIV-1 that may react with commonly used HIV diagnostic tests, a phenomenon known as vaccine-induced seropositivity/seroreactivity (VISP/VISR). We sought to determine, under clinic conditions, whether a patient-controlled HIV test, OraQuick ADVANCE Rapid HIV-1/2 Antibody Test, detected HIV-1 vaccine-induced antibodies.

Methods: Plasma assessment of HIV-1 cross-reactivity was examined in end-of-study samples from 57 healthy, HIV-uninfected participants who received a candidate vaccine that has entered Phase 2B and 3 testing.

Comparison of shortened mosaic HIV-1 vaccine schedules: a randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) and a preclinical study in rhesus monkeys (NHP 17-22).

Background: Current efficacy studies of a mosaic HIV-1 prophylactic vaccine require four vaccination visits over one year, which is a complex regimen that could prove challenging for vaccine delivery at the community level, both for recipients and clinics. In this study, we evaluated the safety, tolerability, and immunogenicity of shorter, simpler regimens of trivalent Ad26.Mos.

Does bacterial vaginosis modify the effect of hormonal contraception on HIV seroconversion.

Objectives: A recent study of HIV serodiscordant couples found that depot medroxyprogesterone acetate (DMPA) and oral contraceptive pills (OCPs) were associated with increased HIV risk in the presence, but not in the absence, of bacterial vaginosis. We assessed whether bacterial vaginosis is an effect modifier of the association between hormonal contraception and HIV seroconversion in female sex workers (FSWs) in Mombasa, Kenya.

Design: Prospective cohort study.

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19).

Background: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies.

Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

Objective: VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients.

Methods: In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (⩾8 weeks) who needed to change regimen for virologic failure (viral load ⩾ 500 copies/mL) or simplification/adverse events (viral load < 50 copies/mL) received etravirine 200 mg bid with ⩾1 other active antiretroviral, excluding darunavir/ritonavir or only nucleoside/tide reverse transcriptase inhibitors.

Results: Of 211 treated patients, 73% (n = 155) had baseline viral load ⩾ 50 copies/mL and 27% (n = 56) had baseline viral load < 50 copies/mL.

Targeted screening of at-risk adults for acute HIV-1 infection in sub-Saharan Africa.

Background: Patients with acute HIV-1 infection (AHI) have elevated infectivity, but cannot be diagnosed using antibody-based testing. Approaches to screen patients for AHI are urgently needed to enable counselling and treatment to reduce onward transmission.

Methods: We pooled data from four African studies of high-risk adults that evaluated symptoms and signs compatible with acute retroviral syndrome and tested for HIV-1 at each visit.

Pharmacokinetics of Etravirine Combined with Atazanavir/Ritonavir and a Nucleoside Reverse Transcriptase Inhibitor in Antiretroviral Treatment-Experienced, HIV-1-Infected Patients.

Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between etravirine and atazanavir/ritonavir and safety and efficacy in treatment-experienced, HIV-1-infected patients. Methods.

Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults.

Introduction: In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r.

Materials And Methods: This was a 48 week, Phase IV, open-label, single-arm, multicentre study.

Pharmacokinetics of darunavir after administration of an oral suspension with low-dose ritonavir and with or without food.

This 2-part, phase 1, open-label, randomized, crossover study (NCT00752310) assessed ritonavir-boosted darunavir bioavailability (oral suspension vs. tablets), and steady-state darunavir pharmacokinetics (suspension). Part 1: 20 healthy adults randomly received 3 treatments with a ≥7-day washout between treatments; twice-daily ritonavir (100 mg, days 1-5) with darunavir (600 mg, day 3) as 2 × 300-mg tablets (fed, reference), or 6 mL of a 100-mg/mL suspension (fed or fasted, test).

Safety and immunogenicity of an adjuvanted protein therapeutic HIV-1 vaccine in subjects with HIV-1 infection: a randomised placebo-controlled study.

The human immunodeficiency virus type-1 (HIV-1) vaccine candidate F4/AS01 has previously been shown to induce potent and persistent polyfunctional CD4(+) T-cell responses in HIV-1-seronegative volunteers. This placebo-controlled study evaluated two doses of F4/AS01 1-month apart in antiretroviral treatment (ART)-experienced and ART-naïve HIV-1-infected subjects (1:1 randomisation in each cohort). Safety, HIV-1-specific CD4(+) and CD8(+) T-cell responses, absolute CD4(+) T-cell counts and HIV-1 viral load were monitored for 12 months post-vaccination.

Effect of baseline characteristics on the efficacy and safety of once-daily darunavir/ ritonavir in HIV-1-infected, treatment-naïve ARTEMIS patients at week 96.

Objectives: ARTEMIS demonstrated significantly greater efficacy of once-daily darunavir/ritonavir (DRV/r) 800/100 mg versus lopinavir/ritonavir 800/200 mg (total daily dose) in treatment-naïve, HIV-1-infected patients at week 96. The influence of baseline characteristics on efficacy and safety was analyzed in DRV/r patients.

Methods: Patients received once-daily DRV/r plus fixed-dose tenofovir/emtricitabine.

Virological characterization of patients failing darunavir/ritonavir or lopinavir/ritonavir treatment in the ARTEMIS study: 96-week analysis.

Background: In the Phase III ARTEMIS Trial, treatment-naive patients received once-daily darunavir/ritonavir (DRV/r) 800/100 mg (n = 343) or lopinavir/ritonavir (LPV/r) 800/200 mg (total daily dose; n = 346) plus fixed-dose tenofovir disoproxil fumarate/emtricitabine. The primary outcome measure was non-inferiority of DRV/r versus LPV/r (HIV type-1 [HIV-1] RNA<50 copies/ml). Here, a detailed 96-week resistance analysis is presented.

Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.

The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13.

Suboptimal adherence to darunavir/ritonavir has minimal effect on efficacy compared with lopinavir/ritonavir in treatment-naive, HIV-infected patients: 96 week ARTEMIS data.

Objectives: To examine how treatment adherence differences in ARTEMIS (96 week analysis) affected clinical outcome, and to assess factors impacting adherence.

Patients And Methods: ARTEMIS is a Phase III trial, in HIV-1-infected treatment-naive patients, comparing efficacy and safety of once-daily darunavir/ritonavir (800/100 mg) versus lopinavir/ritonavir (800/200 mg total daily dose), each with a fixed-dose background tenofovir and emtricitabine regimen. Self-reported treatment adherence was assessed using the Modified Medication Adherence Self-Report Inventory (M-MASRI).

Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis.

Objective: Present 96-week data from ongoing ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In Naive Subjects) trial.

Methods: Randomized, open-label, phase III trial of antiretroviral-naive patients with HIV-1 RNA at least 5000 copies/ml (stratified by HIV-1 RNA and CD4 cell count) receiving darunavir/ritonavir (DRV/r) 800/100 mg once daily or lopinavir/ritonavir (LPV/r) 800/200 mg total daily dose (twice daily or once daily) and fixed-dose tenofovir/emtricitabine. Primary outcome measure was noninferiority of DRV/r vs.

Improvement of vaginal health for Kenyan women at risk for acquisition of human immunodeficiency virus type 1: results of a randomized trial.

Background: Vaginal infections are common and have been associated with increased risk for acquisition of human immunodeficiency virus type 1 (HIV-1).

Methods: We conducted a randomized trial of directly observed oral treatment administered monthly to reduce vaginal infections among Kenyan women at risk for HIV-1 acquisition. A trial intervention of 2 g of metronidazole plus 150 mg of fluconazole was compared with metronidazole placebo plus fluconazole placebo.

A prospective study of risk factors for bacterial vaginosis in HIV-1-seronegative African women.

Background: Bacterial vaginosis (BV) is common and has been associated with increased HIV-1 susceptibility. The objective of this study was to identify risk factors for BV in African women at high risk for acquiring HIV-1.

Methods: We conducted a prospective study among 151 HIV-1-seronegative Kenyan female sex workers.

A decrease in albumin in early HIV type 1 infection predicts subsequent disease progression.

We investigated the association between albumin levels and HIV-1 disease progression among 78 Kenyan women followed from before infection through a median of 70 months. With HIV-1 acquisition, median albumin decreased from 38.5 g/liter to 36.