Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial

Purpose of reviewTo review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs). Recent findingsThe greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.

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“…aStudies included are as follows: FEM-PrEP [30], iPrEX [31], TDF2 [32], Partners PrEP [33], VOICE [34], DISCOVER [15 ▪▪ ] and HPTN-083 [16 ▪▪ ].…”

Section: Resistance Risk With Nucleoside/nucleotide Reverse Transcrip...mentioning

confidence: 99%

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

Parikh

Mellors

2022

Current Opinion in HIV and AIDS

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“…Individuals have described apprehensions around being experimented on and others have expressed skepticism towards investigators’ motives and whether the interventions will truly benefit their communities [ 20 , 49 , 50 , 53 ]. In the DISCOVER trial, which demonstrated the non-inferior efficacy of emtricitabine/tenofovir alafenamide to emtricitabine/tenofovir disoproxil fumarate, the enrollment of underrepresented and disproportionately affected populations was suboptimal [ 48 , 54 ]. For example, the percentage of US participants in the study who identified as Black was only 13%, while transgender women comprised less than 1% of the total study sample [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Proactive strategies to optimize engagement of Black, Hispanic/Latinx, transgender, and nonbinary individuals in a trial of a novel agent for HIV pre-exposure prophylaxis (PrEP)

et al. 2022

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Introduction Black and Hispanic/Latinx cisgender men who have sex with men (MSM), transgender women, transgender men, and gender nonbinary (TGNB) individuals have been historically underrepresented in HIV pre-exposure prophylaxis (PrEP) clinical trials. There is an urgent need for ongoing engagement with communities that have been the most impacted by HIV and diverse representation in clinical trials. Here we describe strategic approaches undertaken in the PURPOSE 2 trial to optimize engagement of underrepresented individuals. Methods and results PURPOSE 2 is an ongoing Phase 3 trial evaluating the safety and efficacy of lenacapavir as PrEP in cisgender MSM and TGNB individuals. In PURPOSE 2, we used a multipronged approach aimed at enriching participation of underrepresented individuals. We conducted a review to identify evidence-informed recommendations from literature, engaged with stakeholders, and established the Global Community Advisory and Accountability Group (GCAG) to represent the needs of the community. Insights from stakeholders and GCAG members resulted in an expansion of the study population to include transgender men, gender nonbinary persons, and adolescents, and evaluation of population-specific outcomes. Feedback from stakeholders and GCAG members also informed investigator and site selection; these were selected based on prior experience working with persons from diverse racial, ethnic and gender identities, and estimates of local HIV incidence. Site selection was also expanded to include community-based clinics with services tailored towards Black, Hispanic/Latinx, and TGNB populations. We established a study-wide recruitment goal of 50% Black MSM and 20% Hispanic/Latinx MSM in US sites and 20% transgender women globally. Site-specific recruitment goals were also developed based on local demographics and HIV incidence. Mandatory trainings included Good Participatory Practice guidelines, gender inclusivity, and antiracism. Conclusion While further work is needed to achieve equitable representation, the strategies we describe may serve as a framework for future clinical trials. Trial registration Clinical Trial Number: NCT04925752.

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“…Due to specific intracellular activation of the prodrug in infected immune cells, circulating tenofovir concentrations are lower with TAF and a lower BMD decrease is observed with TAF than with TDF. The effect of TDF on bone metabolism is at least partly independent of the context of HIV infection since the decrease of BMD has also been reported, compared to placebo or TAF, in the context of HIV pre-exposure prophylaxis (PrEP) [ 50 , 51 ]. However, the magnitude of bone loss in these studies appears to be lower than in PLWH (0.8% to 1% BMD loss at the spine after 1 year) (Fig.…”

Section: Pathophysiology and Risk Factors Of Osteoporosis And Bone Fr...mentioning

confidence: 99%

Osteoporosis and HIV Infection

Biver

2022

Calcif Tissue Int

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Life expectancy of people living with HIV (PLWH) is now close to that of the HIV-uninfected population. As a result, age-related comorbidities, including osteoporosis, are increasing in PLWH. This narrative review describes the epidemiology of bone fragility in PLWH, changes of bone features over the course of HIV infection and their determinants, as well as the available evidence regarding the management of osteoporosis in PLWH. The risk of fracture is higher and increases about 10 years earlier compared to the general population. The classical risk factors of bone fragility are very widespread and are major determinants of bone health in this population. The majority of bone loss occurs during virus replication and during immune reconstitution at antiretroviral therapies (ART) initiation, which both increase osteoclast activity. Abnormalities in bone formation and mineralization have also been shown in histomorphometric studies in untreated PLWH. Measurement of bone mineral density (BMD) is the first line tool for assessing fracture risk in postmenopausal women, men above 50 years, and other HIV-infected patients with clinical risk factors for osteoporosis. FRAX underestimates fracture probability in PLWH. In case of indication for anti-osteoporotic drug, bisphosphonates remain the reference option. Calcium and vitamin D supplementation should be considered as ART initiation, since it may attenuate bone loss at this stage. Bone-protective ART regimens improve BMD compared to other regimens, but to a lesser extent than bisphosphonate, and without available data on their influence on the incidence of fracture.

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Long-term safety and efficacy of emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis: week 96 results from a randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 52 publications

References 33 publications

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

How could HIV-1 drug resistance impact preexposure prophylaxis for HIV prevention?

Proactive strategies to optimize engagement of Black, Hispanic/Latinx, transgender, and nonbinary individuals in a trial of a novel agent for HIV pre-exposure prophylaxis (PrEP)

Osteoporosis and HIV Infection

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