key: cord-0860504-7ldtc0ji
authors: Spiegel, Hans M L
title: DISCOVER: much accomplished, but not yet for all
date: 2020-07-23
journal: Lancet
DOI: 10.1016/s0140-6736(20)31530-0
sha: 95af4cbcc713005041312ae7d1397f7ee15c9aaa
doc_id: 860504
cord_uid: 7ldtc0ji

nan

The clinical trial 3 was well conducted according to the protocol. The conclusion that daily F/TAF showed non-inferior efficacy to daily F/TDF for HIV prevention, with similarly low numbers of clinical adverse events reported in both groups, is supported by a robust analysis of the data.

The limitations of the DISCOVER trial 3 are the restricted eligibility, as cisgender women, people who inject drugs, and adolescents were excluded. Further, participation of transgender women was low (74 [1%] of 5387 participants), and only 9% of participants (n=474) were Black or mixed Black race.

On the basis of the primary efficacy data from the DISCOVER trial, 3 the US Food and Drug Administration (FDA) approved F/TAF for HIV PrEP on Oct 3, 2019, but limited its approval to men and transgender women who have sex with men, thus excluding individuals at risk of HIV-1 infection from receptive vaginal intercourse, since the effectiveness of F/TAF in this population had not been evaluated.

According to a recent UNAIDS report (March, 2020), 5 in 2018, approximately 52% of people aged 15 years or older living with HIV were female, 64% of whom were living in resource-limited settings in eastern and southern Africa. There is a clear need for affordable PrEP that can serve all key populations.

Among the strengths of F/TDF for PrEP is the proven effectiveness of this regimen in a wider range of key populations, both within the USA and internationally. Additionally, it is the only PrEP combination regimen that has been evaluated and shown to be effective for on-demand use in MSM.

As part of its PrEP postmarketing commitment to the FDA, Gilead (the company producing F/TAF) is now planning to conduct a randomised, comparative trial to evaluate the safety and efficacy of F/TAF for HIV PrEP in cisgender women and adolescent girls weighing at least 35 kg who are at risk of HIV infection. The clinical trial is expected to be completed as early as 2024.

Although much needed attention is on the effective response to the COVID-19 pandemic at present, all efforts to also end the HIV pandemic are continuing. There remains an urgent need to increase the integration of PrEP into the global HIV prevention effort, and to secure reliable access to affordable Atopic dermatitis is one of the most common chronic inflammatory skin diseases worldwide with a global annual prevalence of 3-4%. 1 Few data are available on disease activity strata, but in a 2018 multinational survey between 10% and 20% of adults with incident atopic dermatitis reported severe disease. 2 Atopic dermatitis patho physi ology is characterised by epidermal dysfunction and T-cell-driven inflammation, with increased production of inflammatory cytokines, in particular type 2 cytokines such as interleukin (IL)-4,

PrEP for all populations at risk. A well designed pharmacokinetic study of F/TDF for PrEP in pregnant adolescents and young women in Africa, completed in early 2020, showed that tenofovir diphosphate concentrations, measured in dried blood spots, were lower during pregnancy than post partum. 6 Although there is no evidence that PrEP during pregnancy is not protective, few data corre lating protection against HIV infection with tenofovir diphosphate concentrations are available for women at risk. The safe inclusion of women and pregnant women in studies of new promising PrEP combinations should be a priority. The DISCOVER trial 3 confirmed the more efficient loading of peripheral blood mononuclear cells (PBMCs) with tenofovir diphosphate by F/TAF compared with F/TDF, resulting in trough tenofovir diphosphate concen trations above the 90% effective concentration for HIV prevention in 155 (98%) of 158 participants in the F/TAF group, and 6·3 times higher steady-state tenofovir diphosphate concentrations in PBMCs than in the F/TDF group. This higher concentration could potentially result in better protection during pregnancy, if the drug combination is first shown to be safe in women.

Based on extrapolation of the data 3 to adolescents younger than 18 years and weighing at least 35 kg, supplemented by clinical trial data for F/TAF-containing HIV treatment regimens for adolescents, the FDA has approved F/TAF for PrEP in adolescents, excluding those at risk of HIV from vaginal intercourse. Further assessment of safety, acceptance, efficacy, and effectiveness of F/TAF for PrEP in this key population is urgently needed, as we continue the roll-out of adolescent supportive adherence programmes for PrEP. [7] [8] [9] Globally, we need to expedite the continued scaleup of effective, safe, and affordable PrEP, which will also include long-acting systemic and possibly topical PrEP. Generic oral F/TDF for PrEP is already available in more than 30 countries worldwide, 10 and the patent for this regimen will expire in the USA later this year. To achieve effective global HIV prevention, it is not only crucial that no one is left behind because of PrEP access barriers, but also that we strive to make the most acceptable, safest, and effective HIV PrEP available to all key populations. 

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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

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