GESTIÓN EN SALUD PÚBLICA: DESCOVY for PrEP

The DESCOVY (emtricitabine 200 mg and tenofovir alafenamide 25 mg) product labeling was updated to include a new indication in at-risk adults and adolescents weighing at least 35kg for HIV-1 pre-exposure prophylaxis (PrEP) to reduce the risk of HIV-1 infection from sex, excluding those who have receptive vaginal sex. Descovy is not indicated in individuals at risk of HIV-1 infection from receptive vaginal sex because the effectivness in this population has not been evaluated.

The safety and efficacy of Descovy for PrEP were evaluated in a randomized, double-blind multinational trial in 5,387 HIV-negative men and transgender women who have sex with men and were at risk of HIV-1 infection. The trial compared once daily Descovy to Truvada (emtricitabine, tenofovir disoproxil fumarate, 200 mg/300 mg), a daily fixed dose combination of two drugs approved in 2012 to prevent the sexual acquisition of HIV; participants were followed for 48 to 96 weeks. The primary endpoint was the rate of HIV-1 infection in each group. The trial showed that Descovy was similar to Truvada in reducing the risk of acquiring HIV-1 infection. The most common adverse reaction in individuals without HIV who were taking Descovy for PrEP was diarrhea.

Below is a summary of the product labeling changes.

BOX WARNING

RISK OF DRUG RESISTANCE WITH USE OF DESCOVY FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED EARLY HIV-1 INFECTION

DESCOVY used for HIV-1 PrEP must only be prescribed to individuals confirmed to be HIV-negative immediately prior to initiating and at least every 3 months during use. Drug-resistant HIV-1 variants have been identified with use of FTC/TDF for HIV-1 PrEP following undetected acute HIV-1 infection. Do not initiate DESCOVY for HIV-1 PrEP if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed.

DOSAGE AND ADMINISTRATION

2.2 HIV-1 Screening for Individuals Receiving DESCOVY for HIV-1 PrEP

Screen all individuals for HIV-1 infection immediately prior to initiating DESCOVY for HIV-1 PrEP and at least once every 3 months while taking DESCOVY, and upon diagnosis of any other sexually transmitted infections (STIs)

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2.4 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg

The dosage of DESCOVY for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 25 mg of TAF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg and with a creatinine clearance greater than or equal to 30 mL per minute, excluding individuals at risk from receptive vaginal sex.

CONTRAINDICATIONS

DESCOVY for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status

WARNINGS AND PRECAUTIONS

5.2 Comprehensive Management to Reduce the Risk of Sexually Transmitted Infections, Including HIV-1, and Development of HIV-1 Resistance When DESCOVY Is Used for HIV-1 PrEP

Use DESCOVY for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). The time from initiation of DESCOVY for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown.

Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network.

Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior.

Use DESCOVY to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-1 negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only DESCOVY, because DESCOVY alone does not constitute a complete regimen for HIV-1 treatment ; therefore, care should be taken to minimize the risk of initiating or continuing DESCOVY before confirming the individual is HIV-1 negative.

Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating DESCOVY for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash).
If recent (< 1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

While using DESCOVY for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs.

If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection.

Counsel HIV-1 uninfected individuals to strictly adhere to the once daily DESCOVY dosing schedule. The effectiveness of DESCOVY in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in a clinical trial of DESCOVY for HIV-1 PrEP. Some individuals, such as adolescents, may benefit from more frequent visits and counseling to support adherence

ADVERSE REACTIONS

6.1 Clinical Trials Experience

Adverse Reactions from Clinical Trial Experience in HIV-1 Uninfected Individuals Taking DESCOVY for HIV-1 PrEP

The safety profile of DESCOVY for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on a double-blind, randomized, active-controlled trial (DISCOVER) in which a total of 5,387 HIV-1 uninfected adult men and transgender women who have sex with men received DESCOVY (N=2,694) or TRUVADA (N=2,693) once daily for HIV-1 PrEP. Median duration of exposure was 86 and 87 weeks, respectively. The most common adverse reaction in participants who received DESCOVY (incidence greater than or equal to 5%, all grades) was diarrhea (5%). The proportion of participants who discontinued treatment with DESCOVY or TRUVADA due to adverse events, regardless of severity, was 1.3% and 1.8%, respectively.

Renal Laboratory Tests

The Serum Creatinine change at Week 48 was -0.01 mg/dL for DESCOVY and 0.01 mg/dL for TRUVADA.

The eGFR change at Week 48 forwas 1.8 mL/min for DESCOVY and -2.3 mL/min for TRUVADA.

At Week 48, 0.7% of participants in the DESCOVY group developed UPCR > 200 mg/g compared to 1.5% of participants in the TRUVADA group.

The long-term clinical significance of these renal laboratory changes on adverse reaction frequencies between DESCOVY and TRUVADA is not known.

Bone Mineral Density Effects

In the DISCOVER trial, mean increases from baseline to Week 48 of 0.5% at the lumbar spine (N=159) and 0.2% at the total hip (N=158) were observed in participants receiving DESCOVY, compared to mean decreases of 1.1% at the lumbar spine (N=160) and 1.0% at the total hip (N=158) in participants receiving TRUVADA. BMD declines of 5% or greater at the lumbar spine and 7% or greater at the total hip were experienced by 4% and 1% of participants, respectively, in both treatment groups at Week 48. The long-term clinical significance of these BMD changes is not known.

Serum Lipids

Please refer to the full product labeling for changes from baseline to Week 48 in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio

6.2 Postmarketing Experience

The following reactions have been identified during postapproval use of products containing TAF. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders

Angioedema, urticaria, and rash

USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

HIV-1 PrEP

Safety and effectiveness of DESCOVY for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg, excluding individuals at risk from receptive vaginal sex, is supported by data from an adequate and well-controlled trial of DESCOVY for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TAF, with EVG+COBI, in HIV-1 infected adults and pediatric subjects.

While using DESCOVY for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs. Previous studies in at-risk adolescents indicated waning adherence to a daily oral PrEP regimen once visits were switched from monthly to quarterly visits. Adolescents may therefore benefit from more frequent visits and counseling.

Safety and effectiveness of DESCOVY for HIV-1 PrEP in pediatric patients less than 35 kg have not been established.

CLINICAL PHARMACOLOGY

12.3 Pharmacokinetics

HIV status has no effect on the pharmacokinetics of FTC and TAF in adults.

HIV-1 PrEP: The pharmacokinetic data for FTC and TAF following administration of DESCOVY in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of DESCOVY for HIV-1 PrEP in this population are based on known pharmacokinetic information in HIV-infected adolescents taking FTC and TAF for treatment.

12.4 Microbiology

Prophylactic Activity in a Nonhuman Primate Model of HIV-1 Transmission

Emtricitabine and Tenofovir Alafenamide: The prophylactic activity of the combination of oral FTC and TAF was evaluated in a controlled study of macaques administered once weekly intra-rectal inoculations of chimeric simian/human immunodeficiency type 1 virus (SHIV) for up to 19 weeks (n=6). All 6 macaques that received FTC and TAF at doses resulting in PBMC exposures consistent with those achieved in humans administered a dose of FTC/TAF 200/25 mg remained SHIV uninfected.

Resistance

HIV-1 PrEP

In the DISCOVER trial of HIV-1 uninfected men and transgender women who have sex with men and who are at risk of HIV-1 infection receiving DESCOVY or TRUVADA for HIV-1 PrEP, genotyping was performed on participants found to be infected during the trial who had HIV-1 RNA ≥400 copies/mL (6 of 7 participants receiving DESCOVY and 13 of 15 participants receiving TRUVADA). The development of FTC resistance-associated substitutions, M184I and/or M184V, was observed in 4 HIV-1 infected participants in the TRUVADA group who had suspected baseline infections.

CLINICAL STUDIES

14.3 Clinical Trial Results for HIV-1 PrEP

The efficacy and safety of DESCOVY to reduce the risk of acquiring HIV-1 infection were evaluated in a randomized, double-blind multinational trial (DISCOVER) in HIV-seronegative men (N=5,262) or transgender women (N=73) who have sex with men and are at risk of HIV-1 infection, comparing once daily DESCOVY (N=2,670) to TRUVADA (FTC/TDF 200 mg/300 mg; N=2,665). Evidence of risk behavior at entry into the trial included at least one of the following: two or more unique condomless anal sex partners in the past 12 weeks or a diagnosis of rectal gonorrhea/chlamydia or syphilis in the past 24 weeks. The median age of participants was 34 years (range, 18-76); 84% were White, 9% Black/Mixed Black, 4% Asian, and 24% Hispanic/Latino. At baseline, 897 participants (17%) reported receiving TRUVADA for PrEP.

At weeks 4, 12, and every 12 weeks thereafter, all participants received local standard of care HIV-1 prevention services, including HIV-1 testing, evaluation of adherence, safety evaluations, risk-reduction counseling, condoms, management of sexually transmitted infections, and assessment of sexual behavior.

Trial participants maintained a high risk of sexual HIV-1 acquisition, with high rates of rectal gonorrhea (DESCOVY, 24%; TRUVADA, 25%), rectal chlamydia (DESCOVY, 30%; TRUVADA, 31%), and syphilis (14% in both treatment groups) during the trial.

The primary outcome was the incidence of documented HIV-1 infection per 100 person-years in participants randomized to DESCOVY and TRUVADA (with a minimum follow-up of 48 weeks and at least 50% of participants having 96 weeks of follow-up). DESCOVY was non-inferior to TRUVADA in reducing the risk of acquiring HIV-1 infection. The results were similar across the subgroups of age, race, gender identity, and baseline TRUVADA for PrEP use.

In the DISCOVER trial the person-years of follow-up was 4,370 and 4,386 for DESCOVY and TRUVADA, respectively. The number of HIV-1 infections was 7 in the DESCOVY group compared to 15 in the TRUVADA group. The rate of HI-1 infections per 100 person-years was 0.16 in the DESCOVY group compared to 0.34 in the TRUVADA group. The rate ratio and 95% confidence interval is 0.468 (0.19, 1.15)

Of the 22 participants diagnosed with HIV-1 infection in the trial, five had suspected baseline infection prior to study entry (DESCOVY, 1; TRUVADA, 4). In a case-control substudy of intracellular drug levels and estimated number of daily doses as measured by dried blood spot testing, median intracellular tenofovir diphosphate concentrations were substantially lower in participants infected with HIV-1 at the time of diagnosis compared with uninfected matched control participants. For both DESCOVY and TRUVADA, efficacy was therefore strongly correlated to adherence to daily dosing.