The Lancet OCTOBER 03, 2019

Emtricitabine and Tenofovir Alafenamide (F/TAF) versus Emtricitabine and Tenofovir Disoproxil Fumarate (F/TDF) for HIV Pre-Exposure Prophylaxis (DISCOVER Trial)

Mayer KH, Molina JM, Thompson MA, et al.

Bottom Line

The DISCOVER trial demonstrated that F/TAF is non-inferior to F/TDF for HIV pre-exposure prophylaxis among cisgender men and transgender women who have sex with men, with a more favorable safety profile regarding bone mineral density and renal biomarkers.

Key Findings

1. F/TAF was non-inferior to F/TDF in preventing HIV infection, with 7 infections (0.16 per 100 person-years) in the F/TAF group and 15 infections (0.34 per 100 person-years) in the F/TDF group.

2. F/TAF demonstrated statistically significant superiority over F/TDF regarding bone mineral density, showing smaller decreases in hip and spine BMD compared to the F/TDF group.

3. Renal safety biomarkers (e.g., urine protein-to-creatinine ratio) favored F/TAF over F/TDF, indicating improved safety regarding potential drug-related proximal tubular injury.

4. Modest weight increases and lipid concentration elevations were more frequent in the F/TAF arm compared to the F/TDF arm, consistent with previous observations of TDF's lipid-lowering effects.

5. Both regimens were well tolerated with similarly low rates of serious adverse events, confirming their suitability for long-term daily prophylactic use.

Study Design

Design

RCT

Double-Blind

Sample

5,387

Patients

Duration

96 wk

Median

Setting

Multicenter, North America and Europe

Population Cisgender men and transgender women who have sex with men at high risk of sexually acquired HIV infection.

Intervention Daily oral emtricitabine (200 mg) and tenofovir alafenamide (25 mg).

Comparator Daily oral emtricitabine (200 mg) and tenofovir disoproxil fumarate (300 mg).

Outcome Incidence of HIV infection.

Study Limitations

• The study population was restricted to cisgender men and transgender women who have sex with men, limiting the generalizability of results to other populations at risk, such as cisgender women.

• The trial had low representation of transgender women and racial minorities, which may impact the applicability of the findings across diverse demographic groups.

• Clinical significance of the observed differences in bone and renal biomarkers remains a subject of ongoing study, particularly in older patients or those with existing comorbidities.

• The study did not evaluate efficacy for HIV prevention associated with receptive vaginal intercourse.

Clinical Significance

The DISCOVER trial supported the regulatory approval of F/TAF as a daily oral PrEP option, providing an alternative to F/TDF for specific populations. Its improved profile concerning renal and bone safety makes it a beneficial choice for patients at higher risk of osteopenia or renal impairment, though the potential for weight gain and lipid changes should be monitored in clinical practice.

Historical Context

Since the inception of PrEP, F/TDF (Truvada) has been the gold standard for HIV prevention. As chronic PrEP use increases globally, there has been a demand for safer alternatives with fewer long-term side effects on bone and kidneys. F/TAF, a novel prodrug of tenofovir, was developed to achieve higher intracellular concentrations in target cells with lower plasma exposure, thereby theoretically improving the safety profile compared to the older F/TDF formulation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pharmacological distinction between Tenofovir Disoproxil Fumarate (TDF) and Tenofovir Alafenamide (TAF) regarding their plasma stability and intracellular delivery mechanism?

Key Response

TDF is a prodrug that is rapidly converted to tenofovir in the plasma, leading to high systemic concentrations which can cause off-target effects in the kidneys and bones. In contrast, TAF is more stable in plasma and is primarily hydrolyzed within target cells (like PBMCs), allowing for a much lower total dose (25mg vs 300mg) while achieving higher intracellular concentrations of the active metabolite, tenofovir diphosphate.

Resident

In the DISCOVER trial, F/TAF was found to be non-inferior to F/TDF. Based on the safety outcomes, for which specific patient comorbidities would you prioritize F/TAF over F/TDF for PrEP?

Key Response

The trial demonstrated that F/TAF led to significantly fewer declines in bone mineral density (at both the hip and spine) and better renal safety markers (such as lower increases in serum creatinine and lower rates of proteinuria). Therefore, F/TAF should be prioritized for patients with pre-existing chronic kidney disease (eGFR < 60 mL/min), osteoporosis, or osteopenia.

Fellow

The DISCOVER trial excluded cisgender women. How do the pharmacokinetic differences in tenofovir diphosphate (TFV-DP) accumulation in cervicovaginal tissue compared to rectal tissue complicate the extrapolation of F/TAF's efficacy to women?

Key Response

Studies show that TFV-DP concentrations in vaginal and cervical tissues are significantly lower and accumulate more slowly with TAF compared to TDF. Because the DISCOVER trial only included MSM and TGW, and since rectal tissue reaches protective levels faster than vaginal tissue, the trial's non-inferiority results cannot be applied to cisgender women. Clinicians must strictly follow the FDA indication, which currently limits F/TAF PrEP to those at risk through sexual intercourse excluding receptive vaginal sex.

Attending

The DISCOVER trial reported a more favorable lipid profile for F/TDF compared to F/TAF. How should this impact the long-term cardiovascular risk assessment for older MSM starting PrEP?

Key Response

TDF has a known 'statin-like' lipid-lowering effect, whereas TAF is associated with increases in total cholesterol, LDL, and triglycerides (partially due to the lack of TDF's suppressive effect). In an aging population at risk for cardiovascular disease, the modest bone/renal benefits of TAF must be weighed against the metabolic profile, especially since F/TDF is generally safe in patients with preserved renal function.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critique the use of a 'putative placebo' analysis in the DISCOVER trial's non-inferiority design. What are the primary assumptions required to validate this statistical approach when active-controlled trials have no concurrent placebo arm?

Key Response

Because a placebo arm would be unethical given the proven efficacy of F/TDF, DISCOVER compared F/TAF to F/TDF and then used a 'putative placebo' model to ensure F/TAF would have been superior to no treatment. This assumes that the efficacy of F/TDF in the current trial population is consistent with historical TDF trials (the constancy assumption) and that the background HIV incidence in the study's geographic locations remained high enough to demonstrate a treatment effect.

Journal Editor

The DISCOVER trial reported a very low number of HIV infections (22 total). How does this 'success' of the PrEP agents potentially compromise the statistical power to detect meaningful differences in efficacy between the two arms?

Key Response

When event rates are extremely low, the 95% confidence intervals for the rate ratio become very wide. A 'non-inferiority' result in this context might be 'underpowered to find a difference' rather than 'proof of similarity.' A tough reviewer would flag that if only a few more infections had occurred in the TAF arm, the upper bound of the confidence interval might have crossed the pre-specified non-inferiority margin of 1.62, changing the trial's conclusion.

Guideline Committee

Current CDC guidelines (2021) recommend both F/TDF and F/TAF for MSM. Given the DISCOVER trial results, should F/TAF be elevated to 'preferred' status over F/TDF, or should its use remain nuanced based on cost-effectiveness and generic availability?

Key Response

While F/TAF is safer regarding biomarkers, clinical fractures and end-stage renal disease are rare on F/TDF. The committee must consider that F/TDF is available as a low-cost generic, whereas F/TAF is often more expensive. Current guidelines (CDC and WHO) emphasize F/TDF as a primary option for most patients due to long-term data and cost, reserving F/TAF for those with specific renal or bone concerns, thus balancing individual safety with public health access.

Clinical Landscape

Noteworthy Related Trials

2010

iPrEx Trial

n = 2,499 · NEJM

Tested

Daily oral TDF/FTC

Population

HIV-uninfected men or transgender women who have sex with men

Comparator

Placebo

Endpoint

Incidence of HIV infection

Key result: Daily oral TDF/FTC reduced the risk of HIV acquisition by 44% compared to placebo in the overall population.

2012

Partners PrEP Study

n = 4,758 · NEJM

Tested

Daily oral TDF or TDF/FTC

Population

HIV-uninfected adults in HIV-discordant heterosexual partnerships

Comparator

Placebo

Endpoint

Incidence of HIV infection

Key result: Both TDF and TDF/FTC significantly reduced the risk of HIV acquisition in heterosexual populations.

2015

PROUD Study

n = 544 · Lancet

Tested

Daily oral TDF/FTC

Population

Men who have sex with men at high risk of HIV infection

Comparator

Deferred PrEP initiation

Endpoint

Incidence of HIV infection

Key result: Immediate initiation of TDF/FTC was associated with an 86% relative reduction in HIV infection compared to deferred initiation.

Tailored to your role

Want this tailored to you?

Add your specialty or training stage to get role-specific takeaways and more questions.

Personalize this analysis