HIV infection has been a global public health issue since it was first discovered in the 1980s, but significant progress in treatment and prevention has been made over the intervening decades. Individuals with HIV taking antiretroviral therapy daily can reduce the risk of transmitting HIV to other individuals to effectively zero.

Another important tool for prevention of HIV infection is pre-exposure prophylaxis (PrEP), the use of HIV antiretroviral medication by persons without HIV to prevent acquisition of infection. This regimen is recommended for people at high risk of exposure to HIV through sexual contact or injection drug use. The Centers for Disease Control and Prevention (CDC) reports that PrEP reduces the risk of HIV infection through sexual contact by about 99 percent and by at least 74 percent among people who inject drugs. However, according to the CDC, four in five people who could benefit from PrEP are not prescribed the regimen.

Emtricitabine/tenofovir disoproxil fumarate (Truvada) was originally approved in 2004 for treatment of HIV-1 infection (used in combination with a third antiretroviral drug for this indication). In 2012, the FDA approved the drug for an expanded indication: pre-exposure prophylaxis in individuals without HIV at high risk of acquiring HIV infection. Serious, but rare safety concerns were observed once emtricitabine/tenofovir disoproxil fumarate (TDF) was on the market in those with and without HIV infection. Reports of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) were observed with people taking TDF portion of the drug. TDF is a prodrug that is metabolized in the plasma into active tenofovir diphosphate and then eliminated renally. Kidney toxicity is thought to be due to renal accumulation prior to elimination. Furthermore, TDF is also associated with bone toxicities observed with decrease in bone mineral density.

Candidates for PrEP are generally healthy individuals, so concerns were expressed about using TDF in the PrEP regimen. A few clinical trials were conducted to assess the renal safety. One study showed a statistically significant decrease in creatinine clearance from baseline that was resolved once the drug was stopped, but the clinical significance of this finding was unclear.

To improve the safety profile, a newer formulation of tenofovir, tenofovir alafenamide (TAF), was developed in 2015 and subsequently combined with emtricitabine (emtricitabine/tenofovir alafenamide, Descovy). TAF, considered a novel prodrug of tenofovir diphosphate with a longer half-life than TDF, is metabolized immediately after cellular uptake into active drug. This is an improvement to TDF because it decreases the effective plasma level by 90 percent and decreases accumulation in the kidneys since TAF is eliminated hepatically, while maintaining high intracellular levels of the drug. As a result, less drug is required to achieve the same effect.

The DISCOVER trial, an ongoing Phase 3 study with published 96-week results, found that emtricitabine/TAF was noninferior in efficacy to emtricitabine/TDF. TAF, however, showed a favorable safety profile (less renal toxicity) compared to TDF among persons taking PrEP. In this trial, TAF showed a statistically significant difference in median creatinine clearance and markers of proximal tubular function. It also showed less decrease in bone mineral density compared to TDF. As renal toxicity is a rare adverse event, it is hard to determine the clinical impact of using TAF over TDF.

Due to the rarity of adverse effects, it is difficult to predict if one formulation is better than the other. However, all patients should be assessed for renal function prior to initiating PrEP. Among people with renal disease, emtricitabine/TDF should not be initiated in patients with a creatinine clearance ≤ 30 mL/min, and emtricitabine/TAF should not be initiated in patients with a creatinine clearance < 60 mL/min.

Another caveat that physicians should be mindful of is that emtricitabine/TAF is currently not FDA approved for PrEP in individuals at risk of HIV-1 infection due to receptive vaginal sex because its effectiveness has not yet been studied in this patient population. This may be something that would be approved in the future pending clinical trials.

Choosing between Truvada and Descovy depends on the individual patient and clinical judgement. PrEP is one of the most effective ways to reduce the risk of HIV transmission with little adverse effects. Clinicians should not be afraid to utilize this important tool.