HIV Drug Tenofovir Alafenamide Offers Safety, Noninferiority to Abacavir

The array of streamlined drug regimens that treat HIV has been nothing short of lifesaving. As more options become available, patients and providers need to weigh the pros and cons of particular regimens based on the needs of each patient. One frequently prescribed drug, tenofovir disoproxil fumarate (TDF), can have serious adverse effects (AEs) such as kidney and liver toxicity, as well as bone softening or thinning,¹ so several years ago, scientists introduced an alternative drug, tenofovir alafenamide (TAF). According to numerous studies, TAF has a safer profile. Both of these drugs are nucleoside analog reverse-transcriptase inhibitors (NRTIs), which typically form the backbone of an HIV regimen.

Although research compared TAF with TDF, a group of scientists noted a dearth of data regarding the safety of TAF compared with abacavir (ABC), another commonly prescribed NRTI. After an online search confirmed that no such studies had been conducted, they decided to launch their own.

The double-blind study began in 2015 and continues today, run by scientists at universities and medical centers in England, France, Ireland, Spain, and the United States. Initially, it enrolled 556 individuals screened at 79 sites in Belgium, Canada, Denmark, France, Germany, Ireland, Italy, Spain, Sweden, the United Kingdom, and the United States. Those participants, described in a recent report in The Lancet HIV,² were followed from 2015 to 2016. All were HIV positive, on a 3-drug regimen including ABC plus lamivudine (3TC), and had achieved viral suppression. Roughly half (280) were randomly assigned to switch from ABC plus 3TC to TAF plus emtricitabine (FTC), and 276 continued taking ABC plus 3TC. (The third drug in the regimens was not changed.) Participants agreed to in-person visits at weeks 4, 8, 12, 24, 36, and 48, at which numerous lab tests measured the efficacy of the regimens. After 48 weeks, participants were assessed for viral suppression, measured as an RNA level less than 50 copies per mL.

During the first 48 weeks, some individuals dropped out for various reasons, including AEs, noncompliance, and death, and not all participants were assessed for all possible outcomes. Therefore, the number of participants in the outcomes data varies.

The results showed virtually no difference in virological suppression between the 2 groups—90% of 253 participants in the TAF/FTC group achieved virological suppression by week 48, compared with 93% of 248 in the ABC/3TC group. There also was almost no difference between the groups regarding changes in hip and lumbar spine bone mineral density. By week 48, spine density decreased in 8 of 213 in the TAF/FTC group compared with 8 of 217 in the ABC/3TC group, and hip density decreased in 3 of 212 versus 4 of 212, respectively.

To measure renal function, the investigators recorded the levels of creatinine clearance at week 48 and found that both groups experienced minimal issues, with a decrease of 25% or more in just 2 of 279 participants taking TAF/ FTC and 4 of 275 taking ABC/3TC. There was a slight difference in protein levels in the urine between the 2 groups right after treatment began, with 6 of 279 in the TAF/FTC group and 20 of 275 in the ABC/3TC group experiencing grade 2 proteinuria or higher. By week 48, tubular proteinuria levels between the groups were much more similar. In general, the authors reported, any AEs experienced were mild or moderate—and those did not occur often.

The results were welcome news to the study authors, who knew that both drug regimens were solid choices for many patients with HIV, but were unsure if 1 was inherently inferior to the other. “Both TAF/FTC and ABC/3TC have displayed high rates of efficacy in previous studies,” Alan Winston, MD, professor of HIV and genitourinary medicine at Imperial College London in England and the lead author of the study, told Contagion^®. “[Therefore,] our expectation was that virological efficacy would be similar in both arms as observed. Differences in safety between these 2 strategies were less well understood prior to our study, and we were pleased to observe similar safety profiles for both strategies,” he said. “The double-blind design of our study makes the safety results unbiased and more interpretable.”

DECIDING WHICH MEDICATION TO PRESCRIBE

The increased understanding of the safety and efficacy of both pairings gives patients with HIV options for treatment. “We think that TAF/FTC would be an appropriate backbone for patients in whom neither TDF nor ABC is appropriate for safety reasons, such as those at high risk [of] renal or bone toxicities or cardiovascular events, respectively,” Dr. Winston said. “Initiation of TAF/ FTC does not require HLA-B*5701 testing to rule out concerns for ABC hypersensitivity. Also, in people living with both HIV and HBV [hepatitis B virus] coinfection, TAF/FTC is an appropriate backbone.”

Should people living with HIV who take ABC plus 3TC switch to TAF plus FTC? “We think that the decision to switch from ABC/3TC to TAF/FTC should be based on the unique clinical circumstances of an individual person living with HIV,” said Dr. Winston, noting that the results point to TAF/FTC as a noninferior choice for some patients. “Our data suggest that after switching from ABC/3TC to TAF/FTC, there should be no safety concerns from a renal, bone, and lipid standpoint. In people living with HIV with high cardiovascular risk, switching from ABC/3TC may have clinical benefits, and our study reassures people living with HIV—and their physicians—that no safety concerns emerge.”

However, clinicians should not necessarily rush to prescribe TAF plus FTC—the key takeaway is that this regimen offers another option. “Today, in the HIV world, we have a whole mess of magic bullets,” Sharon Nachman, MD, chief of the Division of Pediatric Infectious Diseases at Stony Brook University in New York, who was not affiliated with the study, told Contagion^®. “Some drugs work better on some patients, some drugs work better on other patients, and some patients can no longer tolerate drugs they once did. There’s no 1 right choice for everybody. There’s a bunch of right choices.”

Although the study evaluated patients who already were doing well on ABC plus 3TC, Dr. Nachman said, plenty of other people with HIV have never taken an HIV drug and might respond differently. She recommends that a clinician test a patient for resistance to HIV drugs, do HLA-B*5701 testing to determine if the patient can take any regimen containing ABC, and then consult guidelines to learn which drugs may be off limits due to contraindications such as heart disease and high cholesterol. Other considerations include cost, insurance coverage, and how often a medication needs to be taken. Ideally, the physician and patient will be able to choose from several first-line HIV drugs.

FURTHER STUDY NEEDED TO ADDRESS LIMITATIONS

More years of study are needed to confirm this trial’s promising results. “The hope behind TAF was that it would do the trick that Truvada [TDF/FTC] did in a way that was less toxic to the kidneys,” said Payal Patel, MD, MPH, a Contagion^® editorial advisory board member and an assistant professor at the University of Michigan Health System in Ann Arbor, who was not involved in the study. “I think this is a reassuring trial [showing] that what HIV providers wanted in the drug seems to be true in the short term, though they only followed patients for less than a year. The long term is really where the question lies, and since TAF is new, we won’t know the answer to this for a while. Many people who had [adverse] effects with Truvada would not manifest issues in the first year of treatment.”

The authors agreed regarding the study’s limitations. “The sample size was not large enough, nor was the duration of follow-up long enough, to evaluate rare events such as cardiovascular events,” Dr. Winston said. “However, our objective was not to evaluate the rate of such rare events but rather to evaluate the general safety of switching from ABC/3TC to TAF/FTC, particularly from a renal and bone standpoint. [This] can be evaluated with clinical markers [such as] serum creatinine or bone mineral density.” The authors also noted in their report a few additional limitations, such as an underrepresentation of women and a disproportionate percentage of white men who have sex with men.

Ms. Saloman is a health writer with more than 20 years of experience working for both consumer- and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.

References:

1. US Department of Health and Human Services. Tenofovir disoproxil fumarate. AIDSinfo website. aidsinfo.nih.gov/drugs/290/tenofovir-disoproxil-fumarate/0/patient. Updated April 17, 2017. Accessed March 17, 2018.
2. Winston A, Post FA, DeJesus E, et al. Tenofovir alafenamide plus emtricitabine versus abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a randomised, double-blind, active-controlled, non-inferiority phase 3 trial. Lancet HIV. doi: 10.1016/S2352-3018(18)30010-9.