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New Tenofovir Outperforms Old Version in HIV Treatment

Efficacy and safety improve in open-label trial

A human immunodeficiency virus (HIV) drug regimen using a novel prodrug of tenofovir was more efficacious than a standard single-pill regimen using the older prodrug, new researcher has found.

After 48 weeks of treatment, patients taking the regimen with the novel prodrug, tenofovir alafenomide (TAF), were significantly more likely to have suppressed virus, according to David Shamblaw, MD, of La Playa Medical Group in San Diego. The investigational regimen also appeared to have better bone and renal safety and fewer central nervous system adverse events, according to a MedPage Today report on Shamblaw’s presentation at the Interscience Conference on Antimicrobial Agents and Chemotherapy in San Diego.

Three-drug HIV regimens involving tenofovir are widely used, but the standard prodrug, tenofovir disoproxil (TDF), results in high plasma levels of tenofovir, which leads in turn to bone and renal side effects, Shamblaw noted. TAF, he said, is a more stable molecule, so less tenofovir remains in the plasma, in theory resulting in similar efficacy with reduced risk.

The drug's maker, Gilead Sciences, is testing a single-pill combination of cobicistat-boosted elvitegravir, emtricitabine, and TAF against several TDF-containing regimens in a 96-week open-label switch study. Shamblaw presented outcomes after 48 weeks of treatment among patients who had been taking the single-pill combination of efavirenz, emtricitabine, and TDF (Atripla).

Patients who had been virologically suppressed for at least 48 weeks on Atripla were randomly assigned on a 2-1 basis to switch to the TAF-containing pill or to stay on their original TDF-containing regimen. All told, Shamblaw said, 251 patients switched and 125 stayed on Atripla.

The 48-week efficacy results showed that 96% of those who switched still had suppressed HIV, defined as a plasma viral load of fewer than 50 copies of HIV RNA per milliliter. In contrast, just 90% of those who stayed on Atripla still had suppressed HIV.

The treatment difference, he said, was 6.4 percentage points with a 95% confidence interval of 0.5 to 12.3. Since the lower end of the confidence interval was greater than zero, he and colleagues concluded that the TAF regimen was better.

The difference was largely driven by withdrawals from the Atripla arm, he reported, with seven patients lost to follow-up, withdrawal of consent, or removal from the study by an investigator, compared with just one in the TAF arm.

Analysis suggested there were no important differences in grades 2 through 4 lab abnormalities, he reported, and changes in lipid profiles during the trial were also not much different, with the exception of a slightly better improvement in total/high-density lipoprotein-cholesterol ratio for the TAF patients.

Throughout the study, he noted, patients are having their urine regularly tested for evidence of renal issues. For both proteinuria and tubular proteinuria, he reported, the TAF users had significant improvements that began by the second week of treatment and persisted.

They also had bone scans at baseline, week 24, and week 48, he said. For both spine and hip, the TAF users had increases from baseline in bone density that were significant at both later times. Those changes translated into a reduction in the proportion of patients with osteopenia in the TAF arm, with no changes in the Atripla arm, Shamblaw reported.

Overall, adverse events were similar between the arms, he said, and only 2% of patients in the TAF arm and 3% in the Atripla arm stopped therapy owing to such events. In the TAF arm, there was no "real common thread" that stood out as a reason, Shamblaw said, but the Atripla patients commonly cited some of the central nervous system side effects associated with efavirenz.

The findings suggest that TAF might be safer for patients than TDF, said Sally Hodder, MD, of West Virginia Clinical and Translational Science Institute at West Virginia University, who was not part of the study.

TDF has been a "workhorse" that is part of the majority of HIV regimens used in the U.S., she told MedPage Today. But increasing experience with the drug has shown that it has "side effects that over the long term are concerning," Hodder said, including the renal and bone effects.

"Efficacy is the most important thing," she said, and the study shows that the TAF regimen is highly efficacious. "But the advantage and the truly attractive thing going forward is that this regimen may well have a better safety profile as related to some of the long-term complications of antiretroviral therapy."

Source: MedPage Today; September 22, 2015.

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