CROI 2013: New Pro-drug Tenofovir Alafenamide Appears Equally Effective but Better Tolerated

Tenofovir alafenamide fumarate, or TAF (formerly GS-7340), a new pro-drug of the widely used NRTI tenofovir, reaches cells harboring HIV more easily than the older disoproxil fumarate (TDF), allowing for similar antiviral efficacy with smaller doses and with less adverse effect on kidneys and bones,researchers reported Tuesday at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.

Gilead Sciences' tenofovir is highly effective and a recommended component of first-line HIV treatment, but it can cause impaired kidney function and bone loss in some people. Moreover, it is not very bioavailable. TDF(Viread, also in the Truvada, Atripla, Complera, and Stribild co-formulations) is a pro-drug that delivers tenofovir diphosphate, the active form, efficiently to blood plasma.

TAF has a different structure than TDF and is metabolized by a protein known as cadapsin A, reaching higher concentrations in lymphoid cells such as CD4 T-cells. With the new formulation, adequate tenofovir concentrations in cells can be achieved using a much lower dose, which has less potential to harm kidney and bone tissue.

Andrew Zolopa from Stanford University and colleagues conducted a Phase 2 study comparing the safety and efficacy of TAF vs TDF in 170 previously untreated people with HIV. At study entry participants had normal kidney function and no known resistance to tenofovir or emtricitabine.

Almost all participants in Study 102 were men, two-thirds were white, most of the rest were black, and about 20% were of Hispanic/Latino ethnicity. The mean age was approximately 35 years. The median CD4 T-cell count was just under 400 cells/mm³ and about 20% had high baseline viral load (HIV RNA >100,000 copies/mL). None had hepatitis B or C co-infection.

The 58 participants randomly assigned to the TDF arm used the Stribild single-tablet regimen, which also contains the integrase inhibitor elvitegravir, the boosting agent cobicistat, and emtricitabine. The 112 people in other arm used a similar once-daily "quad" coformulation with TAF replacing TDF. Stribild contains 300 mg TDF while the new formulation contains just 10 mg TAF; doses of the other 3 components are the same.

Zolopa reported primary endpoint data on the proportions of participants with undetectable HIV viral load (< 50 copies/mL) at week 24 of treatment. Follow-up is continuing through week 48.

Results

• People using TAF had about 5-fold higher concentrations of tenofovir diphosphate in peripheral blood mononuclear cells and about 90% lower plasma levels relative to those taking TDF.
• In an intent-to-treat analysis at 24 weeks, 88% of participants taking the TAF coformulation achieved HIV RNA <50 copies/mL, compared with 90% of those taking Stribild -- not a statistically significant difference.
• Virological failure at week 24 was observed in 13% of TAF recipients and 10% of TDF, again not a significant difference.
• Mean CD4 cell count increases were also similar in both treatment arms, 163 vs 177 cells/mm³, respectively.
• Treatment was generally safe and well-tolerated, with similar overall drug safety profiles in both arms; most side-effects were mild-to-moderate.
• No treatment-related serious adverse events were reported in either treatment arm.
• Although 4 TAF recipients discontinued treatment prematurely due to adverse events compared with none in the TDF arm, only 1 such event (photosensitivity) was judged to be related to study drugs.
• The most common adverse events reported by at least 10% of participants included nausea (18% with the TAF coormulation vs 12% with Stribild), diarrhea (12% in both arms), fatigue (12% vs 9%), headache (10% in both arms), and upper respiratory tract infections (7% vs 12%). 
• There were no significant differences in the frequency or type of grade 3-4 laboratory abnormalities.
• Levels of total, LDL ("bad"), and HDL ("good") cholesterol rose across the board, but significantly more so in the TAF arm; triglycerides levels were similar in both arms.
• TAF recipients had significantly smaller increases in serum creatinine (0.07 vs 0.12 mg/dL)and declines in estimated glomerular filtration rate or eGFR (–4.9 vs –11.8 mL/min) at week 24.
• These changes were evident by week 2, but stabilized by week 24.
• Plasma albumin and retina binding protein levels were also lower in the TAF arm. There were no cases of proximal renal tubulopathy and no discontinuations due to kidney-related problems in either treatment arm.
• DEXA measurements performed at baseline and week 24 showed significantly smaller decreases in bone mineral density in the TAF arm compared with the TDF arm at both the spine (mean –0.8% vs –2.5%) and the hip (mean –0.3% vs –2.0%).

In this first Phase 2 study comparing 2 tenofovir pro-drugs, the TAF-containing coformulation "demonstrated comparable efficacy and a statistically significant improvement in the renal and bone safety profile at 24 weeks" relative to the TDF-containing regimen, the researchers concluded.

These results support further evaluation of the TAF coformulation in Phase 3 clinical trials, they added. Gilead announced in January that one such trial (Study 104) is now underway and another (Study 111) is expected to start soon.

"I'm not so worried about virus [developing resistance], we have to worry more about long-term consequences to our patients" of remaining on treatment, Zolopa said at a CROI press conference discussing new antiretroviral agents and approaches to therapy.

Compared with TDF, the new TAF is "safer and equally effective," he continued. "All markers studied look either equal or favorable for TAF" and the kidneys "see about 90% less tenofovir [with TAF] vs the current formulation."

SEE ALSO: CROI 2013: New Tenofovir Alafenamide Looks Easier on Kidneys [VIDEO]

3/7/13

Reference

A Zolopa, R Ortiz, P Sax^, et al. Comparative Study of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate, Each with Elvitegravir, Cobicistat, and Emtricitabine, for HIV Treatment. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, GA, March 3-6, 2013. Abstract 99LB.

Other Source

Gilead Sciences. Gilead Announces Full 24-Week Phase 2 Results for Once-Daily Single Tablet HIV Regimen Containing Novel Prodrug Tenofovir Alafenamide (TAF). Press release. March 5, 2013.