People with HIV and hepatitis B virus (HBV) co-infection maintained HIV viral suppression, maintained or achieved HBV suppression and showed improvements in kidney and bone markers when they switched to a single-tablet regimen containing the integrase inhibitor elvitegravir and a new safer formulation of tenofovir. These findings were presented on a late-breaking poster at the Eighth International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015) last month in Vancouver.
Gilead Sciences' tenofovir disoproxil fumarate (TDF, Viread) is one of the most widely used antiretroviral drugs for HIV and is a highly effective antiviral therapy for hepatitis B. It is a component of the Truvada coformulation – used for both HIV treatment and pre-exposure prophylaxis (PrEP) – and of the single-tablet regimens Atripla, Eviplera and Stribild. TDF is generally considered safe and well tolerated, but it causes a small amount of bone loss soon after starting treatment and can lead to kidney problems in susceptible people.
Tenofovir alafenamide (TAF) is a new pro-drug that delivers the active agent, tenofovir diphosphate, more efficiently to cells. TAF produces adequate intracellular drug levels with lower doses, which means lower concentrations in the blood plasma and less drug exposure for the kidneys, bones and other organs and tissues.
Phase 3 clinical trials presented at this year's Conference on Retroviruses and Opportunistic Infections showed that TAF is as effective as TDF for previously untreated people, but has less detrimental effects on the kidneys and bones. Another phase 3 study presented at IAS 2015 showed that people who switched from a TDF-containing combo to a single-tablet regimen consisting of cobicistat-boosted elvitegravir, emtricitabine and TAF – essentially a new version of Stribild that replaces TDF with TAF – maintained undetectable viral load and saw improvements in kidney function and bone density.
Because tenofovir is active against HBV as well as HIV, it is important to test whether TAF and its co-formulations are safe and effective for people with both viruses.
Joel Gallant from the Southwest CARE Center in Santa Fe, New Mexico, and colleagues evaluated the safety and efficacy of switching from TDF-containing combination antiretroviral therapy (ART) to the elvitegravir/cobicistat/emtricitabine/TAF single-tablet regimen in HIV/HBV co-infected patients.
This open-label phase 3 trial enrolled 75 participants with HIV and chronic hepatitis B in North America and Japan. Most (92%) were men, about 70% were white, 18% were black, 10% were Asian and the median age was 51 years – older than participants in most HIV treatment trials. At baseline they had no liver cirrhosis and had normal kidney function based on estimated glomerular filtration rate (eGFR >50 ml/min).
At study entry participants were on ART with stable HIV suppression (<50 copies/ml for at least 6 months). Almost all (96%) were taking TDF and the majority were on regimens containing two or more pills a day. The median CD4 T-cell count was approximately 600 cells/mm3.
Most (86%) also had HBV suppression (<29 IU/ml). All but one were hepatitis B surface antigen (HBsAg)-positive and 42% were hepatitis B 'e' antigen (HBeAg)-positive at baseline. Also, 86% had normal alanine aminotransferase (ALT), a biomarker of liver inflammation.
At 24 weeks after switching to the TAF single-tablet regimen, 94% of participants had HIV RNA <50 copies/ml, falling to 92% at week 48. In addition 86% had HBV DNA suppression at week 24 and 92% did so at week 48. No one who started with HBV DNA <29 IU/ml had detectable levels at week 48, while seven of the ten with detectable levels at baseline had become undetectable at week 48.
Looking at HBV serological response, two of 70 initially HBsAg-positive patients (3%) experienced HBsAg loss with HBs antibody seroconversion by week 48, and two of 30 initially HBeAg-positive participants (7%) experienced HBeAg loss with seroconversion.
Three people (5%) with normal ALT at baseline had elevated levels at week 48, while four of the ten people with initially elevated levels experienced ALT normalisation. No participants met the criteria for hepatitis 'flares', which can occur when a HBV-active drug is discontinued (confirmed serum ALT >2 x baseline value and >10 x upper limit of normal). Among 60 people with pre- and post-treatment FibroTest scores (a biomarker index of liver fibrosis), 75% remained stable, 15% showed improvement and 10% worsened.
The TAF single-tablet regimen was generally safe and well tolerated. Most adverse events were mild or moderate, and the six serious adverse events were considered unrelated to the study drug. One person discontinued treatment early due to an adverse event (increased appetite and weight gain).
With regard to kidney function, eGFR improved significantly, rising from a median of 95.0 ml/min at baseline to 99.4 ml/min at week 48. Proteinuria (protein in the urine) improved after switching to TAF, though the significant decreases in retinol blinding protein-to-creatinine ratio and beta-2-microglobulin-to-creatinine ratio at week 24 were reduced by week 48.
Bone biomarkers also improved, including a significant decrease in bone pro-collagen type 1 N-terminal pro-peptide. Fasting lipid levels rose after the switch, but the total cholesterol-to-HDL ratio did not change significantly.
Through week 48, simplifying to single-tablet elvitegravir/cobicistat/emtricitabine/TAF from primarily TDF-based ART regimens maintained HIV suppression and maintained or achieved HBV suppression, with improved eGFR and bone turnover biomarkers, the researchers concluded, indicating that the coformulation "shows promise for treating HIV/HBV co-infection."
The elvitegravir/cobicistat/emtricitabine/TAF coformulation is undergoing regulatory review in Europe and the US, with the US Food and Drug Administration expected to make a decision by November. In addition, Gilead has requested approval of a dual coformulation of TAF and emtricitabine – a successor to Truvada – and is developing two other TAF-containing single-tablet HIV regimens. Stand-alone TAF is in phase 3 developed as a treatment for hepatitis B.
Gallant J et al. Efficacy and safety of switching to simpler single tablet regimen of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in HIV-1/hepatitis B co-infected adults in North America and Japan (NCT02071082): week 48 results. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2015), Vancouver, abstract WELBPE13, 2015.
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