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People with HIV and hepatitis B co-infection can safely switch to simpler TAF single-tablet regimen
Liz Highleyman, 2015-08-18 08:50:00
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
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
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
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."
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.