BOSTON, MA—No resistance to tenofovir alafenamide (TAF) was detected through week 48 in adults with chronic hepatitis B virus (HBV) regardless of whether they were treatment-naïve or -experienced, results of two Phase 3 studies presented at The Liver Meeting® 2016 have shown.
Henry Lik-Yuen Chan, MD, The Chinese University of Hong Kong, Hong Kong, China, and colleagues presented Week 48 resistance analyses for the two studies, GS-US-320-0108 (HBeAg-) and GS-US-320-0110 (HBeAg+), in which 1298 patients were randomly assigned 2:1 and stratified by HBV DNA and treatment status to TAF (n=866) or tenofovir disoproxil fumarate (TDF; n=432).
Resistance mutations were evaluated in all patients at baseline. HBV pol/RT population sequencing was conducted for patients with ≥24 weeks of treatment who experienced virologic breakthrough at Week 48 or discontinued with viremia.
The investigators defined virologic breakthrough as HBV DNA ≥69 IU/mL after achieving <69 IU/mL or a ≥1.0-log10 increase from nadir confirmed at the second visit. Deep sequencing was conducted for patients with virologic breakthrough with HBV DNA >159 IU/mL. For patients with virologic breakthrough who were adherent to study drug, phenotypic analysis using recombinant HBV in HepG2 cells was performed to determine plasma drug levels.
At baseline, the majority of patients harbored wild type HBV, with no resistance mutations detected, they noted. Mutations were detected in two or three times more patients who were oral antiviral experienced, with primary mutations detected in 1% to 2% of those who were oral antiviral-naïve and 20% to 25% of patients who were oral antiviral-experienced.
Through Week 48, of the 38 patients who qualified for sequence analysis, 17 (45%) “were found to be nonadherent to study medication,” they found. This included 24 patients in the TAF arm and 14 in the TDF arm.
In the TAF arm, 15 patients had no change from baseline, four were unable to be sequenced, and five had polymorphic site substitutions. In the TDF arm, 14 subjects qualified: six had no change, four were unable to be sequenced, two had polymorphic site substitutions, and two had conserved site substitutions, rtQ67Q/H and rtQ288Q/stop.
Of the five patients in the TAF group and 4 in the TDF group who qualified for phenotypic analysis, they found that all isolates remained sensitive to tenofovir, while two patients on TDF qualified with conserved site mutations; these isolates also remained sensitive to tenofovir.
Of the 16 patients who qualified for deep sequencing, two polymorphic substitutions were detected in two patients each (rtN123D, TAF n=1 and TDF n=1; rtH124D, TAF n=2), and one adefovir resistance-associated substitution was detected in one patient (rtN236T, TDF n=1).
In that one patient, the rtN236T polymorphic substitution was detected at a level of 15% at week 48 after a period of nonadherence; however, it was not observed at baseline or in visits preceding or following week 48, and the patient re-suppressed HBV DNA by week 80.
“No substitutions detected by population or deep sequencing were associated with sustained virologic breakthrough,” they concluded.