Most people with chronic hepatitis B who are treated with tenofovir for eight years continued to maintain viral suppression, researchers reported at the American Association for the Study of Liver Diseases (AASLD) Liver Meeting earlier this month in Boston, United States. Serological response rates continued to increase over time and kidney and bone-related side-effects remained uncommon.
Antiviral therapy using nucleoside/nucleotide analogues like tenofovir (Viread), entecavir (Baraclude), adefovir (Hepsera) or lamivudine (Epivir) is the mainstay of chronic hepatitis B treatment. Although these drugs can effectively suppress hepatitis B virus (HBV) replication during therapy, they typically do not eradicate the virus and therefore may need to be taken long term. Viral suppression has been shown to improve liver fibrosis and reduce the risk of complications such as liver cancer.
Patrick Marcellin from Hôpital Beaujon in Paris and colleagues presented the latest findings from Gilead Sciences' Study 102 and Study 103, a pair of phase 3 trials evaluating tenofovir in hepatitis B 'e' antigen (HBeAg)-negative and HBeAg-positive patients, respectively.
Together, the studies enrolled more than 600 participants, most previously untreated. Nearly three-quarters were men, about 60% were white, about 30% were Asian, the mean age was approximately 40 years and 24% had liver cirrhosis. A majority of HBeAg-negative participants (64%) had HBV genotype D, with 11% having genotypes A, B and C; genotypes were more evenly distributed in the HBeAg-positive study.
Participants in both trials were randomly assigned to receive 300mg tenofovir or 10mg adefovir for 48 weeks, after which they could elect to continue on open-label tenofovir. People with continued detectable HBV DNA while on tenofovir had the option of adding emtricitabine (Emtriva) at week 72 or later. Safety and efficacy were assessed every three months, resistance testing was performed annually and DEXA bone mineral density scans were done starting at year 4 of follow-up.
About 90% of participants completed the initial blinded 48-week phase and entered the open-label phase. A total of 266 HBeAg-negative patients (71% of those initially randomised and treated) and 146 HBeAg-positive patients (55%) completed follow-up through week 384, or approximately eight years – the original planned study duration.
At 384 weeks, 75% of HBeAg-negative participants and 58% of HBeAg-positive patients had viral suppression (HBV DNA <69 IU/ml) in an intent-to-treat analysis. In an as-treated or observed analysis of those who stayed on treatment, the corresponding rates reached 99% and 98%, respectively.
Looking at serological markers, 1.1% of HBeAg-negative participants and 13% of HBeAg-positive patients experienced hepatitis B surface antigen (HBsAg) loss, while 0.7% and 10%, respectively, achieved HBsAg seroconversion – the closest indicator of a cure for hepatitis B.
Predictors of HBsAg loss in a multivariate analysis included white race/ethnicity, HBV genotype A or D, being HBV-infected for four years or less and a lower baseline HBsAg level.
In the HBeAg-positive study, 32% of patients experienced HBeAg loss and 21% achieved HBeAg seroconversion.
In a subset of 90 patients evaluated at 165 time points over eight years, there was no evidence of tenofovir resistance.
Tenofovir remained generally safe and well-tolerated throughout the course of follow-up. There were seven (1.2%) drug-related serious adverse events and 13 (2.2%) adverse events leading to treatment discontinuation during the open-label phase.
Twenty patients (3.4%) reduced their tenofovir doses or interrupted or discontinued treatment due to kidney-related side-effects including elevated creatinine (2.2%), elevated phosphate (1.7%) and reduced creatinine clearance (1.0%).
Turning to effects on bone, 2.0% and 3.1% of patients developed osteopenia (low bone mineral density) at the hip and spine, respectively; 1.2% and 1.9% progressed from osteopenia to more severe osteoporosis, but none went from normal bone density to osteoporosis over four years. Conversely, 2.0% and 4.4% improved from osteopenia to normal bone density at the hip and spine, respectively; 0.8% and 1.1% improved from osteoporosis to osteopenia. A total of 34 bone fractures occurred in 31 patients (5.3%), but these were mostly due to trauma rather than bone loss.
Over an eight-year period of treatment with tenofovir, "virologic and serologic responses were durable" and viral suppression was "consistently maintained," the researchers concluded. "Renal events were uncommon," they added, and there was "no clinically relevant bone loss over four-year follow-up."
Another study presented at the meeting found that adding pegylated interferon to tenofovir increased the likelihood of HBsAg loss in people with chronic hepatitis B.
Marcellin P et al. Long term treatment with tenofovir disoproxil fumarate for chronic hepatitis B infection is safe and well tolerated and associated with durable virologic response with no detectable resistance: 8 year results from two phase 3 trials. American Association for the Study of Liver Diseases (AASLD) Liver Meeting, Boston, abstract 229, 2014.