Medical Director of Liver Transplant
Comprehensive Transplant Center
Cedars Sinai Medical Center
Professor of Medicine
Division of Gastroenterology
Geffen UCLA School of Medicine
Los Angeles, California
Tram T. Tran, MD, has disclosed that she has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck.
At AASLD 2017 in Washington, DC, the rapid advancement of research in HBV treatment was on full display. Exciting new data were presented on both current and investigational therapies. Here, I have highlighted some of the abstracts I found most interesting.
We have excellent first-line oral therapies for patients with chronic HBV infection, including entecavir (ETV), tenofovir disoproxil fumarate (TDF), and more recently, tenofovir alafenamide (TAF). Current guidance recommends initiating treatment in patients with high viral load (HBV DNA > 20,000 IU/mL) and substantial elevations in ALT (> 2 x ULN). In studies presented at AASLD, investigators evaluated the efficacy of initiating treatment in patients with lower ALT levels. Hsu and colleagues presented preliminary results from a randomized, triple-blind study of TDF vs placebo in 161 patients with ALT levels 1-2 x ULN and HBV DNA > 2000 IU/mL (Capsule Summary). Of note, median ALT was 53 U/L, so many of these patients may have been on the high end of the range, at 2 x ULN. The primary endpoint was histological progression of liver fibrosis at 3 years. Preliminary analysis of 105 patients showed a significantly lower incidence of fibrosis progression with TDF vs placebo (22% vs 44%, respectively; P = .02), suggesting that initiating treatment sooner may be effective. Moreover, this study demonstrates that progression occurs in a considerable number of patients with mildly elevated ALT. Close follow-up and staging are important for patients in these “gray zones” to identify any degree of progression that would be an indication for treatment even if they do not meet recommended ALT criteria for initiating therapy.
Several studies at AASLD reviewed the efficacy and safety of TAF, the most recently approved oral antiviral. In an analysis of 2 randomized phase III studies of TAF vs TDF (Study 108 and Study 110), Chan and colleagues (Capsule Summary) found no resistance associated substitutions in patients receiving TAF through Week 96. Comparing patients in the TAF and TDF arms, there was no significant difference in the proportion of patients with HBV sequence changes or in the type of substitution detected, with most occurring at polymorphic positions. Thus, consistent with the similar efficacy of TAF and TDF, the resistance profile of TAF appears comparable to that of TDF. TAF safety findings were presented in a separate analysis of the open-label segments of the same phase III trials, where patients who had completed 96 weeks of treatment with TDF were switched to TAF. Pan and colleagues showed improvements in CrCl rates and bone mineral density as well as increased rates of ALT normalization with maintained virologic control after the switch (Week 144). These results were noteworthy considering that the impetus for TAF development was bone and renal safety concerns for patients receiving long-term TDF.
Among other approved agents, the large prospective, randomized REALM trial examined long-term clinical outcomes with ETV. More than 12,000 treatment-naive and treatment-experienced patients, both HBeAg-positive and HBeAg-negative, were randomized 1:1 to receive ETV or an investigator-selected non-ETV nuclueos(t)ide analogue. The mean duration of initial therapy was 86 months and 78 months, respectively. Investigators reported no significant difference in the ETV vs non-ETV arms in malignant neoplasms (including hepatocellular carcinoma [HCC] related and non-HCC related), liver-related HBV disease progression, or deaths.
Future Therapies Directed at Cure
The first goal of developing curative treatment for chronic HBV infection is developing markers predictive of cure or treatment relapse that can be used in clinical trials going forward. Several studies at AASLD evaluated such markers. One study measured serum HBV RNA in HBeAg-positive patients who received add-on peginterferon after 24 weeks of ETV therapy. At Week 72, serum HBV RNA levels were independently associated with HBeAg loss (odds ratio: 0.4; 95% CI: 0.2-0.6; P < .001), suggesting that serum HBV RNA may be a useful predictor of response to add-on peginterferon therapy. Slaets and colleagues performed a meta-analysis of HBsAg seroclearance in patients with chronic HBV infection who received nucleos(t)ide analogue therapy. The analysis of more than 90 studies found that early (24 weeks) decreases in serum HBsAg levels are associated with long-term (1 year) rates of HBsAg seroclearance. In the setting of nucleos(t)ide analogue discontinuation, high serum anti-HBc levels at the time of discontinuation were associated with a reduced risk of clinical relapse.
Therapies in Early Development
New therapies will be focused on different targets than the current nucleos(t)ide analogues, including strategies aimed at modulating the host immune response, and will likely be administered in combination with current therapies. Novel therapeutic strategies under evaluation in early-phase trials that were presented at AASLD include ARB-1467, a novel RNA interference product designed to inhibit HBV viral replication; JNJ-379, a pan-genotypic capsid assembly modulator (CAM); SB 9200, a novel oral immunomodulator targeting the host receptors retinoic acid inducible gene (RIG-I) and nucleotide oligomerization domain protein 2 (NOD2); and nivolumab, the PD-1 inhibitor approved for the treatment of several cancers. Research in these new targets are early in development and will be interesting to follow.
How do you see the studies discussed above informing the HBV treatment landscape? Please share your experiences and insights by joining the conversation in the comments box below.
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