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Professor of Medicine
Director of Hepatology
Stanford University School of Medicine
Palo Alto, California
Paul Y. Kwo, MD, has disclosed that he has received funds for research support from AbbVie, Allergan, Assembly, Bristol-Myers Squibb, Gilead Sciences, and Intercept and consulting fees from AbbVie and Gilead Sciences.
Whereas the efficacy of direct-acting antiviral therapy has ushered in the possibility that we can eliminate hepatitis C without a vaccination, a cure for hepatitis B has been more elusive and we remain early in the journey toward a cure. Despite the availability of effective HBV therapies that can suppress viral replication, these therapies must be continued indefinitely for most patients. The AASLD 2020 meeting highlighted some of the strategies that are being pursued to improve functional cure rates, as well as provided insights into how we can further refine the use of our current treatments.
Nucleos(t)ide Analogue Therapy
Several very interesting presentations at the conference addressed whether or not patients with hepatitis B, or at least select patients with hepatitis B, receiving nucleos(t)ide analogues can stop therapy. The first was a prospective study from the Hepatitis B Network that examined whether or not a 24-week course of peginterferon (pegIFN) in combination with tenofovir disoproxil fumarate (TDF) given for a total of 192 weeks could lead to improved hepatitis B surface antigen (HBsAg) loss at Week 240. In the study, investigators randomized 201 individuals to either TDF alone or TDF plus an initial 24-week course of pegIFN alfa-2a, followed by protocolized TDF withdrawal at Week 192 (for patients without cirrhosis who were hepatitis B e antigen [HBeAg] negative by Week 144, who were anti-HBe positive by Week 180, and who had HBV DNA levels < 1000 IU/mL by Week 192). Overall, the rates of HBsAg loss were not significantly different for patients in the TDF vs TDF plus pegIFN groups at either Week 192 (1.0% vs 4.3%; P = .21) or Week 240 (4.5% vs 5.7%; P = .74). Alanine aminotransferase (ALT) flares requiring retreatment occurred in 24% and 31% of patients in the TDF vs TDF plus pegIFN groups, respectively, but occurred earlier in the pegIFN group. Taken together, this prospective study demonstrated that withdrawal of TDF can be done safely in select patients, but the addition of pegIFN for 24 weeks does not improve the rate of HBsAg loss.
The second study I would like to discuss on this topic is RETRACT-B, a retrospective cohort study of 1541 patients with chronic HBV infection who discontinued nucleos(t)ide analogue therapy at 12 centers across North America, Europe, and Asia. For inclusion, patients were required to have undetectable HBV DNA and to be HBeAg negative when stopping therapy and could not have received interferon within 12 months prior to stopping nucleos(t)ide analogue therapy. The results demonstrated that HBsAg loss increased over time with 3%, 8%, 12%, and 14% of patients achieving HBsAg loss at 1, 2, 3, and 4 years, respectively. A multivariate analysis of factors associated with HBsAg loss showed that White race (vs Asian race) was significantly predictive of HBsAg loss (HR: 5.8; 95% CI: 3.6-9.5). Indeed, at 4 years, 41% of White patients vs only 11% of Asian patients had HBsAg loss. In addition, an age of 50 years or older was significantly predictive of retreatment (HR: 1.6; 95% CI: 1.3-1.9). A total of 56% of patients experienced virologic and biochemical relapse, defined as HBV DNA ≥ 2000 IU/mL and ALT ≥ 2 x the upper limit of normal, and one third of individuals had an ALT flare.
Finally, a single-center study from Calgary examined outcomes in a real-world study of stopping long-term nucleos(t)ide analogue therapy. In this retrospective study of 1337 individuals with hepatitis B and minimal fibrosis, 47 stopped therapy. Of these, 6 had to restart therapy due to viral load rebound (HBV DNA ≥ 2000 IU/mL) or ALT flares (ALT ≥ 2 x the upper limit of normal). Only 1 of the individuals achieved HBsAg loss, but this individual also experienced ALT flares highlighting that these patients must still be followed carefully.
Overall, discontinuation of long-term nucleos(t)ide analogue therapy in select patients is a very interesting approach that needs to be explored further. The data presented at the conference suggest that the strategy is safe but that these individuals must be followed very carefully. Personally, I do not believe this approach is ready for primetime yet, and I will anxiously await further data before integrating it into my practice.
Tenofovir Alafenamide for Prevention of Vertical HBV Transmission in Mothers With High Viremia
Current guidance to prevent vertical transmission in women with high HBV viral loads (HBV DNA > 200,000 IU/mL) is to administer TDF during the third trimester. Two studies at the 2020 conference examined whether tenofovir alafenamide (TAF), which is known to have a better bone and renal safety profile vs TDF, is also safe and effective in this population. The first study was a retrospective study presented by Pan and colleagues of 71 HBeAg-positive mothers with HBV DNA > 200,000 IU/mL who received TAF during the second/third trimester. The second study presented by Zang and colleagues was a multicenter, prospective, observational study of TAF or TDF administered from gestational Weeks 24-35 to delivery in 232 mothers with HBV DNA > 200,000 IU/mL. Both trials showed similar results, which were that TAF was highly effective and well tolerated; no women discontinued therapy due to adverse events; and no adverse outcomes, such as congenital defects or malformations, were observed in the infants. These data suggest, therefore, that although our primary treatment for this population remains TDF, data supporting the efficacy and safety of TAF, both in HBV and HIV, are rapidly accumulating such that TAF may soon be added to the sanctioned regimens to prevent mother-to-child transmission in patients with high HBV viral loads.
Reduction of HBV DNA Integration Into the Human Genome With Nucleos(t)ide Analogue Therapy
One of the very interesting aspects of HBV is that it can integrate into the human genome, and this seems to be a major driver of hepatitis B–related hepatocellular carcinoma. To add to our knowledge on this topic, 2 interesting presentations at the conference examined the impact of nucleos(t)ide analogue therapy on HBV DNA integration into the human genome. Historically, we have thought of nucleos(t)ide analogue therapy as being strictly suppressive therapy, but data on viral integrations presented with these therapies may suggest otherwise.
The first study by Hsu and colleagues examined integration events from 66 patients receiving TDF and 61 patients receiving placebo from a randomized, placebo-controlled trial of TDF in patients with chronic HBV infection. Investigators were able to show a significantly lower number of viral integrations in the TDF group vs the placebo group at 3 years (P = .037). Furthermore, they found that patients receiving TDF experienced a greater decrease in the number of dysregulated protein coding genes vs placebo (P = .007), perhaps suggesting that the risk of cancer may be decreased.
The second study was a longer-term study that examined the effect of nucleos(t)ide analogue therapy on HBV DNA integration in 28 patients with chronic HBV infection for up to 10 years. Patients received a variety of nucleos(t)ide analogues and had paired liver biopsies before treatment and 1 year after treatment, and 5 patients had a third liver biopsy 10 years later. Using inverse PCR, investigators were able to show that, although HBV DNA integration was detectable in all baseline and 1-year posttreatment biopsies, 1 year of nucleos(t)ide analogue therapy significantly reduced the extent of hepatitis B integration (P = .003). Furthermore, for the 5 individuals with 10-year posttreatment biopsies, integration was even further reduced with 3 individuals having no evidence of hepatitis B integration. Taken together, these data may suggest potential advantages of treating patients with hepatitis B even earlier in the course of their disease than is currently recommended, considering that integration events could be reduced.
Finally, there were several presentations at the conference detailing the safety and efficacy of novel agents with novel mechanisms of action for the treatment of hepatitis B. A general theme of these presentations is that it is becoming possible to reduce HBsAg levels more rapidly than we have typically observed with our currently approved therapies with ≥ 1 dose of treatment with novel agents such as small interfering RNAs (siRNAs) or antisense oligonucleotides, which provides promise that we are on the pathway to improving rates of functional cure. Ultimately, we will need to combine treatment regimens with multiple mechanisms of action, and these will likely comprise both antiviral and immunomodulatory therapies.
What data were you most excited about from AASLD 2020? Please answer the polling question and share your thoughts in the discussion section.