By Dr. Geoffrey Modest
There was a systematic review of discontinuation of antivirals in patients with chronic hepatitis B infection (see 10.1002/hep.28438).
Details:
- 25 studies were reviewed, with 1716 patients
- Patients with hepatitis B e Antigen (HBeAg-positive) had a durable virologic remission (VR) at 12, 24, and 36 months of 62.5%, 53.4% and 51.5%; no difference if VR defined as HBV DNA <200, <2,000, or <20,000 IU/ml
- Patients without hepatitis B e Antigen (HBeAg-negative) had a durable virologic remission at 12, 24, and 36 months of 43.7%, 31.3% and 30.1%; those with VR on therapy >24 months vs <24 months had remission in 75.0% vs 35.6%, p=0.005.
- The probability of a durable VR in patients who were initially HBeAg-positive was not associated with the duration of on-therapy VR (remaining in the 90% range after stopping the antiviral med)—i.e., these response rates were achieved in patients on meds who had HBeAg conversion and undetectable HBV viral loads followed by >=6 months of consolidation therapy in all the studies they found
- Overall, the likelihood for a durable biochemical remission (no increased ALT, etc.) was about 20% higher than that of a durable viral remission, independent of whether the person was HBeAg positive or negative.
- There are limited data on stopping meds in patients with pre-existing cirrhosis [and liver decompensation developed in 2 of 243 patients with cirrhosis (0.8%), jaundice in 6 (2.5%). retreatment was effective in all but one patient, who died of liver failure]
- The weighted probability of becoming surface antigen negative (HBsAg loss) was 2.0%
So, a few points.
- There are much better treatments for chronic hepatitis B than before, both for suppression of detectable viral loads and for lack of development of viral resistance. My experience with both entecavir and tenofovir has confirmed sustained viral suppression (and, I hope that the new formulation of tenofovir, tenofovir alafenamide, will be available soon as a solo agent, since it has much less renal or bone toxicities)
- Data are pretty consistent that using these drugs leads to improvement in liver fibrosis and can reverse cirrhosis (perhaps the most remarkable patient I’ve seen was an older Vietnamese woman with end-stage cirrhosis/portal hypertension/ascites who was discharged from the GI clinic 18 years ago to go back to Vietnam to die. The first article on 3TC (lamivudine) efficacy had just been released in NEJM (see N Engl J Med 1998; 339:61), so I decided to try it, since there seemed to be no downside. remarkably, her ascites resolved completely within a couple of months. And she lived another 5 years in Vietnam. Pretty astounding….
- Treating patients who are HBeAg positive is easier: they have a definable endpoint (becoming HBeAg negative/HBeAb positive) and seem to respond better to therapy, as confirmed in this systematic review
- Those who are HBeAg-negative are more complicated, and typically have been relegated to life-long therapy. There have been some small, intriguing studies looking at this group. I sent an email/blog on this in 2012 (see org/10.1053/j.gastro.2012.05.039), prior to the BMJ blog webpage, where 33 patients who were HBeAg-negative, were on adefovir (a more toxic cousin of tenofovir) for 4-5 years with undetectable viral loads, then the med was stopped and the patients followed 5.5 years. All had a viral rebound in the first few months and 76% had biochemical relapse. These viral rebounds and increased ALT levels were transient and reversed spontaneously even in the group of 18 patients who did not resume antiviral therapy. In fact, 15 patients who did not receive additional therapy had sustained remissions at the end of the first year, increasing to 18 after 3 years!! And by the end of follow-up, 13/18 (72%) cleared their HBsAg!!! The thought was that there was pretty consistent viral rebound early, but that the prolonged suppression of HBV (by effective treatment for 4-5 years) modulated the immunologic response so that the innate immune system was able to clear the hepatocytes that had resumed HBV replication and were able to contain the virus (similar to what happens in patients effectively treated with interferon alfa).
- The above systematic review was a difficult one to interpret, since there was pretty great heterogeneity among the studies, including no consistency in when to consider stopping meds, definition of relapse, definition of VR, consensus on when to restart therapy, etc. But, bottom line seems to be that there is a pretty good chance of sustained viral and biochemical remissions in patients with chronic hepatitis B, even those who are HBeAg-negative, after stopping meds (though in this case, one should wait at least 2 years and probably more of having a suppressed viral load, and should anticipate a short-term flare in viral and biochemical markers), though it is important to have close follow-up for at least one year. And the newer meds (entecavir, tenofovir) seem to have a pretty consistent low level of developing resistance. So there does not seem to be much of an issue of developing resistance by stopping and restarting these meds. And, for several of my patients on meds for chronic hepatitis B beginning in their youth, the prospect of not taking meds for the rest of their lives is an appealing one. Though I would be hesitant to stop meds in a patient with pre-existing cirrhosis at this point, given the limited data and the above-noted death.
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