By Dr. Geoffrey Modest
Thanks to Dr. Jon Pincus for his suggestions on this blog.
A brief report was just published with 2 cases of hepatitis B virus (HBV) reactivation during successful treatment of hepatitis C virus (HCV) –see Clin Infect Dis 2015;61:1304.
Details of the Cases:
- 55yo male with chronic HBV and genotype 1a HCV infections. The patient had failed 2 prior courses of interferon-based therapy and had underlying compensated cirrhosis. His HBV viral load prior to the new treatment for HCV was 2300 IU/ml and had been consistently <2000 before; ALT 62 and AST 59, bili 0.7, normal INR. Hepatitis B e antigen was negative and antibody positive. Given sofosbuvir and simeprevir for the HCV. The HCV VL (viral load) was undetectable by week 4 of treatment. By week 7 he developed symptoms of hepatitis and by week 8 had tender hepatomegaly and jaundice, with ALT 1495, AST 1792, bili 12.2 and INR 1.96. HCV VL was still undetectable, no evidence of drugs or acetaminophen to cause the hepatitis, and his HBV VL increased to 22 million. They stopped the HCV treatment, and began tenofovir/emtricitabine. By week 14, symptoms had resolved, and LFTs were back to baseline. At week 28 (20 weeks after stopping HCV drugs), his HCV and HBV VLs were both undetectable
- 57 yo male with chronic HCV genotype 1a, ALT of 54, and hepatitis B serologies of: positive hep b core antibody (HBcAb), negative hep b surface antigen (HBsAg) and antibody (HBsAb), and undetectable HBV VL. He had received interferon-based therapy 5 years before. Begun on sofosbuvir and simeprevir for HCV with undetectable HCV VL at 2 weeks, though HBV VL increased to 353. At 4 weeks, HCV VL undetectable, but HBV VL increased to 11,255. Patient remained asymptomatic and LFTs remained normal. Tenofovir was added and both HCV and HBV VLs were undetectable after 12 weeks of therapy.
So, raises a few issues:
- Treatment of HCV infection can cause reactivation of HBV, so it is important to test for HBV infection in those with HCV.
- There can be significant HBV flares which are asymptomatic, as in the second patient. Also in this case, there can be HBV flares with no detectable serum HBV VL beforehand.
- In general I usually consider that anyone with an isolated HBcAb (which I do see pretty commonly, and as in the second case above) and an undetectable HBV VL are likely to either have a false-positive HBcAb or an old infection with waning and undetectable HBsAb (or, rarely, be in the window of an acute infection with a clearing HBsAg and prior to the emergence of a detectable HBsAb, and actually have the IgM HBcAb, if you check it). This study raises the issue that even with hepatitis B serologies that appear to indicate no active infection, there is still the possibility of a dormant HBV infection which may energize with HCV treatment (as sometimes happens in those getting transplants or biologicals with the attendant immunosuppression). This phenomenon is referred to as an “occult HBV infection”, found in people who do not have detectable HBsAg in the blood, where there is HBV in the liver but sometimes with no VL found in the blood. The prevalence of this varies in studies, perhaps due to differing definitions/methodology, but seems to be more frequent in those with HCV infection (also in injection drug users and those with HIV or hepatocellular carcinoma) — see doi:10.1128/CMR.00018-11. Interestingly, an older study from 1999 found 20 people without any of the serologic markers of HBV infection had liver biopsies finding HBV sequences, more commonly in those with concommitant HCV infection (see http://www.nejm.org/doi/full/10.1056/NEJM199907013410104 ), raising the importance to check for acute HBV in anyone with acute hepatitis, even if recently checked serologies are totally normal. And those with HCV and occult HBV together had more cirrhosis (and, those without HCV but only occult HBV had more “cryptogentic liver disease”)
- The editorialists (see Clin Infect Dis 2015;61:1307) feel that the likely pathophysiology, with some experimental evidence in support, is that HCV creates a host immune state in the liver which suppresses HBV replication, and that the effective treatment of HCV disrupts this control. for clinical management, they suggest the following:
- Always check the full array of hepatitis B serologies (HBsAg, HBsAb, HBcAb), and if negative, immunize.
- Check HBV VL prior to starting HCV therapy in those who are either HBsAg or HBcAb positive.
- If the HBV VL is negative, repeat “at least every 4 weeks”, and initiate treatment if they reach the usual criteria to start HBV therapy.
- Those with evidence of immune recovery from prior HBV infection (with both HBsAb and HBcAb positive) should get one HBV VL at 4 weeks, even though their chances of reactivation are low. If the 4 week VL is negative, then no further testing is needed.
- The editorialists are less aggressive in treatment of those with asymptomatic HBV reactivation, noting that the optimal treatment is unknown (the second patient above had dramatically increasing HBV levels but was asymptomatic). I personally would argue that, in the absence of clear studies, treatment to prevent acute clinical HBV infection seems reasonable, given the real morbidity and mortality of HBV and the relatively benign nature of current HBV treatment (i.e., so I would have treated the second patient above, though the editorialists were equivocal).
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