Hepatitis C ; Can We Use the “C” Word With Confidence?

Can We Use the “C” Word With Confidence? Cure for Chronic Hepatitis C

Jennifer Y. Chen

Raymond T. Chung (Associate Editor)
published online 24 January 2011.

Article Outline
References
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Hepatitis C virus (HCV) infects 180 million people worldwide, and is a major cause of death from liver disease. Depending on the cohort studied, 55%–88% of individuals who develop acute hepatitis C will remain HCV infected, and the risk of developing cirrhosis is as high as 25% over 25 years.1 The primary treatment goal for patients with chronic hepatitis C has been achievement of a sustained virologic response (SVR), defined as an undetectable serum HCV RNA using a high sensitivity HCV RNA assay (usually less then 50 IU/mL) measured 24 weeks after the end of treatment. Current best therapy with peginterferon-alfa and ribavirin produces a 54%–56% rate of SVR,2, 3 which is associated with normalization of liver biochemical tests, improvement in liver histology, and even reduced risk of hepatocellular carcinoma.4, 5 Recent advances have led to the development of novel antiviral therapeutics, and have now brought even higher rates of SVR within reach. With direct acting agents targeting viral enzymatic pathways at our doorstep, it becomes important to revisit the relationship between achievement of SVR and long-term response. Does achievement of SVR translate to a clinical cure? Several reports have raised the possibility of persistent viral reservoirs, even among those who achieve SVR, which in theory may undermine the likelihood of a long-term cure.6 But is there evidence to suggest that reservoirs exist, and are they clinically significant? To better inform the debate, it is worth considering our current understanding of the HCV life cycle, the durability of SVR, and the relevance of viral reservoirs.
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HCV is a linear, single-strand, 9600-nucleotide RNA virus. The HCV genome contains an open reading frame that encodes a single, long polyprotein of approximately 3000 amino acids. The viral genomic RNA is plus-stranded, that is, it acts as an mRNA, and is replicated by the viral RNA-dependent RNA polymerase into a complementary RNA minus-strand, which in turn acts as a replicative intermediate for copies of new genomic plus-strand RNA. Because the virus does not replicate via a DNA intermediate, it does not integrate into the host genome. To maintain infection, uninterrupted viral replication is required. The hepatocyte is the primary target cell, but negative-strand HCV RNA has been detected in extrahepatic cells, including peripheral blood mononuclear cells (PBMCs). However, the significance of this finding is unclear.
Over the past 20 years, clinical experience has revealed that achievement of SVR is highly durable and corresponds clinically with cure. In an article published in the November issue of Gastroenterology, Swain et al7 highlighted the durability of SVR among a large cohort of subjects with chronic hepatitis C: Of 1343 subjects who achieved SVR, 1331 (99.1%) had undetectable levels of HCV RNA in serum samples after a mean follow-up of 3.9 years (range, 0.8–7.1). In addition, there was little difference in the durability of SVR according to treatment regimen: Maintenance of SVR was 98.8% among patients who received peginterferon alfa-2a monotherapy compared with 99.1% among patients who received combination therapy with peginterferon alfa-2a plus ribavirin, suggesting that durability of response is not related to composition of treatment, but rather to the accomplishment of SVR. Smaller observational studies reported a similar rate of SVR durability (96%–100%) among patients who received interferon monotherapy or interferon in combination with ribavirin.5, 8, 9 In a review of 4228 patients who achieved SVR and were enrolled in 44 studies between 1994 and 2008, Welker and Zeuzem10 reported a late recurrence of HCV RNA of only 3%. Durability of SVR was also observed among subgroups, including those coinfected with HIV. Achievement of SVR thus implies viral eradication and a cure from chronic HCV infection, and suggests that long-term virologic monitoring among patients who achieve SVR is unnecessary.

Although the rate of virologic relapse may be as low as 0.9% among patients who achieve SVR, several theories have been advanced to explain potential mechanisms of recurrence, including the presence of hepatic and extrahepatic reservoirs of HCV. In the literature, patients with “occult” infection have been described, which is defined as absence of HCV RNA in the serum (spontaneous or treatment-induced clearance) but presence of HCV RNA in liver tissue. Studies have detected the presence of HCV RNA in liver biopsy specimens as well as in PBMCs from patients who have achieved SVR, with varying results. For example, in a study of 20 patients who achieved SVR, Castillo et al6 reported detection of positive-strand HCV RNA in 19 (95%) liver biopsy specimens and negative-strand HCV RNA in 15 (79%) of the 19 samples that had positive-strand HCV RNA. Similarly, they found positive-strand HCV RNA in 13 (65%) PBMC samples and negative-strand HCV RNA in 12 (92%) of the 13 samples with positive-strand HCV RNA.6 Based on these findings, the authors concluded that HCV actively replicates in the livers and PBMCs of a high percentage of patients with clearance of serum HCV RNA, and suggested additional testing such as liver biopsies to diagnose occult HCV infection, particularly during periods of immunosuppression when patients may be at an even higher risk for virologic relapse.
A review of the literature, however, suggests that the prevalence of hepatic and extrahepatic reservoirs of HCV among patients who achieve SVR is significantly lower than that suggested by Castillo et al6; furthermore, even if they do exist, the presence of HCV RNA reservoirs seems to have little clinical relevance. In an analysis of 934 patients who achieved SVR after enrollment in 18 studies from 1994 to 2008, including that led by Castillo, the overall rate of hepatic HCV RNA detectability was 5%.10 The isolated presence of hepatic HCV RNA has not been associated with an increased risk for virologic relapse or disease progression. Indeed, several studies reported an improvement in liver histology even among those with isolated hepatic HCV RNA.6, 11 In addition, there have been no case reports of HCV transmission from a patient with isolated hepatic HCV RNA. The low prevalence of hepatic HCV RNA among patients who achieve SVR, coupled with the lack of clinical relevance, would seem to undermine the credence of viral reservoirs as a major contributor to relapsing disease.

Moreover, although the concern for increased risk of late virologic relapse during immunosuppression has been raised, a review of current data suggests that this concern has not been realized. In a review of 399 immunocompromised patients who enrolled in 13 trials and achieved SVR, which included liver and kidney transplant patients, the rate of late virologic relapse was 2%, which was comparable to the rate of 3% observed among immunocompetent patients.10 In addition, Everson et al12 studied the outcomes of patients with advanced HCV who received antiviral therapy before undergoing liver transplantation. Among those recipients who accomplished SVR before transplantation, 10 of 10 (100%) remained HCV-RNA negative ≥6 months after transplantation.12 This finding further suggests that receipt of immunosuppression does not impact virologic relapse, and argues against the relevance, if not existence, of extrahepatic reservoirs. Thus, in stark contrast with the reactivation behavior of HBV, which integrates in a highly stable form into the host nucleus, HCV should not as a rule reactivate once SVR is accomplished, because it does not integrate into the host genome.
Even as we acknowledge that late virologic relapse is a rare occurrence, it is also likely that the true rate of late relapse is even lower than the 0.9% observed.7 Included in the proportion of late relapses are those who truly clear HCV but are reinfected; and those who have a persistent, low level replication of HCV, which was undetected during treatment, and are subsequently misclassified as having achieved virologic response. With the use of more sensitive HCV RNA assays, future studies will be better able to distinguish between reinfection, low-level viremia, and true virologic relapse, although interpretation of clinical trial data will be limited by the rare number of events as well as the inherent difficulty in capturing long-term follow-up data. Perhaps it is most important to consider that with the passage of a sufficient number of years since the advent of antiviral therapy for chronic hepatitis C, we are now witnessing bona fide improvements in survival after achievement of SVR.13, 14 Thus, the clinical benefits of SVR seem to be solid.

As the next chapter of HCV treatment unfolds, it is important to define goals for treatment and clarify misconceptions regarding virologic relapse for clinicians and patients. Although it will be important to verify the durability of SVR in the protease inhibitor era, among patients who achieve SVR, virologic relapse is extremely rare. There is no evidence to suggest that they should undergo serial liver biopsies or molecular testing of PBMCs or other extrahepatic compartments to search for “occult” HCV infection; rather, they should be monitored serially for clinical complications if they have evidence of advanced fibrosis or cirrhosis. The presence of HCV RNA in liver samples and PBMCs has not been shown to correlate with the durability of SVR, and instead could represent defective virions or residual nucleic acid from prior infection. Thus, for patients who have attained the coveted SVR, irrespective of the route taken, the concept of clinical cure of infection with HCV is valid, and merits strong reinforcement to our patients.

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