A siege of hepatitis: Fighting a defiant virus

Journal name:
Nature Medicine
Year published:
Published online

Hepatitis C is the leading cause of liver cancer in the US and Europe, where approximately 3% of the general populations are infected. At least 20% of untreated persons will progress to cirrhosis1, and 15% of individuals with cirrhosis will develop hepatocellular carcinoma within ten years.

In the late 1990s, it was shown that, in contrast to HIV-1 infection, hepatitis C could be eradicated with antiviral therapy. Clinical trials with 12 months of interferon and ribavirin resulted in sustained virologic response—undetectable virus 24 weeks after last dose—in 50% of subjects2, 3, which correlated with viral cure, as well as a 60% decrease in overall mortality. But this regimen has incomplete and unpredictable clinical efficacy, frequent dose-related toxicities and treatment costs of approximately $35,000 per year—a source of frustration for patients and providers4.

A consequence of interferon and ribavirin therapy for hepatitis C was the recognition that the replication dynamics of hepatitis C are rapid. Like in HIV-1 infection, in hepatitis C infection turnover of viruses is high—free viral half-life is from 11 to 19 h5—and chronic infection is maintained by rapid viral replication in the liver and other anatomic reservoirs of infection6. Hepatitis C, however, replicates via an RNA-dependent RNA polymerase in the cytosol, and, unlike HIV-1, lacks a stable reservoir within infected cells. Intracellular HCV RNA particles are fragile and short lived, and rapid replenishment is needed to sustain infection. The RNA-dependent polymerase is error prone and lacks a proofreading function, creating a diverse array of variants that allow for immune evasion.

The rapid kinetics of hepatitis C infection, and the success of targeted agents for HIV-1 infection, spurred the pharmaceutical industry to develop small-molecule inhibitors of viral replication. There are numerous compounds in phase 2 or phase 3 trials, including NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase (RdRp) nucleoside analogs, RdRp nonnucleoside inhibitors and an NS5A assembly protein inhibitor.

Telaprevir, an NS3/4A protease inhibitor, showed promise in two clinical trials: approximately 65% of treatment-naive, genotype 1 hepatitis C–infected patients who received only 24 weeks of pegylated interferon and ribavirin therapy with 12 weeks of telepravir treatment achieved a sustained virologic response, compared to 43% in the placebo arms7, 8. Notably, viral sequencing revealed that more than half of the therapeutic failures were associated with mutations in the protease-encoding gene that are known to confer drug resistance7, 8. These findings emphasize the formidable therapeutic hurdles that prevent elimination of highly replicating RNA viruses.

Recent inroads toward understanding antiviral resistance have been made by Rong et al.9, who showed that hepatitis C resistance occurs due to preexisting mutations in circulating viruses. Using probability and dynamic mathematical models, in combination with data from four previously untreated individuals who received 14 days of telaprevir alone, the authors considered two genotypic variants that confer resistance to protease inhibitors and estimated the number of single- (8.7 × 1010), double- (4.2 × 109) and triple- (1.3 × 108) mutant viruses among the estimated 1 × 1012 circulating HCV virions in a typical chronically infected person9. Their data suggest that every possible single- or double-mutant virus was likely to have existed before therapy, and one additional mutation may have occurred after 24 h of treatment9.

Viral load decreases by 99.97% within two days of therapy but often rebounds within seven to ten days during telaprevir monotherapy10. Preexisting mutant viruses avoid killing and represent 50% of circulating viruses after five to six days of antiviral initiation (Fig. 1)9. These surviving virions expand, accrue further mutations and rapidly predominate. The high error rate of hepatitis C RdRp11 in combination with the high burden of replicating virus leads to high numbers of new mutants each day. Therefore, hepatitis C continually explores a large genetic space to select for resistant variants with the highest replicative and immune evasion capabilities. This plasticity allows the virus to escape antiviral agents in a mechanism similar to that of HIV-1.

Figure 1: Drug resistance dynamics during hepatitis C monotherapy.
Drug resistance dynamics during hepatitis C monotherapy.

Before monotherapy with a protease inhibitor, drug-resistant mutant viruses (red) represent a minority among drug-susceptible viruses. At days 5–6 after therapy, drug-susceptible viral levels decrease substantially, whereas resistant viruses expand only slightly but become the predominant viral form. At day 10, drug-resistant clones reexpand.

The major implication of this study is that monotherapy results in resistance and treatment failure, underscoring a lesson learned from HIV-1, hepatitis B, influenza A and tuberculosis trials12, 13. With the availability of precisely targeted agents, interferon and ribavirin may eventually be suboptimal backbones to multidrug therapy. Yet these agents are currently necessary, given the incidence of resistance to protease inhibitors when these are used alone.

Ultimately, nucleoside analog RNA polymerase inhibitors, which seem to have a higher barrier to resistance, may be key agents in multiagent trials14. Another potential interim solution may be to initiate interferon and ribavirin before protease inhibitor therapy to decrease circulating virus concentrations and to limit the probability of preexisting mutations.

A key component of therapeutic evaluation will be early detection of resistant viruses, but standard population sequencing is an ineffective means to detect low-frequency variants with resistance. Studies will also need to assess whether drug resistance is archived and whether transmission of resistant virus occurs.

Additionally, certain individuals may have a genetic predisposition to poor treatment outcomes, such as those with polymorphisms in IL28B (encoding interleukin-28B) that correlate with low rates of sustained virologic response after treatment with interferon, ribavirin15 and telaprevir. This issue may be of particular relevance to African American individuals. Similar genetic relationships may exist for newer agents, suggesting the need for personalized regimens. Finally, given the high price of new agents, cost-effectiveness models will be necessary to compare different strategies.

Within the next five years, the management of hepatitis C will change dramatically, ushering in a historic period at a time of great urgency for this globally important infection. We have arrived at a crucial juncture in the epidemic. Ill-advised trial designs that do not prioritize avoidance of resistance could lead to inadequate therapies. Moreover, insensitive screening assays for resistant strains could leave clinicians stymied when individuals fail first-line treatment. If these key concepts are recognized, then hepatitis C–infected patients may soon benefit from a broad array of effective therapies.


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  1. Joshua T. Schiffer, John Scott and Lawrence Corey are in the Department of Medicine, University of Washington, Seattle, Washington, USA.

  2. Joshua T. Schiffer and Lawrence Corey are also in the Vaccine and Infectious Diseases Division, The Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Competing financial interests

J.S. has received research funding from Genentech, Tibotec and Anadys. He serves on the Speaker’s Bureau for Genentech, Gilead, Merck and Vertex. He has served on advisory boards in the last year for Vertex.

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