The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.


Semin Liver Dis. 2011;31(4):399-409. 

In This Article

New Concepts of DAA Use

Several new concepts arose with the development of DAAs to treat hepatitis C. Because DAAs are true antivirals that target critical steps of HCV replication, similar to antiretrovirals inhibiting HIV, selection of resistant mutants is inevitable with monotherapy.[1] The HCV replication cycle and the different sites at which DAAs can interfere with HCV replication are thoroughly reviewed elsewhere.[2,3] RNA viruses like HCV inherently possess an error-prone RNA-dependent RNA polymerase that lacks the proofreading function. As a result, and with the rapid HCV viral turnover (up to 1012 virions produced each day), it is estimated that one mutation is contained in every single genome copied.[4] There are thus many variant populations coexisting in a given individual, the patient's quasispecies. Most of these variant populations are susceptible to DAAs because wild-type viruses usually have the advantage of fitness, but some of these preexisting variants are drug-resistant at baseline.[5,6] When selection pressure is applied with the use of a DAA in monotherapy, these preexistent variants are rapidly selected and can become the predominant circulating population, potentially leading to treatment failure.[7–9] Resistance profiles differ between drug classes. Some drugs have different resistance mutations within the same class. A new concept that emerged as part of PI development is the difference in resistance profile between genotype 1a and genotype 1b. For example, the R155K substitution typically emerges when HCV genotype 1a is exposed to telaprevir.[8] Only one nucleotide change is required for the 1a subtype to develop resistance whereas two nucleotide changes must occur in genotype 1b.[10] This is not specific to PI use and has been described with other drug classes, for example, nonnucleoside polymerase inhibitors.[10] As a result, antiviral responses can vary between HCV genotype 1 subtypes during treatment with DAAs, while response was similar when treated with pegIFN and RBV dual therapy.

Response-guided therapy (RGT) refers to the use of on-treatment virologic response to tailor the duration of therapy for an individual patient.[11] This concept was used with pegIFN/RBV treatment but really emerged in the era of DAAs. Both telaprevir and boceprevir can be used for a shorter treatment duration in patients who achieve HCV RNA undetectability early on in treatment.[12,13] This is RGT. In the telaprevir studies, extended rapid virologic response (eRVR) was used to determine if RGT could be used.[12,14] The definition of eRVR was HCV RNA <10 IU/mL at week 4 and 12. In the boceprevir studies, RGT was used when HCV RNA was less than 9.3 IU/mL at week 8 through week 24.[13] Most phase II and III clinical trials of DAAs are exploring this possibility of shortening treatment duration in patients who achieve eRVR.

The concept of lead-in is also widely discussed in the DAA literature. Lead-in is the use of pegIFN and RBV for a short duration preceding the initiation of DAA. Lead-in was initially introduced in an attempt to lower HCV RNA levels before PI exposure to minimize the emergence of resistance. Also, by achieving proper pegIFN and RBV drug levels before the initiation of the DAA, it would avoid functional monotherapy. Studies of boceprevir used a 4-week lead-in of pegIFN and RBV. It turns out the lead-in was most useful in the assessment of interferon responsiveness. In the SPRINT-2 study evaluating boceprevir in combination with pegIFN/RBV in previously untreated patients with chronic HCV genotype 1, a decrease in the HCV RNA level by ≥1 log10 IU/mL after the 4-week lead-in increased the chances of sustained virologic response (SVR; undetectable HCV RNA 24 weeks after the end of treatment) ninefold (adjusted odds ratio [AOR], 9.0; 95% confidence interval [CI], 6.3–12.8; P <.001).[13] There was no advantage to lead-in when used with other DAAs, for example, with telaprevir and BI 201335.[14,15]


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