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

Lower Limit of Detection (LLOD) Versus Lower Limit of Quantification (LLOQ)

The LLOD is the HCV RNA concentration at which less than 5% of the samples that contain a known amount of an RNA standard yield a signal that can be detected. The LLOQ refers to the lowest HCV RNA concentration that is within the validated quantitative range of an assay. An undetectable result indicates that HCV RNA was not detected in the sample. The limit of detection and the limit of quantification vary according to the assay used. Both the boceprevir and telaprevir phase III studies used the COBAS TaqMan HCV RNA assay, version 2.0 (Roche), with a LLOD of 10 IU/mL and a LLOQ of 25 IU/mL. Eligibility for RGT was based on the lower limit of detection (<10 IU/mL) of the assay. There is thus a range in which HCV RNA can be detectable, but falls below the level of quantification. This situation is not uncommon during HCV treatment and is associated with lower SVR rates. In the SPRINT-2 trial, 53% of the 1071 patients enrolled had at least one on-treatment result showing detectable HCV RNA, but below the level of quantification.[13] For example, in the patients who received boceprevir and who had detectable HCV RNA at week 6 (any level), detectable HCV RNA at week 8 but below level of quantification, and undetectable HCV RNA at week 10, the SVR rate was 74%. In the patients who received boceprevir and who had detectable HCV RNA at week 6 (any level) but undetectable HCV RNA at weeks 8 and 10, the SVR rate was 86%. When assessing eligibility to response-guided therapy with DAAs, an undetectable HCV RNA (<LLOD) is not equivalent to a detectable HCV RNA that is below the limit of quantification of the assay (detectable but <LLOQ). The package inserts of telaprevir and boceprevir reflect this fact.

NS3/4A PIs

HCV NS3/4A PIs are often divided in two classes. The first generation PIs include the linear α-ketoamide derivatives, boceprevir and telaprevir. They bind the catalytic site of the enzyme covalently in a reversible reaction. Boceprevir and telaprevir are considered the first wave of the first-generation PIs. These two PIs are the first DAAs to have completed phase III clinical trials for treatment of HCV genotype 1 and to have received FDA approval. Second-wave PIs are mostly linear and macrocyclic noncovalent inhibitors of the NS3/4A enzyme. Both waves are highly potent inhibitors of the NS3/4A enzyme. The advantages of second wave PIs over first wave PIs are their convenience and improved side effect profile. Unfortunately, they share the same basic resistance mutations that are generated by the first wave of PIs. The truly second-generation PIs are the two drugs MK-5172 and the ACH-2684. They do not share the same resistance mutations and are pangenotypic. There are currently two first-generation, second-wave PIs that recently initiated phase III of clinical development: TMC435 and BI-201335.


In phase I studies, TMC435 was generally safe and well tolerated. It showed potent anti-HCV activity. After 5 days of TMC-435 at a dose of 200 mg once daily, HCV RNA decreased by a median of 3.9 log10 IU/mL in HCV genotype 1-infected patients who failed prior interferon-based therapy.[16] The phase IIb PILLAR study is ongoing and week 24 results have recently been presented.[17] PILLAR is investigating the use of once-daily TMC435 at two different dosages (75 mg vs 150 mg) for 12 versus 24 weeks in combination with pegIFN/RBV for 24 vs 48 weeks (vs placebo/pegIFN/RBV for 48 weeks), in 386 patients with HCV genotype 1 naïve to HCV treatment. Patients with HCV RNA less than 25 IU/mL from week 4 to week 20 were eligible for RGT and stopped treatment at week 24. Of the patients receiving TMC435, 83% achieved eRVR and 94 to 97% achieved undetectable HCV RNA at week 24 of treatment compared with a high 82% in the pegIFN/RBV control group. Of the 83% of patients who achieved eRVR and stopped therapy at week 24, 88 to 97% achieved SVR12 (undetectable HCV RNA 12 weeks after the end of treatment). Discontinuation of TMC435 or placebo occurred in 7.1% of patients receiving TMC435/pegIFN/RBV versus 7.8% of patients receiving placebo/pegIFN/RBV. The most common adverse events occurred in a similar proportion of patients receiving or not receiving TMC435. TMC435 at the 150 mg once-daily dose was associated with mild and reversible increases in direct and indirect bilirubin. Elevation in bilirubin is thought to occur through inhibition of the two transporters: organic anion transporting polypeptide 1B1 (OATP1B1) and multidrug resistance-associated protein 2 (MRP2). OATP1B1 is responsible for bilirubin uptake into hepatocytes (influx) and MRP2 is responsible for efflux into bile. No inhibition of bilirubin conjugation has been observed.[18]

The ASPIRE study is the ongoing phase IIb study in prior partial responders (≥2 log10 drop in HCV RNA at week 12 but detectable HCV RNA at week 24), prior null responders (<2 log10 drop in HCV RNA at week 12 of treatment) and prior relapsers (undetectable HCV RNA at the end of treatment, but detectable HCV RNA within 24 weeks of end of treatment) to interferon-based therapy. Patients received TMC435 at doses of 100 mg versus 150 mg once daily in combination with pegIFN/RBV for 12, 24, or 48 weeks. In all seven arms of the trial, patients received pegIFN/RBV to complete 48 weeks of treatment. There was no RGT. The week 24 interim analysis showed that 92 to 96% of prior relapsers who received TMC435 had undetectable HCV RNA at week 24 compared with 83% of patients in the control group. Of the prior partial responders receiving TMC435, 83 to 89% had undetectable HCV RNA at week 24 versus 20% of the control group. Of the prior null responders, 70 to 87% had undetectable HCV RNA at week 24 versus 45% of the control group (higher than expected). The prior null responders typically have the lowest response rates to retreatment. The end of treatment and SVR data are eagerly awaited.

In summary, TMC435 is a highly potent once-daily dosing PI. Duration of treatment can be shortened to 24 weeks for the majority of patients; viral breakthroughs are low when used in combination with pegIFN and RBV. The 150 mg once-daily dose is being used in phase III trials in both patients who are naïve to HCV treatment and patients who previously relapsed to an interferon-based therapy. Patients will receive once-daily 150 mg of TMC435 during 12 weeks in combination with pegIFN/RBV for a 24 versus 48 weeks. A trial for HIV-infected patients has started enrollment in the second half of 2011.

BI 201335

BI201335 is a HCV NS3 PI given once daily currently in phase III. The phase IIb SILEN-C1 trial was conducted in patients with HCV genotype 1 naïve to HCV treatment to evaluate safety and efficacy of BI 201335 given once daily at a dose of 120 mg or 240 mg for 24 weeks in combination with pegIFN and RBV for 24 vs 48 weeks.[14] A lead-in of pegIFN and RBV for 3 days was also evaluated in 2 of the 4 arms (with 120 mg and 240 mg once daily). In the two arms using BI 201335 at a dose of 240 mg (with and without a lead-in), patients achieving eRVR were rerandomized to either stop treatment at week 24 or continue with pegIFN/RBV for a total of 48 weeks. Patients receiving 240 mg once daily without a lead-in achieved the highest eRVR rate of 87% and were thus eligible for shortened treatment duration. As expected with this high eRVR rate, this arm also had the highest SVR rate of 83% versus 73% of patients receiving 240 mg with a lead-in and 56% of patients in the pegIFN/RBV control group. Prolonging treatment to 48 weeks in those patients achieving eRVR did not result in higher SVR rates. Of those who completed 24 weeks, 93% achieved SVR versus 90% of those who completed 48 weeks. Viral breakthroughs occurred in 2.8 to 5.8% of patients receiving BI 201335 with the highest rate in those of the 120 mg daily with lead-in arm.

The phase IIb SILEN-C2 trial evaluated BI 201335 for 24 weeks in combination with pegIFN/RBV for 24 versus 48 weeks, with or without a 3-day lead-in of pegIFN/RBV in previous partial and null responders infected with HCV genotype 1.[19] The 240 mg once-daily dose (with and without a lead-in) was compared with 240 mg twice daily with a lead-in. Patients of the 240 mg once-daily group with lead-in achieving eRVR were rerandomized to stopping therapy or continuing 48 weeks with pegIFN/RBV. Similar to the SILEN-C1 trial, the lead-in did not appear to be useful. The 240 mg once-daily dosing without a lead-in led to the highest SVR rates. Overall, eRVR was achieved by 45% of patients and SVR was achieved by 27 to 41% of patients. The lowest SVR rate was observed in the 240 mg once daily with the lead-in arm, the one group that used RGT for those achieving eRVR. In comparison to the good results observed with 24 weeks of treatment in the naïve patients achieving eRVR in the SILEN-C1 trial,[14] prior partial and null responders achieving eRVR in SILEN-C2 achieved lower SVR rates when stopped at week 24. Only 40% of patients achieved SVR when stopped at week 24 compared with 72% of those who completed 48 weeks of treatment. The additional 24 weeks of peg/RBV greatly impacted the relapse rate. Sixty percent of those who stopped at week 24 relapsed compared with 21% of those who completed 48 weeks of treatment. Viral breakthroughs occurred predominantly on BI 201335 compared with peg/RBV (17–28% vs 5–7%). Several adverse events were reported in a higher proportion of patients receiving BI 201335 compared with those on placebo and were dose-dependent. Jaundice, skin manifestations including rash, photosensitivity reactions, pruritus and dry skin, and gastrointestinal side effects, mostly nausea, vomiting, and diarrhea were reported in the BI 201335 arms in a proportion exceeding 10% of the placebo/peg/RBV group. Jaundice was secondary to predominantly indirect or unconjugated hyperbilirubinemia. This was dose-dependent, rapidly reversible in all cases at cessation of BI 201335, and not associated with liver injury. The mechanism of action is inhibition of hepatic uptake of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1).[20]


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