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Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1: 'this was the proof-of-concept study showing SVR ('cured') could be achieved without peg/rbv & with only 2 new oral HCV drugs'
 
 
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N Engl J Med Jan 19 2012

"4 of 11 prior null responder patients (the hardest to treat patients) achieved 'cure' (SVR with only 2 new oral HCV drugs)....10 of 10 prior null responder patients had SVR 12 weeks after finishing treatment with QUAD therapy (4 drugs: the 2 new oral drugs+the standard of care peginterferon/ribavirin)..........A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment.........Study conducted in 21 prior 'null responders' to peg/rbv; 11 patients received only 2 new oral HCV drugs (BMS NS5A+BMS protease) without peg/rbv): Coadministration of daclatasvir (first-in-class, highly selective HCV NS5A replication complex inhibitor with picomolar potency in vitro )and asunaprevir (highly active HCV NS3 protease inhibitor ) alone in group A initially led to a rapid reduction in HCV RNA, with all 11 patients achieving greater than a 4-log10 decline. Ultimately, 5 patients had undetectable HCV RNA at the end of the treatment period, and 4 had sustained virologic response at weeks 12 and 24 after treatment, establishing proof-of-concept that sustained virologic response can be achieved without peginterferon or ribavirin.......Although there were only 2 patients with HCV genotype 1b infection in group A, the observation that both of the patients had a sustained virologic response after treatment with two direct-acting antiviral agents alone may reflect a higher resistance barrier for this combination of drugs in patients with HCV genotype 1b infection than in patients with HCV genotype 1a infection. A similar finding of a high rate of sustained virologic response among patients with HCV genotype 1b infection was shown in a pilot study of combination therapy with asunaprevir and daclatasvir in 10 Japanese patients who had HCV genotype 1b infection and who had not had a response to previous therapy with peginterferon and ribavirin".....

Anna S. Lok, M.D., David F. Gardiner, M.D., Eric Lawitz, M.D., Claudia Martorell, M.D., Gregory T. Everson, M.D., Reem Ghalib, M.D., Robert Reindollar, M.D., Vinod Rustgi, M.D., Fiona McPhee, Ph.D., Megan Wind-Rotolo, Ph.D., Anna Persson, Ph.D., Kurt Zhu, Ph.D., Dessislava I. Dimitrova, M.D., Timothy Eley, Ph.D., Tong Guo, Ph.D., Dennis M. Grasela, Pharm.D., Ph.D., and Claudio Pasquinelli, M.D., Ph.D.

Presented in part at the annual meeting of the American Association for the Study of Liver Diseases, Boston, October 29–November 2, 2010; and at the European Association for the Study of the Liver International Liver Congress, Berlin, March 30–April 3, 2011.

ABSTRACT

Background


Patients with chronic hepatitis C virus (HCV) infection who have not had a response to therapy with peginterferon and ribavirin may benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen.

Methods

This open-label, phase 2a study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not had a response to previous therapy (i.e., had not had ≥2 log10 decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). We randomly assigned patients to receive the NS5A replication complex inhibitor daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600 mg twice daily) alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.

Results

A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment..
Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.

Conclusions

This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb)

Approximately 180 million people worldwide are infected with hepatitis C virus (HCV), including 4.1 million in the United States.1,2 HCV infection is the most common cause of chronic liver disease in the United States and a leading cause of cirrhosis and hepatocellular carcinoma globally.3,4 HCV is classified into six major genotypes; genotype 1 is predominant in the United States and is the most difficult to treat.5,6

Treatment of HCV genotype 1 infection with peginterferon alfa and ribavirin for 48 weeks results in 24-week sustained virologic response (undetectable HCV RNA 24 weeks after the end of therapy) in 40 to 50% of patients who have not received previous treatment.7-10 Patients are considered as not having had a response if they do not have a reduction in HCV RNA levels by at least 2 log10 IU per milliliter after a minimum of 12 weeks of treatment with peginterferon and ribavirin.6 Retreatment with triple therapy — a protease inhibitor, peginterferon, and ribavirin — yields rates of sustained virologic response of only 14 to 33%.11,12 Gane and colleagues found that treatment for 13 days with a combination of two direct-acting antiviral agents without peginterferon or ribavirin can suppress HCV RNA levels in patients who have not had a response to previous treatment with peginterferon and ribavirin.13 These results suggest that additional studies of combinations of direct-acting antiviral agents are warranted.

Daclatasvir is a first-in-class, highly selective HCV NS5A replication complex inhibitor with picomolar potency in vitro.14 Asunaprevir is a highly active HCV NS3 protease inhibitor.15 Both daclatasvir and asunaprevir produce robust declines in HCV RNA levels in patients with HCV genotype 1 infection,16,17 and administration of the two drugs in combination did not produce a clinically meaningful pharmacokinetic interaction.18 In this study, daclatasvir and asunaprevir were administered in combination, with or without peginterferon alfa-2a and ribavirin, for 24 weeks in patients with HCV genotype 1 infection who had not had a response to previous treatment with peginterferon and ribavirin. We report preliminary data from the exploratory cohort, including the percentages of patients with sustained virologic response at 12, 24, and 48 weeks after the end of the treatment period.

Results

Patients


A total of 21 patients were enrolled (11 in group A and 10 in group B) (Fig. 1 in the Supplementary Appendix). The baseline characteristics of the treatment groups are shown in Table 1 As expected in the case of a cohort of patients who did not have a response to prior treatment with peginterferon and ribavirin, genotyping of the IL28B rs12979860 SNP showed that 19 patients had a CT or TT genotype.

Virologic Response

Group A


HCV RNA levels in the patients in group A declined rapidly after the initiation of treatment (Figure 1A). At week 2, the median decrease in HCV RNA from baseline was 5.1 log10 IU per milliliter, and seven patients (64%) had undetectable HCV RNA at week 4 (rapid virologic response). Four patients (36%) had a sustained virologic response at 12 weeks after the end of the treatment period, and all four also had a sustained virologic response at week 24 after treatment (Table 2). Three of these patients also had a sustained virologic response at week 48 after treatment; the fourth had HCV RNA of less than 25 IU per milliliter at week 48 after treatment and undetectable HCV RNA 43 days later.

Viral relapse occurred in one patient (with HCV genotype 1a) at week 4 after treatment. This patient had had undetectable HCV RNA at week 4 during the treatment period, and the levels had remained undetectable through week 24 (end of treatment). An analysis of baseline samples revealed a preexisting variant conferring resistance to asunaprevir (see below). Viral breakthrough occurred in six patients (55%), all with HCV genotype 1a, as early as week 3 and as late as week 12. All six patients had peginterferon and ribavirin added to their regimen (rescue therapy), resulting in initial reductions in HCV RNA in all cases (Figure 1B). Peak HCV RNA levels at the initiation of rescue therapy ranged from 6.5x102 to 3.2x106 IU per milliliter. In four of these six patients, HCV RNA became undetectable while they were receiving rescue therapy; two of them had a relapse after the treatment period, whereas HCV RNA remained undetectable in the other two at the most recent testing, one at 14 weeks and one at 42 weeks after treatment. The remaining two patients never achieved undetectable HCV RNA, and treatment was discontinued.

Group B


HCV RNA levels declined rapidly and remained suppressed throughout the study in all the patients in group B (Figure 1C). At week 2, the median decrease from baseline in HCV RNA was 5.3 log10 IU per milliliter, and 6 patients (60%) had a rapid virologic response. All 10 patients had undetectable HCV RNA by week 6, and no patient had viral breakthrough. Several patients had transiently detectable HCV RNA at levels below the limit of quantification (<25 IU per milliliter) during or after therapy (Figure 1C). All 10 patients had a sustained virologic response at week 12 after treatment and all but 1 had a sustained virologic response at week 24 after treatment (Table 2, and Fig. 1 in the Supplementary Appendix). One patient had transiently detectable HCV RNA (<25 IU per milliliter) at week 8 after treatment; HCV RNA was undetectable at week 12 after treatment (Figure 1C). Another patient had transiently detectable HCV RNA (<25 IU per milliliter) at week 24 after treatment, and undetectable HCV RNA when levels were measured again 35 days later. Nine of the 10 patients had a sustained virologic response at week 48 after treatment; 1 patient had HCV RNA of less than 25 IU per milliliter at week 48 after treatment and undetectable HCV RNA 13 days later.

Resistance


An analysis of samples from the six patients in group A with viral breakthrough showed that there were no resistance variants at baseline and that resistance variants to both daclatasvir and asunaprevir had emerged in all cases by the time of viral breakthrough. Viral variants in the NS5A domain included Q30R, L31 M/V, and Y93C/N; variants in the NS3 protease domain included R155K and D168A/E/T/V/Y. The patient with viral relapse had a preexisting NS3 protease resistance variant, R155K, at baseline and at the time of viral relapse, whereas the NS5A resistance variant Q30E was detected only at relapse.

Safety

All the patients completed at least 24 weeks of therapy. The most common adverse events were diarrhea, fatigue, headache, and nausea (Table 3). Most adverse events were mild to moderate. There were no deaths, serious adverse events, or discontinuations of study treatment due to adverse events during the analysis period. One serious adverse event of hospitalization for alcohol abuse was reported 1 month after the completion of rescue therapy. Grade 3 or 4 adverse events and laboratory-test abnormalities included fatigue (one patient in group A), neutropenia (six patients, all of whom were receiving peginterferon alfa-2a and ribavirin), and elevations of alanine aminotransferase levels (two patients in group A and one in group B). There were no instances of grade 3 or 4 anemia or thrombocytopenia. There were no clinically relevant changes in electrocardiographic findings. There were seven adverse events leading to dose reductions of peginterferon or ribavirin in four patients in group B, including neutropenia (three events), anemia (two), leukopenia (one), and depression (one).

Six patients (four from group A, including two who were receiving peginterferon and ribavirin after viral breakthrough, and two from group B) had transient elevations of alanine aminotransferase levels to greater than 3 times the upper limit of the normal range (Fig. 2A and 2B in the Supplementary Appendix). Elevated aminotransferase levels generally occurred between weeks 8 and 20. The peak alanine aminotransferase level was 370 U per liter, and the maximum direct bilirubin level was 0.6 mg per deciliter. There was no evidence of an association between elevations of alanine aminotransferase levels and response to therapy or viral breakthrough. No discontinuations or interruptions of study treatment were required, and alanine aminotransferase levels stabilized or improved in all patients.

Discussion

In this study, we assessed the effect of coadministration for 24 weeks of two direct-acting antiviral agents with different mechanisms of action, daclatasvir and asunaprevir, alone or with peginterferon alfa-2a and ribavirin, in an exploratory cohort of patients with HCV infection, who typically do not have a response to retreatment with peginterferon and ribavirin and are expected to have a poor response to triple therapy with peginterferon and ribavirin plus a protease inhibitor (boceprevir or telaprevir).11,12 A total of 90% of the patients carried IL28B genotypes (the rs12979860 SNP CT or TT), which are associated with poor response to peginterferon and ribavirin,22 and most of the patients had HCV genotype 1a infection.

The low rate of sustained virologic response achieved with peginterferon and ribavirin among patients with HCV genotype 1 infection, coupled with high rates of adverse effects, have stimulated the development of direct-acting antiviral agents and the study of regimens that exclude peginterferon, ribavirin, or both.13,23,24 Coadministration of daclatasvir and asunaprevir alone in group A initially led to a rapid reduction in HCV RNA, with all 11 patients achieving greater than a 4-log10 decline. Ultimately, 5 patients had undetectable HCV RNA at the end of the treatment period, and 4 had sustained virologic response at weeks 12 and 24 after treatment, establishing proof-of-concept that sustained virologic response can be achieved without peginterferon or ribavirin.

Both of the patients in group A who were infected with HCV genotype 1b had sustained virologic response at weeks 12 and 24 after treatment. Six patients in group A (all with HCV genotype 1a infection) had viral breakthrough. Previous studies have also shown that some patients receiving combinations of direct-acting antiviral agents without interferon have had viral breakthrough.23,24 In our study, viral breakthrough correlated with baseline HCV RNA levels (Table 1 in the Supplementary Appendix) and did not appear to be associated with pharmacokinetic findings at day 14 (data not shown). Although there were only 2 patients with HCV genotype 1b infection in group A, the observation that both of the patients had a sustained virologic response after treatment with two direct-acting antiviral agents alone may reflect a higher resistance barrier for this combination of drugs in patients with HCV genotype 1b infection than in patients with HCV genotype 1a infection. A similar finding of a high rate of sustained virologic response among patients with HCV genotype 1b infection was shown in a pilot study of combination therapy with asunaprevir and daclatasvir in 10 Japanese patients who had HCV genotype 1b infection and who had not had a response to previous therapy with peginterferon and ribavirin.25

Although all six patients with viral breakthrough initially had a response to the addition of peginterferon and ribavirin as rescue therapy, most ultimately had therapeutic failure during or after the treatment period, which was consistent with their previous lack of response to those agents. The high frequency of resistance to two classes of drugs that was seen in patients with HCV genotype 1a infection who were treated with direct-acting antiviral agents alone suggests that studies of combinations of direct-acting antiviral agents without peginterferon and ribavirin in patients with HCV genotype 1a infection should proceed carefully.

In contrast to group A, no viral breakthrough occurred in patients in group B, who were receiving quadruple therapy. All 10 patients in group B achieved a sustained virologic response at week 12 after treatment and all but 1 had a sustained virologic response at week 24 after treatment. The inclusion of peginterferon alfa-2a and ribavirin with daclatasvir and asunaprevir provided sufficient antiviral activity to suppress the emergence of resistance, an observation that is consistent with in vitro data showing a synergism of interferon and ribavirin with both direct-acting antiviral agents.14,15 Retreatment with peginterferon and ribavirin in patients who have not had a previous response to those drugs is generally unsuccessful, and even triple therapy with peginterferon, ribavirin, and telaprevir in these patients produced rates of sustained virologic response of approximately 30% at week 24 after treatment.12 Gane and colleagues found that a combination of two direct-acting antiviral agents can suppress HCV RNA in patients who have not had a response to peginterferon and ribavirin, but the treatment with the combination of direct-acting antiviral agents was limited to 13 days and was followed immediately by treatment with peginterferon and ribavirin, thus preventing the assessment of sustained response to the direct-acting antiviral agents only.13

Among the 14 patients who had a sustained virologic response at week 12 after treatment, an HCV RNA level of less than 25 IU per milliliter was detected in 1 patient at week 24 after treatment and in 2 other patients at week 48 after treatment. All 3 patients had undetectable HCV RNA on retesting. These data indicate that late relapse is unlikely to occur in patients who have a sustained virologic response with combination direct-acting antiviral agents at week 12 after treatment.

The most common adverse event was diarrhea, which was mild or moderate in all cases. Grade 3 or 4 neutropenia occurred in six patients, all of whom were receiving peginterferon and ribavirin in addition to the two direct-acting antiviral agents. No grade 3 or 4 events related to hemoglobin levels or platelet counts were observed. Transient elevations of alanine aminotransferase levels were observed in six patients; these elevations were not associated with clinically significant increases in bilirubin level. In addition, we did not find any association between these elevations and a reduction in HCV RNA levels, viral breakthrough, or pharmacokinetic findings at day 14. Similar elevations of alanine aminotransferase levels were observed in a separate dose-ranging study of asunaprevir in combination with peginterferon and ribavirin,26 and a lower dose of asunaprevir was selected for ongoing and future studies.

In conclusion, therapy with daclatasvir, asunaprevir, peginterferon alfa-2a, and ribavirin for 24 weeks provided a high rate of sustained virologic response in patients with HCV genotype 1 infection who had not had a response to previous therapy with peginterferon and ribavirin. The response in some patients to the combination of daclatasvir and asunaprevir alone showed proof-of-concept that a sustained virologic response can be achieved without peginterferon and ribavirin therapy. Both patients with HCV genotype 1b infection who were treated with the combination of direct-acting antiviral agents alone had a sustained virologic response. In contrast, the response rate was low in patients with genotype 1a infection. Overall, these results suggest that further research with combinations of direct-acting antiviral agents, with or without peginterferon and ribavirin, is warranted. Future studies should evaluate other combinations of direct-acting antiviral agents with high potency and nonoverlapping resistance profiles and investigate treatments tailored to specific characteristics of the patient and the virus.

 
 
 
 
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