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Grazoprevir (a NS3/4 protease inhibitor) and elbasvir (a NS5A inhibitor) are being developed by Merck. The combination is being studied as a once-daily single-tablet regimen, with or without ribavirin. The 2 drugs are active against multiple genotypes of hepatitis C.

C-EDGE Treatment-experienced

The C-EDGE treatment-experienced study is part of a suite of trials including previously untreated, treatment-experienced, and HIV/HCV coinfected patients. Results from the treatment-naive C-EDGE studies are reported in a separate article.

Results from the treatment-experienced arms of the C-EDGE study were presented as a conference poster by Paul Kwo of the University of Indiana and colleagues.

The study recruited participants with HCV genotypes 1, 4, or 6, including people coinfected with HIV. People were eligible to join the study if they had failed to respond to previous treatment with pegylated interferon and ribavirin.

In this study participants were randomized to 4 arms:

• Grazoprevir and elbasvir once-daily for 12 weeks;
• Grazoprevir and elbasvir once-daily for 12 weeks, plus twice-daily weight-based ribavirin;
• Grazoprevir and elbasvir once-daily for 16 weeks;
• Grazoprevir and elbasvir once-daily for 16 weeks, plus twice-daily weight-based ribavirin.

Study arms were stratified by liver cirrhosis and prior treatment response (null responder, partial responder, or post-treatment relapse) in order to ensure equal distribution of these factors across study arms.

A total of 420 participants were randomized (209 to the 12-week arms and 211 to the 16-week arms), of which 58% in the 12-week arm had genotype 1a infection and 12% had genotype 4 infection. The remainder in the 12-week arm had genotype 1b.

In the 16-week arms genotype 1a representation was slightly lower in the ribavirin-free arm than in the ribavirin-containing arm (46% vs 55%), and 16-week arms had a lower representation of genotype 4 participants (6%).

Approximately 5% of participants were coinfected with HIV and HCV. The distribution by previous treatment history was 35% relapse, 22% partial response, and 43% null response. 73 participants had cirrhosis.

The primary efficacy results showed a high level of efficacy in all study arms, with marginally greater efficacy in the 16-week plus ribavirin arm. However, subgroup analyses that excluded patients counted as non-virological failures (e.g., lost to follow up or protocol violation) found a stronger tendency towards greater efficacy in those randomized to 16 weeks plus ribavirin, except in prior relapsers.

		Response by baseline characteristics
Study arm (grazoprevir + elbasvir)	SVR12 (all)	Cirrhosis	Prior relapse	Prior partial or null response
12 weeks	92%	89%	100%	91%
12 weeks + ribavirin	94%	88%	100%	91%
16 weeks	92%	92%	92%	94%
16 weeks + ribavirin	97%	100%	100%	100%

When responses were analyzed by genotype in an intent-to-treat analysis, genotype 1b participants showed better responses to the 12-week ribavirin-sparing regimen when compared to genotype 1a, but no other substantive differences were evident. The small number of genotype 4 patients (n=37) and HIV/HCV coinfected patients (n=21) do not permit comparisons between regimens, except to note that HIV-positive patients did not respond less well.

	Response by baseline characteristics
Study arm (grazoprevir + elbasvir)	Genotype 1a	Genotype 1b	Genotype 4	HIV/HCV coinfection
12 weeks	90%	100%	78%	100%
12 weeks + ribavirin	93%	96%	96%	100%
16 weeks	94%	96%	93%	83%
16 weeks + ribavirin	95%	100%	100%	100%

As in previously untreated patients, the presence of resistance-associated variants (RAVs) conferring a greater than 5-fold reduction in sensitivity to elbasvir (NS5A inhibitor) was associated with a substantially poorer SVR12 rate in 21 genotype 1a patients (52%, compared to 99% in patients without any RAVs). In comparison, variants associated with reduced sensitivity to grazoprevir (NS3 protease inhibitor) did not affect virological response.

Treatment was well tolerated. Approximately 3% of participants in each arm experienced a serious adverse event and a total of 7 participants (5 of them in the 16-week plus ribavirin arm) discontinued study medication due to adverse events. In the ribavirin-containing arms 8% of the 12-week and 20% of the 16-week group developed anemia (hemoglobin below 10 g/dL).

These findings indicate that for genotype 1b patients and for people with a history of prior relapse after treatment response, a 12-week course of grazoprevir/elbasvir without ribavirin is highly effective, curing 100% of those patient groups in this study. But for cirrhotics and for prior partial or null responders, a 16-week course of treatment with ribavirin may be necessary to achieve a 100% cure rate, the investigators concluded.

C-EDGE Coinfected

The Phase 3 C-EDGE study in people coinfected with HIV and HCV was an open-label study of grazoprevir/elbasvir without ribavirin, in which participants were randomized to 12 or 16 weeks of treatment. Jürgen Rockstroh of University Hospital in Bonn and colleagues presented SVR 12 results from the 12-week arm in a poster at the International Liver Congress.

The C-EDGE Coinfected study recruited 218 HIV/HCV coinfected participants, either on stable antiretroviral therapy with a CD4 cell count above 200 cells/mm³ and undetectable viral load (<50 copies/mL) or previously untreated with a CD4 cell count above 500 cells/mm³ and viral load <50,000 copies/mL. The median CD4 cell count among study participants was 614 cells/mm³.

The study permitted participants to take an antiretroviral regimen containing either raltegravir (Isentress; 51%), dolutegravir (Tivicay; 24%), or rilpivirine (Edurant; 17%), paired with tenofovir/emtricitabine (the drugs in Truvada; 75%) or abacavir/lamivudine (the drugs in Epzicom; 21%). The remaining 5% were not taking antiretroviral therapy. Other regimens were excluded owing to the potential for drug-drug interactions between some antiretrovirals and direct-acting HCV antivirals.

The study recruited participants with HCV genotypes 1, 4, or 6. Approximately two-thirds of participants had genotype 1a (66%), 20% had genotype 1b, and 12% had genotype 4. 16% of participants had cirrhosis.

The SVR12 rate was 95% across all participants. There was no significant difference in response by baseline viral load, cirrhosis, or any other variable. 6 participants experienced viral relapse after completing treatment and before SVR12, with 4 relapses occurring among genotype 1a patients. No cases of viral breakthrough during treatment occurred. A single participant became reinfected with a different HCV genotype before week 12, after having achieved undetectable viral load at the end of the treatment course. This case was counted as virological failure as per protocol.

Serious adverse events were reported in 6 patients but none was considered to be drug-related. The only commonly reported adverse events -- fatigue, nausea, and headache -- occurred with similar frequencies to other studies of grazoprevir/elbasvir. Laboratory abnormalities were also rare; 3.7% of participants experienced bilirubin elevations 2-5 times the upper limit of normal (ULN), and 1 patient experienced an elevation of greater than 5 xULN.

Two participants with previously undetectable HIV viral load experienced brief episodes of viremia during the study, but resuppressed viral load after receiving additional adherence support.

Results in this coinfected population are broadly comparable with those from studies of the grazoprevir/elbasvir combination in other patient groups, the investigators concluded, indicating that this combination will be suitable for treatment of hepatitis C in HIV/HCV coinfected individuals.

4/27/15

References

P Kwo, E Gane, C-Y Peng, et al. Efficacy and safety of grazoprevir/elbasvir +/− RBV for 12 weeks in patients with HCV G1 or G4 infection who previously failed peginterferon/RBV: C-EDGE treatment-experienced trial. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract P0886.

JK Rockstroh, M Nelson, C Katlama, et al. C-EDGE co-infected: phase 3 study of grazoprevir/elbasvir in patients with HCV/HIV. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract P0887.

Other Source

Merck. Merck’s Pivotal Phase 3 C-EDGE Program Evaluating Grazoprevir/Elbasvir Shows High Sustained Virologic Responses Across Broad Range of Patients with Chronic Hepatitis C Virus Infection. Press release. April 24, 2015.