Grazoprevir/elbasvir highly effective in treatment-experienced and HIV-coinfected hepatitis C patients

The combination of grazoprevir and elbasvir without ribavirin is highly effective in curing hepatitis C infection in 12 weeks in some groups of treatment-experienced patients and in people with HIV co-infection, and a 16-week course of treatment with ribavirin was highly effective even in the hardest-to-treat groups of treatment-experienced patients, two studies presented this week at the International Liver Congress in Vienna, Austria, show.

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

The C-EDGE treatment-experienced study forms part of a suite of studies in previously untreated people (treatment naive), people who have taken treatment before (treatment experienced) and people with HIV co-infection.

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

The study recruited participants with genotypes 1, 4 or 6 hepatitis C infection, including people with HIV and hepatitis C co-infection. People were eligible to join the study if their hepatitis C had failed to respond to previous treatment with pegylated interferon and ribavirin.

In this study, participants were randomised to one of four arms:

• Grazoprevir & elbasvir once daily for 12 weeks.

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

• Grazoprevir & elbasvir once daily for 16 weeks.

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

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

In total, 420 participants were randomised (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 11.5% had genotype 4 infection. The remainder in the 12-week arm had genotype 1b infection.

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 the 16-week arms had a lower representation of participants with genotype 4 (6%).

Approximately 5% of participants had HIV and hepatitis C co-infection. The distribution by previous treatment history was 35% relapse, 22% partial response and 43% null response. Seventy-three people 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 which excluded patients counted as non-virologic failures (e.g lost to follow up or protocol violation), found a stronger tendency towards greater efficacy in those randomised 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 analysed 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 difference were evident. The small number of genotype 4 patients (n = 37) and people with HIV co-infection (n = 21) do not permit comparisons between regimens, except to note that people with HIV co-infection did not respond less well.

	Response by baseline characteristics
Study arm (grazoprevir & elbasvir)	Genotype 1a	Genotype 1b	Genotype 4	HIV co-infection
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 fivefold 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.

Study medication was well tolerated. Approximately 3% of participants in each study arm experienced a serious adverse event and a total of 7 participants (5 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 haemoglobin below 10 g/dL.

These findings indicate that for people with genotype 1b and for people with a history of prior relapse after treatment response, a 12-week course of treatment without ribavirin is highly effective, curing 100% of those patient groups in this study. But for people with cirrhosis 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.

The phase III C-EDGE study in people with HIV and hepatitis C co-infection was an open-label study of grazoprevir and elbasvir without ribavirin, in which participants were randomised to 12 or 16 weeks of treatment. Professor Jurgen Rockstroh of University Hospital, Bonn, presented SVR12 results from the 12-week arm in a poster at the International Liver Congress on Friday.

The C-EDGE Co-Infected study recruited 218 people with HIV and hepatitis C co-infection, either on stable antiretroviral treatment 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 study permitted participants to take an antiretroviral regimen containing either raltegravir (51%), dolutegravir (24%) or rilpivirine (17%), paired with tenofovir/emtricitabine (75%) or abacavir/lamivudine (21%). The remaining 5% were not taking antiretroviral treatment. Other regimens were excluded owing to the potential for drug-drug interactions between some antiretrovirals and direct-acting antivirals. The median CD4 cell count among study participanst was 614 cells/mm³.

The study recruited participants with genotypes 1, 4 or 6 hepatitis C infection. Approximately two-thirds of participants had genotype 1a infection (66%), 20% genotype 1b and 12% genotype 4. Sixteen per cent of participants had cirrhosis.

The sustained virologic response rate 12 weeks after completion of treatment (SVR12) was 95% across all participants. There was no significant difference in response by baseline viral load, cirrhosis or any other variable. Six participants experienced viral relapse after completing treatment and before SVR12, four of these occurring in genotype 1a patients. No cases of viral breakthrough during treatment occurred. One participant became reinfected with a different genotype before week 12, after having achieved undetectable viral load at the end of the treatment course. This case was counted as virologic failure as per protocol.

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

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

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