'Sensational' Hep C Response Rates in HIV Coinfection Trial

Pam Harrison

July 30, 2015

VANCOUVER, British Columbia — An investigational combination of a protease inhibitor and an NS5A inhibitor led to a sustained virologic response after 12 weeks of treatment in almost all patients coinfected with HIV and hepatitis C in the C-EDGE coinfection study.

"Twelve weeks after stopping treatment, the sustained virologic response was 96.3% overall," said Jürgen Rockstroh, MD, from the University of Bonn in Germany.

Of the 218 study patients, two experienced a relapse after stopping therapy, but both had been reinfected with hepatitis C. "Without these two patients, our cure rate would have been even higher," Dr Rockstroh told Medscape Medical News.

"It's a sensationally good response rate. That's good because the more combinations we have for hepatitis C and HIV coinfection, the more competition there will be, and the more competition, the lower the cost of these drugs," he explained. "That would benefit everyone because cost reimbursement right now is a major issue."

The study results were presented here at the 8th International AIDS Society Conference.

C-EDGE Trial

The phase 3, open-label, single-group, multicenter C-EDGE coinfection study involved 218 treatment-naïve patients infected with hepatitis C genotypes 1, 4, or 6, although 86% of the cohort had genotype 1a or 1b. All patients were also infected with HIV.

At study enrollment, about 97% of patients had an undetectable level of HIV RNA. About three-quarters of patients were being treated with tenofovir and about half were being treated with raltegravir.

All patients received the protease inhibitor grazoprevir 100 mg and the NS5A inhibitor elbasvir 50 mg — coformulated by Merck in a single tablet — once a day for 12 weeks.

Twelve weeks after stopping treatment, the sustained virologic response in the cohort was 96.3%, and in the 35 patients with cirrhosis at baseline, the response was 100.0%.

Patients with cirrhosis are more difficult to treat, Dr Rockstroh pointed out.

Response rates were virtually identical in the subset of patients infected with hepatitis C genotype 4. And only two patients in the study had hepatitis C genotype 6, but both achieved a sustained virologic response.

"It looks like genotype 4 and genotype 6 also respond very well to this treatment," he explained.

Response rates were slightly lower than the 96.3% rate in the subset of patients whose antiviral regimen contained abacavir (93.6%) or rilpivirine (94.7%). In contrast, sustained virologic response was virtually identical in patients whose antiviral regimen contained tenofovir (97.6%) or raltegravir (96.5%).

Of the five patients who relapsed, three were on a tenofovir-based regimen, one was on an abacavir-based regimen, and one was not taking antiretrovirals.

No patient developed a serious drug-related adverse event, and no patient discontinued because of an adverse event.

"The great thing about this new combination is that no ribavirin was needed in this patient population," Dr Rockstroh said. "And any regimen without ribavirin is better than one with," because ribavirin is associated with a number of serious adverse events, including anemia and rash.

Better Overall Survival

Achieving an undetectable level of hepatitis C RNA 12 to 24 weeks after stopping treatment means that not only does treatment decrease the risk for liver disease, it also increases overall survival, he explained during a news conference.

"This indicates that hepatitis C is something that not only affects the liver, ongoing viral inflammation has an impact on other organs as well," he added.

Data from another study, presented at the meeting by Santiago Moreno, MD, from Hospital Ramón y Cajal in Madrid (abstract TUAB0204), showed that when treatment induces fibrosis regression on top of inducing a sustained virologic response, "that has the biggest impact on improving survival," Dr Rockstroh reported.

Regression of fibrosis is more difficult to achieve in patients with advanced cirrhosis, and any benefit of enhanced survival from hepatitis C therapy might be limited in this patient group. "This is a very strong argument in favor of earlier treatment," he pointed out.

"The challenge now is to convince payers that everyone with coinfection should be treated, regardless of the stage of fibrosis," he added.

Depending on geographic region, the use of direct-acting antiretrovirals for the treatment of hepatitis C might be limited to patients with advanced liver disease," said Marina Klein, MD, from McGill University in Montreal. This restriction is likely a reflection of the enormous cost of even a short course of treatment. In Canada, the list price for a course of treatment is $50,000 to $80,000 (US$39,000 to US$62,000).

The development of direct-acting antiretrovirals for the treatment of patients coinfected with HIV and hepatitis C has been rightfully described as revolutionary, Dr Klein said.

Revolution in Hep C Treatment

However, as leader of the Canadian Co-infection Cohort Study for the past 15 years, Dr Klein said she is acutely aware that end-stage liver disease has become the predominant cause of morbidity and mortality in this patient population.

"This is followed closely by death from overdose," she explained, "so we can't forget that these things are intimately intertwined."

In Canada and in many other parts of the world, the hepatitis C epidemic is largely driven by people who inject drugs. In fact, more than 85% of the Canadian Co-infection Cohort Study has been exposed to injection drug use, and 30% of the cohort continues to inject.

Injection drug use and accompanying comorbidities in patients coinfected with HIV and hepatitis C in the real world are of no small consequence when interpreting direct-acting antiretroviral clinical trial results, Dr Klein said.

In the real world, substance abuse, comorbid medical and psychiatric conditions, advanced liver disease, and drug–drug interactions between direct-acting antiretrovirals and existing HIV regimens are common, she pointed out.

However, to date, the eligibility criteria for clinical trials of direct-acting antiretrovirals have been very strict, so coinfected patients such as those in the Canadian cohort would never qualify for study participation.

In fact, Dr Klein was involved in a study presented at the meeting that looked at the participants involved in clinical trials of direct-acting antiretrovirals (abstract TUAB0205). Only about 6% of patients in the Canadian cohort would have been eligible to participate in any of the hepatitis C clinical trials, principally because they are on regimens that interact with direct-acting antiretrovirals or because they still actively inject drugs, she explained.

"We know that injection drug users actually do quite well on treatment, so there is no reason to deny treatment to people who are injecting," Dr Klein said.

"We should be thinking about ways to support these patients to maintain adherence during hepatitis C treatment because, clearly, response rates are very much linked to taking almost every single pill," she said.

"And unlike many infectious diseases, there is no life-long immunity after you've acquired and cured hepatitis C," Dr Klein explained. "Patients are at risk of being reinfected if they are re-exposed to anyone who continues to engage in risky behavior, such as people who share needles or men who have sex with men who acquire hepatitis C sexually."

The C-EDGE co-infection study was funded by Merck. Dr Rockstroh reports receiving honoraria for speaking at educational events or consulting from Merck, Abbott, AbbVie, Bionor Pharma, BMS, Cipla, Gilead, Janssen, and ViiV. Dr Klein has disclosed no relevant financial relationships.

8th International AIDS Society (IAS) Conference. Abstract TUAB0208. Presented July 21, 2015.

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