Hepatitis C A Focus at CROI

New interferon-free treatment can cure nearly 100 percent of HIV-positive people coinfected with hepatitis C virus, researchers reported at the recent 2015 Conference on Retroviruses and Opportunistic Infections in Seattle. But another study showed that delaying treatment results in a higher risk of liver-related complications and death even after being cured.

CROI has emphasized hepatitis C along with HIV in recent years, coinciding with the development of highly effective, interferon-free antiviral therapy.

HCV was not identified as a distinct virus until 1989, noted Charles Rice from the Rockefeller University, who gave the opening lecture on the evolution of hepatitis C treatment. Today, an estimated 3 million people in the U.S. and as many as 170 million worldwide are living with hepatitis C, and about one-third of people with HIV are thought to also have HCV.

Over years or decades, chronic HCV infection can lead to liver cirrhosis, liver cancer, and the need for a liver transplant. Progression happens faster, on average, among HIV/HCV coinfected people.

Interferon-free treatment "represents a very significant, almost revolutionary, medical advance," Rice said. Clearing HCV lowers the risk of cirrhosis and liver cancer, "which is a very good reason for treating and getting rid of this virus in all patients that can be identified."

Treatment for Coinfected People

Two studies presented at the conference showed that HIV/HCV coinfected people can expect the same high cure rates as HIV-negative people using recently or soon-to-be approved antivirals.

Susanna Naggie from Duke Clinical Research Institute presented results from ION-4, a trial evaluating Gilead Science's HCV polymerase inhibitor sofosbuvir and NS5A inhibitor ledipasvir - the drugs in the Harvoni coformulation approved last October. The study enrolled 335 coinfected participants, mostly with HCV genotype 1 (the most common type in the U.S.).

After 12 weeks of treatment plus 12 weeks of post-treatment follow-up, 96 percent of patients had sustained virological response, considered to be cured. Response rates were similar for previously untreated people and non-responders to prior treatment, and for those with and without cirrhosis. Sofosbuvir/ledipasvir was generally safe and well tolerated with no major adverse effects.

David Wyles from UC San Diego reported findings from the ALLY-2 trial, which looked at sofosbuvir plus another NS5A inhibitor, Bristol-Myers Squibb's daclatasvir, in 203 coinfected people with a range of HCV genotypes. Daclatasvir, which is currently awaiting FDA approval, is active against multiple genotypes, while sofosbuvir only works against genotype 1.

Sustained response rates were 96 percent for previously untreated participants and 98 percent for prior non-responders treated for 12 weeks. But the cure rate fell to just 76 percent for people treated for only eight weeks. Patients with cirrhosis had lower cure rates regardless of treatment duration. Again, treatment was generally safe and well-tolerated.

Speaking at a CROI news conference, Naggie and Wyles both noted that their studies saw response rates for HIV/HCV coinfected people as high as those for HIV-negative people in previous studies. In contrast, the old interferon-based treatment did not work as well for coinfected patients.

"These are really exceptional cure rates and they are very safe regimens," Naggie said. "ION-4 and ALLY-2 offer great options for people who are coinfected."

Who Needs Treatment, and When?

Monina Klevens, from the Centers for Disease Control and Prevention, presented a study of the distribution of liver disease among people with hepatitis C, focusing on the 1945-1965 birth cohort that accounts for around 80 percent of cases in the U.S. The CDC recommends that everyone in this age group should be screened for HCV at least once regardless of risk factors.

The researchers collected anonymous data from Quest Diagnostics about nearly 300,000 positive HCV viral load tests during 2010-2013. They used three liver function tests (ALT, AST, and platelet count) to calculate a FIB-4 score, which can be used instead of a liver biopsy to estimate the stage of liver damage.

Overall, FIB-4 scores indicated that 22 percent of tested patients had severe fibrosis and 18 percent had cirrhosis, while 20 percent had little or no fibrosis. Looking at just the 1945-1965 age group, nearly half had severe fibrosis or cirrhosis.

"Persons with this stage of severe HCV-related liver disease are a high priority for treatment," the researchers concluded.

When interferon was the standard of care for hepatitis C, experts generally recommended that patients delay treatment until they developed advanced liver disease, allowing those who never progressed to that stage to avoid difficult and often futile treatment.

Now that highly effective and well-tolerated interferon-free therapy is available, many providers and advocates think everyone living with hepatitis C should be eligible for treatment. But the high cost of the new drugs has led to restrictions on their use, with some insurers and public payers covering treatment only for the sickest patients.

Cindy Zahnd from the University of Bern presented another study that showed the dangers of delaying treatment until advanced disease.

Zahnd's team used a mathematical model to predict how many HIV/HCV coinfected people would develop decompensated liver disease (liver failure), liver cancer, and liver-related death according to whether they started treatment one month after HCV diagnosis, one year after diagnosis, or when they progressed to moderate fibrosis (stage F2), severe fibrosis (stage F3), or cirrhosis (stage F4).

Starting interferon-free treatment soon after HCV diagnosis dramatically reduced the risk of decompensation, liver cancer, and liver-related death to 3 percent or less. But starting at later stages increased the likelihood of complications and death. If people did not start treatment until they developed cirrhosis, the risk of liver cancer was about 20 percent and the risk of liver-related death was around 25 percent. Starting treatment at stage F3 instead of F2 doubled the death rate, while waiting until stage F4 increased it by nearly five-fold. The risk of complications and death did not fall to zero even after successful treatment, with many such events occurring after people were cured.

While starting treating after one month versus one year "did not really make a difference," Zahnd concluded, whether treatment is started at stage F2, F3, or F4 "really matters."

Cost Remains a Barrier

During the last session of the conference experts discussed new frontiers and challenges in the hepatitis C field, which include too few people with HCV being diagnosed and the high cost of treatment. The U.S. list price for Gilead's Harvoni is $94,500, while AbbVie's Viekira Pak regimen runs around $83,300, both for a typical 12-week course.

"If we could identify all people and treat them tomorrow, our health care system couldn't support it," Rice emphasized at the start of the conference.

Marion Peters from UCSF wrapped up the meeting with a focus on the elephant in the room.

"The problem is not that direct-acting antivirals are too expensive," she said, "it's that too many people need treatment."

Treating all 3 million people with hepatitis C in the U.S. at a cost approaching $100,000 "is coming close to the GDP of a moderate-sized country," according to Ashwin Balagopal from Johns Hopkins.

The approval of Viekira Pak last December kicked off a price war between Gilead and AbbVie, with insurers, state governments, and national health programs making exclusive deals with one company or the other. While these deals have reduced prices by 30 to 40 percent, they prevent doctors from prescribing the treatment they think is best.

"Patients will get what insurers will cover," Peters emphasized.

The cost of treatment is a concern not only in the U.S. but also worldwide, as low- and middle-income countries have some of the highest numbers of people living with hepatitis C.

"There's been a rapid and remarkable translation of laboratory discoveries into approved drugs, and if treated, most people with hepatitis C can now be cured," concluded Mark Sulkowski from Johns Hopkins. "The bigger challenge is translation of clinical findings into global treatment."