Six weeks of sofosbuvir/ledipasvir is enough to cure acute hepatitis C in HIV-negative people

A regimen of sofosbuvir/ledipasvir (Harvoni) taken for six weeks cured all patients with genotype 1 acute hepatitis C virus (HCV) infection, including those with high viral loads, according to findings from a German study presented on Saturday at the 2016 International Liver Congress in Barcelona. The researchers said treating hepatitis C early with a short regimen would improve symptoms sooner, prevent HCV transmission and cost less than treatment initiated during chronic infection.

Studies done in the interferon era showed that treating people in the acute phase of HCV infection led to higher response rates and required a shorter duration than treatment of chronic infection. But because interferon-based therapy is poorly tolerated, many preferred to wait to see if the immune system would naturally clear HCV, which happens approximately 25% of the time.

The advent of interferon-free direct-acting antiviral (DAA) therapy has made chronic hepatitis C treatment shorter, better tolerated and more effective, leading experts to expect the same may be true for acute HCV infection. Yet there are currently no DAA regimens approved specifically for the treatment of acute hepatitis C, with current guidelines recommending the same options as used for chronic infection.

Katja Deterding and Heiner Wedemeyer of Hannover Medical School and fellow investigators with the German HepNet Acute HCV IV Study evaluated the safety and efficacy of sofosbuvir/ledipasvir for people with acute hepatitis C mono-infection. Dr Deterding presented the findings at a late-breaker session and Prof. Wedemeyer gave an overview during a press briefing.

This is the latest in a series of HepNet investigator-initiated acute hepatitis C studies. The others looked at interferon-based regimens taken for six months and saw sustained response rates ranging from 90 to 98%.

The prospective pilot study enrolled 20 participants at 10 centres in Germany between November 2014 and October 2015. Most (60%) were men and the mean age was 46 years. People with HIV co-infection were not included.

Acute HCV infection was defined as having known or suspected exposure to HCV within the prior four months, documented seroconversion from HCV antibody negative to positive, or an alanine aminotransferase (ALT) liver enzyme level more than 10 times the upper limit of normal – an indicator of acute liver inflammation.

The most commonly reported risk factors for HCV infection were sexual transmission (11 people or 55%) and medical procedures or needlestick injuries (five patients or 25%); only one reported injection drug use. Five of the suspected sexual transmissions were among men who have sex with men, with the remainder among heterosexual men and women. Although outbreaks of sexually transmitted HCV have been seen among HIV-positive gay men, heterosexual transmission is thought to be rare and HIV-negative gay men have HCV infection rates similar to those of the general population.

Eleven people had harder-to-treat HCV genotype 1a, while nine had 1b. Pre-treatment HCV viral load ranged from 3.3 to 6.7 log₁₀ IU/ml. The mean ALT level was 463 IU/l and the mean bilirubin level was 24 mg/dl. But some patients had very high levels, Prof. Wedemeyer said; the highest ALT level was over 2700 IU/ml and some patients had such high bilirubin levels they had icterus or jaundice, with yellowing of the skin and eyes.

All study participants were treated with sofosbuvir/ledipasvir in a fixed-dose co-formulation (400/90mg), without ribavirin, for six weeks. The usual recommended duration of sofosbuvir/ledipasvir for chronic hepatitis C treatment is 12 weeks, though people with no prior treatment experience, no cirrhosis and low viral load can be treated for eight weeks.

Everyone completed the full course of treatment and all had sustained virological response, or continued undetectable HCV RNA at the end of a 12-week post-treatment follow-up period (SVR12).

The researchers looked at the relationship between baseline viral load and early virological response. People with higher viral loads suppressed HCV more slowly, but all were undetectable by the end of treatment. This raises the prospect that an even shorter treatment duration may be adequate for some people.

Along with viral suppression, the patients experienced rapid biochemical response, or sharp declines in liver enzymes and bilirubin, with ALT normalisation and normal bilirubin levels by the end of treatment.

Treatment was generally safe and well-tolerated. There was one unrelated serious adverse event and no-one discontinued treatment early due to side-effects. The most frequently reported adverse events were gastrointestinal symptoms (20%), fatigue (15%) and hair loss (15%).

"Short treatment of only six weeks was highly effective with an SVR12 rate of 100% in acute HCV genotype 1 mono-infected patients," the researchers concluded. "High baseline viral load was associated with a delayed virological response, which however did not lead to treatment failures."

After Dr Deterding’s presentation, Prof. Jürgen Rockstroh of the University of Bonn pointed out that his group conducted a study of the same regimen for HIV-positive men with acute HCV co-infection. As he reported at the recent Conference on Retroviruses and Opportunistic Infections, six weeks of therapy cured co-infected people with low HCV viral load, but there were three relapses among patients with high baseline HCV RNA levels. These, along with a case of reinfection and two people lost to follow-up, resulted in an SVR12 rate of just 77%.

Prof. Wedemeyer told aidsmap.com that unlike in Prof. Rockstroh’s study, the HIV-negative patients with high viral load in the HepNet study "cleared more slowly but stayed cleared." While some experts are now saying people with HIV and HCV co-infection are no longer a ‘special population’ when it comes to hepatitis C, he suggested "there is still a difference", even if they have high CD4 counts and HIV suppression.

At both the press briefing and the late-breaker session, attendees brought up the issue of delaying treatment for acute HCV infection to see if spontaneous clearance will occur, as was common practice in the interferon era.

"I would recommend to start [during acute infection] due to the high SVR rate and rapid improvement of symptoms," Dr Deterding responded.

If treatment is delayed, "patients would be ill for months," which could interfere with employment and lead to stigma due to jaundice, Prof. Wedemeyer elaborated. It usually takes up to eight weeks for liver enzymes and bilirubin to normalise after acute infection, compared to just one week in this study.

Prof. Wedemeyer added that early treatment is also important for preventing HCV transmission, given that viral load is often high during the acute stage. Further, he noted, cutting treatment duration from 12 weeks during chronic infection to six weeks during acute infection would reduce the price by half, which "could be an enormous health cost savings."