Predicting response to acute hepatitis C treatment in HIV/HCV co-infected people

HIV/HCV co-infected people with higher HCV viral load, lower CD4 cell counts, older age and unfavourable IL28B status may not respond as well to interferon-based treatment for acute hepatitis C and may benefit from adding a direct-acting antiviral agent, researchers reported at the IDWeek 2013 meeting last week in San Francisco.

Up to 25% of people infected with hepatitis C virus (HCV) clear it spontaneously without treatment, whilst the rest go on to develop chronic hepatitis C lasting more than six months. Most people treated with pegylated interferon and ribavirin during acute infection achieve sustained virological response (SVR), considered a cure.

People with HIV/HCV co-infection are less likely to clear HCV spontaneously and less likely to respond to treatment during acute infection, making them more likely to develop chronic infection.

Leah Burke from Weill Cornell Medical Center, Daniel Fierer from Mt Sinai School of Medicine and colleagues looked at factors that predict treatment response amongst co-infected individuals treated during acute HCV infection.

Clinicians do not want, unnecessarily, to treat people who would have cleared HCV on their own, so therapy is typically recommended if people have detectable HCV RNA 12 weeks after exposure. The usual course of treatment for acute hepatitis C in HIV-negative people is pegylated interferon/ribavirin for 24 weeks, but the European AIDS Treatment Network recommends considering 48 weeks for co-infected people who do not experience rapid virological response (RVR), or undetectable HCV at four weeks.

Fierer's team has been following a cohort of HIV-positive gay men with presumed sexually transmitted hepatitis C for several years, reporting that they appear to experience rapid and aggressive liver disease progression.

At this year's Conference on Retroviruses and Opportunistic Infections (CROI), Fierer reported that adding the HCV protease inhibitor telaprevir (Incivo or Incivek) to pegylated interferon/ribavirin shortens the duration of treatment for acute hepatitis C and increases the likelihood of a cure for this group. But adding a direct-acting antiviral increases cost, side-effects and the potential for drug interactions with antiretrovirals, so it would be useful to predict which patients are most likely to respond to interferon/ribavirin alone and who could use extra help.

This retrospective analysis included 75 HIV-positive patients with acute HCV infection who were treated at Weill Cornell or Mt Sinai in New York City between January 2004 and January 2013. Participants were identified through referral from primary care and HIV physicians, city sexually transmitted disease and public health clinics and community outreach in high-risk populations.

Acute HCV infection was defined as having a first positive HCV antibody or HCV RNA test within the previous six month after having a previous negative test, or symptoms of acute infection such as jaundice or elevated alanine aminotransferase (ALT).

All but one of the participants were men who have sex with men, 61% were white, 23% were Hispanic, 16% were black; the median age was 42 years; about one-third had a history of injecting drug use. They had been HIV-positive for a median of seven years, had a median CD4 count of 551 cells/mm³, three-quarters were on antiretroviral therapy (ART) and 63% had undetectable HIV viral load.

Most participants (92%) had HCV genotype 1, the most difficult type to treat. A high proportion (41%) of those tested had the favourable IL28B CC gene variant. Nearly half had high pre-treatment HCV viral load (>1,000,000 IU/ml). All started treatment with pegylated interferon and ribavirin.

The overall SVR rate at 12 or 24 weeks after finishing therapy was 71%. At four weeks, 45% of participants experienced RVR, of whom 91% went on to achieve SVR; two patients relapsed and one did not have follow-up data.

Amongst the 53% who did not experience RVR, half nevertheless went on to achieve a cure. In addition, there were eight non-responders, four people who had HCV rebound while still on treatment, seven who experienced either relapse or reinfection and one with missing data.

Factors that significantly predicted RVR in a multivariate analysis were pre-treatment HCV viral load <1,000,000 IU/ml (odds ratio [OR] 17.24, or 17-fold higher likelihood), peak pre-treatment ALT >600 IU/ml (OR 5.69) and having a CD4 count greater than 500 cells/mm³ (OR 4.88).

Turning to SVR, significant predictors in a multivariate analysis that controlled for other factors were high baseline HCV viral load (OR 6.17) and being aged 40 or older (OR 5.68). Achieving RVR was a strong predictor of SVR, with an odds ratio of 13.50, or 13-fold higher likelihood.

Black race was a significant predictor of RVR in a univariate analysis and was of borderline significance for predicting SVR; being Hispanic was also a significant predictor of SVR in a univariate analysis. The association between race/ethnicity and treatment response has been shown to be primarily attributable to differences in the IL28B gene, which plays a role in interferon responsiveness. The favourable IL28B CC variant is less common amongst people of African descent. The researchers explained that they used race/ethnicity in their statistical analysis because data about IL28B – identified in 2009 – was only available for a subset of participants.

"The majority of HIV-infected patients respond favourably to treatment with [pegylated interferon] plus ribavirin in the acute stage of HCV infection," the investigators concluded. However, "there is a need for improved identification and optimisation of therapy in those who are at high risk of acute HCV treatment failure."

They recommended that clinicians consider adding a direct-acting antiviral for patients with "poor prognostic factors", including CD4 count below 500 cells/mm³, peak pre-treatment ALT below 600 IU/mL, age greater than 40 years, baseline pre-treatment HCV RNA >1,000,000 IU/mL or black race, or for anyone who does not experience RVR.

While adding telaprevir or boceprevir (Victrelis) can substantially increase side-effects and risk of antiretroviral drug interactions, next-generation direct-acting antivirals in the pipeline are better tolerated and produce higher cure rates with a shorter course of treatment. Interferon-free regimens are expected to be available within about three years.