DAA therapy cures most people with HIV/HCV co-infection with decompensated cirrhosis or liver transplants

People with HIV/hepatitis C virus (HCV) co-infection with liver cirrhosis or liver failure, and those who received liver transplants, saw high rates of sustained virological response using interferon-free direct-acting antiviral (DAA) therapy for hepatitis C, according to three Spanish studies presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2017) last month in Seattle.

As expected, cure rates were not as high as those seen in people with less advanced liver disease. However, they were similar to those of HIV-negative people with HCV mono-infection at similar stages of liver disease.

Over years or decades chronic HCV infection can lead to serious complications including cirrhosis, liver failure and the need for a liver transplant. Liver function typically diminishes gradually, as the liver can compensate for some damage. But eventually scar tissue blocks normal blood flow and the liver cannot carry out its vital functions – a condition known as decompensated cirrhosis.

People with decompensated liver disease may develop symptoms such as ascites (abdominal fluid build-up), bleeding veins in the oesophagus and stomach and hepatic encephalopathy (brain impairment). People with HIV/HCV co-infection appear to progress to decompensation more frequently and more rapidly than those with HCV alone.

Decompensated patients are classified as Child-Pugh class B or C, based on a set of liver function biomarkers and symptoms. The MELD scoring system (based on bilirubin, creatinine and blood clotting capacity) is used to prioritise candidates for liver transplants.

During the interferon era many people with decompensated cirrhosis and liver transplant recipients could not tolerate hepatitis C treatment, and pegylated interferon plus ribavirin was not very effective for these groups. Many experts once considered decompensation a contraindication for treatment, but the advent of DAAs has changed this.

People with advanced cirrhosis

Jordi Navarro of University Hospital Vall d’Hebron in Barcelona and colleagues did a prospective cohort study of 170 people with HIV/HCV co-infection with cirrhosis who started DAA therapy at 13 Spanish centres during 2015.

About three-quarters were men and the average age was 51 years. The most common HCV genotypes were 1a (40%), 1b (12%), 3 (15%) and 4 (28%). Most (75%) had compensated cirrhosis, but 12% were Child-Pugh class B and 17% had a history of prior decompensation.

Participants were on stable antiretroviral therapy (ART), most (89%) had undetectable HIV viral load and the median CD4 T-cell count was approximately 500 cells/mm³. About half were starting hepatitis C treatment for the first time, 38% had been treated before with pegylated interferon plus ribavirin and about 14% had tried early HCV protease inhibitors with pegylated interferon/ribavirin.

Most cohort participants were treated with interferon-free DAA regimens for 12 or 24 weeks, most commonly sofosbuvir/ledipasvir (Harvoni) plus ribavirin (25%), sofosbuvir/ledipasvir alone (15%), sofosbuvir and simeprevir (Olysio) plus ribavirin (20%), or sofosbuvir and daclatasvir (Daklinza) plus ribavirin (15%).

Overall, 98% of previously untreated and 89% of treatment-experienced participants achieved sustained virological response, or continued undetectable HCV RNA at 12 weeks post-treatment (SVR12). Previously treated people with HCV genotype 1a or 4 had somewhat lower response rates (87% and 83%). Cure rates were 95% or higher for all regimens except sofosbuvir and simeprevir without ribavirin for 12 weeks (63%).

Treatment was generally safe and well tolerated. However, 16% had to reduce their ribavirin dose, mostly due to anaemia. Four people experienced liver decompensation while on treatment. Liver stiffness, an indicator of fibrosis severity, decreased by an average of 5.6 kPa after treatment.

In another study, Juan Berenguer of Gregorio Maranon Hospital in Madrid and colleagues looked at real-life outcomes among people with HIV/HCV co-infection with advanced liver disease in the MADRID-CoRe registry who received interferon-free DAA therapy between November 2014 and May 2016.

Of the 2662 DAA-treated individuals with co-infection in the registry, 146 – about 5% – fell within the study's definition of decompensated cirrhosis (having ever had Child-Pugh class B or C or hepatocellular carcinoma). Of these, 51% were currently classified as Child-Pugh class A, 43% as class B and 6% as class stage C. The median MELD score was 10, 10% had a history of hepatocellular carcinoma, one person had received a liver transplant and seven (5%) were on a transplant waiting list.

Again most participants (70%) were men and the median age was 52. The most common HCV genotypes were 1a (34%), 1b (22%), 3 (15%) and 4 (21%). Most were on ART and the median CD4 count was 474 cells/mm³. A majority (60%) had not been treated before for hepatitis C.

The most common interferon-free regimens were sofosbuvir/ledipasvir (50%), sofosbuvir and daclatasvir (25%) or sofosbuvir and simeprevir (18%). Across all regimens, about half included ribavirin and half did not.

Looking at the entire MADRID-CoRe cohort, sustained response rates were 94% for people without cirrhosis, 91% for those with compensated cirrhosis and 81% for those with decompensated cirrhosis. Two people with decompensation had to stop treatment due to adverse events.

The difference was driven by people with the most severe liver disease: people with Child-Pugh class A and B did well (87% and 79%), but the SVR12 rate fell to just 44% for class C. Rates were 74% and 88% for people with MELD scores above and below 10, respectively. Male sex and Child-Pugh class C were the only significant predictors of treatment failure.

Liver transplant recipients

Finally, Christian Manzardo of the University of Barcelona and colleagues assessed the safety and effectiveness of DAA regimens in a nationwide cohort of HIV-positive and HIV-negative people who received liver transplants at 22 centres in Spain between 2002 and 2012 and were followed to December 2016.

Studies have shown that people with co-infection who undergo liver transplants have lower overall survival rates than people with HCV mono-infection. But people with co-infection who are cured of recurrent hepatitis C have 5-year survival rates similar to those of the HCV mono-infected population, the researchers noted as background.

This analysis included 41 people with HIV/HCV co-infection with post-transplant HCV recurrence who were treated with interferon-free regimens consisting of at least two DAAs, with or without ribavirin. Most were on ART with undetectable HIV viral load and the median CD4 count was 367 cells/mm³.

They were compared against a matched cohort of 149 transplant recipients with HCV mono-infection who received similar treatment. In both groups most (around 80%) were men and the average age was about 48 years. Just over half had previously been treated for hepatitis C.

Participants started DAA therapy about 75 months after transplantation; 39% of the co-infection group and 29% of the mono-infection group already had cirrhosis in their new liver. The most common regimens used by the individuals with co-infection were sofosbuvir and daclatasvir (27%), sofosbuvir and simeprevir plus ribavirin (27%), sofosbuvir/ledipasvir plus ribavirin (20%) and sofosbuvir/ledipasvir alone (12%).

SVR12 rates were similar for people with HIV/HCV co-infection and people with HCV mono-infection – 93% and 95%, respectively. Response rates did not differ according to the genotype or degree of liver fibrosis.
 Half of the eight people who experienced virological failure were taking regimens now considered suboptimal. Treatment was well tolerated and only one person in the mono-infection group died due to liver decompensation.

"Interferon-free regimens for treatment of post-liver transplant HCV recurrence in HIV-infected individuals are highly effective and well tolerated, with results comparable to HCV mono-infected patients," the researchers concluded.

Treatment recommendations

Taken together, these studies show that people with decompensated cirrhosis and liver transplant recipients can be treated using some of the same DAA combinations as people with less advanced liver disease, but they may need to add ribavirin or lengthen the duration of therapy.

EASL and AASLD/IDSA hepatitis C treatment guidelines recommend sofosbuvir-based regimens for these groups. Ribavirin may be started at a low dose and increased if tolerated. Regimens containing paritaprevir (Viekirax) are not recommended for people with decompensated cirrhosis due to risk of worsening liver injury.

Recommended regimens are the same for people with or without HIV co-infection, taking into account possible interactions with antiretrovirals. Response rates for the people with HIV/HCV co-infection in these studies were similar to cure rates for people with HCV mono-infection in the SOLAR (sofosbuvir/ledipasvir), ALLY-1 (sofosbuvir and daclatasvir) and ASTRAL-4 (sofosbuvir/velpatasvir; Epclusa) trials.

Successful treatment can slow liver disease progression and may partially restore lost liver function – some people improve enough to be taken off the transplant waiting list. But prompt treatment can avoid decompensation and the need for a transplant altogether, and guidelines now recommend treatment for everyone with hepatitis C regardless of liver disease stage.