People with HIV and HCV co-infection who have fibrosis stages F2 and above should be prioritised for new anti-HCV therapies

People with HIV and hepatitis C virus (HCV) co-infection who have advanced liver fibrosis should be prioritised for therapy with new anti-HCV drugs, investigators argue in AIDS. Analysis of people in the EuroSIDA cohort showed that people with co-infection who have moderate (F2/F3) or advanced (F4) liver fibrosis had a significant risk of liver-related death. Early antiretroviral treatment (ART) was advocated for all patients as a way of avoiding liver disease and delaying the need for HCV therapy.

A significant number of people with HIV have HCV co-infection. The progression of HCV-related liver fibrosis is accelerated in people with untreated HIV infection, and liver disease caused by HCV is now a leading cause of death in these individuals. The development of direct-acting antiviral agents (DAAs) has revolutionised care for people with HCV. These new drugs are potent, tolerable, have manageable interactions and are associated with high cure rates. But a major drawback is their cost, a single course of treatment costing between 50,000 and 90,000 euros. It is highly likely, therefore, that access to DAAs for people with HIV and HCV co-infection will be rationed, with priority given to people with the greatest need – a high risk of liver-related death (LRD) in the short-to-medium term.

Investigators from the EuroSIDA cohort therefore designed a study to determine the characteristics associated with an increased risk of liver-related death for people with co-infection in the EuroSIDA cohort.

Glossary

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver. See also ‘cirrhosis’, which is more severe scarring.

hepatitis B virus (HBV)

The hepatitis B virus can be spread through sexual contact, sharing of contaminated needles and syringes, needlestick injuries and during childbirth. Hepatitis B infection may be either short-lived and rapidly cleared in less than six months by the immune system (acute infection) or lifelong (chronic). The infection can lead to serious illnesses such as cirrhosis and liver cancer. A vaccine is available to prevent the infection.

direct-acting antiviral (DAA)

Modern drugs for the treatment of hepatitis C, which work directly against the hepatitis C virus. They stop the virus from reproducing by blocking certain steps in its lifecycle.

tolerability

Term used to indicate how well a particular drug is tolerated when taken by people at the usual dosage. Good tolerability means that drug side-effects do not cause people to stop using the drug.

person years

In a study “100 person years of follow-up” could mean that information was collected on 100 people for one year, or on 50 people for two years each, or on ten people over ten years. In practice, each person’s duration of follow-up is likely to be different.

Their study sample comprised 3941 individuals with HIV and HCV co-infection who received care after 2000. None received HCV treatment based on interferon therapies.

Most of the patients were white (94%) and male (68%). The median age was 37 years and 70% were people who inject drugs.

Patients were followed for a median of 3.5 years and contributed just over 16,000 person-years of follow-up (PYFU). During this time, 670 deaths were recorded. The overall morality incidence was therefore 42 per 1000 PYFU. Just over a fifth (22%) of deaths were categorised as liver-related; the liver-related death incidence was 9.0 per 1000 PYFU.

The authors emphasise that liver-related death was the second most common cause of death after AIDS (24%).

Overall, mortality peaked among people aged 55 and over. However, rates of liver-related death were highest among people in the 35-45 and 45-55 age groups.

Mortality rates were significantly elevated among those with detectable HCV RNA, alcohol abuse and individuals with hepatitis B virus surface antigen (HBsAg) positivity.

Compared to people with no or mild fibrosis (F0/F1), death rates were 35 times higher among people with F4 stage fibrosis compared to those with stages F0/F1 (crude death rates [CDR] = 42.2 vs 1.2), and were eight times higher for individuals with F2/3 fibrosis (CDR = 10.0).

After controlling for potential confounders, fibrosis stage was the single biggest risk factor for liver-related death. Compared to people with F0/F1 fibrosis, those with F4 fibrosis had a sixfold increase in the risk of liver-related death (p < 0.0001), with the risk increased 2.5-fold for people with F2/F3 fibrosis (p < 0.0001).

Other risk factors were HBsAg positivity (p = 0.0024), infection with HCV for ten years or more (p = 0.041), lower CD4 cell count and age between 35 and 45 years (compared to younger age, p = 0.045).

When the investigators omitted baseline CD4 count from their model, a low nadir (lowest ever) CD4 count also became predictive of liver-related death (p = 0.0045).

The five-year probability of liver-related death was clearly related to fibrosis stage. It was low for people with F0/F1 disease (2%), but substantial for individuals with stages F2/F3 (10%) and F4 (14%).

CD4 count was related to the risk of liver-related death at all fibrosis levels. The five-year probability of liver-related death was lowest for individuals with F0/F1 fibrosis and a CD4 count above 300 cells/mm3 (1.7%), increasing to 3.3% for patients with F0/F1 disease and a lower CD4 count. People with F2 stage disease and above had a 9% five-year mortality probability if their CD4 count was above 300 cells/mm3, increasing to 15% if their CD4 count was below this level.

“Those with significant liver fibrosis (F2 >) should be prioritized for treatment with DAAs,” conclude the authors. “It is essential to identify co-infected individuals as soon as possible so that they may start cART [combination antiretroviral treatment] early in the course of HIV infection…to prevent rapid progression of liver fibrosis and reduce the need for expensive treatments.”

References

Grint D et al. Liver-related death among HIV/hepatitis C-virus-co-infected individuals: implications for the era of directly acting antivirals. AIDS 29: 1205-15, 2015.