People with HIV who were cured of hepatitis C remained at higher risk of a number of serious health outcomes including liver disease and heart disease than people without HIV in the five years after being cured, even after controlling for liver disease stage, the AIDS Clinical Trials Group reports in the journal Open Forum Infectious Diseases.
Similarly, French researchers found that even after excluding people with cirrhosis of the liver, people with HIV who were cured of hepatitis C remained at higher risk of several serious health outcomes than people with HIV who had never had hepatitis C.
HIV speeds up the liver damage caused by hepatitis C, leading to an increased risk of decompensated cirrhosis and death from liver failure in people with HIV and hepatitis C. Curing hepatitis C with direct-acting antiviral treatment halts liver damage, but studies have shown mixed results regarding the capacity of the liver to regenerate after hepatitis C is cured.
If the liver does not regenerate after hepatitis C, a person may remain at higher risk of liver-related disease than people without hepatitis C. It is unclear if HIV affects the capacity of the liver to regenerate.
Hepatitis C infection also has negative effects on other organ systems, notably the kidneys and the cardiovascular system, leading to a higher risk of kidney failure and heart attack. HIV exacerbates damage in these systems and tissues as well, and again, it is unclear to what extent this damage is ameliorated after hepatitis C cure in people with HIV.
To look at the impact of HIV on long-term outcomes after curing hepatitis C, the US AIDS Clinical Trials Group recruited a cohort of people with and without HIV within one year of completing direct-acting antiviral treatment, aiming to follow them for five years.
The study recruited 332 people, 184 with HIV and hepatitis C (including 54 who did not achieve a cure) and 125 with hepatitis C alone (including 23 who did not achieve a cure). Approximately three quarters were male, just under half were Black, and cirrhosis of the liver was significantly more common in people with HIV than those without (26% vs 13% in people cured of hepatitis C, p= 0.008). Among those cured, people with HIV were younger (median age 53) than people without HIV (59). People with HIV had well-controlled HIV (95% of those cured and 82% of those not cured) and CD4 counts were in the normal range (700 in those cured in 555 in those not cured).
The researchers compared the rates of death and 'targeted diagnoses' (blood and lymphatic system, cardiac, gastrointestinal, liver, kidney and vascular disorders, plus other complications of chronic liver disease including pulmonary hypertension and lichen planus, metabolic disease, cancers strongly associated with hepatitis C, and substance use disorders) between cured and uncured people, and according to whether people were living with HIV or not.
The endpoints of death and targeted diagnoses were combined, as there were only 15 deaths and 75 targeted diagnoses among study participants. Over four years of follow-up the estimated cumulative rate of targeted diagnoses or deaths was 24% in people with HIV who were cured of hepatitis C and 17% in people without HIV who were cured of hepatitis C. However, when comparing people with HIV cured or not cured of hepatitis C, there was no significant difference in the cumulative rate of deaths or targeted diagnoses.
Among people with HIV cured of hepatitis C, the most common diagnoses and causes of death were cardiovascular.
A regression analysis that adjusted for demographic characteristics, body mass index, a measure of liver fibrosis (FIB-4), CD4 count and viral load showed that the only factor significantly associated with the composite outcome was HIV status (adjusted hazard ratio 2.0, p=0.047) in those who were cured. More advanced fibrosis (FIB-4>3.25, aHR 5.0, p=0.009) was the only significant factor in those who were not cured.
The researchers say that their study is the first to systematically compare post-cure outcomes in people with and without HIV. “Even with comparable baseline liver disease stage and other risk characteristics, […] more adverse clinical outcomes were realized in the younger HIV group,” they note. Although inflammation caused by HIV coupled with accelerated ageing may contribute to this outcome, they say more research is needed to understand the interaction between harm caused by HIV and hepatitis C in people who have been cured of hepatitis C.
A second study, which looked at post-cure outcomes only in people with HIV, matched 3,961 people with HIV cured of hepatitis C between 2013 and 2020 with 33,872 people with HIV without hepatitis C. Participants were matched by age, sex, HIV transmission group, history of AIDS diagnosis and body mass index. All participants were virally suppressed.
During a median follow-up period of 3.7 years, people with HIV cured of hepatitis C were approximately twice as likely to die as people with HIV without hepatitis C (incidence rate ratio 1.9). After the first 12 months of follow-up, previous coinfection with hepatitis C was associated with more than twice the incidence of death from any cause during the follow-up period (IRR 2.4). The association between past hepatitis C infection and increased risk of death was not affected by duration of antiretroviral treatment, CD4 count or viral suppression.
Cause of death was reported for 518 out of 659 deaths. Liver-related deaths were more common in those cured of hepatitis C (17% vs 3%). Non-AIDS, non-liver-related cancer was the most common cause of death in both groups (17% vs 26%).
Critically, this study excluded people with liver cirrhosis, so it screened out people who would have been at high risk of liver-related death despite hepatitis C cure. Nevertheless, people with HIV and hepatitis C had been living with hepatitis C for a median of 15 years before starting direct-acting antiviral treatment, suggesting that longstanding hepatitis C infection might lead to harm even without severe liver damage.
The authors say that more research is needed to understand why people with HIV cured of hepatitis C have a higher long-term risk of death than those without hepatitis C.
Wyles DL et al Adverse impact of HIV-1 on long-term outcomes following HCV DAA treatment: final results of ACTG A5320, the Viral Hepatitis C Infection Long-term Cohort Study (VHICS). Open Forum Infectious Diseases, 10 (3): ofad115, 2023.
Requena MB et al. Mortality in HCV-cured versus HCV-uninfected people with HIV: a matched analysis in the ANRS CO4 FHDH cohort. AIDS, published online 6 April 2023.