Hepatitis C virus (HCV) infection in people with HIV co-infection is associated with an increased risk of liver disease and liver-related death and also several important non-liver related disorders, including kidney disease and osteoporosis and fractures, according to data from the Swiss HIV Cohort published in the online edition of Clinical Infectious Diseases. Restricting analysis to HCV-positive people showed that ongoing HCV replication was associated with liver disease and death and an increased risk of diabetes.
“In this large nationwide community-based HIV cohort study HCV exposure was associated with an increased risk of kidney disease and osteoporosis,” comment the authors. “This risk did not seem to be related to persistent HCV replication. Compared with those with SVR [sustained virological response to HCV therapy], non-SVR participants had an increased risk of diabetes mellitus.”
Up to 30% of HIV-positive people have co-infection with HCV. It is well known that chronic HCV infection is associated with an increased risk of serious liver disease and liver-related death. However, it is less clear if the infection is also associated with an increased risk of serious non-liver-related events, such as diabetes, cardiovascular disease, malignancies and bone complications. Cohort studies – some involving people with HIV co-infection – have yielded conflicting results.
Highly effective therapy with direct acting agents (DAA) is now available. Treatment strategies are still being devised. It is important to know whether eradication of HCV with DAAs also reduces the risk of non-liver-related illnesses.
Investigators from the Swiss HIV Cohort therefore designed a study comparing the incidence of liver- and non-liver-related illnesses and death between HIV-positive people with and without HCV exposure. A second analysis compared outcomes between HCV-positive people.
The study population comprised approximately 2500 HCV-seropositive people and 2500 HCV-seronegative controls. The HCV-exposed group included 540 individuals with spontaneous clearance, 1294 untreated HCV-RNA-positive people, 345 treated people with SVR and 281 treated individuals without SVR. Only 10% of treated people received a regimen that included a direct-acting agent.
HCV-positive people were more likely than HIV-monoinfected people to be female (34% vs 22%), to have acquired HIV through injecting drug use (68% vs 2%), had longer duration of HIV infection (median duration 19 vs 16 years) and were less likely to be taking antiretroviral therapy (96% vs 98%). In addition, HCV-positive people were more likely to be current smokers (74% vs 37%), active injecting drug users (13% vs 0.4%) and have heavy alcohol consumption (14% vs 6%) (all comparisons p = < 0.001).
Individuals were followed for a median of 8.2 years. The following events were observed in HCV-positive vs HCV-negative people:
- liver events: 107/18
- kidney events: 41/14
- osteoporosis/fractures: 230/121
- diabetes mellitus: 82/94
- cardiovascular disease: 114/129
- non-AIDS cancers: 119/147
- serious HIV-related disease: 162/126
- liver-related death: 106/10
- non-liver-related death: 227/218.
A total of 412 (17%) HCV-positive people died. The main causes of death were liver-related (32%), sepsis (16%), substance abuse (15%), HIV/AIDS (14%), non-AIDS-related cancers (14%). There were 283 deaths (11%) among the HCV-negative individuals. The main causes of death were non-AIDS cancers (23%), HIV/AIDS (16%) and cardiovascular disease (12%).
When compared to HCV-negative people, individuals with HCV exposure had an increased risk of liver disease (IRR = 6.29; 95% CI, 3.52-11.22), liver-related death (IRR = 8.24; 95% CI, 3.61-18.83), kidney disease (IRR = 2.43; 95% CI, 1.11-5.33) and osteoporosis/fracture (IRR = 1.03-2.01). There was no significant association with diabetes mellitus, cardiovascular disease, non-AIDS cancers, HIV-related disease and non-liver-related death.
HCV-treated non-SVR individuals had the highest incidence of liver disease, liver-related death, diabetes mellitus and serious HIV-related events compared to the HCV-negative controls. The risk of osteoporosis/fracture was significantly increased for people with spontaneous HCV clearance compared to the HIV-mono-infected controls. Rates of non-liver-related death were similar in all HCV-exposed groups, regardless of treatment and SVR status compared to the controls.
Analysis was restricted to the HCV-positive people. Treated individuals without SVR had an increased risk of liver-related events (IRR = 6.79; 95% CI, 2.33-19.81), liver-related death (IRR = 3.29; 95% CI, 1.35-8.05) and diabetes mellitus (IRR = 4.62; 95% CI, 1.53-13.96), compared to people with SVR. Similar differences – but without statistical significance – were found between untreated HCV viraemic individuals and people with SVR.
“HCV exposed HIV-positive individuals have an increased risk of kidney disease and bone-related events which does not seem to be related to persistent viral replication,” conclude the authors. “In addition to a significant decrease of liver-related disease and death therapeutic viral eradication leads to a reduction in diabetes mellitus.”
The author of an accompanying editorial suggests that behavioural factors may be behind the increased risk of bone disease and renal problems seen in the people with HCV co-infection
“Specific cohorts, or preferably cohort collaborations, that include large samples of DAA-treated patients with long-term follow-up are needed to determine the impact of successful treatment with these new regimens on extrahepatic diseases among HIV/HCV patients,” he writes. “These data will help inform whether reductions in rates of extrahepatic outcomes can help to justify DAA-based HCV treatment and if extrahepatitc disease should be included as a major indication for DAA therapy even in the absence of significant liver fibrosis.”
Kovan, H et al. Hepatitis C infection and the risk of non-liver-related morbidity and mortality in HIV-positive persons in the Swiss HIV Cohort Study. Clin Infect Dis, online edition, 2016.
Lo Re, V. Extrahepatic complications of hepatitis C virus infection in HIV and the impact of successful antiviral treatment. Clin Infect Dis, online edition, 2016.