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Lack of HCV Genetic Diversity Tied to
Higher Liver Disease Risk in Women With HIV
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IDWeek, October 2-6, 2013, San Francisco
Mark Mascolini
Lack of hepatitis C virus (HCV) genetic diversity in HCV/HIV-coinfected women independently raised the odds of liver disease in an analysis of the Women's Interagency HIV Study (WIHS) [1]. WIHS investigators believe absence of HCV diversity could prove a useful predictor of progression to liver disease.
HCV quasispecies represent viral mutations that happen spontaneously over time as HCV responds to immune pressure [2]. HIV infection speeds development of fibrosis in people with HIV, but factors contributing to progression remain unknown. No research addressed the potential impact of HCV quasispecies diversity on liver disease progression in HIV-positive people until this WIHS study.
WIHS investigators conducted a case-control study of HCV/HIV-coinfected women enrolled in this prospective cohort in six US cities in 1994-1995 or in 2002. Cases were 29 coinfected women in whom liver disease developed during follow-up but before antiretroviral therapy began. All had an HIV load above 1000 copies at the liver disease case-ascertainment visit and had sufficient plasma samples at the baseline visit and the case-ascertainment visit. Controls were 56 coinfected women matched to cases by age (under 45 versus 45 or older), WIHS enrollment period, WIHS visit in which liver disease was first detected in cases, and HIV load above 1000 copies at the corresponding liver disease visit. Liver disease did not develop during follow-up in controls.
The investigators defined liver disease as an aspartate aminotransferase-to-platelet ratio index (APRI) above 1.5 or FIB-4 above 3.25 at two consecutive visits, or liver-related death before antiretroviral therapy began. They used a heteroduplex mobility assay to evaluate HCV E1E2/HVR1 genetic diversity in plasma samples from cases and controls at the baseline visit and the case-ascertainment visit. Counting heteroduplex bands on the assay indicated no diversity when no bands were visible and diversity when 1 or more bands were visible.
At the baseline visit, one third of cases and controls were between 35 and 40, while a lower proportion of cases were under 35 (11% versus 26%) and a higher proportion over 40 (56% versus 42%). Race was balanced between cases and controls, with three quarters in each group black. Baseline CD4 counts, HIV load, and HCV load did not differ significantly between cases and controls. While 16% of both cases and controls were moderate drinkers (3 to 13 drinks per week), 24% of cases and 14% of controls were heavier drinkers (14 or more drinks per week). All cases and three quarters of controls currently smoked, and about one quarter in each group injected drugs.
Among the 165 samples tested for HCV quasispecies diversity, 61 (37%) had no diversity and 104 did. To identify factors associated with HCV quasispecies diversity, the investigators applied generalized estimating equation regression to data from both the baseline visit and the case-ascertainment visit. Three factors predicted lack of diversity: Women with a lower CD4 count were significantly more likely to have no diversity (odds ratio [OR] 3.45, 95% CI 1.54 to 7.76, for 350 to 499 CD4s versus 500 or more, P = 0.048). Hispanic women were less likely to have no diversity (OR 0.23, 95% CI 0.05 to 1.03, P = 0.03), as were women with a history of smoking (OR 0.16, 95% CI 0.03 to 0.79, P = 0.04). Variables that did not predict diversity in this analysis were age, HIV or HCV load, drinking in the past 6 months, or injecting drugs in the past 6 months.
To weigh the impact of HCV diversity on liver disease, the WIHS team used logistic regression adjusted for age, HIV and HCV load, CD4 count, and alcohol, drug injection, or smoking in the past 6 months. In these analyses, lack of HCV quasispecies diversity at the baseline visit raised the odds of liver disease more than 6-fold (OR 6.37, 95% CI 1.27 to 32.0). Lack of diversity at the case-ascertainment visit almost quadrupled the odds, although this association lacked statistical significance (OR 3.82, 95% CI 0.85 to 17.06).
The researchers speculated that lack of HCV diversity predicts progression to liver disease because lower viral diversity reflects the decreased immune pressure that comes with immune suppression. They proposed that absence of HCV quasispecies diversity "may be useful in predicting progression to liver disease" [1]. And they suggested that the heteroduplex mobility assay "is a simple, fast, and cost-effective method to assess HCV diversity."
References
1. Xu J, Operskalski E, Zhou H, et al. Hepatitis C virus diversity and liver disease development in HIV/HCV co-infected women. IDWeek 2013. October 2-6, 2013. San Francisco. Abstract 1510.
2. United States Department of Veterans Affairs. Hepatitis C genotypes and quasispecies. http://www.hepatitis.va.gov/provider/reviews/genotypes.asp
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