Genital tract a 'sanctuary site' for hepatitis C virus in coinfected HIV-positive women

Hepatitis C virus (HCV) appears to be compartmentalised in the genital tract of women coinfected with HIV, and may replicate independently, according to a study from the United States and Poland published in the November 1^st issue of The Journal of Infectious Diseases, now available online. The study, which also found that HIV interacts with HCV in the genital tract, may help to explain why mother-to-child transmission of HCV occurs at a comparatively higher rate in coinfected women than in women who are monoinfected with HCV, and suggests that the risk of female-to-male sexually transmitted HCV infection may be increased in coinfected women.

Despite growing evidence suggesting that female-to-male and mother-to-child transmission of HCV is on the increase, little is known about vaginal and cervical shedding of HCV in HIV-positive women. Consequently, researchers from the University of California Los Angeles, the Mayo Clinic in Scottsdale, Arizona and the Medical Academy in Warsaw, Poland, sought to examine factors that correlated with HCV genital shedding as well as examine HCV quasispecies composition in a group of HCV/HIV-coinfected women.

They undertook a cross-sectional study of 71 women that was nested within the Women's Interagency HIV Study (WIHS); a prospective, multicentre study that has been examining the impact of HIV infection on women since 1993.

This study included 58 of the 113 HCV/HIV-coinfected women enrolled at the Los Angeles WIHS site, as well as thirteen of the 23 women monoinfected with HCV. HCV was measured in the genital tract by cervicovaginal lavage (CVL). This is a method of "washing" the vaginal cavity to test the resulting fluid in order to determine HCV viral load in a woman's genital tract secretions.

Most (65.5%) of the coinfected women were aged 35 or older, 40% were black, 31% Hispanic, and 15% white, and 79% reported a history of injection drug use. Seventy percent had received highly active antiretroviral therapy (HAART) within the previous six months, but the researchers provide no further information on HAART or on the anti-HCV therapy, if any, undertaken by the women.

HCV RNA (viral load, with limit of detection of 600 copies/mL in plasma) was detected in plasma from 67% (39/58) of the coinfected women, compared with 46% (6/13) of the monoinfected women. The coinfected women also had higher HCV plasma viral loads than the monoinfected women (data not shown).

HCV RNA (viral load, with limit of detection of 60 copies/mL in CVL) was detected in CVL fluid from 31% (18/58) of the coinfected women, although the researchers note that the viral loads were relatively low (median 1500 copies/mL; range, undetectable to 4000 copies/mL); 16 of the 58 women had CVL HCV viral loads below 800 copies/mL. The only significant difference between the coinfected women with and without detectable HCV shedding was that the women with HCV shedding had higher plasma HCV viral loads (p=0.04). None of the monoinfected women had detectable HCV viral load in CVL (p=0.03).

Univariate analysis showed that there was no correlation between HCV viral load in CVL fluid and HIV viral load in plasma, the number of white blood cells in CVL fluid, or anti-HIV therapy. There were, however, possible associations between the presence of HCV viral load in CVL fluid and CD4 cell count, the presence of HCV viral load in plasma, the presence of HIV viral load in CVL fluid, and blood contamination.

However, in multivariate analysis that adjusted for plasma HCV viral load, CVL HIV viral load, plasma HIV viral load and CD4 cell count, the only statistically significant predictors of HCV shedding in CVL fluid were the presence of HCV viral load in plasma (OR, 16.81; 95% CI, 1.53-185.31) and the presence of HIV viral load in CVL fluid (OR 19.87; 95% CI, 1.70-231.65).

Nine women (six coinfected women and three monoinfected women) were randomly selected for intense molecular evaluations in order to assess whether compartmentalisation of HCV led to genetic diversity between blood and genital HCV. HCV viral load was detected by a highly sensitive RT-PCR method in both plasma and CVL fluid from five women (three coinfected and two monoinfected women). In the three coinfected women, HCV from CVL contained unique sequences that were not seen in HCV derived from their plasma or PBMCs. This suggests, say the study's authors, "that a local HCV genital tract reservoir may exist and that this may be the source of infection for those suspected to have been infected sexually, a possibility further supported by the analysis of HCV quasispecies isolated from plasma, PBMCs, and CVL fluid."

This is the first study to demonstrate that HCV is compartmentalised in the genital tract of HCV/HIV coinfected women. In addition, it is also the first to suggest the possibility that HCV replicates in the genital tract independently of plasma. "These findings have important implications for both sexual and perinatal transmission of HCV," comment the study's authors, adding that "increased mother-to-infant and sexual HCV transmission in HCV/HIV-1-coinfected women makes it especially urgent to study and understand the dynamics of HCV in this subset of patients."

The add that "our study also suggests that, among HIV- 1-infected women who are HCV viremic, there is an association between shedding of both viruses and that local control of both viruses may be impaired in those found to be shedding. This may explain the increased rate of perinatal HCV transmission to HIV-1-infected newborns and the observation that sexual transmission may be increased in coinfected patients."

Currently it is unclear exactly how HIV and HCV may interact in the genital tract resulting in increased shedding. The authors suggest two plausible explanations: HIV and HCV may be infecting the same cells, resulting in increased HCV turnover; or local immune dysfunction allows both viruses to replicate.

The authors conclude: "we have found that HCV RNA can be detected in almost 30% of HCV/HIV-1-coinfected women and that viral diversity does exist between local HCV and plasma HCV extracted from HCV/HIV-1-coinfected women. Our findings may explain a comparatively higher rate of HCV vertical transmission by HIV-1-coinfected women reported in several studies. The relationship between HIV-1 and HCV shedding is intriguing and suggests a unique local interaction between these two viruses in the genital tract."