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Hepatitis C Virus Viremia in HIV-Infected Individuals With Negative HCV Antibody Tests
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Abstract: Hepatitis C virus (HCV) viremia may occur in persons without detectable HCV antibodies and has been reported in as many as 5.5% of HIV-positive persons. To better characterize serosilent HCV infection, the authors prospectively tested 131 HIV-positive persons and 102 HIV-negative control subjects with diabetes for the presence of HCV antibody (Ab) and HCV RNA. Thirty of 31 HCV Ab-positive (AbP) HIV-positive people tested positive for HCV RNA as did both HCV AbP, HIV-negative control subjects. Similarly, none of the 100 HIV-negative, HCV Ab-negative (AbN) control subjects was HCV RNA positive (p < .001). In contrast, 19 of 100 HIV-positive, HCV AbN persons met stringent criteria for HCV viremia, and 9 of these 19 people were HCV RNA positive when tested by a commercially available HCV RNA detection method. The mean duration of HCV viremia in HCV AbN people was 26.8 months (range, 1-99 months). None of the subjects developed HCV antibody during the study. The HIV-positive, HCV AbP, and RNA-positive group was significantly more likely to have acquired HIV parenterally (p < .001), have higher initial CD4 counts (p = .029), and have higher ALT values than the HCV AbN group (p < .002). In summary, HCV infection appears to occur more frequently among HIV-infected, HCV-seronegative persons than appreciated, especially if HIV acquisition was through sexual as opposed to parenteral risk factors and was associated with a lower initial CD4 count and lower ALT values.
Sarah L. George; Departments of Internal Medicine and Research, Iowa City Veterans Administration Medical Center and The University of Iowa College of Medicine, Iowa City, Iowa, U.S.A. JAIDS Journal of Acquired Immune Deficiency Syndromes 2002; 31(2):154-162
Discussion: People infected with HIV are frequently coinfected with hepatitis C virus (HCV) due to shared modes of transmission. Persons acquiring HIV through transfusion of blood products or injection drug use are more likely to be coinfected with HCV than are people who acquire HIV through sexual contact (1), and up to 90% of HIV-positive intravenous drug users (IDUs) test positive for HCV antibody (2-5). In contrast, only 4% to 8% of people who acquire HIV through sexual contact have detectable HCV antibodies (6-9). Before the availability of effective antiretroviral therapy (ART), HCV coinfection did not appear to increase mortality among HIV-infected people (10), although some studies (11-14) found increased levels of HCV RNA in the plasma of HIV-positive patients compared with HIV-negative control
patients (15-17). In addition, some reports suggested that cirrhosis and hepatocellular carcinoma developed more rapidly in HIV-positive persons compared with HIV-negative control subjects (18-21), and in one study, the cumulative risk of
liver-related mortality in HCV-HIV-coinfected people was greater than in those infected only with HCV (6.5% vs. 1.4%) (19). Since the development of effective ART, there have been several reports of rapidly progressive hepatitis and liver failure in HIV-infected persons after institution of therapy (22-26). Several groups have reported the detection of HCV RNA in people who lack detectable antibodies to HCV (27-32), particularly among HCV antibody-negative people with chronic liver disease (32-35). We found that the use of whole blood RNA was a more sensitive template for HCV RNA amplification than was plasma-derived RNA in HIV-negative patients and that approximately 16% of HCV viremic persons who lacked detectable HCV antibodies in commercial assays had HCV antibodies directed against recombinant HCV virus-like particles, suggesting that some of these HCV antibody-negative patients mount a humoral immune response against conformational HCV antigens (36).
Abnormal HCV antibody and cellular immune responses have been described in HIV-positive people (16, 37-42). Bonacini et al. (39) recently reported that 6 of 110 HIV-positive, HCV antibody-negative persons (5.5%) had detectable HCV RNA in their sera using a commercially available HCV RNA assay. The median CD4 count of the
antibody-negative group was significantly lower than the median CD4 count of the HCV antibody-positive group (36 cells/mm3 and 235 cells/mm3, respectively) (39), suggesting that failure to mount an antibody response was due to immune deficiency.
Given the clinical impact of HCV coinfection on HIV infection and the unknown prevalence of seronegative HCV infection in HIV-infected patients, we sought to determine the frequency of HCV antibody-negative, RNA-positive infection among HIV-positive persons using our previously described whole blood HCV RNA detection method (32). Positive results were confirmed by testing additional whole blood and plasma samples from these HCV antibody-negative, HCV RNA-positive subjects and by testing samples using commercial HCV RNA methods. We also determined the frequency of HCV infection in HCV antibody-negative, HIV-negative people with diabetes.
Several studies have reported the detection of HCV-RNA without detectable antibodies to HCV in people who are not infected with HIV (28-32, 45). Rossi et al. (27) found that 5 of 13 patients infected with HCV by contaminated IVIG failed to develop antibodies to HCV, despite prolonged HCV viremia. Durand et al. (29) identified a healthy 46-year-old blood donor with no evidence of hepatitis but with HCV RNA present in his serum, and no detectable HCV antibody by either ELISA or immunoblot testing. Eight of the 11 recipients of this person's blood products had detectable HCV antibodies, and 3 recipients shared HCV sequence identity with the blood donor. Similarly, prolonged HCV viremia in the absence of detectable HCV antibodies was found in chimpanzees experimentally infected with HCV (30).
In HIV-positive people coinfected with HCV, abnormal antibody and cellular immune responses to HCV have also been described (16, 37-42). John et al. reported 2 patients with HCV viremia for up to 2 years who did not develop HCV antibodies until the institution of effective ART, after which both developed HCV antibodies (22). Cribier et al. (16) found a higher rate of indeterminate third generation RIBA testing (14.7% vs. 4%) in 75 HIV-positive patients when compared with 75 HIV-negative HCV-positive patients, suggesting that HIV-infected people have impaired HCV antibody production. A variety of HCV diagnostic test findings have been described in people with HIV, including the detection of HCV RNA without serum antibody detection (39), seroreversion with decline in immune status (37, 38), seroconversion with effective ART (22), and weakened or variable immune response to HCV (16). Bonacini et al. (39) recently detected HCV viremia in plasma samples from 6 of 110 HIV-infected HCV antibody-negative patients (5.5%).
Our results are very similar, as 6 of the 100 HIV-infected HCV-seronegative patients had HCV RNA detected in plasma using the standard commercial assay. Using the more sensitive whole blood HCV RNA methods (32), we found HCV viremia in 20 of 100 (20.0%) HIV-infected, HCV antibody-negative patients tested during a 14-month period. Sixteen of the 20 HCV viremic, HCV antibody-negative patients had HCV RNA detectable in previous serum samples. None of 20 patients seroconverted during the study period even though HCV viremia was documented for up to 99 months in 1
patient. Using the same whole blood HCV RNA detection methods, none of 102 control patients with diabetes tested positive for HCV RNA in the absence of HCV antibody. HCV RNA was detected more frequently in the 31 HCV-seropositive patients (84.4% of tests) than in the 20 HCV viremic HCV-seronegative patients (51.5% of tests).
This may reflect intermittent viremia or lower concentrations of HCV RNA that are near the limits of detection of the RT-PCR method in this group of patients.
Among the three groups of HIV-infected patients studied, HCV-seropositive patients were more likely to have parenteral transmission risk factors (p < .001) and to have higher initial, peak, and mean ALT than either group of HCV seronegative subjects (p < .002). The initial CD4 counts in the HCV-seropositive group were significantly higher than the CD4 counts in the HCV viremic, HCV-seronegative group (392 cells/mm3 vs. 225 cells/mm3, respectively), a finding also noted by Bonacini (39). As HCV-related liver disease is mediated at least in part by host cellular immune function, the higher ALT values observed in the HCV-seropositive group may reflect a more effective immune response to HCV. The higher occurrence of parenteral risk factors in the HCV seropositive group is consistent with the findings of Thio et al. (5). Persons with hemophilia and IDUs are usually infected with HCV before being infected with HIV and
are frequently exposed repeatedly to HCV (5). Infection with HCV through mucosal or sexual exposure would presumably involve a lower HCV inoculum, which may result in differences in clinical presentation. It is possible that sexual transmission of HCV may lead to occult infection in sites other than the liver, such as peripheral blood
mononuclear cells (34, 46). Previous studies have shown that people infected with HIV through sexual transmission have approximately threefold higher rates of HCV antibody positivity (4%-8%) than the general population (1), suggesting that sexual transmission of HCV may be increased in HIV-infected people (1). The ALT and CD4 values in HCV-seropositive patients who had attended our clinic since 1988 tended to be lower in subjects reporting a sexual mode of HIV acquisition as opposed to a parenteral mode of HIV transmission. These data suggest that differences in
HCV seropositivity and ALT values may exist between HIV-infected patients who acquire HCV through sexual versus parenteral exposure, although further studies are needed to evaluate this hypothesis.
Although the initial CD4+ T-cell counts in the HCV viremic, HCV-seronegative patients were lower than in the HCV-seropositive patients, we found HCV viremia in 6 of 20 subjects who had more than 300 CD4+ T cells/mm3 (range, 4-944 CD4+ T cells/mm3). Because we do not have pre-HIV seroconversion samples to test for HCV antibody,
we cannot determine whether the seronegative infection resulted from the loss of HCV antibody due to immune deterioration, as suggested by others (37, 38). Nonetheless, we did not identify any subjects who lost detectable HCV antibodies during these studies. Delayed seroconversion during effective ART, as seen in Figure 3, is consistent with a previous report (22). The temporal relationship between developing HCV antibodies and the increase in CD4+ T-cell counts suggests that the lack of HCV antibody in this person reflected impaired cellular immunity. Three of the HCV viremic, HCV antibody-negative patients, patients R, S, and T (Table 1), were followed for less than 6 months and thus may potentially represent recent infection that may ultimately develop HCV antibody. Alternatively, patient P may have
been transiently infected and resolved infection without development of antibody, a phenomenon described in HIV-negative persons and experimentally infected chimpanzees (30).
In summary, whole blood testing for HCV RNA demonstrated a high rate of HCV infection in HIV-infected HCV antibody-negative patients. The HCV infection rate among patients without HCV antibodies was 6.0% using the standard commercial assay, 9.0% using a modification of the commercial assay, and 19% using non-FDA-approved, in-house methodologies that were verified on samples from at least two different dates. In the absence of liver biopsies from these HCV antibody-negative, HCV viremic patients, we cannot predict the implications for morbidity and
mortality from liver disease. It seems prudent to consider HCV infection in HIV-positive persons who test negative for HCV antibody, especially those with elevations in liver-associated enzymes. Testing plasma using a sensitive HCV RNA detection method would be a reasonable approach for evaluation of antibody-negative HCV infection, although our results indicate that this would still miss some patients with HCV viremia. While it is not known if HCV therapy would be beneficial in this setting, it should be considered if a liver biopsy demonstrates evidence of significant fibrosis (47, 48), and abstention from alcohol should be encouraged (11).
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