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Department of Infectious Diseases and Liver Unit, Hospital Carlos III, Madrid, Spain
Because most patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are injection drug users (IDUs) who might have been exposed to multiple HCV genotypes while sharing needles, coinfection with distinct HCV genotypes could be frequent in them. Blood samples from 203 coinfected IDUs who did not respond to at least 24 weeks of interferon (IFN)based therapies were analyzed. At baseline, 131 patients had HCV genotype 1, 4 had HCV genotype 2, 52 had HCV genotype 3, and 16 had HCV genotype 4. Changes in HCV genotype were not found in any patient when samples obtained before and after HCV therapy were compared. HCV therapy did not appear to select for IFN-resistant HCV genotypes that might have been present at baseline. Coinfection with distinct HCV genotypes is unlikely in former IDUs coinfected with HIV and does not explain the lower efficacy of HCV therapy in this population.
Most injection drug users (IDUs) are infected with hepatitis C virus (HCV), and they are expected to have been exposed to multiple HCV genotypes because of their engagement in parenteral behaviors that put them at high risk for infection. In experimental models, HCV infection does not seem to provide protective immunity against infection with another genotype [1]. Therefore, coinfection with several HCV genotypes could be frequent among IDUs. This possibility, particularly in IDUs coinfected with HCV and HIV, was suggested in a study published elsewhere [2]. In this situation, it was hypothesized that the immunodeficiency caused by HIV could increase the chances that a person will acquire several HCV genotypes. However, most recent studies suggest that mixed HCV genotype infections are rare, even in IDUs coinfected with HIV [3, 4], and that methodological issues, such as cross-reactivity when older nonspecific hybridization assays are used, could explain the apparent high rate of coinfection with multiple HCV genotypes reported previously [5].
The progression to end-stage liver disease due to chronic HCV infection is faster in subjects coinfected with HIV [6] than it is in those who are not coinfected, and HCV-related liver disease has become a leading cause of morbidity and mortality in HIV-infected IDUs worldwide [6]. Moreover, the hepatotoxicity of antiretroviral drugs is clearly enhanced in the presence of chronic HCV infection [6] and is a primary reason for the discontinuation of these drugs. Thus, treatment of chronic HCV infection is particularly important in HIV-coinfected patients [6]. Unfortunately, the results of recent trials suggest that sustained virological response rates are lower in patients coinfected with HCV and HIV than they are in patients infected with only HIV [79]. So far, it is unclear why there is a low response to HCV therapy in the setting of HIV infection.
Because most patients coinfected with HCV and HIV are former IDUs, we were intrigued to know whether the low response to HCV therapy reported in this population could be due to infection with multiple HCV genotypes. The presence of some HCV genotypes as minor populations at baseline could have been undetected by use of the present diagnostic tests. If they were, the presence of interferon (IFN)resistant genotypes would have become apparent only under therapeutic pressure. Because HCV genotype 3 is relatively more frequent in IDUs than in other populations [3] and shows a greater susceptibility to IFN-based therapies than do HCV genotypes 1 and 4, we hypothesized that the failure to clear HCV infection in IDUs exposed to HCV therapy could be associated with a shift in HCV genotype, in which IFN-sensitive HCV genotypes were replaced by IFN-resistant HCV genotypes that could have been represented as minor populations before the initiation of HCV therapy. To our knowledge, this is the first study examining the parity of genotypes before and after the failure of HCV therapy in a relatively large group of IDUs coinfected with HCV and HIV.
Patients and methods.
Patients enrolled into the present study included 58 patients coinfected with HCV and HIV who were treated at our institution with pegylated IFN (pegIFN) plus ribavirin (RBV), by use of the doses and schedules from an earlier trial [7], and 145 patients who were selected from those enrolled in 4 different clinical trials of HCV therapy in HIV-coinfected patients in Spain [7, 1012]. Briefly, the first trial included 90 HIV-infected patients enrolled in 1992 in a trial of treatment with 3 million U of IFN monotherapy 3 times a week [10]. The second trial evaluated the efficacy and safety of escalating doses of IFN monotherapy in 29 coinfected patients in 1995 [11]. The third trial, conducted in 2000, assessed the performance of 3 million U of IFN 3 times a week and 400 mg of RBV 2 times a day in 106 coinfected patients [12]. The fourth trial examined the efficacy of 1.5 g of pegIFN-2b per week and 400 mg of RBV 2 times a day in 68 coinfected patients [7]. In all these trials, coinfected patients who tested positive for hepatitis B surface antigen, had CD4 cell counts <200 cells/L, had active drug addiction, or abused alcohol were excluded. For the purposes of the present study, only patients who were former IDUs and who did not have a sustained virological response to HCV therapy (defined as negative for HCV RNA for 6 months after the discontinuation of HCV therapy) were selected for analysis.
HCV genotyping was performed using a commercial polymerase chain reactionbased hybridization assay (HCV LiPA-II; Innogenetics), in accordance with the manufacturer's instructions [5], on plasma samples obtained at baseline and at least 6 months after the discontinuation of HCV therapy. This test can detect HCV genotypes present at 2% of the total virus population [13].
Results are expressed in absolute values and percentages. Continuous variables are expressed as means ± SD. Means were compared using Student's t test. Categorical variables were compared using Fisher's exact test or the 2 test. All P values were 2-tailed, and P < .05 was considered to be statistically significant. All data analyses were conducted using SPSS for Windows (version 10.0; SPSS).
Results.
A total of 351 patients coinfected with HCV and HIV and exposed to different IFN-based therapies were assessed for enrollment into the study. A sustained virological response occurred in 77 patients (21.9%), and there were differences between the distinct treatment modalities in the percentage of patients who had a sustained virological response: 18.5% of patients who received IFN monotherapy [10, 11], 16% of patients who received IFN and RBV [12], and 30.2% of patients who received pegIFN and RBV [7]. Overall, 274 patients (78.1%) did not have a sustained virological response. Twenty-three patients did not complete 6 months of HCV therapy and were excluded from the analysis. Of the remaining patients, only 231 were former IDUs. Information on HCV genotypes at baseline and after the discontinuation of therapy could be obtained for 203 of these patients, and plasma samples were unavailable for 28 of these patients. There were no significant differences in demographics or in baseline HCV genotype distribution between these 28 patients and the 203 patients who were enrolled into the study. Table 1 summarizes the baseline characteristics of the screened population.
The distribution of HCV genotypes at baseline was as follows: 131 patients (64.5%) were infected with HCV genotype 1, 4 patients (2.0%) were infected with HCV genotype 2, 52 patients (25.6%) were infected with HCV genotype 3, and 16 patients (7.9%) were infected with HCV genotype 4. Only 3 patients showed mixed HCV genotype infections at baseline (2 had HCV genotypes 1 and 4 and 1 had HCV genotypes 2 and 4). When the presence or absence of detectable HCV RNA at the discontinuation of therapy was considered, 141 patients were nonresponders, and 62 patients were relapsers. Relapses were more frequently found in patients with HCV genotype 2 or 3 than in patients with HCV genotype 1 or 4 (44/56 [78.6%] vs. 16/147 [10.9%]; P < .001).
Changes in HCV genotype could not be demonstrated in any patient when samples obtained before and after exposure to HCV therapy were compared. Of note, this result was confirmed even for the 3 subjects who had mixed HCV genotype infections at baseline.
Discussion.
Coinfection with several HCV genotypes has been described in humans after recent exposure, either sexually [14] or by injection, to an infectious HCV inoculum, such as occurs in IDUs [15] and occurred in patients with hemophilia or thalassemia before HCV antibody screening of donated blood became mandatory [16]. However, no data definitively prove the long-term persistence of multiple HCV genotypes in persons no longer exposed to HCV infectious sources. In our experience, <1% of plasma samples from patients with chronic HCV infection who are assessed for enrollment into studies of HCV therapies show mixed HCV genotype infections, although active IDUs are uniformly excluded from these therapeutic trials. Because HCV replicates in the cytosol and does not integrate into target cells, there is no stable genomic reservoir of the virus, which is in contrast with what occurs in HIV infection. Therefore, any competition in replication between distinct HCV genotypes that could coexist in a patient (as the result of either coinfection or superinfection) should be followed by a decline in numbers and the disappearance of the less-fit genotype over time. If this is so, coinfection with multiple HCV genotypes might be recognized only shortly after acute exposure, as has been reported elsewhere [1416], because the less-fit genotype tends to decline in numbers and is cleared in patients with chronic HCV infection who are no longer engaged in behaviors that put them at high risk for infection, and then the more-fit HCV genotype takes over. In agreement with this hypothesis, a study of 5 patients undergoing hemodialysis showed that they had a progressive loss of mixed HCV genotype infections over time, and the eventual presence of a single HCV genotype was noted in each patient [13].
In a pilot study of 30 patients coinfected with HCV and HIV for whom standard IFN and RBV combination therapy had failed, we found no significant changes in HCV viremia or in HCV genotypes with respect to baseline data [17]. Similar findings were reported for a small group of patients with hemophilia in Edinburgh in the 1990s [18]. However, the populations that were studied were small, and mixed HCV genotype infections were absent or very rare, respectively, in them. In the present study, HCV genotypes were assessed in samples obtained before and after the initiation of HCV therapy in 203 IDUs coinfected with HCV and HIV who did not have a sustained virological response. No evidence of a shift in HCV genotype was shown, even in the 3 patients with mixed HCV genotype infections at baseline. It should be stressed that, at baseline, 56 of these patients were found to be infected with HCV genotype 2 or 3, and these genotypes tend to be more sensitive to IFN-based therapies than are genotypes 1 and 4; in none of the patients was virological failure found to be due to a selection of HCV genotype 1 or 4.
Our findings have implications from 2 perspectives. First, from a clinical perspective, our results suggest that the low response to HCV therapy seen in IDUs coinfected with HCV and HIV is not due to a replacement of IFN-sensitive HCV genotypes by IFN-resistant genotypes that could have been present as minor populations at baseline and were undetected by the present diagnostic tools. Thus, coinfection with multiple HCV genotypes, even in IDUs and in the setting of HIV infection, should be considered to be a very rare event. Other causes of the low efficacy of HCV therapy in coinfected individuals should be investigated. Because both IFN and RBV may act, at least in part, as immunomodulatory agents, it is possible that their activity against HCV may be somewhat limited in the setting of HIV infection.
Second, from a biological perspective, our results indirectly prove that the eradication of HCV is feasible and that there is no stable cell or tissue reservoir from which any HCV genotype could reemerge under special situations, such as the removal of an IFN-sensitive genotype that had been predominant. This is consistent with the finding that patients coinfected with HCV and HIV who have a sustained virological response after HCV therapy do not have relapses or clinical progression of liver disease over an extended follow-up period of nearly 5 years [19]. Moreover, if mixed HCV genotype infections are expected to be found only transiently in people actively engaged in practices that put them at high risk for infection, the opportunities for recombination events between distinct HCV genotypes should be rare, as seems to be the case, in contrast with HIV infection, in which viral recombination may occur throughout the course of chronic disease.
Acknowledgment
We thank Peter Simmonds, for helpful comments.
References
1. Farci P, Alter H, Govindarajan S. Lack of protective immunity against reinfection with hepatitis C virus. Science 1992; 258:13540. First citation in article
2. Soriano V, Bravo R, Garcia-Samaniego J, et al. Co-infection with several HCV genotypes enhances liver damage in patients with chronic hepatitis C. The Hepatitis/HIV Spanish Study Group. J Infect 1997; 35:2023. First citation in article
3. Perez-Olmeda M, Rios P, Nunez M, Garcia-Samaniego J, Romero M, Soriano V. Virological characteristics of hepatitis C virus infection in HIV-infected individuals with chronic hepatitis C: implications for treatment. AIDS 2002; 16:4935. First citation in article
4. van Astena L, Prinsa M. Infection with concurrent multiple hepatitis C virus genotypes is associated with faster HIV disease progression. AIDS 2004; 18:231924. First citation in article
5. Stuyver L, Wyseur A, van Arnhem W, Hernandez F, Maertens G. Second-generation line probe assay for hepatitis C virus genotyping. J Clin Microbiol 1996; 34:225966. First citation in article
6. Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV-coinfection: updated recommendations from the HCV-HIV International Panel. AIDS 2004; 18:112. First citation in article
7. Perez-Olmeda M, Nuez M, Romero M, Soriano V. Pegylated IFN-alpha2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients. AIDS 2003; 17:10238. First citation in article
8. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alpha-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:43850. First citation in article
9. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292:283948. First citation in article
10. Soriano V, Garcia-Samaniego J, Bravo R, Gonzalez-Lahoz J. Interferon alpha for the treatment of chronic hepatitis C in patients infected with HIV. Hepatitis-HIV Spanish Study Group. Clin Infect Dis 1996; 23:58591. First citation in article
11. Soriano V, Bravo R, Garcia-Samaniego J, Gonzalez-Lahoz J. A pilot study on the efficacy of escalating dosage of alpha-interferon for chronic hepatitis C in HIV-infected patients. J Infect 1997; 35:22530. First citation in article
12. Perez-Olmeda M, Soriano V, Asensi V. Treatment of chronic hepatitis C in HIV-infected patients with interferon alpha-2b plus ribavirin. AIDS Res Hum Retroviruses 2003; 19:10839. First citation in article
13. Qian K, Natov S, Pereira B, Lau J. Hepatitis C virus mixed genotype infections in patients on hemodialysis. J Viral Hepat 2000; 7:15360. First citation in article
14. Sanchez-Beiza L, Bravo R, Toribio R, Navarro S, Soriano V. Sexual transmission of two different HCV types causing acute hepatitis C. Vox Sang 1996; 71:2445. First citation in article
15. Proust B, Dubois F, Baco Y. Two successive hepatitis C virus infections in an intravenous drug user. J Clin Microbiol 2000; 38:31257. First citation in article
16. Lai M, Mazzoleni A, Argiolu F, et al. Hepatitis C virus in multiple episodes of acute hepatitis in polytransfused thalassaemic children. Lancet 1994; 343:38890. First citation in article
17. Soriano V, Perez-Olmeda M, Rios P, Nuez M, Garcia-Samaniego J, Gonzalez-Lahoz J. Is treatment failure for hepatitis C virus infection in HIV-positive drug users associated with a shift in HCV genotypes J Acquir Immune Defic Syndr 2003; 32:4656. First citation in article
18. Hanley JP, Jarvis LM, Andrew J, et al. Interferon treatment for chronic hepatitis C infection in hemophiliacsinfluence of virus load, genotype, and liver pathology on response. Blood 1996; 87:17049. First citation in article
19. Soriano V, Maida I, Nuez M, et al. Long-term follow-up of HIV-infected patients with chronic hepatitis C virus infection treated with interferon-based therapies. Antivir Ther 2004; 9:98792. First citation in article