Hepatitis C virus (HCV) and HIV infections are global health concerns (1–7). Due to shared routes of transmission, coinfection with HIV and HCV is common. The prevalence of HCV in patients with HIV is dependent on risk behaviors and is highest in intravenous drug users (60%–90%) and hemophiliacs (50%–70%) compared with homosexual men (4%–8%) (1,2). Until recently, the clinical course of HCV in coinfected individuals was overshadowed by the high morbidity and mortality of HIV disease. With the introduction of highly active antiretroviral therapy (HAART) and its associated improvement in survival rates (8), HCV has now emerged as a significant viral pathogen with associated morbidity and mortality in patients with HIV-HCV coinfection (9–14).
Several investigators have examined the histopathology of HCV in patients with coinfection. Although some of these reports suggested that there is no difference in liver histology between coinfected patients and HCV controls (15,16), others have observed more inflammation and fibrosis in coinfected individuals (17–20). The discrepancies in these reports may be explained by the populations studied, because most were limited to a subset of coinfected patients, namely, those with abnormal liver chemistries or clinically advanced liver disease. As a result, the true spectrum of liver disease in coinfection has not been well defined. In addition, many of these studies were performed prior to HAART, and the effect this may have on the natural history of HCV in HIV-coinfected patients remains controversial. The aims of this study were to describe the spectrum of liver disease in patients with HIV-HCV coinfection and to compare this with a group of HCV controls.
PATIENTS AND METHODS
A cross-sectional retrospective analysis of consecutive coinfected patients evaluated by the Hepatology Section at Virginia Commonwealth University Health System/Medical College of Virginia (VCUHS/MCV) from 1997 to 2001 was performed. The control group comprised consecutive patients with chronic HCV without anti-HIV antibodies evaluated by the Section of Hepatology at VCUHS/MCV during the same time period. Inclusion criteria for both coinfected and control patients included presence of anti-HIV antibody (coinfected group only) and anti-HCV antibody, presence of HCV RNA, platelet count of ≥80,000, and normal renal function. Most (92%) coinfected patients were on stable HAART therapy consisting of a combination of nucleoside reverse transcription inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs). Coinfected patients were excluded if they had evidence of decompensated advanced HIV (CD4 <50 cells/mm3, with a life expectancy of less than 1 year) or active or recent (within 3 months) opportunistic infection. Patients in both groups were excluded if they had decompensated liver disease (i.e., bilirubin >4 mg/dL, albumin <2.5 g/L, prothrombin time prolonged >2 seconds, presence of ascites or hepatic encephalopathy), renal failure, presence of hepatitis B surface antigen, or another cause of liver disease.
All clinical, demographic, biochemical, and virologic parameters were obtained within 3 months of liver biopsy and extracted from medical records. HIV RNA (Roche Amplicor Monitor, Hoffman-La Roche) and CD4 counts were obtained in HIV-positive patients only. HCV RNA (Roche COBAS Amplicor Monitor, Hoffman-La Roche) and alanine aminotransferase (ALT) values were obtained for all patients. Formalin-fixed and paraffin-embedded liver tissue was stained by hematoxylin-eosin and Masson trichrome and was assessed by the histologic activity index (HAI) of Knodell et al. (21). The following definitions were used for analysis: normal ALT value of ≤75 U/L in male patients and ≤50 U/L in female patients, low CD4 count of <200 cells/mm3, advanced HIV as detectable HIV RNA and a CD4 count <200 cells/mm3, high HCV RNA ≥850,000 IU/mL, and advanced fibrosis as bridging fibrosis or cirrhosis (Knodell score 3–4).
For quantitative continuous variables, the Student t test (for parametric data) and Mann-Whitney rank sum test (for nonparametric data) were used. For comparison of multiple groups, Kruskal-Wallis one-way ANOVA (with the Dunn test as appropriate) was performed. For qualitative data, χ2 and Fisher exact tests were applied as indicated. All data are reported as mean ± SD, and a p value of < .05 was required for statistical significance. Median values are given for nonnormalized continuous data. Pearson product moment correlation was used to determine correlation of variables, and multivariate logistic regression analysis was used on those variables found to be significant on univariate analysis.
Spectrum of Liver Disease in HIV–Hepatitis C Virus Coinfection Compared with Hepatitis C Virus Controls
The characteristics of the 66 patients with HIV-HCV coinfection are shown in Table 1. This reflects our primary indigent inner city HIV clinic population (mean age = 42 years, 76% male, and 85% African American). Most (92%) patients were taking HAART, including NRTIs in 90%, NRTIs in 46%, and PIs in 44%. The median and mean HIV loads were 2.5 and 1.9log copies/mL; 47% of patients were negative for HIV RNA on HAART therapy. The median and mean CD4 counts were 503 and 555 cells/mm3 (range: 52–2332 cells/mm3), and 14% of patients had CD4 counts under 200 cells/mm3. The median and mean ALT values were 65 and 80 U/L (range: 18–278 U/L), and 51% of patients had normal ALT values at the time of evaluation. The median and mean HCV RNA level was 5.7log IU/mL, and 56% of patients had values greater than 850,000 IU/mL (the upper limit for the Amplicor assay without dilution). The majority of coinfected patients were of genotype 1 (92%). The mean HAI was 6.86, with a mean inflammatory score of 5.4 and a fibrosis score of 1.4. Advanced fibrosis was observed in 32% of patients (bridging fibrosis in 18% and cirrhosis in 14%).
There were no significant differences in age and gender between coinfected patients and HCV controls (Table 1). Although there were more African Americans in the coinfection cohort (85% vs. 44%), when the control group was stratified by race (50 African Americans and 64 whites), no differences in ALT value, HCV RNA level, or HAI were observed between HCV patients with or without HIV coinfection. Furthermore, no significant differences were observed in the proportion of patients with advanced fibrosis between coinfected patients and HCV controls (32% vs. 27%).
Half of those with coinfection had a normal ALT value at the time of evaluation. When stratified by ALT, no significant differences were observed in clinical, demographic, virologic, or histologic parameters between coinfected patients and HCV controls (Table 2). In patients with coinfection, we observed no significant differences in CD4 count, HIV or HCV RNA titer, or use or type of HAART between those with normal and elevated ALT values. Patients with normal ALT values in both groups had less advanced fibrosis compared with patients with an elevated ALT value.
One third of coinfected patients had advanced fibrosis. When comparing those with and without advanced fibrosis, there were no differences in mean ALT value (85 vs. 77 U/L), proportion with a normal ALT value (43% vs. 53%), HCV RNA or HIV RNA level, CD4 count, CD4 percentage, or proportion of those with a CD4 count <200 cells/mm3 (Table 3). Those with advanced fibrosis did have higher necroinflammatory scores (6.5 vs. 4.8;p = .022). Biochemical and virologic testing could not accurately identify which patients had advanced fibrosis on liver biopsy. Furthermore, we observed no significant differences in the percentage of those on NRTIs (89 vs. 97), NNRTIs (57 vs. 44), or PIs (63 vs. 48) in those with or without advanced fibrosis, respectively.
When stratifying patients by HCV RNA level, no difference in patient demographics, HIV RNA level, proportion negative for HIV RNA, total CD4 count, percentage with a CD4 count <200 cells/mm3, and serum ALT values were observed between those with low (<850,000 IU/mL) vs. high (≥850,000 IU/mL) HCV RNA titers. There were differences in mean HAI (5.75 vs. 7.72;p = .027) between these groups attributed more to fibrosis (0.96 vs. 1.8;p = .019) than to inflammation (4.79 vs. 5.89;p = .089) scores. As a result, those with higher HCV RNA levels had more advanced fibrosis (43% vs. 17%;p = .047). Although those coinfected patients with higher HCV RNA titers had more significant histology on univariate analysis, we were unable to demonstrate by multivariate logistic regression analysis any predictive factor, including clinical, patient demographics, serum ALT value, HIV RNA or HCV RNA level, or CD4 count, that predicted hepatic fibrosis.
Analysis of Immunologic Status
The majority of coinfected patients had CD4 counts greater than 200 cells/mm3, and almost half had an undetectable HIV RNA level. When coinfected patients were stratified by CD4 cell count, we observed no significant differences in mean HIV titers (2.8 vs. 1.8log copies/mL), percentage with undetectable HIV RNA (33 vs. 49), ALT values (76 vs. 80 U/L), proportion with normal ALT values (44 vs. 51), HCV RNA titers (5.8 vs. 5.7log copies/mL), HAI (5.8 vs. 7.0), or proportion of advanced fibrosis (33 vs. 32) in those with a CD4 count <200 cells/mm3 compared with those with a CD4 count >200 cells/mm3, respectively. When patients were further stratified by HIV RNA status, we also found no differences in clinical, biochemical, or virologic parameters between those with a high and low CD4 count with or without detectable HIV RNA (Table 4). Finally, we found no correlation between CD4 count, ALT values, and total HAI or its inflammatory or fibrosis score.
Several reports have described hepatic histopathology in patients with HIV (22–29). Most of these reports were published prior to the identification of HCV and in patients with abnormal liver chemistries, however. The most common findings were macrovesicular steatosis, granulomas, and cholestasis. Histopathologic findings typical of viral hepatitis were not commonly seen. Cirrhosis was rarely if ever seen in patients with only HIV infection (19).
Several reports have also described the liver histologic findings observed in patients with HIV-HCV coinfection (15–20,30–32). Some studies found no difference in histologic severity between coinfected patients and those with only HCV (15,16), whereas others reported more significant inflammation and/or fibrosis in patients with coinfection (18–20,30,32). The heterogeneity of these findings may be explained in part by the subpopulations of patients studied, the immunologic status of HIV, the exclusion of patients with normal ALT values, the degree of alcohol consumption, and the age at infection. These factors have been shown to affect the natural history of HCV (20).
The present study evaluated consecutive coinfected patients identified by HCV RNA screening irrespective of liver chemistries and compared this group with a cohort of HIV-uninfected HCV controls. This allowed us to obtain a more realistic perspective of HCV infection in patients with HIV in the era of HAART. The majority of the coinfected cohort had well-controlled HIV on HAART as demonstrated by a mean CD4 count of 555 cells/mm3. Only 14% had a CD4 count less than 200 cells/mm3, and almost half of the patients had undetectable HIV RNA levels. Although advanced fibrosis was observed in 32% of those with coinfection, no significant histologic differences were observed between coinfected patients and HCV controls. The 14% prevalence of cirrhosis observed in coinfected patients in the current report is similar to that reported by others (19,20,32). No clinical, demographic, biochemical, or virologic parameters could accurately identify patients with significant fibrosis. Liver biopsy is therefore required to determine which patients with coinfection have significant liver histopathology.
There have been several recent studies of liver histology in HCV patients with normal ALT values. In general, 5% to 12% of such patients have significant fibrosis (33–35). In the current report, 51% of coinfected patients had a normal ALT value, which was similar to our control population (47%) and that reported by others (36). Although those with normal ALT values had a lower HAI and a lower proportion of advanced fibrosis compared with coinfected patients with an elevated ALT value, 23% of coinfected patients with normal ALT values had advanced fibrosis, including 14% with cirrhosis. This underscores the importance of liver biopsy in coinfected populations.
The exact mechanism for the pathogenesis of HCV is not known. Because HCV is not believed to be cytopathic, the liver injury associated with chronic disease is thought, in part, to be related to the host immune system (37). Consequently, HCV may have a different natural history in HIV infection. Analysis of studies that have examined the impact of immunologic status on coinfection has yielded mixed results. Some studies have described less inflammation in those with lower CD4 counts (16), whereas others observed more significant histopathology (15,18,20,32). Furthermore, it has been proposed that HIV itself may affect the virulence of HCV through either direct viral interference or interactions mediated through CD4-positive cells (15,38).
The use of combination antiretroviral therapy for HIV is associated with restoration of the immune system and increases in both CD4+ and CD8+ lymphocytes (39,40). Since HAART was introduced, a significant number of HCV-related liver deaths have been observed in patients with well-controlled HIV disease (11,41,42). Liver chemistries have been known to increase in coinfected patients treated with HAART (43–49). There are limited data on liver histology in coinfected patients while on HAART. In the short term, liver histology can worsen (50). In the long term, HAART has been associated with a lower rate of progression to cirrhosis (31). The exact mechanism of worsening HCV during HAART is unknown, because serum HCV levels have been reported to decrease (51,52), increase (53,54), or remain unchanged (55,56). Although our study was not powered to determine the effect of HAART, we observed no differences in the use of NRTIs, NNRTIs, or PIs with respect to serum ALT values or liver histology.
The significance of HCV RNA titer in patients with coinfection remains unclear. In patients with chronic HCV alone, HCV titer does not correlate with histologic severity (36,37). Some studies have demonstrated that HCV RNA levels were higher in those with coinfection compared with HCV controls (1,3,7,38,57), especially in those patients with low CD4 counts (32). Others (36), however, including the current study, found no difference in HCV RNA titers in patients with HIV-HCV coinfection and HCV controls. When coinfected patients were stratified by HCV RNA level (<850,000 vs. ≥850,000 IU/mL), however, the current study did find a relationship between HCV RNA titer and HAI, fibrosis, and the proportion of patients with advanced fibrosis. This was similar to findings of previous reports (32). HCV genotype has been shown to correlate with liver disease severity in some (17) but not all studies (15,31,57) as well as with HIV disease progression (58). The majority of our patients with coinfection were of genotype 1 (92%); therefore, we were not able to assess the effect of HCV genotype on liver histology or HIV severity.
Antibodies to HCV are two to three times more common among African Americans than whites in the United States (59). In the state of Virginia, African Americans account for over half of the HIV-positive population (Virginia Department of Heath, 2001). In our population of coinfected patients, African Americans make up the majority (85%). Whether the natural history of HCV in African Americans differs from that in whites remains controversial (60–64). In the current report, which included patients on stable HIV therapy, we found no increase in histologic severity or the proportion with advanced fibrosis compared with matched HCV controls. When stratified by race, we also observed no differences in African Americans with or without HIV. Due to the small proportion of whites in our coinfected patient population, we were not able to adequately assess the difference in histologic severity between races.
There are several possible explanations for the discrepancy between our results and those of other studies (15–20,30–32). We included patients in both the study and control groups regardless of ALT values. Excluding these patients in other studies, which may represent half of the coinfected population, may have led to an overestimation of the histologic severity of HCV in this population. Our coinfected population is representative of our urban HIV clinic, which consists predominantly of African Americans and men who acquired HIV through illicit drug use. Whether our results our applicable to other coinfected patients such as white homosexual men remains to be tested. Thirdly, there may have been selection bias in our coinfected patients referred for biopsy. We excluded those with obvious hepatic dysfunction (jaundice, ascites, or coagulopathy) as well as those with significant thrombocytopenia. By doing so, we may have underestimated the overall proportion with cirrhosis. Those with decompensated liver disease or significant thrombocytopenia were also excluded from the control group, however, which should have minimized any referral bias differences comparing the spectrum of liver disease due to chronic HCV in those with and without HIV coinfection. We also excluded HIV patients with advanced HIV disease (persistent CD4 count <50 cells/mm3). Although doing so may have biased our results, liver biopsy in these individuals rarely affects their clinical management and therefore is not routinely performed. Fourth, although all patients were abstinent for at least 6 months prior to biopsy, our results did not take into account lifetime alcohol consumption. This was true for both coinfected patients and controls, however, which should have minimized any differences. Another limitation is the dynamic processes of HIV and HCV infections. Consequently, the single point in time laboratory values used without knowledge of nadir CD4 levels may have limited our analysis. Finally, we did not take into account duration of disease in either group; because most of our patients were not able to give a precise date of infection, such data were not included.
In summary, we found that the spectrum of HCV disease in patients with HIV-HCV coinfection on HAART includes a significant proportion of patients with normal ALT values. By including these patients, the histologic picture of HIV-HCV coinfection is similar to that observed in HCV controls. Biochemical and virologic measures were not predictive of liver histology. Consequently, liver biopsy is needed to identify those coinfected patients with significant liver disease. Further long-term prospective studies are needed to determine the clinical impact of antiretroviral therapy on the natural history of HCV.
The authors thank Martha Behnke for her help in the statistical analysis of the data.
1. Spengler U, Rockstroh JK. Hepatitis C in the patients with human immunodeficiency virus infection. J Hepatol 1998; 29:1023–30.
2. Dieterich DT. Hepatitis C virus and human immunodeficiency virus: clinical issues in coinfection. Am J Med 1999; 107(Suppl): 79S–84S.
3. Dieterich DT, Purow JM, Rajapaksa R. Activity of combination therapy with interferon alfa-2b plus ribavirin in chronic hepatitis C patients co-infected with HIV. Semin Liver Dis 1999;(Suppl 1): 87–94.
4. Dove L, Alonzo J, Wright TL. Clinicopathologic conference: hepatitis C in a patient with human immunodeficiency virus infection. Hepatology 2000; 32:147–52.
5. Collier J, Heathcote J. Hepatitis C viral infection in the immunosuppressed patient. Hepatology 1998; 27:2–6.
6. Moorman JP. Issues in HIV/hepatitis C co-infection. Curr Infect Dis Rep 2001; 3:131–6.
7. Sulkowski MS. Hepatitis C virus infection in HIV-infected patients. Curr Infect Dis Rep 2001; 3:469–76.
8. Palella FJ, Delaney KM, Mooreman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338:853–60.
9. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000; 356:1800–5.
10. Darby SC, Ewart DW, Giangrande PLF, et al. Mortality from liver cancer and liver disease in hemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet 1997; 350:1425–31.
11. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32:492–7.
12. Monga HK, Rodriguez-Barradas MC, Breaux K, et al. Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 33:240–7.
13. Ragni MV, Belle SH. Impact of human immunodeficiency virus infection on progression to end-stage liver disease in individuals with hemophilia and hepatitis C virus infection. J Infect Dis 2001; 183:1112–5.
14. Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33:562–9.
15. Puoti M, Bonacini M, Spinetti A, et al. Liver fibrosis progression is related to CD4 cell depletion in patients co-infected with hepatitis C virus and human immunodeficiency virus. J Infect Dis 2001; 183:134–7.
16. Guido M, Rugge M, Fattovich G, et al. Human immunodeficiency virus infection and hepatitis C pathology. Liver 1994; 14:314–9.
17. Garcia-Samaniego J, Soriano V, Castilla J, et al. Influence of hepatitis C virus genotypes and HIV infection on histologic severity of chronic hepatitis C. Am J Gastroenterol 1997; 92:1130–4.
18. Allory Y, Charlotte F, Benhamou Y, et al. Impact of human immunodeficiency virus infection on the histologic features of chronic hepatitis C: a case-control study. Hum Pathol 2000; 31:69–74.
19. Bierhoff E, Fischer HP, Willsch E, et al. Liver histopathology in patients with concurrent chronic hepatitis C and HIV infection. Virchows Arch 1997; 430:271–7.
20. Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus co-infected patients. Hepatology 1999; 30:1054–8.
21. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histologic activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1:431–5.
22. Lebovics E, Thung SN, Schaffner F, et al. The liver in the acquired immunodeficiency syndrome: a clinical and histologic study. Hepatology 1985; 5:293–8.
23. Gordon SC, Reddy KR, Gould EE, et al. The spectrum of liver disease in the acquired immunodeficiency syndrome. J Hepatol 1986; 2:475–84.
24. Schneiderman DJ, Arenson DM, Cello JP, et al. Hepatic disease in patients with the acquired immune deficiency syndrome (AIDS). Hepatology 1987; 7:925–30.
25. Grumbach K, Coleman BG, Gal AA, et al. Hepatic and biliary tract abnormalities in patients with AIDS. J Ultrasound Med 1989; 8:247–54.
26. Cappell MS, Schwartz MS, Biempica L. Clinical utility of liver biopsy in patients with serum antibodies to the human immunodeficiency virus. Am J Med 1990; 88:123–30.
27. Bach N, Theise ND, Schaffner F. Hepatic histopathology in the acquired immunodeficiency syndrome. Semin Liver Dis 1992; 12:205–12.
28. Poles MA, Dieterich DT, Schwarz ED, et al. Liver biopsy findings in 501 patients with human immunodeficiency virus (HIV). J Acquir Immune Defic Syndr Hum Retrovirol 1996; 11:170–7.
29. Wilkins MJ, Lindley R, Dourakis SP, et al. Surgical pathology of the liver in HIV infection. Histopathology 1991; 18:459–64.
30. Boldorini R, Vigano P, Monga G, et al. Hepatic histology of patients with HIV infection and chronic hepatitis C treated with interferon. J Clin Pathol 1997; 50:735–40.
31. Benhamou Y, Di Martino V, Bochet M, et al. Factors affecting liver fibrosis in human immunodeficiency virus- and hepatitis C virus-co-infected patients: impact of protease inhibitor therapy. Hepatology 2001; 34:283–7.
32. Di Martino V, Rufat P, Boyer N, et al. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology 2001; 34:1193–9.
33. Sterling RK, Sanyal AJ, Luketic VA, et al. Chronic hepatitis C infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94:3576–82.
34. Shiffman ML, Stewart CA, Hofmann CM, et al. Chronic infection with hepatitis C virus in patients with elevated or persistently normal serum alanine aminotransferase levels: comparison of hepatitis histology and response to interferon therapy. J Infect Dis 2000; 182:1595–601.
35. Martinot-Peignoux M, Boyer N, Cazals-Hatem D, et al. Prospective study on anti-hepatitis C virus positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA. Hepatology 2001; 34:1000–5.
36. Ghany MG, Leissinger C, Lagier R, et al. Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophiliacs. Dig Dis Sci 1996; 41:1265–72.
37. Rehermann B. Interaction between the hepatitis C virus and the immune system. Semin Liver Dis 2000; 20:127–41.
38. Eyster E, Fried MW, Di Bisceglie AM, et al. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Blood 1994; 84:1020–3.
39. Levy JA. HIV pathogenesis and long-term survival. AIDS 1993; 7:1401–10.
40. Lederman MM. Immune restoration and CD4+ T-cell function with antiretroviral therapies. AIDS 2001; 15(Suppl 2):S11–5.
41. Jenny-Avital ER. Does hepatitis C virus really have no effect on survival in cases of infection with human immunodeficiency virus? Clin Infect Dis 2000; 30:409–10.
42. Greub G, Ledergerber B, Telenti A. Authors reply to HIV-1 progression in hepatitis-C-infected drug users. Lancet 2001; 357:1361–3.
43. Rutschmann OT, Negro F, Hirschel B, et al. Impact of treatment with human immunodeficiency virus protease inhibitors on hepatitis C viremia in patients co-infected with HIV. J Infect Dis 1998; 177:783–5.
44. John M, Flexman J, French MAH. Hepatitis C virus associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 1998; 12:2289–93.
45. Zylberberg H, Pialoux G, Carnot F, et al. Rapidly evolving hepatitis C virus-related cirrhosis in a human immunodeficiency virus-infected patient receiving triple antiretroviral therapy. Clin Infect Dis 1998; 27:1255–8.
46. Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283:74–80.
47. Melvin DC, Lee JK, Belsey E, et al. The impact of coinfection with hepatitis C virus and HIV on the tolerability of antiretroviral therapy. AIDS 2000; 14:463–5.
48. Torre D, Tambini R, Cadario F, et al. Evolution of coinfection with human immunodeficiency virus and hepatitis C virus in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2001; 33:1579–85.
49. Gavazzi G, Bouchard O, Leclercq P, et al. Change in transaminases in hepatitis C virus- and HIV-co-infected patients after highly active antiretroviral therapy: differences between complete and partial virologic responders? AIDS Res Hum Retroviruses 2000; 16:1021–3.
50. Vento S, Garofano T, Renzini C, et al. Enhancement of hepatitis C virus replication and liver damage in HIV-co-infected patients on antiretroviral combination therapy. AIDS 1998; 12:116–7.
51. Perez-Olmeda M, Garcia-Samaniego J, Soriano V. Hepatitis C viremia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy. AIDS 2000; 14:212.
52. Yokozaki S, Takamatsu J, Nakano I, et al. Immunologic dynamics in hemophiliac patients infected with hepatitis C virus and human immunodeficiency virus: influence of antiretroviral therapy. Blood 2000; 96:4293–9.
53. Ragni MV, Bontempo FA. Increased hepatitis C virus load in hemophiliacs during treatment with highly active antiretroviral therapy. J Infect Dis 1999; 180:2027–9.
54. Puoti M, Gargiulo F, Roldan EQ, et al. Liver damage and kinetics of hepatitis C virus and human immunodeficiency virus replication during the early phases of combination antiretroviral treatment. J Infect Dis 2000; 181:2033–6.
55. Zylberberg H, Chaix ML, Rabian C, et al. Tritherapy for human immunodeficiency virus infection does not modify replication of hepatitis C virus in co-infected subjects. Clin Infect Dis 1998; 26:1104–6.
56. Rockstroh JK, Theisen A, Kaiser R, et al. Antiretroviral triple therapy decreases HIV viral load but does not alter hepatitis C serum levels in HIV-HCV co-infected hemophiliacs. AIDS 1998; 12:829–30.
57. Goedert JJ, Hatzakis A, Sherman KE, et al. Lack of association of hepatitis C virus load and genotype with risk of end-stage liver disease in patients with human immunodeficiency virus coinfection. J Infect Dis 2001; 184:1202–5.
58. Sabin CA, Telfer P, Phillips AN, et al. The association between hepatitis C virus genotype and human immunodeficiency virus disease progression in a cohort of hemophilic men. J Infect Dis 1997; 175:164–8.
59. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999; 341:556–62.
60. Howell C, Jeffers L, Hoofnagle JH. Hepatitis C in African Americans: summary of a workshop. Gastroenterology 2000; 119:1385–96.
61. McHutchinson JG, Poynard T, Pianko S, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. Gastroenterology 2000; 119:1317–23.
62. Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in response to therapy with interferon in chronic hepatitis C. Hepatology 1999; 30:787–93.
63. Wiley TE, Mika BP, McCarthy ME, et al. Pre-treatment differences between HCV-infected African Americans and non-African American patients [abstract 417]. Hepatology 1999; 30:265A.
64. Gill R, Salvatori JJ, Hofmann CM, et al. The spectrum of hepatitis C in African Americans [abstract 1887]. Gastroenterology 2001; 120:A-367.