Sustained Virologic Response
An EOT virologic response was observed in 28 subjects (19 daily and 9 TIW IFN) (OR, 2.31; 95% CI, 1.12–4.78). Among those with an EOT virologic response, 22 subjects had an SVR, 3 subjects experienced a virologic relapse, and 3 subjects failed to complete any scheduled follow-up visit after discontinuation of therapy. Overall, SVR was observed in 15 of 79 subjects (19.0%) receiving daily IFN and 7 of 83 subjects (8.4%) receiving TIW IFN, based on the modified intention-to-treat populations (RR, 2.25; 95% CI, 0.98–5.22, P = 0.05) (Fig. 1). Among those with an SVR, 15 subjects (10 daily, 5 TIW) were infected with HCV genotype 1; 6 subjects (4 daily, 2 TIW) were infected with HCV genotype 2 or 3; and 1 subject did not have genotype testing available. Virologic relapse was documented in 3 of 25 (12%) of subjects with an undetectable HCV RNA level at the EOT who had at least 1 posttreatment HCV RNA test. After inclusion of the 3 subjects without any documented posttreatment HCV testing as failures, the virologic relapse rate was 21% (6 of 28 subjects).
In multivariate logistic regression analysis, SVR was independently associated with nonblack race (OR, 4.78; 95% CI, 1.04–21.81), baseline HCV RNA level <6.0 log10 copies/mL (OR, 3.14; 95% CI, 1.17–8.47), and daily IFN (OR, 2.51; 95% CI, 1.01–6.80) (Table 2). Conversely, SVR was not associated with baseline CD4+ T-cell count or log HIV RNA level, stable psychiatric disease, history of injection drug use, gender, or age (data not shown). Notably, due to incomplete data, the effect of HCV genotype could not be accurately assessed in the model.
Predictive Value of Early Virologic Response
Only 34 of the 122 subjects (28%) who underwent HCV RNA testing at treatment week 12 completed 48 weeks of antiviral therapy. However, most treatment discontinuations were observed among subjects who failed to achieve an EVR; 70 of 76 (92%) week 12 virologic failures did not complete the 48-week course. Conversely, 28 of 46 (60%) of subjects who achieved an EVR completed the 48-week course and SVR was observed in 22 of 46 subjects (48%) with evidence of a week 12 EVR. Of the 24 subjects with an EVR who failed to achieve an SVR, 3 subjects experienced a documented virologic relapse after discontinuation of therapy at 48 weeks, 3 subjects were lost to follow-up after discontinuation of therapy at 48 weeks, 11 discontinued therapy due to an adverse event, 4 experienced virologic failure (at treatment week 24), and 3 were nonadherent to the protocol. Importantly, both subjects and investigators received HCV response information in real time during the study, suggesting that the knowledge of treatment futility or success influenced the decision to discontinue or continue treatment. The high rate of treatment discontinuation precludes the calculation of the negative predictive value of week 12 response since the impact of additional therapy cannot be assessed.
Clinical and Laboratory Adverse Events
Serious adverse events were observed in 7 subjects (5, daily and 2, TIW IFN) including neuropsychiatric events (e.g., depression), 3 subjects; bacterial pneumonia, 3 subjects; and symptomatic hyperlactemia syndrome/pancreatitis, 1 subject. No subjects died during the study period. In addition, 35 subjects (17, daily and 18, TIW IFN) discontinued therapy due to a nonserious adverse event (Table 4). In multivariate logistic regression analysis, discontinuation of treatment due to an adverse event (n = 42) was independently associated with a hemoglobin level < 12 g/dL at study entry (OR, 4.64; 95% CI, 1.35–16.0) but not HCV treatment group, age, ethnicity, gender, body weight, baseline CD4+ T-cell count or HIV RNA level, history of psychiatric disease or injection drug use, or the use of zidovudine or didanosine.
In addition, no adverse effect on control of HIV replication was detected, including among those subjects receiving zidovudine and stavudine. The absolute CD4 cell count decreased in both treatment groups; however, no significant change was observed in the CD4 cell percentage and no subjects experienced an opportunistic infection (Table 5). Overall, 14 subjects received didanosine in conjunction with RBV, of whom 1 subject experienced symptomatic hyperlactemia, characterized by lactic acidosis, pancreatitis, and hepatitis. This serious adverse event resulted in hospitalization followed by complete recovery after discontinuation of study medication and antiretroviral therapy.
Due to an increased risk of liver disease in the setting of HIV infection, current guidelines recommend that HIV coinfected patients be considered for HCV treatment with IFN- and RBV-based therapies. 9–11 However, published data on the safety and efficacy of these therapies in persons with HIV/HCV coinfection are limited. In this community-based, randomized controlled trial, we found that the SVR rate was significantly higher in persons randomized to receive daily IFN injections plus RBV (19.0%) compared with those receiving TIW IFN injections plus RBV (8.4%).
While our study did not directly compare HIV-infected with HIV-uninfected patients, the SVR rate observed in our population receiving TIW IFN plus RBV is substantially lower than historical SVR rates (~ 42–46%) observed with a similar regimen in HIV-negative patient populations. 13,14 This observation is consistent with other published studies of standard IFN plus RBV in HIV-infected persons. However, the majority of these studies have been uncontrolled, nonrandomized trials of IFN, which enrolled relatively heterogeneous patient populations (e.g., IFN-experienced and -naive persons). For example, Sauleda et al. 17 reported that 8 of 20 HCV/HIV coinfected hemophiliacs achieved an SVR with IFN alfa-2b TIW and RBV. Similarly, Landau et al. 16 observed an SVR rate of 21% among 51 HIV/HCV coinfected subjects treated with a similar regimen for 12 months. Interestingly, Kostman et al. 21 treated 110 coinfected persons with IFN alfa-2b TIW plus RBV or placebo; and similar to our findings, SVR was observed in 8% of subjects who received TIW IFN and RBV. Taken together with our findings, the available data indicate that standard TIW IFN plus RBV is ineffective in HIV-infected persons, and, while daily IFN plus RBV was associated with greater efficacy, the SVR rate observed in our study (19%) was significantly lower than rates observed historically in HIV-negative patients with TIW IFN combination therapy.
The reasons for limited efficacy of standard IFN plus RBV in coinfected patients have not been fully elucidated. Interestingly, in our study, the rate of virologic relapse among EOT virologic responders (21%) was not substantially different than that observed in HIV-uninfected historical controls, suggesting that factors related to early HCV response may be more important than those related to viral eradication among those with complete suppression of HCV replication. 13,14 In our study, multivariate analysis suggested lower viral response rates among patients of African American ethnicity and higher baseline HCV RNA levels. In our analysis, one measure of immune function, the baseline CD4 cell count, was not associated with SVR; however, the baseline HCV RNA level may better reflect the status of the host interaction with the HCV, serving as an indirect measure of HCV-specific immunity. Unfortunately, the evaluation of other factors associated with SVR was limited due to the relatively small number of SVR outcomes and the lack of complete data on HCV genotype; larger studies are needed to better understand host and disease factors associated with virologic response in HIV-infected persons.
In addition, the limited efficacy of treatment in our population may be explained, in part, by the HCV treatment regimen studied. Similar to other ongoing studies involving HIV coinfected patients, the RBV dose of 800 mg daily was selected based on the predicted tolerability and efficacy of this dose. However, among HIV-negative patients infected with HCV genotype 1, recent data indicate that higher doses of RBV (1000–1200 mg daily) are associated with greater antiviral efficacy compared with the lower dose (800 mg daily). 22 Furthermore, we used daily IFN to deliver continuous antiviral therapy and, while our data indicate that daily IFN was more effective, the current HCV therapies involve the use of once-weekly peginterferon alfa (PEG-IFA) alfa plus RBV. 9,12,22,23 Among HIV-uninfected patients, 2 randomized, controlled trials demonstrated that PEG-IFN alfa-2a or alfa-2b plus RBV is superior to standard IFN alfa-2b and RBV, with a similar frequency of adverse events. 12,23 To date, only one published study has reported SVR data among HIV/HCV coinfected patients treated with PEG-IFN/RBV. Perez-Olmeda et al. 19 reported that 28% of 68 coinfected patients treated with PEG-IFN alfa-2b plus RBV achieved an SVR. Additionally, preliminary data from an ongoing AIDS Clinical Trials Group Study, which randomized 134 persons to receive IFN alfa-2a or standard IFN plus RBV, demonstrated higher rates of on-treatment viral suppression among patients receiving PEG-IFN (44%) compared with those receiving standard IFN (15%). 20 Thus, while more robust efficacy and safety data are anticipated from ongoing large, randomized controlled trials, the preliminary reports indicate that the virologic response rates among HIV-infected persons treated with PEG-IFN/RBV may be significantly lower than those historically observed among HIV-negative persons treated with similar regimens. Even so, in light of its greater efficacy and the convenience of once-weekly dosing, PEG-IFN plus RBV represents the current standard of care for treatment of HCV in HIV-infected persons. 9
While our study did not evaluate PEG-IFN/RBV, the other principal finding of the study, the relatively poor tolerability of anti-HCV therapy, is directly applicable to current regimens since the safety and adverse effects of PEG-IFN are similar to those of standard IFN. Although the nature of the adverse events was similar to those reported in HIV-uninfected patients, we found that approximately 25% of subjects failed to complete at least 12 weeks of therapy. Since these subjects stopped therapy before the first assessment of HCV response, these treatment discontinuations were driven by adverse effects and poor tolerability rather than knowledge of virologic efficacy. 24,25 Conversely, our data also indicate that >90% of subjects without an EVR at treatment week 12 stopped anti-HCV therapy, suggesting that investigators (and subjects) were influenced by the observation among HIV-negative subjects that the lack of an EVR was strongly associated with subsequent failure to achieve an SVR (negative predictive value, 97–99%). 26 Additional large studies will be needed to validate the negative predicative value of week 12 viral response patterns among HIV-infected patients.
Nonetheless, we found that nearly one-third of subjects stopped treatment due to an adverse event, including 11 subjects (24%) who achieved an EVR. Specifically, psychiatric and hematologic (e.g., neutropenia, anemia) toxicity accounted for approximately 40 and 15% of these early discontinuations, respectively. These observations suggest that strategies to manage psychiatric complications, such as close supervision or the use of psychotropic medications, may reduce early treatment dropout. Moreover, the use of growth factors, such as filgrastim and epoetin alfa, may prevent treatment interruptions due to hematologic toxicity. 27 In addition to these documented toxicities, nearly 20% of our subjects were lost to follow-up or were nonadherent to therapy. While it is likely that treatment-related toxicity contributed to the failure in such subjects, strategies to improve adherence such as directly administered, weekly PEG-IFN injections or moderated support groups may lead to the more effective delivery of HCV care. Such comprehensive approaches will also serve to better address the physical and psychiatric morbidity associated with PEG-IFN/RBV.
Importantly, although drug-related toxicity substantially limited the effectiveness of anti-HCV therapy, we did not detect evidence of a significant adverse impact of IFN/RBV on markers of HIV disease or on the effectiveness of its treatment with antiretroviral drugs. 10,28,29 As previously reported, the absolute CD4+ T-cell count decreased as a result of IFN-related lymphopenia, but the proportion of these lymphocytes that were CD4+ cells increased. 20,30 In addition, while 3 cases of bacterial pneumonia were observed, no subject developed an acute opportunistic infection. Furthermore, among subjects taking antiretroviral therapy, we did not detect an adverse impact on suppression of HIV replication, including in those subjects taking drugs that, in vitro are antagonized by RBV, such as zidovudine or stavudine. 28,29 Conversely, 1 subject receiving didanosine developed symptomatic hyperlactemia, highlighting recent data indicating that didanosine and RBV should not be coadministered. 31,32 While we did not observe substantial adverse effects on the management of HIV disease, additional studies are needed to define the appropriate sequencing of antiretroviral and HCV therapy as well as to formally evaluate the significance of potential drug-drug interactions.
Our findings are subject to several other potential limitations. First, subjects in our study discontinued therapy at a relatively high rate; however, this is an important observation as a marker of tolerability and all analyses were conducted as modified intention to treat. Second, the majorities of subjects were effectively treated with HAART and had relatively intact immune function (<7% had a CD4 cell count <200 cells/mm3). Consequently, our findings cannot be applied to HIV-infected patients with compromised immune function (e.g., CD4 cell count <100 cells/mm3). Lastly, enrolled subjects met strict criteria regarding their health status and comorbidities, which may limit the applicability of these results to some patient groups such as those with active drug and alcohol use or renal disease. However, one-third had stable psychiatric disease and nearly two-thirds had a history of injection drug use, suggesting our data are generalizable to many patients with HIV/HCV coinfection. 2,33,34
In conclusion, our data indicate that chronic HCV can be safely and effectively treated in HIV-infected persons. However, the observed EVR and SVR rates were substantially lower than historical rates seen in HIV-negative persons receiving similar ant-HCV regimens. Similarly, while no adverse impact was detected on HIV disease or its treatment with HAART, the overall effectiveness of therapy was diminished by relatively high rates of discontinuation due to medication-related toxicity. Clearly, more research is needed to understand the host, virus, and treatment factors that limit the effectiveness of anti-HCV therapy among persons with HIV/HCV coinfection. Finally, although we anticipate that many of our findings will be directly applicable to the current standard therapy—PEG-IFN plus RBV—large, well-designed clinical trials are needed to assess the safety, tolerability, and efficacy of these regimens in this population.
1. Sherman KE, Rouster SD, Chung R, et al. Hepatitis C virus prevalence among patients infected with Human Immunodeficiency Virus: a cross-sectional analysis of the US adult AIDS Clinical Trials Group. Clin Infect Dis
2. Sulkowski MS, Moore RD, Mehta SH, et al. Hepatitis C and progression of HIV disease. JAMA
3. 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
4. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med
5. 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
6. Rosenthal E, Poiree M, Pradier C, et al. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS
7. 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
8. Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet
9. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: 2002—June 10–12, 2002. Hepatology
10. Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS
11. Masur Pb PH, Kaplan JE, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons-2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. Ann Intern Med
12. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med
13. Poynard T, Marcellin P, Lee SS, et al. Int Hepatitis Intervention Therapy Grp. randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet
14. McHutchison JG, Gordon SC, Schiff ER, et al, for the International Hepatitis Interventional Therapy Group. (IHIT). Interferon Alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med
15. Zylberberg H, Benhamou Y, Lagneaux JL, et al. Safety and efficacy of interferon-ribavirin combination therapy in HCV-HIV coinfected subjects: an early report. Gut
16. Landau A, Batisse D, Piketty C, et al. Long-term efficacy of combination therapy with interferon-alpha2b and ribavirin for severe chronic hepatitis C in HIV-infected patients. AIDS
17. Sauleda S, Juarez A, Esteban JI, et al. Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus-infected patients with congenital coagulation disorders. Hepatology
18. Perez-Olmeda M, Gonzalez J, Garcia-Samaniego J, et al. Interferon plus ribavirin in HIV-infected patients with chronic hepatitis C. J Acquir Immune Defic Syndr
19. Perez-Olmeda M, Nunez M, Romero M, et al. Pegylated IFN-alpha 2b plus ribavirin as therapy for chronic hepatitis C in HIV-infected patients. AIDS
20. Chung RT, Anderson J, Alston B, et al. et al. A randomized, controlled trial of pegylated interferon alpha-2s with ribavirin versus interferon alpha-2a with ribavirin for the treatment of chronic HCV in HIV co-infection: ACTG 5071. Paper presented at: Ninth Conference on Retrovirus and Opportunistic Infections; February 24–25, 2002; Seattle. Abstract LB15.
21. Kostman JR, Smith J, Giffen C, et al., for the amFAR DCR1 010 Study Group. Interferon alfa-2b/ribavirin combination therapy in HIV/HCV co-infected persons: results of a multi-center, randomized, double-blind, controlled trial. Hepatology
. 2001;34:330A. Abstract no. 634.
22. Hadziyannis SJ, Cheinquer H, Morgan T, et al. Peginterferon alfa-2a (40kd) (PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose. Paper presented at: 37th Annual Meeting of the European Association for the Study of the Liver; April 15–21, 2002; Madrid. Abstract no. 536.
23. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet
24. Fattovich G, Giustina G, Favarato S, et al. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol
25. Fried MW. Side effects of therapy of hepatitis C and their management. Hepatology
26. Davis GL. Monitoring of viral levels during therapy of hepatitis C. Hepatology
27. Dieterich DT, Wasserman R, Brau N, et al. Once-weekly epoetin alfa facilitates maintenance of ribavirin dosing in hepatitis C virus-infected patients receiving interferon α-2b plus ribavirin. Am J Gastroenterol
. 2003. In press.
28. Vogt MW, Hartshorn KL, Furman PA, et al. Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science
29. Baba M, Pauwels R, Balzarini J, et al. Ribavirin antagonizes inhibitory effects of pyrimidine 2′,3′-dideoxynucleosides but enhances inhibitory effects of purine 2′,3′-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Antimicrob Agents Chemother
30. Lane HC, Davey V, Kovacs JA, et al. Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection: a randomized, placebo-controlled trial. Ann Intern Med
31. Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet
32. Videx EC [prescribing information]. Princeton, NJ: Bristol-Myers-Squibb Co.; revised September 2002.
33. Brau N, Bini EJ, Shahidi A, et al. Prevalence of hepatitis C and coinfection with HIV among United States veterans in the New York City metropolitan area. Am J Gastroenterol
34. Fleming CA, Craven DE, Thornton D, et al. Hepatitis C virus and human immunodeficiency virus coinfection in an urban population: low eligibility for interferon treatment. Clin Infect Dis
Keywords:© 2004 Lippincott Williams & Wilkins, Inc.
HCV; HIV; interferon; ribaviron