Hepatitis C in HIV-infected patients therapeutic approach I. Fernández 1, R. Rubio 2 and C. Lumbreras 3

Transcription

1 REVIEW Hepatitis C in HIV-infected patients therapeutic approach I. Fernández 1, R. Rubio 2 and C. Lumbreras 3 1 Department of Gastroenterology and Hepatology, 2 HIV Unit, Department of Internal Medicine, and 3 Unit of Infectious Diseases, Hospital 12 de Octubre, Madrid, Spain The use of highly active antiretroviral therapy (HAART) has extended the lifespan of patients infected with human immunodeficiency virus (HIV). As the prognosis of HIV infection has improved, liver disease associated with hepatitis C virus (HCV) has become clinically significant in patients with HIV, liver failure being a frequent cause of death in this population. HIV infection may accelerate the course of liver disease in patients coinfected with HCV, so infection with HCV should be treated like any other opportunistic disease in these patients. Nowadays, combination therapy with interferon-alpha and ribavirin is the standard treatment for chronic hepatitis C in HIV-negative patients. Preliminary results of combination therapy in HIV/HCV co-infected patients have been promising, showing a sustained response rate in 40% of these patients. Patients with higher CD4 counts and lower HCV/HIV viral load and those infected with HCV genotype 3a have a better response to therapy. Potential drug interactions between HAART therapy and interferon and ribavirin treatment emphasize the importance of initiating treatment of HCV infection in HIV-positive individuals as soon as possible and ideally before the need for anti-hiv therapy. Recent case reports have suggested that liver transplantation might be an appropriate procedure in HIV patients with undetectable HIV viral load, high CD4 counts and HCV advanced liver disease. However, the limited amount of available information and the complexities of drug interactions between HAART therapy and immunosuppressive drugs oblige us to be prudent within considering such a procedure. Keywords Hepatitis C, HIV, therapy Clin Microbiol Infect 2002; 8: HIV and hepatitis C virus (HCV) co-infection is a significant clinical phenomenon. As many as 33% of patients with HIV infection are also infected by HCV, but this figure rises to 60 90% of injection drug users and of persons with hemophilia [1]. Since 1996, the use of highly active antiretroviral therapy (HAART) has extended the lifespan of patients infected with human immunodeficiency virus (HIV). As the prognosis for HIV infection has improved, liver disease associated with HCV has become clinically significant in patients with HIV, liver failure being a frequent cause of death in this population [2]. Studies on the natural history of HCV infection in immunocompetent persons have shown that 6% of them will develop liver decompensation due to Corresponding author and reprint requests: C. Lumbreras, Unidad de Enfermedades Infecciosas, Hospital 12 de Octubre, Avenida de Córdoba s/n, Madrid, Spain clumbrerasb@medynet.com cirrhosis during a 20-year period [3]. A number of studies have suggested that HIV infection may accelerate the course of liver disease in patients co-infected with HCV [3,4], fibrosis occurring at a faster rate [5,6] and hepatic decompensation, liverrelated death and hepatocarcinoma developing more often, than in non-hiv patients [7]. Benhamou et al. [6] have recently estimated the mean time for developing liver cirrhosis in patients with HIV/HCV co-infection as 26 years (range 22 34) in comparison with 34 years (range 32 47), in non- HIV-infected patients. On the other hand, although it is less clear whether HCV infection has an effect on the natural history of HIV infection, it has been suggested [8] that co-infection by HCV may affect it adversely. HIV/HCV-co-infected patients are more likely to have increasing HIV viral load and decreasing CD4 counts compared with those not infected with both viruses [9]. It is important to consider that the risk of liver failure in HIV patients with hepatitis C ß 2002 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Fernández et al Hepatitis C in HIV-infected patients therapeutic approach 81 is inversely correlated with CD4 cell counts [10,11], so maintenance of CD4 lymphocyte levels must be viewed as an absolute priority in these patients. Thus, appropriate therapy for decreasing HIV replication is an important strategy in the treatment of HCV-related chronic liver disease in these patients. Because of the effect of HIV on the natural history of HCV disease, infection with HCV should be treated like any other opportunistic disease, as has been stated by the US Public Health Service and the Infectious Diseases Society of America in their 1999 guidelines: HIV HCV coinfected patients have a higher incidence of chronic liver disease than patients infected with HIV alone and should be evaluated for chronic liver disease and for the possible need for treatment [12]. The goals for the treatment of HCV infection in HCV/ HIV-co-infected individuals are: (1) to prevent the development of cirrhosis and its complications; (2) to reduce the extrahepatic manifestations; and (3) to prevent the contamination of other people. Several studies have shown a beneficial effect of recombinant interferon-alpha (IFN-a) in HIV-positive patients with chronic hepatitis C [13 17]. The response rate is not significantly different from that observed in HIV-non-infected patients [16,18]. Alanine aminotransferase level normalization at the end of treatment is achieved in 32 55% of patients, and a sustained response occurred in 8 38% of patients with HIV/HCV after a 12-month follow-up. A prospective trial, which included 119 patients with chronic hepatitis C, 90 of whom were infected with HIV and 29 of whom were not, showed a complete response after 12 months of therapy in 32.5% of HIV-infected patients and in 37% of non-hiv-infected patients (P ¼ 0,66), and relapses occurred in 30.8% of the HIV-infected patients and in 12.5% of non-hiv-infected patients (P ¼ 0.4) [16]. This study, in addition to others, demonstrated a tendency toward better response among HIV-co-infected patients who had a higher CD4 count (> /L) [15 17]. Lower HCV viremia and genotype 3a were also found to be predictors of response among these patients [19]. Histologic improvement 1 year after the end of therapy was observed not only in responders but also in non-responders and those who relapsed [15,16,19]. In the majority of these studies, the tolerance and side-effects of treatment were found to be no different between the HCV/ HIV-co-infected patients and the HIV-uninfected patients. The more frequent side-effects associated with interferon therapy are flu-like syndrome, headache, fatigue, myalgia, anorexia and thrombocytopenia. Although interferon treatment was usually generally well tolerated, in a recent prospective study of 153 patients with chronic hepatitis C, 76 of whom were co-infected with HIV, four serious side-effects were reported, two among HIV-negative patients and two among HIV-positive patients: two patients (one from each group) made unsuccessful suicide attempts, an HIV-infected patient died during follow-up 11.9 months after starting treatment from decompensated cirrhosis with ascites and septicemia, and one non-hiv-infected patient showed a flare-up of transaminases without known etiology [18]. During IFN-a therapy, a decrease in the CD4 cell count may occur in about 5% of patients [20,21], but this decline is transient and reversible, and does not appear to increase the risk of opportunistic infection [22]. Although this decrease in CD4 count is a rare event, it is mandatory to control the CD4 cell count during IFN-a treatment of HIV-infected patients. In HIV-negative patients, several reports have suggested that rates of sustained response can be markedly improved with the addition of ribavirin to IFN-a therapy. Ribavirin is a guanosine analog with broad-spectrum antiviral activity against many RNA and DNA viruses. Although ribavirin does not inhibit HCV replication when given alone, it may significantly reduce transaminase levels and can improve liver histology. Large multicenter randomized controlled trials in HIV-seronegative patients have shown that a combination of interferon and ribavirin results in sustained response rates of 28 40% or at least two-fold higher than those seen with interferon monotherapy [23]. Sustained virologic response is strongly related to HCV genotype, ranging from 17% to 29% in patients with genotype 1, to 65 67% in those with genotypes 2 or 3, with 6 or 12 months of therapy, respectively. In addition to viral genotype, sustained virologic response depends on different factors such as duration of therapy and viral load, as well as the age and sex of patients. As yet, there are few published articles on the effect of IFN-a and ribavirin combination therapy in HCV/HIV-co-infected patients, but preliminary results seem very promising [24 27]. The majority of patients included in these trials were young men, former drug users or hemophiliacs receiving

3 82 Clinical Microbiology and Infection, Volume 8 Number 2, February 2002 HAART, with high CD4 cell counts and low HIV viral loads. Landau et al. [26] achieved, with combination therapy, clearing of serum HCV RNA at the end of 6 months of treatment in 50% of 20 patients. In a second study, end-of-treatment response was achieved in 73% of 12 patients treated for 6 months [27]. However, a sustained virologic response was found by Zylberberg et al. [24] in only 14% of 20 patients who were previous nonresponders to interferon therapy. This very low sustained rate of response to interferon in nonresponders parallels those obtained in the general population [28]. Very limited data are currently available on the safety and tolerance of the IFN-a and ribavirin combination therapy in HIV infection. The most serious side-effect of ribavirin is hemolytic anemia. The incidence of anemia seems to be much higher in HIV-infected patients than among HIV-noninfected patients [24]. Treatment discontinuation is usually the result of anemia and neutropenia, particularly in patients receiving zidovudine at the same time as ribavirin. Moreover, a recent report suggests that ribavirin, a nucleoside analog, can increase the risk of mitochondrial toxicity in HIVinfected patients already treated with nucleoside analogs, leading to clinical deterioration in some cases [29]. On the other hand, there has been some concern about administering ribavirin to HIVinfected individuals because of potential inhibition of the phosphorylation of zidovudine and stavudine [30]. In a recent study, however, there was no significant variation in HIV viral load after 6 months of treatment with ribavirin in HCV/HIVco-infected patients receiving zidovudine and stavudine [24]. The usual dose of rivabirin in immunocompetent individuals is mg/day plus 3 MU of interferon, three times weekly, for 6 12 months. However, severe depletions of CD4 cells have been observed with doses of mg [31]. Thus, a lower dose of ribavirin would probably be better in HIV/HCV-coinfected patients (i.e. 800 mg/day); several clinical trials are currently in progress to confirm this. Recent reports have suggested that HAART may result in severe liver disease as a result of an improvement in T-cell-mediated immunity upon effective immune restoration, or through direct hepatotoxicity of protease inhibitors in HIV-seropositive patients co-infected with HCV [32]. Hepatotoxic manifestations are seen in nearly 14% of HIV/HCV-co-infected patients after starting HAART. Such results emphasize the convenience of treating HIV-infected patients suffering from chronic hepatitis C with IFN-a and ribavirin before the introduction of antiretroviral therapy (i.e. with CD4þ T-lymphocyte count >350/mm 3 ). Moreover, early treatment before the need for anti-hiv therapy, would overcome the potential problem of drug interactions during the treatment of HIV-positive patients. Despite efforts to achieve HCV eradication with the incorporation of new drugs and new therapeutic strategies, no more than half of the patients with chronic hepatitis C infection respond to standard treatment with interferon plus ribavirin. Thus, new pharmacologic options are needed. Investigations on viral kinetics have shown that daily dosing of interferon is superior to administration every other day. Therefore, pegylated interferons which are given once a week were designed and have been shown to result in stable plasma trough levels. Preliminary results in HIV-seronegative patients look very promising [33]. Unfortunately, there are no published reports of experience with this drug in HIV-infected individuals. Orthotopic liver transplantation is the only effective treatment for immunocompetent patients with HCV advanced liver disease. In the 1980s, before the availability of HIV screening tests, several transplant recipients acquired HIV from contaminated organs or blood products [34,35]. At this time, it was observed that the survival rate of HIVpositive transplant recipients was inferior to that of HIV-negative recipients. Many of these patients died prematurely as a consequence of opportunistic infection and rapid progression to AIDS. With the development of effective HAART, increasing numbers of patients with stable HIV infection are progressing to end-stage liver failure. Nevertheless, attitudes to the transplantation of HIV-infected patients have been slow to adjust, and many transplant centers still consider HIV infection to be a contraindication to organ transplantation. Currently, there is little published data concerning liver transplantation for stable HIV-infected patients with a low viral load. Recent case reports demonstrate that a good short-term outcome can be expected and long-term survival with a good quality of life is possible [36 38]. Ideally, HIVinfected liver transplant candidates should not

4 Fernández et al Hepatitis C in HIV-infected patients therapeutic approach 83 be addicted to drugs should have undetectable HIV viral load, should have a CD4 count above 200/mm 3, should have no opportunistic infections, and should be able to fulfill all the sociological and psychological requirements for a liver transplant within the general population [39]. Unfortunately, HAART therapy has side-effects: the interaction with other drugs is such that concomitant use with immunosuppressive drugs after transplantation is a challenge. In view of the complexities and uncertainties of liver transplantation in HIV-infected patients, it seems prudent for such procedures to be limited to a small number of centers which can develop the appropriate experience. In summary as the life-expectancy of HIVinfected patients increases, it is increasingly more important to consider the deleterious impact of HIV infection in their treatment. As in immunocompetent patients, HCV therapy in HIV-infected individuals is associated with modest clinical and virologic success. Future studies have to focus on the impact of new therapies, including liver transplantation, in the natural history of HCV infection in HIV-infected individuals. REFERENCES 1. Thomas DL, Shih JW, Alter AJ et al. Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users. J Infect Dis 1996; 174: Soriano V, Garcia Samaniego J, Valencia E, Rodriguez-Rosado R, Muñoz F, Gonzalez-Lahoz J. Impact of chronic liver disease due to hepatitis viruses as a cause of hospital admission and death in HIV-infected drug users. Eur J Epidemiol 1999; 15: Graham CS, Baden LR, Yu E et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a metaanalysis. Clin Infect Dis 2001; 33: Soto B, Sanchez-Quijano A, Rodrigo L et al. Human immunodeficiency virus infection modifies the natural history of chronic parenterally acquired hepatitis C with an unusually rapid progression to cirrhosis. J Hepatol 1997; 26: Garcia-Samaniego J, Soriano V, Castilla J et al. Influence of hepatitis C virus genotypes and HIV infection on histological severity of chronic hepatitis C. Hepatitis/HIV Spanish Study Group. Am J Gastroenterol 1997; 92: 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: 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. UK Haemophilia Centre Directors organisation. Lancet 1997; 350: Haydon GH, Flegg PJ, Blair CS, Brettle RP, Burns SM, Hayes PC. The impact of chronic hepatitis C virus infection on HIV disease and progression in intravenous drug users. Eur J Gastroenterol Hepatol 1998; 10: Piroth L, Bourgeois C, Dantin S et al. Hepatitis C virus (HCV) genotype does not appear to be a significant prognostic factor in HIV HCV-coinfected patients. AIDS 1999; 13: Makris M, Preston FE, Rosendaal FR, Underwood JC, Rice KM, Triger DR. The natural history of chronic hepatitis C in haemophiliacs. Br J Haematol 1996; 94: Telfer P, Sabin C, Devereux H, Lee CA, Dusheiko GM. The progression of HCV-associated liver disease in a cohort of haemophilic patients. Br J Haematol 1994; 87: Prevention of Opportunistic Infections Working Group, Infectious Diseases Society of America USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. USPHS/IDSA. Ann Intern Med 1999; 131: Boyer N, Marcellin P, Degott C et al. Recombinant interferon-alfa for chronic hepatitis C in patients positive for antibody to human immunodeficiency virus. J Infect Dis 1992; 165: Marriott E, Navas S, del Romero J et al. Treatment with recombinant alfa-interferon of chronic hepatitis C in anti-hiv-positive patients. J Med Virol 1993; 40: Mauss S, Heintges T, Adams O, Albrecht H, Niederau D, Jablonowski H. Treatment of chronic hepatitis C with interferon-alfa in patients infected with the human immunodeficiency virus. Hepatogastroenterology 1995; 42: Soriano V, Garcia-Samaniego J, Bravo R et al. Interferon alfa for the treatment of chronic hepatitis C in patients infected with human immunodeficiency virus. Clin Infect Dis 1996; 23: Del Pozo MA, Arias JR, Pinilla J et al. Interferon alpha treatment of chronic hepatitis C in HIVinfected patients receiving zidovudine: efficacy, tolerance and response related factors. Hepatogastroenterology 1998; 45: Causse X, Payen J-L, Izopet J, Babany G, Girardin MF, the French Multicenter Study Group. Does HIVinfection influence the response of chronic hepatitis C to interferon treatment? A French multicenter prospective study. J Hepatol 2000; 32:

5 84 Clinical Microbiology and Infection, Volume 8 Number 2, February Soriano V, Bravo R, Garcia-Samaniego J et al. A pilot study on the efficacy of escalating dosage of alpha-interferon for chronic hepatitis C in anti-hiv positive patients. J Infect 1997; 35: Vento S, Di Perri G, Cruciani M, Garofano T, Concia E, Bassetti D. Rapid decline of CDþ cells after IFN-a treatment in HIV-1 infection. Lancet 1993; 341: Pesce A, Taillan B, Rosenthal E et al. Opportunistic infections and CD4 lymphocytopenia with interferon treatment in HIV-1-infected patients. Lancet 1993; 341: Soriano V, Bravo R, Samaniego JG et al. CD4þ T- lymphocytopenia in HIV-infected patients receiving interferon therapy for chronic hepatitis C. AIDS 1994; 8: Reichard O, Norkrans G, Fryden A, Braconier JH, Sonnerborg A, Weiland O. Randomised, doubleblind, placebo-controlled trial of interferon a2b with and without ribavirin for chronic hepatitis C. Lancet 1998; 351: 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 2000; 47: Perez-Olmeda M, Gonzalez J, Garcia-Samaniego J, Arribas JR, Peña JM, Soriano V. Interferon plus ribavirin in HIV-infected patients with chronic hepatitis C. J AIDS 1999; 22: Landau A, Batisse D, Van Huyen JP et al. Efficacy and safety of combination therapy with interferonalpha2b and ribavirin for chronic hepatitis C in HIV-infected patients. AIDS 2000; 14: Morsica G, De Bona A, Foppa CU, Sitia G, Finazzi R, Lazzarin A. Ribavirin therapy for chronic hepatitis C does not modify HIV viral load in HIV-1 positive patients under antiretroviral treatment. AIDS 2000; 14: Pol S, Couzigou P, Bourliere M et al. A randomized trial of ribavirin and interferon-a vs. interferon-a alone in patients with chronic hepatitis C who were non-responders to a previous treatment. J Hepatol 1999; 31: Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet 2001; 357: Sim SM, Hoggard PG, Sales SD, Phiboonbanakit D, Hart CA, Back DL. Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentrationdependent interaction. AIDS Res Hum Retroviruses 1998; 14: Roberts RB, Jurica K, Meyer WA, Paxton H, Makuch RW. A phase 1 study of ribavirin in human immunodeficiency virus-infected patients. J Infect Dis 1990; 162: Rodriguez-Rosado R, García-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS 1998; 12: Heathcote EJ, Shiffman ML, Cooksley WG et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: Tzakis AG, Cooper MH, Dummer JS, Ragni M, Ward JW, Starzl TE. Transplantation in HIVþ patients. Transplantation 1990; 49: Bouscarat F, Samuel D, Simon F, Debat P, Bismuth H, Saimot AG. An observational study of 11 French liver transplant recipients infected with human immunodeficiency virus type 1. Clin Infect Dis 1994; 19: Gow PJ, Mutimer D. Liver transplantation for an HIV-positive patient in the era of highly active antiretroviral therapy. AIDS 2001; 15: Ragni MV, Dodson SF, Hunt SC, Bontempo FA, Fung JJ. Liver transplantation in a hemophilia patient with acquired immunodeficiency syndrome. Blood 1999; 93: Gow PJ, Pillay D, Mutimer D. Solid organ transplantation in patients with HIV infection. Transplantation 2001; 72: Torre-Cisneros J, Miró JM. Trasplante hepático en pacientes infectados por el virus de la inmunodeficiencia humana: el difícil reto de una nueva etapa. Med Clin (Barc) 1999; 113: