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Risks and benefits of antiretroviral therapy in HIV–HCV co-infected patients

2004; Elsevier BV; Volume: 42; Issue: 3 Linguagem: Inglês

10.1016/j.jhep.2004.12.011

1600-0641

Marina Núñez, Vincent Soriano,

HIV/AIDS drug development and treatment

The causes of morbidity and mortality in HIV-infected individuals have evolved considerably since the beginning of the AIDS pandemia and particularly since the introduction of highly active antiretroviral therapy (HAART) in 1996. Of note, in regions where intravenous drug users represent a large proportion of the HIV-infected population, hepatitis C virus (HCV) -related liver disease currently represents a problem of first magnitude [1Bica I. McGovern B. Dhar R. et al.Increasing mortality due to end-stage liver disease in patients with HIV infection.Clin Infect Dis. 2001; 32: 492-497Crossref PubMed Scopus (908) Google Scholar, 2Cacoub P. Geffray L. Rosenthal E. et al.Mortality among HIV-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French departments of internal medicine/infectious diseases, in 1995 and 1997.Clin Infect Dis. 2001; 32: 1207-1214Crossref PubMed Scopus (143) Google Scholar, 3Martín-Carbonero L. Soriano V. Valencia E. García-Samaniego J. López M. González-Lahoz J. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients.AIDS Res Hum Retroviruses. 2001; 17: 1467-1472Crossref PubMed Scopus (206) Google Scholar, 4Rosenthal 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. 2003; 17: 1803-1809Crossref PubMed Scopus (247) Google Scholar, 5Gebo K. Diener-West M. Moore R. Hospitalization rates differ by hepatitis C status in an urban HIV cohort.J Acquir Immune Defic Syndr. 2003; 34: 165-173Crossref PubMed Scopus (84) Google Scholar]. The increased weight of liver complications, mainly in the context of advanced cirrhosis and hepatocellular carcinoma [[6]Puoti M. Bruno R. Soriano V. Donato F. Gaeta G. Quinzan G. et al.Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.AIDS. 2004; 18: 2285-2293Crossref PubMed Scopus (220) Google Scholar], among HIV-infected patients runs in parallel with a dramatic reduction in opportunistic infections as a result of the widespread use of HAART, and with aging in HIV–HCV co-infected individuals. This increased mortality due to liver disease translates into higher death rates among HIV–HCV-coinfected subjects compared to HCV-negative HIV-positive patients [[7]Klein M. Lalonde R. Suissa S. The impact of hepatitis C virus co-infection on HIV progression before and after highly active antiretroviral therapy.J Acquir Immune Defic Syndr. 2003; 33: 365-372Crossref PubMed Scopus (99) Google Scholar]. In this issue of the Journal, Kramer and colleagues bring to our attention another cause of liver-related mortality among HIV–HCV co-infected subjects [[8]Kramer J.R. Giordano T.P. Souchek J. El-Serag H.B. Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era.J Hepatol. 2005; 42: 309-314Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar], which is the occurrence of fulminant hepatitis. Kramer and colleagues examined the risk of fulminant hepatic failure (FHF) among 16,439 HIV-infected US Veterans, assessing the role of HCV co-infection and HAART use [[8]Kramer J.R. Giordano T.P. Souchek J. El-Serag H.B. Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era.J Hepatol. 2005; 42: 309-314Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. They excluded from the study individuals with advanced liver disease. Even after adjustment for high alcohol intake, which was significantly more frequent among HIV–HCV co-infected individuals, the hazard ratio for FHF was 2.7 for HIV–HCV co-infected individuals with respect to HIV-monoinfected patients. Interestingly, the authors found that these differences were more pronounced during the HAART era, in which the hazard ratio fro FHF was 5.9 in HIV–HCV co-infected patients compared to HIV-monoinfected individuals. This deleterious synergistic interplay between HAART and underlying hepatitis C at least with respect to the risk of FHF should be balanced with the growing evidence supporting a beneficial effect of HAART on liver disease progression in subjects with chronic hepatitis C [9Qurishi N. Kreuzberg C. Lüchters G. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C coinfection.Lancet. 2003; 362: 1708-1713Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 10Bonacini M. Bzowej N. Louie S. Wohl A. Survival in patients with HIV infection and viral hepatitis B or C.AIDS. 2004; 18: 2039-2046Crossref PubMed Scopus (237) Google Scholar, 11Benhamou Y. De Martino V. Bochet M. Factors affecting liver fibrosis in HIV and hepatitis C virus coinfected patients: impact of protease inhibitor therapy.Hepatology. 2001; 34: 283-287Crossref PubMed Scopus (402) Google Scholar, 12Mariné-Barjoan E. Saint-Paul M. Pradier C. Chaillou S. Anty R. Michiels J. et al.Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients.AIDS. 2004; 18: 2163-2170Crossref PubMed Scopus (98) Google Scholar]. The faster progression of HCV-related liver fibrosis classically seen in HIV-coinfected patients seems to be somewhat halted when patients are successfully treated with HAART. Accordingly, many experts feel that the presence of chronic hepatitis C should favor the early prescription of antiretroviral therapy in HIV-infected individuals [13Nuñez M. Soriano V. How effective is HAART in HCV and HIV coinfection.AIDS. 2004; 18: 2081-2084Crossref PubMed Scopus (5) Google Scholar, 14Braitstein P. Palepu A. Dieterich D. Benhamou Y. Montaner J. Special considerations in the initiation and management of antiretroviral therapy in individuals coinfected with HIV and hepatitis C.AIDS. 2004; 18: 2221-2234Crossref PubMed Scopus (34) Google Scholar], given the negative effect of immune deficiency on HCV-related liver damage [[15]Puoti M. Bonacini M. Spinetti A. Putzolu V. Govindarajan S. Zaltron S. et al.Liver fibrosis progression is related to CD4+ cells depletion in patients with hepatitis C and HIV coinfection.J Infect Dis. 2001; 183: 134-137Crossref PubMed Scopus (213) Google Scholar]. Clearly, depending on the antiretrovirals in use, the positive effects of HAART over HCV-related liver disease might be overshadowed by the development of drug-associated liver toxicities. The clinical presentation of antiretroviral-related hepatotoxicity ranges from asymptomatic liver enzyme elevations to hepatic decompensation; and the outcomes vary from spontaneous resolution to liver failure and death [[16]Clark S. Creighton S. Portmann B. Taylor C. Wendon J. Cramp M. Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases.J Hepatol. 2002; 36: 295-301Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar]. While asymptomatic liver enzyme elevations may be recognized in up to 10% of patients who initiated HAART, liver failure secondary to antiretroviral-associated hepatotoxicity is very uncommon [[17]Núñez M. Soriano V. Hepatotoxicity of antiretrovirals. Incidence, mechanisms, and management.Drug Safety. 2004; (in press)Google Scholar]. In a recent US retrospective survey, severe hepatotoxicity following the use of antiretrovirals accounted for only 2% of deaths in HIV-infected individuals; and this complication was mainly seen in patients with underlying chronic liver disease [[18]Selik R. Byers R. Dworkin M. Trends in diseases reported on U.S. death certificates that mentioned HIV infection, 1987–1999.J Acquir Immune Defic Syndr. 2002; 29: 378-387PubMed Google Scholar]. Thus, hepatotoxic drugs may lead to liver failure by aggravating a pre-existing liver disease. Four main mechanisms of drug-related liver toxicity have been recognized in HIV-infected individuals exposed to antiretroviral therapy: i) direct drug toxicity; ii) immune reconstitution following initiation of HAART in the presence of HCV and/or HBV co-infections; iii) hypersensitivity reactions with liver involvement; and iv) mitochondrial toxicity. Kramer and colleagues did not provide enough information in their series of patients with FHF as to figure out the causes and/or triggering agents. However, the events were more frequent in HCV–HIV co-infected individuals than in HIV-monoinfected patients. Chronic hepatitis C is known to increase the toxic effects of drugs on the liver, most likely by impairing the mechanisms of cytoprotection in liver cells [[19]Bissell D. Gores G. Laskin D. Hoofnagle J. Drug-induced liver injury: mechanisms and test systems.Hepatology. 2001; 33: 1009-1013Crossref PubMed Scopus (218) Google Scholar]. This is why exposure to drugs like ritonavir at full doses (600 mg bid) is associated with a high risk of hepatotoxicity [[20]Sulkowski M. Thomas D. Chaisson R. Moore R. Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of Hepatitis C or B virus infection.JAMA. 2000; 283: 74-80Crossref PubMed Scopus (906) Google Scholar]. Immune reconstitution may explain some episodes of liver enzyme elevations following the initiation of HAART, particularly in severely immunossuppressed patients with chronic hepatitis B or C [21John M. Flexman J. French A. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease?.AIDS. 1998; 12: 2289-2293Crossref PubMed Scopus (266) Google Scholar, 22Vento S. Garofano T. Renzini C. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy.AIDS. 1998; 12: 116-117PubMed Google Scholar, 23Gavazzi G. Bouchard O. Leclercq P. Change in transaminases in hepatitis C virus- and HIV-coinfected patients after highly active antiretroviral therapy: differences between complete and partial virologic responders?.AIDS Res Hum Retroviruses. 2000; 16: 1021-1023Crossref PubMed Scopus (44) Google Scholar]. The rationale behind this phenomenon is that the inhibition of HIV replication with HAART leads to rapid immune recovery, and consequently to immune response to HBV and/or HCV antigens exposed in the surface of hepatocytes, which are destroyed [[24]Stone S. Lee S. Keane N. Price P. French M. Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in HIV-HCV-coinfected patients.J Infect Dis. 2002; 186: 1498-1502Crossref PubMed Scopus (49) Google Scholar]. Mitochondrial toxicity of some nucleoside analogues is a well known cause of liver damage [[25]McKenzie R. Fried M. Sallie R. Conjeevaram H. Di Bisceglie A. Park Y. et al.Hepatic failure and lactic acidosis due to fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B.N Engl J Med. 1995; 333: 1099-1105Crossref PubMed Scopus (543) Google Scholar], and has been clearly established for some HIV reverse transcriptase inhibitors, such as didanosine and stavudine [26Lonergan J. Behling C. Pfander H. Hassanein T. Mathews W. Hyperlactatemia and hepatic abnormalities in 10 HIV-infected patients receiving nucleoside analogue combination regimens.Clin Infect Dis. 2000; 31: 162-166Crossref PubMed Scopus (208) Google Scholar, 27Coghlan M. Sommadossi J. Jhala N. Many W. Saag M. Johnson V. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with HIV infection: a report of 12 cases.Clin Infect Dis. 2001; 33: 1914-1921Crossref PubMed Scopus (112) Google Scholar], sporadically accompanying a syndrome of lactic acidosis. Cumulative exposure to HIV nucleoside inhibitors (especially didanosine and/or stavudine), female sex, and obesity are some of the predisposing factors for developing lactic acidosis, but the role of underlying chronic HCV infection is unclear [19Bissell D. Gores G. Laskin D. Hoofnagle J. Drug-induced liver injury: mechanisms and test systems.Hepatology. 2001; 33: 1009-1013Crossref PubMed Scopus (218) Google Scholar, 26Lonergan J. Behling C. Pfander H. Hassanein T. Mathews W. Hyperlactatemia and hepatic abnormalities in 10 HIV-infected patients receiving nucleoside analogue combination regimens.Clin Infect Dis. 2000; 31: 162-166Crossref PubMed Scopus (208) Google Scholar, 27Coghlan M. Sommadossi J. Jhala N. Many W. Saag M. Johnson V. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with HIV infection: a report of 12 cases.Clin Infect Dis. 2001; 33: 1914-1921Crossref PubMed Scopus (112) Google Scholar, 28Barbaro G. Di Lorenzo G. Asti A. Ribersani M. Belloni G. Grisorio B. et al.Hepatocellular mitochondrial alterations in patients with chronic hepatitis C: ultrastructural and biochemical findings.Am J Gastroenterol. 1999; 94: 2198-2205Crossref PubMed Scopus (167) Google Scholar, 29De Mendoza C. Sánchez-Conde M. Rivera E. Domingo P. Soriano V. Could mitochondrial DNA quantitation be a surrogate marker for drug mitochondrial toxicity?.AIDS Rev. 2004; 6: 169-180PubMed Google Scholar]. Finally, hypersensitivity reactions to drugs such as nevirapine, abacavir or amprenavir, may involve multiple organs including the liver. In this situation, liver enzyme elevations occur within the first weeks following the initiation of HAART and tend to resolve after drug discontinuation. As expected, allergic reactions may be more frequent in patients with high CD4 counts and do not seem to be favored by the presence of HCV co-infection [[30]Gonzalez de Requena D. Nuñez M. Jimenez-Nacher I. Soriano V. Liver toxicity caused by nevirapine.AIDS. 2002; 16: 290-291Crossref PubMed Scopus (168) Google Scholar]. Whatever the causes, Kramer and colleagues found that FHF accounts for a significant proportion of deaths in HIV-infected persons, particularly among those with HCV co-infection [[8]Kramer J.R. Giordano T.P. Souchek J. El-Serag H.B. Hepatitis C coinfection increases the risk of fulminant hepatic failure in patients with HIV in the HAART era.J Hepatol. 2005; 42: 309-314Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. The knowledge of which are the predisposing factors for FHF is crucial to prevent further episodes as much as possible. In this way, the use of certain nucleoside analogue combinations, especially those particularly associated to mitochondrial toxicity, should be avoided in HCV–HIV co-infected patients. Counseling about alcohol abstinence, avoidance of potentially hepatotoxic drugs other than antiretrovirals, and close monitoring following the initiation of HAART in HCV-coinfected patients is warranted to prevent further episodes of FHF. Not less importantly, a further consideration to prevent HCV-associated episodes of FHF should consider the eradication of HCV infection with specific therapy before initiating HAART. In this regard, major progress has been made with the advent of the new pegylated forms of interferon-alfa administered along with ribavirin [[31]Soriano V. Puoti M. Sulkowski M. Mauss S. Cacoub P. Cargnel A. et al.Care of patients with hepatitis C and HIV co-infection. Updated recommendations from the HCV–HIV international panel.AIDS. 2004; 18: 1-12Crossref PubMed Scopus (216) Google Scholar]. Financial support: This work was supported in part by grants from FIS (project # 02/3040), RIS, Fundación IES and VIRGIL.