| |
HAART and the HCV-infected liver: friend or foe?
|
| |
| |
Mark Sulkowski
Jnl of hepatology
July 2004 Volume 41, Issue 1, Pages 181-184
Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection.
Qurishi N, Kreuzberg C, Lüchters G, Effenberger W, Kupfer B, Sauerbruch T, Rockstroh JK, Spengler U.
Background. Highly active antiretroviral therapy (HAART) has improved the prognosis of HIV infection. However, replication of hepatitis C virus (HCV) is not inhibited by HAART, and treatment-related hepatotoxicity is common. To clarify the effect of HAART in HIV/HCV-coinfected patients, we studied liver-related mortality and overall mortality in 285 patients who were regularly treated during the period 1990–2002 at our department. Methods. Survival was analysed retrospectively by Kaplan–Meier and Cox's regression analyses after patients (81% haemophiliacs) had been stratified into three groups according to their antiretroviral therapy (HAART n=93, available after 1995; treatment exclusively with nucleoside analogues n=55, available after 1992; or no treatment, n=137). Findings. Liver-related mortality rates were 0.45, 0.69, and 1.70 per 100 person-years in the HAART, antiretroviral-treatment, and untreated groups. Kaplan–Meier analysis of liver-related mortality confirmed the significant survival benefit in patients with antiretroviral therapy (P=0.018), and regression analysis identified HAART (odds ratio 0.106 [95% CI 0.020–0.564]), antiretroviral treatment (0.283 [0.103–0.780]), CD4-positive T-cell count (0.746 [0.641–0.868] per 0.05 x 109cells/l), serum cholinesterase (0.962 [0.938–0.986] per 100 U/l), and age (1.065 [1.027–1.105] per year) as independent predictors of liver-related survival. Severe drug-related hepatotoxicity was seen in five patients treated with nucleoside analogues alone and 13 treated with HAART. No patient died from drug-related hepatotoxicity. Interpretation. In addition to improved overall survival, antiretroviral therapy significantly reduced long-term liver-related mortality in our patients. This survival benefit seems to outweigh by far the associated risks of severe hepatotoxicity. [Abstract reproduced by permission of Lancet 2003; 362:1708–13]
Due to shared routes of transmission, HCV and HIV coinfection is common, affecting approximately one-third of all HIV-infected persons in the United States and Western Europe [1,2]. Largely as a consequence of dramatic reductions in deaths from AIDS and opportunistic infections, HCV-related liver disease has emerged as an important cause of morbidity and mortality among HIV-infected persons receiving highly active antiretroviral therapy (HAART) [3]. Moreover, HIV infection has been associated with higher HCV RNA viral load and, in most studies, a more rapid progression of cirrhosis, end-stage liver disease (ESLD) and hepatocellular carcinoma [4,5]. While the precise biologic effects of HIV infection on hepatitis C are unknown, advanced immunosuppression has been consistently associated with an increased risk of clinically significant HCV disease [6–10]. Since HAART effectively improves HIV-related immune dysfunction and substantially reduces the risk of opportunistic diseases, it is possible that the progression of HCV will also be altered with a decreased risk of progression to cirrhosis and ESLD among patients successfully treated with HAART compared to those untreated. Conversely, HAART-related hepatotoxicity and other hepatic effects (e.g. steatosis) may lead to accelerated HCV-related fibrosis progression negating any potential benefits of immune recovery [11–14]. Accordingly, the study by Qurishi and coworkers addresses an important question facing hepatologists and HIV specialists who care for HIV/HCV coinfected persons: what is the effect of HAART on HCV-related liver disease? [15]
While the null hypothesis is that HIV treatment has no effect on HCV-related liver disease, there is solid, albeit circumstantial, evidence to support each of the two alternative hypotheses that HAART negatively or positively impacts liver disease in HIV/HCV coinfected patients. Importantly, the definitive answer to this question may impact the medical management of both hepatitis C and HIV infection. For example, the goal of HIV treatment is to prevent progression to AIDS and death while minimizing the acute/chronic antiretroviral-related toxicity (e.g. diabetes mellitus, cardiac disease); accordingly, current treatment guidelines recommend that HAART be deferred in persons with relatively high CD4 cell counts (e.g. >350 mm3), including those with hepatitis C [16]. Similarly, the goal of HCV treatment is to eradicate hepatitis C and prevent clinical outcomes of liver disease (e.g. ESLD, hepatocellular carcinoma) [17]. Based on studies demonstrating an increased risk of cirrhosis and ESLD among HIV/HCV-coinfected patients compared to monoinfected patients, current HCV treatment guidelines recommend the use of peginterferon/ribavirin therapy in all eligible coinfected patients, even those with minimal liver disease [18]. However, these aggressive HCV treatment recommendations are based on assumption that the rate of HCV disease progression will be undeterred by the effective use of HAART. Although HAART has been widely used since 1996 and its beneficial effect on the course of other opportunistic infections has been well documented, the natural history of hepatitis C in HIV-infected patients treated with HAART is unknown. If, as suggested by Qurishi et al. HAART has a beneficial effect on hepatitis C, treatment guidelines might be revised to suggest the earlier initiation of HAART in HIV/HCV coinfected patients (independent of HIV disease risk), and the later initiation of HCV therapy in those with minimal liver disease (e.g. no or minimal portal fibrosis). On the other hand, if HAART has a detrimental effect or no effect on hepatitis C, current HIV and HCV treatment guidelines would be appropriate.
In many studies, advanced immunosuppression (e.g. CD4 cell count<200 mm3) has been independently associated with an increased risk of advanced histologic and/or clinical liver disease in persons coinfected with HIV and hepatitis C [6,9,19,20]. This inverse relationship of CD4 cell count and liver disease supports the hypothesis that reversal or prevention of immunosuppression with HAART will decrease the rate of HCV fibrosis progression and the risk of cirrhosis and its clinical consequences (ESLD, hepatocellular carcinoma and death) in HIV-infected patients. Indeed, Benhamou and collaborators reported that HIV/HCV coinfected patients treated with HIV-1 protease inhibitor based HAART had a significantly decreased rate of fibrosis progression compared to those untreated or treated with less effective ART regimens [21]. Similarly, Macias and colleagues reported that HCV-infected patients exposed to PI-based HAART had less fibrosis to those untreated or treated with other antiretroviral regimens [10]. Additionally, Tural and coworkers found that time on antiretroviral drugs was independently associated with the absence of fibrosis on liver biopsy [8]. Finally, while Rosenthal et al. reported that a greater proportion of deaths observed in HIV-infected patients in the HAART era were attributable to liver disease, the incidence of liver-related deaths actually decreased in the HAART era (HAART: 0.6 liver deaths per 100-persons infected with HIV/HCV; Pre-HAART: 0.8 liver deaths per 100-persons exposed to HIV/HCV) [3]. Taken together, these data appear to support the hypothesis that HAART has a beneficial effect on the natural history of HCV disease progression in HIV-infected patients.
On the other hand, HCV coinfection has been associated with an increased risk of acute or chronic HAART-related liver enzyme elevations (i.e. hepatotoxicity), presumably as a consequence of increased hepatic necroinflammatory activity [11,12]. While the clinical significance of these events is often uncertain, Vento and colleagues reported significantly increased histologic markers of inflammation and necrosis among HIV/HCV coinfected patients who underwent paired liver biopsies before and after starting HAART [22]. Moreover, in the study by Macias and coworkers more than 75% of patients treated with nevirapine had a greater than 2.5-fold increase in serum alanine aminotransferase levels, and, more importantly, nevirapine-based HAART was associated with a greater risk of having advanced hepatic fibrosis [10]. While the mechanisms of HAART-associated hepatic injury are not fully understood, studies have suggested that intrinsic drug effect and/or elevated plasma drug levels in the setting of decreased hepatic metabolism may play a role. Other research has suggested that, rather than improving liver disease, HAART-induced immune reconstitution may lead to enhanced HCV-specific immune responses in the liver, resulting in hepatic injury and elevation of serum HCV RNA and liver enzymes levels [23,24].
Note from Jules Levin: At the 39th EASL (European Liver Conference) in april 2004, Norbert Brau from the Bronx VA and Maribel Rodriguez reported on what I think is the first study to examine the association between HIV viral load in patients and HCV disease progression. This study was a retrospective chart review of 560 patients from 2000 to 2002 in the Bronx and PR. The authors found HCV/HIV coinfected patients with suppressed HIV RNA (<400 copies/ml) have similar Fibrosis Progression Rare as HIV-negative patients with hepatitis C. Coinfected patients with uncontrolled HIV viremia have more rapid FPR than patients with suppressed HIV RNA and than HIV-negative patients. This applies when CD4 count is <500. In coinfection, FPR is independently predicted by log HIV viral load, Ishak necroinflammatory score, age at HCV infection, and not by CD4 cell count and alcohol use. The study author said: when deciding when to begin HAART, "our data suggests a role for HAART to slow down HCV-related fibrosis progression, HAART should be considered when CD4 cells are <500". YOU CAN READ THE ENTIRE REPORT AT: http://www.natap.org/2004/EASL/easl_04.htm
[24] Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine.
Walker UA, Bäuerle J, Laguno M, Murillas J, Mauss S, Schmutz G, Setzer B, Miquel R, Gatell JM, Mallolas J
Hepatology 2004; 39:311-7.
Abstract
The "D drug" HIV reverse-transcriptase inhibitors zalcitabine, didanosine, and stavudine are relatively strong inhibitors of polymerase-gamma compared with the "non-D drugs" zidovudine, lamivudine, and abacavir. D drugs deplete mitochondrial DNA (mtDNA) in cultured hepatocytes. This mtDNA depletion is associated with an increased in vitro production of lactate. To investigate the origin of hyperlactatemia in HIV-infected patients and the effects of antiretroviral therapy on liver mtDNA, we biopsied liver tissue from 94 individuals with chronic hepatitis C virus (HCV) infection. Eighty subjects were coinfected with HIV. Serum lactate was measured at the time of biopsy. Hepatic mtDNA and liver histology were centrally assessed. Liver mtDNA content of HIV-infected patients receiving D drugs at the time of biopsy (n = 34) was decreased by 47% (P<.0001) compared with those without D drugs (n = 35). Aside from a possible association between HCV genotype I status and mtDNA depletion in multivariate analysis, there were no other virologic, immunologic, histologic, demographic or treatment-related variables that could explain the mtDNA depletion. Lactate was above the upper limit of normal in only three patients, all of whom were treated with D drugs. The mtDNA in each of them was lower than in any non-D drug patient and significantly (P =.017) depleted compared with D drug patients with normal lactate. In conclusion, D drug treatment is associated with decreased hepatic mtDNA in HIV-infected patients with chronic HCV infection. Moderate mtDNA depletion in liver does not necessarily lead to hyperlactatemia, but more pronounced decreases in hepatic mtDNA may be an important contributor to lactate elevation.
In addition, other hepatic effects of antiretroviral drugs have been described; hepatic steatosis has been clearly linked to use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) such as stavudine (d4T) and zidovudine (AZT), presumably as a result of inhibition of mitochondrial DNA polymerase-gamma [25,26]. While early case reports characterized a severe, even fatal, syndrome of lactic acidosis with hepatomegaly and steatosis, HIV treating physicians are increasingly concerned about potential chronic effects of NRTI exposure on the liver [27]. Indeed, Sutinen and colleagues found that hepatic fat accumulation was significantly greater in men with HAART-associated lipodystrophy compared to HIV negative men [28]. Furthermore, case reports have described the development of liver failure attributed to long-term NRTI therapy in HIV-infected patients in the absence of viral hepatitis [29,30]. In addition, hepatomegaly and steatosis has been observed in mice with hypertrigylceridemia during treatment with the HIV-1 protease inhibitor, ritonavir [31]. Hence, independent of acute liver enzyme elevations, metabolic effects of HAART may cause hepatic steatosis, which in HCV-monoinfected persons has been associated with increased rates of HCV-related fibrosis progression [14]. Taken together, these data support the hypothesis that HAART and its related hepatic effects may worsen the progression of HCV-related liver disease, leading to greater or unchanged risk of HCV disease progression in HIV/HCV coinfected patients treated with HAART compared to those with untreated HIV disease.
Not surprisingly, these conflicting observations contribute to the ongoing uncertainty of the effect of HAART on the progression of liver disease. Interestingly, Qurishi and colleagues observed that the protective effects of HAART on liver mortality were not negated by the development of hepatotoxicity in nearly 14% of HAART recipients, suggesting that the hepatic benefits of HAART outweigh any detrimental effects of HAART-associated hepatotoxicity. However, as eloquently discussed by del Amo and colleagues and Guardiola in their correspondence to the Lancet, the study by Qurishi et al. has important limitations since the relationship of HAART exposure and liver mortality in this cohort of hemophiliacs is potentially impacted by survival bias and the effect of competing causes of death prior to the advent of HAART [32,33]. Given the limitations of the study, it is premature to conclude that effective antiretroviral therapy will lower the rate of fibrosis progression and the risk of ESLD or death in HIV/HCV coinfected patients, and these data alone are insufficient to support recommendations that HAART be initiated in coinfected patients with high CD4 cell counts (>350cell/mm3). Nonetheless, the study provides strong evidence to support the recommendation that HIV treating physicians not withhold HAART from HCV-infected patients based on concerns of acute or chronic medication related-hepatic injury. At the end of the day, Qurishi and colleagues highlight the need for prospective research designed to better understand the effects of HIV disease and its treatment on HCV-related liver disease.
References
[1]. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. The Journal of the American Medical Association. 2002;288:199-206
[2]. Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, 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;356:1800-1805 MEDLINE | CrossRef
[3]. Rosenthal E, Poiree M, Pradier C, Perronne C, Salmon-Ceron D, Geffray L, et al. Mortality due to hepatitis C-related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS. 2003;17:1803-1809 MEDLINE
[4]. Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, et al. Influence of human immunodeficiency virus infection on the course of hepatitis c virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-569 MEDLINE | CrossRef
[5]. Darby SC, Ewart DW, Giangrande PL, Spooner RJ, Rizza CR, Dusheiko GM, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. Lancet. 1997;350:1425-1431 MEDLINE | CrossRef
[6]. Benhamou Y, Bochet M, Di M V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054-1058 MEDLINE
[7]. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, et al. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood. 2002;100:1584-1589 MEDLINE
[8]. Tural C, Fuster D, Tor J, Ojanguren I, Sirera G, Ballesteros A, et al. Time on antiretroviral therapy is a protective factor for liver fibrosis in HIV and hepatitis C virus (HCV) co-infected patients. J Viral Hepat. 2003;10:118-125 MEDLINE
[9]. Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, et al. Incidence and predictors of severe liver fibrosis in human immunodeficiency virus-infected patients with chronic hepatitis C: a European collaborative study. Clin Infect Dis. 2004;38:128-133
[10]. Macias J, Castellano V, Merchante N, Palacios RB, Mira JA, Saez C, et al. Effect of antiretroviral drugs on liver fibrosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS. 2004;18:767-774 MEDLINE
[11]. Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. The Journal of the American Medical Association. 2000;283:74-80
[12]. den Brinker M, Wit FW, Wertheim-van Dillen PM, Jurriaans S, Weel J, van Leeuwen R, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14:2895-2902 MEDLINE | CrossRef
[13]. Fortgang IS, Belitsos PC, Chaisson RE, Moore RD. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol. 1995;90:1433-1436 MEDLINE
[14]. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126:586-597 MEDLINE | CrossRef
[15]. Qurishi N, Kreuzberg C, Lüchters G, Effenberger W, Kupfer B, Sauerbruch T, et al. Effect of antiretroviral therapy on liver-related mortality in patients with HIV and hepatitis C virus coinfection. Lancet. 2003;362:1708-1713 CrossRef
[16]. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents; November 10, 2003. http://aidsinfo.nih.gov/guidelines .
[17]. National Institutes of Health Consensus Development Conference Statement: Management of hepatitis, C: 2002—June 10–12, 2002. Hepatology 2002; 36:S3–20.
[18]. Soriano V, Sulkowski M, Bergin C, Hatzakis A, Cacoub P, Katlama C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813-828 MEDLINE | CrossRef
[19]. Mohsen AH, Easterbrook PJ, Taylor C, Portmann B, Kulasegaram R, Murad S, et al. Impact of human immunodeficiency virus (HIV) infection on the progression of liver fibrosis in hepatitis C virus infected patients. Gut. 2003;52:1035-1040 MEDLINE | CrossRef
[20]. Puoti M, Bonacini M, Spinetti A, Putzolu V, Govindarajan S, Zaltron S, et al. Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. J Infect Dis. 2001;183:134-137 MEDLINE | CrossRef
[21]. Benhamou Y, Di M V, Bochet M, Colombet G, Thibault V, Liou A, et al. Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients: impact of protease inhibitor therapy. Hepatology. 2001;34:283-287 MEDLINE | CrossRef
[22]. Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy. AIDS. 1998;12:116-117 MEDLINE
[23]. Ragni MV, Bontempo FA. Increase in hepatitis C virus load in hemophiliacs during treatment with highly active antiretroviral therapy. J Infect Dis. 1999;180:2027-2029 MEDLINE | CrossRef
[24]. Stone SF, Lee S, Keane NM, Price P, French MA. 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 human immunodeficiency virus-HCV-coinfected patients. J Infect Dis. 2002;186:1498-1502 MEDLINE | CrossRef
[25]. Miller KD, Cameron M, Wood LV, Dalakas MC, Kovacs JA. Lactic acidosis and hepatic steatosis associated with use of stavudine: report of four cases. Ann Intern Med. 2000;133:192-196 MEDLINE
[26]. Walker UA, Bauerle J, Laguno M, Murillas J, Mauss S, Schmutz G, et al. Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine. Hepatology. 2004;39:311-317 MEDLINE
[27]. Powderly WG. Antiretroviral therapy in patients with hepatitis and HIV: weighing risks and benefits. Clin Infect. 2004;38:S109-S113
[28]. Sutinen J, Hakkinen AM, Westerbacka J, Seppala-Lindroos A, Vehkavaara S, Halavaara J, et al. Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy. AIDS. 2002;16:2183-2193 MEDLINE | CrossRef
[29]. Kronenberg A, Riehle HM, Gunthard HF. Liver failure after long-term nucleoside antiretroviral therapy. Lancet. 2001;358:601-759 MEDLINE | CrossRef
[30]. Carr A, Morey A, Mallon P, Williams D, Thorburn DR. Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia. Lancet. 2001;357:1412-1414 MEDLINE | CrossRef
[31]. Riddle TM, Kuhel DG, Woollett LA, Fichtenbaum CJ, Hui DY. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem. 2001;276:37514-37519 MEDLINE | CrossRef
[32]. del Amo J, Hernandez-Aguado I, Perez-Hoyos S. Effect of HAART on liver-related mortality in patients with HIV/HCV coinfection. Lancet. 2004;363:570 CrossRef
[33]. Guardiola P. Effect of HAART on liver-related mortality in patients with HIV/HCV coinfection. Lancet. 2004;363:570
|
|
| |
| |
|
|
|
