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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31818ce821
Letters to the Editor

Does Early Antiretroviral Treatment Prevent Liver Fibrosis in HIV/HCV-Coinfected Patients?

Bani-Sadr, Firouzé*; Bedossa, Pierre†; Rosenthal, Eric‡; Merrien, Dominique§; Perre, Philippe‖; Lascoux-Combe, Caroline¶; Cacoub, Patrice*; Perronne, Christian#; Pol, Stanislas*; The ANRS HC02-Ribavic Study Team

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*Groupe Hospitalier Universitaire Est Paris, France †Groupe Hospitalier Universitaire Nord Paris, France ‡Hôpital de l'Archet Nice, France §Centre Hospitalier de Compiègne ‖Centre Hospitalier de la Roche sur Yon ¶Hôpital Saint Louis Paris, France #Centre Hospitalier Universitaire Raymond Poincaré, Université de Versailles Garches, Paris, France

Supported by Agence Nationale de Recherche sur le SIDA and SIDACTION.

To the Editor:

Despite widespread use of highly active antiretroviral therapy (HAART), hepatitis C virus (HCV)-induced liver disease is a leading cause of death among HIV/HCV-coinfected patients.1 In the pre-HAART era, HIV infection was linked to accelerated progression to HCV cirrhosis, especially in patients with low CD4 cell counts.2,3 The impact of anti-HIV therapy on HCV-related liver fibrosis is controversial.2,4-6 The aim of this study was to identify factors associated with liver fibrosis and cirrhosis in HIV/HCV-coinfected patients in the era of HAART regimen.

The study focused on 395 HIV/HCV-coinfected patients who were enrolled in the ANRS HC02-Ribavic trial and for whom histologic data were available.7 Briefly, patients were eligible for the trial if they had never received interferon or ribavirin and had detectable serum HCV RNA, a liver biopsy showing at least mild activity or fibrosis, a CD4 cell count above 200 cells per cubic millimeter, stable HIV RNA load, and stable or no antiretroviral treatment during the previous 3 months. The main ineligibility criteria were active narcotic consumption and/or self-reported daily alcohol intake exceeding 40 g (women) or 50 g (men) within 3 months before entry to the study, decompensated cirrhosis, and positive HBs antigenemia.

The patients were divided into 2 groups based on the Metavir liver fibrosis scores, as follows: group 1, nonsignificant fibrosis (stages F1 and F2) and group 2, significant fibrosis (stages F3 and F4). The χ2 test or Fisher exact test was used to analyze qualitative variables, and the Mann-Whitney test was used for quantitative variables. Logistic regression models were used to test associations between severe fibrosis (outcome variable) and baseline characteristics (input variables). Characteristics with P values below 0.05 in univariate analysis were included in multivariate models based on a backward elimination procedure. All statistical tests were 2 sided, with a type I error of 5%.

Group 1 consisted of 286 patients with Metavir fibrosis score of F1 (periportal fibrosis; n = 128) or F2 (periportal fibrosis with few septa; n = 158), and group 2 consisted of 109 patients with scores of F3 (septal fibrosis; n = 88) or F4 (cirrhosis; n = 21) (Table 1). The mean interval between liver biopsy and study entry was 7.15 ± 7.08 months. In total, 297 (75%) patients received antiretroviral therapy before or at the time of liver biopsy.

Table 1
Table 1
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In univariate analysis, older age, antiretroviral therapy exposure, longer interval between the diagnosis of HIV infection and antiretroviral treatment initiation, longer duration of antiretroviral therarapy, nucleoside reverse transcriptase inhibitor (NRTI)-based treatment and, among NRTIs, the use of lamivudine and steatosis (graded according to the percentage of hepatocytes containing visible macrovesicular steatosis) were significantly associated with significant fibrosis. In multivariate analysis, the presence of steatosis (odds ratio 1.912, 95% confidence interval, 1.179 to 3.102; P = 0.0086) and the interval between HIV diagnosis and antiretroviral treatment initiation (for each 1 year: odds ratio 1.084, 95% confidence interval, 1.029 to 1.143; P = 0.025) were significantly associated with significant fibrosis.

In this study of 395 HIV/HCV-coinfected patients, the interval between diagnosis of HIV infection and initiation of antiretroviral therapy was longer among patients with significant fibrosis (F3-F4). These latter patients were less likely to be antiretroviral naive and had received antiretroviral therapy for longer than patients with mild fibrosis. This suggests that it is not the prescription or duration of HAART that protects from hepatic fibrosis but rather its early initiation after diagnosis of HIV infection. Our results are in line with those of 2 recent studies. Verma et al8 also found that fibrosis progressed more slowly in patients who started HAART early after HIV diagnosis. Likewise, Marine-Barjoan et al9 found that the interval between the presumed date of HCV infection and HAART initiation was significantly longer among patients with severe fibrosis than among patients with no fibrosis or moderate fibrosis. A recent study suggests that cytotoxic CD8 T-cell accumulation, and associated release of inflammatory mediators, may augment liver damage (mainly fibrosis) in HIV/HCV-coinfected patients.10 The protective effect of HAART on liver damage could thus be linked to an attenuation of inflammation. Independent links have been reported between hepatic fibrosis progression on the one hand and CD4 cell depletion and HIV nonsuppression on the other hand.3,11 However, we found no significant association between severe fibrosis and the CD4 cell count, the CD4 cell nadir, prior CD4 cell counts below 100 cells per cubic millimeter, the Centers for Disease Control and Prevention class of HIV disease, or detectable HIV viral load.

The beneficial impact of antiretroviral therapy on fibrosis progression might be offset by its liver toxicity. In our study, antiretroviral treatment itself, along with its duration, the use of NRTIs, and, among NRTIs, the use of lamivudine, were associated in univariate analysis (but not in multivariate analysis) with advanced liver disease. This association with lamivudine reflects the frequent use of this drug in dual-NRTI combinations (69.7% of our patients). In contrast to other authors, we found no deleterious effect of nonnucleoside reverse transcriptase inhibitors (including nevirapine) and no beneficial effect of protease inhibitors.5,12

In HCV-monoinfected patients, the onset and progression of steatosis are strong independent predictors of both the severity and the progression of fibrosis.13 We have previously reported in the same patients that the more severe the steatosis, the higher the stage of fibrosis.13 Necroinflammation has also been linked to fibrosis progression both in HCV-monoinfected patients and in HIV/HCV-coinfected patients.11 In contrast, baseline necroinflammatory status did not differ between patients with severe fibrosis and other patients in our study.

Being retrospective, this study has certain limitations. As the liver biopsies were all performed to determine whether or not anti-HCV therapy was indicated, the patients may not be representative of the general population of HIV/HCV-coinfected patients. Another limitation is the lack of information on alcohol consumption, an independent risk factor for liver fibrosis.6 Nonetheless, these results suggest that if a sustained virologic response to anti-HCV therapy cannot be achieved in HIV/HCV-coinfected patients, then early HAART may help to protect the liver.

Firouzé Bani-Sadr*

Pierre Bedossa†

Eric Rosenthal‡

Dominique Merrien§

Philippe Perre‖

Caroline Lascoux-Combe¶

Patrice Cacoub*

Christian Perronne#

Stanislas Pol*

The ANRS HC02-Ribavic Study Team

*Groupe Hospitalier Universitaire Est

Paris, France

†Groupe Hospitalier Universitaire Nord

Paris, France

‡Hôpital de l'Archet

Nice, France

§Centre Hospitalier de Compiègne

Compiègne, France

‖Centre Hospitalier de la Roche sur Yon

La Roche sur Yon, France

¶Hôpital Saint Louis

Paris, France

#Centre Hospitalier Universitaire Raymond Poincaré, Université de Versailles

Garches, France

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REFERENCES

1. Salmon-Ceron D, Lewden C, Morlat P, et al. Liver disease as a major cause of death among HIV infected patients: role of hepatitis C and B viruses and alcohol. J Hepatol. 2005;42:799-805.

2. Brau N. Update on chronic hepatitis C in HIV/HCV-coinfected patients: viral interactions and therapy. AIDS. 2003;17:2279-2290.

3. Shafran SD. Early initiation of antiretroviral therapy: the current best way to reduce liver-related deaths in HIV/hepatitis C virus-coinfected patients. J Acquir Immune Defic Syndr. 2007;44:551-556.

4. Martin-Carbonero L, Benhamou Y, Puoti M, 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.

5. Macias J, Mira JA, Lopez-Cortes LF, et al. Antiretroviral therapy based on protease inhibitors as a protective factor against liver fibrosis progression in patients with chronic hepatitis C. Antivir Ther. 2006;11:839-846.

6. Tural C, Fuster D, Tor J, 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.

7. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b versus standard interferon alfa-2b, plus ribavirin for chronic hepatitis C in HIV-infected patients. randomized controlled trial. JAMA. 2004;292:2839-2848.

8. Verma S, Wang CH, Govindarajan S, et al. Do type and duration of antiretroviral therapy attenuate liver fibrosis in HIV-hepatitis C virus-coinfected patients? Clin Infect Dis. 2006;42:262-270.

9. Marine-Barjoan E, Saint-Paul MC, Pradier C, et al. Impact of antiretroviral treatment on progression of hepatic fibrosis in HIV/hepatitis C virus co-infected patients. AIDS. 2004;18:2163-2170.

10. Kuntzen T, Tural C, Li B, et al. Intrahepatic mRNA expression in hepatitis C virus and HIV/hepatitis C virus co-infection: infiltrating cells, cytokines, and influence of HAART. AIDS. 2008;22:203-210.

11. Brau N, Salvatore M, Rios-Bedoya CF, et al. Slower fibrosis progression in HIV/HCV-coinfected patients with successful HIV suppression using antiretroviral therapy. J Hepatol. 2006;44:47-55.

12. Macias J, Castellano V, Merchante N, 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.

13. Bani-Sadr F, Carrat F, Bedossa P, et al. Hepatic steatosis in HIV-HCV coinfected patients: analysis of risk factors. AIDS. 2006;20:525-531.

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