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JAC Advance Access published online on October 24, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn429
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Hepatic safety of tipranavir plus ritonavir (TPV/r)-based antiretroviral combinations: effect of hepatitis virus co-infection and pre-existing fibrosis

Juan Macías1,2, Francisco Orihuela3, Antonio Rivero4, Pompeyo Viciana5, Manuel Márquez6, Joaquín Portilla7, María J. Ríos8, Leopoldo Muñoz9, Juan Pasquau10, Manuel A. Castaño3, Laila Abdel-Kader1,11, Juan A. Pineda1,* for the Hepatip Study Group

1 Unidad de Enfermedades Infecciosas, Hospital Universitario de Valme, Seville, Spain 2 Servicio de Medicina Interna, Hospital Universitario de Valme, Seville, Spain 3 Unidad de Enfermedades Infecciosas, Hospital Universitario Carlos de Haya, Malaga, Spain 4 Unidad de Enfermedades Infecciosas, Hospital Universitario de Reina Sofía, Córdoba, Spain 5 Servicio de Enfermedades Infecciosas, Hospital Universitario de Virgen del Rocío, Seville, Spain 6 Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen de la Victoria, Malaga, Spain 7 Unidad de Enfermedades Infecciosas, Hospital General Universitario de Alicante, Alicante, Spain 8 Unidad de Enfermedades Infecciosas, Hospital Universitario de Virgen Macarena, Seville, Spain 9 Unidad de Enfermedades Infecciosas, Hospital Universitario San Cecilio, Granada, Spain 10 Unidad de Enfermedades Infecciosas, Hospital Universitario Virgen de las Nieves, Granada, Spain 11 Servicio de Farmacia, Hospital Universitario de Valme, Seville, Spain

* Corresponding author. Tel: +34-955015864; Fax: +34-955015787; E-mail: japineda{at}telefonica.net

Received 13 May 2008; returned 15 July 2008; revised 11 September 2008; accepted 18 September 2008


   Abstract
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Objectives: The aim of this study was to evaluate the incidence and risk factors of severe liver events among HIV-infected patients treated with drug combinations including tipranavir boosted with ritonavir (TPV/r).

Methods: One hundred and fifty patients were selected because they started a regimen that included TPV/r (500/200 mg twice a day) and had clinical visits at least every 3 months. Patients who discontinued TPV/r before their first visit were included.

Results: Twelve (8%) individuals developed grade ≥3 transaminase elevation (G ≥ 3TE). Nine (6%) patients discontinued TPV/r due to liver events. Six (8.6%) of 70 hepatitis C virus (HCV) co-infected patients and 6 (7.5%) of 80 subjects without HCV co-infection developed G ≥ 3TE (P = 1). Liver fibrosis was evaluable in 48 (63%) of 76 individuals with hepatitis B virus and/or HCV infection. Four (13%) of 30 subjects with moderate-to-severe fibrosis and none of 18 with mild fibrosis showed G ≥ 3TE (P = 0.3). None of nine patients with cirrhosis showed G ≥ 3TE.

Conclusions: Liver tolerability of TPV/r was generally good in a cohort of patients with a high proportion of HCV co-infection, including subjects with advanced fibrosis. The presence of HCV co-infection was not associated with an increased risk of severe transaminase elevations.

Key Words: hepatotoxicity , HBV , HCV , liver fibrosis


   Introduction
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Antiretroviral drug therapy (ART) that includes tipranavir boosted with ritonavir (TPV/r) has been associated with a higher incidence of liver enzyme elevations [transaminase elevations (TEs)] than the comparator-boosted protease inhibitor in clinical trials.1–3 Subgroup liver safety analysis of the RESIST trials has shown a higher risk of severe TEs for the HIV/hepatitis co-infected groups.4 In addition, the report of cases of severe liver events in patients receiving TPV/r has led to the inclusion of a warning in the prescribing information,5 advising a close follow-up of patients with frequent monitoring of liver enzymes, especially of those with chronic viral hepatitis (VH), throughout the duration of treatment.5

Despite concerns of hepatic safety of TPV/r, there are few data on this issue from clinical cohorts. The liver tolerance of these combinations could be different under real-life conditions of use. Patients included in clinical trials are highly selected. In this regard, patients with higher risk of developing TEs were not included in the RESIST trials, as patients with baseline liver enzymes above grade 1 were excluded.1,2 In addition, only a few patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) were included in clinical trials.3 Because of this, it is necessary to obtain information on the hepatic toxicity of TPV/r from cohorts including patients with a wide range of liver diseases.

The present study was aimed at evaluating the incidence and risk factors of severe liver events among HIV-infected patients treated with antiretroviral drug combinations including TPV/r.


   Patients and methods
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Patients

This was a retrospective cohort study. One hundred and fifty seven patients started TPV/r in 14 hospitals in Spain from January 2004 to May 2007. From this cohort, we selected those patients who met the following criteria: (i) ART that included TPV 500 mg plus ritonavir 200 mg twice a day; and (ii) clinical visits and blood tests at least every 3 months. If ART was discontinued due to any reason before the third month of follow-up, patients were included in the analysis.

Definition of severe liver enzyme elevations

If baseline alanine aminotransferase (ALT) levels were normal, ALT elevations 5–10 times above the upper limit of normal (ULN) were considered grade 3 TEs and ALT increases ≥10 times the ULN were considered grade 4 TEs. If baseline ALT levels were above the ULN, ALT elevations 3.5–5 times the baseline values were considered grade 3 TEs and ALT increases ≥5 times the baseline values were considered grade 4 TEs.

Liver fibrosis assessment

Baseline liver fibrosis was assessed applying a stepwise algorithm (Figure 1), which has been reported elsewhere in detail.6 Briefly, if a liver biopsy was available 12 months before or after starting TPV/r, the stage of fibrosis observed in the biopsy was considered the baseline fibrosis. If liver biopsy was not available within that period of time, fibrosis was estimated by non-invasive means7,8 (Figure 1).


Figure 1
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  		Figure 1. Algorithm for liver fibrosis assessment, with number (percentage) of patients classified in each step. In the first step, if a liver biopsy was available 12 months before or after starting TPV/r, the stage of fibrosis observed in the biopsy was considered the baseline fibrosis. In the second step, patients without liver biopsy, liver stiffness was measured by transient elastometry (FibroScanTM, Echosens, Paris, France), if it was available 12 months before or after starting TPV/r. Liver stiffness values ≥7.2 kPa were regarded as indicative of F ≥ 2, and measurements ≥14.6 kPa were considered diagnostic of F4. In the third step, the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the Forns index [calculated using platelet count, gamma glutamyl transferase (GGT), age and cholesterol] were applied to patients without evaluable transient elastometry. If APRI is ≥1.5, patients can be classified as having F ≥ 2. The Forns index is calculated for patients with APRI <1.5. If Forns index is ≥6.9, patients are regarded to show F ≥ 2. If APRI is <1, patients can be considered non-cirrhotics.

 
Fibrosis was staged in liver biopsies using the Scheuer index.9 Liver fibrosis stage ≥2 was defined as significant fibrosis (F ≥ 2). Patients with previous decompensations of liver cirrhosis or with clinical, laboratory and imaging data suggestive of liver cirrhosis were classified as having fibrosis stage 4.

Statistical analysis

Continuous variables are expressed as median (Q1–Q3) and categorical variables as number (percentage). Continuous variables were compared using the Mann–Whitney U-test. Categorical variables were compared using the {chi}2 test or Fisher's test, when applicable. The general linear model for repeated measures was used to compare continuous variables during follow-up. All variables potentially related to severe TEs [grade ≥3 (G ≥ 3)] were entered in a forward stepwise logistic regression model. The statistical software package SPSS 14.0 (SPSS, Chicago, IL, USA) was used for statistical analysis.

Ethical aspects

The study was approved by the Ethics Committee of the Hospital Universitario San Cecilio (Granada, Spain). Patients gave their informed consent to participate in the study.


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Characteristics of the patients

One hundred and fifty patients met the inclusion criteria. The demographic and baseline characteristics of the patients are summarized in Table 1. Co-infection by HBV was observed in 11 (7%) patients, by HCV in 70 (47%) and by both HBV and HCV in 5 (3%). The study patients showed multiple virological failures before starting TPV/r. Patients had been extensively exposed to multiple drugs (Table 1). The median number of antiretroviral drugs previously used was 12 (10–13). Background antiretroviral drugs combined with TPV/r at baseline are shown in Table 2.


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  		Table 1. Baseline characteristics of the study patients (n = 150)

 


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  		Table 2. Antiretroviral drugs combined with TPV/r

 
The median follow-up of the study patients was 12 (6–18) months. Four (2.7%) patients died during the observation period, two due to AIDS, one due to lung cancer and one due to oesophageal variceal bleeding. Eighteen (12%) individuals were lost to follow-up.

Baseline liver fibrosis could be assessed in 48 (63%) of 76 patients with HBV and/or HCV co-infection (VH) (Figure 1). Thirty (62%) of them were diagnosed with F ≥ 2 and 18 (38%) with F < 2. Compensated cirrhosis was detected in 8 (11%) co-infected patients at baseline. Another patient without VH showed cirrhosis at baseline. Six cirrhotics, with data to calculate the score, were Child–Pugh class A.

Response to combination therapy including TPV/r during follow-up

The median gain of CD4 cell counts was 68 cells/mm3 from baseline to 12 months of therapy. Patients with and without VH showed similar increases in CD4 cell counts and similar proportions of plasma HIV RNA <50 copies/mL, during follow-up (Figure 2).


Figure 2
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  		Figure 2. Virological and immunological responses in the group without (VH-negative) and with (VH-positive) HBV and/or HCV infection over 12 months of therapy with boosted-tipranavir. (a) Changes in median (Q1–Q3) CD4 cell counts (VH-negative, broken line; VH-positive, continuous line). General linear model for repeated measures, P = 0.99. (b) Percentage of patients with plasma HIV RNA <50 copies/mL (VH-negative, light bars; VH-positive, dark bars). {chi}2 test, P = 0.9 for the comparison of VH-positive versus VH-negative at month 12.

 
Liver safety

Twelve (8%) patients developed G ≥ 3TEs. Grade 4 TEs during the study period were observed in nine (6%) individuals. The density of incidence of G ≥ 3TEs was 7.5 [95% confidence interval (CI): 4.2–12.5] per 100 person-years.

Sixteen (10.7%) patients discontinued therapy due to adverse effects. Nine (6%) patients discontinued therapy because of hepatic side effects. Seven of them showed grade 4 TEs, one a decompensation of cirrhosis and one died of variceal bleeding. Two patients with grade 4 and three with grade 3 TEs continued on therapy. They showed a decrease to below grade 3 levels in the next visits.

Patients with and without VH showed a similar incidence of G ≥ 3TEs (Table 3). A non-significantly higher frequency of severe TEs was observed in patients with HBV infection (Table 3). Two (40%) of five patients with HBV and HCV co-infection showed severe TEs.


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  		Table 3. Associations with grade 3 or 4 TEs during TPV/r-based therapy

 
Among individuals with VH, patients with F ≥ 2 showed a non-significantly higher frequency of severe TEs (Table 3). None of the eight patients with cirrhosis due to VH showed TEs G ≥ 3 (Table 3). One patient without VH presented with an episode of portal thrombosis and died of variceal bleeding. One patient with HCV and cirrhosis at baseline developed ascites, without G ≥ 3TEs during decompensation.

There was no relationship between severe TEs and antiretroviral drugs used in combination with TPV/r. Multivariate analyses of the global cohort and of the subgroup with VH did not detect any independent association with G ≥ 3TEs, except for dual HBV and HCV co-infection (adjusted OR 8.3, 95% CI: 1.2–55.8, P = 0.03).


   Discussion
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The liver tolerability of TPV/r was generally good in a cohort of patients with a high proportion of HBV and/or HCV co-infection, including patients with advanced fibrosis. The incidence of severe asymptomatic TEs during TPV/r-containing ART in this cohort was similar to that found in clinical trials. In contrast, the presence of HCV co-infection was not associated with an increased risk of severe asymptomatic TEs. Patients with VH included in the cohort were followed up and monitored as other HIV/VH co-infected patients receiving ART. Monitoring of liver enzymes every 3 months was not associated with an increased risk of symptomatic liver events among co-infected patients in this study. Thus, more frequent blood testing does not seem to be warranted for these patients.

Data on adverse liver events from clinical cohorts are critical, because selection and management of patients in clinical trials do not reflect real life. In the RESIST trials, only 10% of the patients were co-infected by HBV and/or HCV.3 However, HBV and HCV co-infections are more prevalent in areas of Europe and the USA.10–13 Additionally, patients with baseline laboratory levels grade ≥2 were excluded.1–3 Due to these factors, the hepatic safety of TPV/r could be different in routine clinical practice than reported previously. However, symptomatic liver events were very infrequent in the present study. In fact, only one patient died because of oesophageal variceal bleeding and another suffered a decompensation of cirrhosis. Remarkably, half of the study patients showed VH. Moreover, patients were included in the cohort regardless of their baseline liver enzymes. Because of these reasons, TPV/r seems to be safe in patients with a wide variety of liver disease.

In the present study, the frequency of severe asymptomatic TEs in patients with and without HCV co-infection was similar. This finding may be surprising. In fact, HCV co-infection has been reported to increase the risk of severe TEs.6,14–18 Subanalyses of the RESIST trials have estimated a 2-fold increase in the risk of severe TEs for co-infected patients.4 There are some possible explanations for the discordant results. First, the group with VH might have had less exposure to TPV/r, due to a worse adherence to ART. However, the efficacy of TPV/r-based regimens was comparable between the groups with and without VH. Secondly, patients were followed intensively after starting TPV/r in clinical trials, with four scheduled visits up to the third month of therapy.3 In this cohort, patients were only required to have at least one visit every 3 months. Most asymptomatic severe TEs emerge in first months of ART.18 The majority of these resolve without further consequences.18,19 Thus, some early TEs could have been missed in the co-infected group. Indeed, another cohort study did not find differences in the incidence of G ≥ 3TEs between patients with and without HCV co-infection under boosted indinavir.14 Thirdly, prescription of enfuvirtide in the cohort was more frequent than that in the RESIST trials.3 TPV/r and enfuvirtide were combined in over two-thirds of the patients in the cohort. This might have allowed less hepatotoxic drug combinations in the cohort than in the RESIST trials, which could explain the lower rates of severe TEs.

There were a few patients with HBV co-infection in the cohort. This reflects the epidemiology of HBV co-infection in Western Europe.11 ALT flares in HBV co-infected patients can be due to liver toxicity, control of HBV replication after starting ART, interruption of an active drug against HBV or hepatotoxicity associated with dual infection with HCV.11 Patients with HBV infection who showed severe TEs in this study were also co-infected by HCV, which suggests that double co-infection rather than single HBV infection increases the risk of liver toxicity in patients taking TPV/r.

Pre-existing liver fibrosis could be a risk factor for developing severe TEs.6,20–22 In this study, liver fibrosis could be assessed in a large proportion of patients with VH. A trend to a higher frequency of G ≥ 3TEs was observed in co-infected patients with F ≥ 2 at baseline. This result is in agreement with previous studies.6,20–22 In contrast, a small number of compensated cirrhotic patients were included. Only one cirrhotic developed ascites during follow-up, without concomitant severe TEs. This liver event probably represents the natural course of the hepatic disease and not a drug adverse event. These outcomes suggest that TPV/r could be used cautiously in well-compensated cirrhotics, as can most protease inhibitors.23

This study has some limitations. First, this was a retrospective study. Patients were attended to at three-monthly scheduled visits. This could have precluded the detection of some TEs between visits and, consequently, it may have led to an underestimation of liver toxicity of TPV/r. However, missed episodes of TEs would be transient and asymptomatic, unlikely to have any impact on the management of patients. Secondly, liver fibrosis evaluated within 12 months before or after starting TPV/r was considered as baseline fibrosis. As one stage of fibrosis progression is very unlikely over 1 year, even in very fast progressors,24 no important misclassification could have occurred in this study. Thirdly, the diagnosis of fibrosis was performed using different techniques. However, transient elastometry has a high performance to diagnose F ≥ 2 and cirrhosis.7 APRI and Forns index are also highly predictive for F ≥ 2, and APRI can be used to discard cirrhosis with a high negative predictive value.8

In conclusion, the liver safety of TPV/r in real-life conditions of use is good. Frequent monitoring of liver function tests does not seem necessary to manage safely VH co-infected patients receiving TPV/r. These individuals can be evaluated and followed as any other patient on ART. In addition, the efficacy of TPV/r-based regimens in patients with and without VH is similar and comparable with that reported in clinical trials.3 ART including TPV/r is therefore a good option for treatment-experienced patients with or without chronic VH co-infection.


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This study was partly supported by a grant from Boehringer-Ingelheim and by a grant from Fondo de Investigaciones Sanitarias (EC07/90104). We wish to thank the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red de SIDA from Spain for their support (ISCIII-RETIC RD06/006).


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J. M. has been an investigator in clinical trials supported by Roche, Bristol–Myers Squibb and Abbott Pharmaceuticals. He has received lectures fees from Roche, Gilead, Boehringer Ingelheim and Bristol–Myers Squibb and consulting fees from Boehringer Ingelheim, Bristol–Myers Squibb and Merck Sharp & Dome. A. R. reports having received consulting fees from Bristol–Myers Squibb, Abbott, Gilead, Roche and Boehringer Ingelheim. Mercedes González-Serrano reports having participated as an investigator in clinical trials supported by Roche and GlaxoSmith-Kline. She has received lecture fees from Boehringer Ingelheim. J. A. P. reports having received consulting fees from GlaxoSmithKline, Bristol–Myers Squibb, Abbott, Gilead, Merck Sharp & Dohme, Jansen Cilag and Boehringer Ingelheim. He has received research support from GlaxoSmithKline, Roche, Bristol–Myers Squibb, Schering-Plough, Abbott and Boehringer Ingelheim and has received lecture fees from GlaxoSmithKline, Roche, Abbott, Bristol–Myers Squibb, Boehringer Ingelheim and Schering-Plough. The remaining authors have no conflicts of interest.


   References
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1 . Cahn P, Villacian J, Lazzarin A, et al. Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIV-infected patients: 24-week results of the RESIST-2 trial. Clin Infect Dis (2006) 43:1347–56.[CrossRef][Web of Science][Medline]

2 . Gathe J, Cooper DA, Farthing C, et al. Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin Infect Dis (2006) 43:1337–46.[CrossRef][Web of Science][Medline]

3 . Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir–ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet (2006) 368:466–75.[CrossRef][Web of Science][Medline]

4 . Mauss S, Stern J, Elgadi M, et al. RESIST 24-week efficacy and safety of tipranavir boosted with ritonavir (TPV/r) in hepatitis B (HBV) or hepatitis C (HCV) co-infected patient. Abstracts of the Tenth European AIDS Conference, Dublin, Ireland, 2005. Abstract PE13.3/4.

5 . Aptivus. Full prescribing information, including boxed warnings. Updated in October 2007.

6 . Pineda JA, Santos J, Rivero A, et al. Liver toxicity of antiretroviral combinations including atazanavir/ritonavir in patients co-infected with HIV and hepatitis viruses: impact of pre-existing liver fibrosis. J Antimicrob Chemother (2008) 61:925–32.[Abstract/Free Full Text]

7 . Vergara S, Macías J, Rivero A, et al. The use of transient elastometry for assessing liver fibrosis in patients with HIV and hepatitis C coinfection. Clin Infect Dis (2007) 45:969–74.[CrossRef][Web of Science][Medline]

8 . Macías J, Girón-González JA, González-Serrano M, et al. Prediction of liver fibrosis in HIV/HCV-coinfected patients by simple noninvasive indexes. Gut (2006) 55:409–14.[Abstract/Free Full Text]

9 . Scheuer PJ. Classification of chronic viral hepatitis: a need for reassessment. J Hepatol (1991) 13:372–4.[CrossRef][Web of Science][Medline]

10 . Konopnicki D, Mocroft A, de Wit S, et al. Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort. AIDS (2005) 19:593–601.[Web of Science][Medline]

11 . Benhamou Y. Hepatitis B in the HIV-coinfected patient. J Acquir Immune Defic Syndr (2007) 45:S57–65.[CrossRef][Web of Science][Medline]

12 . Rockstroh JK, Mocroft A, Soriano V, et al. Influence of hepatitis C virus infection on HIV-1 disease progression and response to highly active antiretroviral therapy. J Infect Dis (2005) 192:992–1002.[CrossRef][Web of Science][Medline]

13 . Anderson KB, Guest JL, Rimland D. Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA Cohort Study. Clin Infect Dis (2004) 39:1507–13.[CrossRef][Web of Science][Medline]

14 . Sulkowski MS, Mehta SH, Chaisson RE, et al. Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS (2004) 18:2277–84.[CrossRef][Web of Science][Medline]

15 . Benhamou Y, Mats V, Walczak D. Systemic overview of HAART-associated liver enzyme elevations in patients infected with HIV and co-infected with HCV. In: Abstracts of the Thirteenth Conference on Retroviruses and Opportunistic Infections, Denver, USA, 2006. Alexandria, VA, USA: Foundation for Retrovirology and Human Health. Abstract 88.

16 . Sherman KE, Shire NJ, Cernohous P, et al. Liver injury and changes in hepatitis C virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir–ritonavir versus nelfinavir. Clin Infect Dis (2005) 41:1186–95.[CrossRef][Web of Science][Medline]

17 . Palacios R, Vergara S, Rivero A, et al. Low incidence of severe liver events in HIV patients with and without hepatitis C or B coinfection receiving lopinavir/ritonavir. HIV Clin Trials (2006) 7:319–23.[CrossRef][Web of Science][Medline]

18 . Sulkowski M, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA (2000) 283:74–80.[Abstract/Free Full Text]

19 . Pol S, Benhamou Y, Rockstroh J, et al. Hepatic profile of tipranavir in treatment experienced HIV-1 infected individuals. Abstracts of the Eleventh European AIDS Conference Madrid, Spain, 2007. Abstract P4.5/03.

20 . Aranzabal L, Casado JL, Moya J, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clin Infect Dis (2005) 40:588–93.[CrossRef][Web of Science][Medline]

21 . Labarga P, Soriano V, Vispo ME, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis (2007) 196:670–6.[CrossRef][Web of Science][Medline]

22 . Mira JA, Macías J, Girón-González JA, et al. Incidence of and risk factors for severe hepatotoxicity of nelfinavir-containing regimens among HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother (2006) 58:140–6.[Abstract/Free Full Text]

23 . Panel on Antiretroviral Guidelines for Adult and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents. Department of Health and Human Services, 29 January 2008. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

24 . Sulkowski MS, Mehta SH, Torbenson MS, et al. Rapid fibrosis progression among HIV/hepatitis C virus-co-infected adults. AIDS (2007) 21:2209–16.[Web of Science][Medline]


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