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Association between Exposure to Nevirapine and Reduced Liver Fibrosis Progression in Patients with HIV and Hepatitis C Virus Coinfection

  1. Juan Berenguer1⇓,
  2. José M. Bellón2,
  3. Pilar Miralles1,
  4. Emilio Álvarez3,
  5. Isabel Castillo4,
  6. Jaime Cosín1,
  7. Juan Carlos López1,
  8. Matilde Sánchez Conde1,
  9. Belén Padilla1, and
  10. Salvador Resino5
  1. 1HIV Infectious Diseases Unit, Madrid, Spain
  2. 2Biomedical Research Foundation, Madrid, Spain
  3. 3Histopathology Service, Madrid, Spain
  4. 4Pharmacy Service, Madrid, Spain
  5. 5Molecular Immunobiology Laboratory, Hospital General Universitario “Gregorio Marañón,” Madrid, Spain
  1. Reprints or correspondence: Dr. Juan Berenguer, Unidad de Enfermedades Infecciosas/VIH (4100), Hospital General Gregorio Marañón, Doctor Esquerdo 46, 28007 Madrid (juaberber{at}terra.es).
 
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Abstract

Background. We analyzed the effect of exposure to nonnucleoside reverse‐transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) on the progression of liver fibrosis in patients with human immunodeficiency virus (HIV) and hepatitis C virus coinfection.

Methods. We analyzed data and liver biopsy findings for 201 coinfected patients. Fibrosis was scored following the French METAVIR Cooperative Study Group. We used multinomial logistic regression analysis and the fibrosis progression rate to assess the association between cumulative exposure to antiretroviral drugs and stage of fibrosis.

Results. The adjusted odds ratio (AOR) and 95% confidence interval (CI) of having a fibrosis stage score of 0 or 1, compared with 3 or 4, increased with each additional year of exposure to HAART (AOR, 1.32; 95% CI, 1.04–1,67), to NNRTIs as a class (AOR, 1.64; 95% CI, 1.18–2.27), to efavirenz (AOR, 1.54; 95% CI, 1.03–2.30), and to nevirapine (AOR, 1.72; 95% CI, 1.15–2.78). This effect was not found with PIs as a class. The AOR (95% CI) of having a fibrosis stage score of 2 versus 3 or 4 increased with each additional year of exposure to NNRTIs (AOR, 1.51; 95% CI, 1.08–2.10) and nevirapine (AOR, 1.58; 95% CI, 1.06–2.37). This effect was not found with highly active antiretroviral therapy, PIs, or efavirenz. The AOR (95% CI) of having a fibrosis progression rate ⩽0.1 versus >0.1 increased with each additional year of exposure to highly active antiretroviral therapy (AOR, 1.31; 95% CI, 1.07–1.60), to NNRTIs (AOR, 1.33; 95% CI, 1.03–1.70), and to nevirapine (AOR, 1.44; 95% CI, 1.07–1.95). This effect was not found with PIs or with efavirenz.

Conclusions. In contrast with previous studies, we found that exposure to NNRTIs was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis progression than was exposure to efavirenz. Prospective work is needed in this area.

HIV infection adversely impacts the natural history of hepatitis C virus (HCV) infection, promoting a more rapid progression to fibrosis and the development of cirrhosis [1–3]. Despite a decrease in morbidity and mortality associated with opportunistic infections since the introduction of HAART, end‐stage liver disease due to HCV coinfection continues to be a frequent cause of hospitalization and mortality among individuals with HIV and HCV coinfection [4, 5].

Observational studies involving HIV‐HCV—coinfected patients have found that HAART can curb progression to end‐stage liver disease [6] and reduce liver‐related mortality [7], even among patients with end‐stage liver disease [8]. It remains unclear whether the beneficial effect of HAART on progression of liver fibrosis depends on the type of drugs used. A recent biopsy‐based cross‐sectional study that investigated the associations between the use of different antiretroviral drugs and liver fibrosis in HIV‐HCV—coinfected patients showed that HAART regimens that included nevirapine were associated with faster progression of liver fibrosis, whereas HAART regimens including protease inhibitors (PIs) were associated with a slower progression of fibrosis [9].

The confirmation of these findings by other groups is important, because HIV‐HCV coinfection is a frequent problem [10, 11], and because regimens based on 2 nucleoside or nucleotide reverse‐transcriptase inhibitors (NRTIs) and 1 nonnucleoside reverse‐transcriptase inhibitor (NNRTI)—either efavirenz or nevirapine—are recommended for initial therapy of HIV infection, as are regimens based on 2 NRTIs and a ritonavir‐boosted or unboosted PI [12]. In the present study, we aimed to assess the association between exposure to PIs and NNRTIs and fibrosis progression in HIV‐HCV—coinfected patients who were anti‐HCV therapy naive.

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Patients and Methods

Patients. The patients for this study came from the HIV outpatient clinic of the Hospital Gregorio Marañón in Madrid, Spain. Starting in September 2000, when therapy with IFN‐α and ribavirin was approved for the treatment of chronic hepatitis C in HIV‐infected patients at our institution, we performed a liver biopsy for all HIV‐HCV—coinfected patients who were potential candidates for this therapy. These patients had confirmed HCV infection; test results negative for hepatitis B surface antigen; a CD4+ lymphocyte count >200 cells/µL; stable antiretroviral therapy or no need for antiretroviral therapy; absence of active opportunistic infections, active drug addiction, and active alcohol addiction; and contraindications for IFN‐α and ribavirin therapy. All patients gave their written informed consent for the liver biopsy, and the Institutional Ethics Committee approved the study. Of a total of 296 patients, we selected 201 who had acquired HCV infection by intravenous drug use and for whom the date of HCV infection could be ascertained.

Clinical data. On the day of the biopsy, the following information was obtained from the medical records and entered into a database: age, sex, risk category, Centers for Disease Control and Prevention clinical category, complete blood counts, the results of a liver panel, the results of a basic metabolic panel, coagulation test results, plasma HIV RNA level, and CD4+ T cell count (nadir and baseline). Duration of HCV infection was calculated on the basis of the assumption that HCV infection was acquired during the first year that needles were shared. Patients were also asked about their alcohol intake. We considered the consumption of >50 g of alcohol per day for ⩾12 months to be a high intake. Cumulative exposure to antiretroviral drugs prior to liver biopsy was calculated by reviewing the computerized registers of the hospital pharmacy.

Virological analysis. HIV infection was documented in all patients by ELISA and a Western blot assay. All patients had test results that were positive for specific HCV antibodies and had a detectable serum HCV RNA level as assessed by PCR. The HCV load was measured by PCR (Cobas Amplicor HCV Monitor Test; Roche), and the results were reported in IU/mL. HCV genotype was determined by hybridization of biotin‐labeled PCR products to oligonucleotide probes bound to nitrocellulose membrane strips (INNO‐LiPA HCV II; Innogenetics).

Liver biopsy. Liver biopsy was performed on an outpatient basis following the recommendations of the Patient Care Committee of the American Gastroenterological Association [13]. Ultrasound was routinely used to determine the percutaneous biopsy site. All patients gave their written informed consent.

Histological analysis. Formalin‐fixed, paraffin‐embedded liver tissue sections were stained by hematoxylin‐eosin, Mason's trichrome, and Perl's iron. The stage of liver fibrosis was estimated following the criteria established by Batts and Ludwig [14]. Fibrosis was scored as follows: 0, no fibrosis; 1, portal fibrosis; 2, periportal fibrosis or rare portal‐portal septa; 3, fibrous septa with architectural distortion but no obvious cirrhosis (bridging fibrosis); and 4, definite cirrhosis.

Statistics. An analysis of variance analysis was used to compare the means between groups. The Fisher's exact test was used for all other comparisons between groups. All tests were 2‐tailed, with P values <.05 considered to be significant. Statistical analysis was performed using SPSS, version 12.0 (SPSS).

We assessed the association between cumulative exposure to antiretroviral drugs (in years) and stage of fibrosis by a multinomial logistic regression model (with 3 categories). Taking having a fibrosis stage score of 3 or 4 as the reference category, we calculated the adjusted OR (AOR) and the 95% CI of having a score of 0 or 1 and the AOR and 95% CI of having a score of 2 per year of exposure to HAART, PIs, and NNRTIs (both as a group and for efavirenz and nevirapine separately). This analysis was adjusted for age, sex, high alcohol intake, prior AIDS diagnosis, CD4+ cell count (both nadir and at biopsy), HIV load, HCV load, and HCV genotype.

We also assessed the association between exposure to antiretroviral drugs and fibrosis progression rate (FPR) by logistic regression (with 2 categories). In each patient, FPR was calculated by dividing the fibrosis stage score (0–4) by the estimated duration of HCV infection in years. For example, for a patient with a fibrosis stage score of 2 and a 10‐year duration of HCV infection, the FPR is 0.2. We selected a cutoff point of 0.1 (near the 50th percentile) to classify the patients (i.e., as the dependent variable). Considering FPR >0.1 as the reference category, we calculated the AOR and the 95% CI of having an FPR ⩽0.1 per year of exposure to HAART, to PIs, and to NNRTIs (both as a group and for efavirenz and nevirapine separately). This analysis was adjusted for the same variables mentioned earlier.

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Results

The characteristics of the 201 patients at biopsy are shown in table 1. Overall, the median age was 39 years, 79.6% of the patients were male, 33% had received a prior diagnosis of AIDS, the median CD4+ cell count was 462 cells/mm3, and 74.6% had an HIV load <50 copies/mL. The estimated median time since HCV infection was 21.3 years, and 57% of the patients were infected with HCV genotype 1.

Figure 1
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Figure 1

Association of cumulative exposure to antiretroviral drugs (in years) and liver fibrosis progression in patients coinfected with HIV and hepatitis C virus (HCV) coinfection. A, Adjusted OR (AOR) and 95% CI (bars) of having a fibrosis stage score of 0 or 1 (F—1) per year of drug exposure, taking having a score of 3 or 4 (F—3) as the reference category. B, AOR and 95% CI of having a fibrosis stage score of 2 (F2) per year of drug exposure, taking F—3 as the reference category. C, AOR and 95% CI of having an fibrosis progression rate (FPR) ∼0.1 per year of drug exposure, taking having a FPR 10.1 as the reference category. All analyses were adjusted for age, sex, high alcohol intake, prior AIDS diagnosis, CD4+ cell count (both nadir and at biopsy), HIV load, HCV load, and HCV genotype. NNRTI, nonnucleoside analogue reverse-transcriptase inhibitor; PI, protease inhibitor

Table 1
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Table 1

Characteristics of 201 patients with HIV and hepatitis C virus (HCV) coinfection categorized according to fibrosis stage score as determined by liver biopsy.

The distribution of liver fibrosis in our cohort, by fibrosis stage score, was as follows: 0, 0.5%; 1, 37.1%; 2, 31.9%; 3, 18.8%; and 4, 11.7%. When the biopsy sample was obtained, all patients had been receiving HAART for a median of 4.3 years. When we categorized patients according to the stage of fibrosis, we found no significant differences in patient characteristics, with the exception that the duration of exposure to HAART was lower in patients with fibrosis scores of 3 or 4 than it was in patients with scores of 0 or 1. We also found that the proportion of patients with an HCV RNA level >850,000 copies/mL was lower among patients with a fibrosis score of 3 or 4 than it was among either patients with a score of 0 or 1 or patients with a score of 2.

Tables 2 and 3 show qualitative and cumulative exposure to antiretroviral drugs categorized by stage of fibrosis. Figure 1 shows the association of cumulative exposure to antiretroviral drugs in years and liver fibrosis progression adjusted for age, sex, high alcohol intake, prior AIDS diagnosis, nadir CD4+ cell count, baseline CD4+ cell count, HIV load, HCV load, and HCV genotype. Taking having a fibrosis stage score of 3 or 4 as the reference category, we found that the AOR of having a score of 0 or 1 increased significantly with each additional year of exposure to HAART, to NNRTIs as a class, and to efavirenz and nevirapine as individual drugs. This effect was not found with PIs as a class (figure 1A). When having a score of 3 or 4 was again taken as the reference category, we found that the AOR of having a score of 2 increased significantly with each additional year of exposure to NNRTIs as a class and to nevirapine as an individual drug. This effect was not found with HAART, with PIs as a class, or with efavirenz as an individual drug (figure 1B). Finally, when FPR >0.1 was taken as the reference category, we found that the AOR of having an FPR ⩽0.1 increased significantly with each additional year of exposure to HAART, NNRTIs as a class, and nevirapine as an individual drug. This effect was not found with PIs as a class or with efavirenz as an individual drug (figure 1C).

Table 2
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Table 2

Qualitative exposure to antiretroviral drugs in 201 patients with HIV and hepatitis C virus (HCV) coinfection categorized according to fibrosis stage score as determined by liver biopsy.

Table 3
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Table 3

Quantitative exposure to protease inhibitors (PIs) and nonnucleoside analogue reversetranscriptase inhibitors (NNRTIs) in 201 patients with HIV and hepatitis C virus coinfection categorized according to fibrosis stage score as determined by liver biopsy.

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Discussion

We performed a cross‐sectional study that analyzed the association between exposure to antiretroviral drugs and liver fibrosis progression in 201 HIV‐HCV—coinfected patients. We confirmed that exposure to HAART was associated with a reduction in the FPR and a reduction in the progression to bridging fibrosis and cirrhosis. When we analyzed the association between cumulative exposure to NNRTIs and PIs and fibrosis progression—by adjusting for clinical, immunological, and virological characteristics—we found that exposure to NNRTIs as a class was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs as a class was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis than was exposure to efavirenz.

There is much support in the medical literature for HIV infection acting as a promoter of hepatitis C disease progression [1–3]. Although the exact mechanisms by which this occurs are not clear, the literature suggests that CD4+ cell depletion [15, 16] and exacerbation by proinflammatory cytokines play a role [17]. Other factors that have been found to be associated with a higher liver FPR among HIV‐HCV—coinfected patients are increasing age and alcohol consumption [15].

It is well known that HAART increases CD4+ cell count and corrects HIV‐induced immunodeficiency [18], and there is evidence that inhibition of HIV replication following HAART is associated with a reduction in the immune‐mediated inflammatory response in the liver [17]. Therefore, it is plausible that HAART can correct the harmful effect of HIV infection in chronic hepatitis C. This has been proved in cross‐sectional studies based on liver biopsies that have shown a slower fibrosis progression in patients receiving antiretroviral therapy [9, 19–24] and in clinical cohorts that have shown an association between HAART and reduced mortality or better hepatic outcomes among HIV‐HCV—coinfected patients [6–8, 25].

The existing information suggests that HAART is a key to preventing the progression of liver disease in HIV‐HCV—coinfected patients, even in those individuals with end‐stage liver disease. The question is, do PIs have intrinsic antifibrogenic properties that make them more convenient than NNRTIs for treating HIV infection in patients with HIV‐HCV coinfection? There is some ground to support this hypothesis. First, there is a close relationship between renin and HIV type 1 protease [26]. Second, recent data indicate that the renin‐angiotensin system plays a pivotal role in liver fibrosis through activation of hepatic stellate cells by circulatory angiotensin II [27, 28], and some experimental studies have shown that both angiotensin II type 1 receptor inhibitors and angiotensin‐converting enzyme inhibitors may block the activation of hepatic stellate cells [27]. Third, there is an anecdotal report of renin‐angiotensin system inhibition in a patient who took an overdose of saquinavir [29].

However, there is a huge difference between theoretical speculation and clinical evidence. To date, few clinical studies have analyzed this question. In a retrospective cohort study performed in a French institution [19], factors affecting liver fibrosis were analyzed in 182 consecutive HIV‐HCV—coinfected patients. Multivariate analysis identified 4 independent predictors of progression to cirrhosis: absence of PI therapy, heavy alcohol consumption, low CD4+ cell count, and age when HCV infection was acquired [19]. In a study from Spain [9], the association between the use of different antiretroviral drugs and liver fibrosis was studied in 152 HIV‐HCV—coinfected patients with an available liver biopsy sample and known or estimated duration of HCV infection. Variables independently associated with having a fibrosis stage score of 3 or 4 were age at HCV infection <20 years (protective effect), receipt of PI‐based HAART (protective effect), and receipt of nevirapine‐based HAART (harmful effect). Variables independently associated with FPR >0.2 were age at HCV infection <20 years (protective effect), CD4+ cell count ⩽250 cells/mm3 at biopsy (protective effect), receipt of PI‐based HAART (protective effect), and receipt of nevirapine‐based HAART (harmful effect) [9].

The results of our study stand in sharp contrast to those of the 2 studies mentioned above. We confirmed that exposure to HAART was associated with a reduction in both the FPR and the progression to bridging fibrosis and cirrhosis. However, when we analyzed the association of cumulative exposure to different drugs and fibrosis progression, by adjusting for clinical, immunological, and virological characteristics, we found that exposure to NNRTIs as a class was clearly associated with a reduction in fibrosis progression, whereas exposure to PIs as a class was not. Of note, exposure to nevirapine was more consistently associated with a reduction in fibrosis than was exposure to efavirenz. We want to emphasize that our study outperformed the 2 studies mentioned above in some important aspects, such as cohort size and method of analysis of exposure to PIs and NNRTIs. We did not address this issue in a simple yes or no qualitative way but calculated the cumulative exposure to these drugs by review of computerized pharmacy reports.

It is important to remember that all studies that have analyzed the association between drug exposure and fibrosis progression in HIV‐HCV—coinfected patients, including ours, are subject to bias. For example, they are all retrospective, based on only 1 biopsy sample per patient (not sequential biopsies), and they assume that fibrosis progression is linear. Another potential source of bias is patient selection, because most of the patients included in these studies had good clinical profiles and underwent biopsy to determine the extent of liver fibrosis to assess suitability for treatment.

The potential advantages of PIs over NNRTIs or vice versa with respect to fibrosis progression in HIV‐HCV—coinfected patients is an open question that needs to be addressed with prospective randomized clinical trials. This is a pertinent area of research, because current therapies for HCV infection based on pegylated IFN‐α plus ribavirin are less efficacious and more toxic in HIV‐HCV—coinfected patients than in HCV‐monoinfected patients [30–32], and because the applicability of this therapy among the former group is low [33], resulting in an overall cure rate of ∼4% [34]. We are aware that what we propose is difficult to carry out in clinical practice, given the limitations of performing sequential liver biopsies and the drawbacks that this technique entails. Nevertheless, the availability of noninvasive methods to assess liver fibrosis, such as transient elastography [35, 36], provides us with an excellent opportunity for performing this type of study.

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acknowledgments

We thank Thomas O'Boyle for writing assistance during the preparation of the manuscript.

Financial support. Fundación para la Investigación Sanitaria (FIS), Spanish Ministry of Health (PI052411 and ISCIII‐RETIC RD06/006; CP04/00090 to S.R.) and Fundación para la Investigación y la Prevención del SIDA en España (36443/03).

Potential conflicts of interest. J.B. has received recent research funding from Bristol‐Myers Squibb; is a consultant for Roche, GlaxoSmithKline, and Schering Plough; and is a member of the speakers' bureau of GlaxoSmithKline, Gilead Sciences, Boehringer, Tibotec, Abbott, and Roche. All other authors: no conflicts.

  • Received July 14, 2007.
  • Accepted September 6, 2007.
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  1. Clin Infect Dis. (2008) 46 (1): 137-143. doi: 10.1086/524080
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