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HIV Accelerates HCV, Spanish study finds
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"Progression of Chronic Hepatitis C to Liver Fibrosis and Cirrhosis in Patients Coinfected with Hepatitis C Virus and Human Immunodeficiency Virus"
Summary: To evaluate the factors associated with the evolution of chronic hepatitis C in human immunodeficiency virus (HIV) infected patients, a cross-sectional analysis of 41 HIV-infected patients with chronic hepatitis C (known as "HIV-HCV [hepatitis C virus]coinfected patients") and a control group of patients with chronic hepatitis C who did not have HIV infection (known as "non-HIV-infected patients") was performed. The association of histological variables with demographic parameters, HCV load and genotype, HIV load, CD4+ T cell count, and response to highly active antiretroviral therapy (HAART) was evaluated. HIV-HCVcoinfected patients showed a significantly higher HCV load, more-advanced fibrosis, and a higher liver fibrosis progression rate (FPR) than did nonHIV-infected patients. A high HCV load and a low CD4+ T cell count were associated with a higher FPR. The immune response induced by HAART did not influence this progression. In conclusion, HIV-HCVinfected patients, mainly such patients with a high HCV load and an immunodepressed state, have a higher FPR. An independent effect of the immune response to HAART was not evident.
".. The fibrosis score was significantly higher for HIV-HCVcoinfected patients than for non-HIV-infected patients..[it appears as though a single biopsy was performed] We have calculated the FPR as the ratio of the fibrosis stage to the duration of infection... Sex, age at infection, alcohol consumption, HCV load, and HCV genotype were similar for patients with and without cirrhosis. In contrast, 22% of HIV-HCVcoinfected patients had cirrhosis at liver biopsy, whereas, for the non-HIV-infected group, this percentage was 6% [estimated duration of HCV was about the same for coinfected & HCV infected, 17 years; and more HCV infected had HCV for greater than 20 years 55% vs 46%].. The HIV-HCV coinfected group showed a significantly higher FPR than did the non-HIV-infected group. The FPR correlated with the HCV load in both groups of patients... the CD4+ T cell count before receipt of treatment is the factor more clearly implicated in the FPR... a higher HCV load and a lower immunocompetence level influence the natural history of chronic hepatitis C, with rapid progression of fibrosis and cirrhosis occurring in HIV-HCVcoinfected patients. Immune reconstitution induced by HAART did not modify the progression of liver fibrosis. The accelerated progression of liver fibrosis and cirrhosis support a more aggressive approach to the treatment of HCV infection in these patients."
Clinical Infectious Diseases 2003;36:491-498
Carmen Martinez-Sierra,1 Ana Arizcorreta,2 Fernando Diaz,1 Rafael Roldan,3 Leopoldo Martin-Herrera,1 Eugenio Perez-Guzman,2 and Jose A. Giron-Gonzalez2 1Gastroenterology, 2Infectious Diseases, and 3Pathology Units, Hospital Universitario Puerta del Mar, Cadiz, Spain
Studies of the natural history of hepatitis C virus (HCV) infection in immunocompetent patients have demonstrated that death associated with chronic hepatitis C results mainly from the development of liver fibrosis and the subsequent occurrence of cirrhosis and its complications. Approximately 6% of immunocompetent HCV-infected hosts can be expected to develop hepatic decompensation due to cirrhosis during a 20-year period, although the time frame in which the various stages of liver disease develop is highly variable. Numerous factors have been associated with an increased risk of progression of HCV infection to cirrhosis, including male sex, older age at the time of infection, and alcohol consumption.
The increase in the survival of HIV-infected patients, related to the use of HAART, has been associated with higher morbidity and mortality rates attributable to chronic HCV infection. HCV-induced liver disease has an accelerated course in HIV-coinfected patients. This accelerated progression of disease in HIV-infected patients with chronic hepatitis C (i.e. "HIV-HCVcoinfected patients") could be explained by several factors, such as the higher HCV load detected in such patients or the immunodeficiency state (as this factor can be related to the CD4+ T cell count). However, the effect of the HCV load on histopathologic liver lesions in these patients had not been previously established. Likewise, although it could be postulated that improvement of immune function associated with antiretroviral therapy might reduce the liver fibrosis progression rate (FPR), the influence of the effects of modifications of immune parameters induced by HAART remains controversial or unknown. The aim of the present study was to investigate the independent effects of HCV load and of immune reconstitution induced by therapy on the accelerated evolution of liver fibrosis and cirrhosis in HIV-HCVcoinfected patients.
Histological evaluation. Liver biopsy specimens, which measured >10 mm in length, were fixed, paraffin embedded, and stained with hematoxylin-eosin safranin and Masson trichrome or picrosirius red for collagen. All specimens were assessed by the same experienced pathologist (R.R.), who was not aware of the clinical or biological data. For each liver biopsy specimen, a numerical score was established, both for the grading of necroinflammatory activity (NIA) and for determining the stage of fibrosis, with use of the index of histological activity proposed by Knodell et al., as modified by Scheuer and Desmet et al. NIA was graded according to 3 components: periportal inflammation with or without bridging necrosis (scale, 010), intralobular degeneration and focal necrosis (scale, 04), and portal inflammation (scale, 04). In accordance with the previously cited studies, the intensity of NIA was scaled as follows: A0 denoted no histological activity; A1, minimal activity (scale units, 13); A2, mild activity (scale units, 48); A3, moderate activity (scale units, 912); and A4, severe activity (scale units, >12). The stage of liver fibrosis was determined using a scale of F0F4 (F0 denoted no fibrosis; F1, periportal fibrosis without septa; F2, few septa; F3, numerous septa without cirrhosis; and F4, cirrhosis).
We have calculated the FPR as the ratio of the fibrosis stage to the duration of infection. A validation method was made by comparing the estimated FPRs with the FPR observed for paired liver biopsy specimens obtained from 12 patients who had never received treatment. For these patients, the FPR was calculated as the difference between the scores for specimens obtained from 2 consecutive biopsies, divided by the time (in years) elapsed between performance of the 2 biopsies.
RESULTS
The groups of HIV-HCVcoinfected patients and nonHIV-infected patients were comparable with respect to sex, age at infection, age at biopsy, mean duration of HCV infection, and alcohol consumption, but their risk factors for HIV infection were different, mainly because there were more injection drug users in the group of HIV-HCVcoinfected patients.
HIV-infected patients had received their diagnosis a mean (±SD) of 8.1 ± 3.8 years (range, 314 years) before the present study. At diagnosis, the mean CD4+ T cell count was 334 cells/L (95% CI, 244424 cells/L), with 81% of HIV-infected patients having <500 CD4+ T cells/L and 31% having <200 cells/L. All patients had been receiving HAART for a median of 36 months (95% CI, 2743 months); 32 of the patients had an undetectable HIV load. The median increase in the number of CD4+ T cells was 225 cells/L (range, -27 to 431 cells/L). At liver biopsy, the mean CD4+ T cell count (±SD) was 577 ± 280 cells/L (range, 2451496 cells/L), with 56% of the patients having >500 CD4+ T cells/L.
The distribution of HCV genotypes was similar between groups. HIV-HCVcoinfected patients had significantly higher HCV loads. Likewise, the percentage of patients with an HCV load of >2 “ 106 copies/mL was significantly higher among coinfected patients than among nonHIV-infected patients (71% vs. 37%; P < .005). Serum ALT levels were similar for groups. In the HIV-HCVcoinfected group, the HCV load had a significantly negative correlation with the CD4+ T cell count (r = -.34; P = .032) and a positive correlation with age at HCV infection (r = .35; P = .032).
NIA. The NIA score was similar for both groups. For HIV-HCVcoinfected patients, a similar NIA score was detected in groups of subjects classified according to their degree of immunodeficiency (the NIA score was 4.89 [95% CI, 3.356.42] for patients with CD4+ T cell counts of 200 cells/L vs. 4.22 [95% CI, 3.105.34] for patients with CD4+ T cell counts of >200 cells/L; P = .45). The NIA score showed a significant correlation with serum ALT concentrations in both groups (for HIV-HCVcoinfected patients, r = .48 [P < .005]; for nonHIV-infected patients, r = .28 [P < .05]). Only in the nonHIV-infected group did the correlation between the NIA score and the HCV load approach statistical significance (for HIV-HCVcoinfected patients, r = .00 [P > .05]; for nonHIV-infected patients, r = .24 [P = .05]). For both groups, the variables of sex, age at infection or age at biopsy, estimated duration of infection, alcohol consumption, and genotype were not correlated with either the NIA score or the serum ALT concentrations (data not shown).
The fibrosis score was significantly higher for HIV-HCVcoinfected patients than for non-HIV-infected patients. The fibrosis score showed a positive and significant correlation with the estimated duration of infection in both groups (for HIV-HCVcoinfected patients, r = .49 [P = .001]; for nonHIV-infected patients, r = .255 [P = .01]).
Liver biopsy showed the presence of cirrhosis in 18 patients. Sex, age at infection, alcohol consumption, HCV load, and HCV genotype were similar for patients with and without cirrhosis. In contrast, 22% of HIV-HCVcoinfected patients had cirrhosis at liver biopsy, whereas, for the nonHIV-infected group, this percentage was 6% (P = .03). In addition, HIV-HCVcoinfected patients developed cirrhosis earlier than did nonHIV-infected patients. Of the HIV-HCVcoinfected patients, 19% had cirrhosis 15 years after HCV infection, and 35% had cirrhosis 20 years after HCV infection. Of the nonHIV-infected patients, 2% of patients had cirrhosis 15 years after HCV infection, and 3% of patients had cirrhosis 20 years of infection. For the HIV-HCVcoinfected group, the immunodeficiency state was significantly associated with the presence of cirrhosis. Patients with CD4+ T cell counts of 200 cells/L at the time of diagnosis of HIV infection or with a CD4+ T cell count of 500 cells/L at liver biopsy (after receipt of HAART), had a higher percentage of cirrhosis than did patients with >200 cells/L at the time of diagnosis of HIV infection or patients with >500 cells/L at liver biopsy.
FPR. The HIV-HCVcoinfected group showed a significantly higher FPR than did the non-HIV-infected group. The FPR correlated with the HCV load in both groups of patients (for the HIV-HCVcoinfected group, r = .51 [P = .003]; for the nonHIV-infected group, r = .39 [P = .03]).
The accelerated progression of fibrosis was more significant among patients who were more immunosuppressed. Persons with a CD4+ T cell count of 200 cells/L at the time of diagnosis of HIV infection had a statistically higher FPR than did patients with a CD4+ T cell count of >200 cells/L (0.212 [95% CI, 0.1500.271] vs. 0.127 [95% CI, 0.0920.151]; P = .007). Moreover, differences in the FPR between HIV-HCVcoinfected patients with >200 CD4+ T cells/L and nonHIV-infected patients were not statistically significant (0.127 [95% CI, 0.0890.152] vs. 0.106 [95% CI, 0.0810.129]; P = .3).
A HAART-induced increase in the CD4+ T cell count to >500 cells/L was detected in 56% of HIV-infected patients at the time of liver biopsy. The difference in the FPR between those patients with an increase of 225 or >225 CD4+ T cells/L (the median increase in this series) continued to be nonsignificant (0.167 [95% CI, 0.1220.212] vs. 0.145 [95% CI, 0.1230.191]; P = .5). Although FPR was more accelerated in HIV-HCVcoinfected patients with either no response or a poor immune response to HAART (<500 CD4+ T cells/L at biopsy) (n = 18), compared with patients with a good response to these drugs (>500 CD4+ T cells/L) (n = 23), differences did not reach statistical significance (0.168 [95% CI, 0.1110.212] vs. 0.139 [95% CI, 0.0940.177]; P = .45).
The effect of the putative variables associated with the FPR was evaluated. As shown in, alcohol consumption and age of >20 years at the time of infection, together with the NIA score, were associated with a more accelerated FPR among nonHIV-infected patients. In the HIV-HCVcoinfected group, age of >20 years at the time of infection and a CD4+ T cell count of 200 cells/L at the time of diagnosis were associated with a rapid FPR. Multivariate analysis showed that alcohol consumption and age at infection were independent factors that influenced the FPR in nonHIV-infected patients, whereas age at infection, HCV load, and an immunodepressed state at the time of diagnosis of HIV infection (CD4+ T cell count, 200 cells/L) were the independent factors associated with the FPR in HIV-HCVcoinfected patients.
DISCUSSION
HIV infection modifies the natural history of chronic hepatitis C, with rapid progression of fibrosis and cirrhosis. In fact, the prevalence of cirrhosis was significantly higher at each of the stages of evolution of HIV disease in HIV-HCVcoinfected patients analyzed in our study. Those patients with a CD4+ T cell count of <200 cells/L had a higher prevalence of cirrhosis, a finding that supports the importance of immune surveillance for the development of liver lesions.
We have identified 2 different patterns of evolution of chronic HCV infection as a function of the presence or absence of HIV coinfection. In nonHIV-infected patients, the FPR was associated with older age at the time of infection and with alcohol consumption. These parameters previously have been related to this accelerated evolution. In the HIV-HCVcoinfected group, an accelerated FPR was associated with the CD4+ T cell count and with the HCV load. The decrease in cell-mediated immunity associated with HIV infection is believed to permit greater replication of HCV and, consequently, greater infection of and injury to hepatocytes. Also, coinfection with HIV probably alters the response of immune cells to HCV. Whereas patients with >200 CD4+ T cells/L had an FPR similar to that of nonHIV-infected patients, patients with CD4+ T cell counts of 200/L had the highest FPR. The other parameter associated with a rapid FPR was HCV load. It previously had been demonstrated that the HCV load was higher in HIV-HCVcoinfected patients with low CD4+ T cell counts than in patients with high CD4+ T cell counts; this was also detected in our study. However, the effect of HCV load on histopathologic liver lesions in these patients, which is demonstrated in the present study, had not been previously established.
Neither sex, risk factors for HCV infection, nor HCV genotypes were associated with an accelerated FPR. It previously has been demonstrated that risk factors for HCV infection have no effect on the stage of histopathologic lesions of the liver. Also, although infection by genotypes 1 or 4 has been associated with a higher HCV load and worse evolution, we and other investigators did not detect worse evolution in those patients infected by genotypes 1 or 4 than in those infected by other genotypes.
It has been hypothesized that immune restoration induced by HAART may lead to better control of HCV replication. Benhamou et al. have analyzed the role of HAART in the progression of liver fibrosis due to HCV. They have demonstrated a lower FPR for patients who have been receiving HAART for a median period of 14 months, although some methodological variables are doubtful; thus, patients who did not receive HAART had significantly lower CD4+ T cell counts and higher HIV loads than did patients who received HAART. Likewise, the effect of HAART on CD4+ T cell count or HIV load was unknown. Hence, our work could be considered the first study in which, after a median period of 36 months of treatment, the effects of the immune response to HAART on liver lesions were evaluated. Patients with immune reconstitution induced by HAART had a lower prevalence of liver cirrhosis; however, on the basis of the results of multiple linear regression, an independent effect of immune reconstitution can be discounted. This supports, in contrast, the CD4+ T cell count before receipt of treatment as the factor more clearly implicated in the FPR. The results for the effect of HAART are similar to those observed with HCV load. No differences were seen between those with and those without immunologic response. It could be stated that anti-HIV regimens and improvement of immunologic parameters are not sufficient to control HCV infection.
In conclusion, a higher HCV load and a lower immunocompetence level influence the natural history of chronic hepatitis C, with rapid progression of fibrosis and cirrhosis occurring in HIV-HCV coinfected patients. Immune reconstitution induced by HAART did not modify the progression of liver fibrosis. The accelerated progression of liver fibrosis and cirrhosis support a more aggressive approach to the treatment of HCV infection in these patients.
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