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Impact of chronic hepatitis C and/or D on liver fibrosis severity in patients co-infected with HIV and hepatitis B virus
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AIDS:Volume 21(18)30 November 2007p 2546-2549
[Research Letters]
Lacombe, Karinea,b,c; Boyd, Andersa,c; Desvarieux, Moisea,b,d; Serfaty, Lawrencee; Bonnord, Philippef; Gozlan, Joelg,h; Molina, Jean-Micheli; Miailhes, Patrickj; Lascoux-Combe, Carolinek; Gault, Elyannel,m; Girard, Pierre-Marieb,c
aInserm, UMR S707, Paris, F-75012, France
bUniversite Pierre et Marie Curie - Paris 6, Paris, F75012, France
cAP HP, Hopital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, Paris, F-75012, France
dDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
eAP HP, Hopital Saint-Antoine, Service d'hepato-gastro-enterologie, Paris, F-75012, France
fAP HP, Hopital Tenon, Service de Maladies Infectieuses et Tropicales, Paris, F-75020, France
gAP HP, Hopital Saint-Antoine, Service de bacteriologie-virologie, Paris, F-75012, France
hUniversite Pierre et Marie Curie - Paris 6, UMR 7079, Les Cordeliers, Paris, F-75006, France
iAP HP, Hopital Saint-Louis, Service de Maladies Infectieuses et Tropicales, Paris, F-75012, France
jHospices civils de Lyon, Hopital de l'Hotel-Dieu, Service d'Hepatologie, Lyon, F-69288, France
kAP HP, Hopital Saint-Louis, Service de Medecine interne, Paris, F-75012, France
lAP HP, Hopital Avicenne, Service de Bacteriologie-Virologie-Hygiene, Bobigny, F-93000, France
mUniversite Paris 13, EA-3604, Bobigny, F-93000, France.
"....In these HIV-infected patients, the adjusted odds of liver fibrosis increased in patients with HBV-HDV and HBV-HCV-HDV (OR = 7.73, 95% CI = 1.11-53.78; OR = 8.54, 95% CI = 1.24-56.10, respectively, for fibrosis stage F3-F4), but not in HBV-HCV co-infected patients (OR = 1.76, 95% CI = 0.50-6.17) compared to patients with HBV alone.... a recent longitudinal study comparing HIV-HBV and HIV-HBV-HDV co-infections demonstrated significantly higher number of cirrhosis and hepatic decompensation cases with HDV infection.... One clinical trial using high doses of interferon in HIV-negative, HBV-HDV co-infected patients showed promising results on survival and fibrosis regression [23]. Furthermore, Lamivudine with Peg-Interferon may be more efficient than Peg-Interferon alone in controlling HBV and HDV replication [24]. Aside from Lamivudine, more effective antiviral treatments (i.e. Tenofovir) must be examined longitudinally to assess any indirect effect on HDV in multiple hepatic co-infection."
Abstract
The histological study on the reciprocal influence of chronic hepatitis C (HCV) and/or delta (HDV) on liver damage in a cohort of 134 HIV-HBV co-infected patients concluded on a significant association between HDV co-infection (noted in 13 patients) and Metavir F3-F4 liver fibrosis score [odds ratio (OR) = 7.08, 95% confidence interval (CI) = 1.06-47.28 for HBV-HDV, OR = 10.02, 95% CI = 1.03-97.42 for HBV-HCV-HDV, compared to OR = 1.76, 95% CI = 0.50-6.17 for HBV alone]. Co-treatment of other multiple viral hepatitis infections should also be taken into consideration, especially in the case of chronic HDV.
Overlapping routes of transmission in hepatitis B (HBV), delta (HDV) and/or C (HCV) viruses induce a high prevalence of multiple hepatic co-infection in HIV-infected patients, which contributes to an increased liver-related morbidity [1,2]. Several studies have focused on the role of HIV-induced immunosupression and hepatic viral interference as co-factors of liver damage [3,4], but none has specifically studied the implication of each hepatic virus in the fibrogenic process. The present study aimed to determine and quantify the respective contribution of HCV and/or HDV on liver fibrosis among HIV-HBV co-infected patients.
Patients in this cross-sectional study were prior enrolled in the HIV-HBV Cohort Study, for which the design has been described previously [5]. Serum antibodies to HCV and HDV, with quantification of HCV-RNA or HDV-RNA and genotyping, were determined. Four mutually exclusive groups were defined per positive concordant serology 6 months prior to and at inclusion: (i) HBV; (ii) HBV-HCV; (iii) HBV-HDV; and (iv) HBV-HCV-HDV. Liver fibrosis was assessed by histological evaluation of liver paraffin-embedded biopsies obtained within 18 months of inclusion (2002-2003). Samples were stained with hematoxylin-phloxin-saffran and picrosirius red and were then blindly read by four pathologists who were unaware of the clinical and biological data. Histological fibrosis was scored using the METAVIR classification [6] and trichotomized on levels of fibrosis (F0-F1 versus F2 versus F3-F4). An ordinal logistic regression model was fitted and adjusted odds ratios (ORs), with 95% confidence interval (CI) and P-values, were calculated for each variable. Variables included a priori in the model were age, body mass index, log10 viral copies of HBV DNA, CD4+ cell count, current treatment with Lamivudine and Tenofovir, alcoholic consumption, and sex; which are known factors affecting liver fibrosis.
Among the 134 patients with at least one liver biopsy at inclusion (median age = 40.2 years, interquartile range (IQR) = 35.8-44.4; sex ratio = 18), 23 patients were identified with additional hepatitis co-infection (HBV-HCV, n = 10; HBV-HDV, n = 6; HBV-HCV-HDV, n = 7). Levels of median CD4+ cells (423/mm3, IQR = 283-545) and combined antiretroviral therapy (cART) exposure (80.8% of all patients and 76% treated with a drug of dual HIV-HBV activity) were similar across all groups. HIV-RNA was above the detection limit (50 copies/ml) in 69.2% of HDV-co-infected patients (9/13) versus 57.8% of non-HDV co-infected patients (70/121). Active HBV replication (> 200 copies/ml) was noted in 100 of 134 (74.6%) patients. HBV genotypes were distributed as follows (n = 97): A = 63 (66.7%), D = 10 (10.8%), E = 7 (7.5%), G = 13 (14.2%). Replicative HCV infection was noted in eight of 17 patients (47.1%), revealing a predominance of genotype 1 (n = 4), followed by genotype 3 (n = 2) and genotype 4 (n = 2). Active HDV replication was also observed in ten of 12 patients (nine patients with genotype 1 and one patient with genotype 5). A METAVIR fibrosis score of 2 or greater was found in 83.4% (5/6) of HBV-HDV and 100% (7/7) of HBV-HCV-HDV co-infected patients. Prevalence of activity in the liver (METAVIR activity score of 2 or greater) in patients with HCV and/or HDV co-infection was 65% versus 35% in the HBV group (P = 0.007). In these HIV-infected patients, the adjusted odds of liver fibrosis increased in patients with HBV-HDV and HBV-HCV-HDV (OR = 7.73, 95% CI = 1.11-53.78; OR = 8.54, 95% CI = 1.24-56.10, respectively, for fibrosis stage F3-F4), but not in HBV-HCV co-infected patients (OR = 1.76, 95% CI = 0.50-6.17) compared to patients with HBV alone. A secondary analysis conducted after regrouping HDV co-infection groups (Table 1, model 2) yielded similar results with an 8.17-fold increased odds of liver fibrosis compared to only HBV (95% CI = 1.94-34.28, P = 0.004), whereas the increase of odds related to HBV-HCV was not significant (OR = 1.76, 95% CI = 0.50-6.18).
Outside the context of HIV, studies regarding multiple hepatic co-infections focused on viral interactions in which HDV played a dominant role with a subsequent inhibition of HBV and HCV replication [7,8]. In HIV-infected patients, data on viral interference are controversial and those reporting histological evidence of a dominant viral influence over another are non-existent. Studies predating the extensive use of cART either demonstrated an absence of an inhibitory effect of HDV or an inhibitory role of HDV replication over HBV and HCV [9], the latter of which was confirmed by two recent studies in a less immunocompromised population [10,11]. The level of viral replication in chronic HCV might not be a determinant to the degree of liver fibrosis [12]; however the putative direct cytopathic effect of replicating HDV [13] may hasten the liver fibrosis process, leading to a more rapid fibrosis evolution in the case of HDV infection compared to HCV alone [14]. Genotype 1 was the most prevalent genotype in HCV and HDV co-infection. This is consistent with the geographical repartition of such genotypes in HIV-negative patients born in Europe [15,16], whereas the only patient infected with an HDV genotype 5 strain, identified as a newly-characterized African clade [17], came from Mali. These data show that the prevalences of HCV and HDV genotypic characteristics in HIV-infected patients are similar to those of HIV-negative populations and influenced by geographical origin.
Two main limitations arise in this study. First, liver progression in these groups could not be established due to the cross-sectional design. However, a recent longitudinal study comparing HIV-HBV and HIV-HBV-HDV co-infections demonstrated significantly higher number of cirrhosis and hepatic decompensation cases with HDV infection [11]. Second, although our population was well characterized, the patient sample size was relatively small, in line with other reports [10,11,18] and reflecting the difficulty of identifying these rare multiinfected patients. This problem was attenuated by using exact ordinal logistic models with all HDV-infected patients merged together.
Recently published guidelines on HIV-HBV co-infection management outlined the importance of early treatment of chronic HBV [19]. Co-treatment of all multiple viral hepatitis infections should be taken into consideration [18]. However, although efficient antiviral drugs are available to treat HCV in HIV-infected patients [20,21], the treatment of HDV is still an unsolved issue [22]. One clinical trial using high doses of interferon in HIV-negative, HBV-HDV co-infected patients showed promising results on survival and fibrosis regression [23]. Furthermore, Lamivudine with Peg-Interferon may be more efficient than Peg-Interferon alone in controlling HBV and HDV replication [24]. Aside from Lamivudine, more effective antiviral treatments (i.e. Tenofovir) must be examined longitudinally to assess any indirect effect on HDV in multiple hepatic co-infection.
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