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Multiple viral infections
Journal of Hepatology 44 (2006) S108–S113 www.elsevier.com/locate/jhep
Multiple viral infections Giovanni B. Gaeta1,*, Davide F. Precone1, Alessandro Cozzi-Lepri2, Paola Cicconi3, Antonella D’Arminio Monforte3 1
Department of Infectious Diseases, Viral Hepatitis Unit, Second University of Naples, Naples 80135, Italy 2 Royal Free and University College Medical School, London, UK 3 Institute of Infectious and Tropical Diseases, University of Milan, Milan, Italy
Individuals at risk of HIV are concomitantly at risk of acquiring parenterally or sexually transmitted viruses. Multiple hepatitis co-infection (HBVCHCV; HBVCHDV; HBVCHDVCHCV) has not been systematically sought after in the large cohorts of HIV-infected patients, but has been reported in 0.4% to more than 50% of patients. HIVinfected patients with multiple hepatitis have a higher rate of liver-related morbidity and mortality than patients with HIV infection alone or with a single hepatitis co-infection. The degree of immunodepression is an important factor in liver disease progression. Since GBV-C virus is transmitted parenterally or by sexual contact, a high prevalence was found in chronic hepatitis C and in HIV-infected patients. Patients with multiple hepatitis have been excluded from randomised therapeutic trials of viral hepatitis in HIV-infected and HIV-negative patients. Thus, the therapeutic approach is based on the results of a small series and empirically oriented toward the prevailing infection. HIV-infected patients should be tested for hepatitis B, C and D systematically and hepatitis B vaccination should be considered for those with HCV co-infection and absence of HBV markers. Studies are needed to assess treatment strategies. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Hepatitis B; Hepatitis D; HIV; Multiple infection 1. Introduction Individuals at risk for HIV are concomitantly at risk for acquiring parenterally transmitted viruses. Thus, a high prevalence of multiple hepatitis co-infections (i.e. infection with two or more hepatitis viruses) may be expected among HIV-infected subjects. This statement, although sounding acceptable, has rarely been verified in analyses of clinical data. Indeed, the presence of multiple hepatitis co-infections in the large series of HIV-infected patients is overshadowed by the huge number of single hepatitis C virus (HCV) co-infections [1–6] or hepatitis B virus (HBV) co-infection [7]. In addition, therapeutic trials of chronic viral hepatitis rigorously exclude dual or triple hepatitis co-infections [8,9]. We have reviewed the data available on multiple hepatitis infection in the literature and we have analysed
* Corresponding author. Tel.: C39 081 566 6208; fax: C39 081 566 6206. E-mail address: [email protected] (G.B. Gaeta).
the individual data from some case studies to cover the epidemiological, clinical and therapeutic aspects of multiple HBV, hepatitis D virus (HDV) and HCV infections in HIV patients. Moreover, we reviewed the data on GBV-C coinfection and its impact on HIV disease progression both in antiretroviral naive and treated patients.
2. Epidemiology and natural history of multiple hepatitis co-infections The proportion of patients with multiple hepatitis co-infections (HBVCHCV, HBVCHDV, or HCVCHBV CHDV) depends on the environmental and clinical setting. In general, there is a North to South gradient in Europe in the proportion of HIV patients with hepatitis co-infection [6]; multiple co-infection may be expected more frequently in the Mediterranean area, particularly HBV/HDV coinfection, reflecting the epidemiological background of the disease [10,11]. Patients with a history of intravenuous drug use (IDU) generally present dual or triple infection more
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.11.023
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often than patients whose risk factor was sexual behaviour [12,13]. Both in HIV-positive or -negative cohorts, the presence of HBV/HCV, HBV/HDV or triple hepatitis infection was strongly associated to IDU. Overall, 0.4% to more than 50% of HIV patients may carry more than one hepatitis virus, depending on the geographical origin and type of risk exposure [1–6]. We have analysed individual data of 387 HBsAg positive, HIV positive patients recruited from the Italian cohort naive from antiretrovirals (I.Co.N.A.), a cohort that was set up in 1997 and includes patients consecutively enrolled from 69 departments of infectious diseases all over Italy; to be recruited, patients have to be naive to antiretroviral treatment, irrespective of the reason for being so. More details of the I.Co.N.A cohort study are given elsewhere [14]. A variable proportion of these patients had also been tested for other hepatitis viruses before or at the same time as being tested for anti-HBV antibodies. For the purpose of comparison, we used a cohort of 800 HBsAg positive, HIV-negative patients, recruited in a multicentre survey [11]. Table 1 reports the proportions of HCV, HDV and HCV plus HDV infections recorded in these two populations of HBsAg-positive patients according to whether intravenuous drug use was the mode of acquiring HIV and the cohort of origin (I.Co.N.A. or HIVnegative cohort). It is clear from Table 1 that the prevalence of multiple hepatitis infections was much higher in intravenous drug users compared to patients who acquired these infections through other routes, independent of HIV sero-status. Viral interaction between the hepatitis viruses has been described firstly in non-HIV-infected settings. The inhibition of HBV replication by HDV is well known and its clinical consequence is the exceptional presence of HBeAg and clinically significant serum HBV DNA level [15–17]. In a study of 16 HIV-positive patients with HDV chronic hepatitis, documented by the presence of HDV-RNA in serum, only one of them at enrolment had detectable HBV DNA in serum by PCR [18]. This proportion did not appear to be different in 21 HIV-negative HDV-positive patients enrolled in the same study. Although these data suggest that the inhibition of HBV by HDV occurs also in HIV
co-infection, we should note that the focus of this study was IFN treatment, thus only patients with non-advanced HIV disease were included (the mean CD4 cell count/mm3 was 622G284). In patients with more advanced HIV disease and HDV coinfection, HDAg was detected in serum in one-third of the cases and HBV-DNA in 25%. Thus, HIV infection seemed to favour HDV replication and to counter the inhibitory effect of HDV on HBV replication [19]. Interestingly, in this study the degree of liver inflammation and fibrosis was similar in the HIV-positive vs. the HIV-negative group with hepatitis delta. Buti et al. [20] suggested that the clinical prognosis of hepatitis delta in HIV-infected patients was worse when it was associated with hepatitis C. Reciprocal interaction of HBV and HCV has been investigated in several studies in HIV-negative patients [21– 26], but there are few data in HIV infection. A superimposed virus tends to suppress the replication of a pre-existing virus, at least initially. However, almost all studies that examined viral interactions were cross-sectional, giving, therefore, an instant picture. Only in one study, to date published in abstract form [27], a group of HIV-negative patients with dual HBV/HCV infection have been followedup for 1 year and the authors found that in about 30% of the cases the replicative status of each virus may change spontaneously. This approach may be relevant to HIV positive, HBV/HCV co-infected patients, in whom the degree of immunosuppression changes over time as a consequence of natural progression and/or use of antiretroviral treatment. HIV patients with dual hepatitis B/C infection have a worse clinical prognosis than HIV mono-infected or coinfected with a single hepatitis virus. Of 35 HIV/HBV coinfected patients who died in hospital of liver failure during pre-HAART period, 33/35 were HCV co-infected [28]. Bonacini et al. [29] prospectively followed-up 472 HIV positive patients referred for abnormal liver function tests, 18 (3.8%) of whom had dual or triple hepatitis co-infection and 328 (69.5%) were hepatitis B or C mono-infected. The crude mortality rate due to liver disease was 28% in the
Table 1 HCV and HDV co-infections in HBsAg-positive patients according to injecting drug use
Non-IDU HCVK HDVK HCVC HDVK HDVK HDVC HCVC HDVC HCV and/or HDV not tested IDU HCVK HDVK HCVC HDVK HDVK HDVC HCVC HDVC HCV and/or HDV not tested
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HIV-negative cohort (nZ800)
HIV-positive cohort (nZ387)
nZ790 646 (81.7%) 55 (6.9%) 49 (6.2%) 4 (0.51%) 36 (4.6%) nZ10 3 (30.0%) 2 (20.0%) 3 (30.0%) 2 (20.0%) 0 (0.0%)
nZ223 84 (37.7%) 16 (7.2%) 10 (4.5%) 5 (2.2%) 108 (48.4%) nZ164 8 (4.9%) 3 (1.8%) 35 (21.3%) 46 (28.1%) 72 (43.9%)
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multiple hepatitis group vs. 6% in HIV mono-infected and 15 and 13% in hepatitis B or C single infections, respectively. Interestingly, De Luca et al. [30] found that in HIV-infected patients on potent antiretroviral treatment, the presence of double HBV/HCV or single HCV infection was associated with less intense CD4 recoveries than those observed in patients without hepatitis. In 366 HIV/HCV co-infected patients Puoti et al. (personal communication) found that F3–F4 fibrosis was significantly associated with triple HBV/HDV/HCV infection (age adjusted ORZ4.5; 95%CIZ2–9.5). Patients with HBV/HCV co-infection and cirrhosis are a subset of patients at a very high risk for hepatocellular carcinoma (HCC) [31–33]. Also, HDV infection was associated with a 3-fold increased risk of HCC as compared with single HBV-infected patients [34]. In patients with HIV infection and hepatitis, the incidence of HCC was higher than in patients with HIV infection without hepatitis (adjusted HRZ5.07; 95%CIZ1.72–14.99; P!0.003) [35]. HCC is responsible for an increasing proportion of liverrelated deaths in HIV-infected patients; an increasing proportion of patients who died of liver disease had multiple hepatitis co-infection [36–38]. We have analysed the individual data of 41 patients with HIV and HCC recruited in Italy and Spain, and of 701 HCC in non-HIV patients recruited in Italy, who had been included in a multicentre clinical study [39]. HBV/HCV coinfection was present in 5 (12.1%) and in 33 (4.7%) cases, respectively. Interestingly, among the HIV positive patients, the age (meanGSD) of HBV/HCV co-infected cases (36.4G6.1) was younger than that observed in HCV or HBV mono-infected (44.2G7.1). A similar difference in age between groups of mono- and dual-infected patients was seen in the HIV-negative series of HCC patients, which is in keeping with another study [40]. Overall, these data indicate that dual or triple hepatitis co-infection in HIV positive patients causes a worse clinical prognosis. The potential confounding effect of other cofactors, particularly alcohol use and CD4 count, should be analysed in larger samples.
3. GBV-C co-infection Many people are infected with GBV-C, but no association between the virus and any known disease has been demonstrated (reviewed in Ref. [41]). Since the virus is transmitted parenterally or by sexual contact, a high prevalence was found in chronic hepatitis C and in HIVinfected patients. The presence of the virus in the blood is detected by seeking GBV-RNA; spontaneous or IFNinduced clearance of the virus is generally followed by the appearance in serum of antibodies against envelope E2 protein (anti-E2 antibodies). Two independent studies published in the year 2001 [42,43] showed an association between the presence of
GBV-C viraemia at baseline and a better survival or a delay in disease progression in HIV-infected patients. An inverse correlation between HIV and GBV-C viraemia was noted. In one study GBV-C was shown to inhibit HIV replication in PBMC cultures, measured by p24 antigen detection in supernatants [43]. Whether the presence of GBV-C is a true marker of better survival or a spurious association is not clear. In a recent paper, Bjorkman et al. [44] found that GBV-C viraemia tended to disappear without the appearance of antiE2 antibodies in patients with progressive HIV disease. Hence, the absence of GBV-C viraemia in patients with AIDS may be interpreted as a secondary phenomenon and not as a prognostic marker. Also the group of Iowa University noted that the poorest prognosis was associated with the loss of GBV-C viraemia during the observation period, but they did not discard a role for GBV-C as a prognostic marker for HIV progression [45,46]. A further point was suggested by Antonucci et al. [47], who found that GBV-C-infected patients on HAART had a lower risk of HIV rebound than those without GBV-C infection.
4. Occult HBV HBV infection may persist in the liver in the absence of circulating HBsAg, mostly in individuals with anti-HBc and/or anti-HBs in serum, but also in some patients negative for all serum markers of HBV. The gold standard for the diagnosis of occult HBV infection is the presence of HBVDNA in the liver tissue (reviewed in Refs. [48,49]). Up to 30% of the patients with chronic hepatitis C and 60% of HBsAg negative patients with HCC had occult HBV [50]. Studies in HIV-infected subjects sought occult HBV only in serum and found prevalences ranging from 0 to 45% [51– 55]. In HIV-infected patients with occult HBV, the lack of detectable HBsAg in serum was not due to an antigenically modified S protein that is not recognized by commercial kits [56]. One study found more severe liver histology in HIVinfected patients with HCV infection and isolated anti-HBc [51]. More research using standardized laboratory methods is needed to clarify the clinical significance of occult HBV in HIV-infected patients.
5. Treatment of multiple hepatitis co-infection Treating a patient with multiple hepatitis virus coinfection is a difficult decision since the data available are scanty and the results somewhat discouraging. 5.1. Hepatitis D So far, the only therapeutic agent that has been shown to have some activity against hepatitis D is interferon-a. From the studies on HIV-negative patients [57,58], we learned
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that the best results were obtained with high doses (9 MU three times weekly) for 1 year, a regimen that caused ALT normalization in about 50% of the patients in the 6 months following the end of therapy. However, clearance of HDVRNA was achieved in less than 10% of the cases. Interestingly, when normal ALT levels were maintained in the long-term period (which occurs in half of the patients with normal ALT in the post-therapy 6 month follow-up) a regression of fibrosis was documented [59]. HIV positive patients with chronic hepatitis D have been treated occasionally, often with a short-term follow-up [60– 62]. In an uncontrolled, open study [18] 16 HIV-infected patients with hepatitis D received 10 MU of recombinant interferon-a2b three times weekly for 6 months and 6 MU three times weekly for an additional 6 months. At the end of therapy, 19% of the patients had normal ALT but 2 years after stopping treatment only one patient showed persistent biochemical remission and absence of HDV RNA in serum with a liver biopsy showing histological improvement. In general, therapy may be attempted in patients without severe immune deficiency, with ALT elevation, HDV RNA in serum and severe histology. 5.2. HBV/HCV co-infection Treatment of hepatitis in patients with dual B/C infection has been based on the prevailing infection at the time of therapeutic decision. In HIV-negative patients with HCVRNA in serum and non-detectable HBV-DNA, higher doses of recombinant interferon-a (9 MU, three times weekly, for 6 months) achieved a better sustained response (31%) than 6 MU, three times weekly for 6 months [63]. Better results were achieved with the combination of interferon-a and ribavirin. A sustained response was seen in 9/21 patients (43%), but in 3 of them HBV reactivated [64]. There are few data available for patients with HIV infection. Treatment with interferon-a alone led to discouraging results [65]. Puoti et al. (personal communication) treated 11 patients with HIV and HCV/HBV co-infection (seven with cirrhosis), using as admission criteria the presence in serum of both HCV RNA and HBV-DNA, even if at low levels (O2000 IU/ml and O 615 copies/ml, respectively). All patients received weekly Peg-interferon-a2a at the standard dose and daily ribavirin for 1 year, plus an ART regimen containing lamivudine or tenofovir. Of eight assessable patients, only three had an end-of-treatment virological response, two of whom completed the post-therapy follow-up and both showed a virological relapse.
6. Conclusions HIV-infected patients should be tested for hepatitis B, C and D systematically and hepatitis B vaccination should be
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considered for those with HCV co-infection and the absence of HBV markers in serum. Several virological and clinical aspects of multiple viral infections in HIV-infected patients are still not completely understood. This is partly due to the small number of patients enrolled in each study; only multicentre studies will achieve adequate statistical power to improve our knowledge of multiple infections.
Acknowledgements GBG thanks Dr Massimo Puoti for his valuable advice.
References [1] Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000;356:1800–1805. [2] Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. J Am Med Assoc 2002; 288:199–206. [3] Lincoln D, Petoumenos K, Dore GJ, on behalf of the Australian HIV Observational Database. HIV/HBV and HIV/HCV co-infection, and outcomes following highly active antiretroviral therapy. HIV Med 2003;4:241–249. [4] Anderson KB, Guest JL, Rimland D. Hepatitis C virus co-infection 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;39:1507–1513. [5] Law WP, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, Lange JM, et al. Impact of viral hepatitis coinfection on response to antiretroviral therapy and HIV disease progression in the HIV–NAT cohort. AIDS 2004;18:1169–1177. [6] Rockstroh J, Konopnicki D, Soriano V. Hepatitis B and hepatitis C in the EuroSida cohort: prevalence and effect on mortality, AIDS progression and response to HAART. Eleventh conference on retroviruses and opportunistic infections; 2004. abs 799. [7] Thio C, Seaberg EC, Skolasky Jr R, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360:1921–1926. [8] Torriani FJ, Rodriguez-Torres M, Rockstroh JM, Lessen E, GonzalezGarcia J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C in HIV-infected patients. N Engl J Med 2004;351: 438–450. [9] Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. J Am Med Assoc 2004;292: 2839–2848. [10] Farci P. Delta hepatitis: an update. J Hepatol 2003;39:S212–S219. [11] Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, Lobello S, et al. Chronic hepatitis D: a vanishing disease? An Italian Multicenter Study. Hepatology 2000;32:824–827. [12] Sterling RK, Sulkowski MS. Hepatitis C Virus in the setting of HIV or hepatitis B virus co-infection. Semin Liver Dis 2004;24:61–68. [13] Novick DM, Farci P, Croxson TS, Taylor MB, Schneebaum CW, Lai ME, et al. Hepatitis D virus and human immunodeficiency virus antidodies in parenteral drug abusers who are hepatitis B surface antigen positive. J Infect Dis 1988;158:795–803.
S112
G.B. Gaeta et al. / Journal of Hepatology 44 (2006) S108–S113
[14] d’Arminio Monforte A, Cozzi- Lepri A, Rezza G, Pezzotti P, Antinori A, Phillips AN, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. ICONA Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS 2000;14:499–507. [15] Hadziyannis SJ, Sherman M, Lieberman HM, Shafritz DA. Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis b virus carriuers. Hepatology 1985;5: 544–547. [16] Chen PJ, Chen DS, Chen CR, Che YY, Chen HM, Lai MY, et al. Delta infection in asymptomatic carriers of hepatitis B surface antigen: low prevalence of delta acivity and effective suppression of hepatitis B virus replication. Hepatology 1988;8:1121–1124. [17] Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T, et al. Virological and clinical expressions of reciprocal inhibitory effect hepatitis B, C and Delta viruses in patients with chronic hepatitis. Hepatology 2000;32:1106–1110. [18] Puoti M, Rossi S, Forleo MA, Zaltron S, Spinetti A, Putzolu V, et al. Treatment of chronic hepatitis D with interferon alpha-2b in patients with human immunodeficiency virus infection. J Hepatol 1998;29: 45–52. [19] Pol S, Wesenfelder L, Dubois F, Roingeard P, Carnot F, Driss F, et al. Influence of human immunodeficiency virus infection on hepatitis delta virus superinfection in chronic HBsAg carriers. J Viral Hepat 1994;1:131–137. [20] Buti M, Jardi R, Allende H, Cotrina M, Rodriguez F, Viladomiu L, et al. Chronic delta hepatitis: is the prognosis worse when associated with hepatitis C and human immunodeficiency virus? J Med Virol 1996;49:66–69. [21] Sheen J-S, Liaw Y-F, Chu C-M, Pao CC. Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection. J Infect Dis 1992;165:831–834. [22] Pontisso P, Rivoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, et al. Clinical and virological profiles in patients with multiple hepatitis virus infection. Gastroenterology 1993;105:1529–1533. [23] Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology 1995;22:1101–1108. [24] Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, BostBesenzeaux F, et al. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol 1998;28:27–33. [25] Squadrito G, Orlando ME, Pollicino T, Raffa G, Restuccia T, Cacciola I, et al. Virological profiles in patients with chronic hepatitis C and overt or occult HBV infection. Am J Gastroenterol 2002;97:1518–1523. [26] Gaeta GB, Stornaiuolo G, Precone DF, Lobello S, Chiaramonte M, Stroffolini T, et al. Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A Multicenter Italian Study. J Hepatol 2003;39:1036–1041. [27] Raimondo G, Brunetto M, Pontisso P, Smedile A, Maina AM, Saitta C, et al. Longitudinal evaluation of virological profiles in HBV/HCV co-infected patients. An Italian Multicentre Study. Hepatology 2004;40 [Abs. 724]. [28] Puoti M, Spinetti A, Ghezzi A. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr 2000;24:211–217. [29] Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS 2004; 18:2039–2045. [30] De Luca A, Bugarini R, Cozzi-Lepri A, Puoti M, Girardi E, Antinori A, et al. Co-infection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 2002;162:2125–2132. [31] Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002;36: S35–S46. [32] El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74–S83.
[33] Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998;75:347–354. [34] Fattovich G, Giustina C, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. Gut 2000; 46:420–426. [35] Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without hepatitis C: a cohort study, 1992–2001. Arch Intern Med 2004;164:2349–2354. [36] Garcia-Samaniego J, Rodriguez M, Bereguer J, Rodriguez-Rosado R, Carbo` J, Asensi V, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol 2001;96: 179–183. [37] Rosenthal E, Poiree M, Pradier C, Perronne C, Salmon-Ceron C, Geffray L, et al. Mortality due to hepatitis-C related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17:1803–1809. [38] Cacoub P, Geffray L, Rosenthal E, Perronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French departments of internal medicine/infectious diseases, in 1995 and 1997. Clin Infect Dis 2001;32:1207–1214. [39] Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004;18: 2285–2293. [40] Gelatti U, Donato F, Tagger A, Fantoni C, Portolani N, Ribero ML, et al. Etiology of hepatocellular carcinoma influences clinical and pathologic features but not patient survival. Am J Gastroenterol 2003; 98:907–914. [41] Stapleton JT. GB virus typeC/hepatitis G virus. Semin Liver Dis 2003; 23:137–148. [42] Tillmann HL, Heiken H, Knapik-Botor A, Heringlake S, Ockenga J, Wilber J, et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N Engl J Med 2001;345:715–724. [43] Xiang J, Wunschumann S, Diekema DJ, Klinzman D, Patick KD, George SL, et al. Effect of co-infection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707–714. [44] Bjorkman P, Flamholc L, Naucler A, Molnegren V, Wallmark E, Widell A. GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality. AIDS 2004;18: 877–886. [45] Williams CF, Klinzman D, Yamashita TE, Xiang J, Polgreen PM, Rinaldo C, et al. Persistent GB virus C infection and survival in HIVinfected men. N Engl J Med 2004;350:981–990. [46] Pomerantz RJ, Nunneri G. HIV and GB virus C—can two viruses be better than one? N Engl J Med 2004;350:963–965. [47] Antonucci G, Girardi E, Cozzi-Lepri A, Capobianchi MR, Morsica G, Pizzaferri P, et al. Response to HAART and GB virus type C coinfection in a cohort of antiretroviral naive HIV-co-infected individuals. Antiviral Ther 2005;10:109–117. [48] Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, PaterliniBrechot P. Persistent hepatitis B infection in subjects without hepatitis B surface antigen: clinically significant or purely ‘occult’? Hepatology 2001;34:194–203. [49] Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002;2:479–486. [50] Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi A, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126:102–110. [51] Piroth L, Binquet C, Vergne M, Minello A, Livry C, Bour JB, et al. The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients. J Hepatol 2002;36:681–686.
G.B. Gaeta et al. / Journal of Hepatology 44 (2006) S108–S113 [52] Nunez M, Ry´os P, Perez-Olmeda M, Soriano V. Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients. AIDS 2002;16: 2099–2100. [53] Shire NJ, Rouster SD, Rajicic N, Sherman KE. Occult hepatitis B in HIVinfected patients. J Acquir Immune Defic Syndr 2004;36:869–875. [54] Santos EA, Yoshida CF, Rolla VC, Mendes JM, Vieira IF, Arabe J, et al. Frequent occult hepatitis B virus infection in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2003;22:92–98. [55] Torbenson M, Kannangai R, Astemborski J, Strathdee SA, Vlahov D, Thomas DL. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology 2004;39:51–57. [56] Wagner AA, Denis F, Weinbreck P, Loustaud V, Autofage F, Rogez S, et al. Serological pattern ‘anti-hepatitis B core alone’ in HIV or hepatitis C virus-infected patients is not fully explained by hepatitis B surface antigen mutants. AIDS 2004;18:569–571. [57] Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized controlled trial of a 12-month course of recombinant human IFN-alfa in chronic delta (type D) hepatitis: a Multicentric Italian Study. Hepatology 1991;13:1052–1056. [58] Farci P, Mandas A, Coiana A, Lai ME, Desmet V, Van Eyken P, et al. Treatment of chronic hepatitis D with IFN alpha-2a. N Engl J Med 1994;330:88–94. [59] Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic
[60] [61]
[62]
[63]
[64]
[65]
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hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004;126:1740–1749. Taillan B, Fuzibert JG, Vinti H, Pesce A, Cassuto JP, Dujardin P. IFN and delta hepatitis. Ann Intern Med 1988;111:160. Madejon A, Cotonat T, Bartolome´ J, Castillo I, Carreno V. Treatment of chronic hepatitis D virus infection with low and high doses of IFN alfa-2a: utility of polymerase chain reaction in monitoring antiviral response. Hepatology 1994;19:1331–1336. Buti M, Esteban R, Jardi R, Rodriguez-Frias F, Allende H, Cotrina M, et al. Treatment of chronic type D hepatitis and concomitant human immunodeficiency infection with alpha-interferon. J Hepatol 1992;14: 412–413. Villa E, Grottola A, Buttafuoco P, Colantoni A, Bagni A, Ferretti I, et al. High doses of alpha-interferon are required in chronic hepatitis due to co-infection with hepatitis B virus and hepatitis C virus: long term results of a prospective randomized trial. Am J Gastroenterol 2001;96:2973–2977. Liu C-J, Chen P-J, Lai M-Y, Kao J-H, Jeng Y-M, Chen D-S. Ribavirin and Interferon is effective for hepatitis C virus clearence in hepatitis B and C dually infected patients. Hepatology 2003;37:568–576. Weltman MD, Brotodihardjo A, Crewe EB, Farrell GC, Bilous M, Grierson JM, et al. Co-infection with hepatitis B and C or B,C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment. J Viral Hepat 1995;2:39–45.
Multiple viral infections Giovanni B. Gaeta1,*, Davide F. Precone1, Alessandro Cozzi-Lepri2, Paola Cicconi3, Antonella D’Arminio Monforte3 1
Department of Infectious Diseases, Viral Hepatitis Unit, Second University of Naples, Naples 80135, Italy 2 Royal Free and University College Medical School, London, UK 3 Institute of Infectious and Tropical Diseases, University of Milan, Milan, Italy
Individuals at risk of HIV are concomitantly at risk of acquiring parenterally or sexually transmitted viruses. Multiple hepatitis co-infection (HBVCHCV; HBVCHDV; HBVCHDVCHCV) has not been systematically sought after in the large cohorts of HIV-infected patients, but has been reported in 0.4% to more than 50% of patients. HIVinfected patients with multiple hepatitis have a higher rate of liver-related morbidity and mortality than patients with HIV infection alone or with a single hepatitis co-infection. The degree of immunodepression is an important factor in liver disease progression. Since GBV-C virus is transmitted parenterally or by sexual contact, a high prevalence was found in chronic hepatitis C and in HIV-infected patients. Patients with multiple hepatitis have been excluded from randomised therapeutic trials of viral hepatitis in HIV-infected and HIV-negative patients. Thus, the therapeutic approach is based on the results of a small series and empirically oriented toward the prevailing infection. HIV-infected patients should be tested for hepatitis B, C and D systematically and hepatitis B vaccination should be considered for those with HCV co-infection and absence of HBV markers. Studies are needed to assess treatment strategies. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Hepatitis C; Hepatitis B; Hepatitis D; HIV; Multiple infection 1. Introduction Individuals at risk for HIV are concomitantly at risk for acquiring parenterally transmitted viruses. Thus, a high prevalence of multiple hepatitis co-infections (i.e. infection with two or more hepatitis viruses) may be expected among HIV-infected subjects. This statement, although sounding acceptable, has rarely been verified in analyses of clinical data. Indeed, the presence of multiple hepatitis co-infections in the large series of HIV-infected patients is overshadowed by the huge number of single hepatitis C virus (HCV) co-infections [1–6] or hepatitis B virus (HBV) co-infection [7]. In addition, therapeutic trials of chronic viral hepatitis rigorously exclude dual or triple hepatitis co-infections [8,9]. We have reviewed the data available on multiple hepatitis infection in the literature and we have analysed
* Corresponding author. Tel.: C39 081 566 6208; fax: C39 081 566 6206. E-mail address: [email protected] (G.B. Gaeta).
the individual data from some case studies to cover the epidemiological, clinical and therapeutic aspects of multiple HBV, hepatitis D virus (HDV) and HCV infections in HIV patients. Moreover, we reviewed the data on GBV-C coinfection and its impact on HIV disease progression both in antiretroviral naive and treated patients.
2. Epidemiology and natural history of multiple hepatitis co-infections The proportion of patients with multiple hepatitis co-infections (HBVCHCV, HBVCHDV, or HCVCHBV CHDV) depends on the environmental and clinical setting. In general, there is a North to South gradient in Europe in the proportion of HIV patients with hepatitis co-infection [6]; multiple co-infection may be expected more frequently in the Mediterranean area, particularly HBV/HDV coinfection, reflecting the epidemiological background of the disease [10,11]. Patients with a history of intravenuous drug use (IDU) generally present dual or triple infection more
0168-8278/$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.11.023
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often than patients whose risk factor was sexual behaviour [12,13]. Both in HIV-positive or -negative cohorts, the presence of HBV/HCV, HBV/HDV or triple hepatitis infection was strongly associated to IDU. Overall, 0.4% to more than 50% of HIV patients may carry more than one hepatitis virus, depending on the geographical origin and type of risk exposure [1–6]. We have analysed individual data of 387 HBsAg positive, HIV positive patients recruited from the Italian cohort naive from antiretrovirals (I.Co.N.A.), a cohort that was set up in 1997 and includes patients consecutively enrolled from 69 departments of infectious diseases all over Italy; to be recruited, patients have to be naive to antiretroviral treatment, irrespective of the reason for being so. More details of the I.Co.N.A cohort study are given elsewhere [14]. A variable proportion of these patients had also been tested for other hepatitis viruses before or at the same time as being tested for anti-HBV antibodies. For the purpose of comparison, we used a cohort of 800 HBsAg positive, HIV-negative patients, recruited in a multicentre survey [11]. Table 1 reports the proportions of HCV, HDV and HCV plus HDV infections recorded in these two populations of HBsAg-positive patients according to whether intravenuous drug use was the mode of acquiring HIV and the cohort of origin (I.Co.N.A. or HIVnegative cohort). It is clear from Table 1 that the prevalence of multiple hepatitis infections was much higher in intravenous drug users compared to patients who acquired these infections through other routes, independent of HIV sero-status. Viral interaction between the hepatitis viruses has been described firstly in non-HIV-infected settings. The inhibition of HBV replication by HDV is well known and its clinical consequence is the exceptional presence of HBeAg and clinically significant serum HBV DNA level [15–17]. In a study of 16 HIV-positive patients with HDV chronic hepatitis, documented by the presence of HDV-RNA in serum, only one of them at enrolment had detectable HBV DNA in serum by PCR [18]. This proportion did not appear to be different in 21 HIV-negative HDV-positive patients enrolled in the same study. Although these data suggest that the inhibition of HBV by HDV occurs also in HIV
co-infection, we should note that the focus of this study was IFN treatment, thus only patients with non-advanced HIV disease were included (the mean CD4 cell count/mm3 was 622G284). In patients with more advanced HIV disease and HDV coinfection, HDAg was detected in serum in one-third of the cases and HBV-DNA in 25%. Thus, HIV infection seemed to favour HDV replication and to counter the inhibitory effect of HDV on HBV replication [19]. Interestingly, in this study the degree of liver inflammation and fibrosis was similar in the HIV-positive vs. the HIV-negative group with hepatitis delta. Buti et al. [20] suggested that the clinical prognosis of hepatitis delta in HIV-infected patients was worse when it was associated with hepatitis C. Reciprocal interaction of HBV and HCV has been investigated in several studies in HIV-negative patients [21– 26], but there are few data in HIV infection. A superimposed virus tends to suppress the replication of a pre-existing virus, at least initially. However, almost all studies that examined viral interactions were cross-sectional, giving, therefore, an instant picture. Only in one study, to date published in abstract form [27], a group of HIV-negative patients with dual HBV/HCV infection have been followedup for 1 year and the authors found that in about 30% of the cases the replicative status of each virus may change spontaneously. This approach may be relevant to HIV positive, HBV/HCV co-infected patients, in whom the degree of immunosuppression changes over time as a consequence of natural progression and/or use of antiretroviral treatment. HIV patients with dual hepatitis B/C infection have a worse clinical prognosis than HIV mono-infected or coinfected with a single hepatitis virus. Of 35 HIV/HBV coinfected patients who died in hospital of liver failure during pre-HAART period, 33/35 were HCV co-infected [28]. Bonacini et al. [29] prospectively followed-up 472 HIV positive patients referred for abnormal liver function tests, 18 (3.8%) of whom had dual or triple hepatitis co-infection and 328 (69.5%) were hepatitis B or C mono-infected. The crude mortality rate due to liver disease was 28% in the
Table 1 HCV and HDV co-infections in HBsAg-positive patients according to injecting drug use
Non-IDU HCVK HDVK HCVC HDVK HDVK HDVC HCVC HDVC HCV and/or HDV not tested IDU HCVK HDVK HCVC HDVK HDVK HDVC HCVC HDVC HCV and/or HDV not tested
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HIV-negative cohort (nZ800)
HIV-positive cohort (nZ387)
nZ790 646 (81.7%) 55 (6.9%) 49 (6.2%) 4 (0.51%) 36 (4.6%) nZ10 3 (30.0%) 2 (20.0%) 3 (30.0%) 2 (20.0%) 0 (0.0%)
nZ223 84 (37.7%) 16 (7.2%) 10 (4.5%) 5 (2.2%) 108 (48.4%) nZ164 8 (4.9%) 3 (1.8%) 35 (21.3%) 46 (28.1%) 72 (43.9%)
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multiple hepatitis group vs. 6% in HIV mono-infected and 15 and 13% in hepatitis B or C single infections, respectively. Interestingly, De Luca et al. [30] found that in HIV-infected patients on potent antiretroviral treatment, the presence of double HBV/HCV or single HCV infection was associated with less intense CD4 recoveries than those observed in patients without hepatitis. In 366 HIV/HCV co-infected patients Puoti et al. (personal communication) found that F3–F4 fibrosis was significantly associated with triple HBV/HDV/HCV infection (age adjusted ORZ4.5; 95%CIZ2–9.5). Patients with HBV/HCV co-infection and cirrhosis are a subset of patients at a very high risk for hepatocellular carcinoma (HCC) [31–33]. Also, HDV infection was associated with a 3-fold increased risk of HCC as compared with single HBV-infected patients [34]. In patients with HIV infection and hepatitis, the incidence of HCC was higher than in patients with HIV infection without hepatitis (adjusted HRZ5.07; 95%CIZ1.72–14.99; P!0.003) [35]. HCC is responsible for an increasing proportion of liverrelated deaths in HIV-infected patients; an increasing proportion of patients who died of liver disease had multiple hepatitis co-infection [36–38]. We have analysed the individual data of 41 patients with HIV and HCC recruited in Italy and Spain, and of 701 HCC in non-HIV patients recruited in Italy, who had been included in a multicentre clinical study [39]. HBV/HCV coinfection was present in 5 (12.1%) and in 33 (4.7%) cases, respectively. Interestingly, among the HIV positive patients, the age (meanGSD) of HBV/HCV co-infected cases (36.4G6.1) was younger than that observed in HCV or HBV mono-infected (44.2G7.1). A similar difference in age between groups of mono- and dual-infected patients was seen in the HIV-negative series of HCC patients, which is in keeping with another study [40]. Overall, these data indicate that dual or triple hepatitis co-infection in HIV positive patients causes a worse clinical prognosis. The potential confounding effect of other cofactors, particularly alcohol use and CD4 count, should be analysed in larger samples.
3. GBV-C co-infection Many people are infected with GBV-C, but no association between the virus and any known disease has been demonstrated (reviewed in Ref. [41]). Since the virus is transmitted parenterally or by sexual contact, a high prevalence was found in chronic hepatitis C and in HIVinfected patients. The presence of the virus in the blood is detected by seeking GBV-RNA; spontaneous or IFNinduced clearance of the virus is generally followed by the appearance in serum of antibodies against envelope E2 protein (anti-E2 antibodies). Two independent studies published in the year 2001 [42,43] showed an association between the presence of
GBV-C viraemia at baseline and a better survival or a delay in disease progression in HIV-infected patients. An inverse correlation between HIV and GBV-C viraemia was noted. In one study GBV-C was shown to inhibit HIV replication in PBMC cultures, measured by p24 antigen detection in supernatants [43]. Whether the presence of GBV-C is a true marker of better survival or a spurious association is not clear. In a recent paper, Bjorkman et al. [44] found that GBV-C viraemia tended to disappear without the appearance of antiE2 antibodies in patients with progressive HIV disease. Hence, the absence of GBV-C viraemia in patients with AIDS may be interpreted as a secondary phenomenon and not as a prognostic marker. Also the group of Iowa University noted that the poorest prognosis was associated with the loss of GBV-C viraemia during the observation period, but they did not discard a role for GBV-C as a prognostic marker for HIV progression [45,46]. A further point was suggested by Antonucci et al. [47], who found that GBV-C-infected patients on HAART had a lower risk of HIV rebound than those without GBV-C infection.
4. Occult HBV HBV infection may persist in the liver in the absence of circulating HBsAg, mostly in individuals with anti-HBc and/or anti-HBs in serum, but also in some patients negative for all serum markers of HBV. The gold standard for the diagnosis of occult HBV infection is the presence of HBVDNA in the liver tissue (reviewed in Refs. [48,49]). Up to 30% of the patients with chronic hepatitis C and 60% of HBsAg negative patients with HCC had occult HBV [50]. Studies in HIV-infected subjects sought occult HBV only in serum and found prevalences ranging from 0 to 45% [51– 55]. In HIV-infected patients with occult HBV, the lack of detectable HBsAg in serum was not due to an antigenically modified S protein that is not recognized by commercial kits [56]. One study found more severe liver histology in HIVinfected patients with HCV infection and isolated anti-HBc [51]. More research using standardized laboratory methods is needed to clarify the clinical significance of occult HBV in HIV-infected patients.
5. Treatment of multiple hepatitis co-infection Treating a patient with multiple hepatitis virus coinfection is a difficult decision since the data available are scanty and the results somewhat discouraging. 5.1. Hepatitis D So far, the only therapeutic agent that has been shown to have some activity against hepatitis D is interferon-a. From the studies on HIV-negative patients [57,58], we learned
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that the best results were obtained with high doses (9 MU three times weekly) for 1 year, a regimen that caused ALT normalization in about 50% of the patients in the 6 months following the end of therapy. However, clearance of HDVRNA was achieved in less than 10% of the cases. Interestingly, when normal ALT levels were maintained in the long-term period (which occurs in half of the patients with normal ALT in the post-therapy 6 month follow-up) a regression of fibrosis was documented [59]. HIV positive patients with chronic hepatitis D have been treated occasionally, often with a short-term follow-up [60– 62]. In an uncontrolled, open study [18] 16 HIV-infected patients with hepatitis D received 10 MU of recombinant interferon-a2b three times weekly for 6 months and 6 MU three times weekly for an additional 6 months. At the end of therapy, 19% of the patients had normal ALT but 2 years after stopping treatment only one patient showed persistent biochemical remission and absence of HDV RNA in serum with a liver biopsy showing histological improvement. In general, therapy may be attempted in patients without severe immune deficiency, with ALT elevation, HDV RNA in serum and severe histology. 5.2. HBV/HCV co-infection Treatment of hepatitis in patients with dual B/C infection has been based on the prevailing infection at the time of therapeutic decision. In HIV-negative patients with HCVRNA in serum and non-detectable HBV-DNA, higher doses of recombinant interferon-a (9 MU, three times weekly, for 6 months) achieved a better sustained response (31%) than 6 MU, three times weekly for 6 months [63]. Better results were achieved with the combination of interferon-a and ribavirin. A sustained response was seen in 9/21 patients (43%), but in 3 of them HBV reactivated [64]. There are few data available for patients with HIV infection. Treatment with interferon-a alone led to discouraging results [65]. Puoti et al. (personal communication) treated 11 patients with HIV and HCV/HBV co-infection (seven with cirrhosis), using as admission criteria the presence in serum of both HCV RNA and HBV-DNA, even if at low levels (O2000 IU/ml and O 615 copies/ml, respectively). All patients received weekly Peg-interferon-a2a at the standard dose and daily ribavirin for 1 year, plus an ART regimen containing lamivudine or tenofovir. Of eight assessable patients, only three had an end-of-treatment virological response, two of whom completed the post-therapy follow-up and both showed a virological relapse.
6. Conclusions HIV-infected patients should be tested for hepatitis B, C and D systematically and hepatitis B vaccination should be
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considered for those with HCV co-infection and the absence of HBV markers in serum. Several virological and clinical aspects of multiple viral infections in HIV-infected patients are still not completely understood. This is partly due to the small number of patients enrolled in each study; only multicentre studies will achieve adequate statistical power to improve our knowledge of multiple infections.
Acknowledgements GBG thanks Dr Massimo Puoti for his valuable advice.
References [1] Greub G, Ledergerber B, Battegay M, Grob P, Perrin L, Furrer H, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study. Lancet 2000;356:1800–1805. [2] Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. J Am Med Assoc 2002; 288:199–206. [3] Lincoln D, Petoumenos K, Dore GJ, on behalf of the Australian HIV Observational Database. HIV/HBV and HIV/HCV co-infection, and outcomes following highly active antiretroviral therapy. HIV Med 2003;4:241–249. [4] Anderson KB, Guest JL, Rimland D. Hepatitis C virus co-infection 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;39:1507–1513. [5] Law WP, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, Lange JM, et al. Impact of viral hepatitis coinfection on response to antiretroviral therapy and HIV disease progression in the HIV–NAT cohort. AIDS 2004;18:1169–1177. [6] Rockstroh J, Konopnicki D, Soriano V. Hepatitis B and hepatitis C in the EuroSida cohort: prevalence and effect on mortality, AIDS progression and response to HAART. Eleventh conference on retroviruses and opportunistic infections; 2004. abs 799. [7] Thio C, Seaberg EC, Skolasky Jr R, Phair J, Visscher B, Munoz A, et al. HIV-1, hepatitis B virus and risk of liver-related mortality in the Multicenter Cohort Study (MACS). Lancet 2002;360:1921–1926. [8] Torriani FJ, Rodriguez-Torres M, Rockstroh JM, Lessen E, GonzalezGarcia J, Lazzarin A, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C in HIV-infected patients. N Engl J Med 2004;351: 438–450. [9] Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. J Am Med Assoc 2004;292: 2839–2848. [10] Farci P. Delta hepatitis: an update. J Hepatol 2003;39:S212–S219. [11] Gaeta GB, Stroffolini T, Chiaramonte M, Ascione T, Stornaiuolo G, Lobello S, et al. Chronic hepatitis D: a vanishing disease? An Italian Multicenter Study. Hepatology 2000;32:824–827. [12] Sterling RK, Sulkowski MS. Hepatitis C Virus in the setting of HIV or hepatitis B virus co-infection. Semin Liver Dis 2004;24:61–68. [13] Novick DM, Farci P, Croxson TS, Taylor MB, Schneebaum CW, Lai ME, et al. Hepatitis D virus and human immunodeficiency virus antidodies in parenteral drug abusers who are hepatitis B surface antigen positive. J Infect Dis 1988;158:795–803.
S112
G.B. Gaeta et al. / Journal of Hepatology 44 (2006) S108–S113
[14] d’Arminio Monforte A, Cozzi- Lepri A, Rezza G, Pezzotti P, Antinori A, Phillips AN, et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. ICONA Study Group. Italian Cohort of Antiretroviral-Naive Patients. AIDS 2000;14:499–507. [15] Hadziyannis SJ, Sherman M, Lieberman HM, Shafritz DA. Liver disease activity and hepatitis B virus replication in chronic delta antigen-positive hepatitis b virus carriuers. Hepatology 1985;5: 544–547. [16] Chen PJ, Chen DS, Chen CR, Che YY, Chen HM, Lai MY, et al. Delta infection in asymptomatic carriers of hepatitis B surface antigen: low prevalence of delta acivity and effective suppression of hepatitis B virus replication. Hepatology 1988;8:1121–1124. [17] Sagnelli E, Coppola N, Scolastico C, Filippini P, Santantonio T, Stroffolini T, et al. Virological and clinical expressions of reciprocal inhibitory effect hepatitis B, C and Delta viruses in patients with chronic hepatitis. Hepatology 2000;32:1106–1110. [18] Puoti M, Rossi S, Forleo MA, Zaltron S, Spinetti A, Putzolu V, et al. Treatment of chronic hepatitis D with interferon alpha-2b in patients with human immunodeficiency virus infection. J Hepatol 1998;29: 45–52. [19] Pol S, Wesenfelder L, Dubois F, Roingeard P, Carnot F, Driss F, et al. Influence of human immunodeficiency virus infection on hepatitis delta virus superinfection in chronic HBsAg carriers. J Viral Hepat 1994;1:131–137. [20] Buti M, Jardi R, Allende H, Cotrina M, Rodriguez F, Viladomiu L, et al. Chronic delta hepatitis: is the prognosis worse when associated with hepatitis C and human immunodeficiency virus? J Med Virol 1996;49:66–69. [21] Sheen J-S, Liaw Y-F, Chu C-M, Pao CC. Role of hepatitis C virus infection in spontaneous hepatitis B surface antigen clearance during chronic hepatitis B virus infection. J Infect Dis 1992;165:831–834. [22] Pontisso P, Rivoletto MG, Fattovich G, Chemello L, Gallorini A, Ruol A, et al. Clinical and virological profiles in patients with multiple hepatitis virus infection. Gastroenterology 1993;105:1529–1533. [23] Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology 1995;22:1101–1108. [24] Zarski JP, Bohn B, Bastie A, Pawlotsky JM, Baud M, BostBesenzeaux F, et al. Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol 1998;28:27–33. [25] Squadrito G, Orlando ME, Pollicino T, Raffa G, Restuccia T, Cacciola I, et al. Virological profiles in patients with chronic hepatitis C and overt or occult HBV infection. Am J Gastroenterol 2002;97:1518–1523. [26] Gaeta GB, Stornaiuolo G, Precone DF, Lobello S, Chiaramonte M, Stroffolini T, et al. Epidemiological and clinical burden of chronic hepatitis B virus/hepatitis C virus infection. A Multicenter Italian Study. J Hepatol 2003;39:1036–1041. [27] Raimondo G, Brunetto M, Pontisso P, Smedile A, Maina AM, Saitta C, et al. Longitudinal evaluation of virological profiles in HBV/HCV co-infected patients. An Italian Multicentre Study. Hepatology 2004;40 [Abs. 724]. [28] Puoti M, Spinetti A, Ghezzi A. Mortality for liver disease in patients with HIV infection: a cohort study. J Acquir Immune Defic Syndr 2000;24:211–217. [29] Bonacini M, Louie S, Bzowej N, Wohl AR. Survival in patients with HIV infection and viral hepatitis B or C: a cohort study. AIDS 2004; 18:2039–2045. [30] De Luca A, Bugarini R, Cozzi-Lepri A, Puoti M, Girardi E, Antinori A, et al. Co-infection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 2002;162:2125–2132. [31] Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002;36: S35–S46. [32] El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology 2002;36:S74–S83.
[33] Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer 1998;75:347–354. [34] Fattovich G, Giustina C, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. Gut 2000; 46:420–426. [35] Giordano TP, Kramer JR, Souchek J, Richardson P, El-Serag HB. Cirrhosis and hepatocellular carcinoma in HIV-infected veterans with and without hepatitis C: a cohort study, 1992–2001. Arch Intern Med 2004;164:2349–2354. [36] Garcia-Samaniego J, Rodriguez M, Bereguer J, Rodriguez-Rosado R, Carbo` J, Asensi V, et al. Hepatocellular carcinoma in HIV-infected patients with chronic hepatitis C. Am J Gastroenterol 2001;96: 179–183. [37] Rosenthal E, Poiree M, Pradier C, Perronne C, Salmon-Ceron C, Geffray L, et al. Mortality due to hepatitis-C related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17:1803–1809. [38] Cacoub P, Geffray L, Rosenthal E, Perronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French departments of internal medicine/infectious diseases, in 1995 and 1997. Clin Infect Dis 2001;32:1207–1214. [39] Puoti M, Bruno R, Soriano V, Donato F, Gaeta GB, Quinzan GP, et al. Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome. AIDS 2004;18: 2285–2293. [40] Gelatti U, Donato F, Tagger A, Fantoni C, Portolani N, Ribero ML, et al. Etiology of hepatocellular carcinoma influences clinical and pathologic features but not patient survival. Am J Gastroenterol 2003; 98:907–914. [41] Stapleton JT. GB virus typeC/hepatitis G virus. Semin Liver Dis 2003; 23:137–148. [42] Tillmann HL, Heiken H, Knapik-Botor A, Heringlake S, Ockenga J, Wilber J, et al. Infection with GB virus C and reduced mortality among HIV-infected patients. N Engl J Med 2001;345:715–724. [43] Xiang J, Wunschumann S, Diekema DJ, Klinzman D, Patick KD, George SL, et al. Effect of co-infection with GB virus C on survival among patients with HIV infection. N Engl J Med 2001;345:707–714. [44] Bjorkman P, Flamholc L, Naucler A, Molnegren V, Wallmark E, Widell A. GB virus C during the natural course of HIV-1 infection: viremia at diagnosis does not predict mortality. AIDS 2004;18: 877–886. [45] Williams CF, Klinzman D, Yamashita TE, Xiang J, Polgreen PM, Rinaldo C, et al. Persistent GB virus C infection and survival in HIVinfected men. N Engl J Med 2004;350:981–990. [46] Pomerantz RJ, Nunneri G. HIV and GB virus C—can two viruses be better than one? N Engl J Med 2004;350:963–965. [47] Antonucci G, Girardi E, Cozzi-Lepri A, Capobianchi MR, Morsica G, Pizzaferri P, et al. Response to HAART and GB virus type C coinfection in a cohort of antiretroviral naive HIV-co-infected individuals. Antiviral Ther 2005;10:109–117. [48] Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, PaterliniBrechot P. Persistent hepatitis B infection in subjects without hepatitis B surface antigen: clinically significant or purely ‘occult’? Hepatology 2001;34:194–203. [49] Torbenson M, Thomas DL. Occult hepatitis B. Lancet Infect Dis 2002;2:479–486. [50] Pollicino T, Squadrito G, Cerenzia G, Cacciola I, Raffa G, Craxi A, et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004;126:102–110. [51] Piroth L, Binquet C, Vergne M, Minello A, Livry C, Bour JB, et al. The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients. J Hepatol 2002;36:681–686.
G.B. Gaeta et al. / Journal of Hepatology 44 (2006) S108–S113 [52] Nunez M, Ry´os P, Perez-Olmeda M, Soriano V. Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients. AIDS 2002;16: 2099–2100. [53] Shire NJ, Rouster SD, Rajicic N, Sherman KE. Occult hepatitis B in HIVinfected patients. J Acquir Immune Defic Syndr 2004;36:869–875. [54] Santos EA, Yoshida CF, Rolla VC, Mendes JM, Vieira IF, Arabe J, et al. Frequent occult hepatitis B virus infection in patients infected with human immunodeficiency virus type 1. Eur J Clin Microbiol Infect Dis 2003;22:92–98. [55] Torbenson M, Kannangai R, Astemborski J, Strathdee SA, Vlahov D, Thomas DL. High prevalence of occult hepatitis B in Baltimore injection drug users. Hepatology 2004;39:51–57. [56] Wagner AA, Denis F, Weinbreck P, Loustaud V, Autofage F, Rogez S, et al. Serological pattern ‘anti-hepatitis B core alone’ in HIV or hepatitis C virus-infected patients is not fully explained by hepatitis B surface antigen mutants. AIDS 2004;18:569–571. [57] Rosina F, Pintus C, Meschievitz C, Rizzetto M. A randomized controlled trial of a 12-month course of recombinant human IFN-alfa in chronic delta (type D) hepatitis: a Multicentric Italian Study. Hepatology 1991;13:1052–1056. [58] Farci P, Mandas A, Coiana A, Lai ME, Desmet V, Van Eyken P, et al. Treatment of chronic hepatitis D with IFN alpha-2a. N Engl J Med 1994;330:88–94. [59] Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon alpha therapy of chronic
[60] [61]
[62]
[63]
[64]
[65]
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hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology 2004;126:1740–1749. Taillan B, Fuzibert JG, Vinti H, Pesce A, Cassuto JP, Dujardin P. IFN and delta hepatitis. Ann Intern Med 1988;111:160. Madejon A, Cotonat T, Bartolome´ J, Castillo I, Carreno V. Treatment of chronic hepatitis D virus infection with low and high doses of IFN alfa-2a: utility of polymerase chain reaction in monitoring antiviral response. Hepatology 1994;19:1331–1336. Buti M, Esteban R, Jardi R, Rodriguez-Frias F, Allende H, Cotrina M, et al. Treatment of chronic type D hepatitis and concomitant human immunodeficiency infection with alpha-interferon. J Hepatol 1992;14: 412–413. Villa E, Grottola A, Buttafuoco P, Colantoni A, Bagni A, Ferretti I, et al. High doses of alpha-interferon are required in chronic hepatitis due to co-infection with hepatitis B virus and hepatitis C virus: long term results of a prospective randomized trial. Am J Gastroenterol 2001;96:2973–2977. Liu C-J, Chen P-J, Lai M-Y, Kao J-H, Jeng Y-M, Chen D-S. Ribavirin and Interferon is effective for hepatitis C virus clearence in hepatitis B and C dually infected patients. Hepatology 2003;37:568–576. Weltman MD, Brotodihardjo A, Crewe EB, Farrell GC, Bilous M, Grierson JM, et al. Co-infection with hepatitis B and C or B,C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment. J Viral Hepat 1995;2:39–45.