Hepatitis C Virus(HCV) Genotypes and Disease Progression in HIV/HCV-Coinfected Patients
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spai
Six major hepatitis C virus (HCV) genotypes have been described, and HCV genotypes 14 are the predominant circulating genotypes in Western countries [1]. These genotypes show a distinct geographic distribution, as well as a different susceptibility to interferon (IFN)based therapies [1]. Only recently have other differences between HCV genotypes been appreciated (table 1). For example, patients carrying HCV genotype 2 and with normal levels of transaminases are at higher risk for experiencing alanine aminotransferase (ALT) flares; however, they have the best response to IFN-based therapies [2]. On the other hand, patients infected with HCV genotype 3 show the highest rate of spontaneous clearance but may show faster liver-fibrosis progression, often accompanied by liver steatosis; however, they tend to respond well to IFN-based therapies [35]. Finally, chronic infection seems to be more frequent in patients after acute infection with HCV genotype 4, and these patients tend to respond less well to IFN-based therapies [6, 7].
In North America, Japan, and western Europe, HCV genotype 1 is by far the predominant HCV genotype [1]. Since the introduction of HCV serological tests in the early 1990s, HCV transmission through blood transfusions and other medical interventions has declined sharply, and, currently, needle sharing among injection drug users (IDUs) represents the major mechanism of acquisition of HCV in the developed world [8]. Given that HCV and HIV share routes of transmission, it is not surprising that the IDU population is largely coinfected with both viruses [9]. In this issue of The Journal of Infectious Diseases, Yoo et al. suggest that coinfection with HCV genotype 1 might have a more deleterious effect on the progression of HIV-1 disease than does coinfection with other HCV genotypes [10].
Since the introduction of highly active antiretroviral therapy (HAART), liver-related complications have emerged as an important cause of hospital admission and death in HIV-infected individuals in the developed world [1114]. Classical opportunistic infections are now less frequent, and, conversely, complications of end-stage liver diseasemainly due to HCV infectionare on the rise [15, 16]. There is no doubt that this is due, in part, to the faster progression to liver cirrhosis seen in HIV/HCV-coinfected patients [17]. This accelerated course of hepatitis C and the higher risk for liver toxicity after beginning to take antiretroviral drugs in HIV/HCV-coinfected patients are the 2 main reasons why HCV therapy is now considered to be a priority in this population [18].
What is not so clear is whether HCV infection influences HIV disease progression. Initial reports claimed that there is an increased risk for progression to clinical AIDS in HIV/HCV-coinfected patients [19, 20], but this finding has not been confirmed by more-recent studies [2123]. Some studies have shown significantly lower CD4+ T cell counts in HIV/HCV-coinfected patients, compared with those in HIV-monoinfected patients, despite similar HIV RNA levels [16, 24], but another study failed to show any difference [23]. Disagreement also exists when assessment is made of the ability of the immune system to recover after antiretroviral therapy. Although initial studies underlined that increases in CD4+ T cell counts might be blunted in HIV/HCV-coinfected patients [20, 25], similar increases in CD4+ T cell counts, compared with those in HIV-monoinfected patients, have been observed by other studies [22, 2628].
Yoo et al. have reported lower CD4+ T cell counts in HIV-1/HCVcoinfected hemophiliacs carrying HCV genotype 1 than in those carrying other HCV genotypes, despite comparable HIV-1 RNA levels [10]. Although details on the use of antiretroviral drugs, which might have influenced those differences, were not provided, the finding of Yoo et al. is of interest. HCV RNA levels were also higher in the HIV-1/HCV genotype 1coinfected participants, confirming the findings of previous studies [2931]. Higher HCV-RNA levels in liver biopsy specimens have been found in patients infected with HCV genotype 1, compared with those in patients infected with HCV genotype 3 [32]. In addition, an inverse correlation between HCV RNA levels and survival has been found in hemophiliacs [33]. In Yoo et al.'s study, do the lower CD4+ T cell counts have anything to do with the higher HCV RNA levels observed in the HIV-1/HCV genotype 1coinfected participants Unfortunately, the authors did not provide information on this aspect, and it warrants further study.
Why might patients coinfected with HIV and HCV genotype 1 have lower CD4+ T cell counts Immune activation driven by chronic HCV infection might favor HIV transcription within CD4+ T cells, leading to a more rapid destruction of these cells. In a study from the Swiss Cohort, persistent CD4+ T cell apoptosis was found to be associated with poor CD4+ T cell recovery, despite the use of maximal suppressive HAART [34]. Alternatively, direct HCV infection of CD4+ T cells might increase their destruction [35, 36]. Fas-mediated apoptosis of peripheral-blood mononuclear cells (PBMCs) has been shown to be increased in HIV/HCV-coinfected patients [37], and we have recently shown significantly higher markers of apoptosis in PBMCs derived from HIV/HCV-coinfected patients than in those derived from HIV-monoinfected patients [38].
That HCV genotype 1 coinfection has a more deleterious effect on HIV disease progression, compared with that of coinfection with other genotypes, was originally reported in the mid 1990s [19]. Contrary to Yoo et al.'s findings, however, that study did not find lower CD4+ T cell counts in HIV/HCV-coinfected hemophiliacs. Why Yoo et al.'s study would find that HCV genotype 1 coinfection has a more deleterious effect on AIDS-related mortality is not completely clear, because the association was weaker after adjustment for HIV-1 and HCV RNA levels.
The issue of a worsened AIDS-related mortality in HIV/HCV genotype 1coinfected patients has important clinical implications. It provides further reason for treating hepatitis C in HIV/HCV genotype 1coinfected patients, even though sustained virological response rates are achieved in <30% of HIV/HCV genotype 1coinfected patients receiving pegylated IFN and ribavirin [39, 40]. Currently, longer courses of anti-HCV therapy are being proposed, to improve treatment outcome in these difficult-to-treat patients [41].
References
1. Hadziyannis S, Koskinas J. Differences in epidemiology, liver disease and treatment response among HCV genotypes. Hepatol Res 2004; 29:12935. First citation in article
2. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon -2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40:9939. First citation in article
3. Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004; 53:40612. First citation in article
4. Hezode C, Roudot-Thoraval F, Zafrani E, Dhumeaux D, Pawlotsky JM. Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections. J Viral Hepat 2004; 11:4558. First citation in article
5. Lehmann M, Meyer M, Monazahian M, Tillmann H, Manns M, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J Med Virol 2004; 73:38791. First citation in article
6. Kamal S, Rasenack J, Bianchi L, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis Cspecific CD4+ T-cell and cytokine response. Gastroenterology 2001; 121:64656. First citation in article
7. Zylberberg H, Chaix ML, Brechot C, et al. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon. Ann Intern Med 2000; 132:8456. First citation in article
8. Alter M, Margolis H, Krawczynski K, et al. The prevalence of hepatitis C virus infection in the United States, 1988 thorough 1994. N Engl J Med 1999; 341:55662. First citation in article
9. van Asten L, Verhaest I, Lamzira S, et al. Spread of HCV among European injection drug users infected with HIV: a phylogenetic analysis. J Infect Dis 2004; 189:292302. First citation in article
10. Yoo TW, Donfield S, Lail A, Lynn HS, Daar ES. Effect of hepatitis C virus (HCV) genotype on HCV and HIV-1 disease. Hemophilia Growth and Development Study. J Infect Dis 2004; 191:410 (in this issue). First citation in article
11. Puoti M, Spinetti A, Ghezzi A, et al. Mortality for liver disease in patients with HIV-infection: a cohort study. J Acquir Immune Defic Syndr 2000; 24:2117. First citation in article
12. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with HIV infection. Clin Infect Dis 2001; 32:4927. First citation in article
13. Martín-Carbonero L, Soriano V, Valencia E, García-Samaniego J, Lopez M, González-Lahoz J. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retrovir 2001; 17:146771. First citation in article
14. Rosenthal E, Poiree M, Pradier C, et al. Mortality due to hepatitis C related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17:18039. First citation in article
15. Klein M, Lalonde R, Suissa S. The impact of hepatitis C virus co-infection on HIV progression before and after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2003; 33:36572. First citation in article
16. Tedaldi E, Baker R, Moorman A, et al. Influence of coinfection with hepatitis C virus on morbidity and mortality due to HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2003; 36:3637. First citation in article
17. Martín-Carbonero L, Benhamou Y, Puoti M, et al. Incidence and predictors of severe liver fibrosis in HIV-infected patients with chronic hepatitis C: a European collaborative study. Clin Infect Dis 2004; 38:12833. First citation in article
18. Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV-coinfection. AIDS 2004; 18:112. First citation in article
19. Sabin C, Telfer P, Phillips A, Bhagani S, Lee C. The association between HCV genotype and HIV disease progression in a cohort of hemophiliacs. J Infect Dis 1997; 175:1648. First citation in article
20. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and HCV coinfections. Lancet 2000; 356:18005. First citation in article
21. Sulkowski M, Moore R, Mehta S, Chaisson R, Thomas D. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199206. First citation in article
22. Rockstroh J, Konopnicki D, Soriano V, et al. Hepatitis B and hepatitis C in the EuroSIDA cohort: prevalence and effect on mortality, AIDS, progression and response to HAART [abstract 799]. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (San Francisco, CA). 2004. First citation in article
23. Amin K, Kaye M, Skidmore S, Pillay D, Cooper D, Dore G. HIV and hepatitis C coinfection within the CAESAR study. HIV Med 2004; 5:1749. First citation in article
24. Martin JC, Castilla J, Lopez M, Arranz R, Gonzalez-Lahoz J. Impact of chronic hepatitis C on HIV-1 disease progression. HIV Clin Trials 2004; 5:12531. First citation in article
25. Moreno A, Dronda F. Immune recovery during antiretroviral therapy in patients infected with HIV-1 and HCV coinfection: a cohort study [abstract 638]. In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections (Seattle, WA). 2002. First citation in article
26. Chung R, Evans S, Yang Y, et al. Immune recovery is associated with persistent rise in HCV-RNA, infrequent liver test flares, and is not impaired by HCV in co-infected subjects. AIDS 2002; 16:191523. First citation in article
27. De Luca A, Bugarini R, Lepri A. Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 2002; 162:212532. First citation in article
28. Law W, Duncombe C, Mahanontharit A, et al. Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort. AIDS 2004; 18:116977. First citation in article
29. Hofmann H. Genotypes and virus load in patients with hepatitis C infection. Infection 1995; 23:1338. First citation in article
30. Herrero-Martínez E, Sabin C, Evans J, Griffioen A, Lee C, Emery V. The prognostic value of a single hepatitis C virus RNA load measurement taken early after HIV seroconversion. J Infect Dis 2002; 186:4706. First citation in article
31. Strasfeld L, Lo Y, Netski D, Thomas D, Klein R. The association of hepatitis C prevalence, activity, and genotype with HIV infection in a cohort of New York City drug users. J Acquir Immune Defic Syndr 2003; 33:35664. First citation in article
32. Tedeschi R, Pivetta E, Zanussi S, et al. Quantification of hepatitis C virus (HCV) in liver specimens and sera from patients with HIV coinfection by using the Versant HCV RNA 3.0 (branched DNAbased) DNA assay. J Clin Microbiol 2003; 41:304650. First citation in article
33. Daar E, Lynn H, Donfield S. HCV load is associated with HIV-1 disease progression in hemophiliacs. J Infect Dis 2001; 183:58995. First citation in article
34. Hansjee N, Kaufmann G, Strub C, et al. Persistent apoptosis in HIV-1infected individuals receiving potent antiretroviral therapy is associated with poor recovery of CD4 T lymphocytes. J Acquir Immune Defic Syndr 2004; 36:6717. First citation in article
35. Laskus T, Radkowski M, Piasek A, et al. Hepatitis C virus in lymphoid cells of patients coinfected with HIV type 1: evidence of active replication in monocytes/ macrophages and lymphocytes. J Infect Dis 2000; 181:4428. First citation in article
36. Di Campli C. Evaluation of recent thymic emigrants (TRECs) in patients affected by HCV chronic hepatitis. J Hepatol 2002; 36(Suppl 1):S222. First citation in article
37. Taya N, Torimoto Y, Shindo M, Hirai K, Hasebe C, Kohgo Y. Fas-mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C. Br J Haematol 2000; 110:8997. First citation in article
38. Núez M, Benito J, López M, González-Lahoz J, Soriano V. Hepatitis C virus increases lymphocyte apoptosis in HIV-infected patients [abstract H-1717]. In: Program and abstracts of the 43th Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). 2003. First citation in article
39. Torriani F, Rodriguez-Torres M, Rockstroh J, et al. Pegylated interferon 2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:43850. First citation in article
40. Laguno M, Murillas J, Blanco J, et al. Peginterferon -2b plus ribavirin compared with interferon -2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004; 18:F2736. First citation in article
41. Soriano V, Nuez M, Camino N, et al. HCV-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin. Antivir Ther 2004; 9:5059. First citation in article, http://www.100md.com(Marina Núez and Vincent S)
Six major hepatitis C virus (HCV) genotypes have been described, and HCV genotypes 14 are the predominant circulating genotypes in Western countries [1]. These genotypes show a distinct geographic distribution, as well as a different susceptibility to interferon (IFN)based therapies [1]. Only recently have other differences between HCV genotypes been appreciated (table 1). For example, patients carrying HCV genotype 2 and with normal levels of transaminases are at higher risk for experiencing alanine aminotransferase (ALT) flares; however, they have the best response to IFN-based therapies [2]. On the other hand, patients infected with HCV genotype 3 show the highest rate of spontaneous clearance but may show faster liver-fibrosis progression, often accompanied by liver steatosis; however, they tend to respond well to IFN-based therapies [35]. Finally, chronic infection seems to be more frequent in patients after acute infection with HCV genotype 4, and these patients tend to respond less well to IFN-based therapies [6, 7].
In North America, Japan, and western Europe, HCV genotype 1 is by far the predominant HCV genotype [1]. Since the introduction of HCV serological tests in the early 1990s, HCV transmission through blood transfusions and other medical interventions has declined sharply, and, currently, needle sharing among injection drug users (IDUs) represents the major mechanism of acquisition of HCV in the developed world [8]. Given that HCV and HIV share routes of transmission, it is not surprising that the IDU population is largely coinfected with both viruses [9]. In this issue of The Journal of Infectious Diseases, Yoo et al. suggest that coinfection with HCV genotype 1 might have a more deleterious effect on the progression of HIV-1 disease than does coinfection with other HCV genotypes [10].
Since the introduction of highly active antiretroviral therapy (HAART), liver-related complications have emerged as an important cause of hospital admission and death in HIV-infected individuals in the developed world [1114]. Classical opportunistic infections are now less frequent, and, conversely, complications of end-stage liver diseasemainly due to HCV infectionare on the rise [15, 16]. There is no doubt that this is due, in part, to the faster progression to liver cirrhosis seen in HIV/HCV-coinfected patients [17]. This accelerated course of hepatitis C and the higher risk for liver toxicity after beginning to take antiretroviral drugs in HIV/HCV-coinfected patients are the 2 main reasons why HCV therapy is now considered to be a priority in this population [18].
What is not so clear is whether HCV infection influences HIV disease progression. Initial reports claimed that there is an increased risk for progression to clinical AIDS in HIV/HCV-coinfected patients [19, 20], but this finding has not been confirmed by more-recent studies [2123]. Some studies have shown significantly lower CD4+ T cell counts in HIV/HCV-coinfected patients, compared with those in HIV-monoinfected patients, despite similar HIV RNA levels [16, 24], but another study failed to show any difference [23]. Disagreement also exists when assessment is made of the ability of the immune system to recover after antiretroviral therapy. Although initial studies underlined that increases in CD4+ T cell counts might be blunted in HIV/HCV-coinfected patients [20, 25], similar increases in CD4+ T cell counts, compared with those in HIV-monoinfected patients, have been observed by other studies [22, 2628].
Yoo et al. have reported lower CD4+ T cell counts in HIV-1/HCVcoinfected hemophiliacs carrying HCV genotype 1 than in those carrying other HCV genotypes, despite comparable HIV-1 RNA levels [10]. Although details on the use of antiretroviral drugs, which might have influenced those differences, were not provided, the finding of Yoo et al. is of interest. HCV RNA levels were also higher in the HIV-1/HCV genotype 1coinfected participants, confirming the findings of previous studies [2931]. Higher HCV-RNA levels in liver biopsy specimens have been found in patients infected with HCV genotype 1, compared with those in patients infected with HCV genotype 3 [32]. In addition, an inverse correlation between HCV RNA levels and survival has been found in hemophiliacs [33]. In Yoo et al.'s study, do the lower CD4+ T cell counts have anything to do with the higher HCV RNA levels observed in the HIV-1/HCV genotype 1coinfected participants Unfortunately, the authors did not provide information on this aspect, and it warrants further study.
Why might patients coinfected with HIV and HCV genotype 1 have lower CD4+ T cell counts Immune activation driven by chronic HCV infection might favor HIV transcription within CD4+ T cells, leading to a more rapid destruction of these cells. In a study from the Swiss Cohort, persistent CD4+ T cell apoptosis was found to be associated with poor CD4+ T cell recovery, despite the use of maximal suppressive HAART [34]. Alternatively, direct HCV infection of CD4+ T cells might increase their destruction [35, 36]. Fas-mediated apoptosis of peripheral-blood mononuclear cells (PBMCs) has been shown to be increased in HIV/HCV-coinfected patients [37], and we have recently shown significantly higher markers of apoptosis in PBMCs derived from HIV/HCV-coinfected patients than in those derived from HIV-monoinfected patients [38].
That HCV genotype 1 coinfection has a more deleterious effect on HIV disease progression, compared with that of coinfection with other genotypes, was originally reported in the mid 1990s [19]. Contrary to Yoo et al.'s findings, however, that study did not find lower CD4+ T cell counts in HIV/HCV-coinfected hemophiliacs. Why Yoo et al.'s study would find that HCV genotype 1 coinfection has a more deleterious effect on AIDS-related mortality is not completely clear, because the association was weaker after adjustment for HIV-1 and HCV RNA levels.
The issue of a worsened AIDS-related mortality in HIV/HCV genotype 1coinfected patients has important clinical implications. It provides further reason for treating hepatitis C in HIV/HCV genotype 1coinfected patients, even though sustained virological response rates are achieved in <30% of HIV/HCV genotype 1coinfected patients receiving pegylated IFN and ribavirin [39, 40]. Currently, longer courses of anti-HCV therapy are being proposed, to improve treatment outcome in these difficult-to-treat patients [41].
References
1. Hadziyannis S, Koskinas J. Differences in epidemiology, liver disease and treatment response among HCV genotypes. Hepatol Res 2004; 29:12935. First citation in article
2. Zeuzem S, Hultcrantz R, Bourliere M, et al. Peginterferon -2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004; 40:9939. First citation in article
3. Rubbia-Brandt L, Fabris P, Paganin S, et al. Steatosis affects chronic hepatitis C progression in a genotype specific way. Gut 2004; 53:40612. First citation in article
4. Hezode C, Roudot-Thoraval F, Zafrani E, Dhumeaux D, Pawlotsky JM. Different mechanisms of steatosis in hepatitis C virus genotypes 1 and 3 infections. J Viral Hepat 2004; 11:4558. First citation in article
5. Lehmann M, Meyer M, Monazahian M, Tillmann H, Manns M, Wedemeyer H. High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J Med Virol 2004; 73:38791. First citation in article
6. Kamal S, Rasenack J, Bianchi L, et al. Acute hepatitis C without and with schistosomiasis: correlation with hepatitis Cspecific CD4+ T-cell and cytokine response. Gastroenterology 2001; 121:64656. First citation in article
7. Zylberberg H, Chaix ML, Brechot C, et al. Infection with hepatitis C virus genotype 4 is associated with a poor response to interferon. Ann Intern Med 2000; 132:8456. First citation in article
8. Alter M, Margolis H, Krawczynski K, et al. The prevalence of hepatitis C virus infection in the United States, 1988 thorough 1994. N Engl J Med 1999; 341:55662. First citation in article
9. van Asten L, Verhaest I, Lamzira S, et al. Spread of HCV among European injection drug users infected with HIV: a phylogenetic analysis. J Infect Dis 2004; 189:292302. First citation in article
10. Yoo TW, Donfield S, Lail A, Lynn HS, Daar ES. Effect of hepatitis C virus (HCV) genotype on HCV and HIV-1 disease. Hemophilia Growth and Development Study. J Infect Dis 2004; 191:410 (in this issue). First citation in article
11. Puoti M, Spinetti A, Ghezzi A, et al. Mortality for liver disease in patients with HIV-infection: a cohort study. J Acquir Immune Defic Syndr 2000; 24:2117. First citation in article
12. Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with HIV infection. Clin Infect Dis 2001; 32:4927. First citation in article
13. Martín-Carbonero L, Soriano V, Valencia E, García-Samaniego J, Lopez M, González-Lahoz J. Increasing impact of chronic viral hepatitis on hospital admissions and mortality among HIV-infected patients. AIDS Res Hum Retrovir 2001; 17:146771. First citation in article
14. Rosenthal E, Poiree M, Pradier C, et al. Mortality due to hepatitis C related liver disease in HIV-infected patients in France (Mortavic 2001 study). AIDS 2003; 17:18039. First citation in article
15. Klein M, Lalonde R, Suissa S. The impact of hepatitis C virus co-infection on HIV progression before and after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2003; 33:36572. First citation in article
16. Tedaldi E, Baker R, Moorman A, et al. Influence of coinfection with hepatitis C virus on morbidity and mortality due to HIV infection in the era of highly active antiretroviral therapy. Clin Infect Dis 2003; 36:3637. First citation in article
17. Martín-Carbonero L, Benhamou Y, Puoti M, et al. Incidence and predictors of severe liver fibrosis in HIV-infected patients with chronic hepatitis C: a European collaborative study. Clin Infect Dis 2004; 38:12833. First citation in article
18. Soriano V, Puoti M, Sulkowski M, et al. Care of patients with hepatitis C and HIV-coinfection. AIDS 2004; 18:112. First citation in article
19. Sabin C, Telfer P, Phillips A, Bhagani S, Lee C. The association between HCV genotype and HIV disease progression in a cohort of hemophiliacs. J Infect Dis 1997; 175:1648. First citation in article
20. Greub G, Ledergerber B, Battegay M, et al. Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and HCV coinfections. Lancet 2000; 356:18005. First citation in article
21. Sulkowski M, Moore R, Mehta S, Chaisson R, Thomas D. Hepatitis C and progression of HIV disease. JAMA 2002; 288:199206. First citation in article
22. Rockstroh J, Konopnicki D, Soriano V, et al. Hepatitis B and hepatitis C in the EuroSIDA cohort: prevalence and effect on mortality, AIDS, progression and response to HAART [abstract 799]. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (San Francisco, CA). 2004. First citation in article
23. Amin K, Kaye M, Skidmore S, Pillay D, Cooper D, Dore G. HIV and hepatitis C coinfection within the CAESAR study. HIV Med 2004; 5:1749. First citation in article
24. Martin JC, Castilla J, Lopez M, Arranz R, Gonzalez-Lahoz J. Impact of chronic hepatitis C on HIV-1 disease progression. HIV Clin Trials 2004; 5:12531. First citation in article
25. Moreno A, Dronda F. Immune recovery during antiretroviral therapy in patients infected with HIV-1 and HCV coinfection: a cohort study [abstract 638]. In: Program and abstracts of the 9th Conference on Retroviruses and Opportunistic Infections (Seattle, WA). 2002. First citation in article
26. Chung R, Evans S, Yang Y, et al. Immune recovery is associated with persistent rise in HCV-RNA, infrequent liver test flares, and is not impaired by HCV in co-infected subjects. AIDS 2002; 16:191523. First citation in article
27. De Luca A, Bugarini R, Lepri A. Coinfection with hepatitis viruses and outcome of initial antiretroviral regimens in previously naive HIV-infected subjects. Arch Intern Med 2002; 162:212532. First citation in article
28. Law W, Duncombe C, Mahanontharit A, et al. Impact of viral hepatitis co-infection on response to antiretroviral therapy and HIV disease progression in the HIV-NAT cohort. AIDS 2004; 18:116977. First citation in article
29. Hofmann H. Genotypes and virus load in patients with hepatitis C infection. Infection 1995; 23:1338. First citation in article
30. Herrero-Martínez E, Sabin C, Evans J, Griffioen A, Lee C, Emery V. The prognostic value of a single hepatitis C virus RNA load measurement taken early after HIV seroconversion. J Infect Dis 2002; 186:4706. First citation in article
31. Strasfeld L, Lo Y, Netski D, Thomas D, Klein R. The association of hepatitis C prevalence, activity, and genotype with HIV infection in a cohort of New York City drug users. J Acquir Immune Defic Syndr 2003; 33:35664. First citation in article
32. Tedeschi R, Pivetta E, Zanussi S, et al. Quantification of hepatitis C virus (HCV) in liver specimens and sera from patients with HIV coinfection by using the Versant HCV RNA 3.0 (branched DNAbased) DNA assay. J Clin Microbiol 2003; 41:304650. First citation in article
33. Daar E, Lynn H, Donfield S. HCV load is associated with HIV-1 disease progression in hemophiliacs. J Infect Dis 2001; 183:58995. First citation in article
34. Hansjee N, Kaufmann G, Strub C, et al. Persistent apoptosis in HIV-1infected individuals receiving potent antiretroviral therapy is associated with poor recovery of CD4 T lymphocytes. J Acquir Immune Defic Syndr 2004; 36:6717. First citation in article
35. Laskus T, Radkowski M, Piasek A, et al. Hepatitis C virus in lymphoid cells of patients coinfected with HIV type 1: evidence of active replication in monocytes/ macrophages and lymphocytes. J Infect Dis 2000; 181:4428. First citation in article
36. Di Campli C. Evaluation of recent thymic emigrants (TRECs) in patients affected by HCV chronic hepatitis. J Hepatol 2002; 36(Suppl 1):S222. First citation in article
37. Taya N, Torimoto Y, Shindo M, Hirai K, Hasebe C, Kohgo Y. Fas-mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C. Br J Haematol 2000; 110:8997. First citation in article
38. Núez M, Benito J, López M, González-Lahoz J, Soriano V. Hepatitis C virus increases lymphocyte apoptosis in HIV-infected patients [abstract H-1717]. In: Program and abstracts of the 43th Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago). 2003. First citation in article
39. Torriani F, Rodriguez-Torres M, Rockstroh J, et al. Pegylated interferon 2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:43850. First citation in article
40. Laguno M, Murillas J, Blanco J, et al. Peginterferon -2b plus ribavirin compared with interferon -2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004; 18:F2736. First citation in article
41. Soriano V, Nuez M, Camino N, et al. HCV-RNA clearance in HIV-coinfected patients with chronic hepatitis C treated with pegylated interferon plus ribavirin. Antivir Ther 2004; 9:5059. First citation in article, http://www.100md.com(Marina Núez and Vincent S)