Privacy Policy Terms of Use. Access your subscriptions. Free access to newly published articles. Purchase access. Rent article Rent this article from DeepDyve. Access to free article PDF downloads. Interestingly, following initiation of highly active antiretroviral therapy HAART , coinfected individuals actually show a paradoxical small increase in serum levels of HCV RNA 23 , 32 , suggesting that immune suppression and the direct effect of HIV are not the only factors involved.
It should be noted that in monoinfected patients, HCV RNA levels are not associated with disease severity, and thus it is unclear whether this biological phenomenon has any clinical significance. Coinfection is associated with a higher mortality than monoinfection with either virus alone. However, as effective therapy for HIV became available and AIDS-related mortality declined, liver-associated mortality emerged as a prominent cause of death in HIV-infected patients, especially in those with coinfections.
In the and surveys, relative mortality rates from liver disease were low at 1. Relative liver-associated mortality, however, increased to These findings were corroborated by other groups as well 6 , 19 , It is unclear whether this increase in liver mortality is affected by the improvement in immune function following HAART.
Excessive consumption of alcohol appears to be a cofactor that increases mortality from liver disease in coinfected patients , Most cases of liver-associated mortality in coinfected patients are due to end-stage liver disease or hepatocellular carcinoma Thus, the increased mortality of coinfected patients over that of HCV-monoinfected ones reflects accelerated progression of chronic liver disease. Moreover, liver biopsies have shown that coinfected patients with recent-onset or acute hepatitis C can already have significant fibrosis Treatment of HIV with nonnucleoside reverse transcriptase inhibitors, especially nevirapine, but not protease inhibitors, was associated with decreased progression of hepatic fibrosis Compared directly to HCV-monoinfected patients, coinfected patients seemed to develop cirrhosis 12 years earlier However, this finding may have been confounded by other factors, as two large American series encompassing more than 12, patients , failed to confirm such an effect.
DC, dendritic cell; MHC, major histocompatibility complex. Dashed arrows represent the effect of viral envelope proteins or possible infection; solid arrows represent productive infection. HIV-induced immune suppression may be a major factor. T-cell responses against HCV play an essential role in preventing progression from acute infection to chronicity In HIV-infected patients that develop acute hepatitis C, HCV-specific T-cell responses are markedly diminished 34 , a finding consistent with a higher rate of progression to chronicity in these patients The importance of T-cell depletion in promoting accelerated progression of hepatitis C is not unique to HIV coinfection.
In a different setting of immune suppression, recurrence of chronic hepatitis C after liver transplantation for monoinfection is accelerated compared to that in patients who have not received transplants. A significant risk factor is the use of steroid boluses 18 or lymphocyte-depleting agents to treat acute rejections.
Nonetheless, these immune-related mechanisms do not fully explain the faster progression of liver fibrosis. The liver injury in coinfection could also occur independently of the immune suppression as a result of the combined effect of the two viruses on hepatocytes.
Whether HIV can directly infect hepatocytes is unclear. Xiao et al. Recently, Ma et al. Interestingly, HCV core antigen levels were increased in coinfected cells, consistent with the finding in vivo of a higher level of viremia. Even in the absence of hepatocyte coinfection, these cells are exposed to the effects of circulating viral proteins. HIV infection of liver cells other than hepatocytes may also play a role in the progression of disease in coinfected patients.
Like other macrophages, Kupffer cells can be infected with HIV 53 , 54 , although monoinfection with HIV is not associated with significant liver pathology Modulation of the antigen-presenting function of the Kupffer cells by HIV in HCV coinfection may also play a role in the progression of liver damage.
In a preliminary study, Tuyama et al. HIV infection of the cells, or even exposure to gp, led to an induction in collagen synthesis. Whether this finding is relevant to the progression of fibrosis in coinfected patients is difficult to determine. The current limitations of robust tissue culture models for HCV and the distinct cell-specific and species-specific tropism of the two viruses limit the ability to study their interaction.
One other potential explanation for disease progression may involve the gut-liver axis. Gut permeability and LPS-induced Kupffer cell activation are associated with liver injury in several conditions, including alcoholic liver disease, celiac sprue, gut graft-versus-host disease, and inflammatory bowel disease. Upon repeated exposure to LPS as well as to other ligands of Toll-like receptors , monocytes and macrophages develop tolerance that limits their immune activation.
In chronic hepatitis C, this tolerance to LPS is lost in peripheral monocytes and possibly in Kupffer cells due to the combined effects of gamma interferon, endotoxin, and HCV core protein Several abnormalities of the lymphoid system in patients with chronic hepatitis C have been described. Many HCV-infected patients exhibit evidence of polyclonal proliferation of B cells with autoantibody production, which can lead to the clinical syndromes of HCV-associated autoimmune disorders, mixed cryoglobulinemia, and non-Hodgkin's lymphoma Furthermore, HCV has been shown to infect and replicate in B cells, T cells, and monocytes, though the evidence is not compelling and the clinical significance of this finding is unclear Dendritic cell dysfunctions have been reported in HCV-infected patients, but this finding is controversial 1 , 38 , In addition to affecting the functions of T cells, HIV alters the functions and phenotypes of dendritic 92 and NK cells 43 , both of which play important roles in innate and adaptive immunity and likely contribute to the diminished HCV-specific immune response in coinfected individuals.
The interplay between HCV and the lymphoid system could theoretically affect, or be affected by, coinfection with HIV. More research is needed to clarify this issue. These rates are generally inferior to published SVR rates in monoinfected patients, but the dose of ribavirin that was used in these three trials was lower than that commonly prescribed for monoinfection. In a study where the full doses were prescribed, response rates still seemed to be lower The kinetics of serum HCV level changes during interferon-based treatment have been extensively studied and modeled.
The parameters derived from the mathematical model are thought to reflect the effectiveness of interferon, the rate of elimination of infected cells, and the rate of clearance of free virions In coinfected patients, the first-phase decline representing effectiveness and the second-phase slope loss of infected cells were similar to those of monoinfected patients , but clearance of free virions was slower.
Coinfected patients became HCV RNA negative later during treatment, mainly due to higher baseline levels of the virus. The dynamics of virological response have been used to guide the duration of treatment for monoinfected patients As with monoinfection, a SVR is associated with nonprogression 14 of, or even improvement 64 in, liver histology, and over long-term follow-up, significantly reduces the occurrence of hepatic decompensation or hepatocellular carcinoma Furthermore, treatment of HCV in coinfected patients was shown to be cost effective Although antiviral therapy for HCV is effective in coinfected patients, it is also associated with an increased risk for complications.
The interaction of ribavirin, a purine analogue, with other nucleoside reverse transcriptase inhibitors can lead to the development of symptomatic mitochondrial toxicity 59 and mortality. This syndrome is seen mostly in patients treated with didanosine ddI 10 and can resolve when ddI is discontinued. Hepatic decompensation is another potential complication of interferon and ribavirin treatment in coinfected patients. Although relatively rare 1. Thus, appropriate selection of treatment candidates is important.
Interestingly, ribavirin appears to have a synergistic effect with ddI on the inhibition of HIV replication in vitro, perhaps through the inhibition of IMP dehydrogenase, which increases ddI phosphorylation Ribavirin can interact with other antiretrovirals as well. In vitro, ribavirin antagonizes the effect of zidovudine AZT on HIV replication , while AZT use in patients receiving peginterferon and ribavirin is associated with a higher rate of anemia 13 , 74 , When abacavir is used as the nucleoside reverse transcriptase inhibitor backbone of antiretroviral therapy, response rates to HCV treatment with peginterferon and ribavirin seem to be lower, though the mechanism is unknown 12 , 73 , In a large number of series for examples, see references 36 and 77 , coinfection with HCV was persistently shown to be associated with an increased risk of HAART hepatotoxicity.
Studies are heterogenous with respect to the relative prevalences of coinfected patients, HAART regimens, and definitions of hepatotoxicity. However, it is clear that most cases of enzyme elevation are not associated with clinical symptoms, resolve when treatment is modified, and may even improve when HAART is continued unchanged However, serious complications can occur; in a large prospective study of Italian patients 96 , severe toxicity defined as an alanine aminotransferase level greater than 10 times the upper limit of the norm or 5 times the baseline level if markedly abnormal was seen in 26 patients 4.
Seven of these 26 patients developed liver failure and died as a consequence. Risk factors for HAART hepatotoxicity in coinfected patients include the preexisting degree of liver fibrosis 5 and infection with HCV genotype 3 88 , No specific medication combination has been shown to be consistently associated with liver injury in coinfected patients, and thus, selection of HAART therapy should be based on other factors.
These patients show accelerated liver disease and are more likely to develop liver enzyme abnormalities and clinical liver toxicity when treated with HAART. Treatment of hepatitis C with peginterferon is thus indicated in most patients and has been shown to be relatively safe and effective.
Treatment should not be prescribed for patients on ddI. Use of AZT should be minimized if possible. Patients with advanced cirrhosis should be treated with caution, preferably in a transplant center. Future research may enhance understanding of the interaction between the two viral infections and improve treatment options for coinfected individuals. National Center for Biotechnology Information , U. Journal List J Virol v. J Virol. Published online May 6. Yaron Rotman and T. Jake Liang.
Author information Copyright and License information Disclaimer. Phone: Fax: E-mail: vog. This article has been cited by other articles in PMC. Open in a separate window. Albert, M. Decalf, and S. Plasmacytoid dendritic cells move down on the list of suspects: in search of the immune pathogenesis of chronic hepatitis C.
Alter, M. Epidemiology of viral hepatitis and HIV co-infection. Antonucci, G. Girardi, A. Cozzi-Lepri, M. Capobianchi, A. De Luca, M. Puoti, E. Petrelli, G. Carnevale, G. Rizzardini, P. Grossi, P.
Vigano, M. Moioli, F. Carletti, M. Solmone, G. Ippolito, and A. Goletti, S. Lanini, E. Girardi, and O. Cell Death Differ. Aranzabal, L. Casado, J. Moya, C. Quereda, S. Diz, A. Moreno, L. Moreno, A.
Antela, M. Perez-Elias, F. Dronda, A. Marin, F. Hernandez-Ranz, A. Moreno, and S. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Arnold, D. Julian, and I. Mortality rates and causes of death among all HIV-positive individuals with hemophilia in Canada over 21 years of follow-up. Blood Babik, J. Balagopal, A. Philp, J.
Astemborski, T. Block, A. Mehta, R. Long, G. Kirk, S. Mehta, A. Cox, D. Thomas, and S. Human immunodeficiency virus-related microbial translocation and progression of hepatitis C.
Gastroenterology Balasubramanian, A. Ganju, and J. Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. Bani-Sadr, F. Carrat, S. Pol, R. Hor, E. Rosenthal, C. Goujard, P. Morand, F. Lunel-Fabiani, D. Salmon-Ceron, L.
Piroth, G. Pialoux, M. Bentata, P. Cacoub, and C. Immune Defic. Carrat, E. Rosenthal, L. Piroth, P. Lunel-Fabiani, M. Bonarek, N. Colin de Verdiere, G. Pialoux, P. Cacoub, S. Pol, and C. Spontaneous hepatic decompensation in patients coinfected with HIV and hepatitis C virus during interferon-ribavirin combination treatment.
Denoeud, P. Lunel-Fabiani, S. Pol, P. Cacoub, C. Perronne, and F. Early virologic failure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirin combination: does abacavir play a role? Goderel, C. Penalba, E. Billaud, J. Doll, Y. Welker, P. Pol, C. Viral Hepat. Barreiro, P. Labarga, L. Martin-Carbonero, A. Amor, A. Ruiz-Sancho, C. Castellares, J. Gonzalez-Lahoz, and V.
Beld, M. Penning, V. Lukashov, M. McMorrow, M. Roos, N. Pakker, A. Virology Benhamou, Y. Bochet, V. Di Martino, F. Charlotte, F. Azria, A. Coutellier, M. Vidaud, F. Bricaire, P. Opolon, C. Katlama, and T. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. Hepatology 30 Berenguer, J. Bellon, P. Miralles, E. Alvarez, I. Castillo, J. Cosin, J. Lopez, M. Sanchez Conde, B. Padilla, and S. Association between exposure to nevirapine and reduced liver fibrosis progression in patients with HIV and hepatitis C virus coinfection.
Berenguer, M. Aguilera, M. Prieto, F. San Juan, J. Rayon, S. Benlloch, and J. Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. Bica, I. McGovern, R. Dhar, D. Stone, K. McGowan, R. Scheib, and D. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Blackard, J. Yang, P. Bordoni, K. Sherman, and R. Bollepalli, S. Mathieson, C. Bay, A. Hillier, J.
Post, D. Van Thiel, and A. Bonacini, M. Govindarajan, L. Blatt, P. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. MMWR ;67 1 Philadelphia, PA, Hepatitis C virus testing in adults living with HIV: a need for improved screening efforts. J Acquir Immune Defic Syndr ;— Centers for Disease Control and Prevention. Viral Hepatitis Surveillance—United States, pdf icon. The progression of HCV-associated liver disease in a cohort of haemophilic patients.
Br J Haematol. Human immunodeficiency virus infection modifies the natural history of chronic parenterally acquired hepatitis C with an unusually rapid progression to cirrhosis. Data Availability All relevant data are within the manuscript. References 1. Country Factsheet Chile Ministerio de Desarrollo Social y Familia.
Rev Chilena Infectol. The Chilean AIDS cohort: a model for evaluating the impact of an expanded access program to antiretroviral therapy in a middle-income country—organization and preliminary results. J Acquir Immune Defic Syndr. Long-term outcomes of a national expanded access program to antiretroviral therapy: the Chilean AIDS cohort. Isapres de Chile. Virological and immunological outcomes to antiretroviral therapy in HIV-infected patients of an academic medical center in Chile.
Causes of death among HIV-infected patients in France in national survey : trends since Impact of hepatitis coinfection on healthcare utilization among persons living with HIV. Challenges in solid organ transplantation in people living with HIV. Intensive Care Med. World Health Organization. Global Hepatitis Report Geneva: World Health Organization: European Centre for Disease Prevention and Control. Stockholm: ECDC; World Health Organization [Internet].
Factsheet Hepatitis B. Alter MJ. Epidemiology of viral hepatitis and HIV co-infection. J Hepatol. HIV-hepatitis B virus coinfection: epidemiology, pathogenesis, and treatment.
The prevalence of hepatitis B virus infection markers and socio-demographic risk factors in HIV-infected patients in Southern Brazil. Rev Soc Bras Med Trop. New Engl J Med. Hepatitis B virus infection as a neglected tropical disease. BMC Infect Dis. Int J Infect Dis. Viral hepatitis and HIV co-infection. Antiviral Res. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: a review.
World J Gastroenterol. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men. The influence of human immunodeficiency virus type 1 infection on the development of the hepatitis B virus carrier state. J Infect Dis. Hoofnagle JH. Reactivation of hepatitis B. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria.
Clin Infect Dis. Impact of hepatitis B virus co-infection on response to highly active antiretroviral treatment and outcome in HIV-infected individuals: a nationwide cohort study. HIV Med. Rockstroh JK. Influence of viral hepatitis on HIV infection. Is sexual contact a major mode of hepatitis C virus transmission? Acute hepatitis C infection in HIV-negative men who have sex with men.
J Viral Hepat. Prevalence of hepatitis viruses in an anti-human immunodeficiency virus-positive population from Argentina. A multicentre study. Ibarra V H. Rev Med Chile. Soza A, Lopez-Lastra M. Hepatitis C in Chile: burden of the disease.
Hepatitis C virus infection in patients with HIV epidemiology, natural history and management. Expert Rev Gastroenterol Hepatol.
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