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== Treatment==
== Treatment==

The primary objective of HCV therapy is permanent eradication of the virus. The secondary potential benefit of eradication is a reduction in the risk of liver failure and liver cancer. Currently, peginterferon alfa-2a plus ribavirin is the only FDA approved treatment for HIV/HCV co-infected patients. [[Interferon]]s bind to specific cell surface receptors of virus-infected cells, which induces a complex cascade of protein-protein interactions and a rapid activation of gene transcription. The antiviral effects of interferons are mediated through inhibition of viral penetration or uncoating, inhibiting viral replication or translation of viral proteins, and/or viral assembly and release. The difference between peginterferon and interferon is the addition of a [[polyethylene glycol]] (PEG) [[polymer]]. The addition of PEG decreases plasma clearance considerably, protects the molecule from proteolytic degradation and reduces its immunogenicity. Peak concentrations are approximately 1.5-2 fold higher than trough concentrations and the half-life is 80 hours (compared to 5.1 hours for interferon alpha-2a). Ribavirin is a synthetic nucleoside analogue, but its mechanism of action is not clearly established. Ribavirin inhibits the replication of a wide range of [[RNA]] and [[DNA]] viruses. Pharmacokinetics are similar in patients with HIV co-infection compared with HCV mono-infection.
The primary objective of HCV therapy is permanent eradication of the virus. The secondary potential benefit of eradication is a reduction in the risk of liver failure and liver cancer. Currently, peginterferon alfa-2a plus ribavirin is the only FDA approved treatment for HIV/HCV co-infected patients. [[Interferon]]s bind to specific cell surface receptors of virus-infected cells, which induces a complex cascade of protein-protein interactions and a rapid activation of gene transcription. The antiviral effects of interferons are mediated through inhibition of viral penetration or uncoating, inhibiting viral replication or translation of viral proteins, and/or viral assembly and release. The difference between peginterferon and interferon is the addition of a [[polyethylene glycol]] (PEG) [[polymer]]. The addition of PEG decreases plasma clearance considerably, protects the molecule from proteolytic degradation and reduces its immunogenicity. Peak concentrations are approximately 1.5-2 fold higher than trough concentrations and the half-life is 80 hours (compared to 5.1 hours for interferon alpha-2a). Ribavirin is a synthetic nucleoside analogue, but its mechanism of action is not clearly established. Ribavirin inhibits the replication of a wide range of [[RNA]] and [[DNA]] viruses. Pharmacokinetics are similar in patients with HIV co-infection compared with HCV mono-infection.


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===Pegylated Interferon Alfa-2A (Pegasys) plus Ribavirin versus Interferon Alfa-2A plus Ribavirin===
===Pegylated Interferon Alfa-2A (Pegasys) plus Ribavirin versus Interferon Alfa-2A plus Ribavirin===
In the study by Chung, ''et al.'' 66 treatment-naïve patients received 180 mcg weekly of peginterferon or 6 million units thrice weekly of interferon for 12 weeks and then switched to 3 million units thrice weekly for 48 weeks.<ref> Chung RT, Anderson J, Volberding P, ''et al.'' "Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons." ''N Engl J Med.'' 2004;351: 451-459.
In the study by Chung, ''et al.'' 66 treatment-naïve patients received 180 mcg weekly of peginterferon or 6 million units thrice weekly of interferon for 12 weeks and then switched to 3 million units thrice weekly for 48 weeks.<ref>{{cite journal |author=Chung RT, Andersen J, Volberding P, ''et al.'' |title=Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=451–9 |year=2004 |month=July |pmid=15282352 |doi=10.1056/NEJMoa032653}}</ref> Both groups received ribavirin (600&nbsp;mg for 4 weeks, 800&nbsp;mg for
</ref> Both groups received ribavirin (600&nbsp;mg for 4 weeks, 800&nbsp;mg for
four weeks and then 1000&nbsp;mg daily for the remainder of the study). The
four weeks and then 1000&nbsp;mg daily for the remainder of the study). The
main endpoint was to detect the differences in virologic response rates between the two groups. At week 24, subjects who did not have a virologic response underwent a [[liver biopsy]] and treatment was continued in patients who showed a histological improvement.
main endpoint was to detect the differences in virologic response rates between the two groups. At week 24, subjects who did not have a virologic response underwent a [[liver biopsy]] and treatment was continued in patients who showed a histological improvement.


===Tolerability===
===Tolerability===
In the first trial, approximately the same number of patients from each group withdrew due to laboratory abnormalities or adverse events.<ref> Carrat F, Bani-Sadr F, Stanislas P, ''et al.'' "Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients." ''JAMA'' 2004; 292: 2839-2847. </ref> The doses were modified more frequently in the peginterferon group due to lab abnormalities (7% vs 20%) or adverse events (7% vs 16%) (p=0.004). Neutropenia (p=0.04) and weight loss (p=0.03) were significantly higher in the peginterferon group; whereas, insomnia was higher in the interferon group (p=0.02). In the second study, 12% in each group withdrew due to lab abnormalities or adverse
In the first trial, approximately the same number of patients from each group withdrew due to laboratory abnormalities or adverse events.<ref>{{cite journal |author=Carrat F, Bani-Sadr F, Pol S, ''et al.'' |title=Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial |journal=JAMA |volume=292 |issue=23 |pages=2839–48 |year=2004 |month=December |pmid=15598915 |doi=10.1001/jama.292.23.2839}}</ref> The doses were modified more frequently in the peginterferon group due to lab abnormalities (7% vs 20%) or adverse events (7% vs 16%) (p=0.004). Neutropenia (p=0.04) and weight loss (p=0.03) were significantly higher in the peginterferon group; whereas, insomnia was higher in the interferon group (p=0.02). In the second study, 12% in each group withdrew due to lab abnormalities or adverse
events.<ref> Chung RT, Anderson J, Volberding P, ''et al.'' "Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons." ''N Engl J Med.'' 2004;351: 451-459.
events.<ref>{{cite journal |author=Chung RT, Andersen J, Volberding P, ''et al.'' |title=Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=451–9 |year=2004 |month=July |pmid=15282352 |doi=10.1056/NEJMoa032653}}</ref> Both groups experienced similar number of episodes of neutropenia, but two subjects in the peginterferon group dropped out due to grade 4 neutropenia.
</ref> Both groups experienced similar number of episodes of neutropenia, but two subjects in the peginterferon group dropped out due to grade 4 neutropenia.


The other patients were managed by dose reduction. One case of
The other patients were managed by dose reduction. One case of
clinically significant pancreatitis occurred in a patient who was receiving didanosine. In the last study, about the same number of patients dropped out of the study due to lab abnormalities, but the patients who dropped out from adverse reactions varied.<ref> Torriani FJ, Rodriguez-Torres M, Rockstroh JK, ''et al.'' "Peginterferon alfa-2a plus ribavirin for chronic hepatits C virus infection in HIV-infected patients." ''N Engl J Med.'' 2004;351:438-450 </ref> Overall, most patients withdrew from the interferon plus ribavirin arm and the least from the peginterferon plus ribavirin arm.
clinically significant pancreatitis occurred in a patient who was receiving didanosine. In the last study, about the same number of patients dropped out of the study due to lab abnormalities, but the patients who dropped out from adverse reactions varied.<ref>{{cite journal |author=Torriani FJ, Rodriguez-Torres M, Rockstroh JK, ''et al.'' |title=Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=438–50 |year=2004 |month=July |pmid=15282351 |doi=10.1056/NEJMoa040842}}</ref> Overall, most patients withdrew from the interferon plus ribavirin arm and the least from the peginterferon plus ribavirin arm.


The major difference was that there was a higher incidence of [[neutropenia]] in the peginterferon groups.
The major difference was that there was a higher incidence of [[neutropenia]] in the peginterferon groups.


===Predictors of an SVR===
===Predictors of an SVR===
In the trials described above, the only common predictor of SVR among all three was the treatment of HCV other than type 1.6-8 In the trial by Chung ''et al.'', patient characteristics that predicted an SVR were treatment with peginterferon and ribavirin, absence of prior drug abuse, a detectable level of HIV-1 RNA, and a Karnofsky score of 100.<ref> Chung RT, Anderson J, Volberding P, ''et al.'' "Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons." ''N Engl J Med.'' 2004;351: 451-459 </ref> The Karnofsky score is a subjective measure of how well the patient is doing. A score of 100 indicates that the patient has no complaints or evidence of disease, a score of 50 indicates that the patient requires considerable assistance and frequent medical care, and a score of 0 indicates that the patient is dead. In the study by Carrat et al., no protease inhibitor therapy, an age of 40 years or younger, or a baseline alanine aminotransferase greater than three times the upper limit of normal predicted a sustained virological response.<ref> Carrat F, Bani-Sadr F, Stanislas P, ''et al.'' "Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients." ''JAMA'' 2004; 292: 2839-2847 </ref> In the study by Torrani ''et al.'', SVR was predicted by HCV [[genotype]] other than 1 and a baseline HCV RNA level of 800,000 IU or less per milliliter.<ref> Torriani FJ, Rodriguez-Torres M, Rockstroh JK, ''et al.'' "Peginterferon alfa-2a plus ribavirin for chronic hepatits C virus infection in HIV-infected patients." ''N Engl J Med.'' 2004;351:438-450 </ref>
In the trials described above, the only common predictor of SVR among all three was the treatment of HCV other than type 1.6-8 In the trial by Chung ''et al.'', patient characteristics that predicted an SVR were treatment with peginterferon and ribavirin, absence of prior drug abuse, a detectable level of HIV-1 RNA, and a Karnofsky score of 100.<ref>{{cite journal |author=Chung RT, Andersen J, Volberding P, ''et al.'' |title=Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=451–9 |year=2004 |month=July |pmid=15282352 |doi=10.1056/NEJMoa032653}}</ref> The Karnofsky score is a subjective measure of how well the patient is doing. A score of 100 indicates that the patient has no complaints or evidence of disease, a score of 50 indicates that the patient requires considerable assistance and frequent medical care, and a score of 0 indicates that the patient is dead. In the study by Carrat et al., no protease inhibitor therapy, an age of 40 years or younger, or a baseline alanine aminotransferase greater than three times the upper limit of normal predicted a sustained virological response.<ref>{{cite journal |author=Carrat F, Bani-Sadr F, Pol S, ''et al.'' |title=Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial |journal=JAMA |volume=292 |issue=23 |pages=2839–48 |year=2004 |month=December |pmid=15598915 |doi=10.1001/jama.292.23.2839}}</ref> In the study by Torrani ''et al.'', SVR was predicted by HCV [[genotype]] other than 1 and a baseline HCV RNA level of 800,000 IU or less per milliliter.<ref>{{cite journal |author=Torriani FJ, Rodriguez-Torres M, Rockstroh JK, ''et al.'' |title=Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=438–50 |year=2004 |month=July |pmid=15282351 |doi=10.1056/NEJMoa040842}}</ref>


In a study involving 21 HIV co-infected patients (DICO) <ref>Falconer et al. HCV/HIV co-infection at a large HIV outpatient clinic in Sweden: feasibility and results of hepatitis C treatment. Scand J Infect Dis. 2009;41(11-12):881-5. [http://www.ncbi.nlm.nih.gov/pubmed/19922074 PMID 19922074]</ref>, pre-treatment baseline plasma levels of IP-10 predicted the reduction of HCV RNA during the first days of interferon/ribavirin therapy (“first phase decline”) for HCV genotypes 1-3 <ref>Falconer et al. IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV. Scand J Infect Dis. 2010 Jul 7. (Epub ahead of print). [http://www.ncbi.nlm.nih.gov/pubmed/ 20608766 PMID 20608766]</ref>, as is also the case in HCV mono-infected patients <ref>Romero et al. Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection. J Infect Dis. 2006 Oct 1;194(7):895-903. [http://www.ncbi.nlm.nih.gov/pubmed/16960776 PMID16960776]</ref><ref>Lagging et al. IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection. Hepatology. 2006 Dec;44(6):1617-25. [http://www.ncbi.nlm.nih.gov/pubmed/17133471 PMID17133471]</ref><ref>Askarieh et al. Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepatology. May;51(5):1523-30. [http://www.ncbi.nlm.nih.gov/pubmed/20186843 PMID20186843]</ref>. Pre-treatment IP-10 levels below 150 pg/mL are predictive of a favorable response, and may thus be useful in encouraging these otherwise difficult-to-treat patients to initiate therapy <ref>Falconer et al. IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV. Scand J Infect Dis. 2010 Jul 7. (Epub ahead of print). [http://www.ncbi.nlm.nih.gov/pubmed/ 20608766 PMID 20608766]</ref>.
In a study involving 21 HIV co-infected patients (DICO),<ref>{{cite journal |author=Falconer K, Sandberg JK, Reichard O, Alaeus A |title=HCV/HIV co-infection at a large HIV outpatient clinic in Sweden: feasibility and results of hepatitis C treatment |journal=Scandinavian Journal of Infectious Diseases |volume=41 |issue=11-12 |pages=881–5 |year=2009 |pmid=19922074 |doi=10.3109/00365540903214272}}</ref> pre-treatment baseline plasma levels of IP-10 predicted the reduction of HCV RNA during the first days of interferon/ribavirin therapy (“first phase decline”) for HCV genotypes 1-3,<ref>{{cite journal |author=Falconer K, Askarieh G, Weis N, Hellstrand K, Alaeus A, Lagging M |title=IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV |journal=Scandinavian Journal of Infectious Diseases |volume= |issue= |pages= |year=2010 |month=July |pmid=20608766 |doi=10.3109/00365548.2010.498019}}</ref> as is also the case in HCV mono-infected patients.<ref>{{cite journal |author=Romero AI, Lagging M, Westin J, ''et al.'' |title=Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection |journal=The Journal of Infectious Diseases |volume=194 |issue=7 |pages=895–903 |year=2006 |month=October |pmid=16960776 |doi=10.1086/507307}}</ref><ref>{{cite journal |author=Lagging M, Romero AI, Westin J, ''et al.'' |title=IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection |journal=Hepatology |volume=44 |issue=6 |pages=1617–25 |year=2006 |month=December |pmid=17133471 |doi=10.1002/hep.21407}}</ref><ref>{{cite journal |author=Askarieh G, Alsiö A, Pugnale P, ''et al.'' |title=Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C |journal=Hepatology |volume=51 |issue=5 |pages=1523–30 |year=2010 |month=May |pmid=20186843 |doi=10.1002/hep.23509}}</ref> Pre-treatment IP-10 levels below 150 pg/mL are predictive of a favorable response, and may thus be useful in encouraging these otherwise difficult-to-treat patients to initiate therapy.<ref>{{cite journal |author=Falconer K, Askarieh G, Weis N, Hellstrand K, Alaeus A, Lagging M |title=IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV |journal=Scandinavian Journal of Infectious Diseases |volume= |issue= |pages= |year=2010 |month=July |pmid=20608766 |doi=10.3109/00365548.2010.498019}}</ref>


==Notes==
==Notes==
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==References==
==References==
{{Refbegin}}
{{Refbegin}}
*Anderson KB, Guest JL, Rimland D.; "Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active retroviral therapy era: data from the HIV Atlanta VA cohort study." ''Clin Inf Dis'' 2004;39:1507-13.
*{{cite journal |title=Hepatitis C virus coinfection increases mortality in HIV-infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA Cohort Study |journal=Clinical Infectious Diseases |volume=39 |issue=10 |pages=1507–13 |year=2004 |month=November |pmid=15546088 |doi=10.1086/425360 |ref=harv}}
*Brau, Norbert. "Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin." ''Semin Liver Dis.'' 2005;25:33-51.
*{{cite journal |title=Treatment of chronic hepatitis C in human immunodeficiency virus/hepatitis C virus-coinfected patients in the era of pegylated interferon and ribavirin |journal=Seminars in Liver Disease |volume=25 |issue=1 |pages=33–51 |year=2005 |month=February |pmid=15731996 |doi=10.1055/s-2005-864780 |ref=harv}}
*Carrat F, Bani-Sadr F, Stanislas P, ''et al.'' "Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients." ''[[Journal of the American Medical Association|JAMA]]'' 2004; 292: 2839-2847.
*{{cite journal |title=Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial |journal=JAMA |volume=292 |issue=23 |pages=2839–48 |year=2004 |month=December |pmid=15598915 |doi=10.1001/jama.292.23.2839 |ref=harv}}
*Chung RT, Anderson J, Volberding P, ''et al.'' "Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons." ''N Engl J Med.'' 2004;351: 451-459.
*{{cite journal |title=Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=451–9 |year=2004 |month=July |pmid=15282352 |doi=10.1056/NEJMoa032653 |ref=harv}}
*{{cite book |first1=Louis Sanford |last1=Goodman |first2=Alfred Goodman |last2=Gilman |editor1-first=Joel G. |editor1-last=Hardman |editor2-first=Lee E. |editor2-last=Limbird |editor3-first=Alfred Goodman |editor3-last=Gilman |title=Goodman & Gilman's the pharmacological basis of therapeutics |publisher=McGraw-Hill |location=New York |year=2001 |pages= |isbn=978-0-07-135469-1 |ref=harv}}
*Goodman and Gilman ''The pharmacological basis of therapeutics.'' c2002.
*{{cite journal |title=Peginterferon-alpha-2a (40kD) plus ribavirin: a review of its use in hepatitis C Virus And HIV co-infection |journal=Drugs |volume=64 |issue=24 |pages=2823–43 |year=2004 |pmid=15563253 |doi= |url=http://content.wkhealth.com/linkback/openurl?issn=0012-6667&volume=64&issue=24&spage=2823 |ref=harv}}
*Plosker GL, Keating GM. "Peginterferon-¿-2a (40kD) plus ribavirin." ''Drugs'' 2004;64: 2823-2843.
*Sulkowski MS, Dieterich DT, Bini EJ, Bräu N, Alvarez D, ''et al.'' "Epoetin alfa once weekly improves anemia in HIV/hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomized controlled trial." ''JAIDS'' 2005; 39:504-506.
*{{cite journal |title=Epoetin alfa once weekly improves anemia in HIV/hepatitis C virus-coinfected patients treated with interferon/ribavirin: a randomized controlled trial |journal=Journal of Acquired Immune Deficiency Syndromes |volume=39 |issue=4 |pages=504–6 |year=2005 |month=August |pmid=16010180 |doi= |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=1525-4135&volume=39&issue=4&spage=504 |ref=harv}}
*{{cite journal |title=Hepatitis C in the HIV-Infected Person |journal=Annals of Internal Medicine |volume=138 |issue=3 |pages=197–207 |year=2003 |month=February |pmid=12558359 |doi= |url=http://www.annals.org/cgi/pmidlookup?view=long&pmid=12558359 |ref=harv}}
*Sulkowski, MS, Thomas, DL. "Hepatitis C in the HIV-infected person." ''Ann Intern Med.'' 2003;138:197-207.
*Torriani FJ, Rodriguez-Torres M, Rockstroh JK, ''et al.'' "Peginterferon alfa-2a plus ribavirin for chronic hepatits C virus infection in HIV-infected patients." ''N Engl J Med.'' 2004;351:438-450.
*{{cite journal |title=Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients |journal=The New England Journal of Medicine |volume=351 |issue=5 |pages=438–50 |year=2004 |month=July |pmid=15282351 |doi=10.1056/NEJMoa040842 |ref=harv}}
{{Refend}}
{{Refend}}


Revision as of 13:32, 26 August 2010

In HIV/HCV co-infected patients, the Hepatitis C (HCV) viral load is higher than in HCV-mono-infected patients in both the plasma and liver tissue. Patients who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission: percutaneous exposure to blood, sexual intercourse, and from a mother to her infant. Infection with HCV can be asymptomatic, self-limiting, or progress to cirrhosis or cancer.

Characteristics

The morbidity and mortality caused by HCV has increased since the inception of highly active antiretroviral therapy (HAART) because HIV patients are living longer from potent antiretroviral therapies and prophylaxis of traditional opportunistic infections. The effect of HCV on the natural history of HIV remains inconclusive due to contradictory studies documenting no effect, while others show an increase to an AIDS defining illness or death. In the United States, approximately 150,000 to 300,000 people are co-infected with HIV and HCV. This represents 15% to 30% of all HIV infected patients and 5% to 10% of all HCV patients. Reduced HCV antibody production, drug interactions, other causes of liver disease, differing epidemiologic characteristics and natural history complicate the management of HCV/HIV patients. Until recently there was little data published regarding treating HIV/HCV co-infected patients; fortunately recent trials have been published about the safety and efficacy of current treatment options.

Treatment

The primary objective of HCV therapy is permanent eradication of the virus. The secondary potential benefit of eradication is a reduction in the risk of liver failure and liver cancer. Currently, peginterferon alfa-2a plus ribavirin is the only FDA approved treatment for HIV/HCV co-infected patients. Interferons bind to specific cell surface receptors of virus-infected cells, which induces a complex cascade of protein-protein interactions and a rapid activation of gene transcription. The antiviral effects of interferons are mediated through inhibition of viral penetration or uncoating, inhibiting viral replication or translation of viral proteins, and/or viral assembly and release. The difference between peginterferon and interferon is the addition of a polyethylene glycol (PEG) polymer. The addition of PEG decreases plasma clearance considerably, protects the molecule from proteolytic degradation and reduces its immunogenicity. Peak concentrations are approximately 1.5-2 fold higher than trough concentrations and the half-life is 80 hours (compared to 5.1 hours for interferon alpha-2a). Ribavirin is a synthetic nucleoside analogue, but its mechanism of action is not clearly established. Ribavirin inhibits the replication of a wide range of RNA and DNA viruses. Pharmacokinetics are similar in patients with HIV co-infection compared with HCV mono-infection.

Pegylated Interferon Alfa-2B (Peg Intron) plus Ribavirin versus Standard Interferon Alfa-2B (Intron A) plus Ribavirin

This was a randomized, phase 3, open-label, parallel group study. Four hundred sixteen treatment naïve patients were assigned to 1.5 mcg/kg peginterferon alfa-2b once weekly plus ribavirin 800 mg daily or 3 million units of standard interferon alfa-2a plus ribavirin 800 mg daily for 48 weeks.6 Patients were evaluated at weeks 2 and 4, then every 4 weeks after treatment and then at weeks 4, 12, and 24 post-treatment until week 72 was reached. The primary end-point was a sustained viral response (SVR), defined as undetectable serum HCV-RNA at week 72. The secondary endpoint was histological improvement. In the standard interferon group, 20% of the 207 patients obtained an SVR, and in the peginterferon group 27% of the 205 patients (p=0.047) obtained an SVR. At week 24, undectable HCV RNA levels were achieved in 28% and 40% of patients, respectively (p=0.004), respectively. At 48 weeks, the end of treatment virologic responses were 21% and 35% of their respective groups (p=0.001). In patients who had genotype 1 or 4, peginterferon achieved a higher rate of SVR (17%) than interferon (6%) p=0.006. However, in genotypes 2, 3 or 5, the rates of SVR were similar. The withdrawal and adverse event rates were similar.

Pegylated Interferon Alfa-2A (Pegasys) plus Ribavirin versus Interferon Alfa-2A plus Ribavirin

In the study by Chung, et al. 66 treatment-naïve patients received 180 mcg weekly of peginterferon or 6 million units thrice weekly of interferon for 12 weeks and then switched to 3 million units thrice weekly for 48 weeks.[1] Both groups received ribavirin (600 mg for 4 weeks, 800 mg for four weeks and then 1000 mg daily for the remainder of the study). The main endpoint was to detect the differences in virologic response rates between the two groups. At week 24, subjects who did not have a virologic response underwent a liver biopsy and treatment was continued in patients who showed a histological improvement.

Tolerability

In the first trial, approximately the same number of patients from each group withdrew due to laboratory abnormalities or adverse events.[2] The doses were modified more frequently in the peginterferon group due to lab abnormalities (7% vs 20%) or adverse events (7% vs 16%) (p=0.004). Neutropenia (p=0.04) and weight loss (p=0.03) were significantly higher in the peginterferon group; whereas, insomnia was higher in the interferon group (p=0.02). In the second study, 12% in each group withdrew due to lab abnormalities or adverse events.[3] Both groups experienced similar number of episodes of neutropenia, but two subjects in the peginterferon group dropped out due to grade 4 neutropenia.

The other patients were managed by dose reduction. One case of clinically significant pancreatitis occurred in a patient who was receiving didanosine. In the last study, about the same number of patients dropped out of the study due to lab abnormalities, but the patients who dropped out from adverse reactions varied.[4] Overall, most patients withdrew from the interferon plus ribavirin arm and the least from the peginterferon plus ribavirin arm.

The major difference was that there was a higher incidence of neutropenia in the peginterferon groups.

Predictors of an SVR

In the trials described above, the only common predictor of SVR among all three was the treatment of HCV other than type 1.6-8 In the trial by Chung et al., patient characteristics that predicted an SVR were treatment with peginterferon and ribavirin, absence of prior drug abuse, a detectable level of HIV-1 RNA, and a Karnofsky score of 100.[5] The Karnofsky score is a subjective measure of how well the patient is doing. A score of 100 indicates that the patient has no complaints or evidence of disease, a score of 50 indicates that the patient requires considerable assistance and frequent medical care, and a score of 0 indicates that the patient is dead. In the study by Carrat et al., no protease inhibitor therapy, an age of 40 years or younger, or a baseline alanine aminotransferase greater than three times the upper limit of normal predicted a sustained virological response.[6] In the study by Torrani et al., SVR was predicted by HCV genotype other than 1 and a baseline HCV RNA level of 800,000 IU or less per milliliter.[7]

In a study involving 21 HIV co-infected patients (DICO),[8] pre-treatment baseline plasma levels of IP-10 predicted the reduction of HCV RNA during the first days of interferon/ribavirin therapy (“first phase decline”) for HCV genotypes 1-3,[9] as is also the case in HCV mono-infected patients.[10][11][12] Pre-treatment IP-10 levels below 150 pg/mL are predictive of a favorable response, and may thus be useful in encouraging these otherwise difficult-to-treat patients to initiate therapy.[13]

Notes

  1. ^ Chung RT, Andersen J, Volberding P; et al. (2004). "Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons". The New England Journal of Medicine. 351 (5): 451–9. doi:10.1056/NEJMoa032653. PMID 15282352. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Carrat F, Bani-Sadr F, Pol S; et al. (2004). "Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial". JAMA. 292 (23): 2839–48. doi:10.1001/jama.292.23.2839. PMID 15598915. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Chung RT, Andersen J, Volberding P; et al. (2004). "Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons". The New England Journal of Medicine. 351 (5): 451–9. doi:10.1056/NEJMoa032653. PMID 15282352. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Torriani FJ, Rodriguez-Torres M, Rockstroh JK; et al. (2004). "Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients". The New England Journal of Medicine. 351 (5): 438–50. doi:10.1056/NEJMoa040842. PMID 15282351. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Chung RT, Andersen J, Volberding P; et al. (2004). "Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons". The New England Journal of Medicine. 351 (5): 451–9. doi:10.1056/NEJMoa032653. PMID 15282352. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Carrat F, Bani-Sadr F, Pol S; et al. (2004). "Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial". JAMA. 292 (23): 2839–48. doi:10.1001/jama.292.23.2839. PMID 15598915. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Torriani FJ, Rodriguez-Torres M, Rockstroh JK; et al. (2004). "Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients". The New England Journal of Medicine. 351 (5): 438–50. doi:10.1056/NEJMoa040842. PMID 15282351. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Falconer K, Sandberg JK, Reichard O, Alaeus A (2009). "HCV/HIV co-infection at a large HIV outpatient clinic in Sweden: feasibility and results of hepatitis C treatment". Scandinavian Journal of Infectious Diseases. 41 (11–12): 881–5. doi:10.3109/00365540903214272. PMID 19922074.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Falconer K, Askarieh G, Weis N, Hellstrand K, Alaeus A, Lagging M (2010). "IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV". Scandinavian Journal of Infectious Diseases. doi:10.3109/00365548.2010.498019. PMID 20608766. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Romero AI, Lagging M, Westin J; et al. (2006). "Interferon (IFN)-gamma-inducible protein-10: association with histological results, viral kinetics, and outcome during treatment with pegylated IFN-alpha 2a and ribavirin for chronic hepatitis C virus infection". The Journal of Infectious Diseases. 194 (7): 895–903. doi:10.1086/507307. PMID 16960776. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Lagging M, Romero AI, Westin J; et al. (2006). "IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection". Hepatology. 44 (6): 1617–25. doi:10.1002/hep.21407. PMID 17133471. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Askarieh G, Alsiö A, Pugnale P; et al. (2010). "Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C". Hepatology. 51 (5): 1523–30. doi:10.1002/hep.23509. PMID 20186843. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Falconer K, Askarieh G, Weis N, Hellstrand K, Alaeus A, Lagging M (2010). "IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV". Scandinavian Journal of Infectious Diseases. doi:10.3109/00365548.2010.498019. PMID 20608766. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

References

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