Hepatitis C/co-infection with HIV

Overview
Patients who are HIV-positive are commonly co-infected with the Hepatitis C virus (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. In HIV/HCV co-infected patients, the HCV viral load is higher than in HCV-mono-infected patients in both the plasma and liver tissue.

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 options
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 Eibavirin
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 800mg daily or 3 million units of standard interferon alfa-2a plus ribavirin 800mg 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 a SVR, and in the peginterferon group 27% of the 205 patients (p=0.047) obtained a 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. Both groups received ribavirin (600mg for 4 weeks, 800mg for four weeks and then 1000mg 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. 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. 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. 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 a 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 a 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. 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. 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.