HIV coinfection with hepatitis c


 * , Ujjwal Rastogi, MBBS [mailto:urastogi@perfuse.org]

Overview
HIV has been an important and familiar health and social crisis for two decades. Less familiar, but also important, is HCV infection. 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.

Similarity between Hepatitis C with HIV: These two viruses are similar in a number of ways, and infection with both is a serious problem. Both HCV and HIV are transmitted by exposure to infected blood. About one-quarter of the people infected with HIV also have HCV.

Cause of Co-infection
Patients who are HIV-positive are commonly co-infected with HCV due to the following:
 * Shared routes of transmission.
 * Percutaneous exposure to blood.
 * Sexual intercourse.
 * From a mother to her infant.

Pathophysiology
HIV’s effect on Hepatitis C: Studies have shown that HIV infection in a person who is also infected with HCV results in higher levels of HCV in the blood, more rapid progression to HCV-related liver disease, and increased risk for cirrhosis and liver cancer. As a result, HCV is now regarded as an opportunistic infection in people with HIV infection, although it is not considered an AIDS-defining illness.

HCV’s effect on HIV: Some research suggests that infection with genotype 1 HCV is associated with more rapid progression to AIDS or death, although this is still controversial. Most people with HCV infection in the U.S. have genotype 1. Genotypes 2 and 3 are more common in Europe. Some evidence also indicates that HCV is associated with impaired CD4+ T cell recovery during antiretroviral therapy.

Epidemiology
The majority of coinfected people are injection drug user (IDUs). HCV is acquired relatively soon after individuals begin injecting drugs. Within 5 years of beginning to inject, 50% to 80% of IDUs are infected with HCV. As a result, many IDUs who become infected with HIV are already infected with HCV. It is estimated that 50% to 90% of IDUs with HIV also have HCV.

Between 1996 and 2000, more than 80% of the patients admitted to a large HIV/AIDS care center in Madrid, Spain, were IDUs. The proportion of these patients who were admitted because of liver failure almost doubled, from 9% to 16%.

Prevalence
About one-third of people with HIV are coinfected with hepatitis B virus (HBV) or hepatitis C virus (HCV), with a considerably higher prevalence among injection-drug users.

Natural History
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. 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. Infection with HCV can be asymptomatic, self-limiting, or progress to cirrhosis or cancer.

Complications
Over years or decades chronic hepatitis B and C can progress to serious liver disease including cirrhosis and liver cancer. HIV positive people with HBV or HCV tend to experience more rapid disease progression and do not respond as well to hepatitis treatment. End-stage liver disease is now the cause of death for 45% of HIV-infected patients in this hospital. HCV infection was the cause of the liver disease in nearly three-quarters of the HIV patients who were admitted or died during the course of the study.

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.

Role & Importance of treatment
The introduction in the mid-1990s of highly active antiretroviral therapy (HAART) for HIV has caused a sharp drop in the number of deaths from AIDS. This means that people with HIV are living longer. Therefore, if they are coinfected, the complications from HCV have more time to develop. These complications (cirrhosis, liver cancer, end-stage liver disease) generally develop over 20-30 years.

Liver disease from HCV is now the leading non-AIDS cause of death in the U.S. in coinfected individuals with HIV. Treatment for each disease is complicated, expensive, and has side effects. This poses difficult issues for patients who are living with both HIV and HCV. Finally, coinfection is important because it has a disproportionate impact on certain communities, including those in prison and jail and communities of color.

Regimen
The Food and Drug Administration (FDA) has approved two antiviral drugs for the treatment of chronic hepatitis C:
 * Alpha interferon or an improved form of interferon, called pegylated interferon
 * Ribavirin

Interferon is given alone or in combination with ribavirin usually for a 12-month period to patients with chronic hepatitis C who are at greatest risk of developing serious liver disease.

Interferon
Mechanism of action: 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.

Difference between peginterferon and interferon: 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.

Ribavirin
It is a synthetic nucleoside analogue, 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.

General recommendations
Coinfected IDUs should do the following:
 * Stop injecting drugs.
 * 1) Get into substance abuse treatment.
 * 2) Stay in treatment.
 * 3) If they are not able to stop, they should use sterile syringes and equipment and not share drug solution, syringes, or preparation equipment (needles, drug solution containers, water, cotton filters).
 * Stop drinking alcoholic beverages; If they are not able to stop, they should limit drinking because alcohol contributes to liver damage; when appropriate, they should be referred to alcohol treatment and relapse-prevention programs.
 * Practice safer personal care and sexual behaviors; Not sharing toothbrushes and razors, using condoms consistently, limiting the number of sex partners, getting treatment for sexually transmitted diseases.
 * Be immunized against hepatitis A and hepatitis B, unless they are already immune from past exposure.
 * Regular check-ups to monitor overall health and status of liver disease; coinfected individuals on HAART may be at increased risk of liver toxicity and should be closely monitored.

Treatment issues for coinfected individuals

 * Treatment for each of these diseases involves long-term therapy with multiple powerful drugs.
 * Adherence to either treatment regimen is critically important to their success, and for HIV, to prevent resistance from developing.
 * These issues are compounded for individuals who are living with both treatment regimens.
 * Treatment for either disease also has side effects, which should be closely monitored.
 * Therapy with interferon alone appears to be reasonably well tolerated in co-infected patients; However, combination therapy (with ribavirin) may result in severe complications, including death. Until further safety data are available, combination therapy should be used with caution.
 * Another factor to consider is that effectiveness of treatment may be influenced by factors such as the person’s age, how healthy he or she is at the beginning of therapy, the degree of existing liver disease, the person’s CD4 count, and the extent of any other HIV-related illnesses.

Landmark Trials
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. 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. 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.

Prevention
There is no vaccine for hepatitis C. The best way to prevent hepatitis C infection is to never inject drugs, or to stop injecting drugs if you currently do so by getting into and staying in a drug treatment program.

If injecting drugs is continued, new sterile syringes must be used and once used or share syringes, needles, water, or other drug preparation equipment should be completely avoided.

==Recommendations for Diagnosis and Treatment of Persons with HIV Coinfection: AASLD Practice Guidelines 2009 == 1. Anti-HCV testing should be performed in all HIV-infected persons (Class I, Level B).

2. HCV RNA testing should be performed to conﬁrm HCV infection in HIV-infected persons who are positive for anti-HCV, as well as in those who are negative and have evidence of unexplained liver disease (Class I, Level B).

3. Hepatitis C should be treated in the HIV/HCV co-infected patient in whom the likelihood of serious liver disease and a treatment response are judged to outweigh the risk of morbidity from the adverse effects of therapy (Class I, Level A).

4. Initial treatment of hepatitis C in most HIV infected patients should be peginterferon alfa plus ribavirin for 48 weeks at doses recommended for HCV mono-infected patients (Class I, Level A).

5. When possible, patients receiving zidovudine (AZT) and especially didanosine (ddI) should be switched to an equivalent antiretroviral agent before beginning therapy with ribavirin (Class I, Level C).

6. HIV-infected patients with decompensated liver disease (CTP Class B or C) should not be treated with peginterferon alfa and ribavirin and may be candidates for liver transplantation (Class IIa, Level C).

Related Chapters

 * Coinfection
 * AIDS
 * HIV disease
 * Hepatitis B with HIV coinfection
 * Tuberculosis and HIV coinfection
 * HIV and tuberculosis coinfection : drug interaction