Current challenges in hepatitis C.

Hepatitis C is a global health problem. Worldwide, approximately 170 million people have been infected with the hepatitis C virus (HCV). In the US, at least 4 million people have been infected with hepatitis C, and an estimated 250,000 are HIV/HCV co-infected. Despite a growing appreciation of the severity of the hepatitis C epidemic, gaps in hepatitis C research and policy span the continuum from prevention to liver transplantation.

Prevention: Policy and research needs

Initiatives to raise awareness of hepatitis C; prevent new infections; offer potentially life-saving hepatitis A and B vaccinations; and diagnose, monitor, and treat people with hepatitis C have been hampered by inadequate funding. Surveillance of acute hepatitis C infections is conducted nationally, but because only 20% of acutely infected persons are symptomatic, most new infections go undiagnosed. In terms of chronic hepatitis C disease, surveillance is conducted only through a pilot program in which physicians report to sentinel sites. Comprehensive data collected from a national surveillance system is needed to advocate for sufficient funding to prevent, diagnose, and treat hepatitis C.

Effective disease prevention combines information about transmission with access to prevention tools and services. People must know how HCV is transmitted and how to reduce their risk of infection. Even though the majority of new hepatitis C infections in the US are acquired through injection drug use (IDU), hepatitis C is also more prevalent among men who have sex with men (MSM), partners of HIV/HCV co-infected persons, sex workers, people who have had multiple sex partners, and non-injection drug users than among the general population. However, the routes of transmission in such cases and the risks of specific sexual acts have not been adequately clarified.

Given that the major route of HCV transmission is via IDU, hepatitis C will continue to spread until injection equipment is widely available through pharmacy sale and syringe exchange programs. We must end the ban on federal funding of syringe exchange programs. These programs are a valuable resource to communities of injection drug users and typically function as an entry point into a range of services and healthcare.

Access to care and treatment

Both hepatitis C and HIV are disproportionately prevalent among African-Americans, people living in poverty, and incarcerated persons--groups who have had little or no access to healthcare. The number of uninsured people in the US has grown to more than 43 million, while inadequate federal funding has left states scrambling to contain the costs of AIDS Drug Assistance Programs (ADAPs) and Medicaid by limiting eligibility. The current scenario is grim for co-infected ADAP beneficiaries seeking hepatitis C treatment because most states cannot afford to add costly hepatitis C treatments to ADAP formularies. It is not clear how the new Medicare prescription drug benefit will affect access to hepatitis C treatment when introduced in 2006.

In the US, more than 2 million people are incarcerated. Hepatitis C is endemic in correctional facilities; estimates of hepatitis C prevalence among inmates range from 255,000 to more than 500,000. To complicate matters, hepatitis C treatment policies differ in each state. Duration of residency requirements are often used by correctional facilities as a method for withholding hepatitis C treatment from prisoners, regardless of the urgency of their need. Making treatment accessible to prisoners entails more than just providing the drugs. Peer support and education about hepatitis C, side effects of therapy, and access to mental health care must be provided as well.

Addressing needs of current and former drug users

Despite an HCV prevalence rate of 50% to 90%, injection drug users face enormous barriers to care and treatment. Until 2002, active injection drug use was a contraindication for treating hepatitis C. Many clinicians still withhold treatment from injection drug users instead of making a case-by-case decision with each patient, as recommended by the National Institutes of Health Consensus Statement on Management of Hepatitis C: 2002.

If we are to treat hepatitis C successfully, the medical and mental health care needs of current and former drug users must be prioritized. Many clinicians do not receive any training on working with patients with drug and/or alcohol dependency. Providers who have received additional education report feeling more confident about their capacity to care for people who are dependent on drugs and/or alcohol.

Harm reduction must be integrated into medical care. Clinicians must provide active drug users with options to reduce the risk of becoming re-infected with hepatitis C, acquiring HIV, and being exposed to other blood-borne pathogens. Options to mitigate consequences of drug use include demonstration of safer injection techniques, prescription of syringes, referral upon request to drug treatment or methadone maintenance programs, and prescription of buprenorphine (a treatment for opiate and cocaine addiction).

Treatment guidelines and provider education

In the US, there are separate treatment guidelines for HIV and hepatitis C. These resources have not been integrated into guidelines specifically for treatment of hepatitis C in persons co-infected with HIV. In turn, there are no guidelines for selecting and monitoring HIV treatment in persons with hepatitis C co-infection, despite their increased risk for antiretroviral-induced hepatotoxicity and metabolic abnormalities. Care and treatment guidelines for HIV/HCV co-infection would be an essential resource for both clinicians and patients.

In the absence of treatment guidelines, the need for provider and patient education is even greater. Primary care providers are not always sufficiently knowledgeable about hepatitis C. Also, HIV/HCV co-infected people do not always receive care from a specialist in liver disease. Some people are left to coordinate their own care between different providers. Peer programming and support groups are an enormous resource for people who are considering treatment or treating hepatitis C, especially because our healthcare system is hobbled by managed care and poorly equipped to provide the multidisciplinary care and support required for a disease as complex as hepatitis C.

Managing side effects of hepatitis C treatment

Hepatitis C treatment may induce many side effects, most commonly fatigue, flu-like symptoms, neuropsychiatric symptoms, and hematologic abnormalities (anemia, neutropenia, and thrombocytopenia). In rare instances, interferon can result in severe depression, suicidal ideation, or suicide. Side effects may be more severe for HIV/HCV co-infected persons, who also may experience interactions between HCV and HIV treatments. A sustained virologic response to hepatitis C treatment is more likely among people who are able to adhere to at least 80% of their full doses of ribavirin and pegylated interferon for at least 80% of the entire duration of therapy. Adherence must be supported by informing patients about all possible side effects of therapy and strategies for their management. Although depression is a common side effect of interferon, we have much to learn about the causal mechanism(s) and management of interferon-induced depression. Pre-emptive treatment of depression is often used clinically, but has not been evaluated in a randomized clinical trial.

Research gaps: Optimizing hepatitis C treatment

Large hepatitis C treatment trials have historically under-enrolled African-Americans and excluded active drug users and those with psychiatric disorders. As these trials do not reflect the demographics of the hepatitis C epidemic, the safety and efficacy data from these trials may not be applicable to members of high-prevalence populations. Hepatitis C therapy has also not been adequately studied in children and the elderly.

More research is needed to improve hepatitis C treatment outcomes for people with HCV genotype 1 and a high viral load, African-Americans, non-responders to previous HCV treatment, and people who are co-infected with HIV. Because hepatitis C treatment is less effective for HIV-positive people, several strategies to increase sustained virologic response rates merit investigation:

* Extending the duration of treatment in co-infected persons with genotype 1 and a high (hepatitis C) viral load from 48 weeks to 72 weeks, while determining which patients are most likely to benefit from this intervention.

* Using weight-based dosing of ribavirin to increase sustained virologic response rates instead of the standard 800 mg/day (because of concerns about anemia). This approach should be accompanied by vigilant monitoring for anemia and swift treatment if it develops.

* Establishing the optimal duration of hepatitis C treatment for co-infected people with genotypes 2 and 3 in a randomized controlled trial by comparing treatment outcomes after 24 and 48 weeks of treatment. High relapse rates were reported in co-infected people with genotype 3 in on trial, but may have been a result of sub-optimal dosing of pegylated interferon, rib avirin, or both.

* Developing strategies to optimize hepatitis C treatment for those with the most urgent need: people with CD4 T cell counts less than 200 cell/[mm.sup.3] and those with advanced liver disease.

Also, the long-term durability and clinical benefit of a sustained virologic response to pegylated interferon-based therapy should be evaluated in cohorts of people receiving HCV treatment, including those co-infected with HIV. Histologic and clinical benefits of HCV treatment for relapsers and non-responders should also be characterized. This is of particular importance to co-infected people, who may be taking hepatotoxic drugs. An improvement in liver histology may increase the capacity to tolerate antiretroviral agents, prophylactic drugs, medications used to treat other co-morbid conditions, and complications of antiretroviral therapy.

Expediting research of novel HCV therapies in HIV-positive people

Co-infected people are in dire need of more effective and tolerable treatments for hepatitis C. Several new anti-HCV drugs are in early-phase development (see article on page 21 in this issue of RITA!). Traditionally, safety and efficacy studies of hepatitis C treatment in co-infected people have been initiated years after mono-infection treatment trials. Given the urgent need in this population, this delay is not acceptable. Sponsors of new HCV therapies should allow co-infected people to participate as soon as a safe and effective dose has been determined.

Pharmacokinetic evaluation of antiretroviral agents in co-infected people

Pharmacokinetic evaluation of antiretroviral drugs in co-infected people is not required, despite the increased risk for hepatotoxicity in this population. Hence, we know little about the drug levels of antiretrovirals in this population. This is crucial information because the liver metabolizes most antiretroviral drugs. People may be experiencing increased liver toxicity, drug interactions, or other side effects because they are receiving too high a dose of a given drug.

Expanding access to and availability of liver transplantation

Hepatitis C is the leading indication for liver transplantation in the US. In 2003, 16,925 people were waitlisted for a liver transplantation. Only 5,327 were transplanted and 2,371 died while waiting. If there was a sufficient supply of organs, the mortality rate among those awaiting transplantation could be drastically decreased.

Transplant candidates have been evaluated with the Model for End-Stage Liver Disease (MELD) system since February 2002. MELD prioritizes people with the most urgent need for transplantation within a 3-month period. MELD is intended to decrease waitlist deaths, but the chronic shortage of donor organs may mean that only candidates with high MELD scores--who may be less likely to survive transplantation--will receive a transplant. Obviously, the donor pool must be increased to meet the need. One possible solution is to consider an opt-out system, in which organ donation is presumed unless otherwise stipulated by the individual.

As highly active antiretroviral therapy has dramatically increased the HIV-related survival of co-infected people, the incidence of hepatitis C-related end-stage liver disease is increasing, and with it, the need for liver transplants. Co-infected people face barriers to liver transplantation beyond the organ shortage. The United Network for Organ Sharing does not regard HIV infection as a contraindication, but the decision of whether or not to perform transplantation in HIV-positive candidates rests with individual centers. Not all are willing to perform transplants in people with HIV. Despite a handful of HAART-era reports on post-transplantation outcomes roughly equivalent to HIV-negative transplant recipients, insurers have withheld reimbursement for transplantation in HIV-positive candidates. They claim that expanding the indication for transplantation to HIV-positive people changes an established procedure into an experimental, and therefore non-reimbursable, procedure.

The National Institutes of Health is funding a multi-center study on the safety and efficacy of kidney and liver transplantation in HIV-positive people. This research, and observational data on transplantation in HIV-positive people, will clarify risks of transplantation and identify clinical strategies to improve quality of life and extend survival of co-infected transplant recipients. Hopefully, this will dispel the reluctance to provide reimbursement for a life-saving procedure.

The need for hepatitis C education, prevention, and broadened access to care and treatment is vast, as is the need for coordinated publicly and privately funded research. Hepatitis C advocacy must chart its own course, but it can draw from the experiences and successes of HIV activism.

Tracy Swan is the Coinfection Project Director with Treatment Action Group (TAG) in New York. She recently co-authored the (TAG) report "Hepatitis C Virus (HCV) and HIV/HCV Coinfection: A Critical Review of Research and Treatment" with Daniel Raymond. This publication is available online at aidsinfonyc.org/tag/coinf/hcv2004.