Hepatitis C is a serious global health problem. Worldwide, an estimated 170 million people have been infected with the hepatitis C virus (HCV). In the United States, an estimated 4 million people have been infected with HCV; 2.7 million of them have developed chronic hepatitis C. The U.S. estimate may be low, as many high-prevalence populations were excluded from HCV surveillance. Up to one quarter of HIV-positive individuals in the U.S. are coinfected with HCV.

Since viral inactivation procedures and effective donor screening have almost completely eliminated the risk of hepatitis C infection from blood transfusions and blood products, the majority of new HCV infections occur via injection drug use with shared, unsterilized equipment. HCV is prevalent among current and former injection drug users; up to 90% have been infected.

Many questions about HCV transmission remain unanswered. HCV can be transmitted through sex, from mother to infant, and via dialysis at centers with inadequate infection control procedures. Men who have sex with men, sex workers, people with multiple sex partners, and partners of HIV/HCV-coinfected persons have higher-than-average HCV prevalence rates, yet the routes and risks of sexual transmission are unclear. The risk of HCV transmission from mother to infant is about 5%; the risk increases if the mother is HIV/HCV coinfected. Interventions to reduce the risk of mother-to-infant transmission have yet to be identified. While it has been speculated that HCV may be transmitted from shared tubes used for intranasal drug use and from crack pipes, the risk of HCV transmission from non-injection drug use has not been quantified. Current HCV prevention strategies for injection drug users are inadequate, and education about HCV transmission and prevention is lacking.

Recommendations:

• Implement national surveillance for chronic HCV infection.
• Provide HCV testing and education for high-risk and high-prevalence populations.
• Increase access to sterile injection equipment.
• Increase access to drug treatment and methadone maintenance programs.
• Institute CDC's recommendations for prevention of HCV transmission in hemodialysis facilities.
• Clarify routes and risks of HCV sexual transmission.
• Clarify the risk of non-injection drug use behaviors associated with HCV transmission, such as smoking or sniffing.
• Research mechanisms and interventions to decrease mother-to-infant transmission.
• Develop protocols for HCV counseling and testing for pregnant women, and offer voluntary HCV counseling and testing to pregnant women.
• Develop and implement HCV prevention strategies for the developing world.

Hepatitis C is not invariably chronic; 15% to 45% of those infected achieve spontaneous viral clearance. Chronic HCV infection can result in fibrosis (mild liver scarring) and cirrhosis (serious liver scarring). Symptoms may include fatigue, depression, and confusion ("brain fog").

The course of chronic HCV varies widely and depends on a number of factors, including age, race, sex, and alcohol consumption. People living with HCV and their health care providers need better information about prognostic factors and risk of disease progression to make informed decisions about care and treatment. The most serious clinical consequences of HCV infection are cirrhosis, hepatocellular carcinoma, and hepatic decompensation (liver failure). HCV-related end-stage liver disease is the leading indication for liver transplants in the United States, where there is a critical shortage of donor livers. Potentially life-saving vaccinations for hepatitis A and B are recommended by CDC, but have not yet been universally incorporated into HCV care.

Recommendations:

• Investigate the role of genetic and ethnic factors in susceptibility to HCV infection, disease progression, and response to treatment.
• Investigate the role of sex differences in HCV disease progression.
• Investigate the role of light-to-moderate alcohol consumption on HCV disease progression.
• Identify possible causes of and interventions for HCV-related "brain fog."
• Promote screening and vaccination for hepatitis A and hepatitis B among individuals infected with HCV or coinfected with HIV/HCV.
• Create an "opt-out" system for organ donation in the United States and include discussion of organ donation as part of school health education programs and regular medical care.

Acute HCV is usually asymptomatic and often goes undiagnosed. A series of blood tests is available to diagnose chronic HCV infection, predict and monitor the effects of treatment, and measure other complications of HCV infection. Liver biopsy is still considered the "gold standard" for assessment of liver damage and determining the need for treatment, although it is expensive, invasive, unpopular with patients, and subject to substantial interpretive variation. Hepatocellular carcinoma (HCC) occurs in 1-4% of cirrhotics annually. Current surveillance techniques are suboptimal for early diagnosis of hepatocellular carcinoma.

Provider education on HCV is limited. Many high-risk and high-prevalence populations lack access to regular medical care. Outreach strategies for diagnosis of HCV and linkage of newly diagnosed HCV-infected persons to care programs are needed.

Recommendations:

• Educate primary care providers about diagnosis of acute and chronic HCV infection.
• Develop and market oral fluid test kits for HCV-antibody testing.
• Promote use of a standardized system for evaluation of liver biopsy.
• Continue research on non-invasive testing methods to replace or reduce the need for liver biopsy.
• Identify and validate prognostic markers and more effective screening methods for early diagnosis of hepatocellular carcinoma.

Treatment for HCV—a 6-to-12 month course of pegylated interferon and ribavirin—has many drawbacks, including potentially severe side effects. On average, treatment eradicates HCV in about half of patients, but various factors can dramatically increase or decrease the likelihood of a sustained virological response. Initial reports suggest that HCV treatment may be particularly effective during acute infection. Treatment may also improve the condition of the liver, even in people who do not have a sustained virological response.

Primary care providers often do not receive adequate information about efficacy and side effects of HCV treatment. Moreover, even for expert clinicians, numerous questions about treatment remain: Can treatment success rates be improved by optimizing dosing regimens? Is treatment safe and effective across all populations with high HCV rates-especially drug and alcohol users and people with psychiatric co-morbidities, who have often been excluded from clinical trials? Is there a role for treatment even in people who don't clear the virus? Can improvements in the management of side effects make treatment more tolerable? When and how should people acutely infected be treated? How effective are herbs such as milk thistle as complementary and alternative therapies for HCV? These questions are relevant not only for HCV monoinfection but also for HCV/HIV coinfection.

Recommendations:

• Increase knowledge of treatment and care for hepatitis C patients among primary care providers.
• Identify optimal dosing strategies.
• Increase research on treatment safety and efficacy in understudied populations.
• Increase research on strategies to manage side effects of HCV treatment.
• Identify when and in whom treatment for acute HCV should be initiated; optimal regimen; and duration of treatment.
• Establish prospective, long-term follow-up studies to assess the durability and clinical benefit of histological responses in virological responders, relapsers, and non-responders.
• Investigate safety and efficacy of alternative therapies for HCV infection.

In 1999, CDC added hepatitis C infection to the list of opportunistic infections (OIs) associated with HIV. HIV accelerates HCV disease progression, and HCV-related end-stage liver disease has become a leading cause of death among HIV-positive people. Although potent antiretroviral therapy has significantly increased survival, some studies have reported a blunted immune response to antiretroviral therapy among HCV-coinfected individuals. HCV coinfection increases the risk of hepatotoxicity from antiretroviral therapy. Vaccination for HAV and HBV may be less immunogenic in individuals with advanced HIV disease.

HCV treatment is less effective for HIV/HCV-coinfected people, and they tend to experience more severe side effects. Although promising data have emerged on the survival of coinfected liver recipients, restrictive policies at transplant centers and refusal to reimburse for transplantation have limited access to transplantation for HIV-positive candidates. For these reasons, people coinfected with HIV and HCV and their health care providers face complicated decisions about care and treatment for both infections.

Recommendations:

• Establish prospective, longitudinal cohort studies of the natural history of HIV/HCV coinfection in the era of HCV treatment and HAART.
• Develop guidelines for the care and treatment of coinfected individuals.
• Establish a universal definition of hepatotoxicity and characterize its severity.
• Explore pharmacokinetics and drug levels of antiretroviral agents and other drugs commonly used by coinfected individuals.
• Include HIV/HCV-coinfected individuals in early-phase HCV treatment trials.
• Explore strategies to optimize HCV treatment for HIV/HCV-coinfected persons.
• Support access to and research on liver transplantation for HIV-positive and HCV/HIV-coinfected individuals.

HCV is prevalent among African Americans, the incarcerated, the poor, current and former injection drug users, people with psychiatric disorders, and HIV-positive persons. These groups face significant barriers to care and treatment. Incarcerated individuals have had to resort to legal action to obtain HCV treatment, and most still do not receive it. Inadequate, decreasing funding of AIDS Drug Assistance Programs (ADAPs) has limited access to HIV and HCV treatment for HIV-positive individuals. Expected cuts in Medicaid threaten access to HCV treatment for many more.

Recommendations:

• Provide full access to hepatitis C care and treatment for all of those in need.
• Do not withhold treatment from active drug users; decisions should be made on an individualized basis.
• Strengthen linkages among substance abuse treatment programs, methadone maintenance programs, medical and mental health providers, and HIV/HCV prevention programs.
• Increase capacity to provide individualized medical care and treatment to coinfected active drug users.
• Develop integrated, multidisciplinary systems of care for individuals with multiple co-morbidities (HIV, HCV, psychiatric disorders, addiction).

It t is in this environment that TAG is releasing Hepatitis C and HIV/HCV Coinfection: A Critical Review of Research and Treatment. This report is meant to serve as a blueprint for activism as well as a source of information.

TAG's Coinfection Project closely monitors new data on the epidemiology and natural history of HIV/HCV coinfection, as well as the development of new diagnostics, prophylaxes, and treatments for hepatitis C in both the pre- and postmarketing stages. We advocate for the expeditious development, proper clinical research and regulation, ease of access, and optimal use of these drugs. We work with the pharmaceutical companies, NIH, FDA, researchers, and other treatment activists to achieve these objectives. TAG also educates members of the HIV community about coinfection with hepatitis C.

Introduction

TAG's Hepatitis C and HIV/HCV Coinfection Report is a comprehensive review of basic and clinical science accompanied by recommendations for research and policy. It was written for people living with hepatitis C or HIV/HCV coinfection, clinicians, researchers, activists, educators, and advocates.

The Hepatitis C and HIV/HCV Coinfection Report reflects my experience. I have worked for more than ten years as a direct service provider to people at risk for, or living with, HCV and HIV, which has contributed to my understanding of their needs. While I was writing this report, I reviewed more than a thousand journal articles and hundreds of conference abstracts, and interviewed researchers, clinicians, coinfected individuals, and advocates.

TAG's original hepatitis report was released in July of 2000. Since then, HCV-related end-stage liver disease has been recognized as a leading cause of death among people with HIV. For people with HCV monoinfection, liver-related deaths are projected to increase by 180% over the next 20 years. Meanwhile, a more effective therapy, pegylated interferon, has been approved for treatment of HCV, and researchers are moving closer towards an understanding of HCV pathogenesis. The Hepatitis C and HIV/HCV Coinfection Report is a synthesis of current knowledge; key issues are highlighted in the Recommendations section at the end of each chapter.

Despite advances in treatment, many barriers to optimal care and treatment of people with HCV and HIV/HCV remain. As with HIV, HCV is a lens that magnifies the intersection of medical and social inequities. In the U.S., both viruses disproportionately affect African Americans and other groups who have traditionally had poor access to care and treatment, including the incarcerated, the poor, people with psychiatric disorders, and injection drug users. Up to 90% of injection drug users are infected with HCV. Injection drug users in particular are regarded with an astounding degree of contempt by most of society. Draconian drug laws and inadequate access to sterile syringes have created penalties for drug use that exceed incarceration alone by costing people their health and, ultimately, their lives. Until we acknowledge that HCV is a disease that is prevalent among injection drug users and demand expansion of needle exchange programs, universal availability of syringes through legalized pharmacy sale, access to methadone maintenance therapy, and drug treatment upon request, we will not be able to mitigate the spread of hepatitis C.

Access to care and treatment is not just an issue for injection drug users. In the United States, access to health care for the poor is restricted; more than 43 million Americans are uninsured. Cuts in federal funding for programs such as AIDS Drug Assistance Programs and Medicaid threaten access to health care for the more than 42 million Americans who rely on them. Drug prices are exorbitant; the 48-week course of treatment for HCV costs as much as $40,000.

Even individuals with access to health care suffer from the constraints of managed care and a lack of provider and patient education about HCV; these factors collectively make it difficult to insure that people with HCV receive optimal care. Many clinicians work in health care settings ill-suited to providing care for dually or multiply diagnosed individuals. Successful models of service delivery to injection drug users and people with psychiatric co-morbidities must be imported into the clinic. Clinicians must take a proactive approach to managing drug-related adverse events by educating people about them before initiating treatment, providing options to ameliorate them and offering access, where indicated, to mental health care. While pressuring the medical system to meet these needs, people must receive clear and direct education about transmission, prevention, diagnostics, care, and treatment of HCV and HIV/HCV.

Preparation and implementation require resources. Very little funding is specifically designated for HCV prevention and education services, nor are there any validated and established models for such programs. HCV prevention and education must be integrated into programming at AIDS service organizations and available to staff and participants at methadone clinics, syringe exchanges, detoxification facilities, residential drug and alcohol treatment programs, homeless shelters, and correctional facilities. Information and services must reach those who need them most, not merely those who are the easiest to reach.

Progress toward new treatments and improvements in efficacy of existing HCV therapy has been hampered by the absence of a coordinated research agenda for hepatitis C. HCV research is currently spread across different NIH institutes without the oversight that exists for HIV research from the NIH Office of AIDS Research (OAR). Currently, there is no mechanism for meaningful community participation in the development of a research agenda for HCV.

The current situation demands intensified, focused action: members of the HCV and HIV communities need to work together to advocate for prevention initiatives, broadened access to care and treatment for HCV and HIV/HCV, and a comprehensive research agenda.