Before 1996, most coinfected people died from complications of AIDS before end-stage liver disease developed. Since highly active antiretroviral therapy (HAART) has greatly increased survival, hepatitis C coinfection has emerged as a significant contributor to morbidity and mortality as HIV accelerates hepatitis C disease progression and increases the risk for antiretroviral-induced hepatotoxicity. End-stage liver disease has become a leading cause of death among people with HIV and hepatitis C.
Until just two years ago, the NIH Consensus Statement on Management of Hepatitis C recommended that hepatitis C treatment be withheld from drug users until they had been drug-free for at least six months. A new Consensus Statement was issued in 2002, recommending that hepatitis C treatment decisions be made on an individualized, case-by-case basis rather than unilaterally withholding treatment from active drug users. Despite this guidance, substantial barriers remain for drug users seeking treatment for hepatitis C. There is little information about safety, efficacy, adherence strategies and management of side effects in injection drug users, regardless of their HIV status. The lack of research on optimizing hepatitis C treatment in injection drug users is outrageous, given that they are the highest-prevalence population.
The dearth of research may continue to support the rationale to withhold hepatitis C treatment from drug users. In the absence of data or specific guidelines for care and treatment of hepatitis C in coinfected people, many clinicians look towards recommendations from a panel of experts on care and treatment, the HIV-HCV International Panel. In January of 2004, the Panel's updated recommendations, Care of Patients with Hepatitis C and HIV Co-infection, were published in AIDS. The panel's recommendation that hepatitis C treatment should be provided to persons with "... no active consumption of illegal drugs" will create additional barriers for coinfected injection drug users.
Fortunately, a handful of clinicians in the United States are developing specialized outreach, care and treatment programs for people with multiple diagnoses -- HIV, hepatitis C coinfection, drug and alcohol dependency and psychiatric illnesses. Lynn Taylor and her colleagues work at Rhode Island's Brown Medical School Immunology Center, which is known for developing innovative ways to provide treatment to disenfranchised populations.
They are treating people for HIV and hepatitis C as they struggle with homelessness, mental illness and addiction. Taylor and her colleagues deliver care to HIV-positive people in shelters, on the streets -- even at donut shops, and the Rhode Island prison system. Until recently, Rhode Island's penalty for syringe possession was a sentence of up to ten years, which Taylor says "forced people to become infected with HIV and hepatitis C." Rhode Island's history of harsh penalties for injection drug use has made it home to an HIV/HCV coinfection epidemic. It is one of only four states where more than 50% of AIDS cases are associated with injection drug use. "We need to focus on bringing HIV and hepatitis C care to people who are incarcerated," says Taylor, "since in this country, people who have drug problems often end up in the correctional setting."
Brown's Project Bridge Program, which links HIV-positive prisoners with intensive case management services, housing, and comprehensive medical care could become the standard of care for incarcerated persons with hepatitis C instead of the current standard of care for hepatitis C, "you have hepatitis C, here's a referral to a physician who may or may not treat you or here's a prescription."
The resistance to treating coinfected injection drug users mirrors the attitude towards treating HIV in rural settings in the developing world. Many doctors have expressed doubts about treating injection drug users. Procedure-driven health care is more lucrative, and simpler, than caring for people who may not have stable housing, may be struggling with mental illness, the constant stress of illegal drug use, and HIV disease. Taylor recently addressed a group of gastroenterologists on hepatitis C treatment for injection drug users. Half of them walked out minutes after she began her talk; she overheard one saying "I don't want to hear about this" as he left the room.
According to Dr. Taylor, there is "no justification" for withholding hepatitis C treatment from coinfected drug users, "until evidence says that it is harmful, it is not responsible to withhold treatment without data to support the rationale." Her program does not use abstinence from drugs or alcohol as criteria for hepatitis C treatment, nor is she currently using a threshold for CD4 cell count, although the International Panel recommends treating HCV infection only in persons with CD4 cell counts of >350/mL.
Taylor questions the Panel's CD4 cell threshold of >350/mL. Although early studies of standard interferon therapy found that HCV treatment was largely unsuccessful for a few coinfected people with CD4 cell counts of <200, recent trials of pegylated interferon-based therapy did not report an association between CD4 cell count and response to HCV treatment. This may be due in part to small sample size in each of the trials. Clearly, more research on hepatitis C treatment in people who have low CD4 cell counts is necessary.
At Brown's immunology clinic, 60% of 1,000 patients are receiving HAART. Half have CD4 cell counts of <350, and half of these have <200 CD4 cells. "We can wait and wait, but their CD4 cell counts may not rise quickly enough despite optimal HIV treatment," says Taylor. "What decision should be made about HCV treatment for a coinfected patient who has cirrhosis, a CD4 cell count of <150 and undetectable HIV RNA? Do we wait [to treat] until s/he has died of liver disease?"
Clearly, hepatitis C treatment in coinfected people with low CD4 cell counts merits more research, since finding patients in the recommended CD4 cell strata may be challenging. Since antiretroviral therapy is often prescribed to injection drug users later than to non-users, many start HAART at low CD4 cell counts. Initiating antiretroviral therapy at a low CD4 cell count is effective virologically -- HAART can suppress HIV replication -- but the CD4 cell count may not increase to the Panel's recommended threshold for HCV treatment. Taylor worries that a low CD4 cell count may be used as criteria for withholding reimbursement. "Is there clinical benefit or does CD4 cell count have an effect on histological response to hepatitis C treatment? I want justification for withholding treatment. Can you give us this?"
Taylor has a slew of ideas for research. She has used interferon therapy as a way to work with people about their drinking. "Several [people] have stopped using alcohol, but we have a small number of patients. A study would be great." She wonders about reproducing programs like hers, where weekly injections of pegylated interferon are directly observed, since "supervised HCV therapy allows us to address safety, adherence, access and efficacy when we see people, and unlike treatment for HIV, hepatitis C treatment is finite.
Directly observed therapy has been extensively studied for TB; it can be modified for hepatitis C treatment in multiple settings -- medical offices, correctional facilities and methadone clinics. Ribavirin can be administered with the morning dose of methadone, and a nurse could come in once a week to give injections. Will optimizing adherence, tolerability, and safety for coinfected active drug users with supervised pegylated interferon translate into improved efficacy? What is impact of these interventions over time?"
Peer education has been an effective method for reducing risk behaviors of injection drug users, many of whom are reluctant to discuss illegal drug use with non-users. Taylor wonders what data are needed to create reproducible, peer-guided HCV treatment models for HIV-positive patients. Does an HCV education program and peer support group help coinfected people make hepatitis C treatment decisions and increase treatment readiness? What impact does hepatitis C education and peer support programming have on adherence to hepatitis C treatment and completion of treatment? Could a peer-driven program be effective for alcohol cessation?
Drug users, activists and like-minded researchers must come together to craft a research agenda. Manufacturers of hepatitis C therapy need to support this research. The failure to support research to optimize treatment of hepatitis C among the highest-prevalence population is unacceptable, and would not be tolerated in another condition. In Taylor's words, "Do cancer doctors give chemotherapy and say come back in three months? We need to be just as present and compassionate with HCV treatment as we are with cancer."
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