Expanding Access to Treatment for HIV/HCV Coinfected Patients

The prevalence of the hepatitis C virus (HCV) may be as high as 30 percent among people living with HIV/AIDS (PLWHA) and as high as 90 percent among PLWHA who contracted HIV infection through injection drug use (IDU).1-3

Today, the standard of care is for all PLWHA to be screened for HCV and for all HIV/HCV-coinfected patients to receive comprehensive care services. Yet, many HCV infections among PLWHA remain undiagnosed, and many coinfected patients have never received HCV counseling and education. One result is that end-stage liver disease associated with HCV is now a major cause of death among PLWHA.

HCV 101

HCV is the most common blood-borne infection in the United States: At least 3.8 million people have been infected.4 To understand the consequences of HIV/HCV coinfection, one must first understand the natural history of HCV monoinfection.

Previously, the blood supply was the major mode of HCV transmission, but now that the blood supply is thoroughly screened for the virus, IDU with shared, unsterilized equipment accounts for 68 percent of new HCV infections.5 HCV is also transmitted through improperly sterilized dialysis equipment, through unprotected sex with an infected partner, and perinatally. Cohort studies report that men who have sex with men (MSM) and people who have sexually transmitted infections are at greater risk for contracting HCV from unprotected sex.6-8

Unlike HIV, HCV infections are not always chronic; some people clear the virus spontaneously (without treatment), usually within a few months after infection. That said, most people who are infected with HCV—55 to 85 percent—will develop chronic infection.5,10-14

The course of HCV varies considerably, making it difficult to predict disease progression (Figure 1).

• Chronic HCV infection may be asymptomatic, with minimal to no liver disease, or it may present with mild to moderate liver disease (fibrosis).15-20
• Each year, 1 to 5 percent of people with HCV-related cirrhosis (serious liver scarring) develop hepatocellular carcinoma.21
• An estimated 20 percent of people with chronic HCV infection will progress to cirrhosis over a 20- to 50-year interval.18-20
• Alcohol consumption, aging, and duration of HCV infection promote liver disease progression.
• In the United States, liver disease due to chronic HCV infection is the leading indication for liver transplantation.22
• Annually, at least 8,000 to 12,000 deaths are attributed to complications from chronic HCV infection.23-24

HIV/HCV

HCV is an opportunistic infection of HIV disease and is a prominent contributor to morbidity and mortality among PLWHA.

Many experts regard HCV infection as a “different animal” in PLWHA, because liver disease progresses more rapidly in people who are HIV positive and HCV-associated liver damage is more likely to develop in HIV/HCV-coinfected people than in those with HCV monoinfection.25-27 Coinfected people with <200 CD4 cells/mL are at greatest risk for end-stage liver disease.25-27 End-stage liver disease is preventable in many patients: The first steps are educating patients about HCV, providing appropriate screening and diagnosis, and assessing need for HCV treatment, all in a supportive context.

HCV Diagnostic Testing

Federal guidelines recommend that all PLWHA be tested for HCV.24,28-31 Antibody testing is not sufficient for diagnosing chronic HCV infection, however, because some people spontaneously clear the virus without treatment but remain antibody positive. A hepatitis C viral load (HCV RNA) test is necessary to confirm or rule out chronic HCV infection (Figure 2). Studies have reported spontaneous viral clearance rates of 15 to 45 percent in HIV-negative persons.10-14 Although spontaneous viral clearance is less likely to occur among people who are HIV positive, some PLWHA, particularly those with higher CD4 cell counts, do spontaneously clear HCV infection.32-37

Prior, resolved infection can be distinguished from chronic infection by the presence of HCV antibodies and the absence of detectable HCV RNA.

• HCV RNA is usually detectable within 2 weeks after infection.38
• HCV antibodies usually develop 6 weeks to 6 months after infection.11 People who have cleared HCV are no longer infected, although antibodies usually remain in the blood stream for years after spontaneous viral clearance.

All positive HCV antibody results should be confirmed by testing for HCV RNA, but the costs for doing so may be prohibitive in some clinical settings. Thus, to hold down costs, some providers may delay RNA testing until patients are considering treatment or require biopsy. HCV antibodies do not always develop in immuno-compromised people, so when HCV infection is suspected or symptoms are present in HCV antibody-negative patients with a CD4 cell count of less than 200/mL, HCV RNA testing should be performed to confirm or rule out chronic HCV infection.39,40

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Improving Access to HCV Services

The CARE Act community is already familiar with the consequences of late diagnosis of HIV disease. Delayed diagnosis of HCV in people who are HIV/HCV coinfected also may have even more serious consequences. Unfortunately, clinicians are reporting that coinfected patients often are evaluated for HCV treatment after they have developed cirrhosis or end-stage liver disease and may be ineligible for HCV treatment.41-43

Sometimes, clinicians forego HCV testing because they realize that for reasons ranging from the nature of HCV progression to the efficacy of available treatments as well as the cost of treatments, most people living with HCV, regardless of HIV status, will never undergo HCV drug treatment. But HCV testing is nonetheless critical, because all HCV-positive individuals must receive vaccinations for hepatitis A (HAV) and hepatitis B (HBV), education, counseling, and support.

HAV and HBV Vaccination

Federal guidelines recommend vaccination against HAV and HBV for people with chronic HCV, HIV, or both.24,28-31,44 Becoming infected with another hepatitis virus has serious consequences for people with HIV/HCV coinfection:

• HAV can cause sudden hepatic failure in people with chronic HCV.45,46
• Coinfection with HBV and HCV has been associated with more rapid HCV disease progression.24,47

Although vaccinations against HAV and HBV are an important part of care for HIV and HCV, research indicates that vaccination rates are low. In HIV-positive people, vaccination for HAV and HBV is preferable when CD4 cell counts are higher than 200/mL because the immune response to HAV and HBV vaccination decreases at lower CD4 cell counts.48-50

Counseling and Support

Successful HCV care programs offer education and counseling, beginning at the initial screening for HCV antibodies (Figure 3).41-43,51-54 Counseling and education must be an ongoing part of care, regardless of whether HCV treatment is initiated. These services support adherence to HCV treatment and remain beneficial after treatment has been completed.

HCV counseling must include an alcohol abuse component, because in some cases, abstaining from alcohol may be the most important intervention for HCV. Thus, it is particularly important for providers to assess alcohol use in coinfected patients, and then offer information, resources, and support on reducing or abstaining from alcohol. Alcohol consumption, particularly more than 50 g per day (approximately four drinks) causes and accelerates liver damage in people with HCV and increases HCV viral load, all of which may compromise efficacy of HCV treatment.55-58

HIV/HCV Coinfection, Pregnancy, and Perinatal Transmission

People with HIV/HCV coinfection have higher serum HCV viral loads than patients with HCV monoinfection.59 HCV has been detected in the semen of coinfected men and in the genital tracts of coinfected women.60,61 HIV-positive female partners of men with HCV infection should be tested for HCV and counseled about the risk of sexual and perinatal transmission of the virus.

Among coinfected women, the risk of perinatal transmission of HCV is approximately 17 percent, or four to five times greater than the risk among women with HCV monoinfection.62,63 Although treatment for chronic HCV infection is contraindicated during pregnancy, coinfected mothers can reduce the risk of vertical transmission of HIV and HCV with antiretroviral therapy and cesarean delivery.

HCV Treatment

As with HIV disease, management of and treatment for HCV infection have evolved.

Until 1989, HCV was treated with injections of interferon, and response was often dismal. In 1998, treatment outcomes improved significantly when interferon was combined with ribavirin, a nucleoside analog (a class of drugs used for HIV treatment). HCV treatment improved again in 2001 with FDA approval of pegylated interferon, a type of interferon that stays in the bloodstream longer and is therefore more effective against HCV. Currently, therapy with pegylated interferon plus ribavirin is the standard treatment for HCV in HIV-positive people and the only FDA-approved treatment for coinfection.

The primary endpoint of HCV therapy is sustained virological response (SVR), defined as no detectable HCV RNA in the bloodstream 6 months after completion of therapy. SVR is an indication of long-term remission of HCV; some experts consider it a cure. In people with HIV/HCV coinfection, the duration of HCV treatment is usually 48 weeks.

Treatment Strategies

Researchers are exploring optimal strategies for treating HIV and HCV in coinfected patients. Initiating highly active antiretroviral therapy (HAART) prior to HCV treatment may improve response rates to HCV treatment.64 Several factors must be considered in making treatment decisions:

• The patient must be willing and ready to treat both HIV and HCV.
• If CD4 cell count is less than 200/mL, HIV treatment should be initiated first.
• If HCV disease is mild, treatment can be delayed. If treatment is indicated according to current guidelines and there is patient readiness, HCV should be treated either before initiation of HAART or while the patient is on a stable antiretroviral drug regimen.
• Antiretroviral regimens for coinfected people should be selected carefully to reduce hepatoxicity and avoid interactions with HCV treatment. HAART regimens that contain didanosine (ddI; Videx) should be avoided because of a potentially life-threatening interaction with ribavirin and potentiation of the risk for hepatic decompensation in coinfected cirrhotic patients during HCV treatment.65 If possible, zidovudine (AZT; Retrovir) should be avoided because it increases the risk of anemia from ribavirin66; stavudine (d4T; Zerit) may increase the risk for lipoatrophy and weight loss during HCV treatment.67

Often, real-life situations are not clear-cut. Because many people present with both advanced HIV disease and advanced HCV disease, clinicians often start HAART first, so that side effects from antiretroviral agents can be identified and managed. Some patients who start HIV treatment with a low CD4 cell count do not achieve a CD4 count of more than 200/mL, although they have a stable or undetectable HIV RNA; those patients should be evaluated for HCV treatment on an individual basis. Although it is possible to initiate treatment for both viruses simultaneously, side effects and toxicities from medications make it difficult to do so.

Side Effects and Strategies for Managing Them

Pegylated and standard interferon and ribavirin may cause numerous side effects, including mood swings, anxiety, irritability, insomnia, and depression.68 Although the side effects can be daunting, strategies exist for managing them. Side effects can be alleviated by interventions such as the following:

• Prophylactic treatment for depression (i.e., before initiation of HCV therapy)
• Treatment of insomnia and anxiety as needed
• Dose reductions or use of growth factors to manage anemia and neutropenia
• Administration of the weekly shot of pegylated interferon on Friday night to mitigate side effects during the work week
• Tylenol for aches and fever
• Small, light meals; antiemetics or dronabinol (Marinol) for nausea and loss of appetite
• Adequate hydration.

The Week 12 Early-Stopping Rule

Although treatment discontinuations occur for other reasons—usually side effects and adverse events—many clinicians and their coinfected patients may decide to stop treatment at Week 12 if the patient does not have an early virological response (EVR). As with HCV monoinfection, the likelihood of SVR in the absence of EVR is extremely low. Some clinicians and patients may prefer to continue HCV treatment in the absence of EVR because some patients may have a delayed response to treatment. The Week 12 “early-stopping rule,” however, spares nonresponders from the side effects and expense of HCV treatment.

Treating HCV: Long-Term Benefits

In HCV monoinfection, follow-up studies of people who experience SVR have found that more than 85 percent maintain undetectable HCV RNA levels for up to 10 years after completion of HCV treatment;69-71 retrospective studies have reported a reduction in liver-related deaths, especially among those who have SVR.72,73

Treatment of HCV offers significant benefits to people with coinfection, even in the absence of SVR. HCV treatment may improve the condition of the liver, even in virologic nonresponders.74,75 Moreover—and crucially—HCV treatment may increase tolerability of antiretroviral therapy for HIV/AIDS.76

Expanding Access to Treatment

Clinical and systemic barriers to treating HCV coinfection are substantial. For example, clinicians often treat patients who have psychiatric or medical comorbidities, struggle with addiction to drugs and alcohol, and have chaotic lives. Nevertheless, they should provide HCV education and screening, HAV and HBV vaccination, and counseling on alcohol use and HCV transmission. Patients should receive these basic services if HCV treatment is offered onsite or before they are referred to off-site specialty care. Some clinics decide to offer HCV treatment and care onsite on the basis of the following factors:

• Local priorities
• Demographics and needs of the patient population
• Access to consultation or collaboration with a gastroenterologist or
  hepatologist
• Lack of an acceptable referral option that offers culturally competent care and treatment.

Models have been developed for addressing HCV in PLWHA, including referral and co-management, co-locating services, and integrated care. Some clinics may not have the capacity to treat coinfected patients for HCV and thus refer patients to a gastroenterologist or hepatologist.

Although referral may be the most economically feasible and realistic option for some sites and providers, this approach has drawbacks and has been shown to be minimally effective in securing continuity of care over time. Disappointing follow-up rates among coinfected patients referred to liver specialists have been reported; for example, Clanon and colleagues reported that less than 10 percent of their coinfected patients kept their appointments.52 Low follow-up rates can be improved by identifying liver specialists who are experienced with or are willing to treat coinfected patients, establishing and maintaining a relationship between HIV specialists and liver specialists, and developing a communication mechanism among providers. Support groups can help bolster referral follow-up rates, both by word of mouth and by group members’ accompanying each other to appointments.43,77

Co-location of liver specialty care in an HIV clinic may be a viable option because many patients with HIV prefer “one-stop shopping” at a familiar and comfortable place. Co-location also enhances communication and collaboration among providers. Care can be co-located by providing a liver specialist at an HIV clinic one or two afternoons per month. When referral and co-location are not feasible, clinicians may need to provide their coinfected patients with educational resources.

Integrating Care: Starting a Coinfection Clinic

Care and treatment for HCV coinfection have been successfully integrated into several different venues, including CARE Act-funded clinics, VA programs, and methadone clinics. Many use a multiple-visit model to counsel, educate, screen, vaccinate, diagnose, and assess patients for HCV treatment. People who have opened coinfection clinics agree that the key element is a dedicated, full-time nurse or physician assistant who is able to schedule appointments, educate patients, facilitate support groups, provide one-on-one counseling, work on reimbursement for medications, manage side effects of treatment, and secure case management and transportation services for patients.78-80,51,52,54,77,81 Most coinfection clinics have a dedicated nurse or doctor who is available by pager on a 24-hour basis; they report that patients do not abuse this service.

The Coinfection Clinic at Alameda County Medical Center, Oakland, CA

Kathleen Clanon and her colleagues established a coinfection clinic in Oakland, CA, in 2001 because so few of their coinfected patients were being treated for HCV by gastroenterolo-gists; less than 10 percent were keeping appointments. The clinic has a monthly coinfection session and weekly support group meetings. Liver bi-opsies are performed at the HIV clinic by a gastroenterologist who uses a borrowed portable ultrasound machine. Patients recover from the biopsy in the HIV clinic, where they are already accustomed to receiving care. The key elements of the program are as follows:

• Sufficient funding to hire a dedicated nurse to provide monitoring and support for patients receiving treatment
• A cooperative relationship with a gastroenterologist, who has become part of the treatment team
• A patient support group.

So far, 35 patients at Alameda County Medical Center have been treated or are currently being treated. “It’s a slow movement and needs to be built up,” says Michael Harank, who coordinates care and facilitates the education and support group.43

The SVR rate among Clanon’s patients is astoundingly high: 53 percent. That rate can be attributed to a combination of factors: favorable HCV genotype, adherence to treatment, prompt management of side effects, consistent support from peers and staff, and eligibility criteria that include abstinence from drugs and alcohol prior to initiating HCV treatment and a CD4 cell count of more than 350/mL.

Clinic staff recommend the following approach to treatment:

• Maintain the full dose of pegylated interferon and ribavirin. Use growth factors instead of dose reduction, and consider pretreatment with erythropoietin.
• Assess for depression before initiating treatment, and reassess on a monthly basis. Pretreat for depression with selective serotonin reuptake inhibitors if the patient has a history of depression or a moderately high depression score prior to treatment. Switch medication if necessary.
• Advise patients to drink at least three liters of water a day; doing so seems to reduce pain, fatigue, and headaches. Almost all patients who drink sufficient quantities of water report no need for additional pain medication.52
• Encourage patients to utilize other services that can help them stay in care and manage quality of life.43,52,81

Miriam Hospital’s Immunology Center, Providence, RI

In contrast to many other coinfection treatment providers, Lynn Taylor and her colleagues at the Miriam Hospital do not exclude coinfected drug and alcohol users from HCV treatment. Patients at Taylor’s coinfection clinic often have advanced liver disease and unfavorable HCV genotypes, so the main goals of treatment often are to delay HCV progression and improve liver histology, not necessarily to achieve SVR.

The coinfection clinic opened in 2001 as part of Miriam Hospital’s Immunology Center, which provides CARE Act-funded clinical care to more than 1,000 PLWHA, 43 percent of whom are coinfected. Care and treatment for HIV and HCV are multidisciplinary. Treatment plans are made on an individualized basis. Coordinated psychiatric care, addiction treatment, and home-based case management are provided through collaboration with a community-based mental health agency, and the clinic has a collaborating hepatologist.42,78

The coinfection clinic takes place on 2 half-day sessions each month. At their first visit, patients receive comprehensive, individualized education. A support group meets once a week, and the clinic offers monthly group educational sessions, the opportunity for individual sessions, and educational materials in English and Spanish. Patients often speak with one another on the telephone when they are unable to come to the clinic in person. An interventional radiologist performs liver biopsies, which are not required for treatment. Weekly injections of pegylated interferon are given at the clinic, and patients are given a week’s supply of ribavirin at that time. Directly observed administration of pegylated interferon allows for assessment and management of side effects. The adherence rate for weekly clinic visits has been 99 percent. So far, none of Taylor’s 17 patients have discontinued treatment because of ongoing drug use or relapse. Five patients are currently receiving therapy, and seven have completed 48 weeks of HCV treatment. So far, one patient completing 48 weeks of treatment has achieved SVR.42,78

Barriers and Key Issues

Working With Patients With Multiple Needs

Underserved coinfected patients may face many barriers to care, but many of those barriers can be successfully addressed. For example, case management can link coinfected patients with services that help mitigate the effects of poverty and lack of health insurance. Users of illicit substances can be offered buprenorphine, methadone or referral to other drug treatment services. Patients with uncontrolled psychiatric disorders can be offered the opportunity to work with a psychiatrist or a psychologist as part of preparing for HCV treatment.

Concerns About Relapse to Active Drug Use and Reinfection

Clinicians and their patients have valid concerns about HCV treatment in active or recovering illicit substance users. The side effects of interferon are similar to those of opiate withdrawal, and patients have relapsed or reported cravings during HCV treatment.41,51 Clinicians have an opportunity to intervene and support such patients by providing referrals to counseling, support groups, 12-step programs, and drug treatment or by initiating therapy with methadone or buprenorphine rather than discontinuing treatment. Some clinicians increase methadone dosage during HCV treatment to ameliorate cravings and side effects of HCV treatment.51,82 No significant difference in response rates to HCV treatment was found among drug-free patients, those who relapsed before reinitiating methadone maintenance, and those who relapsed and did not reinitiate methadone maintenance during HCV treatment.83

The use of pain medication to manage the side effects of HCV treatment may be a problem for patients who want to remain drug free. One clinician has developed an innovative strategy: Patients sign a contract stipulating that they will get help in discontinuing pain medication if needed.54 Reinfection with HCV after treatment has been a concern among clinicians who are considering treating injection drug users. However, few cases of HCV reinfection have been reported.84

Depression and HCV Treatment

Depression is a common cormorbidity of HIV and HCV, and it is common among drug users.85-90 Treating depression among PLWHA has improved adherence to antiretroviral therapy91 and is a key management strategy for interferon-induced depression.

Schaefer and colleagues reported that patients with a psychiatric history could be successfully treated for HCV when a pretreatment psychiatric evaluation and ongoing multidisciplinary care were offered with HCV treatment.92 Some clinicians and patients prefer to start antidepressants prior to HCV treatment, whereas others favor antidepressant use only if it becomes necessary. Because treatment discontinuations often occur due to psychiatric adverse events, it is sensible to avert such events when possible by incorporating mental health care into HCV treatment planning.

Treatment Eligibility and Uptake

According to Practice Guidelines: Diagnosis, Management and Treatment of Hepatitis C from the American Association for the Study of Liver Diseases, the “characteristics of persons for whom therapy is currently contraindicated” are as follows:

• Major, uncontrolled depressive illness
• Renal, heart, or lung transplant recipient
• Autoimmune hepatitis or other condition known to be exacerbated by interferon and ribavirin
• Untreated hyperthyroidism
• Pregnancy or inability or unwillingness to comply with adequate contraception
• Severe concurrent disease, such as severe hypertension, heart failure, significant coronary artery disease, poorly controlled diabetes, or obstructive pulmonary disease
• Younger than 3 years old
• Known hypersensitivity to drugs used to treat HCV.93

Providers should note that alcohol and drug use are not on this list. Many providers establish their own eligibility criteria; some do not treat active drug or alcohol users, whereas others have used adherence to medical appointments as an alternative criterion for active users.42,94

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Conclusion

In the United States, HCV coinfection is a major contributor to morbidity and mortality among PLWHA. Many coinfected people are from traditionally underserved, uninsured, and hard-to-reach communities. HIV/HCV coinfection is linked with psychiatric disorders, drug and alcohol dependence, poverty, homelessness, incarceration, and race.95-97 Those barriers are amplified by limited access to HCV diagnostic testing and treatment and restrictive eligibility criteria for treatment. The side effects and limited efficacy of drug therapy in people with HIV/HCV coinfection create additional obstacles for coinfected patients and their clinicians. Despite these challenges, HCV can be successfully treated in PLWHA.

CARE Act providers have already developed innovative models for delivering HCV care and treatment.42,52,98 The CARE Act community has a wealth of experience in providing culturally competent care and treatment to underserved individuals and diverse communities. Providers have demonstrated the capacity to respond to changes in care and treatment paradigms, patient demographics and, most significantly, decreasing resources in the face of increasing need. Thus, the CARE Act community is ideally suited to tackle HIV/HCV coinfection.

Addressing coinfection seems daunting, but that is not the reality. Not all coinfected patients require HCV treatment, and not every clinic will—or should—provide comprehensive treatment services for coinfected patients. All HIV treatment providers, however, should develop a supportive structure for coinfected patients whether or not they plan to deliver HCV drug treatment onsite. Specifically, providers should provide screening, education, and support services that can be coordinated and delivered by clinic staff, case managers, and peers.42,43,51,52 Those services create the foundation for referrals when onsite care is not feasible.

Referring patients to off-site providers may seem like the best option for many HIV/AIDS service providers. Many liver specialists, however, are not comfortable treating HIV-positive people and do not have experience treating patients with multiple psychosocial needs. Fortunately, experienced HIV providers have many tools at their disposal with which to increase their capacity to deliver HCV care and treatment, including collaboration with culturally competent liver specialists, miniresidency programs, journal clubs, consultation, and co-locating care.

In the coming years, we are likely to see significant progress in HCV treatment, echoing the advent of HAART in HIV disease. Yet, coinfected patients will not benefit from upcoming improvements in HCV treatment unless care and treatment are delivered in a supportive, multidisciplinary context. Coinfected patients require education and integrated medical, mental health, and addiction treatment services.

As CARE Act providers have learned during more than 15 years of experience with HIV disease, a strong infrastructure is crucial for successful delivery of care and treatment, particularly for people with multiple diagnoses. Models for delivering HCV care must be developed now—to meet current needs, anticipate therapeutic improvements, and accommodate corresponding increases in HCV treatment uptake among people with HIV/HCV coinfection. The CARE Act community has successfully reached underserved PLWHA and increased the length and quality of their lives, and it has the skill and expertise to do the same for coinfected persons

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HIV/AIDS Bureau Resources

Care and Treatment for Hepatitis C and HIV Coinfection: Expanding Access Through the Ryan White CARE Act. This book discusses how to deliver improved care to people living with HCV and HIV. It addresses the compound problems patients with coinfection face and how providers can address those problems as well as negotiate treatment options with their patients.

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