- Email: [email protected]
HIV Coinfection: A New Challenge for Nurses in AIDS Care
Features JANAC Vol. 14, No. 5, Supplement to September/October 2003 10.1177/1055329003254332 Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
Hepatitis C Virus/HIV Coinfection: A New Challenge for Nurses in AIDS Care Richard S. Ferri, PhD, ANP, ACRN, FAAN Carl A. Kirton, MA, RN, APRN, BC HIV-infected patients are living longer owing to effective treatment with highly active antiretroviral therapy (HAART). As a result, the extent and impact of hepatitis C virus (HCV) infection in this patient population are now becoming apparent. HIV infection accelerates the progression of HCV to cirrhosis, endstage liver disease, and death. The presence of each disease also influences treatment of the other, and appropriate management of side effects (e.g., anemia, neutropenia, depression) is crucial for treatment success. The HIV nurse is well positioned to treat, counsel, and support the HIV/HCV-coinfected patient by encouraging screening and providing education on the side effects of treatment, the means of managing side effects, and the resources available to assist in problems of substance abuse and depression. Key words: HIV infection, hepatitis C infection, HIV/ HCV coinfection, nurse’s role
Highly active antiretroviral therapy (HAART) has been successful in extending the lifespan of patients infected with the human immunodeficiency virus (HIV) (Palella et al., 1998); however, this benefit has unveiled yet another major challenge for patients and clinicians: coinfection with the hepatitis C virus (HCV). HCV infection is a growing problem in the HIV-infected population, with recent reports estimating that 30%-35% of HIV-positive individuals in the United States are coinfected with HIV and HCV (Lawrence, 2000; Soriano et al., 2002; Sulkowski, Mast, Seeff, & Thomas, 2000). Symptoms of HCV infection in the HIV-infected patient may result from a preexisting, chronic HCV infection that the patient can now
live long enough to manifest or from a more recently acquired HCV infection that the patient can now live long enough to contract. Coinfection with HIV and HCV is common, because the viruses have shared routes of transmission; the chief means of HCV transmission in the United States is injection drug use (Sulkowski, Mast, et al., 2000). Although the prevalence of HIV/HCV coinfection1 varies among HIV patient subpopulations, the highest prevalence is reported among injection drug users (50%-90%) (Sulkowski, Mast, et al., 2000). HCV infection has serious consequences, and it has been shown to increase the likelihood of morbidity (Bica et al., 2001; Graham et al., 2001; Greub et al., 2000) and to have an increased incidence in patients infected with HIV (reviewed in Sulkowski, Mast, et al., 2000). The United States Public Health Service (USPHS)/Infectious Diseases Society of America (IDSA) recently included a section on HCV infection in their report entitled USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With Human Immunodeficiency Virus (Centers for Disease Control and Prevention [CDC], 1999). 1. Throughout the article, the terms coinfection and coinfected refer to HIV/HCV coinfection.
Richard S. Ferri, PhD, ANP, ACRN, FAAN, is an HIV/AIDS nurse practitioner/writer and a men’s health specialist, Provincetown, MA. Carl A. Kirton, MA, RN, APRN, BC, is a clinical associate professor of nursing, coordinator of the Advanced Practice Program at New York University, and a clinical manager and adult nurse practitioner at the AIDS Center, Mount Sinai Hospital, New York.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 14, No. 5, Supplement to September/October 2003, 7S-17S DOI: 10.1177/1055329003254332 Copyright © 2003 Association of Nurses in AIDS Care
8S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
The most recent update of the USPHS/IDSA guidelines (November 2001) emphasizes the importance of screening all HIV-infected persons for HCV (CDC, 2001), because knowledge of HCV status is extremely important for the management of HIV-infected patients. The challenges of managing HCV infection in the HIV-infected patient are numerous, ranging from clinical consequences to treatment adherence difficulties to psychosocial issues. Thus, the aims of this article are to raise awareness among HIV nurses of the issues surrounding this common, serious complication of HIV infection and to encourage patient screening, education, and social support for optimal treatment.
Impact of HCV Infection in the HIV-Infected Patient Chronic HCV infection in an HIV-negative patient may result in cirrhosis, end-stage liver disease (ESLD), hepatocellular carcinoma, and death. Whether HCV infection accelerates the progression of HIV infection to AIDS or death in coinfected patients is the subject of some debate, with conflicting results reported in recent trials (Daar et al., 2001; Greub et al., 2000; Sulkowski, Moore, Mehta, Chaisson, & Thomas, 2002). Recently, Sulkowski and colleagues analyzed 1,955 patients from an urban HIV clinic to determine the effect of HCV infection on clinical and immunologic progression on HIV infection (Sulkowski et al., 2002). Coinfected patients were followed for a median time period of 2 years, and HIV monoinfected patients were followed for a median time period of 2.19 years. When coinfected patients were compared with HIV monoinfected patients, no differences in the risk of acquiring an AIDS-defining illness or in the risk of death were found. In contrast, data from the Swiss HIV Cohort Study suggest that progression to AIDS or death is accelerated in coinfected patients. In that study, 3,111 HIV-infected patients (ages 16 or over) beginning HAART (defined in the study as combinations of at least three drugs, including at least one protease inhibitor) were followed, and causes of death were recorded over a 3-year period (Greub et al., 2000). More than one third (37.2%) of the patients were coinfected with HCV, and 87.7% of these coinfected patients were either actively
using intravenous (IV) drugs or had used IV drugs in the past. The results showed that progression to AIDS or death was significantly faster in coinfected patients, with a relative hazard ratio of 1.7. This association held true regardless of the virologic response to HAART. In addition, there was an independent association between HCV seropositivity and delayed CD4 cell recovery after the start of HAART. Mortality due to ESLD was low in this study (8/181 deaths definitely related and 13/181 deaths possibly related to ESLD; 4 deaths in HCV-negative patients and 17 deaths in HCV-positive patients). A subanalysis to determine potential effects of hepatitis B virus (HBV) infection on progression to AIDS or death determined that for the 879 patients whose HBV status was known, no association existed (Greub et al., 2000). Consistent with the findings of the Swiss HIV Cohort Study, results from a 7-year prospective analysis of 207 coinfected hemophiliacs (ages 6-19) showed an association between HCV RNA levels and relative risk for clinical progression to AIDS (1.66) and AIDS-related death (1.54) (Daar et al., 2001). Conversely, it is widely accepted that HIV infection accelerates the progression of HCV infection to cirrhosis, ESLD, and death. It is well documented that HIV-negative patients infected with HCV have less severe liver damage when compared with coinfected patients; a recent meta-analysis of eight studies that assessed histologic cirrhosis or decompensated liver disease found that the combined adjusted relative risk of severe liver disease with coinfection was 2.92 (Graham et al., 2001). It appears that the immune system of the coinfected patient may allow HCV infection to become more severe. An analysis of the in vitro cytokine response to HCV antigens by peripheral blood mononuclear cells (PBMCs) of asymptomatic coinfected patients, HIV-negative patients with chronic HCV infection, and patients infected with HIV only showed that the PBMCs of coinfected patients had altered cytokine responses compared with those of patients infected with either virus alone (Woitas et al., 1999). These alterations were proposed to contribute to the increased severity of HCV infection in coinfected patients. Furthermore, in coinfected hemophiliacs (n = 49), immune dysfunction (decline in CD4 cell count) was found to be associated independently with the progression of liver failure (Rockstroh et al., 1996). A similar finding, association
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
Deaths due to ESLD (%)
50 40 30 20 10 0 1991
1996
1998-1999
Figure 1. Increasing incidence of death due to end-stage liver disease (ESLD) in HIV-infected patients (Bica et al., 2001). By 1999, the leading cause of death in a population of hospitalized HIV-infected patients was ESLD (50% of deaths; p = .003).
of CD4 cell count with extent of liver fibrosis, was made in a study of 204 coinfected injection drug users (Puoti et al., 2001). ESLD is becoming a leading cause of death in HIVinfected patients (reviewed in Soriano et al., 2002). This trend is illustrated by the results of a retrospective analysis of the causes of death in a U.S. population of hospitalized HIV-positive patients during the time periods of 1991 (26 total deaths [all causes]; mean age, 38.3 years), 1996 (36 total deaths [all causes]; mean age, 39.1 years), and May 1998–April 1999 (22 total deaths [all causes]; mean age, 40.1 years) (Bica et al., 2001). This analysis revealed that the percentage of deaths due to ESLD had increased from 11.5% in 1991 and 13.9% in 1996 to 50% in 1998-1999 (p = .003 for 1998-1999 versus 1991 and 1996) (Figure 1). Of the patients who underwent serologic testing for HCV, the percentages of those with detectable antibodies to HCV in these time periods were 75%, 57.5%, and 93.8%, respectively. Of those who died from ESLD in 1998-1999, 55% either had CD4 cell counts > 200 cells/µL or undetectable plasma levels of HIV RNA, further confirming that their liver disease was responsible for their death. Only 8% (7) of all 84 patients had tested positive for HBV; 4 of these patients were coinfected with HCV. Thus, in this Massachusetts institution, ESLD had become the leading cause of death in HIV-infected patients by 1999 (Bica et al., 2001).
9S
These dramatic clinical consequences in coinfected individuals highlight the need for early detection and effective treatment of HCV infection in this population. Anti-HIV therapies are not effective against HCV infection (Gavazzi et al., 1998) and may compromise liver function (Núñez, Lana, Mendoza, MartinCarbonero, & Soriano, 2001; Sulkowski, Thomas, Chaisson, & Moore, 2000). Therefore, treatments specific for HCV infection must be carefully integrated into existing anti-HIV regimens, and anti-HIV regimens must be carefully selected to avoid drug-drug interactions and exacerbation of HCV-induced liver damage. Above all, the patient’s individual needs must be considered, not only in terms of treatment efficacy but also in relation to any adherence issues or psychosocial factors that may influence treatment success.
How Is HCV Infection Diagnosed and Treated? As stated above, the 2001 USPHS/IDSA guidelines recommend screening of all HIV-infected persons for HCV (CDC, 2001). Diagnosis of HCV infection is typically made using an enzyme-linked immunosorbent assay (ELISA) to detect HCV antibodies in the blood, indicating the patient’s immune system has recognized the presence of HCV in the body. However, HCV ELISAs may yield false negatives, particularly in immunocompromised HIV-infected patients with CD4 counts < 200 cells/µL, who may not be able to produce detectable levels of HCV antibodies (Berggren et al., 2001). Thus, any HIV-infected patient who tests negative on an ELISA but has abnormal results on liver function tests or has a history of drug use should have a blood test for the presence of HCV RNA (CDC, 2001). Although liver biopsy is not used for diagnosis, it is frequently performed to assess the extent of fibrosis and other histologic damage and to assist in treatment decisions, as it is the only direct means of determining disease severity (Saadeh et al., 2001). Liver fibrosis staging assigns scores ranging from 0 (no fibrosis) to 4 (cirrhosis, probable or definite) (Desmet, Gerber, Hoofnagle, Manns, & Scheuer, 1994; Knodell et al., 1981; Scheuer, 1991). The NIH Consensus Panel on HCV suggests that “patients with persistently normal
10S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
or slightly elevated alanine aminotransferase (ALT) and minimal or no fibrosis on liver biopsy may be reassured of a favorable prognosis and decide to defer antiviral therapy” (NIH Consensus Development Conference Statement, 2002). HCV infection is treatable and can be eradicated in many HIV-negative individuals after 24 or 48 weeks of treatment. The duration of treatment depends upon the genotype with which the patient is infected—of the six known genotypes of HCV, genotype 1 is the most common in the United States and the most difficult to treat (Lau et al., 1996; Liang, 1998). Whereas a treatment period of 48 weeks is required for genotype 1, the two next most common genotypes, genotypes 2 and 3, are easier to treat, requiring only 24 weeks of treatment (Lau et al., 1996; Liang, 1998). The first approved treatment for HCV infection was monotherapy with thrice weekly interferon (IFN)α given subcutaneously. In recent years, studies have shown that IFNα monotherapy is less efficacious than combination therapy with IFNα and ribavirin (RBV) (McHutchison et al., 1998; Poynard et al., 1998). RBV is a guanosine nucleoside analog that is administered orally twice daily. It is ineffective as monotherapy against HCV infection (Schering Corporation, 2002). Each of these drugs has side effects about which the patient should be educated prior to treatment. Side effects of IFNα include depression, transient “flu-like” symptoms (headache, fatigue, myalgia, chills, fever), more severe/persistent fatigue, alopecia, bone marrow suppression, and neutropenia. The major dose-limiting side effect of RBV is hemolytic anemia (Schering Corporation, 2002). In addition, because RBV is teratogenic, it must not be used by pregnant women or their partners. Two negative pregnancy tests (a screening test and a confirmatory test) must be obtained before treating a woman of childbearing age with RBV, and two reliable forms of contraception must be used during therapy and for 6 months posttherapy (Schering Corporation, 2002). Combination therapy with IFNα-2b and RBV has been the standard treatment for HCV infection in recent years. The most common side effects of IFNα-2b/RBV combination therapy include a high incidence of anemia and psychiatric events, including depression, insomnia, and irritability (Schering Corporation, 2002; Sulkowski et al., 2001).
Continuing research on treatments for HCV has resulted in the development of an improvement in the IFN/RBV combination regimen. Therapy with the newly approved pegylated IFNα-2b (PEG-IFN) in combination with RBV is more effective than traditional combination therapy with nonpegylated IFNα2b and RBV (Manns et al., 2001). The chemical modification of pegylation allows for once-weekly dosing of IFN due to the longer half-life of the resulting pegylated molecule (Glue et al., 2000), which may allow for maintenance of more uniform levels of IFN in the bloodstream than those provided by the previous thrice-weekly regimen. More than half (54%) of the patients treated with a PEG-IFN/RBV regimen for 48 weeks achieved a sustained virologic response (SVR, defined as undetectable HCV RNA in the serum at 24 weeks of follow-up) (Manns et al., 2001). A combination formulation using PEG-IFNα-2a is showing high rates (61%) of success in clinical trials (Hadziyannis et al., 2002) and is expected to be approved in the near future. Thus, combination therapy with pegylated forms of IFNα is rapidly becoming the new standard treatment for HCV infection. Common side effects with PEG-IFN/RBV combination treatment are anemia and possibly a greater incidence of neutropenia (Manns et al., 2001). Management of the side effects of HCV therapy may help improve adherence and outcomes. As mentioned previously, a dose-limiting side effect of RBV treatment is hemolytic anemia, which results in a mean hemoglobin decrease of 2-3 g/dL within the first weeks of treatment (Schering Corporation, 2002). IFN can also cause anemia by suppressing erythroid progenitor cell production (Rendo et al., 2000), resulting in a risk of “mixed” anemia (anemia resulting from a combination of hemolysis and decreased red blood cell production) with combination therapy. The traditional approach to managing HCV treatment-related anemia has been reduction of RBV dose or discontinuation of RBV. However, this approach compromises treatment success. It has been shown that minimal therapeutic efficacy is achieved when at least 80% of the RBV dose and 80% of the IFN dose is maintained for 80% of the time (McHutchison, 2000). This presents a dilemma for the clinician, because even though avoidance of (or minimization of) RBV dose reduction is important for achieving an SVR, the severity of the
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
anemia demands its correction. Results of a study in HIV-negative, HCV-infected patients have shown that treatment of anemia with recombinant human erythropoietin (epoetin alfa) 40,000 units once weekly increases hemoglobin levels, enables higher RBV doses to be maintained (mean decrease in RBV dose at week 16 of 31 mg/day with epoetin alfa compared with a mean decrease in RBV dose at week 16 of 179 mg/ day with the traditional approach), improves quality of life, and may enable more patients to tolerate HCV therapy, thus increasing the likelihood of achieving an SVR (Sulkowski et al., 2001). Epoetin alfa, approved for the treatment of anemia in multiple patient populations (zidovudine-treated HIV-infected patients, cancer patients on chemotherapy, chronic renal failure patients, and surgery patients), has been used to treat anemia in HIV-infected patients since 1990 (Ortho Biotech Products, 2000), and its efficacy when given once weekly should make it convenient to administer with once-weekly PEG-IFN. Neutropenia can be treated with recombinant granulocyte colony-stimulating factor (G-CSF) (Sulkowski, 2001). The depression often induced by IFNα may be treated effectively with antidepressant therapy (Rupert, Schäfer, & Scheurlen, 2001).
How Should the Coinfected Patient Be Treated? In the past, HCV infection in HIV-infected patients was typically not treated due to concerns about potential IFN and/or RBV toxicity; however, the recent insights into the severity of the clinical consequences of coinfection have changed this point of view. Available data and ongoing clinical trials suggest that HCV is treatable in coinfected patients (Dieterich, Weisz, Goldman, & Malicdem, 1999; Landau et al., 2001; Perez-Olmeda et al., 1999). In a recently published long-term study, Landau and colleagues used an open, prospective design to determine the effects of 12 months of combination therapy with IFNα-2b/RBV in coinfected patients (N = 51) with severe HCV infection (Landau et al., 2001). Fifteen patients (29%) lacked detectable plasma HCV RNA at the end of treatment, and the SVR rate was 21%, indicating that coinfected patients with severe HCV can benefit from
11S
IFNα-2b/RBV combination therapy. However, studies of IFNα-2b/RBV combination treatment for HCV infection in this population are still somewhat preliminary, and even fewer data exist on the effects of treatment of coinfected patients with PEG-IFN/RBV. In the treatment of coinfected patients, the following clinical factors must be taken into consideration: (a) the influence of HCV disease on the utilization of anti-HIV drugs, (b) the influence of HIV disease on the utilization of anti-HCV drugs, (c) the influence of antiHCV drugs on HIV disease, and (d) the appropriate timing for initiation of treatment for each disease. Influence of HCV disease on the utilization of antiHIV drugs. Many antiretroviral drugs undergo hepatic metabolism; thus, their concentrations may be altered in individuals with hepatic impairment. This issue has not been thoroughly studied for all antiretroviral drugs. A review of the prescribing information of currently approved antiretroviral drugs reveals that reduced doses of the protease inhibitors (PIs) amprenavir and indinavir are recommended for patients with hepatic impairment (GlaxoSmithKline, 2002; Merck & Co., 2002). Furthermore, results of a recent study showed that the clearance of the PI nelfinavir was reduced in coinfected patients (Maserati et al., 2002). However, the prescribing information of the remaining PIs (ritonavir, lopinavir/ ritonavir, and saquinavir) indicates that the pharmacokinetics of these drugs have not been studied in patients with hepatic impairment and recommends exercising caution while administering these drugs to such patients (Abbott Laboratories, 2000, 2002; Roche Laboratories, 2000); similar statements are contained in the prescribing information of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, efavirenz, and delavirdine (Aguoron Pharmaceuticals, 2001; Boehringer Ingelheim Pharmaceuticals, 2002; Bristol-Meyers Squibb, 2002a). Information for the nucleoside reverse transcriptase inhibitors (NRTIs) indicates that there are insufficient data to recommend dose adjustment of zidovudine (although frequent monitoring is suggested) or abacavir, that tenofovir and didanosine have not been studied in individuals with hepatic impairment (monitoring is recommended for didanosine), that zalcitabine does not undergo a significant degree of metabolism by the
12S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
liver, and that no alterations in the pharmacokinetics of stavudine or lamivudine were seen in studies of patients with hepatic impairment (Bristol-Myers Squibb, 2001, 2002b; Gilead Sciences, 2001; GlaxoSmithKline, 2001a, 2001b, 2001c; Roche Laboratories, 2001). In addition, antiretroviral drugs are associated with varying degrees of hepatotoxicity (Sulkowski, Thomas, et al., 2000). Studies have shown that coinfected individuals are predisposed to greater druginduced hepatotoxicity than individuals infected with HIV only (Núñez et al., 2001; Rodriguez-Rosado, Garcia-Samaniego, & Soriano, 1998; Sulkowski, Thomas, et al., 2000). A 3-year retrospective analysis of treatment-naive, HIV-infected patients (N = 222) beginning HAART revealed that the relative risk of severe liver toxicity (defined as a > 3.6 × change from baseline in ALT and/or aspartate aminotransferase [AST] levels) was 3.69 for patients coinfected with HCV (Núñez et al., 2001). The relative risk for any grade of liver toxicity in coinfected patients was 3.20. These relationships were independent of the type of HIV treatment the patient was given (PIs, NNRTIs, or a combination of PIs and NNRTIs). Results of an earlier 2-year prospective cohort study (N = 298) also showed that in HIV-infected patients starting new antiretroviral regimens, the risk of severe liver toxicity (defined as a > 3.6 × change from baseline in ALT or AST levels) was increased in HIV/HCV-coinfected patients (Sulkowski, Thomas, et al., 2000). In this study, ritonavir use was associated with a higher incidence of severe hepatotoxicity. Coinfected patients also have a greater risk of toxicity due to drug-drug interactions between RBV and certain HIV medications (Hester, Keiser, & Berggren, 2001; Lafeuillade, Hittinger, & Chadapaud, 2001; Schering Corporation, 2002). Specifically, mitochondrial toxicity resulting in multiorgan dysfunction and lactic acidosis occurred in 2 of 15 coinfected patients on HAART when given treatment with IFNα/RBV (Lafeuillade et al., 2001). There is also an increased risk of pancreatitis when treating patients on didanosine/stavudine-containing regimens with RBV (Hester et al., 2001). Thus, HCV disease makes it more difficult to treat HIV-infected patients with anti-HIV drugs.
Influence of HIV disease on the utilization of antiHCV drugs. Anemia is common in HIV-infected individuals (Mocroft et al., 1999; Sullivan, Hanson, Chu, Jones, & Ward, 1998), and nursing guidelines on the treatment of anemia in patients with HIV infection have been published recently (Ferri et al., 2001, 2002). Because combination therapy with IFN/RBV also causes anemia, this condition may be exacerbated in coinfected patients treated with IFN/RBV. In anemic HIV-infected patients, treatment with epoetin alfa increases hemoglobin levels and improves quality of life (Abrams, Steinhart, & Frascino, 2000; Grossman, Bowers, & Leitz, 2001; Henry et al., 1992; Revicki et al., 1994; Saag, Levine, Leitz, & Bowers, 2001). Although data on the use of epoetin alfa to treat anemia in coinfected patients are limited, preliminary results suggest that epoetin alfa successfully corrects anemia in this patient population as well (Dieterich et al., 1999). In so doing, it may minimize RBV dose reduction in coinfected patients, as it has been shown to do in HIV-negative, HCV-infected patients (Sulkowski et al., 2001). Influence of anti-HCV drugs on HIV disease. Published studies have not reported an effect of RBV on HIV RNA levels in patients taking anti-HIV drugs (Poles & Dieterich, 2001). Epoetin alfa has also been shown to not adversely affect HIV or HCV RNA levels (Henry et al., 1992; Saag et al., 2001; Sulkowski et al., 2001). Timing of initiation of treatment for each disease. It is generally agreed that treatments for HIV and HCV infections should not be initiated simultaneously. Many clinicians feel that in coinfected patients with significant liver disease, anti-HCV therapy should be initiated first, to preserve the liver and restore its function before assault by anti-HIV therapies. Others feel that HIV infection should be treated first, to optimize the immune system and perhaps slow the progression of HCV infection in patients with less advanced disease. Recently published recommendations from the HIV-HCV International Panel state that it is preferred to treat HCV infection first, then HIV infection; however, the panel recognized that in the majority of cases, patients identified as coinfected have already been identified as HIV-infected and are already on HAART
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
(Soriano et al., 2002). Thus, the relative disease status of individual patients and their presenting clinical characteristics at the time of diagnosis may be the best guides for treatment decisions.
Other Complications of Managing the Coinfected Patient In addition to clinical complications, coinfected patients often have other issues that influence outcomes. When one considers the psychological effects of HCV infection in HIV-negative patients, it follows that these effects may exist to an even greater extent in the setting of concomitant HIV infection. For example, it is important to be aware that HCV-infected patients have significantly greater feelings of anger, hostility, depression, and fatigue than patients with nonliver, chronic system illnesses such as diabetes, hypertension, and coronary artery disease (Obhrai, Hall, & Anand, 2001). For the coinfected patient, depression may be further increased resulting from the reality of having HIV, HCV, and, in many cases, a substance abuse issue. Depression is a common side effect of IFN therapy; thus, patients with a history of depression may require a psychiatric evaluation before the initiation of HCV treatment and should be monitored throughout the HCV treatment course. Issues facing coinfected patients that impact adherence include having to take multiple drugs for multiple diseases, as well as the potential for multiple side effects. In the study by Landau and colleagues, 29% of coinfected patients receiving HCV treatment discontinued treatment (Landau et al., 2001). Along with the difficulty of remembering each specific schedule for each drug, the patient may find it hard to stay disciplined. Because patient tolerance of side effects influences adherence, the patient must be made aware of what to expect prior to treatment, and where possible, adjuvant therapies (epoetin alfa, G-CSF, antidepressants) should be made available when side effects occur. Psychosocial factors can represent significant barriers to diagnosis, treatment, and outcome. Injection drug users, who represent the majority of coinfected patients, typically lack preventative health care and seek care later in the disease process. They may have special needs such as poverty, inadequate housing,
13S
Table 1. Ways in Which the HIV Nurse Can Optimize Outcomes in Coinfected Patients Encourage HIV-infected patients to undergo screening for HCV infection Educate patients on the consequences of coinfection and the pros and cons of HCV treatment Explain the implications of HCV genotype on treatment response to provide the patient with appropriate treatment expectations Educate patients on the side effects of treatment for HCV and how they may be managed Aid in the enrollment of patients in drug and/or alcohol abuse treatment programs Provide information on social support services
lack of transportation, and poor nutrition that interfere with their ability and motivation to seek care. Often, these patients have problems with addiction/recovery and may relapse to using; thus, before HCV therapy can be initiated, substance abuse must be evaluated and controlled. In the study by Núñez and colleagues, alcohol abuse was the strongest predictor of severe liver disease in HIV-infected patients on HAART (Núñez et al., 2001), and in HCV-infected patients, alcohol use accelerates the progression of fibrosis (Poynard, Bedossa, & Opolon, 1997).
Nursing Implications The HIV nurse has an important role in the treatment of coinfected patients, in that nursing interventions at many levels can aid in improving outcomes (Table 1). Initially, the nurse can encourage screening of the HIV-infected patient for HCV infection, pointing out that the USPHS/IDSA strongly recommends this practice. If a patient then tests positive for HCV infection, the nurse should explain the pros and cons of treating HCV infection and point out the finite length of HCV treatment (versus chronic treatment for HIV infection). The nurse can also teach patients the meaning of the SVR and explain that different HCV genotypes respond differently to treatment, reinforcing that SVR rates for genotype 1 are lower than for genotypes 2 and 3. Because adherence to treatment is crucial and can be a significant problem in this population, the nurse can educate patients on the side effects of treatment for each disease and explain how some side
14S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
effects can be ameliorated by additional interventions. Because of the impact of substance abuse on these diseases and their treatment, the nurse can counsel the patient on the need to abstain from drugs and alcohol and aid in patient enrollment in programs to help with these addictions. Finally, the nurse can assist the patient in accessing social support services that may impact treatment adherence and appropriate attendance at follow-up visits. Above all, the HIV nurse must avoid assuming that addicted patients cannot adhere to treatment and therefore should become the patient’s advocate.
Summary HCV infection is a common, serious complication of HIV infection and a growing problem in the HAART era. HCV and HIV have shared modes of transmission, and because effective treatment with HAART is enabling more patients to live longer, patients also have an increased potential to show the manifestations of an existing chronic HCV infection or to contract HCV. Not only does coinfection with HIV and HCV accelerate the progression of both diseases, but it also complicates their management. For instance, HCV disease makes it more difficult to treat patients with anti-HIV drugs owing to their associated hepatotoxicity, and HIV disease complicates the treatment of HCV infection—anemia due to HIV infection may be exacerbated by the treatments for HCV infection, which also cause anemia. The resulting anemia, multifactorial in nature, may then be treated by the addition of epoetin alfa to the therapeutic regimen. Treatments for HIV and HCV infections should be initiated sequentially. Recommendations of the HIV/ HCV International Panel state that where possible, treatment for HCV infection should be initiated first (Soriano et al., 2002), although clinicians vary in opinion on this issue (Bonacini, 2002). It is important to be aware that the most useful indicators of the best approach to treatment are the relative disease status of individual patients and their presenting clinical characteristics at the time of diagnosis. In addition, the treatment of coinfected patients is complicated by psychosocial issues (largely because the majority of coinfected patients are injection drug users, who typically have limited access to health care) and adherence
issues. The HIV nurse has a key role in the successful treatment and management of coinfected patients through encouragement of screening for HCV infection, provision of patient education, and referral to social support services.
References Abbott Laboratories. (2000). Norvir® [package insert]. North Chicago, IL: Author. Abbott Laboratories. (2002). Kaletra™ [package insert]. North Chicago, IL: Author. Abrams, D. I., Steinhart, C., & Frascino, R. (2000). Epoetin alfa therapy for anaemia in HIV-infected patients: Impact on quality of life. International Journal of STD & AIDS, 11, 659-665. Agouron Pharmaceuticals. (2001). Rescriptor® [package insert]. La Jolla, CA: Author. Berggren, R., Jain, M., Hester, J., Vinson, G., Dawson, B., & Keiser, P. (2001, February). False-negative hepatitis C antibody is associated with low CD4 cell counts in HIV/HCVcoinfected patients (#562). In the Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, San Francisco. Bica, I., McGovern, B., Dhar R., Stone, D., McGowan, K., Scheib, R., et al. (2001). Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clinical Infectious Diseases, 32, 492-497. Boehringer Ingelheim Pharmaceuticals. (2002). Viramune® [package insert]. Ridgefield, CT: Author. Bonacini M. (2002). Management issues in patients coinfected with hepatitis C virus and HIV. AIDS Read, 12, 19-26. Bristol-Myers Squibb. (2001). Videx® [package insert]. Princeton, NJ: Author. Bristol-Myers Squibb. (2002a). Sustiva® [package insert]. Princeton, NJ: Author. Bristol-Myers Squibb. (2002b). Zerit® [package insert]. Princeton, NJ: Author. Centers for Disease Control and Prevention. (1999). USPHS/ IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR, 48, No. RR-10. Centers for Disease Control and Prevention. (2001). USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Retrieved November 28, 2001, from http://www.thebody.com/cdc/pdfs/ oi_1101.pdf Daar, E. S., Lynn, H., Donfield, S., Gomperts, E., O’Brien, S. J., Hilgartner, M. W., et al. (2001). Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs. Journal of Infectious Diseases, 183, 589-595. Desmet, V. J., Gerber, M., Hoofnagle, J. H., Manns, M., & Scheuer, P. J. (1994). Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology, 19, 1513-1520.
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection Dieterich, D. T., Weisz, K. B., Goldman, D. J., & Malicdem, M. L. (1999, November 5-9). Combination treatment with interferon and ribavirin for hepatitis C in HIV-coinfection patients. In the Program and abstracts of the 50th Annual Meeting of the American Association for the Study of Liver Diseases, Dallas, TX. Ferri, R. S., Adinolfi, A., Orsi, A. J., Sterken, D. J., Keruly, J. C., Davis, S., et al. (2001). Treatment of anemia in patients with HIV infection, Part 1: The need for adequate guidelines. Journal of the Association of Nurses in AIDS Care, 12, 39-51. Ferri, R. S., Adinolfi, A., Orsi, A. J., Sterken, D. J., Keruly, J. C., Davis, S., et al. (2002). Treatment of anemia in patients with HIV infection—Part 2: Guidelines for the management of anemia. Journal of the Association of Nurses in AIDS Care, 13, 5059. Gavazzi, G., Richallet, G., Morand, P., Bouchard, O., Bosseray, A., Leclercq, P., et al. (1998). Effects of double and triple antiretroviral agents on the HCV viral load in patients coinfected with HIV and HCV. Pathologie-biologie, 46, 412-415. Gilead Sciences. (2001). Viread® [package insert]. Foster City, CA: Author. GlaxoSmithKline. (2001a). Epivir® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2001b). Retrovir® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2001c). Ziagen® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2002). Agenerase® [package insert]. Research Triangle Park: Author. Glue, P., Fang, J. W., Rouzier-Panis, R., Raffanel, C., Sabo, R., Gupta, S. K., et al. (2000). Pegylated interferon alfa-2b: Pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data. Clinical Pharmacology and Therapeutics, 68, 556-567. Graham, C. S., Baden, L. R., Yu, E., Mrus, J. M., Carnie, J., Heeren, T., et al. (2001). Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: A meta-analysis. Clinical Infectious Diseases, 33, 562569. Greub, G., Ledergerber, B., Battegay, M., Grob, P., Perrin, L., Furrer, H., et al. (2000). Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: The Swiss Cohort Study. Lancet, 356, 1800-1805. Grossman, H., Bowers, P., & Leitz, G., for the 010 Study Group. (2001, December 16). Once-weekly dosing of 40000 U epoetin alfa is as effective as thrice weekly dosing among HIV+ patients. Poster presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Hadziyannis, S. J., Cheinquer, H., Morgan, T., Diago, M., Jensen, D. M., Sette, H., Jr., et al. (2002, April 18-21). Peginterferon alfa-2a (40KD) (Pegasys) in combination with ribavirin (RBV): Efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose (Abstract 536). Presented at the
15S
37th Annual Meeting of the European Association for the Study of the Liver, Madrid, Spain. Henry, D. H., Beall, G. N., Benson, C. A., Carey, J., Cone L. A., Eron, L. J., et al. (1992). Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy: Overview of four clinical trials. Annals of Internal Medicine, 117, 739-748. Hester, J., Keiser, P., & Berggren, R. (2001, December). Pancreatitis: An emerging complication of HCV treatment in HIV coinfected patients treated with didanosine/stavudine-containing regimens (#739). In the Program and abstracts of the International Conference on Antibiotics and Antimicrobial Therapy, Chicago, IL. Knodell, R. G., Ishak, K. G., Black, W. C., Chen, T. S., Craig, R., Kaplowitz, N., et al. (1981). Formulation and application of a numerical scoring system for assessing histologic activity in asymptomatic chronic active hepatitis. Hepatology, 1, 431435. Lafeuillade A., Hittinger, G., & Chadapaud, S. (2001). Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet, 357, 280-281. Landau, A., Batisse, D., Piketty, C., Duong Van Huyen, J. P., Bloch, F., Belec, L., et al. (2001). Long-term efficacy of combination therapy with interferon-α2b and ribavirin for severe chronic hepatitis C in HIV-infected patients. AIDS, 15, 21492155. Lau, J. Y., Davis, G. L., Prescott, L. E., Maertens, G., Lindsay, K. L., Qian, K., et al. (1996). Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Hepatitis Interventional Therapy Group. Annals of Internal Medicine, 124, 868-876. Lawrence, S. P. (2000). Advances in the treatment of hepatitis C. Advances in Internal Medicine, 45, 65-105. Liang, T. J. (1998). Combination therapy for hepatitis C infection. New England Journal of Medicine, 339, 1549-1550. Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., Reindollar, R., et al. (2001). Peginterferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet, 358, 958-965. Maserati, R., Seminari, E., Villani, P., Marubbi, F., Zucchi, P., & Regazzi, M. B. (2002, April 12-13). Clinical pharmacokinetics of nelfinavir in HIV-HCV coinfected patients (Abstract 6.2). In the Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy, Washington, DC. McHutchison, J. G. (2000). The effect of dose reduction on sustained response in patients with chronic hepatitis C receiving interferon alfa-2b in combination with ribavirin [abstract]. Hepatology, 32, 249. McHutchison, J. G., Gordon, S. C., Schiff, E. R., Shiffman, M. L., Lee, W. M., Rustgi, V., K., et al. (1998). Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic
16S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
hepatitis C. Hepatitis Interventional Therapy Group. New England Journal of Medicine, 339, 1485-1492. Merck & Co. (2002). Crixivan® [package insert]. Whitehouse Station, NJ: Author. Mocroft, A., Kirk, O., Barton, S. E., Dietrich, M., Proenca, R., Colebunders, R., et al. (1999). Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. AIDS, 13, 943-950. NIH consensus development conference statement. Management of hepatitis C. (2002). Retrieved from http://consensus.nih.gov Núñez, M., Lana, R., Mendoza, J. L., Martin-Carbonero, L., & Soriano, V. (2001). Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 27, 426-431. Obhrai, J., Hall, Y., & Anand, B. S. (2001). Assessment of fatigue and psychologic disturbances in patients with hepatitis C virus infection. Jounal of Clinical Gastroenterology, 32, 413-417. Ortho Biotech Products. (2000). Procrit® [package insert]. Raritan, NJ: Author. Palella, F. J. Jr., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine, 338, 853-860. Perez-Olmeda, M., Gonzalez, J., Garcia-Samaniego, J., Arribas, J. R., Pena, J. M., & Soriano, V. (1999). Interferon plus ribavirin in HIV-infected patients with chronic hepatitis C. Journal of Acquired Immune Deficiency Syndromes, 22, 308309. Poles, M. A., & Dieterich, D. T. (2001). HCV infection in HIVinfected patients: Challenges and future outlook. Infectious Medicine, 18, 349-357. Poynard, T., Bedossa, P., & Opolon, P. (1997). Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet, 349, 825-832. Poynard, T., Marcellin, P., Lee, S. S., Niederau, C, Minuk, G. S., Ideo, G., et al. (1998). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet, 352, 1426-1432. Puoti, M., Bonacini, M., Spinetti, A., Putzolu, V., Govindarajan, S., Zaltron, S., et al. (2001). Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. Journal of Infectious Diseases, 183, 134-137. Rendo, P., Rosso, A., Gomez, F., Gonzalez, E., Viola, L., Findor, J., et al. (2000). Anemia in patients with chronic hepatitis C treatment with ribavirin and interferon. Antiviral Therapy, 5(Suppl. 1), C96. Revicki, D. A., Brown, R. E., Henry, D. H., McNeill, M. V., Rios, A., & Watson, T. (1994). Recombinant human erythropoietin and health-related quality of life of AIDS patients with anemia. Journal of Acquired Immune Deficiency Syndromes, 7, 474484.
Roche Laboratories. (2000). Fortovase™ [package insert]. Nutley, NJ: Author. Roche Laboratories. (2001). Hivid® [package insert]. Nutley, NJ: Author. Rockstroh, J. K., Spengler, U., Sudhop, T., Ewig, S., Theisen, A., Hammerstein, U., et al. (1996). Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV. American Journal of Gastroenterology, 91, 2563-2568. Rodriguez-Rosado, R., Garcia-Samaniego, J., & Soriano V. (1998). Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS, 12, 1256. Rupert, M., Schäfer, A., & Scheurlen, M. (2001). Paroxetine for the prevention of depression induced by interferon alfa. New England Journal of Medicine, 345, 375-376. Saadeh, S., Cammell, G., Carey, W. D., Younossi, Z., Barnes, D., & Easley, K. (2001). The role of liver biopsy in chronic hepatitis C. Hepatology, 33, 196-200. Saag, M. S., Levine, A. M., Leitz, G. J., & Bowers, P. J., for the CHAMPS Study Group. (2001, October 27). Once-weekly epoetin alfa increases hemoglobin and improves quality of life in anemic HIV+ patients. Poster presented at the 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco. Schering Corporation. (2002). Rebetron (Rebetol®/Intron A®) [package insert]. Kenilworth, NJ: Author. Scheuer, P. J. (1991). Classification of chronic viral hepatitis: A need for reassessment. Journal of Hepatology, 13, 372-374. Soriano, V., Sulkowski, M., Bergin, C., Hatzakis, A., Cacoub, P., Katlama, C., et al. (2002). Care of patients with chronic hepatitis C and HIV coinfection: Recommendations from the HIVHCV International Panel. AIDS, 16, 813-828. Sulkowski, M. (2001, November 11). Managing hematologic dysfunction during hepatitis C therapy. Oral presentation presented at the American Association for the Study of Liver Diseases (AASLD), Dallas. Sulkowski, M., Wasserman, R., Brau, N., Hassanein, T., Bini, E., & Dieterich, D. (2001, June 15). Once-weekly recombinant human erythropoietin (epoetin alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis C virus-infected patients receiving interferon- -2b (IFN)/RBV therapy. Poster presented at the Hepatitis Single Topic Conference (AASLD), Chicago, IL. Sulkowski, M. S., Mast E. E., Seeff, L. B., & Thomas, D. L. (2000). Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clinical Infectious Diseases, 30, S77-S84. Sulkowski, M. S., Moore, R. D., Mehta, S. H., Chaisson, R. E., & Thomas, D. L. (2002). Hepatitis C and progression of HIV disease. Journal of the American Medical Association, 288, 199206. Sulkowski, M. S., Thomas, D. L., Chaisson, R. E., & Moore, R. D. (2000). Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. Journal of the American Medical Association, 283, 74-80.
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection Sullivan, P. S., Hanson, D. L., Chu, S. Y., Jones, J. L., & Ward, J. W. (1998). Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: Results from the multistate adult and adolescent spectrum of HIV disease surveillance project. Blood, 91, 301-308.
17S
Woitas, R. P., Rockstroh, J. K., Beier, I., Jung, G., Kochan, B., Matz, B., et al. (1999). Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C coinfected patients. AIDS, 13, 1313-1322.
Hepatitis C Virus/HIV Coinfection: A New Challenge for Nurses in AIDS Care Richard S. Ferri, PhD, ANP, ACRN, FAAN Carl A. Kirton, MA, RN, APRN, BC HIV-infected patients are living longer owing to effective treatment with highly active antiretroviral therapy (HAART). As a result, the extent and impact of hepatitis C virus (HCV) infection in this patient population are now becoming apparent. HIV infection accelerates the progression of HCV to cirrhosis, endstage liver disease, and death. The presence of each disease also influences treatment of the other, and appropriate management of side effects (e.g., anemia, neutropenia, depression) is crucial for treatment success. The HIV nurse is well positioned to treat, counsel, and support the HIV/HCV-coinfected patient by encouraging screening and providing education on the side effects of treatment, the means of managing side effects, and the resources available to assist in problems of substance abuse and depression. Key words: HIV infection, hepatitis C infection, HIV/ HCV coinfection, nurse’s role
Highly active antiretroviral therapy (HAART) has been successful in extending the lifespan of patients infected with the human immunodeficiency virus (HIV) (Palella et al., 1998); however, this benefit has unveiled yet another major challenge for patients and clinicians: coinfection with the hepatitis C virus (HCV). HCV infection is a growing problem in the HIV-infected population, with recent reports estimating that 30%-35% of HIV-positive individuals in the United States are coinfected with HIV and HCV (Lawrence, 2000; Soriano et al., 2002; Sulkowski, Mast, Seeff, & Thomas, 2000). Symptoms of HCV infection in the HIV-infected patient may result from a preexisting, chronic HCV infection that the patient can now
live long enough to manifest or from a more recently acquired HCV infection that the patient can now live long enough to contract. Coinfection with HIV and HCV is common, because the viruses have shared routes of transmission; the chief means of HCV transmission in the United States is injection drug use (Sulkowski, Mast, et al., 2000). Although the prevalence of HIV/HCV coinfection1 varies among HIV patient subpopulations, the highest prevalence is reported among injection drug users (50%-90%) (Sulkowski, Mast, et al., 2000). HCV infection has serious consequences, and it has been shown to increase the likelihood of morbidity (Bica et al., 2001; Graham et al., 2001; Greub et al., 2000) and to have an increased incidence in patients infected with HIV (reviewed in Sulkowski, Mast, et al., 2000). The United States Public Health Service (USPHS)/Infectious Diseases Society of America (IDSA) recently included a section on HCV infection in their report entitled USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected With Human Immunodeficiency Virus (Centers for Disease Control and Prevention [CDC], 1999). 1. Throughout the article, the terms coinfection and coinfected refer to HIV/HCV coinfection.
Richard S. Ferri, PhD, ANP, ACRN, FAAN, is an HIV/AIDS nurse practitioner/writer and a men’s health specialist, Provincetown, MA. Carl A. Kirton, MA, RN, APRN, BC, is a clinical associate professor of nursing, coordinator of the Advanced Practice Program at New York University, and a clinical manager and adult nurse practitioner at the AIDS Center, Mount Sinai Hospital, New York.
JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 14, No. 5, Supplement to September/October 2003, 7S-17S DOI: 10.1177/1055329003254332 Copyright © 2003 Association of Nurses in AIDS Care
8S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
The most recent update of the USPHS/IDSA guidelines (November 2001) emphasizes the importance of screening all HIV-infected persons for HCV (CDC, 2001), because knowledge of HCV status is extremely important for the management of HIV-infected patients. The challenges of managing HCV infection in the HIV-infected patient are numerous, ranging from clinical consequences to treatment adherence difficulties to psychosocial issues. Thus, the aims of this article are to raise awareness among HIV nurses of the issues surrounding this common, serious complication of HIV infection and to encourage patient screening, education, and social support for optimal treatment.
Impact of HCV Infection in the HIV-Infected Patient Chronic HCV infection in an HIV-negative patient may result in cirrhosis, end-stage liver disease (ESLD), hepatocellular carcinoma, and death. Whether HCV infection accelerates the progression of HIV infection to AIDS or death in coinfected patients is the subject of some debate, with conflicting results reported in recent trials (Daar et al., 2001; Greub et al., 2000; Sulkowski, Moore, Mehta, Chaisson, & Thomas, 2002). Recently, Sulkowski and colleagues analyzed 1,955 patients from an urban HIV clinic to determine the effect of HCV infection on clinical and immunologic progression on HIV infection (Sulkowski et al., 2002). Coinfected patients were followed for a median time period of 2 years, and HIV monoinfected patients were followed for a median time period of 2.19 years. When coinfected patients were compared with HIV monoinfected patients, no differences in the risk of acquiring an AIDS-defining illness or in the risk of death were found. In contrast, data from the Swiss HIV Cohort Study suggest that progression to AIDS or death is accelerated in coinfected patients. In that study, 3,111 HIV-infected patients (ages 16 or over) beginning HAART (defined in the study as combinations of at least three drugs, including at least one protease inhibitor) were followed, and causes of death were recorded over a 3-year period (Greub et al., 2000). More than one third (37.2%) of the patients were coinfected with HCV, and 87.7% of these coinfected patients were either actively
using intravenous (IV) drugs or had used IV drugs in the past. The results showed that progression to AIDS or death was significantly faster in coinfected patients, with a relative hazard ratio of 1.7. This association held true regardless of the virologic response to HAART. In addition, there was an independent association between HCV seropositivity and delayed CD4 cell recovery after the start of HAART. Mortality due to ESLD was low in this study (8/181 deaths definitely related and 13/181 deaths possibly related to ESLD; 4 deaths in HCV-negative patients and 17 deaths in HCV-positive patients). A subanalysis to determine potential effects of hepatitis B virus (HBV) infection on progression to AIDS or death determined that for the 879 patients whose HBV status was known, no association existed (Greub et al., 2000). Consistent with the findings of the Swiss HIV Cohort Study, results from a 7-year prospective analysis of 207 coinfected hemophiliacs (ages 6-19) showed an association between HCV RNA levels and relative risk for clinical progression to AIDS (1.66) and AIDS-related death (1.54) (Daar et al., 2001). Conversely, it is widely accepted that HIV infection accelerates the progression of HCV infection to cirrhosis, ESLD, and death. It is well documented that HIV-negative patients infected with HCV have less severe liver damage when compared with coinfected patients; a recent meta-analysis of eight studies that assessed histologic cirrhosis or decompensated liver disease found that the combined adjusted relative risk of severe liver disease with coinfection was 2.92 (Graham et al., 2001). It appears that the immune system of the coinfected patient may allow HCV infection to become more severe. An analysis of the in vitro cytokine response to HCV antigens by peripheral blood mononuclear cells (PBMCs) of asymptomatic coinfected patients, HIV-negative patients with chronic HCV infection, and patients infected with HIV only showed that the PBMCs of coinfected patients had altered cytokine responses compared with those of patients infected with either virus alone (Woitas et al., 1999). These alterations were proposed to contribute to the increased severity of HCV infection in coinfected patients. Furthermore, in coinfected hemophiliacs (n = 49), immune dysfunction (decline in CD4 cell count) was found to be associated independently with the progression of liver failure (Rockstroh et al., 1996). A similar finding, association
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
Deaths due to ESLD (%)
50 40 30 20 10 0 1991
1996
1998-1999
Figure 1. Increasing incidence of death due to end-stage liver disease (ESLD) in HIV-infected patients (Bica et al., 2001). By 1999, the leading cause of death in a population of hospitalized HIV-infected patients was ESLD (50% of deaths; p = .003).
of CD4 cell count with extent of liver fibrosis, was made in a study of 204 coinfected injection drug users (Puoti et al., 2001). ESLD is becoming a leading cause of death in HIVinfected patients (reviewed in Soriano et al., 2002). This trend is illustrated by the results of a retrospective analysis of the causes of death in a U.S. population of hospitalized HIV-positive patients during the time periods of 1991 (26 total deaths [all causes]; mean age, 38.3 years), 1996 (36 total deaths [all causes]; mean age, 39.1 years), and May 1998–April 1999 (22 total deaths [all causes]; mean age, 40.1 years) (Bica et al., 2001). This analysis revealed that the percentage of deaths due to ESLD had increased from 11.5% in 1991 and 13.9% in 1996 to 50% in 1998-1999 (p = .003 for 1998-1999 versus 1991 and 1996) (Figure 1). Of the patients who underwent serologic testing for HCV, the percentages of those with detectable antibodies to HCV in these time periods were 75%, 57.5%, and 93.8%, respectively. Of those who died from ESLD in 1998-1999, 55% either had CD4 cell counts > 200 cells/µL or undetectable plasma levels of HIV RNA, further confirming that their liver disease was responsible for their death. Only 8% (7) of all 84 patients had tested positive for HBV; 4 of these patients were coinfected with HCV. Thus, in this Massachusetts institution, ESLD had become the leading cause of death in HIV-infected patients by 1999 (Bica et al., 2001).
9S
These dramatic clinical consequences in coinfected individuals highlight the need for early detection and effective treatment of HCV infection in this population. Anti-HIV therapies are not effective against HCV infection (Gavazzi et al., 1998) and may compromise liver function (Núñez, Lana, Mendoza, MartinCarbonero, & Soriano, 2001; Sulkowski, Thomas, Chaisson, & Moore, 2000). Therefore, treatments specific for HCV infection must be carefully integrated into existing anti-HIV regimens, and anti-HIV regimens must be carefully selected to avoid drug-drug interactions and exacerbation of HCV-induced liver damage. Above all, the patient’s individual needs must be considered, not only in terms of treatment efficacy but also in relation to any adherence issues or psychosocial factors that may influence treatment success.
How Is HCV Infection Diagnosed and Treated? As stated above, the 2001 USPHS/IDSA guidelines recommend screening of all HIV-infected persons for HCV (CDC, 2001). Diagnosis of HCV infection is typically made using an enzyme-linked immunosorbent assay (ELISA) to detect HCV antibodies in the blood, indicating the patient’s immune system has recognized the presence of HCV in the body. However, HCV ELISAs may yield false negatives, particularly in immunocompromised HIV-infected patients with CD4 counts < 200 cells/µL, who may not be able to produce detectable levels of HCV antibodies (Berggren et al., 2001). Thus, any HIV-infected patient who tests negative on an ELISA but has abnormal results on liver function tests or has a history of drug use should have a blood test for the presence of HCV RNA (CDC, 2001). Although liver biopsy is not used for diagnosis, it is frequently performed to assess the extent of fibrosis and other histologic damage and to assist in treatment decisions, as it is the only direct means of determining disease severity (Saadeh et al., 2001). Liver fibrosis staging assigns scores ranging from 0 (no fibrosis) to 4 (cirrhosis, probable or definite) (Desmet, Gerber, Hoofnagle, Manns, & Scheuer, 1994; Knodell et al., 1981; Scheuer, 1991). The NIH Consensus Panel on HCV suggests that “patients with persistently normal
10S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
or slightly elevated alanine aminotransferase (ALT) and minimal or no fibrosis on liver biopsy may be reassured of a favorable prognosis and decide to defer antiviral therapy” (NIH Consensus Development Conference Statement, 2002). HCV infection is treatable and can be eradicated in many HIV-negative individuals after 24 or 48 weeks of treatment. The duration of treatment depends upon the genotype with which the patient is infected—of the six known genotypes of HCV, genotype 1 is the most common in the United States and the most difficult to treat (Lau et al., 1996; Liang, 1998). Whereas a treatment period of 48 weeks is required for genotype 1, the two next most common genotypes, genotypes 2 and 3, are easier to treat, requiring only 24 weeks of treatment (Lau et al., 1996; Liang, 1998). The first approved treatment for HCV infection was monotherapy with thrice weekly interferon (IFN)α given subcutaneously. In recent years, studies have shown that IFNα monotherapy is less efficacious than combination therapy with IFNα and ribavirin (RBV) (McHutchison et al., 1998; Poynard et al., 1998). RBV is a guanosine nucleoside analog that is administered orally twice daily. It is ineffective as monotherapy against HCV infection (Schering Corporation, 2002). Each of these drugs has side effects about which the patient should be educated prior to treatment. Side effects of IFNα include depression, transient “flu-like” symptoms (headache, fatigue, myalgia, chills, fever), more severe/persistent fatigue, alopecia, bone marrow suppression, and neutropenia. The major dose-limiting side effect of RBV is hemolytic anemia (Schering Corporation, 2002). In addition, because RBV is teratogenic, it must not be used by pregnant women or their partners. Two negative pregnancy tests (a screening test and a confirmatory test) must be obtained before treating a woman of childbearing age with RBV, and two reliable forms of contraception must be used during therapy and for 6 months posttherapy (Schering Corporation, 2002). Combination therapy with IFNα-2b and RBV has been the standard treatment for HCV infection in recent years. The most common side effects of IFNα-2b/RBV combination therapy include a high incidence of anemia and psychiatric events, including depression, insomnia, and irritability (Schering Corporation, 2002; Sulkowski et al., 2001).
Continuing research on treatments for HCV has resulted in the development of an improvement in the IFN/RBV combination regimen. Therapy with the newly approved pegylated IFNα-2b (PEG-IFN) in combination with RBV is more effective than traditional combination therapy with nonpegylated IFNα2b and RBV (Manns et al., 2001). The chemical modification of pegylation allows for once-weekly dosing of IFN due to the longer half-life of the resulting pegylated molecule (Glue et al., 2000), which may allow for maintenance of more uniform levels of IFN in the bloodstream than those provided by the previous thrice-weekly regimen. More than half (54%) of the patients treated with a PEG-IFN/RBV regimen for 48 weeks achieved a sustained virologic response (SVR, defined as undetectable HCV RNA in the serum at 24 weeks of follow-up) (Manns et al., 2001). A combination formulation using PEG-IFNα-2a is showing high rates (61%) of success in clinical trials (Hadziyannis et al., 2002) and is expected to be approved in the near future. Thus, combination therapy with pegylated forms of IFNα is rapidly becoming the new standard treatment for HCV infection. Common side effects with PEG-IFN/RBV combination treatment are anemia and possibly a greater incidence of neutropenia (Manns et al., 2001). Management of the side effects of HCV therapy may help improve adherence and outcomes. As mentioned previously, a dose-limiting side effect of RBV treatment is hemolytic anemia, which results in a mean hemoglobin decrease of 2-3 g/dL within the first weeks of treatment (Schering Corporation, 2002). IFN can also cause anemia by suppressing erythroid progenitor cell production (Rendo et al., 2000), resulting in a risk of “mixed” anemia (anemia resulting from a combination of hemolysis and decreased red blood cell production) with combination therapy. The traditional approach to managing HCV treatment-related anemia has been reduction of RBV dose or discontinuation of RBV. However, this approach compromises treatment success. It has been shown that minimal therapeutic efficacy is achieved when at least 80% of the RBV dose and 80% of the IFN dose is maintained for 80% of the time (McHutchison, 2000). This presents a dilemma for the clinician, because even though avoidance of (or minimization of) RBV dose reduction is important for achieving an SVR, the severity of the
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
anemia demands its correction. Results of a study in HIV-negative, HCV-infected patients have shown that treatment of anemia with recombinant human erythropoietin (epoetin alfa) 40,000 units once weekly increases hemoglobin levels, enables higher RBV doses to be maintained (mean decrease in RBV dose at week 16 of 31 mg/day with epoetin alfa compared with a mean decrease in RBV dose at week 16 of 179 mg/ day with the traditional approach), improves quality of life, and may enable more patients to tolerate HCV therapy, thus increasing the likelihood of achieving an SVR (Sulkowski et al., 2001). Epoetin alfa, approved for the treatment of anemia in multiple patient populations (zidovudine-treated HIV-infected patients, cancer patients on chemotherapy, chronic renal failure patients, and surgery patients), has been used to treat anemia in HIV-infected patients since 1990 (Ortho Biotech Products, 2000), and its efficacy when given once weekly should make it convenient to administer with once-weekly PEG-IFN. Neutropenia can be treated with recombinant granulocyte colony-stimulating factor (G-CSF) (Sulkowski, 2001). The depression often induced by IFNα may be treated effectively with antidepressant therapy (Rupert, Schäfer, & Scheurlen, 2001).
How Should the Coinfected Patient Be Treated? In the past, HCV infection in HIV-infected patients was typically not treated due to concerns about potential IFN and/or RBV toxicity; however, the recent insights into the severity of the clinical consequences of coinfection have changed this point of view. Available data and ongoing clinical trials suggest that HCV is treatable in coinfected patients (Dieterich, Weisz, Goldman, & Malicdem, 1999; Landau et al., 2001; Perez-Olmeda et al., 1999). In a recently published long-term study, Landau and colleagues used an open, prospective design to determine the effects of 12 months of combination therapy with IFNα-2b/RBV in coinfected patients (N = 51) with severe HCV infection (Landau et al., 2001). Fifteen patients (29%) lacked detectable plasma HCV RNA at the end of treatment, and the SVR rate was 21%, indicating that coinfected patients with severe HCV can benefit from
11S
IFNα-2b/RBV combination therapy. However, studies of IFNα-2b/RBV combination treatment for HCV infection in this population are still somewhat preliminary, and even fewer data exist on the effects of treatment of coinfected patients with PEG-IFN/RBV. In the treatment of coinfected patients, the following clinical factors must be taken into consideration: (a) the influence of HCV disease on the utilization of anti-HIV drugs, (b) the influence of HIV disease on the utilization of anti-HCV drugs, (c) the influence of antiHCV drugs on HIV disease, and (d) the appropriate timing for initiation of treatment for each disease. Influence of HCV disease on the utilization of antiHIV drugs. Many antiretroviral drugs undergo hepatic metabolism; thus, their concentrations may be altered in individuals with hepatic impairment. This issue has not been thoroughly studied for all antiretroviral drugs. A review of the prescribing information of currently approved antiretroviral drugs reveals that reduced doses of the protease inhibitors (PIs) amprenavir and indinavir are recommended for patients with hepatic impairment (GlaxoSmithKline, 2002; Merck & Co., 2002). Furthermore, results of a recent study showed that the clearance of the PI nelfinavir was reduced in coinfected patients (Maserati et al., 2002). However, the prescribing information of the remaining PIs (ritonavir, lopinavir/ ritonavir, and saquinavir) indicates that the pharmacokinetics of these drugs have not been studied in patients with hepatic impairment and recommends exercising caution while administering these drugs to such patients (Abbott Laboratories, 2000, 2002; Roche Laboratories, 2000); similar statements are contained in the prescribing information of the nonnucleoside reverse transcriptase inhibitors (NNRTIs) nevirapine, efavirenz, and delavirdine (Aguoron Pharmaceuticals, 2001; Boehringer Ingelheim Pharmaceuticals, 2002; Bristol-Meyers Squibb, 2002a). Information for the nucleoside reverse transcriptase inhibitors (NRTIs) indicates that there are insufficient data to recommend dose adjustment of zidovudine (although frequent monitoring is suggested) or abacavir, that tenofovir and didanosine have not been studied in individuals with hepatic impairment (monitoring is recommended for didanosine), that zalcitabine does not undergo a significant degree of metabolism by the
12S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
liver, and that no alterations in the pharmacokinetics of stavudine or lamivudine were seen in studies of patients with hepatic impairment (Bristol-Myers Squibb, 2001, 2002b; Gilead Sciences, 2001; GlaxoSmithKline, 2001a, 2001b, 2001c; Roche Laboratories, 2001). In addition, antiretroviral drugs are associated with varying degrees of hepatotoxicity (Sulkowski, Thomas, et al., 2000). Studies have shown that coinfected individuals are predisposed to greater druginduced hepatotoxicity than individuals infected with HIV only (Núñez et al., 2001; Rodriguez-Rosado, Garcia-Samaniego, & Soriano, 1998; Sulkowski, Thomas, et al., 2000). A 3-year retrospective analysis of treatment-naive, HIV-infected patients (N = 222) beginning HAART revealed that the relative risk of severe liver toxicity (defined as a > 3.6 × change from baseline in ALT and/or aspartate aminotransferase [AST] levels) was 3.69 for patients coinfected with HCV (Núñez et al., 2001). The relative risk for any grade of liver toxicity in coinfected patients was 3.20. These relationships were independent of the type of HIV treatment the patient was given (PIs, NNRTIs, or a combination of PIs and NNRTIs). Results of an earlier 2-year prospective cohort study (N = 298) also showed that in HIV-infected patients starting new antiretroviral regimens, the risk of severe liver toxicity (defined as a > 3.6 × change from baseline in ALT or AST levels) was increased in HIV/HCV-coinfected patients (Sulkowski, Thomas, et al., 2000). In this study, ritonavir use was associated with a higher incidence of severe hepatotoxicity. Coinfected patients also have a greater risk of toxicity due to drug-drug interactions between RBV and certain HIV medications (Hester, Keiser, & Berggren, 2001; Lafeuillade, Hittinger, & Chadapaud, 2001; Schering Corporation, 2002). Specifically, mitochondrial toxicity resulting in multiorgan dysfunction and lactic acidosis occurred in 2 of 15 coinfected patients on HAART when given treatment with IFNα/RBV (Lafeuillade et al., 2001). There is also an increased risk of pancreatitis when treating patients on didanosine/stavudine-containing regimens with RBV (Hester et al., 2001). Thus, HCV disease makes it more difficult to treat HIV-infected patients with anti-HIV drugs.
Influence of HIV disease on the utilization of antiHCV drugs. Anemia is common in HIV-infected individuals (Mocroft et al., 1999; Sullivan, Hanson, Chu, Jones, & Ward, 1998), and nursing guidelines on the treatment of anemia in patients with HIV infection have been published recently (Ferri et al., 2001, 2002). Because combination therapy with IFN/RBV also causes anemia, this condition may be exacerbated in coinfected patients treated with IFN/RBV. In anemic HIV-infected patients, treatment with epoetin alfa increases hemoglobin levels and improves quality of life (Abrams, Steinhart, & Frascino, 2000; Grossman, Bowers, & Leitz, 2001; Henry et al., 1992; Revicki et al., 1994; Saag, Levine, Leitz, & Bowers, 2001). Although data on the use of epoetin alfa to treat anemia in coinfected patients are limited, preliminary results suggest that epoetin alfa successfully corrects anemia in this patient population as well (Dieterich et al., 1999). In so doing, it may minimize RBV dose reduction in coinfected patients, as it has been shown to do in HIV-negative, HCV-infected patients (Sulkowski et al., 2001). Influence of anti-HCV drugs on HIV disease. Published studies have not reported an effect of RBV on HIV RNA levels in patients taking anti-HIV drugs (Poles & Dieterich, 2001). Epoetin alfa has also been shown to not adversely affect HIV or HCV RNA levels (Henry et al., 1992; Saag et al., 2001; Sulkowski et al., 2001). Timing of initiation of treatment for each disease. It is generally agreed that treatments for HIV and HCV infections should not be initiated simultaneously. Many clinicians feel that in coinfected patients with significant liver disease, anti-HCV therapy should be initiated first, to preserve the liver and restore its function before assault by anti-HIV therapies. Others feel that HIV infection should be treated first, to optimize the immune system and perhaps slow the progression of HCV infection in patients with less advanced disease. Recently published recommendations from the HIV-HCV International Panel state that it is preferred to treat HCV infection first, then HIV infection; however, the panel recognized that in the majority of cases, patients identified as coinfected have already been identified as HIV-infected and are already on HAART
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection
(Soriano et al., 2002). Thus, the relative disease status of individual patients and their presenting clinical characteristics at the time of diagnosis may be the best guides for treatment decisions.
Other Complications of Managing the Coinfected Patient In addition to clinical complications, coinfected patients often have other issues that influence outcomes. When one considers the psychological effects of HCV infection in HIV-negative patients, it follows that these effects may exist to an even greater extent in the setting of concomitant HIV infection. For example, it is important to be aware that HCV-infected patients have significantly greater feelings of anger, hostility, depression, and fatigue than patients with nonliver, chronic system illnesses such as diabetes, hypertension, and coronary artery disease (Obhrai, Hall, & Anand, 2001). For the coinfected patient, depression may be further increased resulting from the reality of having HIV, HCV, and, in many cases, a substance abuse issue. Depression is a common side effect of IFN therapy; thus, patients with a history of depression may require a psychiatric evaluation before the initiation of HCV treatment and should be monitored throughout the HCV treatment course. Issues facing coinfected patients that impact adherence include having to take multiple drugs for multiple diseases, as well as the potential for multiple side effects. In the study by Landau and colleagues, 29% of coinfected patients receiving HCV treatment discontinued treatment (Landau et al., 2001). Along with the difficulty of remembering each specific schedule for each drug, the patient may find it hard to stay disciplined. Because patient tolerance of side effects influences adherence, the patient must be made aware of what to expect prior to treatment, and where possible, adjuvant therapies (epoetin alfa, G-CSF, antidepressants) should be made available when side effects occur. Psychosocial factors can represent significant barriers to diagnosis, treatment, and outcome. Injection drug users, who represent the majority of coinfected patients, typically lack preventative health care and seek care later in the disease process. They may have special needs such as poverty, inadequate housing,
13S
Table 1. Ways in Which the HIV Nurse Can Optimize Outcomes in Coinfected Patients Encourage HIV-infected patients to undergo screening for HCV infection Educate patients on the consequences of coinfection and the pros and cons of HCV treatment Explain the implications of HCV genotype on treatment response to provide the patient with appropriate treatment expectations Educate patients on the side effects of treatment for HCV and how they may be managed Aid in the enrollment of patients in drug and/or alcohol abuse treatment programs Provide information on social support services
lack of transportation, and poor nutrition that interfere with their ability and motivation to seek care. Often, these patients have problems with addiction/recovery and may relapse to using; thus, before HCV therapy can be initiated, substance abuse must be evaluated and controlled. In the study by Núñez and colleagues, alcohol abuse was the strongest predictor of severe liver disease in HIV-infected patients on HAART (Núñez et al., 2001), and in HCV-infected patients, alcohol use accelerates the progression of fibrosis (Poynard, Bedossa, & Opolon, 1997).
Nursing Implications The HIV nurse has an important role in the treatment of coinfected patients, in that nursing interventions at many levels can aid in improving outcomes (Table 1). Initially, the nurse can encourage screening of the HIV-infected patient for HCV infection, pointing out that the USPHS/IDSA strongly recommends this practice. If a patient then tests positive for HCV infection, the nurse should explain the pros and cons of treating HCV infection and point out the finite length of HCV treatment (versus chronic treatment for HIV infection). The nurse can also teach patients the meaning of the SVR and explain that different HCV genotypes respond differently to treatment, reinforcing that SVR rates for genotype 1 are lower than for genotypes 2 and 3. Because adherence to treatment is crucial and can be a significant problem in this population, the nurse can educate patients on the side effects of treatment for each disease and explain how some side
14S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
effects can be ameliorated by additional interventions. Because of the impact of substance abuse on these diseases and their treatment, the nurse can counsel the patient on the need to abstain from drugs and alcohol and aid in patient enrollment in programs to help with these addictions. Finally, the nurse can assist the patient in accessing social support services that may impact treatment adherence and appropriate attendance at follow-up visits. Above all, the HIV nurse must avoid assuming that addicted patients cannot adhere to treatment and therefore should become the patient’s advocate.
Summary HCV infection is a common, serious complication of HIV infection and a growing problem in the HAART era. HCV and HIV have shared modes of transmission, and because effective treatment with HAART is enabling more patients to live longer, patients also have an increased potential to show the manifestations of an existing chronic HCV infection or to contract HCV. Not only does coinfection with HIV and HCV accelerate the progression of both diseases, but it also complicates their management. For instance, HCV disease makes it more difficult to treat patients with anti-HIV drugs owing to their associated hepatotoxicity, and HIV disease complicates the treatment of HCV infection—anemia due to HIV infection may be exacerbated by the treatments for HCV infection, which also cause anemia. The resulting anemia, multifactorial in nature, may then be treated by the addition of epoetin alfa to the therapeutic regimen. Treatments for HIV and HCV infections should be initiated sequentially. Recommendations of the HIV/ HCV International Panel state that where possible, treatment for HCV infection should be initiated first (Soriano et al., 2002), although clinicians vary in opinion on this issue (Bonacini, 2002). It is important to be aware that the most useful indicators of the best approach to treatment are the relative disease status of individual patients and their presenting clinical characteristics at the time of diagnosis. In addition, the treatment of coinfected patients is complicated by psychosocial issues (largely because the majority of coinfected patients are injection drug users, who typically have limited access to health care) and adherence
issues. The HIV nurse has a key role in the successful treatment and management of coinfected patients through encouragement of screening for HCV infection, provision of patient education, and referral to social support services.
References Abbott Laboratories. (2000). Norvir® [package insert]. North Chicago, IL: Author. Abbott Laboratories. (2002). Kaletra™ [package insert]. North Chicago, IL: Author. Abrams, D. I., Steinhart, C., & Frascino, R. (2000). Epoetin alfa therapy for anaemia in HIV-infected patients: Impact on quality of life. International Journal of STD & AIDS, 11, 659-665. Agouron Pharmaceuticals. (2001). Rescriptor® [package insert]. La Jolla, CA: Author. Berggren, R., Jain, M., Hester, J., Vinson, G., Dawson, B., & Keiser, P. (2001, February). False-negative hepatitis C antibody is associated with low CD4 cell counts in HIV/HCVcoinfected patients (#562). In the Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, San Francisco. Bica, I., McGovern, B., Dhar R., Stone, D., McGowan, K., Scheib, R., et al. (2001). Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clinical Infectious Diseases, 32, 492-497. Boehringer Ingelheim Pharmaceuticals. (2002). Viramune® [package insert]. Ridgefield, CT: Author. Bonacini M. (2002). Management issues in patients coinfected with hepatitis C virus and HIV. AIDS Read, 12, 19-26. Bristol-Myers Squibb. (2001). Videx® [package insert]. Princeton, NJ: Author. Bristol-Myers Squibb. (2002a). Sustiva® [package insert]. Princeton, NJ: Author. Bristol-Myers Squibb. (2002b). Zerit® [package insert]. Princeton, NJ: Author. Centers for Disease Control and Prevention. (1999). USPHS/ IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. MMWR, 48, No. RR-10. Centers for Disease Control and Prevention. (2001). USPHS/IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus. Retrieved November 28, 2001, from http://www.thebody.com/cdc/pdfs/ oi_1101.pdf Daar, E. S., Lynn, H., Donfield, S., Gomperts, E., O’Brien, S. J., Hilgartner, M. W., et al. (2001). Hepatitis C virus load is associated with human immunodeficiency virus type 1 disease progression in hemophiliacs. Journal of Infectious Diseases, 183, 589-595. Desmet, V. J., Gerber, M., Hoofnagle, J. H., Manns, M., & Scheuer, P. J. (1994). Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology, 19, 1513-1520.
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection Dieterich, D. T., Weisz, K. B., Goldman, D. J., & Malicdem, M. L. (1999, November 5-9). Combination treatment with interferon and ribavirin for hepatitis C in HIV-coinfection patients. In the Program and abstracts of the 50th Annual Meeting of the American Association for the Study of Liver Diseases, Dallas, TX. Ferri, R. S., Adinolfi, A., Orsi, A. J., Sterken, D. J., Keruly, J. C., Davis, S., et al. (2001). Treatment of anemia in patients with HIV infection, Part 1: The need for adequate guidelines. Journal of the Association of Nurses in AIDS Care, 12, 39-51. Ferri, R. S., Adinolfi, A., Orsi, A. J., Sterken, D. J., Keruly, J. C., Davis, S., et al. (2002). Treatment of anemia in patients with HIV infection—Part 2: Guidelines for the management of anemia. Journal of the Association of Nurses in AIDS Care, 13, 5059. Gavazzi, G., Richallet, G., Morand, P., Bouchard, O., Bosseray, A., Leclercq, P., et al. (1998). Effects of double and triple antiretroviral agents on the HCV viral load in patients coinfected with HIV and HCV. Pathologie-biologie, 46, 412-415. Gilead Sciences. (2001). Viread® [package insert]. Foster City, CA: Author. GlaxoSmithKline. (2001a). Epivir® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2001b). Retrovir® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2001c). Ziagen® [package insert]. Research Triangle Park, NC: Author. GlaxoSmithKline. (2002). Agenerase® [package insert]. Research Triangle Park: Author. Glue, P., Fang, J. W., Rouzier-Panis, R., Raffanel, C., Sabo, R., Gupta, S. K., et al. (2000). Pegylated interferon alfa-2b: Pharmacokinetics, pharmacodynamics, safety and preliminary efficacy data. Clinical Pharmacology and Therapeutics, 68, 556-567. Graham, C. S., Baden, L. R., Yu, E., Mrus, J. M., Carnie, J., Heeren, T., et al. (2001). Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: A meta-analysis. Clinical Infectious Diseases, 33, 562569. Greub, G., Ledergerber, B., Battegay, M., Grob, P., Perrin, L., Furrer, H., et al. (2000). Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: The Swiss Cohort Study. Lancet, 356, 1800-1805. Grossman, H., Bowers, P., & Leitz, G., for the 010 Study Group. (2001, December 16). Once-weekly dosing of 40000 U epoetin alfa is as effective as thrice weekly dosing among HIV+ patients. Poster presented at the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL. Hadziyannis, S. J., Cheinquer, H., Morgan, T., Diago, M., Jensen, D. M., Sette, H., Jr., et al. (2002, April 18-21). Peginterferon alfa-2a (40KD) (Pegasys) in combination with ribavirin (RBV): Efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose (Abstract 536). Presented at the
15S
37th Annual Meeting of the European Association for the Study of the Liver, Madrid, Spain. Henry, D. H., Beall, G. N., Benson, C. A., Carey, J., Cone L. A., Eron, L. J., et al. (1992). Recombinant human erythropoietin in the treatment of anemia associated with human immunodeficiency virus (HIV) infection and zidovudine therapy: Overview of four clinical trials. Annals of Internal Medicine, 117, 739-748. Hester, J., Keiser, P., & Berggren, R. (2001, December). Pancreatitis: An emerging complication of HCV treatment in HIV coinfected patients treated with didanosine/stavudine-containing regimens (#739). In the Program and abstracts of the International Conference on Antibiotics and Antimicrobial Therapy, Chicago, IL. Knodell, R. G., Ishak, K. G., Black, W. C., Chen, T. S., Craig, R., Kaplowitz, N., et al. (1981). Formulation and application of a numerical scoring system for assessing histologic activity in asymptomatic chronic active hepatitis. Hepatology, 1, 431435. Lafeuillade A., Hittinger, G., & Chadapaud, S. (2001). Increased mitochondrial toxicity with ribavirin in HIV/HCV coinfection. Lancet, 357, 280-281. Landau, A., Batisse, D., Piketty, C., Duong Van Huyen, J. P., Bloch, F., Belec, L., et al. (2001). Long-term efficacy of combination therapy with interferon-α2b and ribavirin for severe chronic hepatitis C in HIV-infected patients. AIDS, 15, 21492155. Lau, J. Y., Davis, G. L., Prescott, L. E., Maertens, G., Lindsay, K. L., Qian, K., et al. (1996). Distribution of hepatitis C virus genotypes determined by line probe assay in patients with chronic hepatitis C seen at tertiary referral centers in the United States. Hepatitis Interventional Therapy Group. Annals of Internal Medicine, 124, 868-876. Lawrence, S. P. (2000). Advances in the treatment of hepatitis C. Advances in Internal Medicine, 45, 65-105. Liang, T. J. (1998). Combination therapy for hepatitis C infection. New England Journal of Medicine, 339, 1549-1550. Manns, M. P., McHutchison, J. G., Gordon, S. C., Rustgi, V. K., Shiffman, M., Reindollar, R., et al. (2001). Peginterferon alfa2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: A randomised trial. Lancet, 358, 958-965. Maserati, R., Seminari, E., Villani, P., Marubbi, F., Zucchi, P., & Regazzi, M. B. (2002, April 12-13). Clinical pharmacokinetics of nelfinavir in HIV-HCV coinfected patients (Abstract 6.2). In the Program and abstracts of the 3rd International Workshop on Clinical Pharmacology of HIV Therapy, Washington, DC. McHutchison, J. G. (2000). The effect of dose reduction on sustained response in patients with chronic hepatitis C receiving interferon alfa-2b in combination with ribavirin [abstract]. Hepatology, 32, 249. McHutchison, J. G., Gordon, S. C., Schiff, E. R., Shiffman, M. L., Lee, W. M., Rustgi, V., K., et al. (1998). Interferon α-2b alone or in combination with ribavirin as initial treatment for chronic
16S
JANAC Vol. 14, No. 5, Supplement to September/October 2003
hepatitis C. Hepatitis Interventional Therapy Group. New England Journal of Medicine, 339, 1485-1492. Merck & Co. (2002). Crixivan® [package insert]. Whitehouse Station, NJ: Author. Mocroft, A., Kirk, O., Barton, S. E., Dietrich, M., Proenca, R., Colebunders, R., et al. (1999). Anaemia is an independent predictive marker for clinical prognosis in HIV-infected patients from across Europe. AIDS, 13, 943-950. NIH consensus development conference statement. Management of hepatitis C. (2002). Retrieved from http://consensus.nih.gov Núñez, M., Lana, R., Mendoza, J. L., Martin-Carbonero, L., & Soriano, V. (2001). Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy. Journal of Acquired Immune Deficiency Syndromes, 27, 426-431. Obhrai, J., Hall, Y., & Anand, B. S. (2001). Assessment of fatigue and psychologic disturbances in patients with hepatitis C virus infection. Jounal of Clinical Gastroenterology, 32, 413-417. Ortho Biotech Products. (2000). Procrit® [package insert]. Raritan, NJ: Author. Palella, F. J. Jr., Delaney, K. M., Moorman, A. C., Loveless, M. O., Fuhrer, J., Satten, G. A., et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine, 338, 853-860. Perez-Olmeda, M., Gonzalez, J., Garcia-Samaniego, J., Arribas, J. R., Pena, J. M., & Soriano, V. (1999). Interferon plus ribavirin in HIV-infected patients with chronic hepatitis C. Journal of Acquired Immune Deficiency Syndromes, 22, 308309. Poles, M. A., & Dieterich, D. T. (2001). HCV infection in HIVinfected patients: Challenges and future outlook. Infectious Medicine, 18, 349-357. Poynard, T., Bedossa, P., & Opolon, P. (1997). Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet, 349, 825-832. Poynard, T., Marcellin, P., Lee, S. S., Niederau, C, Minuk, G. S., Ideo, G., et al. (1998). Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group. Lancet, 352, 1426-1432. Puoti, M., Bonacini, M., Spinetti, A., Putzolu, V., Govindarajan, S., Zaltron, S., et al. (2001). Liver fibrosis progression is related to CD4 cell depletion in patients coinfected with hepatitis C virus and human immunodeficiency virus. Journal of Infectious Diseases, 183, 134-137. Rendo, P., Rosso, A., Gomez, F., Gonzalez, E., Viola, L., Findor, J., et al. (2000). Anemia in patients with chronic hepatitis C treatment with ribavirin and interferon. Antiviral Therapy, 5(Suppl. 1), C96. Revicki, D. A., Brown, R. E., Henry, D. H., McNeill, M. V., Rios, A., & Watson, T. (1994). Recombinant human erythropoietin and health-related quality of life of AIDS patients with anemia. Journal of Acquired Immune Deficiency Syndromes, 7, 474484.
Roche Laboratories. (2000). Fortovase™ [package insert]. Nutley, NJ: Author. Roche Laboratories. (2001). Hivid® [package insert]. Nutley, NJ: Author. Rockstroh, J. K., Spengler, U., Sudhop, T., Ewig, S., Theisen, A., Hammerstein, U., et al. (1996). Immunosuppression may lead to progression of hepatitis C virus-associated liver disease in hemophiliacs coinfected with HIV. American Journal of Gastroenterology, 91, 2563-2568. Rodriguez-Rosado, R., Garcia-Samaniego, J., & Soriano V. (1998). Hepatotoxicity after introduction of highly active antiretroviral therapy. AIDS, 12, 1256. Rupert, M., Schäfer, A., & Scheurlen, M. (2001). Paroxetine for the prevention of depression induced by interferon alfa. New England Journal of Medicine, 345, 375-376. Saadeh, S., Cammell, G., Carey, W. D., Younossi, Z., Barnes, D., & Easley, K. (2001). The role of liver biopsy in chronic hepatitis C. Hepatology, 33, 196-200. Saag, M. S., Levine, A. M., Leitz, G. J., & Bowers, P. J., for the CHAMPS Study Group. (2001, October 27). Once-weekly epoetin alfa increases hemoglobin and improves quality of life in anemic HIV+ patients. Poster presented at the 39th Annual Meeting of the Infectious Diseases Society of America, San Francisco. Schering Corporation. (2002). Rebetron (Rebetol®/Intron A®) [package insert]. Kenilworth, NJ: Author. Scheuer, P. J. (1991). Classification of chronic viral hepatitis: A need for reassessment. Journal of Hepatology, 13, 372-374. Soriano, V., Sulkowski, M., Bergin, C., Hatzakis, A., Cacoub, P., Katlama, C., et al. (2002). Care of patients with chronic hepatitis C and HIV coinfection: Recommendations from the HIVHCV International Panel. AIDS, 16, 813-828. Sulkowski, M. (2001, November 11). Managing hematologic dysfunction during hepatitis C therapy. Oral presentation presented at the American Association for the Study of Liver Diseases (AASLD), Dallas. Sulkowski, M., Wasserman, R., Brau, N., Hassanein, T., Bini, E., & Dieterich, D. (2001, June 15). Once-weekly recombinant human erythropoietin (epoetin alfa) facilitates optimal ribavirin (RBV) dosing in hepatitis C virus-infected patients receiving interferon- -2b (IFN)/RBV therapy. Poster presented at the Hepatitis Single Topic Conference (AASLD), Chicago, IL. Sulkowski, M. S., Mast E. E., Seeff, L. B., & Thomas, D. L. (2000). Hepatitis C virus infection as an opportunistic disease in persons infected with human immunodeficiency virus. Clinical Infectious Diseases, 30, S77-S84. Sulkowski, M. S., Moore, R. D., Mehta, S. H., Chaisson, R. E., & Thomas, D. L. (2002). Hepatitis C and progression of HIV disease. Journal of the American Medical Association, 288, 199206. Sulkowski, M. S., Thomas, D. L., Chaisson, R. E., & Moore, R. D. (2000). Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. Journal of the American Medical Association, 283, 74-80.
Ferri, Kirton / Hepatitis C Virus/HIV Coinfection Sullivan, P. S., Hanson, D. L., Chu, S. Y., Jones, J. L., & Ward, J. W. (1998). Epidemiology of anemia in human immunodeficiency virus (HIV)-infected persons: Results from the multistate adult and adolescent spectrum of HIV disease surveillance project. Blood, 91, 301-308.
17S
Woitas, R. P., Rockstroh, J. K., Beier, I., Jung, G., Kochan, B., Matz, B., et al. (1999). Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C coinfected patients. AIDS, 13, 1313-1322.