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Alcohol & Depression, Anemia: barriers to HCV treatment
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Quality of life and cost-effectiveness of anti-HCV therapy in HIV-infected patients
Journal of Hepatology
Volume 44, Issue (Supplement 1), Pages S60-S64
Maria Butia, John Wongb, Miguel Angel Casadoc, Rafael Estebana
a Liver Unit, Hospital General Universitario Valle de Hebron, Paseo Valle hebron 117, Barcelona 08035, Spain
b Clinical Decision Making, Tufts-New England Medical Center, Boston, MA, USA
c Pharmacoeconomics & Outcomes Research Iberia, Madrid, Spain
Quality of life studies in chronic hepatitis C using specific questionnaires have been performed in mono-infected patients; however, these studies have just begun in HIV-HCV co-infected patients. The questionnaires used in mono-infected patients are not well adapted for co-infected patients and need to be redesigned. Typically, co-infected patients have multiple symptoms that may be attributable to HIV, to HCV, to a combination of both diseases or even to side effects related to drug therapy. These patients usually need substitutive therapy to manage side effects related to HCV therapy, particularly anaemia, leukopenia and depression. There are no cost-effectiveness studies published on the current HCV standard therapy with pegylated interferon and ribavirin. However, there is some research on the old standard interferon and ribavirin, which shows that HCV therapy is cost-effective. Cost-effectiveness studies in co-infected patients will have to take into account variables that do not affect mono-infected patients, such as the different levels of CD4, the increase in the fibrosis progression rate and the use of other expensive drugs for the management of side effects. Currently, the literature does not provide adequate information on the effect of HCV infection on the quality of life of HIV-HCV co-infected patients or the most cost-effective HCV therapy.
Article Outline
- Abstract
- 1. Introduction
- 2. Limitations to HCV therapy
- 3. Independent effect of alcohol
- 4. Health-related quality of life and depression
- 5. Cost-effectiveness of HCV therapy
1. Introduction
Co-infection with HIV and hepatitis C virus (HCV) is increasing and becoming recognized as a health problem in Europe. About 30% of HIV patients are co-infected with HCV, the majority of them being intravenous drug users [1-3]. HIV is a risk factor for HCV progression and accelerated HCV disease [4,5]. Currently, liver disease is a major cause of morbidity and mortality in co-infected patients [6-8]. Combination therapy with pegylated interferon and ribavirin is the best therapy for these patients, however, the sustained virologic response rate achieved is lower than mono-infected patients [9-13].
2. Limitations to HCV therapy
One of main concerns in the HCV-HIV population is to identify the proportion of patients eligible for therapy. There are few studies evaluating the suitability for HCV therapy with interferon and ribavirin in co-infected patients. In two prospective studies among 180 and 182 co-infected patients, respectively, only 30-33% of them were eligible for HCV treatment [14,15]. The following factors are the main barriers: non-adherence with clinic visits, active psychiatric illness, active drug or alcohol use, decompensated liver disease, or medical illness. These barriers persisted despite ongoing education regarding the severity of HCV disease and the access to psychiatric and substance abuse programmes. However, the acceptance of anti-viral therapy for hepatitis C was similar between eligible persons with and without HIV [14,15]. These findings highlight the need to develop interventions to improve adherence and to manage substance abuse and other comorbidities in order to maximize the impact of interferon and ribavirin therapy on patients with chronic hepatitis C [16].
3. Independent effect of alcohol
The natural history of hepatitis C virus infection is altered by human immunodeficiency virus co-infection. Hepatic fibrosis and clinical features of hepatic dysfunction develop more rapidly in HIV/HCV co-infection than in HCV alone. Although HIV/HCV-co-infected patients may progress more rapidly to AIDS, other confounding variables include comorbidities, substance abuse, and social issues [17-19]. Alcohol consumption accelerates both HCV and HIV disease. It is thought that chronic alcohol abuse mediates liver damage as a result of increased production of free radicals and proinflammatory cytokines. In the setting of chronic HCV infection, alcohol ingestion has an additional effect of diminishing immune clearance and increasing viral burden to hasten the onset of cirrhosis and hepatocellular carcinoma [20]. Clinical and experimental studies have demonstrated that excessive alcohol consumption can result in impairment of the immune system, and can impact several immune functions including immune tolerance and host defense against opportunistic infections, and development of certain tumours. Although, the effects of ethanol on the immune system involve multiple factors, several studies implicate chronic activation of immune cells and impairment of thymus-derived lymphocytes (T lymphocytes). Helper CD4+ T lymphocytes are the central regulators of the immune system and depletion of these lymphocytes is a major contributing factor in ethanol-induced immune dysfunction and exacerbation of HIV and/or HCV pathogenesis. However, the mechanisms involved in the ethanol-induced CD4+ T cell depletion have only recently begun to be elucidated [21]. Thus, the synergistic effects of alcohol abuse and HIV greatly impact on the morbidity and mortality for patients with HCV co-infection. Ultimately, this cumulative disease process will require far more aggressive management with abstinence and counselling for alcohol abuse; highly active anti-retroviral therapy (HAART) for HIV infection and combination anti-viral therapy for HCV infection to stem the rapid progression to end stage liver disease.
4. Health-related quality of life and depression
Health-related quality of life (HRQOL) is increasingly recognized as an important measure for assessing the burden of chronic diseases. Studies suggest that HCV infection significantly reduces HRQOL, even in the absence of cirrhosis, and that successful treatment of HCV is associated with an improvement in HRQOL [22-26]. Results of initial studies involving HIV-infected patients suggest that HIV-infection is also associated with reduced HRQOL, with evidence that concurrent psychiatric conditions and illicit drug use significantly impair HRQOL for these patients [27-29]. However, results of studies on the effects of CD4 lymphocyte count, HIV load, and HAART on HRQOL have been contradictory [27-31].
The impact of HCV/HIV co-infection on HRQOL is unknown. Most available data have been limited to HCV infection, with information obtained largely from patients entering multicentre interferon treatment trials, a highly selected patient group. The impact of HIV and HCV co-infection has been evaluated in a large urban cohort of HIV/HCV co-infected patients. The HRQOL of co-infected patients was compared with that of urban patients infected with either HIV or HCV alone in a cross-sectional study comprising 136 HIV/HCV co-infected patients, 110 patients with only HCV infection, and 53 patients with only HIV infection [32]. HRQOL was assessed using the Hepatitis Quality of Life questionnaire, a survey that has been validated for patients with chronic HCV infection and includes the generic SF-36 survey, three additional generic scales, and two hepatitis-specific scales [33]. In this study, HRQOL was reduced in a similar way for patients infected with HCV alone, with HIV alone, or with HIV/HCV co-infection compared with a sample of the US population adjusted for age, sex, and race. The explanation for these data is unclear, but it could be due to the fact that HRQOL is a subjective evaluation of an individual's perception of their health and well-being [34]. In addition, these data may reflect different expectations of health in the three groups of patients, specifically in those infected with HIV alone, who although having more severe physical disease may also have a reduced expectation of health. Alternatively, patients with HIV infection may have access to additional support services that partly compensate for worsening in physical health. In co-infected patients, HRQOL was not affected by HCV co-infection, CD4 cell count, or HIV load, although non-use of HAART was associated with lower physical component scores. However, a stratified multivariate analysis of the interaction effects between co-infection and the variables associated with HRQOL suggested that, for HIV-infected patients, co-infection with HCV had a negative impact on mental component scores for patients with high Karnofsky scores and for those with a history of depression. All of these results illustrate the complexity of looking at HRQOL in HCV HIV co-infected patients, in which multiple related variables are associated with well-being. HIV-specific parameters, such as low CD4 cell count and high virus load, have previously been shown to adversely affect HRQOL in some studies of HIV-infected patients [30,31].
Concurrent psychiatric conditions and injection drug use were also important predictors of HRQOL for patients with HIV infection. In addition, HIV co-infection may have a negative impact on mental component scores (MCS) for HCV-infected patients with concomitant depression. Some studies have suggested the importance of current or previous depression as independent predictors of diminished MCS in patients with HCV infection. Psychiatric illness, active intravenous drug use, and unemployment were independent predictors of diminished HRQOL scores in all patients, and non-use of HAART was associated with lower scores in patients with HIV infection.
Approximately, 24% of mono-infected patients with chronic hepatitis C, even before HCV therapy, have symptoms of depression [35]. The etiopathogenic mechanisms of depression are unknown although it appears that it could be attributed to excessive asthenia or related to the long-term prognosis of the illness [36]. Although there is broad-based information on the neuropsychiatric disturbances derived from interferon therapy, there have been few studies that analyse these effects of therapy on co-infected HIV/HCV patients [37]. Some studies suggest that the incidence of depressive symptoms in patients with HIV/HCV co-infection treated with interferon is high at around 40%. This rate is higher than that described for mono-infected patients and this could possibly be related to the neurotoxic effect of HIV and secondary effects on the central nervous system of some anti-retrovirals [37]. In addition, there are other risk factors for depression among this population such as past history of intravenous drug use. The way that interferon produces depressive symptoms are speculative and are based on disturbances in the central adrenergic, serotonergic and the neuroendocrine systems and probably also related to tryptophan deficiency [38]. Most of the depressive symptoms were mild and improved with anti-depressant therapy. The majority of them appear during the first 12 weeks of interferon therapy, and usually no reduction or discontinuation of interferon therapy is necessary [39]. Some studies have shown the high efficacy of a selective serotonin re-uptake inhibitor (SSRI) in the treatment of depressive symptoms associated with interferon therapy. In addition, SSRI are shown to be well tolerated and safe in these patients [39-41]. During the first weeks after initiating interferon therapy for HIV/HCV co-infection, close control of the psychiatric symptoms is recommended. Early treatment of these side effects with anti-depressants would help avoid early dropouts from interferon therapy. Given the high incidence of depressive symptoms in patients co-infected with HIV and HCV being treated with interferon, it is crucial that a correct evaluation of the patient is carried out before prescribing treatment and a strict monitoring of the secondary effects by a multidisciplinary team including infection specialists, psychiatrists and hepatologists [42]. In the presence of depressive symptoms after initiation of interferon, an adequate therapeutic approach would be to begin low-dosage SSRI on a rising scale until the desired response is obtained. Later, the same dosage should be maintained until interferon treatment is completed.
5. Cost-effectiveness of HCV therapy
The health and economic consequences of therapy of chronic hepatitis C has been widely analyzed in cost-effectiveness studies in mono-infected patients [43-47]. All of them showed that HCV therapy with interferon monotherapy or combination therapy with interferon and ribavirin are cost-effective [43-46]. Studies on cost-effectiveness of HCV therapy in co-infected patients are scarce. There is some research with interferon and ribavirin, showing that HCV therapy is cost-effective in this setting [47]. Cost-effectiveness studies in co-infected patients have also to take into account some variables, which do not affect mono-infected patients, such as the different levels of CD4, the increase in the fibrosis progression rate and the use of other expensive drugs such as epoetin and filigastrim for the management of side effects. Preliminary data suggested that for co-infected patients with a mean CD4 cell count of 350cells/μl and moderate disease, treatment with combination therapy using interferon or pegylated interferon and ribavirin increases quality-adjusted life expectancy and has a cost-effectiveness ratio comparable to other well-accepted clinical interventions [47,48]. As in mono-infected patients, combination therapy is more cost-effective in patients infected by genotype non-1 than in patients infected by genotype 1.
Currently, the literature does not provide adequate definitive information on the effect of HCV infection on the quality of life of HIV-HCV co-infected patients and no specific recommendations for the most cost-effective HCV therapy in this setting can be given.
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