In the United States, 150 000–300 000 individuals are infected with both HIV-1 and hepatitis C virus (HCV), representing 15–30% of all HIV-infected and 5–10% of all HCV-infected individuals [1,2]. Whereas hepatitis C was once a relatively minor medical problem in HIV/HCV-co-infected patients, with highly active antiretroviral therapy (HAART) there has been a marked decline in most opportunistic illnesses, and HCV infection has emerged as an important cause of morbidity and mortality [3–5]. The principal impact of chronic hepatitis C is advanced liver disease, including cirrhosis, end-stage liver disease, hepatocellular carcinoma, and in some patients, death. In regions where HAART is widely available, HCV-related liver disease has emerged as a leading cause of hospitalization and death [4,6]. Consequently, national and international guidelines recommend universal screening of all HIV-infected patients for chronic hepatitis C, and consideration of treatment with pegylated IFN-α and ribavirin [7,8]. However, the practical implementation of such recommendations in HIV-infected individuals is complicated by significant medical, psychiatric and social conditions, which confound efforts to treat hepatitis C and HIV as well as efforts to study the independent impact of HCV infection on individuals infected with HIV. The objective of this overview is to discuss the complex interrelationship of HIV/HCV co-infection, illicit drug use, and mental illness, and its impact on the delivery of medical care for both infections.
Epidemiology of hepatitis C virus/HIV co-infection
The design and implementation of programmes to deliver effective medical care for HIV and hepatitis C must take into account the striking differences in the psychosocial and medical status of some individuals infected with HIV alone and those infected with both HCV and HIV. These distinct characteristics are largely the consequence of differences in virus transmission efficiency. Both HIV and HCV can be transmitted by percutaneous exposure to blood, through intercourse, and from a mother to her infant. However, HCV is approximately 10 times more infectious by percutaneous blood exposures, being transmitted by 15–30 of every 1000 accidental needlestick exposures, compared with three per 1000 for HIV . Conversely, HIV is more transmissible than HCV between heterosexual and same-sex partners [10–13]. Although a few recent HCV outbreaks have been reported among HIV-infected men who have sex with HCV-infected men, existing data suggest that sexual contact is a relatively inefficient mode of HCV transmission between men and women, and in many studies, the prevalence of HCV is not substantially higher among men who have sex with men [11,14–16].
On the basis of these shared, but relatively distinct patterns of transmission, HCV/HIV-co-infected and HIV-mono-infected individuals are different with regard to many demographic and clinical characteristics. For example, among more than 3000 patients receiving HAART in Switzerland, injection drug use was reported in 88% of HCV-co-infected individuals compared with only 5% of HIV-mono-infected individuals, whereas homosexual contact was reported in 4% of HCV-co-infected individuals compared with 51% of HIV-mono-infected individuals . Similarly, in the United States, compared with patients with HIV infection alone, HCV-infected patients followed in the HIV Outpatient Study were more likely to use or have used injection drugs (69.7 versus 5.4%), to be older (median age 40.5 versus 35.0 years), to be non-white (68.9 versus 62.0% were African American or Hispanic), to have received less than 12 years of education (26.6 versus 17.8%), and to have undergone care with the use of public funds, such as Medicaid, Medicare, and Ryan White funding (75.7 versus 57.7%) . Socioeconomic disparity was also noted among patients receiving medical care in a Boston HIV clinic. Compared with HCV-uninfected individuals, HCV-infected individuals were more likely to be unemployed for more than 6 months (71 > 58%) and were less likely to be high school graduates (57 < 75%) and to have an income of less than US$900 per month (79 < 59%) . Likewise, in San Francisco, HCV-co-infected individuals were more likely to be homeless for more than one year than those infected with HIV alone (62 > 45%) .
Taken together, these data demonstrate many important demographic and socioeconomic characteristics that differentiate HCV/HIV-co-infected and HIV-mono-infected individuals, and impact the incidence of clinical outcomes of both diseases. These factors may also act as formidable barriers to the delivery of effective medical care for HIV and HCV infections. In addition, they confound research aimed at understanding the independent effect of HCV infection on HIV-related conditions such as progression to AIDS, the effectiveness of antiretroviral therapy, and the development of neurocognitive and neuropsychological dysfunction.
Neurocognitive dysfunction and mental illness in HIV/hepatitis C virus-infected patients
In addition to, or perhaps as consequence of, socioeconomic disparities and medical comorbidities, research has consistently identified substantially lower indices of quality of life and cognitive function as well as a higher prevalence of psychiatric disease in HCV-infected individuals compared with those HCV-uninfected. For example, among HIV-uninfected individuals, independent of liver disease stage and injection drug use status, Forton and coworkers  found impaired cognitive function (e.g. concentration and speed of working memory) among hepatitis C viremic patients compared with a control group of individuals with HCV seroreactivity but no evidence of chronic HCV infection (i.e. HCV RNA undetectable). Similarly, among HCV-infected individuals, Hilsabeck and colleagues  reported neuropsychological dysfunction specifically related to tasks requiring concentration and psychomotor speed, which were similar to levels of dysfunction observed among a control group of individuals with other types of chronic liver disease. Among patients with advanced HIV disease, Ryan and colleagues  reported that those with HCV co-infection performed worse on tests of executive functioning than those patients with HIV alone. Therefore, the available data suggest that HCV-infected patients with and without HIV co-infection exhibit a greater prevalence and severity of neurocognitive dysfunction compared with control groups. However, in light of the strong association between HCV infection, injection drug use and measures of socioeconomic marginalization, it is unclear whether these deficits are directly caused by HCV infection or represent confounding by closely associated conditions.
In addition to neurocognitive deficits, psychiatric disorders are common in HCV-infected patients, particularly those co-infected with HIV. In individuals with severe mental illness, the prevalence of HIV (3.1%) and HCV (19.6%) infections are approximately 8 and 11 times greater than the estimated USA population rates, respectively . Likewise, among more than 30 000 HCV-infected veterans with and without HIV co-infection, El-Serag et al.  found that 31% had active psychiatric disease, defined as hospitalization to a psychiatric or drug-detoxification bed. Compared with a control group of HCV-negative veterans, HCV-infected patients were more likely to have had depression, posttraumatic stress disorder, psychosis, and bipolar and anxiety disorders . Similarly, among HIV-uninfected veterans evaluated for HCV treatment, active depression was identified via the Beck–Depression Inventory in 93%, including moderate to severe disease in 21%, and 78% had more than two active psychiatric disorders . As expected, similar high rates of psychiatric comorbidity have also been reported among HIV/HCV-co-infected patients. In Italy, 43% of 62 HIV/HCV-co-infected patients had evidence of mild to moderate or high suicide risk and nearly 20% had active depression .
Regardless of the etiopathogenesis, neurocognitive dysfunction and mental illness are common among HCV/HIV-infected individuals, and may substantially undermine the delivery and effectiveness of antiretroviral or anti-HCV therapy to HCV/HIV-co-infected patients.
HIV treatment in HIV/hepatitis C virus-infected patients
Among HIV-infected patients in western nations, HAART has been associated with dramatic reductions in the incidence of HIV/AIDS-related morbidity and mortality . However, recent studies have exposed the difficulty of effectively treating HIV in individuals with hepatitis C co-infection. For example, in an urban HIV clinic in Baltimore, Maryland, USA, HCV-infected patients were less likely to be treated with HAART (54% of HCV-infected patients and 67% of HCV-uninfected patients) over a 2-year period of time, and the duration of exposure to HAART was significantly shorter for HCV-infected patients compared with HCV-uninfected patients . Furthermore, in a longitudinal study of injection drug users in Baltimore, Maryland, USA, only 37% of 404 HCV/HIV-co-infected subjects who met eligibility criteria received combination antiretroviral therapy in accordance with published guidelines .
To some extent, HCV infection itself may impede HIV treatment by increasing the hepatic toxicity of the medications . However, the disparity in the delivery of HIV treatment to individuals with hepatitis C is more likely to be related to the impact of active injection drug use, psychiatric disease and homelessness. Lucas and colleagues  evaluated virological and immunological outcomes in 273 HIV-infected patients starting antiretroviral therapy, and found that only 37% of patients maintained an HIV-1-RNA level less than 500 copies/ml after starting therapy. Failure to suppress the HIV viral load at one year was associated with injection drug use (27% viral suppression versus 47% in non-users), African-American race (31 versus 54% in white patients) and adherence with clinic visits (23% for those with > 20% missed visits versus 61% for those with < 20% missed visits). Furthermore, the researchers demonstrated that active drug use was strongly associated with the underutilization of antiretroviral therapy, non-adherence and suboptimal responses (e.g. HIV-RNA suppression). More recently, in a longitudinal analysis, Lucas and coworkers  observed that changes in drug use status correlated closely with antiretroviral therapy use and measures of antiretroviral therapy effectiveness. Compared with those remaining free of substance abuse in consecutive surveys, reinitiating substance abuse was associated with decreased antiretroviral utilization and adherence and less frequent HIV-RNA suppression. Alternatively, compared with persistent substance abuse, switching from substance abuse to non-use was associated with improved antiretroviral utilization or adherence and more frequent HIV-RNA suppression.
Similarly, untreated psychiatric disease has been associated with poor adherence to antiretroviral therapy, and in some studies, an increased risk of HIV disease progression. For example, non-adherence to antiretroviral medications in a large AIDS Clinical Trials Group HIV treatment study was strongly correlated with the presence of active depression . Similarly, Bouhnik and colleagues  found that depressive symptoms before starting antiretroviral drugs was predictive of both non-adherence, and more importantly, clinical progression to AIDS. Likewise, among women followed in the Women's Interagency HIV study , women with chronic depression were more likely to progress to an AIDS-related death (adjusted relative risk 1.7), whereas the use of mental health services was associated with a substantially lower risk of AIDS-related death (adjusted relative risk 0.5).
Taken together, these data suggest that the high prevalence of drug use and psychiatric disease may compromise the delivery of antiretroviral therapy to HCV-co-infected patients, placing such individuals at an increased risk of HIV disease progression. However, importantly, treatment of substance abuse and mental illness can improve adherence to therapy and thereby reduce morbidity caused by HIV disease.
Hepatitis C virus treatment in HIV/hepatitis C virus-infected patients
Pegylated IFN-α plus ribavirin have been shown to be relatively safe and effective for the treatment of HCV in HIV-infected individuals. Sustained virological response rates are generally lower than observed in similar studies in HIV-uninfected populations, particularly among those infected with HCV genotype 1 (sustained virological response rate 14–29%) [36–38]. In addition, the lack of a virological response after 12 weeks of HCV therapy (defined as failure to achieve a two log10 reduction in HCV-RNA level from baseline or an undetectable HCV-RNA level) is highly predictive of treatment failure (negative predictive value 99%) in individuals with HIV co-infection. Accordingly, early hepatitis C viral testing can be used to identify treatment virological non-responders and permit the discontinuation of therapy in such individuals, liming treatment-related morbidity.
Current guidelines recommend treatment of HCV infection in HIV-infected individuals, and indicate that therapy should not be withheld from individuals who currently use illicit drugs or have mental illness if they are able and willing to maintain close monitoring and practice contraception [7,8]. However, active drug use and mental illness and their associated morbidities, such as homelessness, represent a formidable barrier to the delivery of HCV treatment with pegylated IFN-α plus ribavirin. For example, at an urban liver clinic in Cleveland, Ohio, USA, only 28% of HIV-negative, HCV-infected patients evaluated were treated with interferon plus ribavirin . The primary reasons cited for non-treatment were non-adherence to the recommended evaluations, active psychiatric disease, and active drug and alcohol abuse. Similarly, among patients receiving HIV care at another urban clinic, Fleming and coworkers  reported that only 30% of 149 HCV/HIV-co-infected patients who completed an evaluation for hepatitis C were eligible for interferon-based therapy. The major barriers to HCV therapy were: non-adherence, 23%; active drug and alcohol use, 23%; and active psychiatric disease, 21%. Furthermore, among those found to be eligible, 64% were not treated for hepatitis C. Notably, this low rate of HCV treatment eligibility and actual delivery was observed among a carefully selected group of patients receiving HIV care in a stable healthcare setting, and who successfully completed an initial medical evaluation after referral to a subspecialty clinic. More recently, Hall and colleagues  assessed access to and delivery of HCV therapy among a cohort of HIV-co-infected individuals who were recruited from single-room occupancy hotels, homeless shelters and free lunch programmes in San Francisco, California, USA. Compared with HCV-uninfected individuals, the HCV-co-infected patients were more likely to be actively using injection drugs (27 > 6%), to be homeless for over one year (62 > 45%) and to be actively depressed. Interestingly, more than 90% of HIV/HCV-co-infected patients had regular access to primary medical care; however, only 21% of co-infected patients were referred to a specialist for evaluation of hepatitis C, and less than 4% were treated with interferon-based therapy. Among this marginalized population, substantial barriers to HCV care identified included: active drug use, depression, and homelessness as well as patient reticence and provider bias towards the population studied.
In addition, the presence of active depression before HCV treatment with interferon-based therapies is highly predictive of the development of clinically significant depression during therapy, which is associated with significantly lower virological response rates compared with those without severe depression . The treatment of mental illness in HIV/HCV-co-infected individuals before the implementation of HCV treatment with interferon-based regimens thus represents a critical step in the successful management of hepatitis C.
As active drug use and mental illness can reduce access to and the effectiveness of treatment of both HIV and HCV infections, programmes to improve the health of co-infected patients must include a multidimensional and multidisciplinary approach, which combines HCV and HIV treatment specialists with individuals experienced with the management of drug use and psychiatric disease. All HIV/HCV-co-infected individuals should be counseled to prevent the progression and transmission of HIV and HCV infections, as well as vaccinated to prevent hepatitis A and hepatitis B, and encouraged in abstinence from alcohol. The most effective programmes will focus resources on those who need treatment the most (i.e. those with CD4 lymphocyte counts < 350 cells/mm3 and those with significant liver fibrosis). Special attention will need to be given to overcoming modifiable treatment barriers to care. For example, individuals with untreated major depression or other psychiatric disease should have access to temporally and geographically contiguous mental healthcare. The treatment of depression and other psychiatric disorders should facilitate HCV treatment. Furthermore, although active drug or alcohol use is no longer considered an absolute contraindication to HCV treatment, and has never been a contraindication to HIV treatment, there is convincing evidence that active substance abuse limits the delivery and effectiveness of medical care. Interventions that transition individuals out of illicit drug use will probably improve the effectiveness of both HCV and HIV treatment.
As a result of shared routes of transmission, HCV is common among HIV-infected individuals. However, the epidemiology of HCV/HIV co-infection and HIV mono-infection differ substantially, characterized by a higher prevalence of injection drug use, poverty, and neurocognitive and psychiatric disorders among co-infected individuals. Consequently, these factors may impede the medical treatment of HIV and hepatitis C infection in many settings. Nonetheless, antiretroviral therapy prevents the progression of HIV disease and its related complications, and HCV therapy may also cure hepatitis C in some co-infected injection drug users. Accordingly, the management of HIV and hepatitis C requires the development of effective paradigms for the provision of care to co-infected patients, and requires a multidimensional and multidisciplinary approach to address barriers related to active drug use, poverty, lack of education and psychiatric disease.
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