Does Hepatitis C Virus Infection Increase the Risk of HIV Disease Progression?

Liver disease is an increasingly common cause of death in patients with human immunodeficiency virus (HIV) infection.¹ Acquisition of hepatitis C virus (HCV) requires blood contact through contaminated needles or by transfusion; sexual transmission of HCV is uncommon.^{2 - 3} HIV accelerates the progression of HCV-related liver disease⁴ ; thus, exploring HCV treatment in coinfected patients with HCV/HIV is a priority. To date, experience with combination therapies using interferon plus ribavirin in coinfected patients has been limited, and there are emerging concerns about interactions between those drugs and HIV therapies, particularly the interaction between ribavirin and zidovudine and between ribavirin and didanosine.⁵ Recent data reveal a more rapid progression to cirrhosis in individuals with HCV/HIV coinfection who have not received protease inhibitor therapy, who have consumed excess alcohol, and who have a low CD4 cell count.⁶ These observations suggest that effective HIV therapy may decrease the progression to advanced HCV-related liver disease.

Less is known about whether, and if so how, HCV infection alters the course of HIV infection. Studies before the advent of highly active antiretroviral therapy (HAART) suggested that survival and progression to AIDS were the same in patients with HCV/HIV coinfection as in those with HIV infection alone.⁷ HCV infection was largely irrelevant because it was the HIV infection that was life-determining. Much has changed since HAART became available. With increased life expectancy of individuals with HIV infection, HCV infection has emerged as a problem that could adversely affect the survival of patients with HIV. Moreover, the hepatotoxicity associated with HIV therapies, particularly that involving ritonavir, nonnucleoside reverse transcriptase inhibitors, didanosine, and stavudine, appears to be greater in patients with underlying HCV disease than in those who are HCV negative.^{8 - 10} Thus, HCV has the potential to cause progressive liver disease, and the underlying liver disease could potentially confound the ability to provide treatment with effective antiretroviral regimens for these patients.

The data on whether HCV infection alters the natural history of HIV infection are conflicting. From a large cohort of HIV-infected individuals in Switzerland, Greub et al¹¹ reported that HCV seropositivity increased the likelihood of progression to a new AIDS-defining clinical event or death with a median of 28 months of follow-up. This was particularly true for HCV-infected individuals with active injection drug use.⁹ However, this decrease in survival did not appear to be due to a reduced responsiveness of patients with coinfection to HAART, since there was no association between HCV seropositivity and probability of reaching an HIV RNA level below 400 copies per mL.¹¹ The increase in CD4 cell count in response to antiretroviral therapy did appear to be less in patients with HCV infection than in those with HIV alone, however. The authors hypothesized that HCV could have a direct pathogenic effect on lymphocytes, impairing the recovery of HIV-related immune function with antiretroviral therapy, thus, explaining both the progression to AIDS and the delay in CD4 cell count recovery in patients with HCV. Other recent studies have reported similarly compromised CD4 cell responsiveness in HIV-HCV infected individuals despite HIV RNA suppression.¹²

These results appear to be at odds with the report from Sulkowski et al¹³ in this issue of THE JOURNAL. In the current study, no difference was found in the risk of death or in the risk of developing a new AIDS-defining illness in patients with and without HCV.¹³ Survival was reduced in HCV-infected patients with baseline CD4 cell counts from 50/µL through 200/µL, but this difference was not sustained in a multivariate model that included an adjustment for HAART. Patients with HCV infection had an increased but nonsignificant likelihood of progression to a CD4 cell count below 200/µL; this association between CD4 cell count and HCV infection was not demonstrated in a multivariate regression analysis.¹³ Thus, the report from Sulkowski et al suggests that HCV does not play a direct role in altering HIV disease progression, but rather that the management of patients with HIV infection is being compromised by coexisting HCV infection. Highly active antiretroviral therapy was less likely to be initiated in patients with HCV (54% of HCV-positive and 67% of HCV-negative patients received HAART) and duration of HAART was shorter in HCV-positive than HCV-negative patients, except in the patient subgroup with baseline CD4 cell count below 50 cells/µL. Differences in survival in HCV-positive and HCV-negative patients observed in the European study were likely not due to differences in antiretroviral therapy, since the adverse effect of HCV was even seen in patients with well-controlled HIV infection on therapy.¹¹ Different outcomes observed may simply be due to differences in the demographics of the study populations. However, the progression from HIV infection diagnosis to AIDS has been shown to be similar in HIV-infected vs coinfected populations in other cohorts, supporting the lack of a direct effect of HCV on HIV immune progression.¹⁴

How should these studies guide clinicians in the management of patients with HCV/HIV coinfection? The low mortality rate (2.9%) among patients with well-controlled HIV replication while receiving HAART in the report by Sulkowski et al¹³ underscores the importance of therapy, even in patients with HCV who actively inject drugs. Yet, selection of specific antiretroviral therapy is problematic. Regimens containing protease inhibitors, especially ritonavir, have been associated with a greater incidence of Grade III through IV liver toxicities in coinfected patients than those without HCV.⁸ The association of these toxicities with the commonly used low-dose ritonavir-containing regimens is not well defined. These toxicities do reverse in many patients and the long-term role of toxicities in the development of advanced liver disease has yet to be demonstrated.¹⁵ Nevirapine is also associated with a hypersensitivity-type reaction that can result in severe liver damage.⁹ Of greatest concern is the lactic acidosis observed with nucleoside analogs (zalcitabine, didanosine, and stavudine).¹⁰ Certain therapies, such as didanosine or stavudine, should be avoided in the setting of severe liver disease or when ribavirin is used as part of HCV treatment.

Although hepatotoxicity does occur with a greater frequency in patients with HCV-HIV coinfection than in those with HIV alone,⁸ many of these toxicities can be managed through careful monitoring, dose adjustments, or by changing to alternate HIV regimens if and when the toxicity occurs. Most important, inadequate suppression of HIV replication has been shown to have a significant adverse effect on HIV disease outcomes, and on HCV disease progression.⁶ Thus, selection of the optimal antiretroviral therapy regimen should take precedent over any concerns of hepatotoxicity. Unfortunately, several studies have demonstrated that clinicians often delay initiating antiretroviral therapy in HCV-infected patients due to concerns about the potential for hepatotoxicity.¹⁶

These studies also have implications for the timing of treatment for HCV vs that for HIV. If fluctuating liver enzyme levels are potentially delaying the initiation of antiretroviral therapy or reducing the duration of antiretroviral therapy once started, coexisting HCV infection may compromise HIV management. Thus, for a patient with early HIV infection, a case could be made to treat the HCV before treating the HIV, even in patients with mild HCV liver disease. If sustained reduction in HCV RNA is achieved with therapy, to the degree typically associated with sustained normalization of serum alanine aminotransferase levels, antiretroviral therapy can be initiated and maintained effectively with less concern for hepatotoxicity.

How likely is it that HCV viral clearance can be achieved with combination interferon and ribavirin therapies? Treatments for HCV disease are improving. Forty-eight weeks of pegylated interferon plus ribavirin resulted in sustained viral clearance in 54% to 56% of patients in a clinical trial population.^{17 - 18} However, response in patients infected with HCV genotype 1 is only about 40%^{17 - 18} ; unfortunately, this genotype is found in 76% to 97% of patients with HIV.³ Moreover, it is likely that relative contraindications to HCV therapies, such as uncontrolled depression, will be common in patients with coinfection, and that many patients will be unable to begin interferon-based treatments. An additional concern involves possible increased toxicity of ribavirin, particularly hematologic toxicity,^{17 - 18} in patients with bone marrow suppression from their antiretroviral therapy, limiting tolerability of current HCV therapies.

Thus, it is likely that many patients with HIV and HCV coinfection will be unable to be treated effectively with current HCV regimens. The HCV therapy should be initiated in patients who are expected to tolerate treatment, either before HIV therapy if the latter can be delayed, or during HIV therapy, to delay progression of liver disease. However, other approaches should also be considered. These include selection of regimens with lower incidences of hepatotoxicities, and continuation of therapy through minor elevations of liver enzyme levels rather than frequent switching of HIV regimens. In addition, optimal HCV/HIV management will require educating clinicians about the potential for drug interactions between HCV and HIV therapies, continued education of patients about the importance of adherence to prescribed regimens, and for both, education about the importance of alcohol cessation. Certainly the patient with coinfection highlights the importance of developing improved HCV regimens that avoid the toxicities of current interferon-based therapies.