Abstract and Introduction
Abstract
Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV–HCV co-infection. Data of 74 interferon-naïve HIV–HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV–HCV patients had rapid progression of fibrosis [0.201 ± 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 ± 13 years), high HCV viral loads (4.83 × 10 IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = −0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV–HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/μL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV–HCV co-infection and largely preserved CD4+ cell counts.
Introduction
Globally, co-infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) account for substantial morbidity and mortality affecting about 5 million people. Because of overlapping routes of transmission co-infection rates with HCV in HIV patients have been reported to be as high as 60–80% among injection drug users and 16–25% among patients who are at risk of infection from sexual contact. As the introduction of highly active anti-retroviral therapy (HAART) increased the life-expectancy of HIV patients, co-morbidities like HCV infections became a leading cause of mortality in these patients.
The natural history of HCV involves the gradual progression of liver fibrosis that can eventually lead to cirrhosis. In HCV mono-infection, the median fibrosis progression rate (FPR) defined as the ratio between fibrosis stage in METAVIR units (FU) and the duration of infection in years (y) was reported as 0.133 (range: 0.125–0.143) FU/y resulting in a median time to cirrhosis (TTC) of 30 (range: 13–42) years. Younger age at infection, daily alcohol consumption above 50 g, male sex, and duration of infection represent independent risk factors for a more rapid disease progression, while necro-inflammatory activity, HCV viraemia or HCV genotype have no significant influence on FPR or TTC.
Several data about the impact of HIV on HCV infection have been published and there is clear evidence for a more rapid disease progression in HIV–HCV co-infection. The development of HCV-related fibrosis is accelerated in HIV–HCV co-infected patients with a median FPR of 0.25 FU/y ranging from 0.12 FU/y in 'slow-progressors' to 0.51 FU/y in 'fast-progressors'. HCV does not exhibit a direct cytotoxic effect and the immune-mediated pathogenesis of HCV-induced liver injury may involve T lymphocyte triggered immune responses directed against HCV-infected hepatocytes. HIV-infected patients are immunocompromised through an overactivated and deranged immune system causing a depletion of CD4+ cell counts, which in turn seems to lead to an accelerated FPR in HIV–HCV co-infected patients.
Several reasons for the rapid disease progression in HIV–HCV co-infection have been proposed: Co-infection with HIV skews the immune response to HCV towards a Th2 cell reaction and Th2 cytokines enhance fibrogenesis. Permanent activation and dysregulation of the immune system by HIV could drive and enhance cytotoxic cell responses of T lymhocytes directed against HCV-infected hepatocytes. Recent data also suggest a direct pro-fibrogenic effect of HIV envelope proteins. In case of HIV–HCV co-infection or under immunosuppression after liver transplantation HCV can also exert direct cytotoxic effects (e.g. fibrosing cholestatic hepatitis) probably caused by high HCV replication. Hepatotoxicity of HAART may also contribute to liver injury, while certain compounds of HAART (e.g. protease inhibitors) may exert beneficial effects in regard to FPR in HIV-HCV co-infected patients.
Similar to HCV mono-infection daily alcohol consumption and age at infection were identified as independent risk factors for disease progression in HIV–HCV co-infection, while no association between FPR and duration of HCV infection or sex was found.
Data about the influence of CD4+ cell counts on HCV disease progression are inconsistent. Some studies report a negative impact of very low CD4+ cell counts and others observe rapid progression rates despite high CD4+ cell counts. HIV–HCV co-infected patients with high CD4+ cell counts show favourable response to interferon, probably reflecting an effective functional immunological control of HCV. Accordingly, the FPR should be closer to HCV mono-infection in patients with largely preserved CD4+ cell count, while it should be accelerated in patients with CD4+ cell depletion. It is not clear whether a history of a low CD4+ cell nadir, reflecting an advanced stage of HIV infection defined by the revised classification of the Centers for Disease control and prevention (CDC), is still a predictor of a more rapid FPR in HIV–HCV patients with recovered CD4+ cell count after successful HAART treatment.
Fibrosis progression ultimately leads to cirrhosis of the liver and consequently to elevation of portal pressure. Once portal hypertension (PHT) has developed, it causes substantial morbidity and mortality, e.g. variceal bleeding, ascites and hepatic encephalopathy. As portal pressure rises with liver fibrosis progression HIV–HCV co-infected patients with rapid FPRs are likely to suffer more frequently and much earlier from consequences derived from PHT than HCV monoinfected patients. The current gold standard for evaluation of PHT is the measurement of the hepatic venous pressure gradient (HVPG), which was shown to correlate with complications of PHT and has a high prognostic value for patients with HCV-related chronic liver disease.
To our knowledge, no data about the prevalence of elevated portal pressure in HIV–HCV co-infected patients have been reported in the literature. In addition, no study up to date has assessed the development of portal PHT in HIV–HCV co-infected patients in relation to immune function.
Our retrospective study was designed (i) to identify factors contributing to the accelerated FPR, (ii) to assess the influence of low CD4+ cell nadirs on disease progression and (iii) to describe the prevalence of PHT in HIV–HCV co-infected patients.