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Human immunodeficiency virus (HIV) is a major global health issue, with an estimated 33.3 million people infected with HIV-1 worldwide.1 In developed countries, mortality from HIV infection has reduced substantially since the introduction of combined antiretroviral therapy (cART) in 1996, resulting in a pronounced decline in occurrence of acquired immune deficiency syndrome (AIDS) and AIDS-related deaths.2 Thus, more than 50% of deaths in patients on cART are not related to AIDS,2 and liver diseases are a major cause of death. In HIV cohorts, liver diseases account for 10%-18% of observed deaths and ranks even as the first cause of death.3 Liver-related deaths were mostly the result of liver failure in patients with cirrhosis or hepatocellular carcinoma (HCC). In this issue of HEPATOLOGY, Ioannou et al.4 demonstrated a dramatic increase in the prevalence of cirrhosis and HCC among more than 24,000 HIV-infected patients, mainly in hepatitis C virus (HCV)-coinfected patients.
These data suggest an urgent need for the prevention and treatment of cirrhosis and HCC in HIV-infected persons. The Ioannou study4 identified five potentially modifiable risk factors for cirrhosis and/or HCC:HCV infection, hepatitis B virus (HBV) infection, diabetes, alcohol abuse, and low CD4+ cell count. 1
In this series, prevalence of HCV infection decreased from 35% in 1996 to 25% in 20094; however, because HCV infection takes an average of 30-40 years to cause cirrhosis or HCC, this decline might not result in a reduction of cirrhosis and HCC before 2026. Sustained virologic response (SVR) to anti-HCV treatment was associated, respectively, with a 39% and a 61% decrease in the probability to develop cirrhosis or decompensated cirrhosis. However, only 18% of HIV/HCV-coinfected patients received treatment and only 17% of them showed SVR.4 Preliminary data from phase II pilot studies5, 6 have shown that the addition of boceprevir and telaprevir to pegylated interferon (IFN) and ribavirin results in increases of 50% in the rate of SVR in HIV-coinfected persons with HCV genotype 1. Nevertheless, given the low rate of treated patients, even a greater increase in efficacy of current treatment cannot significantly change these outcomes. Barriers to treatment could probably be reduced by the availability of a pangenotipic all-oral, IFN-free, highly effective treatment. The results of pivotal proof-of-concept studies actually give a solid basis for this therapeutic perspective.7 In addition, testing for HCV is almost universal in persons living with HIV, thus a “test and treat” strategy could probably be developed in future years.
The tools available to reduce the effect of HBV infection are already in our hands: vaccination and antivirals with dual anti-HIV and anti-HBV activity. It has demonstrated that in HIV-infected persons, HBV prevalence remained stable in the last 10 years,8 and the rate of new HBV infection is still 1.2 per 100 person-years.9 So, implementation of anti-HBV vaccination in HIV-infected persons is still largely incomplete and should be pursued by all HIV-treating physicians.
The low effect of HBV coinfection alone on cirrhosis in this study probably reflects the favorable effect of dual anti-HBV and anti-HIV therapy with lamivudine10 and/or tenofovir11 on the progression of chronic hepatitis B (CHB). However, several data recently showed the association between tenofovir exposure and bone or renal problems in HIV-infected persons.12 Withdrawal of anti-HBV therapy has been associated with a rapid progression of HBV in HIV-infected persons,13 so cost effectiveness of tenofovir withdrawal should be carefully evaluated in patients with CHB.
Heavy drinking among people with HIV infection under medical care has been found to be almost double that of the general population.10 Both HIV infection and chronic alcohol use are associated with increased gut permeability and elevated plasma levels of lipopolysaccharide, a central activator of inflammatory responses.10 For these reasons, alcohol consumption should be strongly discouraged and alcohol abuse should be diagnosed and aggressively treated in persons living with HIV.
Soon after the introduction of first-generation anti-HIV protease inhibitors in 1996, various cohorts of HIV-infected patients were found to show a high prevalence of diabetes with an incidence of 4.4 and 5.7 per 1,000 person-years of follow-up.14 It was observed that diabetes occurred more frequently in HIV-infected patients previously exposed to specific anti-HIV drugs (e.g., indinavir, stavudine, and didanosine) and persisted in most cases after drug withdrawal.14 Diabetes is associated with all-cause mortality in persons living with HIV and specifically with liver-related mortality.2 Most HIV-infected patients in developed countries are currently treated with new-generation cART associated with a lower risk of diabetes; however, they are reaching older ages than before and often continue to gain weight, thus their case management should include measure of adiposity markers (i.e., waist circumference and body mass index) and fasting blood glucose at least yearly to identify at-risk patients.14
In the Ioannou series, a maximal CD4 count lower than 200 or a percentage of CD4 lower than 14% were associated with an increased risk for HCC. Thus, there are good reasons to start antiretroviral therapy earlier in patients with HCV. However, two studies showed an increased risk of liver-related death in those exposed for a longer time to antiretrovirals after adjusting for CD4 counts.2, 15Thus, it is still undefined whether antiretroviral therapy should be started independently from CD4 counts in HCV-coinfected patients or whether starting below 500 CD4 counts could be a better option. Randomized, controlled trials aimed to solve this issue are ongoing and they will probably answer this question.
In conclusions, Ioannou et al.4 have reported a dramatic rise in the prevalence of end-stage complications of liver disease (e.g., cirrhosis, decompensated cirrhosis, and HCC) among HIV-infected patients, particularly in those coinfected with HCV. Thus, end-stage liver disease is likely to constitute one of the most important clinical problems for HIV-infected patients and their physicians during the decade 2010-2020. The availability of new anti-HCV drugs may have the potential for removing barriers to a comprehensive “test and treatment strategy” against HCV in persons living with HIV. Although we are preparing for the challenges given by these new treatments, we have many tasks in our agenda: to vaccinate patients nonimmune to HBV, to optimize treatment of HBV coinfection, to diagnose and treat alcohol abuse, to identify and treat patients at risk for diabetes, and, finally, to identify the most convenient starting point for antiretroviral therapy in persons coinfected with HCV.