Maria Cristina Moioli

Cognitive and affective disorders associated to HIV infection in the HAART era: findings from the NeuroICONA study

Objective: To assess the natural story of HIV‐associated affective and cognitive disorders and the relationship with clinical, pharmacological, immunological and behavioural factors.

Role of hepatitis C virus (HCV) viremia and HCV genotype in the immune recovery from highly active antiretroviral therapy in a cohort of antiretroviral-naive HIV-infected individuals.

BACKGROUND The roles of hepatitis C virus (HCV) viremia and HCV genotype in the immune response to highly active antiretroviral therapy (HAART) are poorly understood. Our aim was to assess the CD4+ cell count recovery after HAART in human immunodeficiency virus (HIV)-infected patients with HCV viremia and HIV-infected patients who tested negative for HCV antibody (HCV-Ab). We also aimed to assess whether the response to HAART in these patients varied according to HCV genotype. METHODS The analysis focused on 1219 HCV-Ab-negative patients and 284 HCV-viremic patients from a cohort of HIV-infected subjects that includes persons who were antiretroviral naive before initiating HAART after cohort enrollment. HCV RNA load and HCV genotype were determined in plasma specimens obtained and stored during the 6-month period preceding the initiation of HAART. RESULTS The chance of achieving a CD4+ cell count increase of > or = 100 cells/microL from the pre-HAART level tended to be poorer in HCV-viremic patients than in patients who tested negative for HCV-Ab (adjusted relative hazard [RH], 0.82; 95% confidence interval [CI], 0.66-1.01; P = .06). In contrast, a comparison of patients who had a HCV RNA load >1 x 10(6) IU/mL with patients who had a HCV RNA load of 5-1 x 10(6) IU/mL revealed no significant association between HCV RNA load and achievement of an increased CD4+ cell count (adjusted RH, 0.97; 95% CI, 0.75-1.27; P = .83). There was no clear association between HCV genotype and the probability of achieving a CD4+ cell count increase. CONCLUSIONS An association between the presence of HCV-Ab and immune reconstitution after HAART has been shown elsewhere. Results of our large, prospective study support a direct role of HCV viremia in the CD4+ cell count response to HAART. Moreover, our results underline the fact that, in individuals coinfected with HIV and HCV, the goal of treating HCV infection is to eradicate HCV, to both slow the rate of HCV progression and limit potential interference with the response to HAART.

The burden of liver disease in human immunodeficiency virus-infected patients.

Introduction of effective combined antiretroviral therapy has made human immunodeficiency virus (HIV) infection a chronic illness. Substantial reductions in the number of acquired immunodeficiency syndrome- (AIDS-) related deaths have been accompanied by an increase in liver-related morbidity and mortality. Liver diseases rank in the first three most-common causes of death in HIV-infected persons. Mortality is mainly due to cirrhosis and hepatocellular carcinoma induced by hepatitis C virus and hepatitis B virus coinfection. However, antiretroviral drugs toxicity also plays a role. Nonalcoholic fatty liver disease is a common cause of liver injury as well. Nevertheless, alcohol consumption probably plays a pivotal role. Noncirrhotic portal hypertension, an uncommon condition observed in less than 1% of patients, is increasingly described. Finally, acute hepatitis A virus (HAV) and acute and even chronic hepatitis E virus infection have also been reported as causes of liver damage in HIV. Anti-HAV vaccination is thus recommended in persons at risk living with HIV.

Optimizing treatment in HIV/HCV coinfection.

Sustained virological response (SVR) to anti-hepatitis C virus (HCV) treatment is an outcome that can improve life expectancy in persons with human immunodeficiency virus (HIV) infection. Results of anti-HCV treatment are poor, and less than 50% of treated patients show SVR to peginterferon plus ribavirin combination therapy; in infections from HCV genotype 1 this proportion is less than 40%. Pilot studies have demonstrated that Boceprevir or Telaprevir in combination with peginterferon plus ribavirin are able to increase the SVR rate from 45% to 74% with Telaprevir, and from 26% to 61% with Boceprevir in persons never treated for hepatitis C. Interim data seem to indicate a high rate of HCV RNA undetectability on treatment also in patients without sustained response to peginterferon plus ribavirin. Both Telaprevir and Boceprevir have drug-drug interactions with antiretrovirals, and options for concurrent antiretroviral therapy are restricted. There are also several new anti-HCV drugs under study with the potential for more tolerable effective future regimens. The indication for treatment in a patient with HCV/HIV coinfection should take into account the priority of treatment, the probability of sustained response, the potential toxicities, the concurrent antiretroviral therapy options, the patients motivation, and the sustainability of current and future therapies.

Top topics in HCV research arena

A significant improvement in the rate of eradication of Hepatitis C Virus Genotype 1 has been achieved with the addition of Boceprevir and Telaprevir to pegylated interferon and ribavirin. These two drugs are the heralds of a new wave of antivirals that will improve the efficacy of pegylated interferon or even will substitute this drug in interferon free combinations. The results of phase II studies in patients naïve to treatment seem to be very promising strongly supporting the possibility of a large success for a first line all oral antiviral combination in interferon naïve. However, data observed in interferon experienced patients are less exciting and probably more complex treatment regimens will be needed to treat this patients’ population.

A Comparison between Abacavir and Efavirenz as the Third Drug Used in Combination with a Background Therapy Regimen of 2 Nucleoside Reverse-Transcriptase Inhibitors in Patients with Initially Suppressed Viral Loads

BACKGROUND Our objective was to compare the rate of viral rebound and therapy failure in patients receiving abacavir or efavirenz as the third drug (in addition to 2 non-abacavir nucleosides) in combination antiretroviral therapy (cART) and to compare the rate of metabolic alteration associated with these regimens. METHODS We conducted a multicohort prospective observational study of human immunodeficiency virus-infected patients who had attained viral loads < or = 80 copies/mL while receiving cART, without having previously received antiretrovirals. The rates of virological rebound, therapy failure, and lipid-level alteration during follow-up were calculated as the number of events divided by person-years of follow-up (PYFU). A multivariable analysis was performed using a Poisson regression model. RESULTS We studied a total of 744 patients; the median age was 37 years, 27% of the patients were female, and 41% were heterosexual. There was a total of 854 PYFU spent receiving efavirenz and 285 spent receiving abacavir. The nucleoside reverse-transcriptase inhibitor pairs most frequently used were zidovudine/lamivudine (66% of PYFU), stavudine/lamivudine (17.6%), and stavudine/didanosine (5.4%). The adjusted relative rates of virological failure and therapy failure for abacavir, compared with those for efavirenz, were 2.17 (95% confidence interval [CI], 1.12-4.18; P = .02) and 1.41 (95% CI, 1.01-2.01; P = .05), respectively. CONCLUSIONS Patients with virological suppression while receiving regimens containing abacavir appear more likely to experience virological and therapy failure than those receiving efavirenz as their third drug. Although this is a selected group of adherent patients, bias cannot be ruled out, because this is a nonrandomized comparison.

Human immunodeficiency virus and hepatitis c virus coinfection: The agenda is full while waiting for new drugs

H uman immunodeficiency virus (HIV) is a major global health issue, with an estimated 33.3 million people infected with HIV-1 worldwide. 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. Thus, more than 50% of deaths in patients on cART are not related to AIDS, 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. 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. 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 HIVinfected persons. The Ioannou study identified five potentially modifiable risk factors for cirrhosis and/or HCC:HCV infection, hepatitis B virus (HBV) infection, diabetes, alcohol abuse, and low CD4þ cell count. In this series, prevalence of HCV infection decreased from 35% in 1996 to 25% in 2009; 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. Preliminary data from phase II pilot studies 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 alloral, IFN-free, highly effective treatment. The results of pivotal proof-of-concept studies actually give a solid basis for this therapeutic perspective. 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, and the rate of new HBV infection is still 1.2 per 100 person-years. 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 lamivudine and/or tenofovir 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. Withdrawal of anti-HBV therapy has been associated with a rapid progression of HBV in HIVinfected persons, so cost effectiveness of tenofovir withdrawal should be carefully evaluated in patients with CHB. Abbreviations: AIDS, acquired immune deficiency syndrome; cART, combination antiretroviral therapy; CHB, chronic hepatitis B; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IFN, interferon; SVR: sustained virologic response. This work was supported by the Italian Ministry of Health Progetto Nazionale AIDS 2010 (grant no.: 40H96). Address reprint requests to: Massimo Puoti, M.D., Department of Infectious Diseases, AO Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore 3, 20162 Milano, Italy. E-mail: massimopuoti@libero.it; fax: þ 390264442681. Copyright VC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.25941 Potential conflict of interest: Nothing to report.

Successful Pre- and Posttransplant Sofosbuvir-Based Anti-Hepatitis C Virus Treatment in Persons Living With Human Immunodeficiency Virus Infection

Abstract This retrospective study reports the data of sofosbuvir-based anti-hepatitis C virus treatment in 24 candidates and 24 recipients of liver transplantation coinfected with human immunodeficiency virus. Sustained virologic response was cumulatively 85% (90% and 100% in those treated with optimal schedules pre- and posttransplant, respectively).

Single-center outbreak of Pneumocystis jirovecii pneumonia in heart transplant recipients

Pneumocystis jirovecii pneumonia (PJP) outbreaks are described in solid organ transplant recipients. Few reports suggest interhuman transmission with important infection control implications. We described a large PJP outbreak in heart transplant (HTx) recipients.

Durability of lopinavir/ritonavir dual-therapies in individuals with viral load <50 copies/mL in the observational setting

We aimed at evaluating the efficacy and durability of a lopinavir/ritonavir‐based dual regimen (LPV/r‐DR) in virologically controlled HIV‐infected individuals in current clinical practice.