Convenience, efficacy, safety, and durability of INSTI-based antiretroviral therapies: evidence from the Italian MaSTER cohort.

BACKGROUND: Integrase strand transferase inhibitors (INSTI), including raltegravir (RAL), elvitegravir (ELV), and dolutegravir (DTG), have demonstrated better efficacy and tolerability than other combination antiretroviral therapy (cART) classes in clinical trials; however, studies of sustainability of INSTI-containing therapy in the long-term are sparse. The purpose of this study was to provide an epidemiological overview comparing the outcome performance of different INSTI-based regimens longitudinally, including the metrics of efficacy, safety, convenience, and durability among a large, nationally representative cohort of persons living with HIV in Italy. METHODS: We selected subjects in the MaSTER cohort (an Italian multicenter, hospital-based cohort established in the mid-1990s that currently has enrolled over 24,000 PLWH) who initiated an INSTI-based regimen either when naïve or following a regimen switch. Cox proportional hazards regression models were fitted to evaluate associations between therapy interruptions and age, sex, nationality, transmission risk group, viral suppression status, CD4 + T-cell count, diagnosis year, cART status (naïve or experienced), and hepatitis coinfection. Results were stratified by cART INSTI type. RESULTS: There were 8173 participants who initiated an INSTI-based cART regimen in the MaSTER cohort between 2009 and 2017. The population was majority male (72.6%), of Italian nationality (88.6%), and cART-experienced (83.0%). Mean age was 49.7 (standard deviation: 13.9) years. In total, interruptions of the 1st INSTI-based treatment were recorded in 34% of cases. The most frequently cited reason for interruption among all three drug types was safety problems. In the survival analysis, past history of cART use was associated with higher hazards of interruption due to poor efficacy for all three drug types when compared to persons who were cART naïve. Non-viral suppression and CD4 + T-cell count < 200/mm3 at baseline were associated with higher hazards of interruption due to efficacy, safety, and durability reasons. Non-Italian nationality was linked to higher hazards of efficacy interruption for RAL and EVG. Age was negatively associated with interruption due to convenience and positively associated with interruption due to safety reasons. People who injects drugs (PWID) were associated with higher hazards of interruption due to convenience problems. Hepatitis coinfection was linked to higher hazards of interruption due to safety concerns for people receiving RAL. CONCLUSION: One-third of the population experienced an interruption of any drugs included in INSTI therapy in this study. The most frequent reason for interruption was safety concerns which accounted for one-fifth of interruptions among the full study population, mainly switched to DTG. The hazard for interruption was higher for low baseline CD4 + T-cell counts, higher baseline HIV-RNA, non-Italian nationality, older age, PWID and possible co-infections with hepatitis viruses. The risk ratio was higher for past history of cART use compared to persons who were cART naive, use of regimens containing 3 drugs compared to regimens containing 2 drugs. Durability worked in favor of DTG which appeared to perform better in this cohort compared to RAL and EVG, though length of follow-up was significantly shorter for DTG. These observational results need to be confirmed in further perspective studies with longer follow-up.

Efficacy, Convenience, Safety and Durability of DTG-Based Antiretroviral Therapies: Evidence from a Prospective Study by the Italian MaSTER Cohort.

Background: Dolutegravir (DTG) is recommended by international guidelines as a main component of an optimal initial regimen of cART (combination antiretroviral treatment) in people living with HIV (PLWH) and in case of switching for failure or optimization strategies. However, studies on the performance of DTG-containing regimens and indications for switching therapies in the long term are sparse. The purpose of this study was to evaluate prospectively the performance of DTG-based regimens, using the metrics of "efficacy", "safety", "convenience" and ''durability'', among a nationally representative cohort of PLWH in Italy. Methods: We selected all PLWH in four centers of the MaSTER cohort who initiated a DTG-based regimen either when naïve or following a regimen switch between 11 July 2018 and 2 July 2021. Participants were followed until the outcomes were recorded or until the end of the study on 4 August 2022, whichever occurred first. Interruption was reported even when a participant switched to another DTG-containing regimen. Survival regression models were fitted to evaluate associations between therapy performance and age, sex, nationality, risk of HIV transmission, HIV RNA suppression status, CD4+ T-cell count, year of HIV diagnosis, cART status (naïve or experienced), cART backbone and viral hepatitis coinfection. Results: There were 371 participants in our cohort who initiated a DTG-based cART regimen in the time frame of the study. The population was predominantly male (75.2%), of Italian nationality (83.3%), with a history of cART use (80.9%), and the majority initiated a DTG-based regimen following a switch strategy in 2019 (80.1%). Median age was 53 years (interquartile range (IQR): 45-58). Prior cART regimen was based mostly on a combination of NRTI drugs plus a PI-boosted drug (34.2%), followed by a combination of NRTIs plus an NNRTI (23.5%). Concerning the NRTI backbone, the majority comprised 3TC plus ABC (34.5%), followed by 3TC alone (28.6%). The most reported transmission risk factor was heterosexual intercourse (44.2%). Total interruptions of the first DTG-based regimen were registered in 58 (15.6%) participants. The most frequent reason for interruption was due to cART simplification strategies, which accounted for 52%. Only 1 death was reported during the study period. The median time of total follow-up was 556 days (IQR: 316.5-722.5). Risk factors for poor performance of DTG-containing-regimens were found to be: a backbone regimen containing tenofovir, being cART naïve, having detectable HIV RNA at baseline, FIB-4 score above 3.25 and having a cancer diagnosis. By contrast, protective factors were found to be: higher CD4+ T-cell counts and higher CD4/CD8 ratio at baseline. Conclusion: DTG-based regimens were used mainly as a switching therapy in our cohort of PLWH who had undetectable HIV RNA and a good immune status. In this type of population, the durability of DTG-based regimens was maintained in 84.4% of participants with a modest incidence of interruptions mostly due to cART simplification strategies. The results of this prospective real-life study confirm the apparent low risk of changing DTG-containing regimens due to virological failure. They may also help physicians to identify people with increased risk of interruption for different reasons, suggesting targeted medical interventions.

Hepatitis B virus reactivation after effective sofosbuvir and ribavirin treatment in a patient with occult hepatitis B virus infection.

Reactivation of the hepatitis B virus (HBV) has been reported in patients with occult infection (OBI), i.e. HBV surface antigen (HBsAg) negative, HBV core antibody (anti-HBc) positive ± antibodies against HBsAg (anti-HBs) and detectable HBV DNA in serum or liver, receiving immunosuppressive or cytotoxic therapies. Recently, concerns have been raised regarding the risk of HBV reactivation in OBI patients treated with direct acting antiviral agents (DAAs) for chronic hepatitis C (CHC). Here we describe a case of HBV reactivation in a 72-year-old woman with OBI as a possible consequence of effective treatment with sofosbuvir (SOF) and ribavirin (Rbv) for genotype 2a/2c CHC.

Fosamprenavir/ritonavir in patients with viral hepatitis coinfection: an observational multicohort study.

OBJECTIVE: Safety and tolerability evaluation of adapted dose regimens containing fosamprenavir/ritonavir (FPV/r) in HIV-infected subjects with viral hepatitis co-infection. METHODS: A retrospective multicohort analysis was conducted. Subjects from three European cohorts who started FPV/r or lopinavir/ritonavir (LPV/r) as a comparator contributed data to a centralized database. Subjects were divided into five groups by treatment regimen and level of hepatic impairment (aspartate aminotransferase [AST] platelet ratio index [APRI] score < or ≥2). Multivariable Cox regression analyses controlling for demographic factors, baseline CD4 count, FIB-4 score, use of antiretroviral therapy, and laboratory markers (bilirubin and platelet count) were performed to identify factors independently associated with risk of developing adverse events or safety events (eg, drug discontinuation, alanine aminotransferase (ALT) elevation, hepatic decompensation/death). RESULTS: A total of 1096 patients contributed data to the study. Fosamprenavir/ritonavir (except in subjects with APRI ≥2 receiving standard dose) was associated with a higher two-year risk of drug discontinuation compared with LPV/r. Restricting the analysis to discontinuations due to adverse events (AEs), only subjects who received the reduced dose were more likely to discontinue ≥1 drug in the FPV/r regimen. There were no statistical differences in ALT elevation between groups. Incidence of hepatic decompensation events was similar among groups except for subjects who received non standard doses of FPV, though the number of events was small. CONCLUSIONS: Fosamprenavir/ritonavir discontinuation rate due to AEs or ALT elevation was similar across all European-approved FPV/r doses and to that of LPV/r subjects.  Although liver tolerated antiretrovirals, such as integrase inhibitor and entry inhibitor, the use of FPV/r is acceptable in HIV infected patients with viral hepatitis.

Effect of aging, glucose level, and HIV viral load on response to treatment with pegylated interferon plus ribavirin in HIV/HCV co-infected women.

BACKGROUND: This was a post-hoc analysis of the Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study, originally designed to document routine clinical and treatment data in HIV/HCV coinfected patients treated with pegylated interferon/ribavirin (PEG-IFN/RBV). The aim of this study was to define the impact of several variables, such as age, glucose metabolism, and HIV viral load, on PEG-IFN/RBV treatment outcomes, in HIV/HCV coinfected women. METHODS: Female subjects from the OPERA database were retrospectively evaluated and factors associated with sustained virological response (SVR) were assessed and compared to the male population by logistic regression analysis. At baseline, clinical and demographic data were collected. Patients were then administered with PEG-IFN/RBV therapy for 48 weeks. After a 24-week follow-up period, SVR was evaluated. RESULTS: A total of 1523 patients were enrolled in 98 centers across Italy, 1284 of whom were IFN therapy naïve and were included in the post-hoc analysis. In the female group, factors associated with SVR were the presence of HCV genotype 2,3 (adjusted odds ratio [AOR]=6.87, p<0.0001), age ≤45 years (AOR=2.61, p=0.014), ≥80% exposure to PEG-IFN (AOR=3.85, p=0.019) and RBV (AOR=3.94, p=0.015) therapy. Also, increased glucose plasma level negatively correlated with SVR (AOR=0.98, p=0.066). In the male population, undetectable HIV-RNA (AOR=1.47, p=0.033) but not glucose level (AOR=1.0, p=0.95) predicted SVR. CONCLUSIONS: Findings from the present study demonstrate that several factors may be predictive of SVR when pegylated interferon plus ribavirin is used (i.e., age, gender, HIV viral load and HCV genotype) that need to be carefully considered prior to therapeutic intervention, since they may hinder successful therapy. Use of PEG-IFN/RBV with novel direct antiviral agents will likely be still maintained until less expensive and effective interferon-free strategies become available.

Risk of Liver Enzyme Elevation During Treatment With Ritonavir-Boosted Protease Inhibitors Among HIV-Monoinfected and HIV/HCV-Coinfected Patients.

BACKGROUND: The risk of liver enzyme elevation (LEE) after different ritonavir-boosted protease inhibitors (PI/r) has not been fully assessed in real-life settings and in populations with high rates of hepatitis C virus (HCV) coinfection. METHODS: Patients introducing a new PI/r between 1998 and 2012 were included, if transaminases and HCV antibody (Ab) were assessed before treatment initiation. Time to grade 3 and 4 LEE were assessed using univariable and multivariable conditional Cox analyses, stratified by HCV serostatus. RESULTS: A total of 6193 HIV-infected patients (3242 HCV-Ab negative and 2951 HCV-Ab positive) were included. Incidence of grade 3 LEE was 1.05, 7.66, and 8.08 per 100 patient-years of follow-up among HCV-Ab negative, HCV-Ab-positive and HCV-RNA-positive patients, respectively. Among HCV-Ab-negative patients, no differences were detected between different PI/r. Use of darunavir/ritonavir was not associated with LEE among HCV-coinfected patients. Atazanavir/ritonavir use was associated with grade 3 LEE but only among HCV-Ab-positive patients (versus LPV/r, hazard ratio: 1.39; 95% confidence interval: 1.1 to 1.75). This risk was not confirmed in a subanalysis restricted to HCV-RNA-positive patients (versus LPV/r, hazard ratio: 1.16; 95% confidence interval: 0.87 to 1.55). Other independent predictors of grade 3 LEE among HCV-Ab-positive patients were older age, male gender, being treatment naive, nonnucleoside reverse transcriptase inhibitor coadministration, increased aspartate aminotransferase at baseline, overweight, positive HCV-RNA, and advanced estimated liver fibrosis. CONCLUSIONS: Occurrence of hepatotoxicity was a rare finding among HCV-Ab-negative patients and was not influenced by the type of PI/r. In particular, the use of darunavir/ritonavir, previously linked with severe cases of hepatotoxicity, was not associated with a greater risk of LEE, irrespective from HCV serostatus.

Cytopenias during treatment of HIV-HCV-coinfection with pegylated interferon and ribavirin: safety analysis of the OPERA study.

BACKGROUND: Until recently, recommendations for HCV treatment in HIV-coinfected patients have been combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV). However, this treatment is often accompanied with cytopenias which lead to drug-dose reduction/discontinuation, therefore influencing sustained virological response (SVR). This study aimed at evaluating incidence and predictors of cytopenias and to define their impact on SVR in Italian HIV-HCV-coinfected patients undergoing PEG-IFN/RBV treatment. METHODS: OPERA was a multicentric, observational study conducted in 98 Italian centres. Patients with HIV-HCV coinfection were administered with PEG-IFN/RBV combination treatment for 48 weeks. Incidence and time of onset of cytopenias and multiple bone marrow toxicity (mBMT) was monitored. Logistic regression analysis assessed factors associated with SVR, anaemia, neutropenia, thrombocytopenia and mBMT. RESULTS: Between 2005 and 2011, 1,523 patients were enrolled. Anaemia (haemoglobin <10 g/dl) occurred in 197 (12.9%) patients and a haemoglobin drop ≥3 g/dl was recorded in 796 (52.3%). Anaemia did not impact on SVR, its rate being 42.1% and 38.1%, respectively, in patients with and without anaemia (P=0.31). Therapy discontinuation due to anaemia occurred in 47 patients (3.1%). Neutropenia (<1,000 neutrophils/mm(3)) occurred in 652 (42.8%) patients, and SVR was higher (P<0.001) for patients with neutropenia (44.8%) compared to without neutropenia (34%). Patients developing neutropenia did not have an increased risk of developing infections. Thrombocytopenia (<100,000 platelets/mm(3)) occurred in 595 (39.1%) patients, SVR was not influenced by it (38.2% versus 38.9% in patients with and without thrombocytopenia, respectively; P=0.79), and 16 patients (1.1%) discontinued therapy due to it. Cirrhosis was found in 148/734 evaluated patients (20.2%) and was significantly associated with thrombocytopenia (P<0.0001). mBMT was found in 417 patients (27.4%). CONCLUSIONS: Cytopenias are frequent side effects of PEG-IFN/RBV combination therapy in HIV-HCV-coinfected patients. However, SVR is not negatively affected by their presence, nor is there an increased risk of infections in patients developing neutropenia. Several predicting factors for the onset of cytopenias have been unravelled, which will help to identify early those patients at high risk of developing cytopenia.

OPERA: responses to peginterferon and ribavirin therapy in a subgroup of interferon-naïve patients with HIV/HCV genotype 2/3 co-infection in Italy.

BACKGROUND & AIMS: Hepatitis C virus (HCV) genotype 3 (G3) is common among HIV/HCV co-infected individuals and associated with moderate sustained virological response (SVR) rates with pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy, while G2 is less frequent and associated with higher SVR. To determine SVR and other response rates, identify SVR predictors and analyse differences between G2 and G3 with PEG-IFN/RBV in a large HIV/HCV G2/3 patient population. METHODS: This subgroup analysis of the prospective, observational OPERA (Optimized Pegylated interferon Efficacy and anti-Retroviral Approach) study was conducted between 2005 and 2011 in Italy in PEG-IFN/RBV-naïve HIV/HCV patients. The primary efficacy endpoint was SVR rate (HCV RNA <50 IU/ml or undetectable 24 weeks after end-of-treatment). RESULTS: Five hundred and fifty-six HCV G2/3 patients (G2 n = 60; G3 n = 496) were treated with PEG-IFN alfa-2a 180 µg/week or PEG-IFN alfa-2b 1.5 µg/kg, + RBV 13.6 ± 2.3 (mean ± SD) mg/kg/day for median 47 (26-54) weeks. SVR rates were 57.7%, 68.3% and 56.5% for G2/3, G2 and G3 respectively) and RVR rates were 53.2%, 57.1% and 45.8% respectively. Independent SVR predictors were undetectable baseline HIV RNA [adjusted odds ratio (AOR), 2.64; 95% CI: 1.523-4.565, P = 0.0005], age (AOR 0.95 per year; 95% CI: 0.908-0.994, P = 0.0258) and anti-HCV treatment duration (AOR 1.034 per week; 95% CI: 1.013-1.057, P = 0.0019). CONCLUSIONS: Undetectable HIV RNA, longer anti-HCV treatment adherence and younger age were independent SVR predictors in treatment-naïve HIV/HCV G2/3 patients receiving PEG-IFN/RBV. Suppressing HIV RNA replication before anti-HCV therapy and increasing adherence to PEG-IFN/RBV treatment SVR rates may improve SVR.

Sustained virological response to peginterferon therapy in patients infected with HCV (genotypes 2 and 3), with or without HIV.

BACKGROUND: HIV infection leads to a faster progression of liver disease in subjects infected with HCV, as compared with HCV mono-infected patients. Previous reports suggest that sustained virological response (SVR) rates are lower in HIV/HCV coinfection than in HCV monoinfection. We aimed to compare SVR rates of these two populations. METHODS: We retrospectively analyzed clinical, biochemical and virological data of HCV and HIV/HCV infected patients with HCV genotypes 2 and 3 who started anti-HCV treatment between March 2004 and November 2012, at a single large center. Intention-to-treat (ITT) and per-protocol (PP) analysis were performed. Univariate and multivariate logistic regression analyses were performed to assess predictors of SVR. RESULTS: 461 patients were analyzed: 307 (66.6%) males, 76 (16.5%) infected with HIV. Several differences at baseline between HCV monoinfected and HIV/HCV coinfected patients were observed. HCV monoinfected group was characterized by higher prevalence of genotype 2 (53% vs 5.3%), higher baseline HCV viral load (50% vs 35%), shorter mean duration of treatment (19 vs 41 weeks), more frequent use of peginterferon alfa-2a (84.5% vs 69.7%), lower prevalence of cirrhosis (6% vs 31.6%). Globally, SVR was achieved by 353 (76.6%) patients and 321 (83.8%) in the PP analysis. No statistically relevant differences were found in SVR rates between the two groups, either in ITT [78.2% (n = 301/385) vs 68.4% (n = 52/76), p =0.066, respectively] than in PP analysis [83.6% (n = 276/330) vs 84.9% (n = 45/53), p = 0.8]. CONCLUSIONS: Higher baseline viral loads and interruption of peginterferon and/or ribavirin were associated with a poor outcome of anti-HCV treatment while HIV infection was not related to major or minor probability to achieve SVR.

OPERA: use of pegylated interferon plus ribavirin for treating HCV-HIV coinfection in interferon-naive patients.

BACKGROUND: The Optimized Pegylated interferons Efficacy and anti-Retroviral Approach (OPERA) study aimed to assess the efficacy and safety profile of treatment with pegylated interferons (PEG-IFNs) in interferon-naive patients with chronic HCV and HIV infection in routine clinical practice. METHODS: This was a multicentre, prospective observational cohort study conducted at 98 Italian referral centres for the treatment of chronic HCV and HIV coinfection. Adult subjects (n=1,523) with a confirmed diagnosis of HCV and stable HIV coinfection were followed between April 2005 and March 2011; of these, 1,284 were interferon-naive and were the focus of this analysis. Patients received PEG-IFN-α2a or -α2b plus ribavirin combination therapy. The choice of treatment and dose was at the investigator's discretion, according to the summary of product characteristics and current guidelines. The primary efficacy end point was sustained virological response (SVR). Secondary end points included rates of rapid viral response, early viral response and response at end of treatment. RESULTS: SVR was achieved by 40.0% of patients; the highest SVR rate was observed in patients with HCV genotypes 2 and 3. More genotype 2 and 3 than genotype 1 and 4 patients achieved rapid and early viral responses, and end of treatment responses. Higher SVR rates were also associated with ≥80% anti-HCV treatment compliance and lower baseline HCV levels. CONCLUSIONS: The OPERA study results show that PEG-IFN plus ribavirin is an effective treatment for HCV-HIV coinfection in interferon-naive patients. Independent predictors of SVR include HCV genotype, undetectable baseline HIV RNA and baseline HCV RNA<500,000 IU/ml.

Evaluation of boosted and unboosted atazanavir plasma concentration in HIV infected patients.

OBJECTIVES: The aim of the study was to identify variables that can influence atazanavir plasma concentration. METHODS: We retrospectively analysed atazanavir trough concentration of HIV infected patients who performed therapeutic drug monitoring between October 2007 and July 2011. Qualitative variables were compared with X(2) test while continuous ones with Mann-Whitney and Student's t-test. A linear regression model was used to investigate factors influencing atazanavir plasma concentration. Therefore, we analysed the impact of cirrhosis on atazanavir pharmacokinetic variability. RESULTS: 255 plasma samples from 179 patients were analysed. At the univariate analysis female gender (+144.4 ng/mL; p=0.05) and tenofovir (+196.8 ng/mL; p=0.002) were associated with higher atazanavir concentrations. The multivariate model confirmed these two variables (+164.6 ng/mL; p=0.02 and +150.4 ng/mL; p=0.01) as independently associated with higher atazanavir trough concentration. The analysis of cirrhotic population showed an influence of tenofovir (-255.9 ng/mL; p=0.01), increased AST (+95.3 ng/mL; p=0.09), ALT (+67.9 ng/mL; p=0.07) and creatinine (+517.2 ng/mL; p=0.04). The multivariate model confirm that tenofovir was associated with lower atazanavir trough concentration (-284.1 ng/mL; p=0.005) while AST values significantly increased atazanavir concentrations (+114.5 ng/mL; p=0.03). DISCUSSION: Atazanavir is a safe and manageable drug. Our results suggest that female patients tend to have higher atazanavir plasma concentration, while the effect of tenofovir needs to be better clarified.

Virological effectiveness and CD4+ T-cell increase over early and late courses in HIV infected patients on antiretroviral therapy: focus on HCV and anchor class received.

BACKGROUND: The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART. METHODS: We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4-8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by ≥100/mm3 from baseline to month 4-8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome. RESULTS: The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining ≥100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up. CONCLUSIONS: In this large cohort, HCV Ab reactivity was associated with an inferior virological outcome and an independent association between HCV Ab-positivity and smaller CD4+ increase was evident up to 12 months of follow-up. Although the difference in CD4+ T-cell count was modest, a stricter follow-up and optimization of HAART strategy appear to be important in HIV patients co-infected by HCV. Moreover, our data support anti-HCV treatment leading to HCV eradication as a means to facilitate the achievement of the viro-immunological goals of HAART.

Circulating sCD14 is associated with virological response to pegylated-interferon-alpha/ribavirin treatment in HIV/HCV co-infected patients.

OBJECTIVES: Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients. METHODS: 98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR. RESULTS: 71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014). CONCLUSIONS: In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.

"Immune activation, aging and gender" and progression of liver disease.

Hepatitis C is the predominant cause of liver disease in the HIV-positive population and the most important of the non-AIDS-related causes of death. HCV disease tends to become chronic more frequently in HIV-positive subjects, and to evolve more rapidly into cirrhosis of the liver. The rapidity of the evolution varies considerably from one individual to the next and, if in HIV-negative subjects cirrhosis manifests itself after approx. 40-50 years of disease, in HIV-positive subjects it emerges 10-15 years earlier (1, 2). The severity of the fibrosis is not a gradual event and can be worsened by many factors. Age, sex, duration of the infection and assumption of alcohol are the most well-known variables; obesity, diabetes, steatosis and metabolic disorders are equally important factors that affect the progression of liver disease (3). The severity of the liver disease is very different in men compared to women. Being male is undoubtedly one of the factors most closely related to the gravity of fibrosis (4). In HCV mono-infected women, cirrhosis appears from the age of 60 onwards. With the onset of the menopause, in fact, the progression of liver disease accelerates and the risk of developing cirrhosis or cancer of the liver becomes particularly significant in women over 50. The conditions of menopause or of amenorrhea, irrespective of age, are therefore correlated with the progression of liver disease (5). This evidence led researchers to theorize on the possible anti-fibrogenic role of estrogens. In fact, estrogens in physiological doses in the plasma of women in fertile age contribute to controlling the progression of liver disease through antioxidant mechanisms and lipid peroxidation control mechanisms (6). The reduction of estrogens during the menopause is closely linked to the increase of metabolic disorders. During the menopause, steatosis and cardiovascular diseases increase in parallel with the increase of atherogenic lipoproteins, the accumulation ofintra-abdominal fat and the onset of insulin resistance (3, 7). Recent works have demonstrated how the concentration of HCV viremia in plasma correlates with the degree of insulin resistance and with the concentration of circulating triglycerides, demonstrating how the role of HCV in altering the hepatic lipid and glucide metabolism is functional to its replicative capacity. The correlation between the HCV viral load and the metabolic set-up is still unclear in the mono-infection and has been rarely studied in the HIV/HCV co-infection, where the picture is further altered by the metabolic impact of certain antiretroviral therapies. Over recent years, most of the HIV/HCV co-infected population, belonging - as is common knowledge - to the old intravenous drug user risk categories, have reached the age of 50 and have 20-25 years' history of liver disease. The women are reaching the menopause and are frequently characterized by prolonged states of amenorrhea. This conditions exposes HIV-positive women and the co-infected population, currently in care in our centres, to a sudden and rapid worsening of the liver condition. Over the last few years, we are also witnessing the launching on the market of new anti-HCV molecules which must, of necessity, find an outlet as new drug applications for HIV/HCV co-infected patients, as well as being used to the best advantage in populations with particular complications. (www.actabiomedica.it)

Clinical validation and applicability of different tipranavir/ritonavir genotypic scores in HIV-1 protease inhibitor-experienced patients.

Tipranavir, a non-peptidic protease inhibitor which shows in vitro efficacy against some HIV-1-resistant strains, can be used in salvage therapies for multi-experienced HIV patients due to its peculiar resistance profile including 21 mutations at 16 protease positions according to International AIDS Society (IAS). Other genotypic scores, however, which attribute a different weight to single amino-acid substitutions, have been recently proposed. To validate the clinical utility of four different genotypic scores for selecting tipranavir responders, the baseline resistance pattern of 176 HIV heavily experienced patients was correlated with virological success (HIV-RNA<50 copies/ml) after 24 weeks of a new treatment based on tipranavir/ritonavir. Virological suppression after 24 weeks was reached by 42.5% of patients. With univariate analysis, genotypic scores were all associated with outcome but showed a low accuracy with ROC analysis, with the weighted score (WS) by Scherer et al. demonstrating the best performance with an AUC of 68%. Only 52% of patients classified as susceptible (WS< or =3) responded to the new therapy. The following variables were significantly associated (p<0.05) to failure with multivariate analysis: WS, log peak of HIV-RNA, IAS mutations: L33F, I54AMV, Q58E, and non-IAS mutation: N37DES. On the contrary, the use of T20 in T20-naïve patients and the V82AFSI and F53LY non-IAS mutations were associated with virological success. The study suggests that even if the "weighted" scores are able to interpret correctly the antiretroviral resistance profile of multi-experienced patients, it is difficult to individuate a cut-off which can be easily applied to this population for discriminating responders.

HIV-related liver disease: ARV drugs, coinfection, and other risk factors.

Highly-active antiretroviral therapy (HAART) has proven remarkably effective for prolonging the life of patients with human immunodeficiency virus (HIV). However, while most HAART agents are safe, many have the potential to cause liver toxicity. Physicians must therefore consider the possibility of drug-induced liver injury in the management of HIV-infected patients, especially those with certain risk factors such as coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV), female gender, alcohol abuse, older age, or obesity. Understanding how, when, and why drug-related liver damage occurs is key to managing these patients safely and effectively. Knowledge of HAART-related liver effects will help ensure that patients receive the most benefit with the least toxicity from any given drug regimen. As more information about the mechanisms of drug related liver injury is known, clinicians will be better able to tailor therapies to suit individual situations, resulting in greater patient safety and outcomes.

Unboosted fosamprenavir is associated with low drug exposure in HIV-infected patients with mild-moderate liver impairment resulting from HCV-related cirrhosis.

OBJECTIVES: The aim of this study was to compare amprenavir pharmacokinetics in HIV/hepatitis C virus (HCV)-co-infected cirrhotic patients receiving non-boosted fosamprenavir 700 mg twice daily with HCV/HIV-co-infected non-cirrhotic subjects and HIV-mono-infected subjects receiving fosamprenavir/ritonavir 700/100 mg twice daily. Liver stiffness at baseline and alanine aminotransferase levels at baseline and during follow-up were measured in order to find a correlation between drug levels and liver fibrosis or hepatotoxicity. METHODS: Amprenavir plasma concentration was determined by HPLC. Liver stiffness was measured by transient elastometry. Liver function tests were determined every 1-3 months during follow-up. RESULTS: Nineteen HIV-infected patients were included. Eight had chronic HCV hepatitis (group NC), five had HCV-related liver cirrhosis (group C) and six were HIV-mono-infected (group M). In group C patients, amprenavir C(trough), AUC(0-12) and half-life were 86%/83%, 64%/55% and 58%/59% lower when compared with controls and co-infected subjects without cirrhosis, respectively; conversely, drug clearance in cirrhotics was 181%/124% higher. In 3/5 cirrhotic patients (60%) and in 2/14 non-cirrhotic patients (14%), C(trough) was below the minimum target concentration of 400 ng/mL; nonetheless, in all these patients, HIV viral load was undetectable. No correlation was found between amprenavir pharmacokinetics and liver stiffness or hepatotoxicity at follow-up. CONCLUSIONS: On the basis of these data, it seems reasonable to boost fosamprenavir with ritonavir even in cirrhotic patients; amprenavir pharmacokinetics could not be predicted by liver stiffness and seem not to predict hepatotoxicity at follow-up.

Self-reported sexual dysfunction is frequent among HIV-infected persons and is associated with suboptimal adherence to antiretrovirals.

Increased occurrence of sexual dysfunction (SD) among patients treated with highly active antiretroviral therapy (HAART) has been reported. To assess prevalence of self-reported SD and to identify factors related to this alteration with special focus to its relationship with adherence behavior, we conducted an intercohort analysis among HIV-infected persons treated with HAART. In an anonymous questionnaire investigating HAART nonadherence, patients were asked to report the occurrence of dysfunction in sexual activity over the previous 4 weeks. Among 612 participants, 125 (21%) reported some degree of SD. "Moderate"/"severe" alterations were reported in 6% and were independently associated with self-reported worsening of viro-immunological parameters (OR 3.90; 95% CI 1.08-14.18), higher symptom score (OR 1.13; 95% CI 1.05-1.22), and reporting abnormal fat accumulation (OR 4.33; 95% CI 1.55-12.11). Furthermore, nonadherent persons had an increased risk of SD (OR 3.44; 95% CI 1.30-9.08). In conclusion, patients' perceived SD represents a relevant problem for HIV-infected persons treated with antiretrovirals and is strongly associated with suboptimal HAART adherence.

Insulin resistance impairs rapid virologic response in HIV/hepatitis C virus coinfected patients on peginterferon-alfa-2a.

OBJECTIVES: To investigate the association between insulin resistance and rapid virologic response. DESIGN: All consecutive HIV/hepatitis C virus coinfected patients who started peg-interferon alpha-2a (180 microg/week) and ribavirin 1000-1200 mg/day were analysed. METHODS: Insulin resistance was defined according to the homeostasis model of assessment-insulin resistance calculated as fasting insulin (mIU/l) x fasting glucose (mmol/l)/22.5. Rapid virologic response was defined as testing negative for hepatitis C virus-RNA after 4 weeks of therapy. Fasting levels of insulin and glucose in plasma were measured in all patients on the first day of treatment. Hepatitis C virus-RNA was determined by quantitative PCR assay (version 3.0). Hepatitis C virus-RNA was measured by qualitative PCR assay (COBAS 2.0) after 4 weeks of treatment. RESULTS: Seventy-four HIV/hepatitis C virus coinfected patients were enrolled [mean age 41.7 years (SD 5.3), 61 men, 54.1% with advanced fibrosis (F3-4 according to METAVIR classification), 52.4% with infection by hepatitis C virus genotype 1 or 4]. Rapid virologic response was reached by 30 subjects. In the multivariate analysis the independent predictors of rapid virologic response were: genotype 1 or 4 [adjusted odds ratio 0.18 (0.06-0.55)], hepatitis C virus-RNA < 400.000 UI/ml [adjusted odds ratio 0.229 (0.09-0.92)] and homeostasis model of assessment-insulin resistance more than 3.00 [adjusted odds ratio 0.1 (0.05-0.6)]. CONCLUSION: The homeostasis model of assessment-insulin resistance score should be evaluated and possibly corrected before starting anti-hepatitis C virus therapy.