Francesca Gatti

Insights into reasons for discontinuation according to year of starting first regimen of highly active antiretroviral therapy in a cohort of antiretroviral‐naïve patients

The aim of the study was to determine whether the incidence of first‐line treatment discontinuations and their causes changed according to the time of starting highly active antiretroviral therapy (HAART) in an Italian cohort.

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.

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 log10 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 Pearsons 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.

Predictors of AIDS-defining events among advanced naïve patients after HAART

Abstract Background: Baseline and follow–up predictors of new AIDS-defining events or death (ADE/death) among patients who started HAART late in their disease history have rarely been assessed simultaneously. Method: ADE and mortality rates were assessed using Cox regression analyses. Variables were tested for prediction of ADE/death within the first 3 months of therapy and from month 3, thereafter. Results: 751 HIV–infected patients with <200 CD4+/mm3 before HAART were followed for a median of 49 months. 207 new ADE occurred (7.06 [6.16–8.10] per 100 patient-years). ADE/deaths clustered within the first 3 months of treatment (106/207, 51%). Higher CD4+ T-cell counts during the follow–up (per loge cells/mm3: hazard ratio [HR] 0.51; 0.41–0.64; p < .001) and use of antiretroviral therapy (HR 0.38; 95% CI 0.21–0.69; p = .001) appeared to protect from ADE/death after month 3. Conversely, increasing follow–up with HIV RNA >400 copies/mL correlated with ADE/death (per month: HR 1.09; 95% CI 1.06-1.12; p = .001). Use of boosted protease inhibitors as first-line HAART and HCV-seropositivity were additional risk factors. Baseline CD4+ T-cell count and HIV RNA had a predominant impact in the first 3 months after HAART initiation. Conclusion: A careful monitoring of patients with low CD4+ is particularly necessary during the first few months of HAART. Length and extent of viral replication during the follow-up appeared to induce a significantly higher risk of HIV disease progression afterwards, implying that new drugs and new strategies aimed at ensuring long-term suppression of HIV RNA are of outstanding importance.

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.

Observational Study on HIV-Infected Subjects Failing HAART Receiving Tenofovir Plus Didanosine as NRTI Backbone

We evaluated the efficacy of tenofovir (TDF) – and didanosine (ddI)-containing backbones in HIV-infected experienced subjects. We included in the study 245 subjects who started a TDF/ddI-containing HAART with HIV-RNA > 3 log10 cp/ml and an available genotypic resistance test at baseline. At baseline, median CD4 counts and HIV-RNA were 278 cell/mmc and 4.32 log10 cp/ml, respectively. Seventy-four subjects (30.2%) discontinued TDF and/or ddI, 23 of them for drug-related toxicities or intolerance. One-hundred and twenty-six (51.4%) subjects achieved virologic success (HIV-RNA < 50 copies/ml in two consecutive determinations) in a median time of 6.1 months; higher HIV-RNA levels (HR: 0.66, 95% CI: 0.54– 0.79, p < 0.001 for each additional log10 copies/ml), and the total number of mutations either for PI and NNRTI at baseline (HR: 0.87, 95% CI: 0.81–0.92, p < 0.001 for each additional mutation) were both predictors of virologic success. M184V was marginally associated with virologic success (HR: 1.34, 95% CI: 0.94–1.90, p = 0.10 vs no M184V), whilst the number of TAMs was not associated. One-hundred-thirty-three (54.3%) subjects achieved immunologic success (increase of ≥ 100 cells/mm3 from baseline) in a median time of 7.5 months; immunologic success was associated with HIV-RNA levels at baseline (HR: 0.91, 95% CI: 0.79–0.98, p = 0.04 for each additional log10 copies/ml), the total number of mutations either for PI or NNRTI (HR: 0.91, 95% CI: 0.85–0.98, p = 0.01 for each additional mutation) and CD4 count at baseline (HR: 1.11, 95% CI: 1.00–1.23, p = 0.05 for each additional 100 cells/mm3). Results obtained by the on-treatment analyses were comparable. In our study, HAART containing TDF/ddI seem associated with a virologic and immunologic response, when such regimens are chosen according to a genotypic resistance test.

Hepatic tolerability of fosamprenavir/ritonavir (FPV/RTV) in HIV/hepatitis C co-infected subjects with severe hepatic fibrosis

Methods HIV/HCV-RNA positive co-infected subjects, treated with FPV/rtv for at least 6 months have been enrolled in a retrospective observational study. Baseline socio-demographic characteristics, data on HIV, HCV and antiretroviral treatments history, immuno-virologic data, and renal and liver function parameters have been recorded at baseline and every 6 months. Liver enzymes (LE) level at baseline has been categorized as normal (LEN) or abnormal (LE-AN) using the local laboratory cut-off of 45 IU/l for females and 50 IU/l for males. The stiffness >14 Kpascal by Fibroscan® and/or a FIB-4 score >3.25 [calculated by: age ([yr] × AST [U/L])/((PLT [109/L]) × (ALT [U/L])1/2)] have been used to define the cirrhosis. LEE after 6 months of treatment has been compared between groups of patients with LE-N or LE-AN and with or without cirrhosis using a Students t-test for normal distribution parameters or the Mann-Whitney U test. A Kaplan Meier analysis has been used to assess the risk of developing a grade 1–2 LEE.

Switching from zidovudine/lamivudine (ZDV/LMV) to tenofovir/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/LMV) in HIV/HCV co-infection (COTKI study)

Methods A total of 150 HIV/HCV co-infected subjects with HIVRNA <50 copies/ml, on BID ZDV/LMV + atazanavir/ritonavir (ATV/rtv) >6 months were randomized 1:1:1 to continue this regimen or to switch to QD TDF/FTC+ATV/rtv or QD ABC/LMV +ATV/rtv. The primary end-point was change in insulin resistance, calculated with HOMA score (Homeostasis Model Assessment: fasting insulin UI/ml x glucose mmol/l/22.5) at 48 weeks. Secondary end-points included changes in absolute haemoglobin, AST, ALT, fasting lipids, CD4, and viral load. Liver fibrosis assessment by Fibroscan was planned at baseline and 96 weeks. Two sample t-test for between group comparison was used.