Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure.

PURPOSE: The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure. METHODS: The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography-ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1. RESULTS: A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels. CONCLUSIONS: A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.

Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients.

BACKGROUND: Despite the availability of potent antiretroviral regimens (combination antiretroviral therapy [cART]), HIV-associated neurocognitive disorders (HAND) are increasingly recognized. Our aim was to investigate the prevalence and treatment-related correlates of HAND, exploring the potential neurotoxicity of antiretrovirals on cognitive functions. METHODS: We performed a cross-sectional single cohort study by consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits. Each patient was submitted to a comprehensive neuropsychological battery and was considered cognitively impaired on the basis of results obtained in matched healthy HIV-negative subjects. CNS penetration effectiveness (CPE) rank was calculated for cART regimens according to 2010 CHARTER criteria. Factors associated with cognitive impairment were investigated by linear or logistic regression analysis. RESULTS: A total of 146 patients were enrolled. Of these, 129 (88.4%) were on cART and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non-Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between CPE rank and cognitive impairment was observed. CONCLUSIONS: A high prevalence of HAND was observed in apparently asymptomatic HIV+ individuals. HAND was associated with efavirenz use, suggesting the potential neurotoxicity of this drug. Routine neuropsychological examinations could help clinicians make correct diagnoses and manage mild, but clinically relevant, forms of HAND.

Predictors of successful genotype-guided antiretroviral therapy in treatment-experienced individuals over calendar years: a cohort study.

BACKGROUND: The continuous development of new drugs for use in triple-drug combination antiretroviral therapy (cART) has dramatically decreased morbidity and mortality in HIV-1 infected individuals. However, increasing drug resistance could be associated with a poor outcome. OBJECTIVES: To determine the efficacy of resistance genotype-guided antiretroviral regimens in combination antiretroviral therapy (cART)-failing patients over calendar years and its predictors. STUDY DESIGN: Patients, with an available resistance genotype performed between 1999 and 2008, who failed a highly active antiretroviral therapy (HAART) regimen, changed therapy within 6 months from genotype and maintained the same salvage regimen, were selected from a clinical cohort database. Virologic efficacy was analyzed using time-to virologic suppression (VS, HIV-1 RNA<50 copies/ml). RESULTS: In 270 sequences analyzed from 212 patients, after a median follow-up of 23 weeks, there were 160 patients with VS (59.3%). Mean regimens' genotypic sensitivity score (GSS) increased from 1.86 (SD+/-0.92) in 1999-2001, to 2.29 (SD+/-0.96) in 2005-2008 (p=0.001 for trend). VS was achieved in 39% of those patients genotyped in 1999-2001, and increased to 69% for patients with genotyping performed between 2005 and 2008 (p<0.001). More recent calendar year, younger age and less use of suboptimal therapy were predictors of more effective HAART regimens but only more recent calendar year maintained a trend toward significance in a multivariable model. More recent genotyping calendar year, younger age, lower number of HAART regimens experienced, lower HIV-1 RNA and higher GSS independently conveyed and increased the probability of VS. CONCLUSIONS: Resistance-guided salvage antiretroviral therapy was more effective during more recent calendar years, independent from other measurable confounders, including the GSS of the employed regimen. Convenience and tolerability of newer agents should account for the observed effect.

Prevalence of transmitted HIV-1 drug resistance in HIV-1-infected patients in Italy: evolution over 12 years and predictors.

OBJECTIVES: Transmitted HIV-1 drug resistance (TDR) can reduce the efficacy of first-line antiretroviral therapy. PATIENTS AND METHODS: A retrospective analysis was performed to assess the prevalence and correlates of TDR in Italy over time. TDR was defined as the presence of at least one of the mutations present in the surveillance drug resistance mutation (SDRM) list. RESULTS: Among 1690 antiretroviral therapy-naive patients, the most frequent HIV subtypes were B (78.8%), CRF02_AG (5.6%) and C (3.6%). Overall, TDR was 15%. TDR was 17.3% in subtype B and 7.0% in non-B carriers (P < 0.001). TDR showed a slight, although not significant, decline (from 16.3% in 1996-2001 to 13.4% in 2006-07, P = 0.15); TDR declined for nucleoside reverse transcriptase inhibitors (from 13.1% to 8.2%, P = 0.003) but remained stable for protease inhibitors (from 3.7% to 2.5%, P = 0.12) and non-nucleoside reverse transcriptase inhibitors (from 3.7% to 5.8%). TDR to any drug was stable in B subtype and showed a decline trend in non-B. In multivariable analysis, F1 subtype or any non-B subtype, compared with B subtype, and higher HIV RNA were independent predictors of reduced odds of TDR. CONCLUSIONS: Prevalence of TDR to nucleoside reverse transcriptase inhibitors seems to have declined in Italy over time. Increased prevalence of non-B subtypes partially justifies this phenomenon.

Impact of hepatitis B vaccination in children born to HBsAg-positive mothers: a 20-year retrospective study.

BACKGROUND: Preventive measures remain the best approach to control the spread of hepatitis B virus (HBV) infection. PATIENTS AND METHODS: To evaluate the effectiveness of vaccination against HBV, we conducted a 20-year retrospective study on 100 subjects, born to hepatitis B surface antigen (HBsAg)-positive mothers, who had received postexposure prophylaxis at the Clinic of Infectious Diseases (Siena University, Italy) during 1984-2004. All patients were tested for the presence of HBsAg, anti-HBs and anti-HB core antigen (anti-HBc). RESULTS: Two subjects (2%) acquired the infection as shown by the presence of anti-HBc. Of the 98 patients who did not acquire the infection, 62 of these (63.3%) had an anti-HBs concentration considered protective (> or =10 mIU/ml). The percentage of protected subjects decreased in relation to time from vaccination with a significant reduction (p = 0.009) of anti-HBs geometric mean titre (GMT) after 5 years, which reached the level of 10 mIU/ml after about 15 years. No patients without protective concentration have acquired the infection as of today. Only 12% of the HBsAg-positive mothers were followed in specialized structures after pregnancy, reflecting the scarce knowledge of the problem in the general population. CONCLUSION: Our data, while confirming the effectiveness of anti hepatitis B vaccination, highlight the need for postvaccination follow-up, particularly in high-risk categories, to prolong protection, through booster doses if necessary. We show, moreover, the importance of maintaining active surveillance in the territory to improve follow-up to chronic carriers and to sensitize families.

Long-term follow-up of nevirapine-treated patients in a single-centre cohort.

OBJECTIVES: We reviewed the safety and efficacy of nevirapine (NVP)-based therapy in all patients initiating NVP-containing combined antiretroviral therapy [cART (>or=3 drugs)] in our clinic since 1994. METHODS: Patient characteristics and laboratory values from the start of the NVP-based cART regimen to the last available follow-up or to NVP discontinuation were retrieved from an observational database. RESULTS: Five hundred and seventy-three patients were treated with NVP-based cART for a median of 18.4 (range 0.1-128.8) months. The 1-year cumulative estimated probability of discontinuing NVP-containing regimens for toxicity was 0.203. Only 1.9% developed a grade 3 alanine aminotransferase (ALT) elevation. Significant increases in high-density lipoprotein cholesterol were observed up to month 12 except in treatment-naïve patients, where the increase was limited to 3 months. Discontinuation because of cutaneous reaction was predicted independently by female gender [Hazard Ratio (HR) 3.21, P<0.001] and Centers for Disease Control class C (HR 0.50, P=0.012). Discontinuation because of liver toxicity was predicted independently by anti-hepatitis C virus positivity (HR 3.84, P<0.001). In patients starting NVP-containing cART with undetectable viral loads, the 5-year estimated probability of viral load >400 HIV-1 RNA copies/mL was 0.34. CONCLUSIONS: Long-term follow-up with an NVP-containing cART showed a low rate of discontinuation caused by liver toxicity and the maintenance of virological suppression in patients switched with undetectable viral loads.

Serological response to hepatitis B virus vaccine in HIV-infected children in Tanzania.

BACKGROUND: HIV-infected children have a lower seroconversion rate to hepatitis B virus (HBV) immunization than healthy children. Previous studies have produced conflicting results on CD4 cell counts as predictors of vaccine response. No study has evaluated the response rate to HBV vaccination in HIV-infected children receiving highly active antiretroviral therapy (HAART). Our aim was to vaccinate HIV-infected children living in a close community and to investigate the anamnestic response rate after vaccination with its predictors. METHODS: Eighty-four HIV-positive children aged 1-10 years who were negative for antibodies to the HBV core antigen (anti-HBc) completed immunization with three doses of 5 microg HBVAXPRO (Aventis, Milan, Italy). Quantitative testing for antibodies to the HBV surface antigen (anti-HBs) was performed: a seroprotective titre was defined as anti-HBs>10 mUI/mL. RESULTS: After the vaccination, the anti-HBs seroconversion rate was 59.5%. It was higher in individuals in Centers for Disease Control and Prevention (CDC) immune category 1 than in those in CDC categories 2 and 3. Seroconversion was found in 70.8% of HAART-treated and 44.4% of treatment-naïve children. In multivariable models, HAART use and absolute CD4 cell counts were independently associated with probability of seroconversion and with higher anti-HBs titres. CONCLUSIONS: We found a higher seroconversion rate compared with previous studies in HIV-infected children. In children who are candidates to receive antiretroviral therapy, it may be advisable to defer HBV vaccination until after treatment initiation.

Cardiovascular risk score change in HIV-1-infected patients switched to an atazanavir-based combination antiretroviral regimen.

BACKGROUND: We aimed to establish whether the limited impact of atazanavir on the plasma lipid profile could translate into a reduction in the predicted cardiovascular risk in antiretroviral (ARV)-experienced patients switching to an atazanavir-containing regimen. METHODS: HIV-1-infected treatment-experienced patients, switched to atazanavir for whatever reason and without prior major cardiovascular events, were selected and followed for at least 1 month. An individual cardiovascular risk score (10-year risk of major cardiovascular events) based on validated events and measurable risk factors in Italian cardiovascular cohorts was calculated using software available online. RESULTS: A total of 197 patients were selected for inclusion in the study. After switching to atazanavir, the mean changes from pre-switch to last available measurement were -6.5% (P<0.001) for total cholesterol, -1.7% (P=0.029) for high-density lipoprotein (HDL) cholesterol, -11.3% (P<0.001) for non-HDL cholesterol and -8.6% (P<0.001) for triglycerides. The crude cardiovascular risk score was reduced from 3.43 to 3.38% (P=0.51); the analysis normalized by age showed a reduction from 3.43 to 3.14% (P<0.001). Subsets of patients with high baseline total cholesterol or triglycerides showed more marked reductions. CONCLUSIONS: A treatment switch to atazanavir caused significant reductions in plasma lipids and a modest but significant reduction in the normalized-for-age cardiovascular risk score. Efforts should be made to concomitantly reduce the other preventable cardiovascular risk factors.