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Objectives: The aim of the study was to determine the prevalence of potential clinically significant drug interactions (CSDIs) in HIV-positive individuals and to identify associated risk factors., Methods: A cross-sectional study was conducted including all HIV-infected out-patients attending the Pharmacy Service of a regional reference hospital in Murcia, south-eastern Spain. The complete treatment was screened for possible CSDIs using the Spanish College of Pharmacists' online software resource, bot. Additionally, the severity level of the CSDIs involving antiretroviral (ARV) drugs was compared with that established in the specific antiretroviral database InteraccionesHIV.com. Multivariate logistic regression was used to identify associated risk factors., Results: Two hundred and sixty-eight patients were included in the study. A total of 292 potential drug interactions were identified, of which 102 (34.9%) were CSDIs, of which 52.9% involved ARV drugs. Seven therapeutic drug classes were involved in 75% of CSDIs (protease inhibitors, benzodiazepines, nonsteroidal anti-inflammatory drugs, nonnucleoside reverse transcriptase inhibitors, corticosteroids, antithrombotics and proton pump inhibitors). Factors independently associated with CSDIs were treatment with more than five drugs [odds ratio (OR) 15.1; 95% confidence interval (CI) 6.3-36.2], and treatment with a protease inhibitor (OR 5.3; 95% CI 2.4-11.74)., Conclusions: The findings of this study suggest that the prevalence of clinically relevant drug-drug interactions is high in HIV-infected patients, and could represent a major health problem. Awareness, recognition and management of drug interactions are important in optimizing the pharmaceutical care of HIV-infected patients and helping to prevent adverse events and/or loss of efficacy of the drugs administered., (© 2014 British HIV Association.)

Objectives: This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. etravirine plus an alternative boosted protease inhibitor (other PI group; n = 116) using pooled European cohort data., Methods: Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland and UK) cohorts provided data (collected in 2007-2012). Stratum-adjusted (for confounding factors) Mantel-Haenszel differences in virological responses (viral load < 50 HIV-1 RNA copies/mL) and odds ratios (ORs) with 95% confidence intervals (CIs) were derived., Results: Baseline characteristics were balanced between groups except for previous use of antiretrovirals (≥ 10: 63% in the DRV group vs. 49% in the other PI group), including previous use of at least three PIs (64% vs. 53%, respectively) and mean number of PI resistance mutations (2.3 vs. 1.9, respectively). Week 24 responses were 73% vs. 75% (observed) and 49% vs. 43% (missing = failure), respectively. Week 48 responses were 75% vs. 73% and 32% vs. 30%, respectively. All 95% CIs around unadjusted and adjusted differences encompassed 0 (difference in responses) or 1 (ORs). While ORs by cohort indicated heterogeneity in response, for pooled data the difference between unadjusted and adjusted for cohort ORs was small., Conclusions: These data do not indicate a difference in response between the DRV and other PI groups, although caution should be applied given the small size of the other PI group and the lack of randomization. This suggests that the efficacy and virology results from DUET can be extrapolated to a regimen of etravirine with a boosted PI other than darunavir/ritonavir., (© 2015 British HIV Association.)

Objectives: We compared reasons for the choice of regimen, time to and reasons for third drug modification, virological response and change in CD4 T-cell counts in patients started on atazanavir/ritonavir (ATV/r)- vs. efavirenz (EFV)-based first-line regimens., Methods: We included patients from the Cohort of the Spanish HIV Research Network (CoRIS), a multicentre cohort of HIV-positive treatment-naïve subjects, in the study. We used logistic regression to assess factors associated with choosing ATV/r vs. EFV, proportional hazards models on the subdistribution hazard to estimate subdistribution hazard ratios (sHRs) for third drug modification, logistic regression to estimate odds ratios (ORs) for virological response and linear regression to assess mean differences in CD4 T-cell count increase from baseline., Results: Of 2167 patients, 10.7% started on ATV/r. ATV/r was more likely than EFV to be prescribed in injecting drug users [adjusted OR 1.85; 95% confidence interval (CI) 1.03-3.33], in 2009-2010 (adjusted OR 1.63; 95% CI 1.08-2.47) and combined with abacavir plus lamivudine (adjusted OR 1.53; 95% CI 0.98-2.43). Multivariate analyses showed no differences, comparing ATV/r vs. EFV, in the risk of third drug modification (sHR 1.04; 95% CI 0.74-1.46) or in virological response (OR 0.81; 95% CI 0.46-1.41); differences in mean CD4 T-cell count increase from baseline were at the limit of statistical significance (mean difference 29.8 cells/μL; 95% CI -4.1 to 63.6 cells/μL). In patients changing from EFV, 48% of changes were attributable to toxicity/adverse events, 16% to treatment failure/resistance, 3% to simplification, and 8 and 12%, respectively, to patients' and physicians' decisions; these percentages were 24, 6, 12, 14 and 24%, respectively, in those changing from ATV/r., Conclusions: ATV/r- and EFV-based regimens meet the requirements of both efficacy and safety for initial combination antiretroviral regimen, which relate to better durability., (© 2014 British HIV Association.)

Background: The aim of this study was to assess the short-term and long-term consequences of stopping antiretroviral therapy (ART) in patients with preserved immune function., Methods: This was a randomized 144-week follow-up CD4⁺ T-cell-count-guided treatment-interruption trial. HIV-1-infected adults with plasma HIV-1 RNA<50 copies/ml, CD4⁺ T-cell count >500 cells/μl and nadir CD4⁺ T-cell count >100 cells/μl were randomized to continuous treatment (CT) or treatment interruption (TI) until CD4⁺ T-cell count decreased to <350 cells/μl. The primary end points were AIDS-defining illnesses, death, CD4⁺ T-cell count <200 cells/μl, or virological failure after restarting ART., Results: A total of 106 patients were included, 50 in the CT arm and 56 in the TI arm. A trend to a higher rate of primary end points was observed in the TI group (26.8% versus 14%, difference 12.8%, 95% CI -2.3, 27.8; P=0.105). In addition, 10 patients presented clinical events related with HIV rebound, including 8 cases of thrombocytopaenia. The CD4⁺ T-cell count significantly decreased in the TI group (even in patients with persistently high CD4⁺ T-cell counts and no clinical events) versus the CT group (median change -408 cells/μl versus -21.5 cells/μl; P<0.001), whereas a significant increase in CD8⁺ T-cell count was observed (256 cells/μl versus -59 cells/μl; P<0.001). The time to ART re-initiation was significantly associated with nadir and baseline CD4⁺ T-cell counts., Conclusions: Discontinuation of ART in patients with preserved immune function is followed by significant immunological impairment even in those with no clinical events, and may be associated with an increased risk of HIV-related complications. Hence, patients who stop ART voluntarily should be closely monitored, regardless of their CD4⁺ T-cell count.

Objectives: To assess the effectiveness of simplification to a dual antiretroviral regimen containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced HIV-1-infected patients., Methods: Retrospective analysis of 131 HIV-1-infected patients on suppressive antiretroviral treatment (HIV-RNA <50 copies/mL) who switched to a maintenance dual antiretroviral regimen, containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV-RNA >50 copies/mL. The percentage of patients remaining free of therapeutic failure was estimated using the time-to-loss-of-therapeutic-response algorithm, by intent-to-treat analysis., Results: Median baseline characteristics of the patients were 14 years on antiretroviral therapy, five prior HAART regimens and 10 different drugs, 24 months on a suppressive regimen and 522 CD4+ cells/mL. Reasons for simplification to dual therapy were nucleoside reverse transcriptase inhibitor-related toxicity (46.6%), removal of lamivudine/emtricitabine due to resistance (16.8%), simplification from regimens containing a dual PI, enfuvirtide or tipranavir (20.6%) and simplification from other complex regimens (16.0%). Darunavir (58.0%), lopinavir (16.8%) or atazanavir (13.0%) were the preferred PIs, used in combination with tenofovir (50.4%), raltegravir (22.1%) or etravirine (12.2%). At the end of follow-up (median 14 months), 90.1% of patients remained free of therapeutic failure; corresponding data at treatment weeks 24, 48 and 96 were 93.6% (95% CI, 89.3-97.9), 90.9% (95% CI, 84.9-95.9) and 87.4% (95% CI, 80.7-94.1), respectively. Two (1.5%) patients had virological failure and 11 (8.4%) discontinued treatment due to side effects or were lost to follow-up., Conclusions: Simplification to a dual-therapy regimen including a PI/r might be useful to enhance convenience and/or diminish toxicity in selected treatment-experienced patients.

Objectives: To assess the efficacy and safety of dual-antiretroviral therapy containing a ritonavir-boosted protease inhibitor (PI/r) in treatment-experienced patients failing a current antiretroviral regimen., Methods: Retrospective analysis of 60 consecutive HIV-1-infected patients who started a dual-antiretroviral rescue regimen containing a PI/r, in three hospitals in Spain. Virological failure was defined as confirmed HIV RNA >50 copies/mL at treatment week 24 or later. The percentage of patients remaining free of therapeutic failure was estimated using the Kaplan-Meier method, by intent-to-treat analysis (missing, changes and virological failure = therapeutic failure)., Results: Median baseline characteristics of patients were: 13 years on antiretroviral therapy (four prior highly active antiretroviral therapy regimens and eight different drugs), 380 CD4 cells/mm(3) and HIV RNA 3.04 log(10) copies/mL. All patients had resistance mutations to at least two drug classes, although only 9.3% had specific mutations to darunavir. A darunavir-based regimen was started in 47 (78.4%) patients, combined with etravirine (26.7%), tenofovir (26.7%) or raltegravir (25%). Three (5%) patients discontinued treatment due to side effects. At the end of follow-up, 86.7% of patients remained free of therapeutic failure; the percentages of patients with no therapeutic failure at treatment weeks 24, 48 and 96 were 96.6% (95% CI, 91.9-101.3); 90.1% (95% CI, 81.9-98.3) and 79.8% (95% CI, 66.1-93.5), respectively., Conclusions: Our results suggest that a dual-therapy rescue regimen including a PI/r is convenient, well tolerated and potent enough to achieve persistent viral suppression in selected pre-treated patients with low viral load and few PI resistance mutations.

Introduction: The use of protease inhibitors (PI) has led to a decrease in HIV-1-related mortality and morbidity. The objective of this study was to collect safety data on treatment with fosamprenavir/ritonavir (FPV/r) 700/100mg BID in HIV-infected patients through an expanded access program., Patients and Methods: Prospective, multicenter, noncomparative study in HIV-1 infected adults, for whom a regimen containing FPV/r 700/100mg BID was appropriate., Results: A total of 678 patients were included in the intention-to-treat (ITT) and safety population. The on-treatment (OT) population contained 587 patients: 76% male, 98% Caucasian, and median age 41 years. Median CD4 cell count was 351 cells/microL, HIV-RNA was 3 log copies/mL, and 49% of patients were in CDC class C. After 24 weeks of treatment, serum viral load decreased a median of 1.3 log copies/mL and 73% of patients had <400 copies/mL (P<.0001 vs. baseline); 48-week results were similar. CD4 cell count increased a median of 49 and 62 cells/microL at 24 and 48 weeks, respectively. Adverse events (AEs) associated with the study medication occurred in 21% of patients., Conclusions: Ritonavir-boosted fosamprenavir as part of antiretroviral therapy is a potent, safe treatment in real-life clinical circumstances.

Purpose: To appraise the incidence of liver toxicity in a population of patients receiving fosamprenavir/ritonavir (FPV/r) with a high frequency of viral hepatitis co-infection., Method: 636 patients, 341 (54%) with HCV antibodies and 38 (5.6%) bearing serum HBsAg, were recruited. All of them received FPV/r 700/100 twice every day. 93 (27%) patients who tested positive for HCV antibodies showed an AST to platelet ratio index (APRI) higher than 1.5, consistent with significant liver fibrosis., Results: After a median (range) follow-up time of 6.91 (0.46-20.66) months, 3 (0.47%) patients developed grade 3 ALT elevation. All the former patients were hepatitis virus co-infected, 2 with hepatitis C virus and 1 with hepatitis B virus. The frequency of grade 3 ALT elevation in patients with HCV antibodies was 0.58% and in those harbouring HBsAg it was 2.63%. 4 (0.62%) patients suffered from a liver decompensation and 1 died due to a hepatic cause while on follow-up. No patients with APRI equal to or higher than 1.5 showed grade 3 ALT elevation., Conclusion: The incidence of adverse hepatic events in patients receiving FPV/r including combinations seems to be low, even in subjects co-infected with hepatitis virus and in those with significant liver fibrosis.

Introduction: The development of resistance to antiretroviral therapy (ART) reduces the effectiveness of these drugs in HIV-infected children., Methods: We performed a cross-sectional study in 86 vertically HIV-infected children, divided into four groups according to prior treatment: group 1: nucleoside reverse transcriptase inhibitor (NRTI), group 2: NRTI and non-nucleoside reverse transcriptase inhibitor (NNRTI), group 3: NRTI and protease inhibitor (PI), group 4: NRTI, NNRTI and PI., Results: In group 1 (11 children), the median treatment duration was 35 months (26 to 108). Nucleoside-associated mutations (NAMs) were found in 10 of these patients and the Q151M multiresistance mutation was found in two. The three children in group 2 were treated for 9, 32 and 42 months with NRTI and NNRTI. One child showed three NAMs and another showed Q151M. Two children had the K103N mutation. Group 3 (36 children) received treatment with NRTI and PI for 48.0 +/- 27.6 and 23.0 +/- 14.6 months, respectively. NAMs were observed in 94 % of the patients in this group, and one child showed the Q151M mutation. In group 4 (36 children) total treatment duration was 70.0 +/- 36.1 months (13.0 +/- 12.1 months with NNRTI, and 39.0 +/- 14.3 months with PI). NAMs were observed in all patients in this group, and Q151M was found in three children. K103N and Y181C were detected in 24 (67%) and 10 (28%) of the children respectively, while 32 (90%) showed primary mutations to PI., Conclusions: A high prevalence of resistance mutations to NRTI and early appearance of resistance to NNRTI were observed in treated children.

Background: The impact of HIV drug resistance mutations in salvage therapy has been widely investigated in adults. By contrast, data available of predictive value of resistance mutations in pediatric population is scarce., Methods: A multicenter, retrospective, observational study was conducted in children who received rescue salvage antiretroviral therapy after virologic failure. CD4 counts and viral load were determined at baseline and 6 months after rescue intervention. Genotypic HIV-1 resistance test and virtual phenotype were assessed at baseline., Results: A total of 33 children met the inclusion criteria and were included in the analysis. The median viral load (VL) and median percentage of CD4+ at baseline was 4.0 HIV-RNA log copies/ml and 23.0% respectively. The median duration that children were taking the new rescue regimen was 24.3 weeks (23.8-30.6). Overall, 47% of the 33 children achieved virological response at 24 weeks. When we compared the group of children who achieved virological response with those who did not, we found out that mean number of PI related mutations among the group of responders was 3.8 vs. 5.4 (p = 0.115). Moreover, the mean number of susceptible drugs according to virtual phenotype clinical cut-off for maximal virologic response was 1.7 vs. 0.8 and mean number of susceptible drugs according to virtual phenotype cut-off for minimal virlologic response was 2.7 vs. 1.3 (p < 0.01 in all cases). Eighteen children were rescued with a regimen containing a boosted-PI and virological response was significantly higher in those subjects compared with the others (61.1% vs. 28.6%, p < 0.01)., Conclusion: Salvage treatment containing ritonavir boosted-PIs in children with virological failure was very efficient. The use of new tools as virtual phenotype could help to improve virologic success in pediatric population.

Evidence is lacking on the possible efficacy and effectiveness of non-occupational postexposure prophylaxis (PEP). However, because of its biological plausibility, the use of antiretroviral (ARV) drugs to prevent the development of infection in certain cases of accidental or sporadic exposure has begun to be considered as common clinical practice. Previous studies performed in Spain have demonstrated both the demand and the prescription of ARV as PEP and especially the diversity and inconsistency in the criteria used. In this context, in April of 2000 the Centre for Epidemiological Studies on AIDS of Catalonia (CEESCAT) (Department of Health and Social Security of the Autonomous Government of Catalonia), in collaboration with the National AIDS Plan and the AIDS Study Group (GESIDA), promoted the creation of a working group for the drafting of recommendations for PEP against HIV outside the occupational health context. The recommendations have been made bearing in mind the exceptional character of the exposure, the time elapsed since exposure, as well as evaluation of the risk of infection according to the type of exposure and the information available on the source of infection. In addition, the recommendations include the immediate measures necessary, as well as the preventive measures and clinical follow-up required both for HIV and for other infectious agents. All PEP regimens should be started within 72 hours of exposure and appropriate daily doses of two nucleoside reverse transcriptase inhibitors (NRTIs) and a protease inhibitor (PI), or two NRTIs and a non-nucleoside reverse transcriptase inhibitor (NNRTIs), should be administered for four weeks, bearing in mind the pharmacological and clinical situation of the source person. These recommendations should be updated periodically.