Network meta-analysis of post-exposure prophylaxis randomized clinical trials.

OBJECTIVES: We performed a network meta-analysis of PEP randomized clinical trials to evaluate the best regimen. METHODS: After MEDLINE/Pubmed search, studies were included if: (1) were randomized, (2) comparing at least 2 PEP three-drug regimens and, (3) reported completion rates or discontinuation at 28 days. Five studies with 1105 PEP initiations were included and compared ritonavir-boosted lopinavir (LPV/r) vs. atazanavir (ATV) (one study), cobicistat-boosted elvitegravir (EVG/c) (one study), raltegravir (RAL) (one study) or maraviroc (MVC) (two studies). We estimated the probability of each treatment of being the best based on the evaluation of five outcomes: PEP non-completion at day 28, PEP discontinuation due to adverse events, PEP switching due to any cause, lost to follow-up and adverse events. RESULTS: Participants were mostly men who have sex with men (n = 832, 75%) with non-occupational exposure to HIV (89.86%). Four-hundred fifty-four (41%) participants failed to complete their PEP course for any reason. The Odds Ratio (OR) for PEP non-completion at day 28 in each antiretroviral compared to LPV/r was: ATV 0.95 (95% CI 0.58-1.56; EVG/c: OR 0.65 95% CI 0.30-1.37; RAL: OR 0.68 95% CI 0.41-1.13; and MVC: OR 0.69 95% CI 0.47-1.01. In addition, the rankogram showed that EVG/c had the highest probability of being the best treatment for the lowest rates in PEP non-completion at day 28, switching, lost to follow-up or adverse events and MVC for PEP discontinuations due to adverse events. CONCLUSIONS: Our study shows the advantages of integrase inhibitors when used as PEP, particularly EVG as a Single-Tablet Regimen.

Epidemiological changes of acute/recent human immunodeficiency virus type 1 infection in Barcelona, Spain (1997-2015): a prospective cohort study.

OBJECTIVE: To describe the epidemiology of acute/recent human immunodeficiency virus (HIV) infection over two decades in Barcelona (Spain). METHODS: Prospective, single-centre cohort including all patients with an acute/recent HIV infection (<180 days) since 1997. Patients were stratified into four periods. Phylogenetic analysis was performed to determine clusters of transmission. RESULTS: A total of 346 consecutive acute/recently infected patients were included. The annual proportion of recent infections among total new HIV diagnoses increased over time from 1% (29 out of 1964) to 8% (112 out of 1474) (p <0.001). Proportion of men who have sex with men (MSM) in the cohort increased from 62% (18 out of 29) to 89% (100 out of 112) (p <0.001). The proportion of migrants showed a non-significant increasing trend (24% (7 of 29) to 40% (45 of 112)) likewise the non-B subtype (0% to 22% (22 of 112)). The mean time from infection to diagnosis was 53.6 days (interquartile range (IQR) 50-57), comparable among all periods. Mean time from infection to treatment decreased over the years from 575 (IQR 467-683) to 471 (IQR 394-549) days (p <0.001) without significant differences between migrants and non-migrants (133 (IQR 71-411) versus 208 (IQR 90-523) days p 0.089). Almost 50% (152 of 311) of recently infected individuals were included in a cluster of transmission, and 92% (137 of 149) of them were MSM. CONCLUSION: The MSM population has progressively grown within acutely/recently infected patients in Barcelona, and is frequently involved in transmission clusters. Although the time between diagnosis and treatment has been reduced, the time between infection and diagnosis still needs to be shortened.

Subclinical cardiovascular disease in patients starting contemporary protease inhibitors.

OBJECTIVES: The aim of the study was to assess changes in and factors associated with anatomical [carotid artery intima-media thickness (CIMT)] and functional (arterial stiffness) markers of subclinical cardiovascular disease progression in antiretroviral-naïve patients starting triple combination antiretroviral therapy containing contemporary protease inhibitors. METHODS: This was a planned substudy of the ATADAR (Metabolic Effects of Atazanavir/Ritonavir Versus Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine in naïve HIV-1 Infected Patients) clinical trial (ClinicalTrials.gov identifier NCT01274780). ATADAR is a multicentre, randomized, open-label clinical trial comparing the effects of ritonavir-boosted atazanavir and darunavir, both with tenofovir/emtricitabine, in antiretroviral-naïve HIV-infected patients. Common CIMT and aortic augmentation index (AIx@75) were measured at baseline and after 12 months of follow-up. Antiretroviral treatment, traditional cardiovascular risk factors and HIV-related factors were assessed as potential predictors of CIMT and Aix@75 changes using linear regression analysis. RESULTS: Thirty-three patients were included in this pilot study. While CIMT significantly increased in the pooled population [median (interquartile range (IQR)) 68 (-13, 128) µm; P = 0.0511], AIx@75 did not [median (IQR) 1 (-6, 5)%; P = 0.8964]. Patients on darunavir showed a trend to faster CIMT progression than those on atazanavir [median change (IQR) 117 (-2, 143) vs. -6 (-58, 89) µm, respectively; P = 0.0917]. However, after adjustment in the multivariate analysis, a higher baseline Framingham score was the only factor associated with CIMT progression (coefficient 16.02; 95% confidence interval -1.04, 33.08; P = 0.064). AIx@75 change was not associated with any baseline factor. CONCLUSIONS: CIMT was a more sensitive marker of subclinical vascular disease progression than arterial stiffness in antiretroviral-naïve patients starting antiretroviral therapy with contemporary protease inhibitors. Classical risk factors but not antiretroviral therapy were associated with faster CIMT progression.

Boceprevir plus pegylated interferon/ribavirin to re-treat hepatitis C virus genotype 1 in HIV-HCV co-infected patients: final results of the Spanish BOC HIV-HCV Study.

INTRODUCTION: Boceprevir (BOC) was one of the first oral inhibitors of hepatitis C virus (HCV) NS3 protease to be developed. This study assessed the safety and efficacy of BOC+pegylated interferon-α2a/ribavirin (PEG-IFN/RBV) in the retreatment of HIV-HCV co-infected patients with HCV genotype 1. METHODS: This was a phase III prospective trial. HIV-HCV (genotype 1) co-infected patients from 16 hospitals in Spain were included. These patients received 4 weeks of PEG-IFN/RBV (lead-in), followed by response-guided therapy with PEG-IFN/RBV plus BOC (a fixed 44 weeks was indicated in the case of cirrhosis). The primary endpoint was the sustained virological response (SVR) rate at 24 weeks post-treatment. Efficacy and safety were evaluated in all patients who received at least one dose of the study drug. RESULTS: From June 2013 to April 2014, 102 patients were enrolled, 98 of whom received at least one treatment dose. Seventy-three percent were male, 34% were cirrhotic, 23% had IL28b CC, 65% had genotype 1a, and 41% were previous null responders. The overall SVR rate was 67%. Previous null-responders and cirrhotic patients had lower SVR rates (57% and 51%, respectively). Seventy-six patients (78%) completed the therapy scheme; the most common reasons for discontinuation were lack of response at week 12 (12 patients) and adverse events (six patients). CONCLUSIONS: Response-guided therapy with BOC in combination with PEG-IFN/RBV led to an overall SVR rate of 67%, but an SVR rate of only 51% in patients with cirrhosis. The therapy was generally well tolerated. Although the current standards of care do not include BOC+PEG-IFN/RBV, the authors believe that this combination can be beneficial in situations where new HCV direct antiviral agent interferon-free therapies are not available yet.

Evaluation of antiretroviral-related errors and interventions by the clinical pharmacist in hospitalized HIV-infected patients.

OBJECTIVES: The aim of the study was to identify antiretroviral-related errors in the prescribing of medication to HIV-infected inpatients and to ascertain the degree of acceptance of the pharmacist's interventions. METHODS: An observational, prospective, 1-year study was conducted in a 750-bed tertiary-care teaching hospital by a pharmacist trained in HIV pharmacotherapy. Interactions with antiretrovirals were checked for contraindicated combinations. Inpatient antiretroviral prescriptions were compared with outpatient dispensing records for reconciliation. Renal and hepatic function was monitored to determine the need for dose adjustments. RESULTS: The prescriptions for 247 admissions (189 patients) were reviewed. Sixty antiretroviral-related problems were identified in 41 patients (21.7%). The most common problem was contraindicated combinations (n=20; 33.3%), followed by incorrect dose (n=10; 16.7%), dose omission (n=9; 15%), lack of dosage reduction in patients with renal or hepatic impairment (n=6; 10% and n=1; 1.7%, respectively), omission of an antiretroviral (n=6; 10%), addition of an alternative antiretroviral (n=5; 8.3%) and incorrect schedule according to outpatient treatment (n=3; 5%). Fifteen out of 20 errors were made during admission. A multivariate analysis showed that factors associated with an increased risk of antiretroviral-related problems included renal impairment [odds ratio (OR) 3.95; 95% confidence interval (CI) 1.39-11.23], treatment with atazanavir (OR 3.53; 95% CI 1.61-7.76) and admission to a unit other than an infectious diseases unit (OR 2.50; 95% CI 1.28-4.88). Use of a nonnucleoside reverse transcriptase inhibitor was a protective factor (OR 0.33; 95% CI 0.13-0.81). Ninety-two per cent of the pharmacist's interventions were accepted. CONCLUSION: Antiretroviral-related errors affected more than one-in-five patients. The most common causes of error were contraindicated or not recommended drug-drug combinations and dose-related errors. A clinical pharmacist trained in HIV pharmacotherapy could help to detect errors and reduce the duration of their effect.

Relationship between adherence level, type of the antiretroviral regimen, and plasma HIV type 1 RNA viral load: a prospective cohort study.

The relationship between adherence, antiretroviral regimen, and viral load (VL) suppression was assessed through a 1 year prospective follow-up study among 1142 HIV-infected patient. Patients on antiretroviral therapy who attended to the pharmacy during a 6-month period were considered eligible. Those included in the final analysis were patients who had been taking the same antiretroviral therapy for > or =6 months since their inclusion. The cohort included patients taking first line therapy (n = 243) and antiretroviral-experienced patients (n = 899). Naive patients who were included had to have reached undetectable VL at enrollment. Antiretroviral-experienced patients with detectable VL determinations in the previous 6 months were excluded. Adherence was measured by means of announced pill counts and dispensation pharmacy records. Of patients, 58% were taking NNRTI, 31.4% boosted PI, and 10.6% unboosted PI-based regimens. Overall, the relative risk of virologic failure was 9.0 (95% CI 4.0-20.1) in patients with adherence 80-89.9%, 45.6 (95% CI 19.9-104.5) with adherence 70-79.9%, and 77.3 (95% CI 34.2-174.9) with adherence <70%, compared with adherence of > or =90%. The risk of virologic failure in patients with adherence <90% taking unboosted PI was 2.5 times higher than the group taking boosted PI (95% CI 1.2-5.3). There were no statistical differences in patients taking boosted PI and those who were taking NNRTI. Less than 95% of adherence is associated with high virologic success. For patients taking NNRTI- or boosted PI-based regimens with adherence rates of 80%, the failure rate is <10%. These data do not affect the goal of achieving the highest level of adherence possible.

Hepatotoxicity of nevirapine in virologically suppressed patients according to gender and CD4 cell counts.

OBJECTIVES: A warning advising a higher risk of hepatotoxicity in antiretroviral-naive patients starting a nevirapine-containing combination antiretroviral therapy (NcART) has been issued by health authorities. It is unclear whether this higher risk also applies to stable virologically suppressed patients starting NcART. METHODS: We performed a meta-analysis of published randomized studies including virologically suppressed patients who switched to NcART with a follow-up >or=3 months. CD4 cell cell counts were classified as high (HCD4) (400 cells/microL for males and 250 cells/microL for females) or low (LCD4). The main endpoint was hepatotoxicity within the first 3 months. RESULTS: Four studies with a pooled total of 410 patients were included. The risk of hepatotoxicity within the first 3 months was 2% and 4% in the LCD4 and HCD4 groups, respectively, with a combined odds ratio of 1.46 [95% confidence interval (CI) 0.43-4.98; P=0.54]. The risk of hepatotoxicity at any point during the study was similar in both groups, with a combined hazard ratio of 0.8 (95% CI 0.3-2.5; P=0.80). CONCLUSIONS: In our study, virologically suppressed patients switching to nevirapine did not have a significantly higher risk of hepatotoxicity or rash when stratified by gender and CD4 cell count, although small differences may have gone undetected because of the sample size limitation.

A randomized trial comparing the efficacy and tolerability of two HAART strategies at two years in antiretroviral naive patients.

BACKGROUND: The use of HAART combining 2 nucleoside analogues reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor (PI) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) has shown comparable efficacy. The study was designed to compare long term (2 years) effectiveness of two antiretroviral (ARV) treatment strategies in patients not previously treated: starting with a nelfinavir based HAART switching to nevirapine in case of failure or side effects or the reverse sequence. METHODS: This multicenter, randomized, open label clinical trial enrolled ARV-naïve HIV patients with CD4 counts below 500 cells/mm3. They were randomly assigned to start ddI + d4T + nelfinavir (switching to ZDV + 3TC + NEV in case of failure or toxicity) (PI-NEV arm) or ddI + d4T + nevirapine, switching to ZDV + 3TC + NFV in case of failure or toxicity (NEV-PI arm). The primary study endpoint was the Kaplan-Meier estimates of the time to failure after switching to second regimen if necessary (considering failure as two consecutive plasma HIV-1 RNA determinations above 200 copies/mL, death, a new category C event or toxicity leading to treatment discontinuation of the second regimen) after a minimum follow-up of two years. RESULTS: A total of 137 patients were evaluable (67 and 70 in the PI-NEV and NEV-PI arms respectively). Baseline characteristics did not differ among groups. Kaplan-Meier estimates of time to failure did not show differences between the two arms neither in the on-treatment (OT) analysis (log rank test, p = 0.81) nor in the intent-to-treat (ITT) analysis (p = 0.58). At 24 months, the estimated proportion of patients free of failure were 72% and 66% respectively in the PI-NEV and NEV-PI arms OT analysis (p = 0.54) and 73% and 64% in the PI-NEV and NEV-PI arms in the ITT analysis (p = 0.49). The difference in the median in CD4+ lymphocyte count at 24 months was not significantly different in the two groups: 393 and 307 CD4 cells/mm3 in the PI-NEV and NEV-PI arms respectively (p = 0.167). The incidence of adverse events (AEs) in the two arms was very similar: 50 (75%) in the PI-NEV and 54 (70%) in the NEV-PI group, as it was for grade 3-4 AEs leading to drug switching. CONCLUSION: At two years both treatments strategies (PI-NEV vs NEV-PI) had a high and comparable efficacy and were generally well tolerated.

Impact of steady-state lopinavir plasma levels on plasma lipids and body composition after 24 weeks of lopinavir/ritonavir-containing therapy free of thymidine analogues.

OBJECTIVES: To study the impact of lopinavir/ritonavir-containing therapy on plasma lipids and body fat of HIV-infected adults and to assess whether lopinavir plasma levels at steady state are correlated with plasma lipids and body fat after 24 weeks. METHODS: Patients had their antiretroviral therapy switched to an antiretroviral regimen containing lopinavir/ritonavir plus one or two non-thymidine analogues. Body composition was assessed by dual energy X-ray absorptiometry at baseline and at week 24 and an intensive pharmacokinetic (PK) 12 h profile was performed at week 2. RESULTS: Twenty-six patients were included. Plasma triglycerides (from 206 mg/dL to 261 mg/dL, P = 0.09) and total cholesterol (from 201 to 206 mg/dL, P = 0.03) increased from baseline to week 24. There was a significant rise in total fat (from 10.9 to 11.9 kg, P = 0.02) and limb fat (from 3.8 to 4.4 kg, P = 0.02) from baseline to week 24. We did not find any correlation between PK lopinavir levels and changes over time for triglycerides, cholesterol or body fat composition. CONCLUSIONS: There was an increase in plasma triglycerides and total cholesterol levels and a gain in both total and limb fat at 24 weeks, but these changes were not correlated with lopinavir plasma levels.

Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area.

BACKGROUND: Since the introduction of highly active antiretroviral therapy (HAART), the incidence of death in HIV-infected patients has dramatically decreased, and causes of death other than those related to HIV infection have increased, although it is unclear how these parameters compare with those in the age-matched general population living in the same geographical region. METHODS: Consecutive HIV-infected adults who were prescribed HAART in our hospital were prospectively followed from January 1997 to December 2004 or until death, loss to follow-up or discontinuation of HAART. Estimations of the annual incidence and causes of death in the general population of similar age in Catalonia per calendar year in the study period were obtained and compared with those in the HIV-infected cohort. RESULTS: There were 235 deaths among the 4471 patients on HAART (5%). The incidence of mortality decreased over time in HIV-infected patients (P<0.001; chi(2) test for trend), although it has remained approximately five times higher than that for the age-matched general population. AIDS-related events were the most common cause of death (n=95; 40%), although they significantly decreased over time (P<0.001; chi(2) test for trend), whereas liver diseases (P<0.001; chi(2) test for trend) and non-AIDS-defining infections (P=0.008; chi(2) test for trend) significantly increased over time. Infections in general (33 times higher), liver diseases (11 times higher) and non-Hodgkin lymphoma (5 times higher) were overrepresented as causes of death in the HIV-infected cohort compared with the age-matched general population. CONCLUSIONS: Non-AIDS-defining infectious diseases, liver diseases, and non-Hodgkin lymphoma represent specific targets for efforts to further decrease mortality in HIV-infected patients receiving HAART.

Intrathoracic fat in HIV-infected patients.

BACKGROUND: The impact of HIV infection or antiretroviral therapy on the intrathoracic fat compartment is unknown. METHODS: Consecutive clinically stable HIV-infected adult patients, irrespective of exposure to antiretroviral therapy, and non-HIV-infected healthy volunteers, both without clinical evidence of body fat changes consistent with lipodystrophy and adjusted for age, gender and body mass index, were recruited for this study. Thoracic and abdominal fat was assessed by computed tomography and compared between patients and controls. RESULTS: There were nine women (33%) and 18 men (67%) in each group. Nineteen patients (70%) had been taking antiretrovirals for a median of 8 months (interquartile range: 6-11). Among the HIV-infected patients, intrathoracic fat (median; interquartile range) did not differ significantly between treated (6.7 cm(2); 4.5-8.3 cm(2)) and untreated (6.9 cm(2); 5.7-10.9 cm(2)) individuals (P=0.288). However, intrathoracic fat content (median; interquartile range) was higher in HIV-infected patients (6.8 cm(2); 5.6-10.5 cm(2)) than in controls (5.6 cm(2); 3.9-6.7 cm(2)) (P=0.025). Intrathoracic fat was positively correlated with intra-abdominal fat both in patients (rho=0.6, P=0.002) and in controls (rho=0.7, P=0.004). CONCLUSION: In HIV-infected adults without clinical evidence of lipodystrophy, intrathoracic fat content was higher than in healthy persons and positively correlated with intra-abdominal fat content.

Staphylococcus lugdunensis infective endocarditis: description of 10 cases and analysis of native valve, prosthetic valve, and pacemaker lead endocarditis clinical profiles.

OBJECTIVE: To evaluate the incidence and the clinical and echocardiographic features of infective endocarditis (IE) caused by Staphylococcus lugdunensis and to identify the prognostic factors of surgery and mortality in this disease. DESIGN: Prospective cohort study. SETTING: Study at two centres (a tertiary care centre and a community hospital). PATIENTS: 10 patients with IE caused by S lugdunensis in 912 consecutive patients with IE between 1990 and 2003. METHODS: Prospective study of consecutive patients carried out by the multidisciplinary team for diagnosis and treatment of IE from the study institutions. English, French, and Spanish literature was searched by computer under the terms "endocarditis" and "Staphylococcus lugdunensis" published between 1989 and December 2003. MAIN OUTCOME MEASURES: Patient characteristics, echocardiographic findings, required surgery, and prognostic factors of mortality in left sided cases of IE. RESULTS: 10 cases of IE caused by S lugdunensis were identified at our institutions, representing 0.8% (four of 467), 1.5% (two of 135), and 7.8% (four of 51) of cases of native valve, prosthetic valve, and pacemaker lead endocarditis in the non-drug misusers. Native valve IE was present in four patients (two aortic, one mitral, and one pulmonary), prosthetic valve aortic IE in two patients, and pacemaker lead IE in the other four patients. All patients with left sided IE had serious complications (heart failure, periannular abscess formation, or shock) requiring surgery in 60% (three of five patients) of cases with an overall mortality rate of 80% (four of five patients). All patients with pacemaker IE underwent combined medical treatment and surgery, and mortality was 25% (one patient). In total 59 cases of IE caused by S lugdunensis were identified in a review of the literature. The combined analysis of these 69 cases showed that native valve IE (53 patients, 77%) is characterised by mitral valve involvement and frequent complications such as heart failure, abscess formation, and embolism. Surgery was needed in 51% of cases and mortality was 42%. Prosthetic valve endocarditis (nine of 60, 13%) predominated in the aortic position and was associated with abscess formation, required surgery, and high mortality (78%). Pacemaker lead IE (seven of 69, 10%) is associated with a better prognosis when antibiotic treatment is combined with surgery. CONCLUSIONS: S lugdunensis IE is an uncommon cause of IE, involving mainly native left sided valves, and it is characterised by an aggressive clinical course. Mortality in left sided native valve IE is high but the prognosis has improved in recent years. Surgery has improved survival in left sided IE and, therefore, early surgery should always be considered. Prosthetic valve S lugdunensis IE carries an ominous prognosis.

Preliminary data of a prospective study on neuropsychiatric side effects after initiation of efavirenz.

OBJECTIVE: To assess baseline variables able to predict neuropsychiatric side effects (NPSEs) associated with the initiation of an efavirenz (EFV)-containing regimen in HIV-1-infected patients. DESIGN: Open-label, prospective, observational study. METHODS: Consecutive HIV-1-infected outpatients in whom EFV was prescribed underwent a psychiatric interview. At baseline and at 2, 4, and 12 weeks, patients completed the Symptoms Check List-90-Revised (SCL-90-R), the Medical Outcome Study for HIV-positive patients (MOS-HIV), and a standardized questionnaire concerning potential NPSEs. RESULTS: Preliminary data showed that discontinuation of EFV because of NPSEs occurred in 4 of 31 patients (13%). Patients who completed the follow-up showed a decrease in SCL-90-R total score (p =.004) and in several subscales such as Interpersonal Sensitivity (p =.009), Depression (p =.001), and Anxiety (p =.040), whereas no changes in MOS-HIV were observed. Having fewer years of education (p =.006), having fewer baseline central nervous symptoms (p =.000), reporting better baseline physical status (p =.013), and having higher baseline scores in the Heath Transition subscale of the MOS-HIV (p =.000) and in the Somatization subscale of the SCL-90-R (p =.002) were associated with more NPSEs. CONCLUSION: Patients maintained on EFV showed a decrease in psychologic distress related to self-image, depression, and anxiety, without any effect on quality of life. Patients with a lower level of education, those who feel physically and psychologically better at baseline than in the past, and those who suffer from more distress as a result of physical complaints may be at greater risk of reporting more NPSEs after EFV initiation.