Inflammation status in HIV-positive individuals correlates with changes in bone tissue quality after initiation of ART.

BACKGROUND: The mechanisms behind ART-induced bone changes in HIV-infected patients are poorly known. We aimed to analyse changes in inflammatory and bone markers in HIV after tenofovir disoproxil fumarate initiation, and the associations with changes in the bone strength parameters. METHODS: HIV-positive participants starting tenofovir disoproxil fumarate-based ART underwent dual-energy X-ray absorptiometry (QDR 4500 SL®, Hologic, Waltham, MA, USA) for bone mineral density (BMD), a microindentation test (OsteoProbe®, Active Life Scientific, Santa Barbara, CA, USA) for bone quality [bone material strength index (BMSi)] and phlebotomy at baseline and 48 weeks after ART. A panel of inflammatory biomarkers and bone turnover markers were measured by ELISA. HIV-negative controls underwent identical procedures once. Values are expressed as medians and IQRs, and non-parametric tests were used to perform the analysis. RESULTS: Twenty HIV-infected individuals and 20 HIV-negative control individuals were matched in terms of age and gender. HIV individuals showed higher levels of inflammatory markers. We found no differences in bone turnover markers. HIV-positive individuals presented lower BMSi values at baseline compared with controls [86 (83-90) versus 89 (88-93), respectively; P = 0.034]. We found no difference in BMD (at either of the sites evaluated). BMSi tended to increase with treatment. IL-1ß at baseline was positively correlated with changes in BMSi after ART (rho = 0.564, P = 0.014). Baseline levels of sclerostin tended to be negatively correlated with changes in BMSi (rho = -0.402, P = 0.097). We found a negative correlation between time since HIV diagnosis and changes in BMSi (rho = -0.466, P = 0.04). CONCLUSIONS: We observed a correlation between changes in bone quality and the inflammatory environment in HIV-positive individuals. Moreover, among the underlying mechanisms we highlight the Wnt pathway as having a potentially significant role in ART bone quality recovery.

Exhaled Breath Profiles Before, During and After Exacerbation of COPD: A Prospective Follow-Up Study.

Many patients with chronic obstructive lung disease (COPD) experience exacerbations. The diagnosis of an exacerbation is solely based on symptoms. We hypothesized that exhaled breath profiles, measured by Gas Chromatography-Mass Spectrometry (GC-MS) or electronic nose (eNose), are different between stable disease and exacerbations and may have the potential to serve as biomarkers for COPD exacerbations. In this prospective follow-up study, breath samples were taken during stable COPD, during a subsequent exacerbation and after recovery. Samples were analyzed by GC-MS and eNose. CCQ symptom scores were associated with univariate outcomes of GC-MS and eNose using analysis of covariance (ANCOVA). After multivariate modeling by Principal Component Analysis (PCA), paired student t-tests were performed. Sixty-eight patients were included, 31 had an exacerbation and 16 patients had breath sampled at all three time points. Significant differences were found in breathprints taken during exacerbation as compared to baseline and recovery for both GC-MS and eNose. Breath profiles obtained by GC-MS as well as by eNose showed a correct classification of 71% (10/14) for baseline vs exacerbation and of 78% (11/14) for exacerbation vs recovery. These results provide proof of principle that exhaled breath can serve as a noninvasive biomarker for the diagnosis of COPD exacerbations.

Exhaled breath profiles in the monitoring of loss of control and clinical recovery in asthma.

BACKGROUND: Asthma is a chronic inflammatory airway disease, associated with episodes of exacerbations. Therapy with inhaled corticosteroids (ICS) targets airway inflammation, which aims to maintain and restore asthma control. Clinical features are only modestly associated with airways inflammation. Therefore, we hypothesized that exhaled volatile metabolites identify longitudinal changes between clinically stable episodes and loss of asthma control. OBJECTIVES: To determine whether exhaled volatile organic compounds (VOCs) as measured by gas-chromatography/mass-spectrometry (GC/MS) and electronic nose (eNose) technology discriminate between clinically stable and unstable episodes of asthma. METHODS: Twenty-three patients with (partly) controlled mild to moderate persistent asthma using ICS were included in this prospective steroid withdrawal study. Exhaled metabolites were measured at baseline, during loss of control and after recovery. Standardized sampling of exhaled air was performed, after which samples were analysed by GC/MS and eNose. Univariate analysis of covariance (ANCOVA), followed by multivariate principal component analysis (PCA) was used to reduce data dimensionality. Next paired t tests were utilized to analyse within-subject breath profile differences at the different time-points. Finally, associations between exhaled metabolites and sputum inflammation markers were examined. RESULTS: Breath profiles by eNose showed 95% (21/22) correct classification for baseline vs loss of control and 86% (19/22) for loss of control vs recovery. Breath profiles using GC/MS showed accuracies of 68% (14/22) and 77% (17/22) for baseline vs loss of control and loss of control vs recovery, respectively. Significant associations between exhaled metabolites captured by GC/MS and sputum eosinophils were found (Pearson r≥.46, P<.01). CONCLUSIONS & CLINICAL RELEVANCE: Loss of asthma control can be discriminated from clinically stable episodes by longitudinal monitoring of exhaled metabolites measured by GC/MS and particularly eNose. Part of the uncovered biomarkers was associated with sputum eosinophils. These findings provide proof of principle for monitoring and identification of loss of asthma control by breathomics.

Abacavir/lamivudine plus darunavir/ritonavir in routine clinical practice: a multicentre experience in antiretroviral therapy-naive and -experienced patients.

OBJECTIVES: To present clinical experience with a regimen including abacavir/lamivudine + darunavir/ritonavir in a cohort of HIV-1-infected patients. METHODS: A retrospective, multicentre cohort study, including all consecutive adult HIV-1-infected patients who started abacavir/lamivudine + darunavir/ritonavir from April 2008 to December 2010 and had at least one follow-up visit. The primary endpoint was HIV-1 viral load (VL) <40 copies/mL at week 48. RESULTS: One hundred and eighty-three patients (42 naive and 141 experienced) from 19 hospitals in Spain were studied. The median follow-up was 26.7 (0.5-58.6) months, 79.8% were men, the median age was 47.1 (21.4-80.5) years, 26.2% had AIDS and 38.8% were positive for hepatitis C virus. At baseline, the median CD4 count was 246 cells/mm(3) in naive patients and 393 cells/mm(3) in experienced patients and the median VL was 4.80 and <1.59 log copies/mL, respectively. At week 48, 81.8% of naive patients and 84.2% of experienced patients receiving the regimen reached a VL <40 copies/mL, whereas at 96 weeks this occurred in 90.5% and 92.8%, respectively. CD4 cell count increases at 48 and 96 weeks were +176.5 and +283.5 cells/mm(3) in naive patients and +74.9 and +93 cells/mm(3) in experienced patients, respectively. Overall, 86 (47%) patients discontinued the study regimen, in many cases possibly related to non-medical reasons, such as drug switches to reduce cost or changes in address due to economic constraints. Three patients died of causes unrelated to therapy and 19 (10.4%) discontinued the regimen due to adverse events. CONCLUSIONS: In our cohort, abacavir/lamivudine + darunavir/ritonavir was safe, well tolerated and achieved high rates of virological suppression. In a proportion of patients, discontinuation of this effective regimen was possibly due to non-medical reasons.

Impact of the COVID-19 pandemic: Community and hospital shared pharmaceutical care model. Satisfaction and acceptability of patients with HIV infection on antiretroviral treatment.

OBJECTIVE: The health crisis due to the COVID-19 pandemic is a challenge in the dispensing of outpatient hospital medication (OHM). Models of Antiretroviral Therapy (ART) based on community pharmacy support (ARTCP) have proven to be successful. The aim was to evaluate the degree of satisfaction, acceptability and limitations of the implementation of ARTCP, in the context of a pandemic, in our environment. METHODS: Descriptive cross-sectional study carried out in a Barcelona hospital, during the months of July-November 2020. A telephone survey was carried out via a questionnaire on the quality dimensions of the model (degree of satisfaction, acceptability) and associated inconveniences. Data collected: demographics, antiretroviral treatment (ART), concomitant medication, drug interactions (DDIs), CD4 lymphocyte count and plasma viraemia. Data analysis included descriptive statistics. RESULTS: A total of 533 (78.0%) HIV patients receiving ART were included. 71.9% (383/533) of these patients were very satisfied and 76.2% preferred attending the community pharmacy rather than the hospital. The mean satisfaction rating was 9.3 (DS: 1.4). The benefits reported were: 1) proximity to home (406: 76.1%); 2) lower risk of contagion of COVID-19 (318: 59.7%); 3) shorter waiting time (201: 37.1%); 4) time flexibility (104: 19.5%); 5) reduction of financial expenses (35: 6.57%). A total of 11 (2%) patients reported no benefit. Only 22.9% reported disadvantages associated with ARTCP: 1) lack of privacy (65: 12.2%); 2) lack of coordinationorganization (57: 10.7%). CONCLUSIONS: The COVID-19 pandemic has had an impact on the provision of pharmaceutical care for HIV patients. The ARTPC model has proved efficient, with patients reporting a high degree of satisfaction.

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Dolutegravir/Abacavir/Lamivudine in Antiretroviral-Naive Adults (SYMTRI): A Multicenter Randomized Open-Label Study (PReEC/RIS-57).

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) is the reference for combination therapy based on protease inhibitors due to its efficacy, tolerability, and convenience. Head-to-head randomized comparisons between D/C/F/TAF and combination therapy based on integrase inhibitors in antiretroviral-naive patients are lacking. METHODS: Adult (>18 years old) human immunodeficiency virus-infected antiretroviral-naive patients (HLA-B∗5701 negative and hepatitis B virus negative), with viral load (VL) ≥500 c/mL, were centrally randomized to initiate D/C/F/TAF or dolutegravir/abacavir/lamivudine (DTG/3TC/ABC) after stratifying by VL and CD4 count. Clinical and analytical assessments were performed at weeks 0, 4, 12, 24, and 48. The primary endpoint was VL <50 c/mL at week 48 in the intention-to-treat (ITT)-exposed population (US Food and Drug Administration snapshot analysis, 10% noninferiority margin). RESULTS: Between September 2018 and 2019, 316 patients were randomized and 306 patients were included in the ITT-exposed analysis (151 D/C/F/TAF and 155 DTG/3TC/ABC). Almost all (94%) participants were male and their median age was 35 years. Forty percent had a baseline VL >100 000 copies/mL, and 13% had <200 CD4 cells/µL. Median weight was 73 kg and median body mass index was 24 kg/m2. At 48 weeks, 79% (D/C/F/TAF) versus 82% (DTG/3TC/ABC) had VL <50 c/mL (difference, -2.4%; 95% confidence interval [CI], -11.3 to 6.6). Eight percent versus four percent experienced virologic failure but no resistance-associated mutations emerged. Four percent versus six percent had drug discontinuation due to adverse events. In the per-protocol analysis, 94% versus 96% of patients had VL <50 c/mL (difference, -2%; 95% CI, -8.1 to 3.5). There were no differences in CD4 cell count or weight changes. CONCLUSIONS: We could not demonstrate the noninferiority of D/C/F/TAF relative to DTG/ABC/3TC as initial antiretroviral therapy, although both regimens were similarly well tolerated.

Exhaled air molecular profiling in relation to inflammatory subtype and activity in COPD.

Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is predictive for responses to inhaled steroids. We hypothesised that the inflammatory subtype in mild and moderate COPD can be assessed by exhaled breath metabolomics. Exhaled compounds were analysed using gas chromatography and mass spectrometry (GC-MS) and electronic nose (eNose) in 28 COPD patients (12/16 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II, respectively). Differential cell counts, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) were measured in induced sputum. Relationships between exhaled compounds, eNose breathprints and sputum inflammatory markers were analysed and receiver operating characteristic (ROC) curves were constructed. Exhaled compounds were highly associated with sputum cell counts (eight compounds with eosinophils, 17 with neutrophils; p < 0.01). Only one compound (alkylated benzene) overlapped between eosinophilic and neutrophilic profiles. GC-MS and eNose breathprints were associated with markers of inflammatory activity in GOLD stage I (ECP: 19 compounds, p < 0.01; eNose breathprint r = 0.84, p = 0.002) (MPO: four compounds, p < 0.01; eNose r = 0.72, p = 0.008). ROC analysis for eNose showed high sensitivity and specificity for inflammatory activity in mild COPD (ECP: area under the curve (AUC) 1.00; MPO: AUC 0.96) but not for moderate COPD. Exhaled molecular profiles are closely associated with the type of inflammatory cell and their activation status in mild and moderate COPD. This suggests that breath analysis may be used for assessment and monitoring of airway inflammation in COPD.

Use of non-nucleoside analogues together with rifampin in HIV patients with tuberculosis.

OBJECTIVE: The concomitant use of rifampin (RFP) with efavirenz (EFV) or nevirapine (NVP) is frequent in HIV patients with tuberculosis (TB). The necessity of increasing the dose of EFV remains controversial. The aim of the study was to evaluate the outcome of HIV infection in patients treated with non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) and RFR. METHODS: Retrospective analysis of HIV patients who were simultaneously treated with RFP and NVP or EFV. The dose of EFV was considered to be adjusted in those patients receiving 600 mg when weighing <60 kg and 800 mg if >60 kg and was considered nonadjusted when the dose given was 600 mg in patients >60 kg. RESULTS: 63 patients were included: 13 received NVP and 50 received EFV-based ART (30 adjusted and 20 nonadjusted). Treatment failure was observed in 7 (53.8%) of the NVP group; 11 (55%) of the nonadjusted EFV group, and 8 (26.7%) of the adjusted EFV group (P = .04). The relative risk (RR) of treatment failure comparing nonadjusted and adjusted EFV was 3.36 (95% Cl, 1.02-11.11). The proportion of treatment failure was 9/18 (50%) in the nonadjusted and 5/27(18.5%) in the adjusted EFV group. CONCLUSIONS: The effectiveness of NVP and nonadjusted EFV was lower than adjusted EFV-based ART. It may be advisable to increase the dose of EFV to 800 mg once daily when administered with rifampin in patients weighing >60 kg.

Clinical characteristics and outcomes of patients with vancomycin-susceptible Enterococcus faecalis and Enterococcus faecium bacteraemia in cancer patients.

The purpose of this investigation was to compare the risk factors, clinical features and outcomes in cancer patients with bacteraemia caused by vancomycin-susceptible Enterococcus faecalis and E. faecium. A retrospective, observational 7-year study was carried out in a 450-bed, acute-care university-affiliated hospital. We performed univariate comparisons between the two groups and then multivariate analysis to identify patient risk factors for E. faecium isolation. Seventy-three patients were included in the analysis: 54 (74.0%) with bacteraemia caused by E. faecalis and 19 (26.0%) by E. faecium. The Simplified Acute Physiological Score (SAPS) value was significantly greater in E. faecium isolates (40.7 vs. 35.2; p = 0.009). Diabetes mellitus was more frequently diagnosed in patients with E. faecium bacteraemia (52.6% vs. 24.1%; p = 0.021). Prior penicillin exposure was more frequent in patients with E. faecium bacteraemia (68.4% vs. 29.6%; p = 0.003). There was a trend toward higher mortality in E. faecium bacteraemia patients (47.4% vs. 25.9%; p = 0.084). Independent patient risk factors for E. faecium isolation were prior penicillin exposure (odds ratio [OR], 6.479; p = 0.003) and SAPS > 34 (OR, 6.896; p = 0.009). When compared to E. faecalis bacteraemia, E. faecium bacteraemia in cancer patients is independently associated with more severe illness and prior use of penicillins; therefore, empiric treatment which would cover E. faecium should be considered in cancer patients suspected of having bacteraemia.

Comparison of antiviral activity of regimens containing nucleos(t)ide (NUC) Pairs in HIV-Infected Patients Initiating REScue therapy (The NUCREST Study).

BACKGROUND: recycling nucleos(t)ides (NUCs) is useful in regions where new antiretrovirals are not available. This study compares the effectiveness of NUC-containing regimens as rescue therapy in routine care. METHODS: retrospective, multicentre cohort study (January 2001 to June 2006) of patients with ≥ 1 virological failure who started therapy with 2 NUCs and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). The primary endpoint was the rate of treatment response at 6 months (intention-to-treat [ITT] analysis). RESULTS: we included 719 patients (average of 4 prior regimens over a median 6.1 years). The most frequent NUC pairs were tenofovir plus lamivudine (TDF+3TC; 25%), tenofovir plus stavudine (TDF+d4T; 23%), and stavudine plus didanosine (d4T+ddI; 15%). A boosted PI was used in 68% of total cases. Resistance to both NUCs was more frequent in zidovudine plus lamivudine (AZT+3TC; 22.0%), abacavir plus lamivudine (ABC+3TC; 35.5%), and stavudine plus lamivudine (d4T+3TC; 31.2%). No significant differences were observed in treatment response (overall 65%, P = .67); ddI+3TC (71%) and d4T+3TC (53%) had the highest and lowest response rates, respectively. Median time to failure was shorter with d4T+3TC, d4T+ddI, and ABC+3TC (48, 51, and 58 weeks, respectively; P = .0012). Lower response rates associated with an increasing number of thymidine analog mutations (TAMs) were observed for ABC+3TC (P = .027). CONCLUSION: the clinical utility of NUCs for rescue therapy is limited and selection should be individualized. Specific combinations (d4T+3TC and d4T+ddI) might be less efficacious.

Risk of cardiovascular disease in patients with HIV infection undergoing antiretroviral therapy. / Riesgo de enfermedad cardiovascular en pacientes con infección VIH en tratamiento antirretroviral.

BACKGROUND: The increased survival of patients with HIV infection thanks to antiretroviral therapy (ART) is accompanied by a higher rate of cardiovascular disease (CVD). We analysed the prevalence of the cardiovascular risk factors (CRFs) and estimated the risk of CVD in a cohort of patients with HIV in Spain. METHODS: We conducted a cross-sectional, observational study of CRFs in the Spanish VACH cohort of patients with HIV who undergo ART. RESULTS: The study assessed 15,559 patients with HIV (76% men; mean age, 46 years). Some 3.7% had experienced at least 1 CVD event. The prevalence of CRFs was high (hyperlipidaemia, 64%; tobacco use, 47%; arterial hypertension, 22%; and diabetes, 16%). According to the Framingham scale, 10.9% of the patients presented a high CVD risk, and 28.8% presented a moderate risk. Of the patients with a high CVD risk, 49% took protease inhibitors and 43% took abacavir. Fifty-three percent of the patients diagnosed with arterial hypertension took antihypertensive drugs, and 2.6% of the patients with diabetes took antidiabetic agents. CONCLUSIONS: Classical CRFs are common in patients with HIV undergoing ART in Spain, and a large proportion of them have a moderate-high risk of CVD. Therefore, controlling the modifiable CRFs in patients with HIV should be improved, and the use of drugs with a better cardiovascular risk profile should be assessed.

Impact of different patterns of nonadherence on the outcome of highly active antiretroviral therapy in patients with long-term follow-up.

OBJECTIVES: The aim of the study was to evaluate the impact of different patterns of nonadherence on treatment outcomes in patients with long-term follow-up. METHODS: This cohort study included patients who began highly active antiretroviral therapy during 1996-1999, with the last follow-up in 2007. Adherence was evaluated every 2 months by monitoring of pharmacy refills and by using self-reports. Patients were considered nonadherent at a specific visit when less than 90% of the prescribed drugs had been taken. Adherence was categorized as follows. (A) Continuous adherence: a patient had to be adherent in all of the evaluations throughout the period of follow-up. (B) Treatment interruption: drugs were not taken for more than 3 days, for any reason. Treatment failure was defined as viral load >500 HIV-1 RNA copies/mL or death. Cox proportional risk models were used to calculate adjusted relative hazards (ARHs) of treatment failure. RESULTS: A total of 540 patients were included in the study, with a median follow-up of 8.3 years. Only 32.78% of patients achieved and maintained continuous adherence, and 42.78% of patients had treatment interruptions. Noncontinuous adherence [ARH 1.48; 95% confidence interval (CI) 1.02-2.14] and treatment interruptions (ARH 1.39; 95% CI 1.04-1.85) were associated with treatment failure for the overall cohort; however, for patients with more than 3 years of follow-up, only treatment interruptions were independently associated with treatment failure. CONCLUSIONS: Only one-third of patients managed to achieve continuous adherence, and almost half of the patients had treatment interruptions, which have a particularly marked effect on treatment outcomes over the long term.

Mortality of COPD patients infected with multi-resistant Pseudomonas aeruginosa: a case and control study.

BACKGROUND: The incidence of infections caused by multiresistant Pseudomonas aeruginosa (MDRP) is increasing, especially in critically ill patients. The relevance of MDRP in the prognosis of chronic obstructive pulmonary disease (COPD) acute exacerbation in patients admitted to the hospital's general ward is not well known. PATIENTS AND METHODS: Case and control study. Cases were patients admitted for COPD acute exacerbation in which a MDRP was isolated from spontaneous sputum. MDRP was defined as the absence of susceptibility to three or more antibiotic families (betalactams, quinolones, carbapenems and aminoglycosides). Patients currently or previously admitted to the intensive care unit (ICU), who had a recent surgery, neoplasia or immunosuppressive treatment were excluded from the study. Patients from the control group were admitted for COPD acute exacerbation and matched 1:1 with each case-patient in terms of age, sex, date of admission and degree of airway obstruction. Pseudomonas aeruginosa susceptible to all antimicrobials or other microorganisms was isolated from sputum. RESULTS: During the study period (2000-2005), 50 case-patients and 50 controls were included. Crude mortality at 2 years was 60% for the case-patients and 28% for the control group. In the logistic regression analysis adjusted for age, FEV(1) and number of previous hospital admissions, MDRP infection was associated to an increased mortality in comparison to patients without MDRP (OR = 6.2; IC 95%: 1.7-22.1; p < 0.01). CONCLUSIONS: In COPD patients admitted to the general ward, acute exacerbation with MDRP in sputum was associated with higher mortality.

Effectiveness and safety of colistin for the treatment of multidrug-resistant Pseudomonas aeruginosa infections.

PURPOSE: To describe the clinical and microbiological outcomes of patients infected with multidrug-resistant Pseudomonas aeruginosa (MDRP) treated with colistin (colistimethate sodium) and the adverse events observed with this treatment. METHODS: Retrospective study of MDRP infections treated with colistin from 1997 to 2006. RESULTS: 121 episodes were identified. The median daily intravenous dose was 240 mg/day; 28.9% of patients received intravenous and nebulized colistin. Clinical outcome was favorable in ten cases of bacteremia (62.5%, n = 16), 43 cases of bronchial infection (72.9%, n = 59), 13 cases of pneumonia (65%, n = 20), 11 cases of urinary infection (84.6%, n = 13), eight cases of skin and soft tissues (72.7%, n = 11), and in the one case of arthritis and one case of otitis. Eradication was achieved in 31 (34.8%) of the 89 patients with available bacteriologic data. Factors associated with bacteriological failure were smoking, chronic obstructive pulmonary disease (COPD), and previous infection with P. aeruginosa. Nephrotoxicity occurred in ten cases (8.3%), with the associated factors being previous chronic renal insufficiency, diabetes mellitus, and aminoglycoside use. Crude mortality was 16.5%, and related MDRP was 12.4%, and was higher in patients with pneumonia or bacteremia (36.1%) than in other types of infections (8.2%). CONCLUSIONS: Colistin is a safe option for the treatment of MDRP infections, with acceptable clinical outcomes. However, bacteriological eradication is difficult to achieve, especially in COPD patients.

Frequency and severity of potential drug interactions in a cohort of HIV-infected patients Identified through a Multidisciplinary team.

OBJECTIVES: Interactions between antiretroviral treatment (ART) and comedications are a concern in HIV-infected patients. This study aimed to determine the frequency and severity of potential drug-drug interactions (PDDIs) with ART in our setting. METHODS: Observational study by a multidisciplinary team in 1259 consecutive HIV patients (March 2015-September 2016). Data on demographics, toxic habits, comorbidities, and current ART were collected. A structured questionnaire recorded concomitant medications (including occasional and over-the-counter drugs). PDDIs were classified into four categories: (1) no interactions, (2) mild (clinically non-significant), (3) moderate (requiring close monitoring or drug modification/dose adjustment), and (4) severe (contraindicated). STATISTICAL ANALYSIS: chi-square test, logistic regression analysis. RESULTS: In total, 881 (70%) patients took comedication, and 563 (44.7%) had ≥ PDDI. Forty-one comedicated patients (4.6%) had severe and 522 (59.2%) moderate PDDIs. Moderate PDDIs mainly involved cardiovascular (53.8%) and central nervous system (40.2%) drugs. Independent risk factors for PDDIs were ART containing a boosted protease inhibitor (odds ratio [OR]=9.11, 95% confidence interval [CI] 5.15-16.11; p = 0.0001) and/or non-nucleoside reverse transcriptase (NNRTI) (OR = 4.34, 95%CI 2.49-7.55; p = 0.0001), HCV co-infection (OR = 3.26, 95%CI 2.15-4.93; p = 0.0001), and use of two or more comedications (OR = 3.36, 95%CI 2.27-4.97; p = 0.0001). Adherence and effectiveness of ART were similar in patients with and without PDDIs. The team made 133 recommendations related to comedications (drug change or dose adjustment) or ART (drug switch or change in administration schedule). CONCLUSIONS: Systematic evaluation detected a significant percentage of PDDIs requiring an intervention in HIV patients on ART. Monitoring and advice about drug-drug interactions should be part of routine practice.

Real World Patient-reported Outcomes in HIV-infected Adults Switching to EVIPLERA®, Because of a Previous Intolerance to cART. PRO-STR Study.

BACKGROUND: To investigate the impact of switching from stable Combined Antiretroviral Therapy (cART) to single-tablet regimen (RPV/FTC/TDF=EVIPLERA® /COMPLERA®) on patient- reported outcomes in HIV-infected adults who cannot tolerate previous cART, in a real-world setting. METHODS: PRO-STR is a 48-week observational, prospective, multicenter study. Presence and magnitude of symptoms (main endpoint), health-related quality-of-life (HRQoL), adherence, satisfaction with treatment and patient preferences were assessed. RESULTS: Three hundred patients with 48-week follow-up, who switched to EVIPLERA® (mean age: 46.6 years; male: 74.0%; 74.7% switched from a non-nucleoside reverse-transcriptase-inhibitor, 25.3% from a protease inhibitor + ritonavir) were included. There was no statistical difference in median CD4+ cell count (baseline: 678.5 cells/mm3; 48-week: 683.0 cells/mm3) neither in virological suppression (≤50 copies/mL) (baseline: 98.3%; 48-week: 95.3%). The most frequent reasons for switching were neuropsychiatric (62.3%), gastrointestinal (19.3%) and biochemical/metabolic (19.3%) events. Only 7.7% of patients permanently discontinued therapy. At 48-week, all outcomes showed an improvement compared to baseline. Overall, there was a significant decrease (pvalue≤ 0.05) in number and magnitude of symptoms, while HRQoL, satisfaction and adherence improved significantly. Most patients prefered EVIPLERA® than previous cART. According to the type of intolerance, HRQoL was improved, but only significantly in patients with neuropsychiatric and gastrointestinal symptoms. Adherence improved significantly in patients with metabolic disturbances and satisfaction with EVIPLERA® was higher in the three groups. CONCLUSION: Switching to EVIPLERA® from non-nucleoside reverse-transcriptase-inhibitor or protease inhibitor-based regimens due to toxicity, improved the presence/magnitude of symptoms, HRQoL, and preference with treatment. EVIPLERA® maintained a virological response, CD4+ cell count and maintained or improved adherence.

Late medical complications and fatigue in Hodgkin's disease survivors.

PURPOSE: Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkin's disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkin's disease (HD) may explain the high level of fatigue among HDSs. PATIENTS AND METHODS: Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies. RESULTS: HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P <.05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P <.01). No associations were found between cardiac sequelae or hypothyroidism and fatigue. CONCLUSION: Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.

Comparison of twice-daily stavudine plus once- or twice-daily didanosine and nevirapine in early stages of HIV infection: the scan study.

OBJECTIVES: To evaluate the safety and effectiveness of once-daily didanosine and nevirapine plus twice-daily stavudine versus twice-daily administration of all three drugs. METHODS: This open-label, randomized, multicentre study enrolled 94 antiretroviral-naive patients with chronic HIV infection, CD4+ cell counts > 500 x 10(6) cells/l, and viral loads > 5000 copies/ml. Patients were treated with either 40 mg stavudine (twice daily) plus 400 mg didanosine (once daily) and 400 mg nevirapine (once daily) or 40 mg stavudine (twice daily) plus 200 mg didanosine (twice daily) and 200 mg nevirapine (twice daily). RESULTS: After 12 months, 68% of patients who received twice-daily didanosine and nevirapine had viral loads < 200 copies/ml in the intention-to-treat and 79% in the on-treatment analysis, respectively. The corresponding values for patients treated with didanosine and nevirapine, taken once-daily, were 73 and 85%. The percentages of patients in each group with viral loads < 5 copies/ml at 12 months were 40% (once daily ) and 45% (twice daily) for the intention-to-treat analysis. Five of 11 patients (45%) with plasma viral loads < 5 copies/ml at 12 months had detectable virus in tonsillar tissue. Genotypic resistance to nevirapine was noted in seven of the 14 patients with detectable viral load at month 12. Mean changes in CD4+ cell counts for patients treated with stavudine plus once- or twice-daily didanosine and nevirapine were 154 and 132 x 10(6) cells/l, respectively. Treatment was interrupted due to adverse events in seven patients (8%) (four who received once-daily didanosine and nevirapine and three treated with twice-daily doses). CONCLUSIONS: The combination of twice-daily stavudine plus once-daily didanosine and nevirapine was as safe and well tolerated as twice-daily administration of all three agents. Both regimens were equally effective in reducing viral loads and in increasing CD4+ cell counts.

A randomized study comparing triple versus double antiretroviral therapy or no treatment in HIV-1-infected patients in very early stage disease: the Spanish Earth-1 study.

BACKGROUND: Most current guidelines state that antiretroviral therapy should be considered for HIV-infected patients with plasma HIV RNA > 5000-10000 copies/ml and CD4 cells > 500 x 10(6) cells/l. However, there is increasing concern about whether this is the optimal point to begin treatment or whether it is better to delay the initiation to more advanced stages. OBJECTIVE: To study the immunological and virological benefits of starting antiretroviral therapy at these early stages. METHODS: A total of 161 HIV-infected asymptomatic patients with CD4 cell count > 500 x 10(6) cells/l and viral load > 10000 copies/ml were randomly assigned to one of five treatment groups: no treatment, twice daily zidovudine and thrice daily zalcitabine (ZDV-ddC), twice daily zidovudine and didanosine (ZDV-ddI), twice daily stavudine and didanosine (D4T-ddI), or a twice daily three-drug regimen with stavudine and lamivudine and ritonavir. The endpoints were progression to < 350 x 10(6) cells/l CD4 cells, to < 500 x 10(6) cells/l with either two Centers for Disease Control class B symptoms or an increase of viral load > 0.5 log10 copies/ml above baseline, or to AIDS or death. In various substudies, the lymphoid tissue and cerebrospinal fluid viral load, development of genotypic resistance, proliferative responses to mitogens and cytomegalovirus, and HIV-1 specific antigens and other immunophenotypic markers were also analysed. RESULTS: Progression rates to study endpoints within 1 year were greater in the control group (31%) than in all groups receiving antiretroviral therapy pooled together (5%; estimated hazard ratio 7.41; 95% confidence interval 5.72-74.55; P < 0.001). The peak mean viral load decrease was greater in the three-drug group when compared with any of the three groups with a two-drug regimen (2.32, 1.65, 1.72 and 1.84, respectively; P < or = 0.001). At 1 year, viral load remained below 20 copies/ml in 30 out of 33 patients in the three-drug group (91%) and in only eight out of 94 patients (9%) in two-drug groups (P = 0.001). The peak mean increase in CD4 cells was also greater in the three-drug group than in the double treatment arms (259 versus 85, 144 and 145 x 10(6) cells/l, respectively; P = 0.001). By comparison, 36% of patients in the three-drug group regimen had to change the therapy as a result of adverse events. Substudies were performed in 60 patients recruited at two sites. Tonsillar tissue HIV RNA was measured in seven patients (two in the two-drug groups and five in the three-drug group) in whom plasma HIV RNA was < 20 copies/ml at 1 year. It was 15151 and 133333 copies/mg tissue in the two patients from the two-drug group, < 40 copies/mg tissue in four patients in the three-drug group, and 485 copies/mg in one patient in the three-drug group. At 1 year there was a mean increase of 4.21+/-2.94% in CD8+CD38+ cells in the control group and a decrease of 9.48+/-3.36% in the two-drug groups (P = 0.01), and 19.87+/-3.64 in the three-drug group (P = 0.001 and P = 0.05, for comparisons with control group and two-drug groups, respectively). Although proliferative responses to cytomegalovirus antigens were significantly greater in those receiving antiretroviral therapy, response to HIV-1 p24 antigen was not detected in any patient in either treatment group. CONCLUSIONS: This study supports the recommendation to start antiretroviral therapy with a three-drug combination during very early stages of HIV-1 disease, at least if viral load is above a cut-off point (10000 copies/ml in our study). The risk of progression was sevenfold higher in non-treated patients at 8 months of follow-up. Some immune system parameters improved toward normal values after 1 year of antiretroviral therapy, but the proliferative response of CD4 T lymphocytes against the p24 HIV-1 antigen was not recovered. Therapeutic approaches with more potent, better-tolerated and more convenient regimens will increasingly favour early intervention with antiretroviral t