Hernando Knobel

Impact of adherence and highly active antiretroviral therapy on survival in HIV-infected patients

Objectives: To assess the effect of antiretroviral therapy (ART) adherence on survival in HIV‐infected patients. Design: Cohort study at a single hospital in Barcelona, Spain. Methods: Data on HIV‐infected patients older than 18 years of age who began ART during the period 1990 to 1999 were analyzed. Patients were considered nonadherent if the total dose of antiretroviral drug was less than 90% of that prescribed. Adherence was assessed through self‐report and hospital pharmacy appointments. Cox regression with time‐dependent variables was used. Results: A total of 1219 patients were included. The first ART was with monotherapy in 23.7% of cases, with two drugs in 30.5%, and with triple therapy in 45.8%. In multivariate analysis, the variables that presented significant differences with respect to mortality were clinical stage at the beginning of treatment (AIDS: relative hazard (RH) = 2.97; 95% confidence interval [CI]: 2.14‐4.13), CD4 cell count (<200 cells/&mgr;L: RH = 5.89; CI: 3.44‐10.10), type of treatment (monotherapy: RH = 9.76; CI: 4.56‐20.90; bi‐therapy: RH = 9.12; CI: 4.23‐19.64), and adherence (nonadherence: RH = 3.87; CI: 1.77‐8.46). Conclusions: The modifiable factors most strongly associated with survival were type of treatment and adherence. It would be desirable to accompany therapy with intervention strategies intended to improve adherence.

Validation of a simplified medication adherence questionnaire in a large cohort of HIV-infected patients: the GEEMA Study

Objective To assess the effectiveness of the simplified medication adherence questionnaire (SMAQ) in identifying non-adherent patients. Design Prospective observational study of adherence. The six-item SMAQ was developed. The following aspects were evaluated: (i) criterion validity, comparison with electronic adherence monitoring; (ii) construct validity, association between adherence, as defined by the SMAQ, and virological outcomes; and (iii) reliability, internal consistency and reproducibility. Patients A group of 3004 unselected HIV patients who had initiated nelfinavir therapy combined with other antiretroviral drugs [21% naive, 15% protease inhibitor (PI)-naive, 64% PI-experienced] between January 1998 and December 1999 were enrolled in 69 hospitals in Spain. The SMAQ was administered at months 3, 6 and 12. Results The SMAQ showed 72% sensitivity, 91% specificity and a likelihood ratio of 7.94 to identified non-adherent patients, compared with the medication-event monitoring system (40 patients evaluated). At month 12, 1797 patients were evaluated, of whom 32.3% were defined as non-adherent; viral load < 500 copies/ml found in 68.3% of the adherent, and 46% of the non-adherent patients. A logistic regression analysis of PI-naive patients was performed, including age, sex, baseline viral load > 5 log10/ml, CD4 cell count < 200 × 106/l, and non-adherence as independent variables. Non-adherence was the only significant risk factor in failing to achieve virological suppression. Cronbachs alpha internal consistency coefficient was 0.75, and overall inter-observer agreement was 88.2%. Conclusion The SMAQ appears to be an adequate instrument with which to assess adherence in HIV-infected patients, and may be applied in most clinical settings.

Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study

Background:Switching to raltegravir in selected patients treated with ritonavir-boosted protease inhibitors may result in similar efficacy and lower plasma lipids. Methods:SPIRAL is a 48-week multicentre, open-label trial in which HIV-infected adults with less than 50 copies/ml of plasma HIV RNA for at least the previous 6 months on ritonavir-boosted protease inhibitor-based therapy were randomized (1: 1) to switch from the ritonavir-boosted protease inhibitor to raltegravir or to continue on ritonavir-boosted protease inhibitor-based therapy. Primary endpoint was the proportion of patients free of treatment failure (noncompleter = failure) at 48 weeks. SPIRAL study was powered to show noninferior efficacy of raltegravir-based therapy with a margin of −12.5%. Results:Two hundred and seventy-three patients assigned to switch to raltegravir (n = 139) or to continue ritonavir-boosted protease inhibitor (n = 134) were included in the efficacy analysis. At 48 weeks, 89.2% (raltegravir-based therapy) and 86.6% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of treatment failure [difference 2.6%; 95% confidence interval (CI) −5.2 to 10.6]. A total of 96.9% (raltegravir-based therapy) and 95.1% (ritonavir-boosted protease inhibitor-based therapy) of the patients remained free of virological failure (difference 1.8%; 95% CI −3.5 to 7.5). Switching to raltegravir was associated with significant decreases in plasma lipids and total-to-HDL cholesterol ratio relative to continuing ritonavir-boosted protease inhibitor. Severe adverse events and study drug discontinuations due to any adverse event occurred in 4 and 2% of the patients in each group. Conclusion:In patients with sustained virological suppression on ritonavir-boosted protease inhibitor-based therapy, switching from ritonavir-boosted protease inhibitor to raltegravir demonstrated noninferior efficacy and resulted in a better lipid profile at 48 weeks than continuing ritonavir-boosted protease inhibitor.

Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis.

Background:The OK04 trial has shown that 48 weeks of lopinavir-ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy with 2 nucleosides and lopinavir-ritonavir in patients with prior stable suppression. However, it is still uncertain if this experimental strategy can maintain suppression in the long term. Methods:Patients entered this noninferiority trial (upper limit 95% confidence interval: +12%) with no history of virological failure while receiving a protease inhibitor and receiving 2 nucleosides plus lopinavir/ritonavir, with HIV RNA <50 copies per milliliter for more than 6 months. Primary end point was percent of patients without therapeutic failure, defined as confirmed HIV RNA >500 copies per milliliter with exclusion of monotherapy patients who resuppressed to <50 copies per milliliter after resuming baseline nucleosides, or loss to follow-up, or change of randomized therapy other than reinduction. Results:Through 96 weeks, percentage of patient without therapeutic failure was 87% (monotherapy, n = 100) vs. 78% (triple therapy, n = 98; 95% confidence interval: −20% to +1.2%). Percentage with HIV RNA <50 copies per milliliter (intention to treat, missing = failure, reinduction = failure): 77% (monotherapy) vs. 78% (triple therapy). Low-level viral rebound was more frequent in the monotherapy group. Twelve patients in the monotherapy group (12%) needed reinduction with nucleosides. Discontinuations due to adverse events were significantly more frequent in the triple therapy group (8%) than in the monotherapy group (0%); P = 0.003. Conclusions:At 96-week lopinavir/ritonavir monotherapy with reintroduction of nucleosides as needed was noninferior to continuation of triple therapy. Incidence of adverse events leading to treatment discontinuation was significantly lower with monotherapy. (ClinicalTrials.gov number, NCT00114933).

Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients

Objectives:To assess the effect of early syphilis on HIV viral load (VL) and CD4 cell count in patients with HIV and to analyze factors associated with changes in HIV VL and CD4 cell count. Design:Multicenter study of a series of patients with HIV who were diagnosed with early syphilis infection during 2004 through 2005. Patients who started or changed their highly active antiretroviral therapy (HAART) regimen during the analysis period were excluded. Results:One hundred eighteen patients were analyzed: 95.8% were men, mean patient age was 38.2 years, 83.9% were homosexual men, 50.8% were on antiretroviral therapy at the time syphilis was diagnosed, and HIV and syphilis diagnoses were coincident in 38 (32.2%) cases. CD4 cell counts were lower during syphilis than before (590 vs. 496 cells/μL; P = 0.0001) and after syphilis treatment (509 vs. 597 cells/μL; P = 0.0001). The HIV VL increased in 27.6% of patients during syphilis. The only factor associated with an HIV VL increase was not being on HAART, and the only factor associated with a CD4 count decrease >100 cells/μL during syphilis was the prior CD4 cell count. Conclusions:Syphilis infection was associated with a decrease in the CD4 cell count and an increase in the HIV VL in almost one third of the patients. In this series, more than two thirds of the syphilis cases were diagnosed in patients who were previously known to be infected with HIV.

A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression.

Background:Data comparing abacavir/lamivudine versus tenofovir/emtricitabine in antiretroviral-naive patients are controversial. We compared 48-week efficacy and safety of these combinations as substitutes of nucleosides in patients with virological suppression. Methods:We randomly assigned 333 HIV-1-infected patients on lamivudine-containing triple regimens with <200 copies per milliliter for at least 6 months to switch their nucleosides to either abacavir/lamivudine (n = 167) or tenofovir/emtricitabine (n = 166). The primary outcome was treatment failure [“switching = failure” intention to treat (ITT) analysis, noninferiority margin 12.5%]. Secondary outcomes were time to treatment failure, virological failure, adverse events, and changes in CD4 count, fasting plasma lipids, lipodystrophy, body fat, bone mineral density, and renal function. Results:Treatment failure occurred in 32 patients (19%) on abacavir/lamivudine and 22 patients (13%) on tenofovir/emtricitabine [difference 5.9%; (95% confidence interval −2.1% to 14.0%), P = 0.06]. Four patients in the abacavir/lamivudine group versus none in the tenofovir/emtricitabine group developed virological failure [difference 2.4; (95% confidence interval 0.05 to 6.0), P = 0.04]. Twenty-three patients (14%) assigned to abacavir/lamivudine and 10 (6%) to tenofovir/lamivudine experienced grade 3 or 4 adverse effects (P = 0.03). CD4 counts and plasma lipids showed higher increments in the abacavir/lamivudine group than in the tenofovir/emtricitabine group. Conclusions:In HIV-1-infected patients with virological suppression, abacavir/lamivudine did not meet the noninferiority outcome for treatment efficacy compared with tenofovir/emtricitabine.

Virologic Outcome and Predictors of Virologic Failure of Highly Active Antiretroviral Therapy Containing Protease Inhibitors

In this observational single-center cohort study outside the clinical trial setting, outcome and predictors of virologic failure of highly active antiretroviral therapy (HAART) containing a protease inhibitor were evaluated in human immunodeficiency (HIV)-infected persons. The study population consisted of 807 protease inhibitor-naive HIV-seropositive patients who initiated antiretroviral therapy with reverse transcriptase inhibitors and protease inhibitors (indinavir, nelfinavir, ritonavir) between January 1997 and January 1999. Demographic variable, plasma HIV-1 RNA levels, CD4+ T-cell count, adverse drug reactions, and adherence to HAART were assessed. Virologic treatment response was defined as a decrease in plasma HIV-1 RNA load from baseline to below 500 copies per milliliter after 12 months of therapy. Levels of HIV-1 RNA were undetectable in 43% of patients at 12 months. Factors associated with failure to suppress viral load included age 40 years or younger, baseline CD4+ T cell count less than 200 x 10(6) per liter baseline viral load greater than 4.3 log(10) per milliliter, and non-adherence to HAART. After adjustment by logistic regression, non-adherence was the only statistically significant variable associated with virologic failure (odds ratio 0.38, 95% confidence interval 0.21 to 0.67). Unselected patients in whom protease inhibitor is started in a usual clinical setting achieve viral suppression less frequently than do patients in controlled clinical trials. Failure to adherence to HAART was the strongest predictor of virologic failure.

HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: A population‐based cohort study

HIV infection and antiretroviral therapies have detrimental effects on bone metabolism, but data on their impact on fracture risk are controversial. We conducted a population‐based cohort study to explore the association between clinical diagnosis of HIV infection and hip and major osteoporotic fracture risk. Data were obtained from the SIDIAPQ database, which contains clinical information for >2 million patients in Catalonia, Spain (30% of the population). We screened the database to identify participants with a clinical diagnosis of HIV infection, and ascertained incident hip and osteoporotic major fractures in the population aged 40 years or older in 2007 to 2009. In addition, data on incident fractures involving hospital admission were obtained from the Hospital Admissions database. Cox regression models were used to estimate hazard ratios (HRs) for the HIV‐infected versus uninfected participants. Models were adjusted for age, sex, body mass index, smoking status, alcohol drinking, oral glucocorticoid use, and comorbid conditions (Charlson index). Among 1,118,156 eligible participants, we identified 2489 (0.22%) subjects with a diagnosis of HIV/AIDS. Age‐ and sex‐adjusted HR for HIV/AIDS were 6.2 (95% confidence interval [CI] 3.5–10.9; p < 0.001) and 2.7 (2.01–3.5; p < 0.001) for hip and major fractures, respectively; this remained significant after adjustment for all mentioned potential confounders: HR 4.7 (2.4–9.5; p < 0.001) and 1.8 (1.2–2.5; p = 0.002). After stratifying by age, the association between HIV infection and major fractures was attenuated for those aged <59 years (adjusted HR 1.35 [0.88–2.07], p = 0.17) but appeared stronger in older patients (adjusted HR 2.11 [1.05–4.22], p = 0.035). We report a strong association between HIV infection and hip fracture incidence, with an almost fivefold increased risk in the HIV infected, independent of sex, age, smoking, alcohol drinking, and comorbidities. Similarly, we demonstrate a 75% higher risk of all clinical fractures and a 60% increase in risk of non‐hip clinical fractures among patients with a diagnosis of HIV infection.

Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study

BackgroundData regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels.MethodsA prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.ResultsOne hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT.ConclusionsWhen using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI.

Subclinical Carotid Atherosclerosis in HIV-Infected Patients Role of Combination Antiretroviral Therapy

Background and Purpose— Whether or not combination antiretroviral therapy (CART) alone directly contributes to accelerating atherosclerosis in HIV-infected patients has not been studied in depth. This study aimed to ascertain the relationship between this therapy and subclinical carotid atherosclerosis according to cardiovascular risk. Methods— Sixty-eight HIV-infected patients with ≤1 cardiovascular risk factors and 64 with ≥2 risk factors completed the study protocol consisting of clinical, laboratory, and vascular evaluation by carotid high-resolution B-mode ultrasonography. Univariate and multivariate logistic regression analyses were performed with the presence of subclinical carotid atherosclerosis, defined by carotid intima-media thickness >0.8 mm or the presence of plaque being the dependent variable. Results— Among the 132 enrolled patients, 93 (70.5%) were on CART and 39 (29.5%) had never been on antiretroviral therapy. In accordance with cardiovascular risk stratification, subclinical carotid atherosclerosis was found in 26.6% (17 of 64 patients) of the very low–risk group (10-year coronary risk <5%), 35.3% (12 of 34 patients) of the low-risk group (10-year coronary risk between 5% and 9%) and 76.5% (26 of 34 patients) of the moderate/high-risk group (10-year coronary risk ≥10%). Thus, 55 (41.7%) of the 132 HIV-infected patients had subclinical carotid atherosclerosis, and independent variables associated with carotid atherosclerosis (odds ratio; 95% CI) were: CART exposure (10.5; 2.8 to 39) and 10-year coronary risk ≥10% (4.2; 1.5 to 12). In very low coronary risk patients (<5%), age (per 10-year increment: 4.01; 1.12 to 14.38), systolic blood pressure (per unit mm Hg 1.07; 1.01 to 1.14), and CART exposure (8.65; 1.54 to 48.54) were independently associated with subclinical carotid atherosclerosis. Conclusions— CART should be considered a strong, independent predictor for the development of subclinical atherosclerosis in HIV-infected patients, regardless of known major cardiovascular risk factors and atherogenic metabolic abnormalities induced by this therapy.