Jhon Rojas

Risk factors for a low linezolid trough plasma concentration in acute infections.

ABSTRACT Linezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC24/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (Cmin) and to determine factors associated with a Cmin < 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a Cmin determination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of low Cmin. A total of 29.5% of patients had a Cmin < 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due to Staphylococcus aureus. The independent predictors of Cmin < 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037; P = 0.001) and infection due to S. aureus (OR, 5.906; 95% CI, 1.651 to 21.126; P = 0.006). A linezolid Cmin of <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due to S. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.

Dolutegravir monotherapy in HIV-infected patients with sustained viral suppression

OBJECTIVES We reviewed the 24 week outcomes of HIV-infected patients from our hospital who had their ART switched to dolutegravir monotherapy on an individual clinical basis. METHODS Retrospective hospital database assessment of virally suppressed patients in whom the treating physician had switched to 50 mg of dolutegravir once daily due to one or more of the following reasons: antiretroviral-related adverse effects; comorbidities; risk of interactions; or archived resistance. Patients had ≥24 weeks of follow-up. Population, virological and immunological responses and safety and tolerability are described. RESULTS Thirty-three (22 on PIs, of whom 18 had ritonavir-boosted PI monotherapy) patients were identified: median (IQR) age of 56 (50-62) years, 55% women, median (IQR) of 19 (17-23) years of known HIV infection, 39% prior AIDS events, median (IQR) of 8 (4-13) years with undetectable plasma HIV-1 RNA and median (IQR) CD4 cell count of 596 (420-843) cells/mm(3). Twenty-five (76%) patients had antiretroviral-related adverse effects, 32 (97%) patients had comorbidities, 28 (85%) patients had risk of interactions and 16 (48%) patients had archived resistance. One patient with suboptimal adherence had low-level virological failure through weeks 4-24. HIV RNA genotypic resistance tests detected no integrase mutations at weeks 4 and 24, but 118R was detected in 7% of the integrated HIV DNA at 24 weeks. Patients had significant median decreases in triglycerides (-117 mg/dL), total cholesterol (-36 mg/dL), the total cholesterol/HDL cholesterol ratio (-0.7) and high-sensitivity C-reactive protein (-0.05 mg/dL) (P ≤ 0.007), although the Chronic Kidney Disease Epidemiology Collaboration equation also decreased (-7.1 mL/min) (P < 0.0001). CONCLUSIONS These data suggest the efficacy of dolutegravir monotherapy as a maintenance strategy to be further confirmed in randomized clinical trials.

Tolerability of integrase inhibitors in a real-life setting

Background Integrase inhibitors have shown better tolerability than other drugs in clinical trials, but some post-marketing data have suggested potential differences among them. Aims We compared rates and reasons for discontinuation of raltegravir-, elvitegravir- and dolutegravir-based regimens in a large cohort of HIV-infected patients. Methods Retrospective analysis of a prospectively followed cohort including all antiretroviral-naive and all virologically suppressed antiretroviral-experienced patients prescribed a first regimen containing raltegravir, elvitegravir or dolutegravir with at least one follow-up visit. Major outcomes were early discontinuation (≤1 year) due to any reason and more specifically due to toxicity. Incidence was calculated as number of episodes per 1000 person-years. Risk factors for discontinuation were assessed by multivariate Cox models. Results Early discontinuations due to any reason were 271 (raltegravir), 168 (elvitegravir) and 264 (dolutegravir) per 1000 patient-years ( P  =   0.0821). Early discontinuations due to toxicity were 76 (raltegravir), 103 (elvitegravir) and 81 (dolutegravir) per 1000 patient-years ( P  =   0.6792). Overall, the most common toxicities leading to discontinuation were neuropsychiatric, osteomuscular or digestive. Most frequent neuropsychiatric manifestations reported at discontinuation were insomnia, dizziness, headache and anxiety irrespective of the integrase inhibitor. Among discontinuations due to toxicity, neuropsychiatric effects were more common with dolutegravir than with raltegravir or elvitegravir ( P  =   0.0046). Age (HR 1.04, 95% CI 1.02-1.07, P  =   0.0007) was the only independent risk factor for early discontinuation due to toxicity. Conclusions Discontinuations due to any reason tended to be less common with elvitegravir, but discontinuations due to toxicity did not differ among integrase inhibitors. Neuropsychiatric toxicity leading to drug discontinuation was more frequent with dolutegravir.

Safety, efficacy and indications of prescription of maraviroc in clinical practice: Factors associated with clinical outcomes

Maraviroc is approved for treatment-experienced HIV+ adults in twice-daily administration. Limited data are available on safety, efficacy and use in routine clinical practice, outside of restrictive clinical trials. This retrospective multicenter (27 centers) study included 667 subjects starting a regimen with maraviroc. The primary endpoint was plasma HIV-RNA <50copies/mL and CD4(+) cell count change at 48 and 96weeks (FDA snapshot analysis). 94.4% had CCR5 tropism (58.3% Trofile™, 29.2% population genotype, and 12% genotyping proviral DNA). Half of the subjects received the drug in scenarios or dosages outside the initial approval. Maraviroc was prescribed for salvage in 346 (51.9%) individuals, as a switch strategy due to toxicity in 135 (38.7%), for immune discordance in 75 (11.2%), and for simplification in 48 (7.2%). After salvage therapy, 223 (64.5%) subjects had HIV-RNA <50copies/mL at 48weeks, and 178 (51.4%) at 96weeks. Darunavir/r was included in 224 (64.7%) subjects and associated with higher rates of virological and immunologic efficacy (p<0.001). In multivariate analysis MSM (OR 2.25; 95%CI 1.29-3.94) and baseline HIV-RNA <100,000copies/mL (OR 1.96; 1.06-3.70) were associated with virological suppression. An increase in CD4(+) counts was seen at 48 and 96weeks in subjects with immune discordance (p<0.001). Maraviroc was used once-daily in 142 (21.3%) subjects overall, and 68 (57.4%) in switch/simplification. No new safety signals were identified. Besides in salvage regimens, maraviroc was frequently used in switch due to toxicity, simplification, and immune discordance. The efficacy in salvage in clinical practice was higher than in phase III clinical trials, likely due to availability of new active drugs in the regimen. These results increase our understanding of the efficacy, safety, and conditions of prescription of maraviroc beyond the initial registrational trials and the early manufacturer pharmacovigilance programs.

A randomized clinical trial comparing ritonavir-boosted lopinavir versus maraviroc each with tenofovir plus emtricitabine for post-exposure prophylaxis for HIV infection

OBJECTIVES The objective of this study was to assess post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus maraviroc, both with tenofovir disoproxil/emtricitabine as the backbone. METHODS We conducted a prospective, open, randomized clinical trial. Individuals attending the emergency room because of potential sexual exposure to HIV and who met criteria for receiving PEP were randomized to one of two groups: tenofovir disoproxil/emtricitabine (245/200 mg) once daily plus either ritonavir-boosted lopinavir (400/100 mg) or maraviroc (300 mg) twice daily. Five follow-up visits were scheduled for days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse events and rate of seroconversions. This study was registered in ClinicalTrials.gov: NCT01533272. RESULTS One-hundred-and-seventeen individuals were randomized to receive ritonavir-boosted lopinavir and 120 to maraviroc (n = 237). PEP non-completion at day 28 was 38% (n = 89), with significant differences between arms [ritonavir-boosted lopinavir 44% (n = 51) versus maraviroc 32% (n = 38), P = 0.05]. We performed a modified ITT analysis including only those patients who attended on day 1 (n = 182). PEP non-completion in this subgroup was also significantly higher in the ritonavir-boosted lopinavir arm (27% versus 13%, P = 0.004). The proportion of patients with low adherence was similar between arms (52% versus 47%, P = 0.56). Adverse events were reported by 111 patients and were significantly more common in the ritonavir-boosted lopinavir arm (72% versus 51%, P = 0.003). No seroconversions were observed during the study. CONCLUSIONS PEP non-completion and adverse events were both significantly higher in patients allocated to ritonavir-boosted lopinavir. These data suggest that maraviroc is a well-tolerated antiretroviral that can be used in this setting.

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.

Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial

Background No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART. Methods We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (≥5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for ≥12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patients wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435. Results Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm. Conclusions In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.

Effectiveness and tolerability of abacavir-lamivudine-nevirapine (ABC/3TC/NVP) in a multicentre cohort of HIV-infected, ARV-naive patients.

Very scarce information has been published to date with the combination of ABC/3TC/NVP but it is currently being used in clinical practice in Spain and Portugal. Our aim was to present the clinical experience with this regimen in a cohort of adult HIV‐infected antiretroviral (ARV)‐naïve patients.

Subclinical cardiovascular disease in patients starting contemporary protease inhibitors

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.

Tenofovir disoproxil fumarate/emtricitabine plus ritonavir-boosted lopinavir or cobicistat-boosted elvitegravir as a single-tablet regimen for HIV post-exposure prophylaxis

Objectives To assess HIV-1 post-exposure prophylaxis (PEP) non-completion at day 28, comparing ritonavir-boosted lopinavir versus cobicistat-boosted elvitegravir as a single-tablet regimen (STR), using tenofovir disoproxil fumarate/emtricitabine with both of these therapies. Methods A prospective, open, randomized clinical trial was performed. Individuals attending the emergency room due to potential sexual exposure to HIV and who met criteria for PEP were randomized 1:3 into two groups receiving either 400/100 mg of lopinavir/ritonavir (n = 38) or 150/150 mg of elvitegravir/cobicistat (n = 119), with both groups also receiving 245/200 mg of tenofovir disoproxil fumarate/emtricitabine. Five follow-up visits were scheduled at days 1, 10, 28, 90 and 180. The primary endpoint was PEP non-completion at day 28. Secondary endpoints were adherence, adverse effects and rate of seroconversions. Clinical trials.gov number: NCT08431173. Results Median age was 32 years and 95% were males. PEP non-completion at day 28 was 36% (n = 57), with a trend to be higher in the lopinavir/ritonavir arm [lopinavir/ritonavir 47% (n = 18) versus elvitegravir/cobicistat 33% (n = 39), P = 0.10]. We performed a modified ITT analysis including only those patients who attended on day 1. PEP non-completion in this subgroup was higher in the lopinavir/ritonavir arm than in the elvitegravir/cobicistat arm (33% versus 15%, respectively, P = 0.04). Poor adherence was significantly higher in the lopinavir/ritonavir arm versus the elvitegravir/cobicistat arm (47% versus 9%, respectively, P < 0.0001). Adverse events were reported by 73 patients (59%), and were significantly more common in the lopinavir/ritonavir arm (90% versus 49%, P = 0.0001). A seroconversion was observed in the elvitegravir/cobicistat arm in a patient with multiple exposures before and after PEP. Conclusions A higher PEP non-completion, poor adherence and adverse events were observed in patients allocated to the lopinavir/ritonavir arm, suggesting that STR elvitegravir/cobicistat is a well-tolerated antiretroviral for PEP.