Mitochondrial Toxicogenomics for Antiretroviral Management: HIV Post-exposure Prophylaxis in Uninfected Patients.

Background: Mitochondrial genome has been used across multiple fields in research, diagnosis, and toxicogenomics. Several compounds damage mitochondrial DNA (mtDNA), including biological and therapeutic agents like the human immunodeficiency virus (HIV) but also its antiretroviral treatment, leading to adverse clinical manifestations. HIV-infected and treated patients may show impaired mitochondrial and metabolic profile, but specific contribution of viral or treatment toxicity remains elusive. The evaluation of HIV consequences without treatment interference has been performed in naïve (non-treated) patients, but assessment of treatment toxicity without viral interference is usually restricted to in vitro assays. Objective: The objective of the present study is to determine whether antiretroviral treatment without HIV interference can lead to mtDNA disturbances. We studied clinical, mitochondrial, and metabolic toxicity in non-infected healthy patients who received HIV post-exposure prophylaxis (PEP) to prevent further infection. We assessed two different PEP regimens according to their composition to ascertain if they were the cause of tolerability issues and derived toxicity. Methods: We analyzed reasons for PEP discontinuation and main secondary effects of treatment withdrawal, mtDNA content from peripheral blood mononuclear cells and metabolic profile, before and after 28 days of PEP, in 23 patients classified depending on PEP composition: one protease inhibitor (PI) plus Zidovudine/Lamivudine (PI plus AZT + 3TC; n = 9) or PI plus Tenofovir/Emtricitabine (PI plus TDF + FTC; n = 14). Results: Zidovudine-containing-regimens showed an increased risk for drug discontinuation (RR = 9.33; 95% CI = 1.34-65.23) due to adverse effects of medication related to gastrointestinal complications. In the absence of metabolic disturbances, 4-week PEP containing PI plus AZT + 3TC led to higher mitochondrial toxicity (-17.9 ± 25.8 decrease in mtDNA/nDNA levels) than PI plus TDF + FTC (which increased by 43.2 ± 24.3 units mtDNA/nDNA; p < 0.05 between groups). MtDNA changes showed a significant and negative correlation with baseline alanine transaminase levels (p < 0.05), suggesting that a proper hepatic function may protect from antiretroviral toxicity. Conclusions: In absence of HIV infection, preventive short antiretroviral treatment can cause secondary effects responsible for treatment discontinuation and subclinical mitochondrial damage, especially pyrimidine analogs such as AZT, which still rank as the alternative option and first choice in certain cohorts for PEP. Forthcoming efforts should be focused on launching new strategies with safer clinical and mitotoxic profile.

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.

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

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 (C(min)) and to determine factors associated with a C(min) < 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with a C(min) 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 C(min). A total of 29.5% of patients had a C(min) < 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 C(min) < 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 C(min) 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.