C. Alcantarini

Clinical pharmacology of tenofovir clearance: a pharmacokinetic/pharmacogenetic study on plasma and urines

The HIV virus and hepatitis B virus nucleotide reverse transcriptase inhibitor tenofovir has been associated with proximal tubular toxicity; the latter was found to be predicted by plasma concentrations and with single-nucleotide polymorphisms in transporters-encoding genes. A cross-sectional analysis in adult HIV-positive patients with estimated creatinine clearance >60 ml min−1 was performed. Twelve-hour plasma and urinary tenofovir concentrations and single-nucleotide polymorphisms in several transporter-encoding genes were analysed. In 289 patients 12-h tenofovir plasma, urinary and urinary to plasma ratios were 69 ng ml−1 (interquartile range 51.5–95), 24.3 mg ml−1 (14.3–37.7) and 384 (209–560). At multivariate analysis estimated creatinine clearance, protease inhibitors co-administration and SLC28A2 CT/TT genotypes were independently associated with plasma tenofovir exposure; ABCC10 GA/AA genotypes and protease inhibitor co-administration were independently associated with the urinary to plasma tenofovir ratio. Tenofovir clearance was associated with genetic polymorphisms in host genes and with co-administered drugs: if confirmed by ongoing studies these data may inform treatment tailoring and/or dose reductions.

Tenofovir clearance is reduced in HIV-positive patients with subclinical tubular impairment.

Objective:To assess if tenofovir (TFV) clearance is associated with urinary retinal-binding protein (RBP) in HIV-positive patients with normal estimated filtration rate. Design:A cross-sectional diagnostic study. Methods:HIV-positive patients with estimated creatinine clearance above 60 ml/min, on tenofovir disoproxil fumarate (TDF)-containing combination since at least 6 months, taking TDF at night, and without significant comorbidities (diabetes, untreated hypertension, known renal malformations, recurrent nephrolithiasis) and nephrotoxic drugs were included. TFV plasma and urinary concentrations were measured 12 h after drug intake (C12). RBP was measured through enzyme immunoassay kit on spot urines and corrected per urinary creatinine (uRBP/uCr); normality ranges were below 130 &mgr;g/g (in patients aged <50 years) and below 172 &mgr;g/g (in patients aged ≥50 years). Results:Two hundred and eighty-nine patients were included (median age of 45.8 years, 71.6% male and 85.4% whites); patients were concomitantly treated with nonnucleoside reverse transcriptase inhibitors (155, 53.6%), protease inhibitors (118, 40.8%), or integrase inhibitors (16, 5.5%)-containing regimens. Estimated creatinine clearance was 89.4 ml/min (78.6–105.9). Urinary RBP (uRBP) and uRBP/uCr were 204.6 ng/ml (92–380) and 169.7 &mgr;g/g (85.8–318.3), respectively; abnormally high uRBP/uCr was observed in 157 patients (54.3%). A multivariate binary logistic regression confirmed that both ethnicity (P = 0.004, &bgr; 2.93, 95% confidence interval 1.41–6.10) and TFV urinary C12 less than 21 mg/ml (P = 0.006, &bgr; 2.04, 95% confidence interval 1.12–3.41) were significantly associated with abnormal uRBP/uCr. Conclusion:HIV-positive TDF-treated patients showed a high prevalence of proximal tubular impairment: ethnicity (whites) and low urinary TFV concentrations were significantly associated with elevated uRBP. SDC video:http://links.lww.com/QAD/A852.

Diagnostic accuracy of new and old cognitive screening tools for HIV-associated neurocognitive disorders

Considering the similarities between HIV‐associated neurocognitive disorders (HAND) and neurodegenerative dementias and the frequency of executive dysfunctions among HIV‐positive patients, we evaluated the accuracy of the Frontal Assessment Battery and Clock‐Drawing Test together with the Three Questions Test and International HIV Dementia Scale to screen for HAND.

Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid

Sir, Among the large spectrum of neurological disorders that can affect people living with HIV, seizures have been commonly reported. Before introducing new anticonvulsants, possible drug– drug interactions (DDIs) with antiretrovirals (ARVs) should be ruled out. DDIs may result in altered concentrations of both classes of drugs, leading to uncontrolled epilepsy, toxicity or emergence of drug-associated resistance mutations and ART failure. In HIV-positive patients, valproic acid is often used due to its mood-modulating properties and its favourable pharmacokinetic profile. Although concurrent use of valproic acid with older ARVs has been described, to date, no study has ruled out potential DDIs between valproic acid and the newest integrase inhibitor, dolutegravir. Both drugs are highly protein-bound and share secondary metabolizing pathways. Valproic acid is metabolized through glucuronidation by several uridine 50-diphospho-glucuronosyltransferase (UGT) enzymes, through b-oxidation in mitochondria and, to a lesser extent, through cytochrome P450. Dolutegravir is mainly metabolized by UGT1A1, but it is also a substrate of UGT1A3, UGT1A9 and CYP3A4. To better understand the determinants of dolutegravir plasma concentration in the clinical setting, we performed a registry analysis on data collected from Torino Therapeutic Drug Monitoring (TDM) laboratory. Plasma concentrations were measured at steady-state through a validated UPLC-MS/MS method with a limit of detection of 0.0117 lg/mL. Three hundred and sixty-three trough samples were withdrawn 21–27 h after drug intake in 149 patients. In seven patients on valproic acid (11 samples) lower dolutegravir trough concentrations were observed (median 0.068 lg/mL, IQR 0.037–0.148 lg/mL, minimum–maximum non-detectable–0.829 lg/mL) versus those not on valproic acid (median 0.557 lg/mL, IQR 0.290–1.135 lg/mL, minimum–maximum non-detectable–6.726 lg/mL). The highest dolutegravir concentration with valproic acid (0.829 lg/mL) was observed in a patient concomitantly receiving atazanavir, which is known to decrease dolutegravir metabolism through UGT1A1 inhibition. One patient had several trough levels measured and, despite other concomitant detectable ARVs, dolutegravir plasma concentrations were persistently low (Figure S1, available as Supplementary data at JAC Online). Following this preliminary observation, we performed detailed pharmacokinetic evaluations in two hospitalized patients requiring valproic acid while on dolutegravir-based regimens. Both signed written informed consent for sample withdrawal and data publication. The first patient was a woman admitted with progressive multifocal leucoencephalopathy and seizures. While on dolutegravir twice daily, she started valproic acid and lacosamide. Valproic acid was first administered intravenously (500 mg q8h) and then as oral modified-release tablets (500 mg q8h); 3 months later the oral dose was reduced to 250 mg q8h. Dolutegravir and valproic acid were measured at steady-state at five timepoints (pre-dose and 1, 3, 5 and 12 h after dose). Dolutegravir AUC, Cmin and Cmax showed variable profiles (Figure 1), while valproic acid concentrations were in the therapeutic range, between 50 and 100 lg/mL. With intravenous valproic acid, dolutegravir AUC was 82% lower than the mean reference AUC value for dolutegravir q12h (75.1 lg h/mL), with oral valproic acid 500 mg q8h it was 87% lower and with oral valproic acid 250 mg q8h it was 90.5% lower. The second instance was a female patient with bipolar disorder taking oral valproic acid 500 mg q8h, admitted with primary HIV infection. Intensified ART was started on admission with darunavir/ritonavir 600/100 mg q12h, dolutegravir 50 mg q24h and emtricitabine/tenofovir 200/245 mg q24h. Dolutegravir and valproic acid were measured 10 days after treatment initiation at six timepoints (pre-dose and 1, 3, 5, 12 and 24 h after dose). AUC was 80% lower than the mean reference value for dolutegravir q24h (53.6 lg h/mL), whereas Cmin was reduced by 87% (mean reference value 1.11 lg/mL). Although this result could partially be explained by the known interaction between dolutegravir and darunavir, the reduction in dolutegravir plasma concentrations was so high that other mechanisms need to be considered. Despite the small number of cases, these data may suggest a possible interaction between valproic acid and dolutegravir; the size of this potential DDI was relevant although both patients had dolutegravir plasma concentrations above the protein-adjusted 90% inhibitory quotient (0.064 lg/mL). Nevertheless this may be important for integrase inhibitor-exposed patients with HIV carrying resistance-associated mutations; the virological outcome of the two patients is unfortunately unavailable (one died and the other one was lost to follow-up). The mechanisms leading to this possible DDI are unknown. Dolutegravir absorption may be limited from excipients contained in some valproic acid gastro-resistant oral formulations, such as magnesium stearate. Magnesium, being a divalent ion, can chelate dolutegravir, reducing its absorption. Dolutegravir plasma concentrations were lower with reduced valproic acid doses at

The outcome of HIV-positive late presenters according to detectable CMV DNA and anti-CMV treatment

BACKGROUND HIV late presenters are at high risk of cytomegalovirus (CMV) reactivation and end-organ disease. CMV viraemia has been associated with poor survival but the effect of anti-CMV treatment has not been studied in this setting. METHODS HIV-positive patients were included in a retrospective study if presenting with <350 CD4+ T-cells/μl and starting an antiretroviral treatment within 3 months of the diagnosis. Primary end point was 5-year survival according to the presence of CMV viraemia, CMV end-organ disease and anti-CMV treatment. RESULTS 302 patients were included. 157 patients (52%) presented CMV viraemia (CMV-V) and 44 (14.6%) CMV end-organ disease (CMV-EOD). 5-year mortality was higher in CMV-EOD and CMV-V patients than in CMV-negative patients (11.4 versus 9.6 versus 0%; P=0.002). In patients with CMV-V, 5-year mortality was numerically higher in untreated patients (12.9% versus 6.9%; P=0.257) without reaching statistical significance. At univariate analysis the diagnosis of serious opportunistic infections (cryptococcosis, progressive multifocal leukoencephalopathy, lymphoma; P=0.001) and the absence of a negative CMV DNA in the follow-up (P<0.001) were associated with poor outcome. At multivariate analysis HCV coinfection (P=0.016; aOR 6.98, 95% CI 1.50, 32.59), the absence of a negative CMV DNA in the follow-up (P<0.001; aOR 19.40, 95% CI 3.70, 101.64) and marginally the absence of anti-CMV treatment (P=0.052; aOR 4.944, 95% CI 0.99, 24.73) were independent predictors of poor outcome. CONCLUSIONS CMV reactivation in HIV-positive patients with poor immunity is associated with worse prognosis: the pre-emptive use of anti-CMV therapy was associated with a better outcome in patients with CMV-V.