Jelena Ivanovic

Transplacental Transfer of Antiretroviral Drugs and Newborn Birth Weight in HIV-Infected Pregnant Women

Although it is well known that antiretroviral drugs (ARVs) across the placenta in different extents, few data are available concerning the impact of the transplacental passage of ARVs on newborn outcome. The aim of this study is to evaluate the transplacental diffusion of ARVs and the clinical assessment of the newborn. Mother and cord lopinavir, nelfinavir, atazanavir and nevirapine plasma levels were determined by high-performance liquid chromatography. Newborn gestational age, weight, and Apgar score were recorded. Cord-to-mother ratio (C:M) was calculated to estimate the placental passage of ARVs. Preterm birth was defined as delivery at <37 weeks of gestation and low birth weight was defined as a birth weight of <2500g. Twenty-six HIV-infected pregnant women were enrolled. Nevirapine presented the highest C:M ratio (0.60 +/- 0.19), the C:M ratio of nelfinavir and atazanavir was 0.37 +/- 0.38 and 0.20 +/- 0.14, respectively. The lopinavir level in the cord was undetectable. The observed prevalence rate of neonatal low birth weight and preterm delivery was 19,2% (n = 5) and 15.4% (n = 4), respectively. A significant linear regression analysis was reported between the C:M ratio and newborn birth weight (p = 0.01). Although the role of highly active antiretroviral therapy (HAART) in preventing mother-to-child transmission is indisputable, these data indicate a pharmacological rationale to the association between birth weight and highly active antiretroviral therapy during pregnancy.

Marked increase in etravirine and saquinavir plasma concentrations during atovaquone/proguanil prophylaxis.

The case of a 32-year-old Caucasian female with multi-drug resistant HIV-1 subtype B infection treated with a salvage regimen including maraviroc, raltegravir, etravirine and unboosted saquinavir who started atovaquone/proguanil prophylaxis, is reported. The potential interactions between atovaquone/proguanil and these anti-retroviral drugs are investigated. Pharmacokinetic analyses documented a marked increase in etravirine and saquinavir plasma concentrations (+55% and +274%, respectively), but not in raltegravir and maraviroc plasma concentrations. The evidence that atovaquone/proguanil significantly interacts with etravirine and saquinavir, but not with raltegravir and maraviroc, suggests that the mechanism of interaction is related to cytochrome P450.

Immediate versus Delayed Surgical Intervention for Reconstructive Therapy of HIV-Associated Facial Lipoatrophy: A Randomized Open-Label Study

We assessed the safety and efficacy of reconstructive therapy with facial fillers for the treatment of HIV-associated facial lipoatrophy (FLA) through a randomized, controlled, open-label single-center study. A total of 134 HIV-infected patients with severe FLA were randomly assigned to receive immediate (67 patients) or delayed (67 patients) facial injections of poly-l-lactic acid (PLA) or polyacrylamide gel (PAIG). Outcome measures included changes in physician and patient FLA severity scale, adverse events, and changes in health-related quality of life (HRQoL) and anxiety using validated measures. The mean average study follow-up was 27 weeks for the immediate and 25 weeks for the delayed subjects. Adverse events were mild and resolved after a mean of 4 days. Compared to patients randomized to the delayed treatment group, patients assigned to the immediate treatment group had significantly lower physician-rated (0.0 versus -3.0; p < 0.0001) and patient-rated (0.1 versus -1.8; p < 0.0001) FLA severity scores. By contrast, measures exploring HRQoL and anxiety did not show any significant difference between patients randomized to the immediate and deferred groups. Reconstructive therapy with facial fillers was effective and safe and led to significant improvements in FLA severity. However, no significant gains in HRQoL, relational and psychological consequences of body changes, and anxiety-related concerns were observed. Studies should be performed to identify patients who could maximally benefit from filling interventions for FLA.

Simultaneous determination of lamivudine, lopinavir, ritonavir, and zidovudine concentration in plasma of HIV‐infected patients by HPLC‐MS/MS

The nucleoside reverse transcriptase inhibitors lamivudine and zidovudine and the protease inhibitors lopinavir and ritonavir are currently used in anti‐human immunodeficiency virus (HIV) therapy. Here, a high‐performance liquid chromatography‐mass spectrometry (HPLC‐MS/MS) method, using a hybrid quadrupole time‐of‐flight mass analyzer, is reported for the simultaneous quantification of lamivudine, lopinavir, ritonavir, and zidovudine in plasma of HIV‐infected patients. The volume of plasma sample was 600 μL. Plasma samples were extracted by solid‐phase using 1 cc Oasis HLB Cartridge (divinylbenzene and N‐vinylpyrrolidone) and evaporated in a water bath under nitrogen stream. The extracted samples were reconstituted with 100‐μL methanol. Five microliters of the reconstituted samples were injected into a HPLC‐MS/MS apparatus, and the analytes were eluted on a Vydac column (250 × 1.0 mm i.d.) filled with 3‐μm C18 particles. The mobile phase was delivered at 70 μL/min with a linear gradient elution, both acetonitrile and ultrapure water solvents contained 0.2% formic acid. The calibration curves were linear from 0.47 to 20 ng/mL. The absolute recovery ranged between 91 and 107%. The minimal concentration of lamivudine, lopinavir, ritonavir, and zidovudine detectable by HPLC‐MS/MS is 0.47, 0.28, 0.30, and 0.66 ng/mL, respectively. The great advantage of the new HPLC‐MS/MS method here reported is the possibility to achieve a very high specificity toward the selected anti‐HIV drugs, despite the simple and rapid sample preparation. Moreover, this method is easily extendible to the analysis of co‐administrated drugs.

Plasma HIV RNA decline and emergence of drug resistance mutations among patients with multiple virologic failures receiving resistance testing-guided HAART.

Early recognition of virologic failure in patients with extensive drug resistance receiving salvage-HAART is essential to avoid exposure to subinhibitory regimens. We studied plasma viral load (PVL) decline and rates of drug-resistance mutation (DRM) accumulation in such patients. A prospective, 48 week study of 38 heavily pretreated patients receiving genotypic resistance testing (GRT)-guided HAART was conducted. The rate of PVL decline was studied by weekly PVL determinations. To assess DRM accumulation, serial GRTs were performed in all nonresponders (never reaching PVL <50 or two PVLs >50 copies/ml after suppression). Over 48 weeks, 10 patients (26%) were nonresponders. Receiving less then two fully active drugs and having an elevated number of PI and NRTI mutations at baseline were strongly associated with virologic failure. There was no evidence of a difference in the change from baseline PVL to week 1 and 2 between responders and nonresponders. By contrast, PVL reductions from week 2 to week 3 and thereafter were significantly greater for responders (p < 0.01). Among nonresponders, the incidence rates per patient-month (95% CI) of emergent DRM were 0.67 (0.13-1.20), 0.40 (0.00-0.74), and 0.37 (0.00-0.75) at weeks 4, 8, and 24, respectively. Having limited baseline resistance, receiving at least two fully active drugs, and showing constant PVL reductions from week 2 to week 3 and thereafter were predictive of virologic response. In contrast, early changes in PVL levels were not. Virologic failure was associated with detection of emergent DRMs. Virologic rebound in patients on salvage-HAART should be addressed aggressively.

Sonographic Assessment of Facial HIV-Related Lypoatrophy

OBJECTIVE To investigate the utility of ultrasonography (US) for assessing and grading facial lypoatrophy (FLA) in patients with HIV. DESIGN The social effect of FLA is huge and may reduce antiretroviral therapy adherence. Strategies for the early detection of FLA are crucial, because complete correction of FLA in late stages is unlikely. METHODS Fifty‐two HIV‐positive patients undergoing highly active antiretroviral therapy underwent US with nasogenian transversal scan using a high‐frequency broadband transducer (5–17 MHz) to detect FLA. Intra‐ and interobserver variability were calculated to assess US reproducibility. Concerning FLA grading, patients were categorized in five clinical classes and four US classes. RESULTS Our results regarding inter‐ and intraobserver coefficients of variation permit the validation of US as a reproducible technique (p<.001), and a high correlation between US and clinical classification was obtained, with complete concordance for more advanced FLA classes. CONCLUSIONS The lack of a reference objective method to quantify subcutaneous fat is a major difficulty in measuring HIV‐related FLA. Our results, in accordance with data from the literature, suggest that US is an ideal tool for assessing and grading FLA. Furthermore, US may be suitable for routine evaluation in HIV‐infected patients for early detection of FLA and to select its optimal management. The authors have indicated no significant interest with commercial supporters.

Cost of surgical intervention for reconstructive therapy of HIV-associated facial lipoatrophy

This study aims to assess direct cost of reconstructive interventions with facial fillers for treatment of HIV (human immunodeficiency virus)-associated facial lipoatrophy (FLA). Evaluation was performed on data from patients enrolled in one arm of a comparative study of immediate versus delayed reconstructive treatment of facial lipoatrophy. Median costs were standardized for efficacy, estimated using data reported by physicians and patient reported outcomes. The variations of the results were evaluated with a sensitivity analysis. Evaluation was performed on 66 patients characterized by significant differences in terms of severity of FLA. Total cost resulted of €140,416.15, with a median cost per patient of €2126.04 (interquartile range [IQR]: 1599–2822). Taking into consideration severity of disease, median costs were €1641.67 (IQR: 1326.67–2126.04) and 2557.12 (IQR: 1939.34–2872.04) (P = 0.0) respectively for patients with low and high severity scores at baseline. Significant differences in term of cost-effectiveness ratios were also found between patients with different severity of FLA, and sensitivity analysis showed that these ratios increase with higher severity scores at baseline and vary widely depending on the costs of filler. Although these results cannot be considered representative because of important limitations, the present study suggests the severity of disease as an important determinant of costs.