Claudia Rodriguez

Update on primary HIV-1 resistance in Argentina: emergence of mutations conferring high-level resistance to nonnucleoside reverse transcriptase inhibitors in drug-naive patients.

Summary: Here we present a survey including 52 drug-naive recently HIV-1-infected subjects from Buenos Aires City and province (79%) and 3 other regions in Argentina (21%). Recent infections were established from previous negative serology (32/52), indeterminate Western blot (12/52), or acute retroviral syndrome after high-risk HIV exposure (8/52) within 9 months before genotyping (median time, 4.2 months). Genotyping was performed from plasma by sequencing both protease and reverse transcriptase. Phylogenetic analysis combined with bootscanning resulted in 21 subtype B sequences and 31 B/F recombinants (RecBF). On protease, minor resistance-related mutations were found in both subtype B and RecBF with low frequencies. The substitution L89M, recently suggested as a resistance-related mutation in some subtype F viruses, was observed in 1 RecBF. On reverse transcriptase, major resistance-related mutations were found in 4 of 52 (7.7%) patients from different health centers: M41L (subtype B) and K103N±P225H (1 RecBF and 2 subtype B). The greater than 5% resistance threshold found indicates a need for sentinel resistance surveillances calling for an update in the current resistance testing guidelines in Argentina.

Potential drug–drug interactions in HIV-perinatally infected adolescents on antiretroviral therapy in Buenos Aires, Argentina

An increasing number of treatment‐experienced perinatally HIV‐infected adolescents (PHA) are being transitioned from paediatric centres to adult HIV‐care [ 1 ]. Most of them had been heavily exposed to antiretroviral drugs (ARVs), harbour drug‐resistant viruses and require non‐antiretroviral medication due to comorbidities [ 2 ]. This may predispose for clinically significant drug–drug interactions (CSDDIs) [ 3 ]. There are no studies concerning CSDDIs in PHA. We aimed to evaluate the prevalence of concomitant medications and CSDDIs in PHA who were transitioned for adult HIV‐care to the Infectious Diseases Unit, Cosme Argerich Hospital, Buenos Aires City, Argentina.

Transmitted drug resistance in women with intrapartum HIV-1 diagnosis: a pilot epidemiological survey in Buenos Aires, Argentina

Surveillance of primary resistance to antiretroviral drugs is particularly important in pregnant population, in which infection by drug‐resistant HIV has not only implications for maternal treatment, but could also jeopardize the efficacy of neonatal prophylaxis. We aim to describe the prevalence of resistance associated mutations (RAMs) in pregnant women with intrapartum HIV diagnosis in a public hospital of Buenos Aires, Argentina.

Etravirine resistance mutations in HIV‐infected pregnant women

Etravirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) that provides an important treatment option for patients who have resistance to other NNRTIs [1]. Reproductive toxicology studies in animals found that etravirine did not affect fertility, early embryonic development or teratogenicity at exposures equivalent to those in humans at the recommended 200 mg twice-daily dose. The drug is classified as belonging to Pregnancy Category B (animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and wellcontrolled studies in pregnant women) [1,2]. Preliminary data showed that etravirine pharmacokinetic parameters in HIV-infected pregnant women (HPW) were comparable to those in nonpregnant adults, suggesting that no dose adjustment is needed during the third trimester [3]. In view of this favourable pharmacokinetic profile, etravirine may constitute a promising therapeutic option for those pregnant women with resistance to first-generation NNRTIs and other antiretroviral agents. In such patients, the benefits in preventing mother-to-child transmission outweigh potential risks, as clinical experience in human pregnancy with the drug is limited. However, the presence of etravirine resistance mutations (ERMs) may reduce its antiviral activity despite adequate concentrations being achieved during pregnancy. No data regarding the prevalence of such mutations in HPW have been published to date. The objective of the present study was to describe the prevalence of ERMs and the impact on the predicted susceptibility to this drug in a population of HPW receiving care at the Cosme Argerich Hospital, Buenos Aires, Argentina. During the period March 2008 to February 2011, baseline plasma samples from 78 HPW were analysed for viral load using the Versant HIV-1 RNA 3.0 Assay (Siemens Healthcare Diagnostics Inc., Tarrytown, NY, USA) and sequenced using the Trugene HIV-1 Genotyping Kit (Siemens Healthcare Diagnostics Inc.). ERMs were identified according to the Tibotec Weighted Genotype Score [4] and Monogram Enhanced Score [5] and analysed according to each weighted mutation score to predict susceptibility. HPW with a weighted score 2.5 for the Tibotec Weighted Genotype Score and 4 for the Monogram Enhanced Score were considered to have possible resistance or reduced susceptibility, respectively. Considering the Tibotec Weighted Genotype Score, patients were substratified as follows: 0–2, highest response; 2.5–3.5, intermediate response; 4, reduced response. The HIV-1 viral subtype was determined using REGA Subtyping Tool 2.0 (REGA Institute, Catholic University of Leuven, Leuven, Belgium). The predominant HIV-1 subtype was B/F, which was found in 70.5% of patients, followed by B/B (24.4%), F/F (2.6%), B/C (1.3%) and B/K (1.3%). Of 78 HPW, 39 (50%) were experienced in antiretroviral therapy: 27 (69%) had prior exposure to NNRTIs (57% to nevirapine, 31% to efavirenz and 12% to both). None of them had received etravirine in the past. At least one ERM was found in 13 of 78 HPW (17%) according to the Tibotec Weighted Genotype Score and in 15 of 78 HPW (19%) according to the Monogram Enhanced Score. Considering all patients with ERMs, the median (interquartile range) age, gestational age, viral load and CD4 T-cell count were 25 (19–34) years, 12 (7–24) weeks, 13851 (2549–50970) HIV-1 RNA copies/mL and 274 (85– 483) cells/mL, respectively. The HIV-1 subtype was B/F in 11 patients (73.3%) and B in four patients (26.7%). No association between the presence of ERMs and any specific HIV-1 subtype was found (data not shown). Eight of 15 patients harbouring ERMs were experienced in antiretroviral therapy, with a median (interquartile range) prior NNRTI exposure of 63 (6-119) months. The prevalence of ERMs in the experienced group was 15% (six of 39) according to the Tibotec Weighted Genotype Score and 20% (eight of 39) according to the Monogram Enhanced Score. All experienced patients harbouring ERMs had prior NNRTI exposure. The prevalence of ERMs in the naïve group was 18% (seven of 39) according to both scores. Correspondence: Diego Martin Cecchini, Infectious Diseases Unit, Hospital Cosme Argerich, Almirante Brown 240, Buenos Aires 1155ADP, Argentina. Tel: +54 11 4121-0828; fax: +54 11 4307-5952; e-mail: diegocec@gmail.com

Possible Drug–Herb Interaction between Herbal Supplement Containing Horsetail (Equisetum arvense) and Antiretroviral Drugs: Report of 2 Cases

The use of alternative medicines, including herbs, is common among HIV-positive patients, even in those on antiretroviral treatment. Equisetum arvense, known as “horsetail,” is mainly used for its diuretic properties. There are limited data about the pharmacological properties of this compound and the potential drug–herb interactions. The authors report 2 cases in which a possible drug–herb interaction may have led to virological breakthrough in patients who were maintained on the same regimen for many years, including lamivudine (3TC)/zidovudine (ZDV)/efavirenz (EFV) and emtricitabine (FTC)/tenofovir (TDF)/EFV, respectively. Therefore, a drug–herb interaction may be expected when these agents are taken concurrently. Until additional data are available, the authors advise clinicians to avoid this combination when possible.

Rilpivirine resistance associated mutations in HIV-1 infected pregnant women☆

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Severe hypokalemia due to a possible drug–drug interaction between vinblastine and antiretrovirals in a HIV-infected patient with Hodgkin’s lymphoma

A 60-year-old HIV-1 infected woman on antiretroviral therapy (emtricitabine/tenofovir, and ritonavir-boosted atazanavir) developed Hodgkin’s lymphoma. The patient initiated ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) chemotherapy and presented with neutropenia and severe hypokalemia. Hypokalemia was considered as part of a proximal tubular renal dysfunction, and other causes of hypokalemia were excluded. Due to suspicion of drug-–drug interactions between antiretrovirals and vinblastine, ritonavir-boosted atazanavir was switched to dolutegravir and the patient continued emtricitabine/tenofovir. In the subsequent ABVD cycles, no neutropenia or hypokalemia were observed. Vinblastine is metabolized by the hepatic P450 cytochrome isoenzyme CYP3A4, therefore, concomitant administration with protease inhibitors may increase plasma levels of vinblastine. Vinblastine is also a substrate and inhibitor of multidrug resistance-associated protein 2 (MRP2) transporter in the proximal renal tubule. Inhibition of this renal transporter could increase tenofovir renal toxicity. Our hypothesis is that the hypokalemia could be a result of a tenofovir-mediated tubular damage triggered by the increased vinblastine serum levels secondary to a CYP3A4 inhibition by ritonavir. To the best of our knowledge, this is the first report of severe hypokalemia and proximal tubular renal dysfunction as a result of a possible drug–drug interaction between vinblastine, tenofovir and ritonavir-boosted atazanavir.

Antiretroviral therapy containing raltegravir to prevent mother-to-child transmission of HIV in infected pregnant women

We conducted a retrospective study in a general hospital in Buenos Aires, Argentina (2009-2015) aimed at evaluating outcomes in HIV-infected pregnant women (HIPW), who were prescribed raltegravir (RAL)-containing antiretroviral therapy (ART). A total of 239 HIPW were enrolled in our study; among them 31 received RAL (12.9%) at different clinical stages: i) intensification (INS): addition of RAL to current ART because of detectable antepartum viral load, 13 (41.9%); ii) late presenter (LP): standard ART + RAL as fourth drug, 15 (48.4%); iii) treatment of resistant-HIV: 3 (9.7%). Median gestational age at RAL initiation was 34 weeks and median exposure was 30 days. In INS-group, median viral load (VL) decrease was 1.48 log10. In LP-group, median VL decline was 2.15 log10. No clinical adverse events or maternal intolerance attributable to RAL were observed. Elective cesarean section was done in 51.7%; mild elevation of transaminases was observed in 35% of neonates. No vertical transmission was documented.