HIV-related immune activation attenuates polyfunctional IgG and memory B-cell responses to Tdap immunization during pregnancy.

BACKGROUND: Maternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown. METHODS: In this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline. FINDINGS: One month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH. INTERPRETATION: Maternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants. FUNDING: This work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIHNIAID1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.

Failure of artemether-lumefantrine therapy in travellers returning to Belgium with Plasmodium falciparum malaria: an observational case series with genomic analysis.

BACKGROUND: Failure of artemisinin-based combination therapy is increasingly reported in patients with Plasmodium falciparum malaria in sub-Saharan Africa. We aimed to describe the clinical and genomic characteristics of recent cases of P. falciparum malaria failing artemether-lumefantrine in Belgium. METHODS: Travel-related cases of malaria confirmed at the national reference laboratory of the Institute of Tropical Medicine, Antwerp, Belgium, were reviewed. All cases for which attending clinicians reported persistence (beyond Day 3 post-treatment initiation, i.e. early failure) or recrudescence (from Day 7 to 42, i.e. late failure) of P. falciparum parasites despite adequate drug intake were analysed. Both initial and persistent/recurrent samples were submitted to next generation sequencing to investigate resistance-conferring mutations. RESULTS: From July 2022 to June 2023, eight P. falciparum cases of failure with artemether-lumefantrine therapy were reported (early failure = 1; late failure = 7). All travellers were returning from sub-Saharan Africa, most (6/8) after a trip to visit friends and relatives. PfKelch13 (PF3D7_1343700) mutations associated with resistance to artemisinin were found in two travellers returning from East Africa, including the validated marker R561H in the patient with early failure and the candidate marker A675V in a patient with late failure. Additional mutations were detected that could contribute to decreased susceptibility to artemisinin in another three cases, lumefantrine in six cases and proguanil in all eight participants. Various regimens were used to treat the persistent/recrudescent cases, with favourable outcome. CONCLUSION: Within a 12-month period, we investigated eight travellers returning from sub-Saharan Africa with P. falciparum malaria and in whom artemether-lumefantrine failure was documented. Mutations conferring resistance to antimalarials were found in all analysed blood samples, especially against lumefantrine and proguanil, but also artemisinin. There is a pressing need for systematic genomic surveillance of resistance to antimalarials in international travellers with P. falciparum malaria, especially those experiencing treatment failure.

Antibiotic Use in Patients Undergoing Complex Clean-Contaminated Head and Neck Surgery: A Prospective Study.

Aims and Objectives: Oncological surgery of the upper aerodigestive tract is a complex procedure and often includes neck dissection and flap reconstruction. It can be complicated by severe surgical site infection (SSI) leading to flap necrosis, delayed wound healing, and increasing mortality and morbidity. The purpose of this study is to perform a systematic descriptive analysis and to evaluate the effect of our adapted antibiotic regimen strategy on postoperative outcomes. Materials and Methods: A prospective cohort analysis of 47 patients undergoing major clean-contaminated head and neck surgery was conducted at the Cervicomaxillofacial Surgery Department (Saint-Pierre Hospital), between 2019 and 2022. The patients were divided into two groups: group I, which received a short-term postoperative antibiotic regimen for 24 h, and group II, which received a more extended postoperative antibiotic course for more than 24 h. Antibioprophylaxy amoxicillin and clavulanate were administered intravenously 30-60 min before making the incision. The antibiotic regimen was continued after surgery. The prognostic significance of the antibiotic regimen on postoperative outcomes, including clinical signs of infection and biological markers such as white blood cells count, and C-reactive protein levels was evaluated using univariate analysis. Results: Eighteen patients developed SSIs. All of these infections were grade 2 and were treated with antibiotics. After univariate analysis, only a history of hypothyroidism seems to be a predictor of SSI (P = 0.038). No significant difference was found in terms of onset and hospital stay when we compared the patients who received antibiotics for 24 h or more. Moreover, the rate of multidrug-resistant bacteria was not different in both groups. Conclusions: Our results suggest that postoperative antibiotics for more than 24 h do not confer benefit in terms of SSI. Oncological patients undergoing complex clean-contaminated head and neck surgery are often suffering from infectious complications and, despite the absence of guidelines, practicians should consider these findings in their decision-making.

The recent natural history of human papillomavirus cervical infection in women living with HIV: A scoping review of meta-analyses and systematic reviews and the construction of a hypothetical model.

BACKGROUND: Women with HIV are more often infected with human papillomavirus (HPV) and are more prone to develop precancerous cervical lesions (squamous intraepithelial lesions, SIL) and invasive cervical cancer (ICC) than HIV-negative women. OBJECTIVE: This scoping-review analyses the impact of HIV on HPV prevalence, incidence and evolution to SIL and ICC. METHODS: We selected all PubMed systematic reviews and meta-analyses published between January 2000 and July 2021 reporting data about HPV, cervical intraepithelial neoplasia (CIN), SIL and ICC prevalence, incidence and evolution in women with HIV. A hypothetical model comparing the history of HPV infection in HIV-negative, combined antiretroviral therapy (cART)-treated and -untreated women with HIV was built. RESULTS: Data from 11 meta-analyses and 10 systematic reviews were selected, which included between 770 and 236 127 women with HIV. Women with HIV have a 3 to 6 times higher risk of being infected by HPV, of progression to high-grade SIL (HSIL) and to ICC. These risks are exacerbated when the CD4 cell counts are low and when they are not using cART, whereas these risks are reduced by 20%-30% when they are optimally treated with cART and have had a suppressed HIV viral load for at least 2 years. In our model, we illustrated that optimal HIV treatment and preventing HIV reduce the number of ICC cases by 2.5 and 6 times, respectively. CONCLUSIONS: Optimal treatment and care of HIV patients are essential to reduce their prevalence of ICC, as are preventive strategies which include HPV vaccination, cervical cancer screening strategies and treatment of HSIL.

Early Antiretroviral Therapy Not Associated With Higher Cryptococcal Meningitis Mortality in People With Human Immunodeficiency Virus in High-Income Countries: An International Collaborative Cohort Study.

BACKGROUND: Randomized controlled trials (RCTs) from low- and middle-income settings suggested that early initiation of antiretroviral therapy (ART) leads to higher mortality rates among people with HIV (PWH) who present with cryptococcal meningitis (CM). There is limited information about the impact of ART timing on mortality rates in similar people in high-income settings. METHODS: Data on ART-naive PWH with CM diagnosed from 1994 to 2012 from Europe/North America were pooled from the COHERE, NA-ACCORD, and CNICS HIV cohort collaborations. Follow-up was considered to span from the date of CM diagnosis to earliest of the following: death, last follow-up, or 6 months. We used marginal structural models to mimic an RCT comparing the effects of early (within 14 days of CM) and late (14-56 days after CM) ART on all-cause mortality, adjusting for potential confounders. RESULTS: Of 190 participants identified, 33 (17%) died within 6 months. At CM diagnosis, their median age (interquartile range) was 38 (33-44) years; the median CD4+ T-cell count, 19/µL (10-56/µL); and median HIV viral load, 5.3 (4.9-5.6) log10 copies/mL. Most participants (n = 157 [83%]) were male, and 145 (76%) started ART. Mimicking an RCT, with 190 people in each group, there were 13 deaths among participants with an early ART regimen and 20 deaths among those with a late ART regimen. The crude and adjusted hazard ratios comparing late with early ART were 1.28 (95% confidence interval, .64-2.56) and 1.40 (.66-2.95), respectively. CONCLUSIONS: We found little evidence that early ART was associated with higher mortality rates among PWH presenting with CM in high-income settings, although confidence intervals were wide.

HPV genotyping in biopsies of HSIL and invasive cervical cancers in women living with HIV: A cohort- and a nested -case control study.

OBJECTIVE: To characterize HPV genotype distribution in HSIL and ICC- biopsies, of WLWH, in Europe, as compared to HIV-negative women. DESIGN: Cohort- and nested -case control study. METHOD: We characterized HPV genotype distribution by performing PCR on HSIL and ICC biopsies from WLWH (n = 170); 85 cases were compared to 85 HIV-negative matched controls. The proportion of patients that might be protected by HPV vaccines was estimated. RESULTS: Among WLWH (median age 36 years-old, median duration of HIV infection 70,5 months, 79% under cART): the most frequently detected HPV were HPV16 (30%), HPV35 (16%), HPV58 (14,7%), HPV31 (13,5%), and HPV52 (11,7%). HPV16 was less frequently found in WLWH, originating from Central Africa (20,5%) compared to other African regions (35,5%) (p = 0,05) or world regions (38,8%) (p = 0,007). Multiple versus single high-risk HPV infections were associated with younger age (≤35 years)(odds ratio (OR) 2,65 (95%IC: 1,3-5,2,p = 0,002), lymphocyte CD4 count < 350 cells / µL (OR 2,7 (95%IC: 2-8,5; p = 0,005), use of cART for < 18 month OR 2,2 (95%IC: 1,1-4,5),p = 0,04) or a cumulative time with undetectable HIV viral load of less than 12 months (OR 4,2 (95%IC: 2-8.5,p = 0,001). HPV 31, 33 and 35 were more frequently detected in samples from WLWH than in HIV-negative controls (p < 0,05). The 9-valent vaccine would increase HPV protection, in HIV-positive and negative women (p < 0,001). CONCLUSION: WLWH are more frequently infected with high-risk HPV other than 16 and 18 than HIV-negative ones. The use of 9-valent vaccine may prevent HSIL or ICC in up to 85% of the women. Adding HPV 35 to the HPV vaccine panel, might improve vaccine effectiveness in WLWH.

Diagnostic Accuracy of Procalcitonin upon Emergency Department Admission during SARS-CoV-2 Pandemic.

INTRODUCTION: Procalcitonin is a marker for bacterial diseases and has been used to guide antibiotic prescription. Procalcitonin accuracy, measured at admission, in patients with community-acquired pneumonia (CAP), is unknown in the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. OBJECTIVES: To evaluate the diagnostic accuracy of procalcitonin to assess the need for antibiotic treatment in patients with CAP presenting to the emergency department during the SARS-CoV-2 pandemic. METHODS: We performed a real-world diagnostic retrospective accuracy study of procalcitonin in patients admitted to the emergency department. Measures of diagnostic accuracy were calculated based on procalcitonin results compared to the reference standard of combined microbiological and radiological analysis. Sensitivity, specificity, positive and negative predictive values, and area under (AUC) the receiver-operating characteristic (ROC) curve were calculated in two analyses: first assessing procalcitonin ability to differentiate microbiologically proven bacteria from viral CAP and then clinically diagnosed bacterial CAP from viral CAP. RESULTS: When using a procalcitonin threshold of 0.5 ng/mL to identify bacterial etiology within patients with CAP, we observed sensitivity and specificity of 50% and 64.1%, and 43% and 82.6%, respectively, in the two analyses. The positive and negative predictive values of a procalcitonin threshold of 0.5 ng/mL to identify patients for whom antibiotics should be advised were 46.4% and 79.7%, and 48.9% and 79% in the two analyses, respectively. The AUC for the two analyses was 0.60 (95% confidence interval [CI] 0.52-0.68) and 0.62 (95% CI, 0.55-0.69). CONCLUSIONS: Procalcitonin measured upon admission during the SARS-CoV-2 pandemic should not guide antibiotic treatment in patients with CAP.

Disseminated histoplasmosis diagnosed by cross-reactivity with the Aspergillus galactomannan antigen in an HIV-positive patient.

Invasive histoplasmosis is the most common AIDS-defining event in endemic regions such as South America. In non-endemic regions, less familiar to the diagnosis, invasive histoplasmosis can be mistakenly diagnosed as miliary tuberculosis leading to a high mortality rate. Here we present the case of an invasive histoplasmosis mistakenly diagnosed as tuberculosis. The diagnosis of histoplasmosis was considered later on, in light of patient's clinical deterioration and positive Aspergillus galactomannan antigens. This case highlights the importance of considering other opportunistic infections when facing a culture-negative miliary tuberculosis without clinical improvement despite anti-tuberculosis therapy. It also draws our attention to the tools available in non-endemic regions that can be helpful in the diagnosis of invasive histoplasmosis.

Multimodal imaging features of transient perivascular inflammation of the carotid artery (TIPIC) syndrome in a patient with Covid-19.

We report the case of a 38-year-old man with transient perivascular inflammation of the carotid artery syndrome that occurred in the course of covid-19. We describe for the first-time multimodal imaging features of the perivascular changes surrounding the carotid artery, and long-term follow-up by ultrasound. The imaging features observed on ultrasound, angiography-CT, MRI and FDG-Pet scan support the hypothesis of the inflammatory nature of the perivascular tissue thickening. The ultrasound follow-up confirmed the spontaneous resolution of the lesion, leaving on site some residual changes as sequelae. The good knowledge of the imaging features reported herein helps to recognize this entity in patients with covid-19.

Tenofovir Alafenamide Plasma Concentrations Are Reduced in Pregnant Women Living With Human Immunodeficiency Virus (HIV): Data From the PANNA Network.

BACKGROUND: Tenofovir alafenamide (TAF), a prodrug of tenofovir (TFV), is included in the majority of the recommended first-line antiretroviral regimens for patients living with human immunodeficiency virus (HIV), but there are limited data on TAF use in pregnant women. We aimed to examine the plasma pharmacokinetics of TAF and TFV in pregnant women from Europe. METHODS: Pregnant women living with HIV were included from treatment centers across Europe, and intensive pharmacokinetic sampling in the third trimester and postpartum was performed. Pharmacokinetic parameters of TAF and TFV were determined with noncompartmental analysis. The proportion of women with a TAF area under the curve (AUClast) below the target of 53.1 ng∗h/mL was determined. Clinical efficacy and safety outcome parameters were reported. RESULTS: In total, 20 pregnant women living with HIV were included. At the third trimester, geometric mean TAF AUClast and Cmax were decreased by 46% and 52%, respectively, compared with postpartum. TFV AUC0-24h, Cmax, and Ctrough decreased by 33%, 30%, and 34%, respectively. The proportion of women with a TAF AUClast < 53.1 ng∗h/mL was 6% at third trimester and 0% postpartum. One out of 20 women had a viral load > 50 copies/mL at third trimester and no mother-to-child transmission occurred. CONCLUSIONS: TAF plasma concentrations were reduced by about half in women living with HIV during third trimester of pregnancy but remained above the predefined efficacy target in the majority of the pregnant women. TFV concentrations were reduced by approximately 30% during third trimester. Despite the observed exposure decrease, high virologic efficacy was observed in this study.

CD4/CD8 Ratio and the Risk of Kaposi Sarcoma or Non-Hodgkin Lymphoma in the Context of Efficiently Treated Human Immunodeficiency Virus (HIV) Infection: A Collaborative Analysis of 20 European Cohort Studies.

BACKGROUND: A persistently low CD4/CD8 ratio has been reported to inversely correlate with the risk of non-AIDS defining cancer in people living with human immunodeficiency virus (HIV; PLWH) efficiently treated by combination antiretroviral therapy (cART). We evaluated the impact of the CD4/CD8 ratio on the risk of Kaposi sarcoma (KS) or non-Hodgkin lymphoma (NHL), still among the most frequent cancers in treated PLWH. METHODS: PLWH from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) were included if they achieved virological control (viral load ≤ 500 copies/mL) within 9 months following cART and without previous KS/LNH diagnosis. Cox models were used to identify factors associated with KS or NHL risk, in all participants and those with CD4 ≥ 500/mm3 at virological control. We analyzed the CD4/CD8 ratio, CD4 count and CD8 count as time-dependent variables, using spline transformations. RESULTS: We included 56 708 PLWH, enrolled between 2000 and 2014. At virological control, the median (interquartile range [IQR]) CD4 count, CD8 count, and CD4/CD8 ratio were 414 (296-552)/mm3, 936 (670-1304)/mm3, and 0.43 (0.28-0.65), respectively. Overall, 221 KS and 187 NHL were diagnosed 9 (2-37) and 18 (7-42) months after virological control. Low CD4/CD8 ratios were associated with KS risk (hazard ratio [HR] = 2.02 [95% confidence interval {CI } = 1.23-3.31]) when comparing CD4/CD8 = 0.3 to CD4/CD8 = 1) but not with NHL risk. High CD8 counts were associated with higher NHL risk (HR = 3.14 [95% CI = 1.58-6.22]) when comparing CD8 = 3000/mm3 to CD8 = 1000/mm3). Similar results with increased associations were found in PLWH with CD4 ≥ 500/mm3 at virological control (HR = 3.27 [95% CI = 1.60-6.56] for KS; HR = 5.28 [95% CI = 2.17-12.83] for NHL). CONCLUSIONS: Low CD4/CD8 ratios and high CD8 counts despite effective cART were associated with increased KS/NHL risks respectively, especially when CD4 ≥ 500/mm3.

Should the management of high grade cervical squamous intraepithelial lesion (HSIL) be different in HIV-positive women?

BACKGROUND: This study compares the management and outcome of high grade squamous intraepithelial lesions (HSIL) in HIV-positive and -negative women and identifies risk factors for treatment failure. METHODS: This retrospective, controlled study includes 146 HIV-positive women, matched for HSIL, age and year of diagnosis, with 146 HIV-negative women. Differences were analysed using parametric and non-parametric tests and Kaplan-Meier survival curves. A binary logistic regression was used to assess risk factors for treatment failure. RESULTS: Persistence of cervical disease was observed most frequently in HIV-positive women (42 versus 17%) (p < 0.001) and the cone biopsy margins were more often invaded in HIV-positive-women than in HIV-negative ones. (37 versus 16%; p < 0.05). HIV-positive women, with successful cervical treatment had better HIV disease control: with significantly longer periods of undetectable HIV viral loads (VL) (19 versus 5 months; p < 0.001) and higher CD4 counts (491 versus 320 cells/mm3; p < 0.001). HIV-positive women with detectable VL at the time of dysplasia had 3.5 times (95% IC: 1.5-8.3) increased risk of treatment failure. Being treated through ablative therapy was associated with a 7.4, four-fold (95% IC: 3.2-17.3) increased risk of treatment failure compared to conization CONCLUSION: HIV-positive women have a higher risk of treatment failure of HSIL than do HIV-negative women, especially when ablative therapy is used and in women with poor control of their HIV infection. The management and the follow- up of HSIL's guidelines in this high-risk population should be adapted consequently: for HIV-positive women with uncontrolled viral load, excisional treatment should be the preferred therapy, whereas for women with undetectable viral load, CD4 + lymphocytes higher than 500 cells/mm3 and with a desire of pregnancy, ablative therapy may be considered.

Efficacy and safety of oral corticosteroids and olfactory training in the management of COVID-19-related loss of smell.

PURPOSE: As the COVID-19 pandemic continues, an increasing number of patients are afflicted by olfactory loss, a now well-recognized symptom of the disease. Though many patients seem to recover their sense of smell after a few weeks, a certain proportion of them seem to develop long-lasting olfactory disorder. Yet, as of October 2020, there is no recommended standardized treatment to reduce the risk of developing long-term olfactory disorder. In this pilot study, we investigated the efficacy and the safety of oral corticosteroids and olfactory training as a treatment for patients with persistent olfactory dysfunction as a result of COVID-19. METHODS: Non-hospitalized patients with a sudden loss of smell and a confirmed COVID-19 diagnosis were recruited by hospital call from February to April 2020. These participants were submitted to an extensive psychophysical testing in order to identify those with persistent dysosmia. Dysosmic patients were then treated either by a 10-day course of oral corticosteroids combined with olfactory training, or by olfactory training alone. All participants were subject to a second olfactory test after a mean of 10 weeks. RESULTS: 72 subjects with documented COVID-19 infection performed the initial olfactory test, on average 5 weeks after losing their sense of smell. Amongst them, 27 (37.5%) patients showed persistent dysosmia and were all included in this study. Nine participants received oral corticosteroids and performed olfactory training (OCS + OT), while 18 performed olfactory training (OT) only. Only participants in the OCS + OT group had significantly improved their olfactory score and did so above the minimal clinically important difference for subjective improvement of smell (p = 0.007). Three of the participants who received oral corticosteroids reported minimal and transient side effects. CONCLUSION: This pilot study may suggest the combination of a short course of oral corticosteroids and olfactory training is safe and may be beneficial in helping patients with enduring dysosmia recover from olfactory loss due to COVID-19. There is a crucial need for further investigation with larger cohorts to corroborate these findings.

Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

The Effect of Pregnancy on the Pharmacokinetics of Total and Unbound Dolutegravir and Its Main Metabolite in Women Living With Human Immunodeficiency Virus.

BACKGROUND: Pharmacokinetic and efficacy data on dolutegravir in pregnant women living with human immunodeficiency virus (HIV) are still limited but needed to support its use as one of the preferred antiretroviral agents. METHODS: Within the multicenter Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) study, pregnant women living with HIV and using dolutegravir once daily (50 mg, with food) underwent 24-hour pharmacokinetic profiling in their third trimester and postpartum. Dolutegravir exposure in the third trimester was considered adequate if geometric mean unbound, pharmacologically active, minimal plasma concentrations (Cmin, unbound) and ≥90% of individual Cmin, unbound levels were >0.85 µg/L, the proposed 90% inhibitory concentration for unbound dolutegravir. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) for comparison of total and unbound pharmacokinetic parameters in the third trimester and postpartum were calculated, including the metabolic ratio for dolutegravir-glucuronide. Safety and virological data were collected. RESULTS: Seventeen women (76% black) were enrolled (25 evaluable pharmacokinetic profiles; 15 in the third trimester, 10 in postpartum). In the third trimester, geometric mean (coefficient of variation, %) Cmin, unbound was 2.87 (87) µg/L and 93% of individual Cmin, unbound levels were >0.85 µg/L. The GMR (90% CI) in the third trimester vs postpartum was 0.86 (.68-1.10) for area under the curve (AUC0-24h), and for Cmax, 0.93 (.77-1.13). GMR (90% CI) for the trough concentrations was 0.71 (.49-1.02), based on total dolutegravir concentrations. Four serious adverse events were reported, unlikely related to dolutegravir. The HIV polymerase chain reaction test was negative in 14/17 infants (result unknown for 3 infants). CONCLUSIONS: Pharmacokinetic changes for dolutegravir in late pregnancy are not clinically relevant and support the use of dolutegravir 50 mg once daily with food in pregnancy. CLINICAL TRIALS REGISTRATION: NCT00825929.

Echtyma gangrenosum caused by coinfection with group A Streptococcus and Staphylococcus aureus: an emerging etiology? Case reports and literature review.

Ecthyma gangrenosum (EG) is a potentially lethal skin infection, most commonly due to Pseudomonas aeruginosa with bacteremic dissemination and affecting mostly immunocompromised patients. We present two cases of EG in two men in Belgium recently admitted to our hospital, caused by a suspected coinfection by group A Streptococcus and Staphylococcus aureus, with a cutaneous dissemination, in which multiple impetigo lesions were the portal of entry. The first patient had no risk factors nor immunodeficiency, but the second was a homeless man with drug and alcohol abuse and advanced HIV infection. Early management of the condition is crucial, with initial broad spectrum antibiotherapy, rapidly narrowed down to the germs identified and skin lesion debridement if necessary. Any immunocompromising condition must be ruled out in any patient suffering from EG.

Clinically Significant Lower Elvitegravir Exposure During the Third Trimester of Pregnant Patients Living With Human Immunodeficiency Virus: Data From the Pharmacokinetics of ANtiretroviral agents in HIV-infected pregNAnt women (PANNA) Network.

This phase 4 study investigated the influence of pregnancy on the pharmacokinetics of elvitegravir/cobicistat in 14 women with human immunodeficiency virus type 1. The results support the recommendation against elvitegravir/cobicistat use during pregnancy, as the elvitegravir concentration at the end of the dosing interval (Ctrough) was reduced by 77%, with 85% of pregnant women having a Ctrough below the effective concentration (EC90). Clinical Trials Registration. NCT00825929.