Higher placental anti-inflammatory IL-10 cytokine expression in HIV-1 infected women receiving longer zidovudine prophylaxis associated with nevirapine

Placental cytokine balance may be critical for the control of mother-to-child transmission (MTCT) of HIV. We assessed whether the type and duration of antiretrovirals used for prevention of HIV-1-MTCT modified the inflammatory cytokine profile. We investigated the levels of cytokine expression in the placentas of 61 HIV-1-infected women who received zidovudine (ZDV) plus single dose nevirapine (SD-NVP) or ZDV only for prevention of MTCT. Placentas of 38 HIV-1-uninfected women were included as controls. All placentas were obtained after vaginal delivery. Levels of mRNA and cytokine expression were quantified using real-time PCR and ELISA, respectively, in placental explants and 24-hour culture supernatants and analyzed in relation to the women's characteristics and the type and duration of antiretroviral prophylaxis. HIV-1-infected and uninfected women did not show any differences in the expression of placental cytokine secretion except for a trend toward lower TNF-10 mRNA levels in HIV-1-infected women. Within the HIV-1-infected group, women who were exposed to a long duration of ZDV (>72 days) or received SD-NVP less than 5h prior to delivery, more frequently expressed detectable levels of IL-10 in their placentas (32% versus 7% (p = 0.01) and 32% versus 5% (p = 0.02), respectively). No infant was found to be HIV-1-infected. Our results showed a normalization of the placental cytokine balance in HIV-1-infected women receiving antiretroviral prophylaxis. Furthermore, the type and duration of antiretroviral prophylaxis have an impact on the placental anti-inflammatory IL-10 expression level, which may contribute to controlling HIV replication at the placental level, thus reducing MTCT of HIV-1.Fil: Pornprasert, Sakorn. Chiang Mai University; TailandiaFil: Mary, Jean-Yves. Université Paris Diderot - Paris 7; FranciaFil: Faye, Albert. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Leechanachai, Pannee. Chiang Mai University; TailandiaFil: Limtrakul, Aram. Health Promotion Center Region; TailandiaFil: Rugpao, Sungwal. Chiang Mai University; TailandiaFil: Sirivatanapa, Pannee. Chiang Mai University; TailandiaFil: Gomuthbutra, Vorapin. Nakornping Hospital; TailandiaFil: Matanasaravoot, Wanmanee. Lamphun Hospital; TailandiaFil: Le Coer, Sophie. Institut National d’Etudes Démographiques; FranciaFil: Lallemant, Marc. Centre National de la Recherche Scientifique. Institut de Recherche pour le Développement; FranciaFil: Barré-Sinoussi, Françoise. Instituto Pasteur; FranciaFil: Menu, Elisabeth. Instituto Pasteur; FranciaFil: Ngo Giang Huong, Nicole. Centre National de la Recherche Scientifique. Institut de Recherche pour le Développement; FranciaFil: Ayouba, Ahidjo. Instituto Pasteur; FranciaFil: Chailert, Sanupong. Chiang Mai University; Tailandia. Instituto Pasteur; FranciaFil: Chaouat, Gérard. Institut National de la Santé et de la Recherche Médicale; FranciaFil: Derrien, Muriel. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Dolcini, Guillermina Laura. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Sanidad Animal y Medicina Preventiva. Laboratorio de Virología; Argentina. Instituto Pasteur; Francia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Eteki, Nicole. Hôpital Central de Yaoundé. Maternité Principale; CamerúnFil: Kfutwah, Anfumbom Jude. Instituto Pasteur; FranciaFil: Kouo, Odette. Instituto Pasteur; FranciaFil: Lemen, Brigitte. Instituto Pasteur; FranciaFil: Abal, Facundo Juan Pablo. Instituto Pasteur; FranciaFil: Nerrienet, Eric. Instituto Pasteur; FranciaFil: Njinku, Bernadette. Instituto Pasteur; FranciaFil: Scarlatti, Gabriella. Suan Dok Hospital; TailandiaFil: Tejiokem, Mathurin. Centre Pasteur du Cameroun; CamerúnFil: Téné, Gilbert. No especifíca

Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy.

ObjectivesTo assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy.Patients and methodsLopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy.ResultsThe median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and volume of distribution (V/F). Population estimates of lopinavir CL/F and V/F were 6.21 L/h/70 kg and 52.6 L/70 kg, respectively. Based on simulations, the highest risk of subtherapeutic trough concentrations was for women weighing >100 kg using the standard dose (∼ 7%), while the risk was <2% with the 600/150 mg dose for women weighing 40-130 kg. After a missed dose, 61% of women have lopinavir concentrations below target prior to the next dose with the standard dose compared with 42% with the increased dose.ConclusionsStandard dosing provides adequate lopinavir trough concentrations for the majority of pregnant women but increased doses may be preferable for women weighing >100 kg and with a history of lopinavir/ritonavir use and/or adherence issues

Impact of body weight and missed doses on lopinavir concentrations with standard and increased lopinavir/ritonavir doses during late pregnancy.

ObjectivesTo assess the influence of body weight and missed doses on lopinavir pharmacokinetics with standard and increased doses of lopinavir/ritonavir melt extrusion tablets during late pregnancy.Patients and methodsLopinavir concentration data during the third trimester of pregnancy were pooled from clinical trials in Thailand (NCT00409591) and the USA (NCT00042289). A total of 154 HIV-infected pregnant women receiving either 400/100 mg (standard) or 600/150 mg (increased) twice daily had lopinavir plasma concentration data available. Population parameters were estimated using non-linear mixed-effects regression models. Monte Carlo simulations were performed to estimate the probability of achieving target lopinavir trough concentrations (>1.0 mg/L) with standard and increased doses of lopinavir/ritonavir during pregnancy.ResultsThe median (range) age, weight and gestational age were 28 years (18-43), 62 kg (45-123) and 33 weeks (29-38), respectively. Body weight influenced lopinavir oral clearance (CL/F) and volume of distribution (V/F). Population estimates of lopinavir CL/F and V/F were 6.21 L/h/70 kg and 52.6 L/70 kg, respectively. Based on simulations, the highest risk of subtherapeutic trough concentrations was for women weighing >100 kg using the standard dose (∼ 7%), while the risk was <2% with the 600/150 mg dose for women weighing 40-130 kg. After a missed dose, 61% of women have lopinavir concentrations below target prior to the next dose with the standard dose compared with 42% with the increased dose.ConclusionsStandard dosing provides adequate lopinavir trough concentrations for the majority of pregnant women but increased doses may be preferable for women weighing >100 kg and with a history of lopinavir/ritonavir use and/or adherence issues

Human Papillomavirus infection and cervical lesions in HIV infected women on antiretroviral treatment in Thailand

International audienceOBJECTIVES: To estimate the prevalence and factors associated with Human Papillomavirus (HPV) infection, HPV genotypes and cytological/histological high-grade (HSIL+/CIN2+) lesions. METHODS: We conducted a cross-sectional study within a prospective cohort of HIV-infected women on combination antiretroviral therapy (cART). Cervical specimens were collected for cytology and HPV genotyping (Papillocheck(R)). Any women with High-Risk-HPV (HR-HPV), and/or potentially HR-HPV (pHR-HPV) and/or ASC-US or higher (ASC-US+) lesions were referred for colposcopy. Factors associated with HR-HPV infection and with HSIL+/CIN2+ lesions were investigated using mixed-effects logistic regression models. RESULTS: 829 women were enrolled: median age 40.4 years, on cART for a median of 6.9 years, median CD4 cell-count 536 cells/mm3, and 788 (96%) with HIV-viral load/=1 HR-HPV, of whom 38 (5%) HPV52, 22 (3%) HPV16, 9 (1%) HPV18; 21 (3%) had pHR-HPV, 34 (4%) low risk-HPV infection, and 56 (26%) had multiple genotypes. Younger age, low CD4 cell-counts and low education were independently associated with HR-HPV infection. 72 women (9%) had ASC-US+ and 28 (3%) HSIL+/CIN2+ lesions. HR-HPV infection was independently associated with HSIL+/CIN2+ lesions. CONCLUSION: The prevalence of HPV infection and of cervical lesions was low. The HPV genotype distribution supports the use of 9-valent vaccine in Thailand

Early HIV-1 diagnosis using in-house real-time PCR amplification on dried blood spots for infants in remote and resource-limited settings.

BACKGROUND: In resource-limited settings, most perinatally HIV-1-infected infants do not receive timely antiretroviral therapy because early HIV-1 diagnosis is not available or affordable. OBJECTIVE: To assess the performance of a low-cost in-house real-time polymerase chain reaction (PCR) assay to detect HIV-1 DNA in infant dried blood spots (DBS). METHODS: One thousand three hundred nineteen DBS collected throughout Thailand from non-breast-fed infants born to HIV-1-infected mothers were shipped at room temperature to a central laboratory.In-house real-time DNA PCR results were compared with Roche Amplicor HIV-1 DNA test (Version 1.5) results. In addition, we verified the Roche test performance on DBS sampled from 1218 other infants using as reference HIV serology result at 18 months of age. RESULTS: Real-time DNA PCR and Roche DNA PCR results were 100% concordant. Compared with HIV serology results, the Roche test sensitivity was 98.6% (95% confidence interval: 92.6% to 100.0%) and its specificity at 4 months of age was 99.7% (95% confidence interval: 99.2% to 99.9%). CONCLUSIONS: In-house real-time PCR performed as well as the Roche test in detecting HIV-1 DNA on DBS in Thailand. Combined use of DBS and real-time PCR assays is a reliable and affordable tool to expand access to early HIV-1 diagnosis in remote and resource-limited settings, enabling timely treatment for HIV-1-infected infants

Tenofovir Versus Placebo to Prevent Perinatal Transmission of Hepatitis B

(Abstracted from N Engl J Med 2018;378:911–923)(Pregnant women with an elevated viral load (>200,000 IU/mL) of hepatitis B virus (HBV), or with a positive Hg e antigen (HBeAg) status, have a risk of transmitting infection to their infants, despite the infantsʼ receiving hepatitis B immune globulin (HBIG). Antiviral agents that inhibit HBV replication, such as lamivudine, tenofovir disoproxil fumarate (TDF), and telbivudine, when administered to pregnant women with a high HBV viral load, may reduce the risk of mother-to-child transmission

Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B

Pregnant women with an elevated viral load of hepatitis B virus (HBV) have a risk of transmitting infection to their infants, despite the infants' receiving hepatitis B immune globulin. In this multicenter, double-blind clinical trial performed in Thailand, we randomly assigned hepatitis B e antigen (HBeAg)-positive pregnant women with an alanine aminotransferase level of 60 IU or less per liter to receive tenofovir disoproxil fumarate (TDF) or placebo from 28 weeks of gestation to 2 months post partum. Infants received hepatitis B immune globulin at birth and hepatitis B vaccine at birth and at 1, 2, 4, and 6 months. The primary end point was a hepatitis B surface antigen (HBsAg)-positive status in the infant, confirmed by the HBV DNA level at 6 months of age. We calculated that a sample of 328 women would provide the trial with 90% power to detect a difference of at least 9 percentage points in the transmission rate (expected rate, 3% in the TDF group vs. 12% in the placebo group). From January 2013 to August 2015, we enrolled 331 women; 168 women were randomly assigned to the TDF group and 163 to the placebo group. At enrollment, the median gestational age was 28.3 weeks, and the median HBV DNA level was 8.0 log IU per milliliter. Among 322 deliveries (97% of the participants), there were 319 singleton births, two twin pairs, and one stillborn infant. The median time from birth to administration of hepatitis B immune globulin was 1.3 hours, and the median time from birth to administration of hepatitis B vaccine was 1.2 hours. In the primary analysis, none of the 147 infants (0%; 95% confidence interval [CI], 0 to 2) in the TDF group were infected, as compared with 3 of 147 (2%; 95% CI, 0 to 6) in the placebo group (P=0.12). The rate of adverse events did not differ significantly between groups. The incidence of a maternal alanine aminotransferase level of more than 300 IU per liter after discontinuation of the trial regimen was 6% in the TDF group and 3% in the placebo group (P=0.29). In a setting in which the rate of mother-to-child HBV transmission was low with the administration of hepatitis B immune globulin and hepatitis B vaccine in infants born to HBeAg-positive mothers, the additional maternal use of TDF did not result in a significantly lower rate of transmission. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01745822 .)