Tenofovir versus Placebo to Prevent Perinatal Transmission of Hepatitis B.

BACKGROUND: 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. METHODS: 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). RESULTS: 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 log10 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). CONCLUSIONS: 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 .).

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

OBJECTIVES: To 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 METHODS: Lopinavir 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. RESULTS: The 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. CONCLUSIONS: Standard 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.

Risk factors and algorithms for chlamydial and gonococcal cervical infections in women attending family planning clinics in Thailand.

AIM: To identify risk factors associated with and evaluate algorithms for predicting Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) cervical infections in women attending family planning clinics in Thailand. METHODS: Eligible women were recruited from family planning clinics from all regions in Thailand. The women were followed at 3-month intervals for 15-24 months. At each visit, the women were interviewed for interval sexually transmitted infection (STI) history in the past 3 months, recent sexual behavior, and contraceptive use. Pelvic examinations were performed and endocervical specimens were collected to test for CT and NG using polymerase chain reaction. RESULTS: Factors associated with incident CT/NG cervical infections in multivariate analyses included region of country other than the north, age

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

OBJECTIVES: 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®). 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<50copies/mL. Of 214 (26%) infected with HPV: 159 (19%) had ≥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.

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-alpha 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.

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.

Risk factors for bacterial vaginosis incidence in young adult Thai women.

OBJECTIVE: To determine risk factors for incident bacterial vaginosis (BV) in young Thai women. STUDY DESIGN: Prospective data from a cohort of 1522 women aged 18 to 35 years, who were enrolled in a study of hormonal contraception and HIV acquisition, were used to evaluate potential risk factors for BV, as diagnosed by Amsel criteria. RESULTS: The median prevalence of BV from 3 to 24 months of follow-up visits was 2.5%. The BV incidence was 10.0 per 100-woman years. Statistically significant factors in multivariable analysis were sex during menstruation [hazard ratio (HR), 1.80; 95% CI, 1.11-2.92], male partners having sex with other women (HR, 2.3; 95% CI, 1.45-2.98), cigarette smoking (HR, 1.79; 95% CI, 1.08-2.98), and trichomoniasis (HR, 15.68; 95% CI, 4.95-49.68). Intravaginal practices were not associated with incident BV in unadjusted or adjusted analysis. CONCLUSIONS: This study supports the association between sexual behaviors and the incident BV. Failure to detect an association between intravaginal practices and incident BV warrants further studies in high-risk populations or in women with a higher prevalence of intravaginal practices.

Risk factors for in utero or intrapartum mother-to-child transmission of human immunodeficiency virus type 1 in Thailand.

BACKGROUND: The identification of risk factors for in utero and intrapartum transmission of human immunodeficiency virus type 1 (HIV-1) is crucial to the design and understanding of preventive interventions. METHODS: The randomized Perinatal HIV Prevention Trial-1 enrolled 1437 pregnant women and their non-breast-fed infants, to compare the efficacy of various durations of zidovudine prophylaxis. Using univariate and multivariate logistic regression analyses, we studied the role that factors known or occurring at various times during gestation or delivery play in in utero and intrapartum transmission. RESULTS: Variables independently associated with in utero transmission were HIV-1 load >35,000 copies/mL (adjusted odds ratio [AOR], 4.2) and delayed initiation of maternal zidovudine prophylaxis until >31.4 weeks gestation (AOR, 3.0). Variables associated with intrapartum transmission were HIV-1 load >10,000 copies/mL (AOR, 3.8 for 10,000-35,000 copies/mL and 7.1 for >35,000 copies/mL), induction of labor (AOR, 2.6), and premature labor with tocolysis (AOR, 15.1). CONCLUSIONS: With the exception of very high HIV-1 load, risk factors for in utero transmission were different from those for intrapartum transmission. Optimal prophylactic interventions must address each of the major risk factors, with appropriate timing.

Effectiveness of short-term and long-term zidovudine prophylaxis on detection of HIV-1 subtype E in human placenta and vertical transmission.

Antiretroviral treatment with zidovudine (ZDV) from the 14th week until the end of pregnancy has markedly reduced the vertical transmission rate of HIV-1 in Europe and North America. A shorter duration of treatment has reduced this rate in Africa and Southeast Asia to a lesser degree. In Southeast Asia, subtype E is the major subtype rather than subtype B as in Western countries. The goals of this study were to determine the optimal duration of ZDV prophylaxis for subtype E and to confirm its effectiveness at the histologic level. Fifty pregnant women seropositive for HIV-1 subtype E were given ZDV prophylaxis consisting of 300 mg administered twice daily, switching to 300 mg administered every 3 hours from the onset of labor until delivery. Twenty-seven received "short-term" ZDV lasting 14 to 35 days before delivery, whereas the other 23 received "long-term" ZDV lasting 62 to 92 days. The effectiveness of ZDV prophylaxis was assessed by detection of HIV-1 in the placenta using in situ polymerase chain reaction (PCR). All babies in this study were tested up to one year of age. Three were not positive until after one month of age, but one was positive as a neonate. Four neonates were positive for HIV-1 as detected by PCR on peripheral blood, including one in the neonatal period. All cases were from the short-term prophylaxis group. Decidual glandular epithelial cells were the only cell type in the placenta that expressed HIV proviral DNA under ZDV prophylaxis. Sixty-seven percent of placentas in the short-term ZDV group showed more than occasional positive cells compared with 22% in the group receiving long-term ZDV prophylaxis (P < 0.02). This is first study to compare the effectiveness of short-term and long-term ZDV prophylaxis with respect to the presence of HIV in the placenta. Our study shows that longer (at least 60 days) prophylaxis is more effective in reducing HIV expression in the placenta and is associated with reduced transmission to neonates.