Jullapong Achalapong

Revisiting the Role of Neutralizing Antibodies in Mother-to-Child Transmission of HIV-1

We analyzed the association between mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) and maternal neutralizing antibodies to heterologous primary isolates of various HIV-1 clades, to test the hypothesis that protective antibodies are those with broad neutralizing activity. Our study sample included 90 Thai women for whom the timing of HIV-1 transmission (in utero or intrapartum) was known. The statistical analysis included a conditional logistic-regression model to control for both plasma viral load and duration of zidovudine prophylaxis. The higher the titer of neutralizing antibodies to a heterologous strain of the same clade, the lower the rate of MTCT of HIV-1. More specifically, high levels of neutralizing antibodies to the MBA (CRF01_AE) strain were associated with low intrapartum transmission of HIV-1. This suggested that such heterologous neutralizing antibodies may be involved in the natural prevention of late perinatal HIV transmission. These data are consistent with the hypothesis that the use of some antibodies might help to prevent perinatal HIV transmission, through passive immunoprophylaxis. Moreover, the study of humoral factors associated with MTCT of HIV-1 may identify correlates of protection that should help in the design of efficient HIV/acquired immunodeficiency syndrome vaccines.

Acceptability of Carraguard vaginal gel use among Thai couples.

Objectives:To evaluate the acceptability of candidate microbicide Carraguard among couples participating in a safety trial. Study design:A 6-month randomized, placebo-controlled trial was conducted in sexually active, low-risk couples in Thailand. Methods:Couples who were monogamous, HIV uninfected, and not regular condom users were enrolled. Acceptability data were collected through structured questionnaires at repeated intervals. At the closing study visit, participants were asked questions about hypothetical product characteristics and future use. Compliance with gel use was assessed by questionnaires, coital diaries, and tracking of used and unused applicators. Results:Among 55 enrolled couples, follow up and adherence with gel use were high and sustained, with 80% of women using gel in over 95% of vaginal sex acts. Because acceptability results from Carraguard and placebo arms were similar, they were combined for this analysis. Overall, 92% of women and 83% of men liked the gel somewhat or very much; 66% of women and 72% of men reported increased sexual pleasure with gel use; and 55% of women and 62% of men reported increased frequency of intercourse. Only 15% of women but 43% of men thought that gel could be used without the man knowing. Although men and women had similar views overall, concordance within couples was low, with no kappa coefficients above 0.31. Conclusion:Carraguard gel use was acceptable to low-risk couples in northern Thailand. Reported associations between gel use and increased sexual pleasure and frequency suggest a potential to market microbicide products for both disease prevention and enhancement of pleasure.

No Increase in Cervicovaginal Proinflammatory Cytokines After Carraguard Use in a Placebo-controlled Randomized Clinical Trial

Background:Assessment of cervicovaginal cytokine levels may be helpful to evaluate subclinical epithelial inflammation during safety evaluations of candidate microbicides. Methods:Fifty-five HIV-seronegative Thai women were enrolled in a safety trial of the candidate microbicide Carraguard and were randomized to use Carraguard or placebo gel before vaginal sex. Cervicovaginal lavages were collected at baseline and after 1 month of gel use; levels of interleukin (IL)-1β, IL-6, IL-8, and secretory leukocyte protease inhibitor (SLPI) were measured using microwell plate-based enzyme immunoassays. Median levels were compared between the baseline and 1-month follow-up visits using paired t tests; the median change between groups was compared using Wilcoxon rank sum tests. Women were examined for the presence of genital findings; the association between genital findings and cytokine levels was studied. Results:No increase in levels of proinflammatory cytokines after use of Carraguard gel or placebo gel was observed during the study. The median change from the baseline to 1 month of follow-up was not significantly different between Carraguard and placebo groups (IL-1β: −0.3 pg/mL vs. −3.93 pg/mL; P = 0.4, IL-6: −0.3 pg/mL vs. 0 pg/mL; P = 0.3, IL-8: −40.1 pg/mL vs. −53.2 pg/mL; P = 0.8, and SLPI: −26.5 pg/mL vs. 12.6 pg/mL; P = 0.07). Genital findings with intact epithelium were found in 16 (29%) women; these women tended to have somewhat higher IL-6 levels than those with normal epithelium (14.9 pg/mL vs. 8.8 pg/mL; P = 0.08). Conclusion:We found no increase in proinflammatory cytokines after Carraguard and placebo gel use, suggesting that neither gel causes inflammation. Further studies to assess the role of cytokines in microbicide safety studies are warranted.

Efficacy and Safety of 1-Month Postpartum Zidovudine-Didanosine to Prevent HIV-Resistance Mutations after Intrapartum Single-Dose Nevirapine

BACKGROUND Intrapartum single-dose nevirapine plus third trimester maternal and infant zidovudine are essential components of programs to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in resource-limited settings. The persistence of nevirapine in the plasma for 3 weeks postpartum risks selection of resistance mutations to nonnucleoside reverse-transcriptase inhibitors (NNRTIs). We hypothesized that a 1-month zidovudine-didanosine course initiated at the same time as single-dose nevirapine (sdNVP) would prevent the selection of nevirapine-resistance mutations. METHODS HIV-infected pregnant women in the PHPT-4 cohort with CD4 cell counts >250 cells/mm3 received antepartum zidovudine from the third trimester until delivery, sdNVP during labor, and a 1-month zidovudine-didanosine course after delivery. These women were matched on the basis of baseline HIV load, CD4 cell count, and duration of antepartum zidovudine to women who received sdNVP in the PHPT-2 trial (control subjects). Consensus sequencing and the more sensitive oligonucleotide ligation assay were performed on samples obtained on postpartum days 7-10, 37-45, and 120 (if the HIV load was >500 copies/mL) to detect K103N/Y181C/G190A mutations. RESULTS The 222 PHPT-4 subjects did not differ from matched control subjects in baseline characteristics except for age. The combined group median CD4 cell count was 421 cells/mm3 (interquartile range [IQR], 322-549 cells/mm3), the median HIV load was 3.45 log10 copies/mL (IQR, 2.79-4.00 log10 copies/mL), and the median duration of zidovudine prophylaxis was 10.4 weeks (IQR, 9.1-11.4 weeks). Using consensus sequencing, major NNRTI resistance mutations were detected after delivery in 0% of PHPT-4 subjects and 10.4% of PHPT-2 controls. The oligonucleotide ligation assay detected resistance in 1.8% of PHPT-4 subjects and 18.9% of controls. Major NNRTI resistance mutations were detected by either method in 1.8% of PHPT-4 subjects and 20.7% of controls (P < .001). CONCLUSIONS A 1-month postpartum course of zidovudine plus didanosine prevented the selection of the vast majority of NNRTI resistance mutations.

HIV genital shedding and safety of Carraguard use by HIV-infected women: a crossover trial in Thailand

Objective:To evaluate the safety, including impact on genital HIV RNA shedding, of Carraguard vaginal gel in HIV-infected women. Design:This is a randomized, controlled, crossover study of Carraguard in HIV-infected women in Thailand. Methods:Each woman (CD4+ cell count 51–500 cells/μl and not on antiretroviral therapy) used each treatment (Carraguard, methylcellulose placebo, and no-product) once daily for 7 days during each 1-month period (3-week wash-out). Women were randomized to one of the six possible treatment sequences. Safety assessments were conducted at baseline (pregel), 15 min postgel, day 7, and day 14, and included HIV RNA measurements in cervicovaginal lavage (CVL) specimens. Results:Sixty women were enrolled, and 99% of scheduled study visits were completed. At baseline, median age (34 years), CD4+ lymphocyte count (296 cells/μl), plasma HIV viral load (4.6 log10 copies/ml), CVL HIV viral load (3.1 log10 total copies per CVL), and sexual behaviors were similar among randomization groups. HIV viral load, leukocyte and hemoglobin levels, and epithelial cell counts in CVLs were lower 15 min after application of Carraguard or placebo compared with no product; CVL HIV viral load was still lower at day 7 but returned to baseline by day 14. Carraguard use was not associated with prevalent or incident genital findings or abnormal vaginal flora. Conclusion:Carraguard appears to be well tolerated for once-daily vaginal use by HIV-infected women. The observed reduction in CVL HIV viral load in the gel months may be clinically relevant but could have resulted from interference with sample collection by study gels.

Reduced indinavir exposure during pregnancy

AIM To describe the pharmacokinetics and safety of indinavir boosted with ritonavir (IDV/r) during the second and third trimesters of pregnancy and in the post-partum period. METHODS IMPAACT P1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics (PK) in HIV-infected pregnant women with a Thai cohort receiving IDV/r 400/100 mg twice daily during pregnancy through to 6-12 weeks post-partum as part of clinical care. Steady-state PK profiles were performed during the second (optional) and third trimesters and at 6-12 weeks post-partum. PK targets were the estimated 10(th) percentile IDV AUC (12.9 μg ml(-1)h) in non-pregnant historical Thai adults and a trough concentration of 0.1 μg ml(-1), the suggested minimum target. RESULTS Twenty-six pregnant women were enrolled; thirteen entered during the second trimester. Median (range) age was 29.8 (18.9-40.8) years and weight 60.5 (50.0-85.0) kg at the third trimester PK visit. The 90% confidence limits for the geometric mean ratio of the indinavir AUC(0,12 h) and Cmax during the second trimester and post-partum (ante : post ratios) were 0.58 (0.49, 0.68) and 0.73 (0.59, 0.91), respectively; third trimester/post-partum AUC(0,12 h) and Cmax ratios were 0.60 (0.53, 0.68) and 0.63 (0.55, 0.72), respectively. IDV/r was well tolerated and 21/26 women had a HIV-1 viral load < 40 copies ml(-1) at delivery. All 26 infants were confirmed HIV negative. CONCLUSION Indinavir exposure during the second and third trimesters was significantly reduced compared with post-partum and ∼30% of women failed to achieve a target trough concentration. Increasing the dose of IDV/r during pregnancy to 600/100 mg twice daily may be preferable to ensure adequate drug concentrations.

Early Postpartum Pharmacokinetics of Lopinavir Initiated Intrapartum in Thai Women

ABSTRACT Lopinavir (LPV) exposure is reduced during the third trimester of pregnancy. We report the pharmacokinetics of standard LPV-ritonavir dosing (400/100 mg twice daily) in the immediate and early postpartum period when initiated during labor. In 16 human immunodeficiency virus-infected Thai women, the median (range) LPV area under the concentration-time curve and maximum and minimum concentrations in plasma were 99.7 (66.1 to 180.5) μg·h/ml, 11.2 (8.0 to 17.5) μg/ml, and 4.6 (1.7 to 12.5) μg/ml, respectively, at 41 (12 to 74) h after delivery. All of the women attained adequate LPV levels through 30 days postpartum. No serious adverse events were reported.

Assessment of Nevirapine Prophylactic and Therapeutic Dosing Regimens for Neonates

Background: Nevirapine (NVP) is a key component of antiretroviral prophylaxis and treatment for neonates. We evaluated current World Health Organization (WHO) weight-band NVP prophylactic dosing recommendations and investigated optimal therapeutic NVP dosing for neonates. Methods: The PHPT-5 study in Thailand assessed the efficacy of “Perinatal Antiretroviral Intensification” to prevent mother-to-child transmission of HIV in women with <8 weeks of antiretroviral treatment before delivery (NCT01511237). Infants received a 2-week course of zidovudine/lamivudine/NVP (NVP syrup/once daily: 2 mg/kg for 7 days; then 4 mg/kg for 7 days). Infant samples were assessed during the first 2 weeks of life. NVP population pharmacokinetics (PK) parameters were estimated using nonlinear mixed-effects models. Simulations were performed to estimate the probability of achieving target NVP trough concentrations for prophylaxis (>0.10 mg/L) and for therapeutic efficacy (>3.0 mg/L) using different infant dosing strategies. Results: Sixty infants (55% male) were included. At birth, median (range) weight was 2.9 (2.3–3.6) kg. NVP concentrations were best described by a 1-compartment PK model. Infant weight and postnatal age influenced NVP PK parameters. Based on simulations for a 3-kg infant, ≥92% would have an NVP trough >0.1 mg/L after 48 hours through 2 weeks using the PHPT-5 and WHO-dosing regimens. For NVP-based therapy, a 6-mg/kg twice daily dose produced a trough >3.0 mg/L in 87% of infants at 48 hours and 80% at 2 weeks. Conclusion: WHO weight-band prophylactic guidelines achieved target concentrations. Starting NVP 6 mg/kg twice daily from birth is expected to achieve therapeutic concentrations during the first 2 weeks of life.

Risk Factors for Human Papillomavirus Infection and Abnormal Cervical Cytology Among Perinatally Human Immunodeficiency Virus-Infected and Uninfected Asian Youth

Background Infection with high-risk human papillomavirus (HR-HPV) may be higher in perinatally human immunodeficiency virus (HIV)-infected (PHIV) than HIV-uninfected (HU) adolescents because of long-standing immune deficiency. Methods PHIV and HU females aged 12-24 years in Thailand and Vietnam were matched by age group and lifetime sexual partners. At enrollment, blood, cervical, vaginal, anal, and oral samples were obtained for HPV-related testing. The Wilcoxon and Fisher exact tests were used for univariate and logistic regression for multivariate analyses. Results Ninety-three PHIV and 99 HU adolescents (median age 19 [18-20] years) were enrolled (June 2013-July 2015). Among PHIV, 94% were currently receiving antiretroviral therapy, median CD4 count was 593 (392-808) cells/mm3, and 62% had a viral load <40 copies/mL. Across anogenital compartments, PHIV had higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02). Higher proportions of PHIV had abnormal Pap smears (eg, atypical squamous cells of unknown significance [ASC-US], 12% vs 14%; low-grade squamous intraepithelial neoplastic lesions, 19% vs 1%). After adjusting for ever being pregnant and asymptomatic sexually transmitted infections (STI) at enrollment, PHIV were more likely to have HR-HPV than HU (odds ratio, 2.02; 95% confidence interval, 1.09-3.77; P = .03). Conclusions Perinatal HIV infection was associated with a higher risk of HR-HPV and abnormal cervical cytology. Our results underscore the need for HPV vaccination for PHIV adolescents and for prevention and screening programs for HPV and other STIs.