Mortality Among Children Aged <5 Years Living with HIV Who Are Receiving Antiretroviral Treatment - U.S. President's Emergency Plan for AIDS Relief, 28 Supported Countries and Regions, October 2020-September 2022.

Globally, children aged <5 years, including those living with HIV who are not receiving antiretroviral treatment (ART), experience disproportionately high mortality. Global mortality among children living with HIV aged <5 years receiving ART is not well described. This report compares mortality and related clinical measures among infants aged <1 year and children aged 1-4 years living with HIV with those among older persons aged 5-14, 15-49, and ≥50 years living with HIV receiving ART services at all clinical sites supported by the U.S. President's Emergency Plan for AIDS Relief. During October 2020-September 2022, an average of 11,980 infants aged <1 year and 105,510 children aged 1-4 years were receiving ART each quarter; among these infants and children receiving ART, 586 (4.9%) and 2,684 (2.5%), respectively, were reported to have died annually. These proportions of infants and children who died ranged from four to nine times higher in infants aged <1 year, and two to five times higher in children aged 1-4 years, than the proportions of older persons aged ≥5 years receiving ART. Compared with persons aged ≥5 years living with HIV, the proportions of children aged <5 years living with HIV who experienced interruptions in treatment were also higher, and the proportions who had a documented HIV viral load result or a suppressed viral load were lower. Prioritizing and optimizing HIV and general health services for children aged <5 years living with HIV receiving ART, including those recommended in the WHO STOP AIDS Package, might help address these disproportionately poorer outcomes.

Assessing sex differences in viral load suppression and reported deaths using routinely collected program data from PEPFAR-supported countries in sub-Saharan Africa.

BACKGROUND: In sub-Saharan Africa, more women than men access HIV testing and treatment and may have better viral load suppression (VLS). We utilized routinely reported aggregated HIV program data from 21 sub-Saharan African countries to examine sex differences in VLS and death rates within antiretroviral therapy (ART) programs supported by the United States President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: We included VLS and reported death data for persons aged 15 + years on ART from October-December 2020 disaggregated by sex and age for each subnational unit (SNU). We used linear mixed-model regression to estimate VLS proportion and negative binomial mixed-model regression to estimate the rates of death and death plus interruptions in treatment (IIT). All models were weighted for SNU-level ART population size and adjusted for sex, age, HIV/tuberculosis coinfection, country, and SNU; models for reported deaths and deaths plus IIT were also adjusted for SNU-level VLS. RESULTS: Mean VLS proportion was higher among women than men (93.0% vs. 92.0%, p-value < 0.0001) and 50 + than 15-49 age group (93.7% vs. 91.2%, p-value < 0.0001). The mean rate of reported deaths was higher among men than women (2.37 vs. 1.51 per 1000 persons, p-value < 0.0001) and 50 + than 15-49 age group (2.39 vs. 1.50 per 1000, p-value < 0.0001); the mean rate of reported deaths plus IIT was higher among men (30.1 in men vs. 26.0 in women per 1000, p-value < 0.0001) and higher among 15-49 than 50 + age group (34.7 vs. 22.6 per 1000, p-value < 0.0001). CONCLUSIONS: The mean rate of reported deaths was higher among men in most models despite adjusting for VLS. Further exploration into differences in care-seeking behaviors; coverage of screening, prophylaxis, and/or treatment of opportunistic infections; and more extensive testing options for men to include CD4 is recommended.

PEPFAR's Role in Protecting and Leveraging HIV Services in the COVID-19 Response in Africa.

PURPOSE OF REVIEW: We describe the impact of COVID-19 on PEPFAR programs in Africa and how PEPFAR adapted and leveraged its interventions to the changing landscape of the COVID-19 pandemic. RECENT FINDINGS: To mitigate the potential impact of COVID-19 on the HIV response and protect the gains, continuity of treatment was the guiding principle regarding the provision of services in PEPFAR-supported countries. As the COVID-19 pandemic matured, PEPFAR's approach evolved from a strictly "protect and salvage" approach to a "restore and accelerate" approach that embraced innovative adaptations in service and "person-centered" care. The impact of service delivery interruptions caused by COVID-19 on progress towards HIV epidemic control in PEPFAR-supported African countries remains undetermined. With COVID vaccine coverage many months away and more transmissible variants being reported, Africa may experience more pandemic surges. HIV programs will depend on nimble and innovative adaptations in prevention and treatment services in order to advance epidemic control objectives.

Maternal and infant renal safety following tenofovir disoproxil fumarate exposure during pregnancy in a randomized control trial.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) in combination with other antiretroviral (ARV) drugs has been in clinical use for HIV treatment since its approval in 2001. Although the effectiveness of TDF in preventing perinatal HIV infection is well established, information about renal safety during pregnancy is still limited. TRIAL DESIGN: The IMPAACT PROMISE study was an open-label, strategy trial that randomized pregnant women to one of three arms: TDF based antiretroviral therapy (ART), zidovudine (ZDV) based ART, and ZDV alone (standard of care at start of enrollment). The P1084s substudy was a nested, comparative study of renal outcomes in women and their infants. METHODS: PROMISE participants (n = 3543) were assessed for renal dysfunction using calculated creatinine clearance (CrCl) at study entry (> 14 weeks gestation), delivery, and postpartum weeks 6, 26, and 74. Of these women, 479 were enrolled in the P1084s substudy that also assessed maternal calcium and phosphate as well as infant calculated CrCl, calcium, and phosphate at birth. RESULTS: Among the 1338 women who could be randomized to TDF, less than 1% had a baseline calculated CrCl below 80 mL/min. The mean (standard deviation) maternal calculated CrCl at delivery in the TDF-ART arm [147.0 mL/min (51.4)] was lower than the ZDV-ART [155.0 mL/min (43.3); primary comparison] and the ZDV Alone [158.5 mL/min (45.0)] arms; the mean differences (95% confidence interval) were - 8.0 mL/min (- 14.5, - 1.5) and - 11.5 mL/min (- 18.0, - 4.9), respectively. The TDF-ART arm had lower mean maternal phosphate at delivery compared with the ZDV-ART [- 0.14 mg/dL (- 0.28, - 0.01)] and the ZDV Alone [- 0.17 mg/dL (- 0.31, - 0.02)] arms, and a greater percentage of maternal hypophosphatemia at delivery (4.23%) compared with the ZDV-ART (1.38%) and the ZDV Alone (1.46%) arms. Maternal calcium was similar between arms. In infants, mean calculated CrCl, calcium, and phosphate at birth were similar between arms (all CIs included 0). CONCLUSIONS: Although mean maternal calculated CrCl at Delivery was lower in the TDF-ART arm, the difference between arms is unlikely to be clinically significant. During pregnancy, the TDF-ART regimen had no observed safety concerns for maternal or infant renal function. TRIAL REGISTRATION: NCT01061151 on 10/02/2010 for PROMISE (1077BF). NCT01066858 on 10/02/2010 for P1084s.

Safety and Efficacy of 48 and 96 Weeks of Alendronate in Children and Adolescents With Perinatal Human Immunodeficiency Virus Infection and Low Bone Mineral Density for Age.

No safety concerns were identified in a randomized, crossover study of alendronate/placebo in youth with perinatal HIV infection and low bone mineral density (BMD). BMD improved with 48 weeks of alendronate and continued to improve with an additional 48 weeks of therapy. Gains were largely maintained 48 weeks after stopping alendronate.

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 .).

Alendronate Improves Bone Mineral Density in Children and Adolescents Perinatally Infected With Human Immunodeficiency Virus With Low Bone Mineral Density for Age.

BACKGROUND: Children and adolescents with perinatal human immunodeficiency virus (HIV) infection and with low bone mineral density (BMD) may be at higher risk of osteoporosis and fractures in later life than their uninfected peers. Bisphosphonate therapy has been shown to reduce fractures in adults with osteoporosis, but has not been formally studied in youths living with HIV. METHODS: Fifty-two children and adolescents (aged 11-24 years) perinatally infected with HIV with low lumbar spine (LS) BMD (Z score < -1.5) were randomized to receive once-weekly alendronate or placebo in a double-blind cross-over study designed to assess the safety and efficacy of 48 and 96 weeks of alendronate in the United States and Brazil. All participants received daily calcium carbonate and vitamin D supplementation and were asked to engage in regular weight-bearing exercise. Safety and efficacy are summarized for the initial 48 weeks of the trial. RESULTS: Grade 3 or higher abnormal laboratory values, signs, or symptoms developed in 5 of 32 (16%) participants on alendronate and 2 of 18 (11%) on placebo (P > .99). No cases of jaw osteonecrosis, atrial fibrillation, or nonhealing fractures were reported. Mean increases (95% confidence interval) in LS BMD over 48 weeks were significantly larger on alendronate (20% [14%-25%]) than placebo (7% [5%-9%]) (P < .001). Similar improvements were seen for whole body BMD. CONCLUSIONS: In this small study in children and adolescents perinatally infected with HIV with low LS BMD, 48 weeks of alendronate was well-tolerated, showed no safety concerns, and significantly improved LS and whole body BMD compared to participants on vitamin D/calcium supplementation and exercise alone. CLINICAL TRIALS REGISTRATION: NCT00921557.

Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus.

In a randomized, double-blind, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) use from 28 weeks gestational age to 2 months postpartum to prevent mother-to-child transmission of hepatitis B virus, there was no significant effect of maternal TDF use on maternal or infant bone mineral density 1 year after delivery/birth. Clinical Trials Registration. NCT01745822.

Benefits and Risks of Antiretroviral Therapy for Perinatal HIV Prevention.

BACKGROUND: Randomized-trial data on the risks and benefits of antiretroviral therapy (ART) as compared with zidovudine and single-dose nevirapine to prevent transmission of the human immunodeficiency virus (HIV) in HIV-infected pregnant women with high CD4 counts are lacking. METHODS: We randomly assigned HIV-infected women at 14 or more weeks of gestation with CD4 counts of at least 350 cells per cubic millimeter to zidovudine and single-dose nevirapine plus a 1-to-2-week postpartum "tail" of tenofovir and emtricitabine (zidovudine alone); zidovudine, lamivudine, and lopinavir-ritonavir (zidovudine-based ART); or tenofovir, emtricitabine, and lopinavir-ritonavir (tenofovir-based ART). The primary outcomes were HIV transmission at 1 week of age in the infant and maternal and infant safety. RESULTS: The median CD4 count was 530 cells per cubic millimeter among 3490 primarily black African HIV-infected women enrolled at a median of 26 weeks of gestation (interquartile range, 21 to 30). The rate of transmission was significantly lower with ART than with zidovudine alone (0.5% in the combined ART groups vs. 1.8%; difference, -1.3 percentage points; repeated confidence interval, -2.1 to -0.4). However, the rate of maternal grade 2 to 4 adverse events was significantly higher with zidovudine-based ART than with zidovudine alone (21.1% vs. 17.3%, P=0.008), and the rate of grade 2 to 4 abnormal blood chemical values was higher with tenofovir-based ART than with zidovudine alone (2.9% vs. 0.8%, P=0.03). Adverse events did not differ significantly between the ART groups (P>0.99). A birth weight of less than 2500 g was more frequent with zidovudine-based ART than with zidovudine alone (23.0% vs. 12.0%, P<0.001) and was more frequent with tenofovir-based ART than with zidovudine alone (16.9% vs. 8.9%, P=0.004); preterm delivery before 37 weeks was more frequent with zidovudine-based ART than with zidovudine alone (20.5% vs. 13.1%, P<0.001). Tenofovir-based ART was associated with higher rates than zidovudine-based ART of very preterm delivery before 34 weeks (6.0% vs. 2.6%, P=0.04) and early infant death (4.4% vs. 0.6%, P=0.001), but there were no significant differences between tenofovir-based ART and zidovudine alone (P=0.10 and P=0.43). The rate of HIV-free survival was highest among infants whose mothers received zidovudine-based ART. CONCLUSIONS: Antenatal ART resulted in significantly lower rates of early HIV transmission than zidovudine alone but a higher risk of adverse maternal and neonatal outcomes. (Funded by the National Institutes of Health; PROMISE ClinicalTrials.gov numbers, NCT01061151 and NCT01253538 .).

Live Respiratory Syncytial Virus (RSV) Vaccine Candidate Containing Stabilized Temperature-Sensitivity Mutations Is Highly Attenuated in RSV-Seronegative Infants and Children.

Background: Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold-passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation. Methods: RSV-seronegative 6-24-month-old children received an intranasal dose of 105.3 plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a ≥4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season. Results: A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log10 PFU/mL by culture and 2.9 log10 copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a ≥4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites. Conclusions: RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6-24-month-old RSV-seronegative children. Clinical Trials Registration: NCT01852266 and NCT01968083.

Live-Attenuated Respiratory Syncytial Virus Vaccine Candidate With Deletion of RNA Synthesis Regulatory Protein M2-2 is Highly Immunogenic in Children.

Background: Live respiratory syncytial virus (RSV) candidate vaccine LIDΔM2-2 is attenuated by deletion of the RSV RNA regulatory protein M2-2, resulting in upregulated viral gene transcription and antigen expression but reduced RNA replication. Methods: RSV-seronegative children ages 6-24 months received a single intranasal dose of 105 plaque forming units (PFU) of LIDΔM2-2 (n = 20) or placebo (n = 9) (NCT02237209, NCT02040831). RSV serum antibodies, vaccine infectivity, and reactogenicity were assessed. During the following RSV season, participants were monitored for respiratory illness and pre- and post-RSV season serum antibodies. Results: Vaccine virus was shed by 95% of vaccinees (median peak titers of 3.8 log10 PFU/mL by quantitative culture and 6.3 log10 copies/mL by PCR); 90% had ≥4-fold rise in serum neutralizing antibodies. Respiratory symptoms and fever were common in vaccine (95%) and placebo (78%). One vaccinee had grade 2 rhonchi concurrent with vaccine shedding, rhinovirus, and enterovirus. Eight of 19 vaccinees versus 2 of 9 placebo recipients had substantially increased RSV antibody titers after the RSV season without medically attended RSV disease, indicating anamnestic vaccine responses to wild-type RSV without significant illness. Conclusion: LIDΔM2-2 had excellent infectivity and immunogenicity, encouraging further study of vaccine candidates attenuated by M2-2 deletion. Clinical Trials Registration: NCT02237209, NCT02040831.

Tenofovir Exposure during Pregnancy and Postpartum in Women Receiving Tenofovir Disoproxil Fumarate for the Prevention of Mother-to-Child Transmission of Hepatitis B Virus.

We assessed tenofovir exposure during pregnancy and postpartum in hepatitis B virus (HBV)-infected HIV-uninfected women receiving tenofovir disoproxil fumarate (TDF) to prevent mother-to-child transmission of HBV. Data from 154 women who received TDF within a randomized controlled trial were included. Individual plasma tenofovir exposures (area under the concentration-time curve from 0 to 24 h [AUC0-24]) were estimated using a population pharmacokinetic approach. The estimated geometric mean tenofovir AUC0-24 was 20% (95% confidence interval [95% CI], 19 to 21%) lower during pregnancy than during postpartum; this modest reduction in the absence of HBV transmission suggests that no dose adjustment is needed.

Long-term pulmonary complications in perinatally HIV-infected youth.

BACKGROUND: Increased incidence and prevalence of asthma have been documented for perinatally HIV-infected youth 10 to 21 years of age compared with HIV-exposed uninfected (HEU) youth. OBJECTIVE: We sought to perform objective pulmonary function tests (PFTs) in HIV-infected and HEU youth with and without diagnosed asthma. METHOD: Asthma was determined in 370 participants (218 HIV-infected and 152 HEU participants) by means of chart review and self-report at 13 sites. Interpretable PFTs (188 HIV-infected and 132 HEU participants) were classified as obstructive, restrictive, or normal, and reversibility was determined after bronchodilator inhalation. Values for HIV-1 RNA, CD4 and CD8 T cells, eosinophils, total IgE, allergen-specific IgE, and urinary cotinine were measured. Adjusted prevalence ratios (PRs) of asthma and PFT outcomes were determined for HIV-infected participants relative to HEU participants, controlling for age, race/ethnicity, and sex. RESULTS: Current asthma was identified in 75 (34%) of 218 HIV-infected participants and 38 (25%) of 152 HEU participants (adjusted PR, 1.33; P = .11). The prevalence of obstructive disease did not differ by HIV status. Reversibility was less likely in HIV-infected youth than in HEU youth (17/183 [9%] vs 21/126 [17%]; adjusted PR, 0.47; P = .020) overall and among just those with obstructive PFT results (adjusted PR, 0.46; P = .016). Among HIV-infected youth with current asthma, serum IgE levels were inversely correlated with CD8 T-cell counts and positively correlated with eosinophil counts and not associated with CD4 T-cell counts. HIV-infected youth had lower association of specific IgE levels to several inhalant and food allergens compared with HEU participants and significantly lower CD4/CD8 T-cell ratios (suggesting immune imbalance). CONCLUSION: Compared with HEU youth, HIV-infected youth demonstrated decreased reversibility of obstructive lung disease, which is atypical of asthma. This might indicate an early stage of chronic obstructive pulmonary disease. Follow-up into adulthood is warranted to further define their pulmonary outcomes.

Impact of Human Immunodeficiency Virus Drug Resistance on Treatment of Human Immunodeficiency Virus Infection in Children in Low- and Middle-Income Countries.

Children living with human immunodeficiency virus (HIV) in low- and middle-income countries (LMICs) experience higher rates of virologic failure than adults. Human immunodeficiency virus drug resistance (HIVDR) plays a major role in pediatric HIV treatment failure because nonsuppressive maternal antiretroviral therapy (ART) during pregnancy and breastfeeding as well as infant antiretroviral prophylaxis lead to high rates of pretreatment drug resistance to regimens most commonly used in children living with HIV. Lack of availability of durable, potent drugs in child-friendly formulations in LMICs and adherence difficulties contribute to acquired drug resistance during treatment. Optimizing drugs available for treating children living with HIV in LMICs, providing robust adherence support, and ensuring virologic monitoring for children receiving ART are essential for reducing HIVDR and improving treatment outcomes for children living with HIV in LMICs.

Severe Vitamin D Deficiency in Human Immunodeficiency Virus-Infected Pregnant Women is Associated with Preterm Birth.

Background Low maternal vitamin D has been associated with preterm birth (PTB). Human immunodeficiency virus (HIV)-infected pregnant women are at risk for PTB, but data on maternal vitamin D and PTB in this population are scarce. Methods In a cohort of Latin American HIV-infected pregnant women from the National Institute of Child Health and Human Development International Site Development Initiative protocol, we examined the association between maternal vitamin D status and PTB. Vitamin D status was defined as the following 25-hydroxyvitamin D levels: severe deficiency (< 10 ng/mL), deficiency (10-20 ng/mL), insufficiency (21-29 ng/mL), and sufficiency (≥30 ng/mL). PTB was defined as delivery at < 37 weeks' gestational age (GA). Logistic regression was used to assess the association between maternal vitamin D status and PTB. Results Of 715 HIV-infected pregnant women, 13 (1.8%) were severely vitamin D deficient, 224 (31.3%) were deficient, and 233 were (32.6%) insufficient. Overall, 23.2% (166/715) of pregnancies resulted in PTB (median GA of PTBs = 36 weeks [interquartile range: 34-36]). In multivariate analysis, severe vitamin D deficiency was associated with PTB (odds ratio = 4.7, 95% confidence interval: 1.3-16.8]). Conclusion Severe maternal vitamin D deficiency is associated with PTB in HIV-infected Latin American pregnant women. Further studies are warranted to determine if vitamin D supplementation in HIV-infected women may impact PTB.

Prevalence and Persistence of Varicella Antibodies in Previously Immunized Children and Youth With Perinatal HIV-1 Infection.

BACKGROUND: Two doses of live-attenuated varicella-zoster vaccine are recommended for human immunodeficiency virus 1 (HIV-1)-infected children with CD4% ≥ 15%. We determined the prevalence and persistence of antibody in immunized children with perinatal HIV (PHIV) and their association with number of vaccinations, combination antiretroviral therapy (cART), and HIV status. METHODS: The Adolescent Master Protocol is an observational study of children with PHIV and perinatally HIV-exposed but uninfected (PHEU) children conducted at 15 US sites. In a cross-sectional analysis, we tested participants' most recent stored sera for varicella antibody using whole-cell and glycoprotein enzyme-linked immunosorbent assay. Seropositivity predictors were identified using multivariable logistic regression models and C statistics. RESULTS: Samples were available for 432 children with PHIV and 221 PHEU children; 82% of children with PHIV and 97% of PHEU children were seropositive (P < .001). Seropositivity after 1 vaccine dose among children with PHIV and PHEU children was 100% at <3 years (both), 73% and 100% at 3-<7 years (P < .05), and 77% and 97% at ≥ 7 years (P < .01), respectively. Seropositivity among recipients of 2 vaccine doses was >94% at all intervals. Independent predictors of seropositivity among children with PHIV were receipt of 2 vaccine doses, receipt of 1 dose while on ≥ 3 months of cART, compared with none (adjusted odds ratio [aOR]: 14.0 and 2.8, respectively; P < .001 for overall dose effect), and in those vaccinated ≥ 3 years previously, duration of cART (aOR: 1.29 per year increase, P = .02). CONCLUSIONS: Humoral immune responses to varicella vaccine are best achieved when children with PHIV receive their first dose ≥ 3 months after cART initiation and maintained by completion of the 2-dose series and long-term cART use.

Prevention of mother-to-child transmission of hepatitis B virus: a phase III, placebo-controlled, double-blind, randomized clinical trial to assess the efficacy and safety of a short course of tenofovir disoproxil fumarate in women with hepatitis B virus e-antigen.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is complicated by cirrhosis and liver cancer. In Thailand, 6-7 % of adults are chronically infected with HBV. The risk of mother-to-child transmission (MTCT) of HBV has been estimated to be about 12 % when mothers have a high hepatitis B viral load, even if infants receive passive-active prophylaxis with HBV immunoglobulin (HBIg) and initiate the hepatitis B vaccine series at birth. We designed a study to assess the efficacy and safety of a short course of maternal tenofovir disoproxil fumarate (TDF) among women with a marker of high viral load for the prevention of MTCT of HBV. METHODS: The study is a phase III, multicenter (17 sites in Thailand), placebo-controlled, double-blind, randomized 1:1, two-arm clinical trial of TDF 300 mg once daily versus placebo among pregnant women from 28 weeks' gestation through 2-month post-partum. All infants receive HBIg at birth, and a hepatitis B (HB) vaccination series according to Thai guidelines: birth, and age 1, 2, 4 and 6 months. Participant women at study entry must be age ≥18 years, hepatitis B surface antigen (HBsAg) and e-antigen (HBeAg) positive, have alanine aminotransferase (ALT) level < 30 IU/L at screening (confirmed < 60 IU/L pre-entry), negative hepatitis C serology, creatinine clearance >50 mL/min, and no history of anti-HBV antiviral treatment. The target sample size of 328 mother/infant pairs assumed 156 evaluable cases per arm to detect a ≥9 % difference in MTCT transmission (3 % experimental arm versus 12 % placebo arm) with 90 % power. Mothers and infants are followed until 12 months after delivery. The primary infant endpoint is detection of HBsAg, confirmed by detection of HBV DNA at six months of age. Secondary endpoints are maternal and infant adverse events, acute exacerbations of maternal hepatitis B disease (ALT >300 IU/L, defined as a "flare") following discontinuation of study treatment, infant HBV infection status and growth up to 12 months of age. DISCUSSION: The results of this randomized trial will clarify the efficacy and safety of a short course of antiviral treatment to prevent mother-to-child transmission of HBV and inform international guidelines. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01745822 .

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.