Timing of maternal isoniazid preventive therapy on tuberculosis infection among infants exposed to HIV in low-income and middle-income settings: a secondary analysis of the TB APPRISE trial.

BACKGROUND: Infants born to women with HIV in settings with a high tuberculosis burden are at risk of tuberculosis infection and rapid progression to active disease. Maternal isoniazid preventive therapy might mitigate this risk, but optimal timing of therapy remains unclear. The TB APPRISE trial showed that initiation of isoniazid during pregnancy resulted in more frequent adverse pregnancy outcomes than when initiated postpartum. We aimed to determine the proportion of infants testing positive for tuberculosis infection born to mothers who initiated isoniazid therapy antepartum compared with postpartum using two commonly used tests, the test agreement, and predictors of test positivity. METHODS: TB APPRISE was a randomised, double-blind, placebo-controlled, non-inferiority trial done at 13 study sites across eight countries (Botswana, Haiti, India, South Africa, Tanzania, Thailand, Uganda, and Zimbabwe). Pregnant women with HIV on antiretroviral therapy were randomly assigned to receive immediate isoniazid preventive therapy (28 weeks isoniazid [300 mg daily], then placebo until week 40 after delivery) or deferred treatment (placebo until week 12 after delivery, then isoniazid [300 mg daily] for 28 weeks). Mother-infant pairs were followed up until 48 weeks after delivery. We included all liveborn infants with a tuberculin skin test or interferon-γ release assay (IGRA) at 44 weeks. The outcomes assessed in this secondary analysis were tuberculosis test positivity by study group, test agreement, and predictors of test positivity. This study was registered with ClinicalTrials.gov, NCT01494038. FINDINGS: Between Aug 19, 2014, and April 4, 2016, 956 mothers were randomly assigned, and 749 mother-child pairs were included in this secondary analysis. Of 749 infants, 694 (93%) received Bacille Calmette-Guérin (BCG) vaccination, 675 (90%) were born to mothers who had completed isoniazid treatment, 20 (3%) were exposed to tuberculosis, seven (1%) became HIV positive, and one (<1%) developed probable tuberculosis. 43 (6%; 95% CI 4-8]) of 732 infants had a positive IGRA test result and 55 (8%; 6-10) of 727 infants had a positive tuberculin skin test result. Test positivity did not differ by study group (p=0·88 for IGRA; p=0·44 for tuberculin skin test). Test agreement was poor (κ=0·107 [95% CI 0·002-0·212]). Infant tuberculin skin test positivity was associated with breastfeeding (adjusted odds ratio 6·63 [95% CI 1·57-27·9]), BCG vaccination (4·97 [1·50-16·43]), and maternal tuberculin skin test positivity at delivery (3·28 [1·70-6·33]); IGRA positivity was associated with female sex (2·09 [1·06-4·14]). INTERPRETATION: Deferral of maternal isoniazid preventive therapy to early postpartum had no effect on infant tuberculosis acquisition in our trial population, regardless of the diagnostic test used; however, tuberculosis test agreement is poor during infancy. FUNDING: US National Institutes of Health.

HIV-1 remission and possible cure in a woman after haplo-cord blood transplant.

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.

Effect of Maternal Immunization With 10-Valent Pneumococcus Conjugate Vaccine (PCV-10), 23-Valent Pneumococcus Polysaccharide Vaccine, or Placebo on the Immunogenicity of PCV-10 in Human Immunodeficiency Virus-Exposed Uninfected Infants: A Randomized Clinical Trial.

BACKGROUND: The effect of pneumococcal vaccination of mothers with human immunodeficiency virus (HIV) on infant responses to childhood vaccination has not been studied. We compared the immunogenicity of 10-valent pneumococcus conjugate vaccine (PCV-10) in HIV-exposed uninfected infants born to mothers who received PCV-10, 23-valent pneumococcus polysaccharide vaccine (PPV-23), or placebo during pregnancy. METHODS: Antibody levels against 7 serotypes were measured at birth, before the first and second doses of PCV-10m and after completion of the 2-dose regimen in 347 infants, including 112 born to mothers who received PPV-23, 112 who received PCV-10, and 119 who received placebo during pregnancy. Seroprotection was defined by antibody levels ≥0.35 µg/mL. RESULTS: At birth and at 8 weeks of life, antibody levels were similar in infants born to PCV-10 or PPV-23 recipients and higher than in those born to placebo recipient. After the last dose of PCV-10, infants in the maternal PCV-10 group had significantly lower antibody levels against 5 serotypes than those in the maternal PPV-23 group and against 3 serotypes than those in the maternal placebo group, and they did not have higher antibody levels against any serotype. The seroprotection rate against 7 serotypes was 50% in infants in the maternal PCV-10 group, compared with 71% in both of the maternal PPV-23 and placebo groups (P < .001). CONCLUSIONS: Administration of PCV-10 during pregnancy was associated with decreased antibody responses to PCV-10 and seroprotection rates in infants. Considering that PCV-10 and PPV-23 had similar immunogenicity in pregnant women with HIV and that administration of PPV-23 did not affect the immunogenicity of PCV-10 in infants, PPV-23 in pregnancy may be preferred over PCV-10.

Immunogenicity of Conjugated and Polysaccharide Pneumococcal Vaccines Administered During Pregnancy or Postpartum to Women With HIV.

BACKGROUND: Pneumococcal vaccination is recommended in people with HIV, prioritizing PCV. We compared the immunogenicity of PCV-10 and PPV-23 administered antepartum or postpartum. METHODS: This double-blind study randomized 346 pregnant women with HIV on antiretrovirals to PCV-10, PPV-23, or placebo at 14-34 weeks gestational age. Women who received placebo antepartum were randomized at 24 weeks postpartum to PCV-10 or PPV-23. Antibodies against 7 serotypes common to both vaccines and 1 serotype only in PPV-23 were measured by ELISA/chemiluminescence; B- and T-cell responses to serotype 1 by FLUOROSPOT; and plasma cytokines/chemokines by chemiluminescence. RESULTS: Antibody responses were higher after postpartum versus antepartum vaccination. PCV-10 generated lower antibody levels than PPV-23 against 4 and higher against 1 of 7 common serotypes. Additional factors associated with high postvaccination antibody concentrations were high prevaccination antibody concentrations and CD4+ cells; low CD8+ cells and plasma HIV RNA; and several plasma cytokines/chemokines. Serotype 1 B- and T-cell memory did not increase after vaccination. CONCLUSIONS: Antepartum immunization generated suboptimal antibody responses, suggesting that postpartum booster doses may be beneficial and warrant further studies. Considering that PCV-10 and PPV-23 had similar immunogenicity, but PPV-23 covered more serotypes, use of PPV-23 may be prioritized in women with HIV on antiretroviral therapy. CLINICAL TRAILS REGISTRATION: NCT02717494.