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.

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.

Association of Dyslipidemia and Glucose Abnormalities With Antiretroviral Treatment in a Cohort of HIV-Infected Latin American Children.

OBJECTIVE: To estimate the incidence of lipid and glucose abnormalities and assess their association with exposure to antiretroviral (ARV) regimens among perinatally HIV-infected Latin American children. DESIGN: Longitudinal cohort study. METHODS: Data were analyzed from the Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Pediatric Latin American Countries Epidemiologic Study. The incidence of dyslipidemia [total cholesterol >200 mg/dL, HDL < 35 mg/dL, LDL ≥ 130 mg/dL, triglycerides > 110 mg/dL (age < 10 years) or >150 mg/dL (≥10 years)] and fasting glucose abnormalities [homeostasis model assessment of insulin resistance >2.5 (Tanner stage 1) or >4.0 (Tanner stage > 1); impaired glucose: 110 to <126 mg/dL; diabetes: ≥126 mg/dL] was estimated. Proportional hazards regression was used to evaluate the risk of abnormalities associated with ARV regimen, adjusted for covariates. RESULTS: There were 385 children eligible for analysis (mean age 6.6 years). Incident cholesterol abnormalities were reported in 18.1% of participants [95% confidence interval (CI): 14.1% to 22.8%], HDL and LDL cholesterol abnormalities in 19.6% (15.1%-24.7%) and 15.0% (11.3%-19.5%), respectively, and triglyceride abnormalities in 44.2% (37.7%-50.8%). In multivariable analysis, ARV regimen was only associated with triglyceride abnormalities; participants receiving a protease inhibitor (PI)-containing regimen were 3.6 times as likely to experience a triglyceride abnormality as those receiving no ARVs (95% CI: 1.3 to 10.5; P = 0.0167). The cumulative incidence of insulin resistance was 3.8% (1.8%-7.1%); there were no incident cases of diabetes and only 2 of impaired fasting glucose. CONCLUSIONS: Children receiving PI-containing regimens were at increased risk of developing triglyceride abnormalities. Continued monitoring of lipid levels in children receiving PI-containing regimens appears warranted.

Alternative, age- and viral load-related routes of nelfinavir resistance in human immunodeficiency virus type 1-infected children receiving highly active antiretroviral therapy.

To assess prevalence of nelfinavir resistance mutations in children receiving highly active antiretroviral therapy, sequencing of protease gene from plasma of 53 human immunodeficiency virus-infected children was performed. The prevalence of L90M was similar to that of D30N. There was a significant correlation with a higher viral load and lower age and the occurrence of L90M. These findings suggest differential molecular age- and viral load-related routes for nelfinavir resistance.

Genotypic resistance and HIV-1 subtype in Brazilian children on dual and triple combination therapy.

BACKGROUND: Antiretroviral therapy is provided by the Brazilian Ministry of Health to eligible HIV-infected individuals. Based on clinical and immunological classification, the Brazilian guidelines recommend dual or triple therapy for children. However, the development of drug-resistant strains or poor adherence to therapy could impact the efficacy of this approach. OBJECTIVES: We examined relationships between RNA levels, CD4+ T-cell counts, treatment history, and the prevalence of drug-resistant variants in a cohort of HIV-1-infected children in Rio de Janeiro, Brazil. STUDY DESIGN: Direct sequencing of reverse transcriptase and protease genes from plasma was performed. Virologic and CD4+ T-cell counts responses to therapy were assessed by changes in HIV-1 RNA levels and CD4+ T-cell counts from baseline. RESULTS: Thirty-seven patients were receiving dual therapy and 38 were on triple therapy at enrollment, segregated by antiretroviral history. Both groups had a higher increase in CD4+ T cell counts and a lower viral load in pre-treatment antiretroviral-naïve subjects. Notably, there was a direct correlation between the higher frequencies of drug-resistance mutations and cross-resistance with previous usage of antiretroviral (ARV) therapy in both groups. Non-B subtypes isolates were found in 21.3% of samples. A smaller increase in CD4+ T cell counts was found between non-B subtypes when compared to B-subtypes. CONCLUSIONS: These results suggest that less immunological recovery and a higher number of mutations related to drug resistance were associated with previous usage of ARV and consequent higher time under drug selective pressure in these HIV-infected Brazilian children. These facts suggest the preferential use of triple drug combination as first line regimen in children.

Expression of APOBEC3G/3F and G-to-A hypermutation levels in HIV-1-infected children with different profiles of disease progression.

OBJECTIVE: Increasing evidence has accumulated showing the role of APOBEC3G (A3G) and 3F (A3F) in the control of HIV-1 replication and disease progression in humans. However, very few studies have been conducted in HIV-infected children. Here, we analyzed the levels of A3G and A3F expression and induced G-to-A hypermutation in a group of children with distinct profiles of disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Perinatally HIV-infected children were classified as progressors or long-term non-progressors according to criteria based on HIV viral load and CD4 T-cell counts over time. A group of uninfected control children were also enrolled in the study. PBMC proviral DNA was assessed for G-to-A hypermutation, whereas A3G and A3F mRNA were isolated and quantified through TaqMan® real-time PCR. No correlation was observed between disease progression and A3G/A3F expression or hypermutation levels. Although all children analyzed showed higher expression levels of A3G compared to A3F (an average fold of 5 times), a surprisingly high A3F-related hypermutation rate was evidenced in the cohort, irrespective of the child's disease progression profile. CONCLUSION: Our results contribute to the current controversy as to whether HIV disease progression is related to A3G/A3F enzymatic activity. To our knowledge, this is the first study analyzing A3G/F expression in HIV-infected children, and it may pave the way to a better understanding of the host factors governing HIV disease in the pediatric setting.

Pregnancy in HIV vertically infected adolescents and young women: a new generation of HIV-exposed infants.

BACKGROUND: Vertically infected individuals are reaching childbearing age and the new generation of HIV-exposed infants is coming to pediatric care. METHODS: Chart review of pregnancies among HIV vertically infected adolescents and young women. RESULTS: Fifteen pregnancies were reviewed. Girls had HIV diagnosis at median age 10.1 years (range 1.3-20). They started sexual life at median age 15 years (range 13-19); median age at pregnancy was 16.9 years (range 14-21.5); 36.4% had presented an AIDS-defining clinical event; have been followed for median 8.5 years (range 2.9-15.8) and had used median two antiretroviral regimens (range 0-7). Fourteen (93.3%) received antiretroviral drugs during pregnancy; median CD4 cell count during pregnancy was 394 (range 117-651) cells/µl and median viral load was 4800 copies/ml (range 50-100 000); 54% had undetectable viral load near delivery. All patients delivered by elective c-section. Median birth weight was 2650 g (range 2085-3595), median length was 47.3 cm (range 42-51) and median gestational age 38 weeks (range 37-39). All newborn received zidovudine for 6 weeks of life and none was breastfed. Fourteen (93%) infants were considered HIV-uninfected; one was lost to follow-up. CONCLUSIONS: This group of adolescents seems to have sexual behavior similar to that of HIV-uninfected. Since this is an experimented antiretroviral population, new drugs may be necessary for adequate viral suppression to avoid HIV mother-to-child transmission. Follow-up of this third generation of HIV-exposed infants needs to be addressed within HIV adolescent care.

Emergence of primary NNRTI resistance mutations without antiretroviral selective pressure in a HAART-treated child.

OBJECTIVE: The use of antiretrovirals (ARV) during pregnancy has drastically reduced the rate of the human immunodeficiency virus perinatal transmission (MTCT). As a consequence of widespread ARV use, transmission of drug resistant strains from mothers to their babies is increasing. Ultra-sensitive PCR techniques have permitted the quantification of minority viral populations, but little is known about the transmission of drug-resistant HIV-1 minority population in the setting of MTCT. METHODOLOGY/PRINCIPAL FINDINGS: We describe the case of a female child born to an HIV-infected mother, which had not taken any ARV during the pregnancy. The child's first genotype demonstrated a minor non-nucleoside reverse transcriptase inhibitor (K101E), and during her treatment with reverse transcriptase and protease inhibitors full resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) emerged (G190A). Phenotypic/genotypic analysis of variant quasispecies through yeast TyHRT assay was conducted to characterize minority resistant viral strains circulating in both mother and child. Maximum likelihood and Bayesian MCMC phylogenetic analyses were performed with samples from the pair to assess genetic relatedness among minor viral strains. The analysis showed that the child received a minor NNRTI resistant variant, containing the mutation K101E that was present in less than 1% of the mother's quasispecies. Phylogenetic analyses have suggested common ancestry between the mother's virus strain carrying K101E with the viral sequences from the child. CONCLUSION: This is the first documentation of MTCT of a minority resistant strain of HIV-1. The transmission of minor resistant variants carries the threat of emergence of multi-drug primary mutations without identified specific selective pressures.

Overview of genotypic and clinical profiles of human immunodeficiency virus type 1-infected children in Rio de Janeiro, Brazil.

Although mother-to-child HIV transmission prevention has slowed down pediatric HIV infection in developed countries, large numbers of infants still become infected in developing nations. Data on pediatric HIV infection is however largely scarce. In this study, we have overviewed clinical, laboratory and genotypic data from a large cohort of HIV-infected infants regularly followed at two pediatric HIV outpatient clinics in Rio de Janeiro, Brazil. Children on antiretroviral therapy, as well as drug-naive, newly diagnosed infants were analyzed. Prevalence of drug resistance mutations, as well as immunological and virological responses to therapy were evaluated. Additionally, HIV-1 subtype frequencies and their distribution over the course of the epidemic were studied. We have found a high prevalence of mutations among ARV-experienced children, whereas mutations were absent in the drug-naive group. Despite the high levels of resistance among treated infants, an important improvement of their immunological status was observed. HIV-1 subtype distribution followed the trends of the adult population, with the appearance of non-B subtypes and recombinant forms after 1990. To our knowledge, this is the largest pediatric cohort ever analyzed in Brazil, and the data provided is of paramount importance to a better understanding of HIV/AIDS evolution in pediatric settings.

Overview of genotypic and clinical profiles of human immunodeficiency virus type 1-infected children in Rio de Janeiro, Brazil

Embora os protocolos de prevenção da transmissão materno-infantil do HIV tenham diminuído a infecção pediátrica pelo HIV nos países desenvolvidos, um grande número de crianças ainda se infectam nas nações em desenvolvimento. Dados disponíveis de infecção pediátrica são entretanto ainda escassos. Neste trabalho, nós conduzimos um levantamento clínico, laboratorial e genotípico de um grande coorte de crianças infectadas pelo HIV em acompanhamento em dois grandes centros de atendimento de HIV/AIDS pediátrica do Rio de Janeiro. Crianças em tratamento anti-retroviral, bem como crianças recentemente diagnosticadas e ainda virgens de tratamento foram analisadas. A prevalência de mutações de resistência às drogas, beem como as respostas imunológicas e virológicas ao tratamento foram avaliadas. Além disso, as frequências dos subtipos do HIV-1 e a sua distrbuição ao longo da epidemia de HIV/AIDS no Brasil foram estudadas. Nós observamos uma alta prevalência de mutações de resistência em vírus de crianças em tratamento, ao passo que o grupo virgem de tratamento não possuía mutações. Apesar dos altos níveis de mutações nas crianças tratadas, uma significativa melhora de sua condição imunológica foi observada. A distribuição de subtipos do HIV-1 seguiu as tendências da população adulta, com o aparecimento de subtipos não-B e de formas recombinantes após 1990. Dentro do nosso conhecimento, este é o maior coorte pediátrico de HIV/AIDS já analisado no Brasil, e os resultados obtidos são de suma importância para um melhor entendimento da evolução do HIV/AIDS em um contexto pediátrico.

Progressive multifocal leukoencephalopathy in a child with acquired immunodeficiency syndrome (AIDS)

Progressive multifocal leukoencephalopathy is a rare viral-induced demyelinating disease associated to immunodeficiency. A 10-year-old boy with AIDS is reported, who developed subacute cerebellar signs and symptoms with multiple cranial nerve involvement and dementia. A computed tomography scan revealed a focal nonenhancing area of low attenuation in the cerebellum. On magnetic resonance imaging high signal lesions in T2 weighted sequences were shown. The biopsy of one of those lesions showed the typical histological findings of progressive multifocal leukoencephalopathy. It seems important to consider this diagnosis in children with AIDS who present with progressive neurological features.