Maternal and neonatal adverse effects of antiretroviral therapy in pregnant women infected with human immunodeficiency virus and their exposed newborns in Campinas between 2000 and 2015

Orientador: Helaine Maria Besteti Pires Mayer MilanezTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: A utilização de medicações antirretrovirais (TARV) na gestação apresenta inquestionável benefício para redução da transmissão vertical (TV) do HIV, mas está associada a efeitos adversos maternos e neonatais. Objetivo: avaliar os efeitos decorrentes da exposição à terapia antirretroviral em gestantes infectadas pelo HIV e seus recém-nascidos. Sujeitos e Métodos: estudo observacional analítico de uma coorte de gestantes infectadas pelo HIV e seus recém-nascidos expostos atendidos no Serviço de Obstetrícia do CAISM/UNICAMP de 2000 a 2015. Foram avaliados os efeitos adversos maternos e neonatais como anemia, plaquetopenia, alergia, alterações hepáticas, dislipidemia e diabetes, além de resultados neonatais como prematuridade, baixo peso e malformações. Os dados foram coletados dos prontuários dos pacientes e inseridos em banco de dados específico. A análise descritiva foi realizada através de frequências simples (n) e relativas (%) e cálculos de média, desvio-padrão e mediana. As associações entre variáveis foram testadas através do Qui-quadrado ou Exato de Fisher (n<5) e Razão de Risco com respectivo valor de p para as categóricas e através do t Student (dados paramétricos) ou Mann-Whitney (não-paramétricos) para as quantitativas. O nível de significância utilizado foi de 0,05. A análise multivariada foi realizada através da Regressão de COX. No processamento e análise dos dados, foi utilizado o programa SAS 9.4. Resultados: foram incluídas 793 gestações e 787 recém-nascidos. A taxa de TV do HIV foi de 2,3%, sendo 0,8% nos últimos cinco anos. Os efeitos adversos maternos encontrados foram dislipidemia (82%), anemia (56%), alteração hepática (54,5%), alteração da glicemia de jejum (19,2%), plaquetopenia (14,1%), hiperbilirrubinemia (11,6%) e alergia (2,7%). Em análise multivariada, as complicações infecciosas e o início de TARV durante a gestação foram fatores de risco para anemia materna, enquanto CD4 maior que 200 células/mm3 se mostrou fator de proteção. Esquemas com nevirapina, nelfinavir e atazanavir aumentaram o risco de alteração hepática e o lopinavir aumentou o risco de alteração da glicemia de jejum durante a gestação. Os efeitos adversos neonatais observados foram alteração hepática (36%), anemia (25,7%), baixo peso (22,5%), prematuridade (21,7%), crianças pequenas para idade gestacional (PIG) (18%), malformações congênitas (10,2%) e plaquetopenia (3,6%). As crianças PIG não apresentaram maior ocorrência de efeitos adversos ou maior TV do HIV. Em análise multivariada, o CD4 periparto maior que 200 células/mm3 foi protetor para baixo peso e prematuridade. A anemia neonatal esteve associada ao parto prematuro. A alteração hepática neonatal esteve associada à carga viral materna periparto detectável. Não houve associação entre exposição aos diferentes esquemas de TARV e o tempo de exposição às drogas maternas e prematuridade, baixo peso e malformação congênita. A exposição ao tenofovir foi protetora para a anemia neonatal em comparação à exposição a zidovudina materna. A exposição ao lopinavir/ritonavir foi protetora para a alteração hepática neonatal em comparação à exposição a nevirapina materna. Conclusão: com o uso de antirretrovirais, foram observadas altas taxas de efeitos adversos maternos e neonatais, porém de gravidade reduzida, corroborando a necessidade do adequado tratamento antirretroviral materno, com total supressão viral, a fim de se alcançar a menor taxa de TVAbstract: Antiretroviral therapy (ART) use in pregnancy presents unquestionable benefits in preventing mother-to-child HIV transmission (MTCT) although it is associated with maternal and neonatal adverse effects. Objective: To evaluate the effects of antiretroviral medication in pregnant women and their newborns. Subjects and Methods: Cohort study of pregnant women infected with HIV and their exposed newborns followed at the CAISM/UNICAMP Obstetric Clinic from 2000 to 2015. Maternal and neonatal adverse effects such as anemia thrombocytopenia, allergy, liver function tests abnormalities, dyslipidemia and diabetes were evaluated along with neonatal results such as preterm birth, low birth weight and birth defects. Data collected from patients' files was added to a specific database. Descriptive analysis was shown in terms of absolute (n) and relative (%) frequencies and mean, median and standard deviation calculations. Chi-square or Fisher exact test (n<5) and relative risk (RR) with its respective p values were used for categorical variables and t-Student (parametric data) or Mann-Whitney (non-parametric data) for the quantitative ones. The significant level used was 0.05. A multivariate Cox Logistic Regression was done. Statistical analysis was performed using SAS version 9.4. Results: Data from 793 pregnancies and 787 newborns were included in the analysis. MTCT rate was 2.3%, with 0.8% in the last 5 years. Maternal adverse effects were: dyslipidemia (82%), anemia (56%), liver function tests abnormalities (54.5%), fasting glycemia alterations (19.2%), thrombocytopenia (14.1%), hyperbilirubinemia (11.6%) and allergy (2.7%). In the multivariate analysis, coinfections and starting ART during pregnancy were risk factors for maternal anemia, while CD4 count higher than 200 cells/mm3 was protective. Nevirapine, nelfinavir and atazanavir regimens increased the risk for hepatic alterations, and lopinavir use during pregnancy increased the risk for fasting glycemia alterations. The observed neonatal adverse effects were: liver function tests abnormalities (36%), anemia (25.7%), low birth weight (22.5%), preterm birth (21.7%), children small for gestational age (SGA) (18%), birth defects (10.2%) and thrombocytopenia (3.6%). The SGA children did not present higher risk for adverse effects or MTCT. In the multivariate analysis, peripartum CD4 higher than 200 cells/mm3 was protective for low birth weight and preterm birth. Neonatal anemia was associated with preterm birth. Neonatal liver function tests abnormalities were associated with maternal detectable viral load at peripartum. There was no association between antiretroviral treatment regimen or time of ART exposure and preterm birth, low birth weight or birth defects. Tenofovir exposure was protective for neonatal anemia when compared to maternal zidovudine exposure. Exposure to lopinavir/ritonavir was protective for liver function tests abnormalities in comparison to maternal nevirapine exposure. Conclusion: ART use showed high rates of maternal and neonatal adverse effects with low severity, corroborating the need to adequate antiretroviral maternal treatment with total viral suppression aiming to reach lower MTCT ratesDoutoradoSaúde Materna e PerinatalDoutora em Ciências da Saúd

Hepatitis B Virus Surface Antigen Seroconversion In Hiv-infected Individual After Pegylated Interferon-alpha Treatment: A Case Report.

Hepatitis B virus (HBV) infects from 6 to 14% of HIV-infected individuals. Concurrent HIV/HBV infection occurs due to the overlapping routes of transmission, particularly sexual and parenteral. HIV-infected patients that have acute hepatitis B have six times greater risk of developing chronic hepatitis B, with higher viral replication, rapid progression to end-stage liver disease and shorter survival. The coinfection is also associated with poor response to hepatitis B treatment with interferon-alpha and increased liver toxicity to the antiretroviral therapy. Herein, we describe the case of a 35-year-old man who engages in sex with men and presented with newly diagnosed HIV-1, serological markers for acute hepatitis B and progression to chronic hepatitis B infection (HBsAg+ > 6 months, high alanine aminotransferase levels and moderate hepatitis as indicated by liver biopsy). Lacking indication of antiretroviral treatment (CD4 768 cells/mm3), he was treated with pegylated-interferon alpha2b (1.5 mg/kg/week) by subcutaneous injection for 48 weeks. Twelve weeks after treatment, the patient presented HBeAg seroconversion to anti-HBe. At the end of 48 weeks, he presented HBsAg seroconversion to anti-HBs. One year after treatment, the patient maintained sustained virological response (undetectable HBV-DNA). The initiation of antiretroviral therapy with nucleosides and nucleotides is recommended earlier for coinfected individuals. However, this report emphasizes that pegylated interferon remains an important therapeutic strategy to be considered for selected patients, in whom the initiation of HAART may be delayed.193

Mother-to-child transmission of human immunodeficiency virus in a cohort of pregnant women in Campinas from 2000 to 2009

Orientador: Helaine Maria Besteli Pires MilanezDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Objetivo: avaliar a transmissão vertical (TV) do HIV e fatores associados em gestantes soropositivas acompanhadas em um serviço universitário brasileiro (CAISM/UNICAMP) entre 2000 e 2009. Sujeitos e Métodos: coorte histórica de 452 gestações e seus recém-nascidos. Os dados foram coletados dos prontuários e registrados em fichas específicas. Crianças sem seguimento foram convocadas para definição diagnóstica. Análise dos dados: análise descritiva através de distribuição percentual e de médias; teste de X², exato de Fisher, t de Student, Mann-Whitney e ANOVA, razão de risco e intervalo de confiança. Resultados: A TV foi de 3,6%. A idade média das gestantes foi 27 anos; principal categoria de exposição foi a sexual (86,5%); 55% já apresentava o diagnóstico prévio à gravidez. Sessenta e dois por cento não estavam em uso de TARV ao engravidar. CD4 médio inicial foi de 474 células/ml e 70.3% apresentaram carga viral indetectável no terceiro trimestre. Como TARV, 55% usaram esquemas com IP e 35% com nevirapina. Monoterapia com AZT foi utilizada em 5,5%. Idade gestacional média no parto foi de 37,2 semanas e em 92% a via foi cesárea; 97,2% receberam AZT endovenoso. Os fatores associados à TV foram: baixa contagem de CD4, elevada carga viral, tempo reduzido de TARV, presença de alterações gestacionais (anemia, RCF, oligoâmnio), coinfecções durante o pré-natal (CMV e toxoplasmose) e presença de trabalho de parto. Uso de TARV potente, parto por cesárea e uso do AZT pelo RN foram fatores protetores. Má adesão ao tratamento esteve presente em 13 dos 15 casos infectados; em sete houve presença de coinfecção neonatal (CMV e toxoplasmose). Conclusão: Fatores de risco para TV foram comprometimento do estado imunológico da gestante, menor tempo de terapia, coinfecções (CMV e toxoplasmose) e presença de trabalho de parto. O uso de TARV potente e a realização de cesárea foram fatores protetores para a TV do HIV.Abstract: Objectives: to evaluate mother-to-child transmission (MTCT) rates and related factors in HIV-infected pregnant women from CAISM/UNICAMP between 2000 and 2009. Subjects and methods: cohort of 452 HIV-infected pregnant women and their newborns. Data was collected from recorded files and undiagnosed children were enrolled for investigation. Statistical analysis: qui-square test, Fisher exact test, Student t test, Mann-Whitney test, ANOVA, risk ratio and confidence intervals. Results: MTCT occurred in 3.6%. The study population displayed a mean age of 27 years; 86.5% were found to have acquired HIV through sexual contact; 55% were aware of the diagnosis prior to the pregnancy; 62% were not using HAART. Mean CD4 cell-count was 474 cells/ml and 70.3% had undetectable viral loads in the third trimester. HAART included nevirapine in 35% of cases and protease inhibitors in 55%; Zidovudine monotherapy was used in 5.5%. Mean gestational age at delivery was 37.2 weeks and in 92% by caesarian section; 97.2% received intravenous zidovudine. Implicated factors related to MTCT were: low CD4 cell counts, elevated viral loads, maternal aids, shorter periods receiving HAART, maternal concurring illnesses (anemia, IUGR, oligodydramnium), coinfections (CMV and toxoplasmosis) and the occurrence of labor. Use of HAART for longer periods, caesarian delivery and oral zidovudine for the newborns were associated with a decreased risk. Poor adhesion to treatment was present in 13 of the 15 cases of transmission; in 7, co-infections were diagnosed (CMV and toxoplasmosis). Conclusion: Use of HAART and caesarian delivery are protective factors in mother-to-child transmission of HIV. Maternal coinfecctions and maternal concurring illnesses were risk factors for MTCT.Universidade Estadual de CampiCiencias BiomedicasMestre em Tocoginecologi

Hepatitis B virus surface antigen seroconversion in HIV-infected individual after pegylated interferon-alpha treatment: a case report

Hepatitis B virus (HBV) infects from 6 to 14% of HIV-infected individuals. Concurrent HIV/HBV infection occurs due to the overlapping routes of transmission, particularly sexual and parenteral. HIV-infected patients that have acute hepatitis B have six times greater risk of developing chronic hepatitis B, with higher viral replication, rapid progression to end-stage liver disease and shorter survival. The coinfection is also associated with poor response to hepatitis B treatment with interferon-alpha and increased liver toxicity to the antiretroviral therapy. Herein, we describe the case of a 35-year-old man who engages in sex with men and presented with newly diagnosed HIV-1, serological markers for acute hepatitis B and progression to chronic hepatitis B infection (HBsAg+ > 6 months, high alanine aminotransferase levels and moderate hepatitis as indicated by liver biopsy). Lacking indication of antiretroviral treatment (CD4 768 cells/mm 3 ), he was treated with pegylated-interferon alpha2b (1.5 mg/kg/week) by subcutaneous injection for 48 weeks. Twelve weeks after treatment, the patient presented HBeAg seroconversion to anti-HBe. At the end of 48 weeks, he presented HBsAg seroconversion to anti-HBs. One year after treatment, the patient maintained sustained virological response (undetectable HBV-DNA). The initiation of antiretroviral therapy with nucleosides and nucleotides is recommended earlier for coinfected individuals. However, this report emphasizes that pegylated interferon remains an important therapeutic strategy to be considered for selected patients, in whom the initiation of HAART may be delayed