Effectiveness of Highly Active Antiretroviral Therapy in HIV patients in resource-limited settings

The HIV pandemic has posed an unprecedented challenge to the global health, devastating communities and reinforcing the historical problems that link ill-health with poverty. Sound evidence for public health decision-making is needed as antiretroviral programmes are being rolled out in developing countries. This thesis discusses the effectiveness of Highly Active Antiretroviral Therapy (HAART) in resource-limited countries from the Antiretroviral Therapy in Lower Income Countries (ART-LINC), a network of HIV/AIDS treatment programmes and cohorts in Africa, South America, and Asia. The objectives of this project were to document the effectiveness of HAART in these settings, defined by changes in immunologic and virologic markers within 6 months of treatment; assess factors associated with 6-month response to therapy; and to assess the association of 6 month response with long-term outcomes.In the first article, the evidence supporting effectiveness of HAART is reviewed, focusing on aspects of immunologic and virologic responses to therapy. Despite the lack of a standardized definition of immunologic and virologic response, we conclude that around one third of the patients who start HAART show a response pattern where either immunologic or virologic response is not achieved, a condition referred to as discordant response. The second and third articles provide a picture of the association between HAART and 6-month response in resource-limited countries. Overall, the effectiveness of HAART in these settings is similar to that reported in resource-rich countries. Finally, we assessed the association between immunologic and virologic discordant responses at 6 months and mortality in ART-LINC. We found that the hazard of death for those showing discordance at 6 months was similar to that reported in resource-rich countries. However, we found that early mortality was high in Africa and Asia, and a significant proportion of patients that did not have access to laboratory measurements were also at greater risk of death. This is the first report on the association of discordant responses and mortality in lower income countries, which provides important evidence for public health decision making in the context of antiretroviral rollout

Rates and Reasons for Early Change of First HAART in HIV-1-Infected Patients in 7 Sites throughout the Caribbean and Latin America

BACKGROUND: HAART rollout in Latin America and the Caribbean has increased from approximately 210,000 in 2003 to 390,000 patients in 2007, covering 62% (51%-70%) of eligible patients, with considerable variation among countries. No multi-cohort study has examined rates of and reasons for change of initial HAART in this region. METHODOLOGY: Antiretroviral-naïve patients >or= 18 years who started HAART between 1996 and 2007 and had at least one follow-up visit from sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico and Peru were included. Time from HAART initiation to change (stopping or switching any antiretrovirals) was estimated using Kaplan-Meier techniques. Cox proportional hazards modeled the associations between change and demographics, initial regimen, baseline CD4 count, and clinical stage. PRINCIPAL FINDINGS: Of 5026 HIV-infected patients, 35% were female, median age at HAART initiation was 37 years (interquartile range [IQR], 31-44), and median CD4 count was 105 cells/uL (IQR, 38-200). Estimated probabilities of changing within 3 months and one year of HAART initiation were 16% (95% confidence interval (CI) 15-17%) and 28% (95% CI 27-29%), respectively. Efavirenz-based regimens and no clinical AIDS at HAART initiation were associated with lower risk of change (hazard ratio (HR) = 1.7 (95% CI 1.1-2.6) and 2.1 (95% CI 1.7-2.5) comparing neverapine-based regimens and other regimens to efavirenz, respectively; HR = 1.3 (95% CI 1.1-1.5) for clinical AIDS at HAART initiation). The primary reason for change among HAART initiators were adverse events (14%), death (5.7%) and failure (1.3%) with specific toxicities varying among sites. After change, most patients remained in first line regimens. CONCLUSIONS: Adverse events were the leading cause for changing initial HAART. Predictors for change due to any reason were AIDS at baseline and the use of a non-efavirenz containing regimen. Differences between participant sites were observed and require further investigation

Increase in Non-AIDS Related Conditions as Causes of Death among HIV-Infected Individuals in the HAART Era in Brazil

Background. In 1996, Brazil became the first developing country to provide free and universal access to HAART. Although a decrease in overall mortality has been documented, there are no published data on the impact of HAART on causes of death among HIV-infected individuals in Brazil. We assessed temporal trends of mortality due to cardiovascular diseases (CVD), diabetes mellitus (DM) and other conditions generally not associated with HIV-infection among persons with and without HIV infection in Brazil between 1999 and 2004. Methodology/Principal Findings. Odds ratios were used to compare causes of death in individuals who had HIV/AIDS listed on any field of the death certificate with those who did not. Logistic regression models were fitted with generalized estimating equations to account for spatial correlation; co-variables were added to the models to control for potential confounding. Of 5,856,056 deaths reported in Brazil between 1999 and 2004 67,249 (1.15%) had HIV/AIDS listed on the death certificate and non-HIV-related conditions were listed on 16.3% in 1999, Increasing to 24.1% by 2004 (p<0.001) The adjusted average yearly increases were 8% and 0.8% for CVD (p<0.001), and 12% and 2.8% for DM (p<0.001), for those who had and kiki not have HIV/AIDS listed on the death certificate respectively. Similar results were found for these conditions as underlying causes of death. Conclusions/Significance. In Brazil between 1999 and 2004 conditions usually considered not to be related to HIV-infection appeared to become more likely causes of death over time than reported causes of death among individuals who had HIV/AIDS listed on the death certificate than in those who did not. This observation has important programmatic implications for developing countries that are scaling-up access to antiretroviral therapy. © 2008 Pacheco et al

Waterborne Toxoplasmosis, Brazil, from Field to Gene

Water was the suspected vehicle of Toxoplasma gondii dissemination in a toxoplasmosis outbreak in Brazil. A case-control study and geographic mapping of cases were performed. T. gondii was isolated directly from the implicated water and genotyped as SAG 2 type I

Continuous increase of cardiovascular diseases, diabetes, and non-HIV related cancers as causes of death in HIV-infected individuals in Brazil: An analysis of nationwide data

Introduction: After antiretroviral therapy (ART) became available, there was a decline in the number of deaths in persons infected with HIV. Thereafter, there was a decrease in the proportion of deaths attributed to opportunistic infections and an increase in the proportion of deaths attributed to chronic comorbidities. Herein we extend previous observations from a nationwide survey on temporal trends in causes of death in HIV-infected patients in Brazil. Methods: We describe temporal trends in causes of death among adults who had HIV/AIDS listed in the death certificate to those who did not. All death certificates issued in Brazil from 1999 to 2011 and listed in the national mortality database were included. Generalized linear mixed-effects logistic models were used to study temporal trends in proportions. Results: In the HIV-infected population, there was an annual adjusted average increase of 6.0%, 12.0%, 4.0% and 4.1% for cancer, external causes, cardiovascular diseases (CVD) and diabetes mellitus (DM), respectively, compared to 3.0%, 4.0%, 1.0% and 3.9%, in the non-HIV group. For tuberculosis (TB), there was an adjusted average increase of 0.3%/year and a decrease of 3.0%/year in the HIV and the non-HIV groups, respectively. Compared to 1999, the odds ratio (OR) for cancer, external causes, CVD, DM, or TB in the HIV group were, respectively, 2.31, 4.17, 1.76, 2.27 and 1.02, while for the non-HIV group, the corresponding OR were 1.31, 1.63, 1.14, 1.62 and 0.67. Interactions between year as a continuous or categorical variable and HIV were significant (p <0.001) for all conditions, except for DM when year was considered as a continuous variable (p = 0.76). Conclusions: Non HIV-related co-morbidities continue to increase more rapidly as causes of death among HIV-infected individuals than in those without HIV infection, highlighting the need for targeting prevention measures and surveillance for chronic diseases among those patients. © 2014 Paula et al

Avaliação da imunogenicidade da vacina contra hepatite B em pacientes infectados pelo virus da imunodeficiencia humana

Orientador: Priscila Maria de Oliveira PapaiordanouDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências MédicasResumo: É freqüente a associação entre o vírus da hepatite B HBV e o vírus da Imunodeficiência Humana (HIV) devido ao fato de ambos compartilharem semelhantes modos de transmissão: parenteral, sexual e vertical. Entre pacientes HIV, a transição para infecção crônica é o padrão evolutivo mais encontrado, possivelmente relacionado à deficiente resposta do sistema imune. A despeito da baixa ocorrência de cirrose entre esses pacientes, observa-se alto grau de replicação do HBV, aumentando, conseqüentemente, seu potencial de contagiosidade. Esse fato é de grande importância no planejamento de estratégias para o controle dessa doença. É reconhecida a precária resposta à vacina contra hepatite B apresentada por pacientes infectados pelo HIV, quando comparados à população hígida. Essa falta de resposta foi bem documentada em diversos trabalhos e refere-se a ambos os tipos de vacina (derivada de plasma e de DNA recombinante). O presente estudo avaliou a imunogenicidade da vacina de DNA recombinante contra hepatite B em 109 portadores do HIV e os fatores associados a melhor resposta. Foram avaliadas as seguintes variáveis: sexo, idade, fudice de massa corpórea, tabagismo, estadiamento clínico, contagem de linfócitos T CD4 e carga viral. A taxa de soroconversão encontrada foi de 59,6%. Pacientes com contagem de linfócitos T CD4 superiores a 500 céls/mm3 tiveram uma chance 5,1 vezes maior de responder à vacinaAbstract: Not informed.MestradoClinica MedicaMestre em Clinica Medic

Safety and immunogenicity of one versus two doses of Takeda\u27s tetravalent dengue vaccine in children in Asia and Latin America: Interim results from a phase 2, randomised, placebo-controlled study

© 2017 Elsevier Ltd Background Dengue is the most common mosquito-borne viral disease in human beings, and vector control has not halted its spread worldwide. A dengue vaccine for individuals aged 9 years and older has been licensed, but there remains urgent medical need for a vaccine that is safe and effective against all four dengue virus serotypes (DENV-1–4) in recipients of all ages. Here, we present the preplanned interim analyses at 6 months of a tetravalent dengue vaccine candidate (TDV), which is comprised of an attenuated DENV-2 virus strain (TDV-2) and three chimeric viruses containing the premembrane and envelope protein genes of DENV-1, DENV-3, and DENV-4 genetically engineered into the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4). Methods An ongoing phase 2, randomised, double-blind, placebo-controlled trial of a TDV is being done at three sites in dengue-endemic countries (Dominican Republic, Panama, and the Philippines) to determine its safety and immunogenicity over 48 months in healthy participants aged 2–17 years who were randomly assigned (1:2:5:1) using an interactive web response system (stratified by age) to subcutaneous TDV injection (one 0·5 mL dose containing 2·5 × 104 plaque-forming units [PFU] of TDV-1; 6·3 × 103 PFU of TDV-2; 3·2 × 104 PFU of TDV-3; and 4·0 × 105 PFU of TDV-4) in different dose schedules (two-dose regimen at 0 and 3 months, one dose at 0 months, or one dose at 0 months and a booster at 12 months) or placebo. The primary endpoint of this 6 month interim analysis was geometric mean titres (GMTs) of neutralising antibodies against DENV-1–4 in the per-protocol immunogenicity subset at 1 month, 3 months, and 6 months after the first injection. Safety was assessed as a secondary outcome as percentage of participants with serious adverse events in all participants who were injected (safety set), and solicited and unsolicited adverse events (immunogenicity subset). This trial is registered with ClinicalTrials.gov, number NCT02302066. Findings 1800 participants were enrolled between Dec 5, 2014, and Feb 13, 2015. 1794 participants were given study injection as follows: 200 participants were given two-dose regimen at 0 and 3 months (group 1), 398 were given one dose at 0 months (group 2), 998 were given one dose at 0 months and will be given (trial ongoing) a booster at 12 months (group 3), and 198 were given placebo (group 4). These 1794 participants were included in the safety set; 562 participants were randomly assigned to the immunogenicity subset, of which 503 were included in the per-protocol set. TDV elicited neutralising antibodies against all DENV serotypes, which peaked at 1 month and remained elevated above baseline at 6 months. At 6 months, GMTs of neutralising antibodies against DENV-1 were 489 (95% CI 321–746) for group 1, 434 (306–615) for group 2, 532 (384–738) for group 3, and 62 (32–120) for group 4; GMTs of neutralising antibodies against DENV-2 were 1565 (1145–2140) for group 1, 1639 (1286–2088) for group 2, 1288 (1031–1610) for group 3, and 86 (44–169) for group 4; GMTs of neutralising antibodies against DENV-3 were 160 (104–248) for group 1, 151 (106–214) for group 2, 173 (124–240) for group 3, and 40 (23–71) for group 4; and GMTs of neutralising antibodies against DENV-4 were 117 (79–175) for group 1, 110 (80–149) for group 2, 93 (69–125) for group 3, and 24 (15–38) for group 4. No vaccine-related serious adverse events occurred; 15 (3%) of 562 participants in the immunogenicity subset reported vaccine-related unsolicited adverse events. The reactogenicity profile of TDV was acceptable, and similar to previous findings with TDV. Interpretation TDV is safe and immunogenic in individuals aged 2–17 years, irrespective of previous dengue exposure. A second TDV dose induced enhanced immunogenicity against DENV-3 and DENV-4 in children who were seronegative before vaccination. These data supported the initiation of phase 3 evaluation of the efficacy and safety of TDV given in a two-dose schedule 3 months apart, with analyses that take into account baseline age and dengue serostatus. Funding Takeda Vaccines