BackgroundThe safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean.Methods480 participants were evenly randomized to receive either: DNA (4 mg IM by Biojector) at 0, 1 and 2 months, followed by rAd5 (1010 PU IM by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost.ResultsThe vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%–94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients.ConclusionThe vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies.Trial Registration:ClinicalTrials.gov NCT00125970

BackgroundDNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques.Methodology/Principal FindingsWe performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response.Conclusions/SignificanceThis combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity.Trial RegistrationClinicaltrials.gov NCT00115960 NCT00111605

Resumo: Dentre os princípios do SUS, o de integralidade talvez seja o mais desafiador na construção da Reforma Sanitária. É objetivo deste estudo identificar momentos críticos do debate conceitual em torno da integralidade e suas contribuições para a reflexão acerca de tecnologias de atenção à saúde no âmbito do SUS. O ensaio percorre algumas construções conceituais que se aproximam da questão da integralidade como princípio norteador de programas e ações de saúde em diversos planos e dimensões da organização da atenção à saúde - das interações intersubjetivas à organização de redes regionais. O estudo se baseou em revisão não sistemática da literatura sobre o tema da integralidade e afins na produção do campo da Saúde Coletiva brasileira nas últimas cinco décadas. Propõe-se uma cronologia/tipologia que se estende dos anos 1960 à década de 2010, dividindo-a em quatro períodos/categorias julgados significativos. A narrativa não pretende ser exaustiva, mas construir uma referência compreensiva capaz de contribuir para análises, avaliações e debates acerca da organização da atenção à saúde no SUS conforme o princípio da integralidade.

We evaluated replication-defective poxvirus vectors (modified vaccinia Ankara [MVA] and fowlpox [FPV]) in a homologous and heterologous vector prime-boost vaccination regimen containing matching HIV inserts (MVA-HIV and FPV-HIV) given at months 0, 1, 3, 5 and 7 in 150 healthy HIV-negative vaccinia-naïve participants. FPV-HIV alone was poorly immunogenic, while the high dose (10 9 NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2011 February 24.Published in final edited form as: Vaccine. 2011 February 24; 29(10): 1948-1958. doi:10.1016/j.vaccine.2010. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript boost. Thus, a heterologous poxvirus vector prime-boost regimen can induce an HIV-specific CD8+ T-cell and CD4+ T-cell responses, which may be an important feature of an optimal regimen for preventive HIV vaccination.

BackgroundThe HIV-Brazil Cohort Study was established to analyze the effectiveness of combination antiretroviral therapy (cART) and the impact of this treatment on morbidity, quality of life (QOL) and mortality. The study design, patients’ profiles and characteristics of cART initiation between 2003 and 2010 were described.Methodology/Principal FindingsSince 2003, the HIV-Brazil Cohort has been following HIV-infected adults receiving cART at 26 public health care facilities, using routine clinical care data and self-reported QOL questionnaires. When not otherwise available, data are obtained from national information systems. The main outcomes of interest are diseases related or unrelated to HIV; suppression of viral replication; adverse events; virological, clinical and immunological failures; changes in the cART; and mortality. For the 5,061 patients who started cART between 2003 and 2010, the median follow-up time was 4.1 years (IQR 2.2–5.9 years) with an 83.4% retention rate. Patient profiles were characterized by a predominance of men (male/female ratio 1.7∶1), with a mean age of 36.9 years (SD 9.9 years); 55.2% had been infected with HIV via heterosexual contact. The majority of patients (53.4%) initiated cART with a CD4+ T-cell count ≤200 cells/mm3. The medications most often used in the various treatment regimens were efavirenz (59.7%) and lopinavir/ritonavir (18.2%). The proportion of individuals achieving viral suppression within the first 12 months of cART use was 77.4% (95% CI 76.1–78.6). Nearly half (45.4%) of the patients presented HIV-related clinical manifestations after starting cART, and the AIDS mortality rate was 13.9 per 1,000 person-years.Conclusions/SignificanceResults from cART use in the daily practice of health services remain relatively unknown in low- and middle-income countries, and studies with the characteristics of the HIV-Brazil Cohort contribute to minimizing these shortcomings, given its scope and patient profile, which is similar to that of the AIDS epidemic in the country.

Introduction Since 2015, the World Health Organization (WHO) has recommended that all people living with HIV (PLHIV) initiate antiretroviral treatment (ART), irrespective of CD4+ count or clinical stage. National adoption of universal treatment has accelerated since WHO's 2015 “Treat All” recommendation; however, little is known about the translation of this guidance into practice. This study aimed to assess the status of Treat All implementation across regions, countries, and levels of the health care delivery system. Methods Between June and December 2017, 201/221 (91%) adult HIV treatment sites that participate in the global IeDEA research consortium completed a survey on capacity and practices related to HIV care. Located in 41 countries across seven geographic regions, sites provided information on the status and timing of site‐level introduction of Treat All, as well as site‐level practices related to ART initiation. Results Almost all sites (93%) reported that they had begun implementing Treat All, and there were no statistically significant differences in site‐level Treat All introduction by health facility type, urban/rural location, sector (public/private) or country income level. The median time between national policy adoption and site‐level introduction was one month. In countries where Treat All was not yet adopted in national guidelines, 69% of sites reported initiating all patients on ART, regardless of clinical criteria, and these sites had been implementing Treat All for a median period of seven months at the time of the survey. The majority of sites (77%) reported typically initiating patients on ART within 14 days of confirming diagnosis, with 60% to 62% of sites implementing Treat All in East, Southern and West Africa reporting same‐day ART initiation for most patients. Conclusions By mid‐ to late‐2017, the Treat All strategy was the standard of care at almost all IeDEA sites, including rural, primary‐level health facilities in low‐resource settings. While further assessments of site‐level capacity to provide high‐quality HIV care under Treat All and to support sustained viral suppression after ART initiation are needed, the widespread introduction of Treat All at the service delivery level is a critical step towards global targets for ending the HIV epidemic as a public health threat.

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