Molecular Epidemiology of the virus of the imunodeficiência human being type 1 (HIV-1) in cities of the interior of the State of Rio de Janeiro, with emphasis in the cities of Miracema, Santo Antonio de Pádua and Saquarema, 2001 the 2006. / Epidemiologia Molecular do Vírus da Imunodeficiência Humana Tipo 1 (HIV-1) em Municípios do Interior do Estado do Rio de Janeiro, com Ênfase nas Cidades de Miracema, Santo Antonio de Pádua e Saquarema, 2001 a 2006.

AUTOR(ES)
DATA DE PUBLICAÇÃO

2007

RESUMO

The AIDS epidemic in Brazil is spreading from the large urban centers to small cities and the innermost parts of the country, yet data on the features of HIV-1 infection in these places are scarce. Such spread is expected to pose formidable medical, social and logistic challenges. By using mainly HIV-1 envelope and polymerase genomic regions, the studies that compose this thesis try to translate HIV-1 nucleotide sequences into knowledge on viral genetic diversity, molecular epidemiology and prevalence of antiretroviral drug resistance in inner Rio de Janeiro State. Not being feasible to study in detail all inner municipalities of the State, we focus our magnifying lens of investigation into three inner cities chosen as a convenience sample: Miracema and Santo Antonio de Pádua, in the northwestern sub-region, and Saquarema, in the Sun Coast sub-region. In these places we might perhaps extract useful information that will lead to a better understanding of the features of HIV-1 spread towards inner Rio de Janeiro State and Brazil. Between July 1999 and May 2006 a total of 208 adult patients received care in the municipal HIV-1/AIDS program established in these cities. A portrait of a heterosexual epidemic emerged, with a male to female ratio of 1.1. Almost 60% of the patients first presented in advanced stages of HIV-1 disease, which suggests the existence of a large pool of undiagnosed cases in the community. Variables age and male gender were independent predictors of an AIDS-defining CDC stage at presentation. More than 90% of the patients were residents of the studied cities, which demonstrate a huge local demand for HIV-1-related counseling, testing and treatment. Therefore, the establishment of as many municipal HIV-1/AIDS programs should stand as a priority in our efforts to halt epidemic spread towards inner Brazil. We report a low frequency of male circumcision, an important determinant of HIV-1 heterosexual transmission. Around one fourth of the cohort reported past use of inhaled cocaine. A total of 14.5% of CDC stage C patients from the 2 northwestern cities developed meningoencephalitis due to Cryptococcus neoformans. To the molecular epidemiology analyses we had the opportunity to study isolated cases from 26 additional, non-metropolitan cities of the State. HIV-1 sequences were generated from samples from a total of 221 patients. Sequences were assigned subtypes B (190; 86%), F1 (14; 6.3%), CEF02_AG (2; 0.9%), and D (2; 0.9%), as well as BF1 intersubtype recombinant forms (13; 5.9%). Subtypes B and F1 are the most prevalent lineages in southeast Brazil, whereas subtypes D and CRF02_AG had previously been reported only from isolated cases in the capital of Rio de Janeiro State. Moreover, we present the first molecular evidence of autochthonous transmission of CRF02_AG in Brazil, an HIV-1 lineage of major global importance. Phylogenetic analysis of subtype D strains, in conjunction with other subtype D representatives generated in our laboratory, demonstrated that Brazilian autochthonous subtype D sequences share close genetic relatedness with subtype D strains reported in the 1980s from South Africa, a country were this lineage occurs only in isolated cases. Our data suggest that this subtype has been successfully introduced in southeast Brazil as the founder effect of an ancestral sequence of possible South African origin. One of the BF1 recombinant strains was sequenced to full genome and found to share the same recombinant breakpoints with other 3 strains recovered from different studies from our laboratory, thus potentially standing as novel Brazilian CRF_BF. Data on the efficacy of antiretroviral therapy, performed by targeting the proviral compartment, demonstrate that 70% of the patients under treatment as of sampling had a plasma viral load below detection limit. One case of primary resistance among 84 treatment-naïve subjects was recorded. Among samples from patients under antiretroviral therapy as of sampling, 31.1% had evidence of reduced susceptibility to at least one antiretroviral drug. Only 5 cases of reduced susceptibility to protease inhibitors were recorded among the whole cohort. The relatively low prevalence of antiretroviral drug resistance in these underprivileged settings contributes to the debate on the convenience of offering universal access to antiretroviral combinations in the underdeveloped world. Our data suggest that underprivileged communities should not have denied their right to state-of-the-art antiretroviral combinations due to the possibility of suboptimal adherence leading to the emergence and spread of resistant variants. Phylogenetic analyses of viral sequences provided evidence of a polyphyletic pattern suggestive of multiple viral introductions in the studied cities. Also, we recorded the occurrence of multiple monophyletic clusters of sequences that share close genetic relatedness. These sequences were generated from samples obtained from patients who probably took part in the same chain of viral spread, suggesting the existence of sexual networks and a high incidence molecular profile. Logistic regression analyses have found that always having lived in the studied city and having a known epidemiologic link within the cohort were independent predictors of being a patient whose sample yielded clustered sequences. The high frequency of samples that generated clustered sequences is an indication that multiple new infections have occurred in a relatively short period of time and further highlights the urgent need to perform incidence studies in inner Brazil. Coalescent analyses suggest that the most recent common ancestors that triggered the 2 largest transmission chains recorded in the city of Miracema were in circulation in the early 1990s. The demonstration that the dissemination of these viral lineages was already taking place at a time AIDS was considered a problem mainly restricted to the large urban areas of the country may have important public health implications. Phylogenetic analyses also demonstrated that monophyletic clusters from Miracema were phylogenetically unrelated to those from the neighboring Santo Antonio de Pádua, suggesting that in spite of being very close to each other, each city experienced the independent introduction and subsequent dissemination of different subtype B lineages, in a pattern that resembles multiple scattered micro-epidemics. Phylogenetic reconstructions of envelope and polymerase data sets yielded the same overall results, thus demonstrating that in spite of being a relatively conserved region of HIV-1 genome, polymerase sequences, which are being increasingly generated to allow genotypic analyses of drug resistance, can also be useful to studies of epidemiologic relationships between populations, groups and people.

ASSUNTO(S)

anti-retroviral agents hiv-1 anti-retrovirais biologia molecular epidemiologia molecular acquired immunodeficiency syndrome hiv-1 epidemiology, molecular síndrome de imunodeficiência adquirida

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