Prevalência de resistência primária em pacientes HIV-1 positivos com diferentes subtipos virais no extremo sul do Brasil 2005-2008

Abstract

Brazil has a program which is a model in the prevention, diagnosis and treatment of HIV-1 infections. Besides, the regional monitoring of molecular epistemology and transmitted drug resistance (TDR) are essential. The studies of HIV-1 mutations usually include protease (PR) and polymerase regions of reverse transcriptase (RT), however, recent studies have shown that mutations in the Cterminal of RT domains may contribute to primary or compensatory resistance in the presence or absence of timidine analog mutation (TAM). Regarding the HIV-1 genetic heterogeneity, the southern region has shown a pattern which is different from the whole countrys: there is predominance of subtype C, followed by B, recombined forms and subtype F1. Objectives: to evaluate the prevalence of TDR in patients who have just been diagnosed with HIV-1 infection with different viral subtypes in the very south of Brazil and to correlate these data to the demographic, behavioral, clinical and laboratorial characteristics of the population under study. Patients and methods: A transversal study with patients who had not undergone HAART (High Activity Antiretroviral Therapy), diagnosed from January 2005 to December 2008 in the university hospital that belongs to the Universidade Federal do Rio Grande, RS, was carried out. Genomic viral regions which refer to the protease (PR) and the polymerase regions, Connection (CN) and the RNase H of the reverse transcriptase (RT) were sequenced. The viral subtype was determined by using reference-sequences obtained from the Los Alamos database. Sequences in which the attributed subtype varied according to the genomic region underwent recombination analyses in the Simplot program. The research on TDR mutations was carried out in the Stanford HIV database and analyzed according to the specific TDR algorithm. In the CN and RNase H domains, the mutations that were considered in this research were: N348I; 360V; T369I/V; A371V and A400T in CN and I506L, Q509L and Q547K in RNase H. A database with the variables under study was assembled in an Excel program for further statistical analysis in Stata10.2. In order to study the association of subtypes and the mutations of resistance with the variables, the Chi square test, the Fischers exact test, the Students t-test and the Kruskal-Wallis non-parametric test were applied. Results: Molecular analyses of 245 isolates were obtained and the correlation with the clinical data was studied in 231 patients; 46.8% of them met the AIDS criteria. Subtype C was responsible for 56.3% of infections and associated with heterosexuality (p=0.001) and the highest LTCD4+ counting (p=0.02). The prevalence of TDR in the polymerase domain of PR and RT was 6.56%, with 3.45% to NRTI and NNRTI; 1.42% to IP and 1.64% MRD. In the CN region, the prevalence of resistance was 36%, with 3.65% to A371V; 1.82% to T369I/V and 32.92% to A400T. In the RNase H domain, the prevalence of resistance was 3.57%, with 2.98% to Q547K and 0.60% to I506L. Mutations A360V, N348I and Q509L were not found. The association of the mutations of resistance in the C-terminal domains with the subtypes showed that C had lower TDR in CN (p=0.001) due to the substitution A400T, present in 36% of the isolates which had lower prevalence in this subtype (p= 0.001) and in RNase H (p= 0.003). Conclusions: The molecular epidemiology of HIV-1 has been stabilized with predominance of subtype C in the very south of Brazil. This is the first study which shows the association of subtype C and the HIV-1 heterosexual transmission in Brazil. The prevalence of TDR in the polymerase region of RT and PR is low and was not associated with the subtypes. However, there was meaningful association among TDR and viral groups in the C-terminal domains.