RESUMO
Associations between HLA class I alleles and HIV progression in populations exhibiting Amerindian and Caucasian genetic admixture remain understudied. Using univariable and multivariable analyses we evaluated HLA associations with five HIV clinical parameters in 3,213 HIV clade B-infected, ART-naïve individuals from Mexico and Central America (MEX/CAM cohort). A Canadian cohort (HOMER, n = 1622) was used for comparison. As expected, HLA allele frequencies in MEX/CAM and HOMER differed markedly. In MEX/CAM, 13 HLA-A, 24 HLA-B, and 14 HLA-C alleles were significantly associated with at least one clinical parameter. These included previously described protective (e.g. B*27:05, B*57:01/02/03 and B*58:01) and risk (e.g. B*35:02) alleles, as well as novel ones (e.g. A*03:01, B*15:39 and B*39:02 identified as protective, and A*68:03/05, B*15:30, B*35:12/14, B*39:01/06, B*39:05~C*07:02, and B*40:01~C*03:04 identified as risk). Interestingly, both protective (e.g. B*39:02) and risk (e.g. B*39:01/05/06) subtypes were identified within the common and genetically diverse HLA-B*39 allele group, characteristic to Amerindian populations. While HLA-HIV associations identified in MEX and CAM separately were similar overall (Spearman's rho = 0.33, p = 0.03), region-specific associations were also noted. The identification of both canonical and novel HLA/HIV associations provides a first step towards improved understanding of HIV immune control among unique and understudied Mestizo populations.
Assuntos
Infecções por HIV/genética , HIV-1/isolamento & purificação , Antígenos HLA/genética , Adulto , Canadá/epidemiologia , América Central/epidemiologia , Estudos de Coortes , Feminino , Frequência do Gene , Genética Populacional , Genótipo , Infecções por HIV/epidemiologia , Humanos , Desequilíbrio de Ligação , Masculino , México/epidemiologia , Polimorfismo Genético , Adulto JovemRESUMO
BACKGROUND: Field-friendly methods for HIV drug resistance (HIVDR) surveillance in resource-limited regions are urgently needed. Despite evidence that dried blood spots (DBS) are suitable for HIV serology, viral load and CD4+ T-cell enumeration, no study has evaluated DBS for HIVDR genotyping. We assessed the feasibility of genotyping HIV-1 from field-collected DBS stored under challenging environmental conditions. METHODS: We prospectively collected specimens from newly diagnosed, treatment-naive HIV-positive subjects in Mexico. Whole blood was spotted onto filter cards, air dried at ambient temperature and stored with desiccant at 37 degrees C and 85% humidity for 3 months. Genotypes obtained from DBS-extracted nucleic acids using an in-house nested reverse transcription-PCR method were compared to genotypes derived from matched plasma. RESULTS: Genotypes from 103 phylogenetically matched plasma and DBS were compared. In total, 90.1% of all DBS specimens could be amplified in either the region of HIV protease or the region of reverse transcriptase. Failure to amplify from DBS did not correlate with low plasma viral loads. Between paired specimens, the median nucleotide similarity was 99.95%. In the nine specimens with drug resistance mutations, all differences between pairs were partial discordances. Mutations identified in plasma were found in the majority of replicate DBS amplifications. CONCLUSION: The results suggest that genotypes obtained from DBS are equivalent to those from plasma. DBS are a promising public health tool for HIVDR surveillance of treatment-naive subjects, especially in regions where specimens might be exposed to severe environmental conditions and where logistical difficulties could prevent timely specimen processing. More studies are needed to validate DBS for patient monitoring.
Assuntos
Coleta de Amostras Sanguíneas/métodos , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , RNA Viral/sangue , Adolescente , Adulto , Idoso , Estudos de Viabilidade , Feminino , Genótipo , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/enzimologia , Humanos , Masculino , México , Pessoa de Meia-Idade , Mutação , Filogenia , Estudos Prospectivos , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Conflicting evidence regarding the impact of baseline plasma HIV RNA and CD4 cell count on survival after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients has resulted in wide variability in the expert recommendations regarding when to start therapy. Early initiation of HAART may result in avoidable toxicities and premature evolution of resistance, whereas delaying HAART may increase the risk of opportunistic infections and/or preclude a worse virological and clinical response to therapy. While there is widespread consensus that HAART can be delayed to a CD4 cell count of 0.350 x 10(9) cells/L, the range between this threshold and 0.200 x 10(9) cells/L remains controversial. Greater uncertainty surrounds the role of baseline plasma HIV RNA, with some guidelines recommending initiating HAART when this level rises above 55,000 c/mL regardless of baseline CD4 cell count. The following review examines the evidence in support of delaying the initiation of HAART to a CD4 cell count of 0.200 x 10(9) cells/L regardless of plasma HIV RNA levels and outlines supporting data from a Canadian prospective cohort study of antiretroviral naive patients treated with HAART.
Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV/genética , RNA/sangue , Contagem de Linfócito CD4 , Humanos , Guias de Prática Clínica como AssuntoRESUMO
Conflicting evidence regarding the impact of baseline plasma HIV RNA and CD4 cell count on survival after the initiation of highly active antiretroviral therapy (HAART) in HIV-infected patients has resulted in wide variability in the expert recommendations regarding the when to start therapy. Early initiation of HAART may result in avoidable toxicities and premature evolution of resistance, whereas delaying HAART may increase the risk of opportunistic infections and/or preclude a worse virological and clinical response to therapy. While there is widespread consensus that HAART can be delayed to a CD4 cell count of 0.350 x 10 9 cells/L, the range between this threshold and 0.200 x 10 9 cells/L remains controversial. Greater uncertainty surrounds the role of baseline plasma HIV RNA, with some guidelines recommending initiating HAART when this level rises above 55,000 c/mL regardless of baseline CD4 cell count. The following review examines the evidence in support of delaying the initiation of HAART to a CD4 cell count of 0.200 x 10 9 cells/L regardless of plasma HIV RNA levels and outlines supporting data from a Canadian prospective cohort study of antiretroviral naïve patients treated with HAART. KEY WORDS. Plasma viral load. Adherence. Viral load supression. Virologic failure. Survival.
La carga viral plasmática y el nivel de los linfocitos CD4+ en la sangre son marcadores biológicos de alto valor pronóstico, en lo que se refiere a la historia natural de la infección por HIV. Esto ha sido demostrado en forma terminante en pacientes no tratados. El impacto y valor relativo de dichos marcadores en el pronóstico de pacientes que inician terapia antirretroviral no está totalmente aclarado. Esto ha generado opiniones diversas en la literatura médica, especialmente en lo que se refiere a las recomendaciones para el inicio del tratamiento en pacientes asintomáticos. Existe acuerdo general que el inicio del tratamiento se puede demorar hasta que los linfocitos CD4+ están en un nivel de 0.350 x 10 9 cells/L. Nuestros resultados, basados en una cohorte prospectiva canadiense, demuestran que es aceptable demorar el inicio del tratamiento hasta que los linfocitos CD4+ están en un nivel de 0.200 x 10 9 cells/L sin importar el nivel de la carga viral plasmática.