Clinical, epidemiological and treatment failure data among HIV-1 non-B-infected patients in the Spanish AIDS Research Network Cohort / Datos clínicos, epidemiológicos y fracaso terapéutico en los pacientes VIH-1 infectados por variantes no-B incluidos en la Cohorte de la Red española de Investigación en Sida (CoRIS)

INTRODUCTION: The prevalence of HIV-1 non-B variants is increasing in Spain, showing a higher number of transmitted drug resistance mutations (TDR) since 2002. This study presents the features of non-B-infected patients enrolled in the cohort of antiretroviral treatment (ART) naïve HIV-infected patients included in the Research Network on HIV/AIDS (CoRIS). METHODS: The study includes a selected group of HIV-1 non-B-infected subjects from 670 subjects with pol sequences collected from 2004 to 2008 in the CoRIS cohort. Epidemiological-clinical-virological data were analyzed since cohort entry until October 2011, considering the presence or absence of treatment failure (TF). RESULTS: Eighty two non-B infected subjects with known HIV-1 variants were selected from 2004 to 2008 in the CoRIS cohort, being mainly female, immigrants, infected by recombinant viruses, and by heterosexual route. They had an intermediate TDR rate (9.4%), a high rate of TF (25.6%), of losses to follow-up (35%), of coinfections (32.9%), and baseline CD4+ counts ≥350 cells/mm3 (61.8%). Non-B subjects with TF showed higher rates of heterosexual infection (85.7% vs. 69.5%, p < 0.05), tuberculosis (30.8%vs. 9.1%, p = 0.10) and hepatitis C (23.8% vs. 13.9%, p = 0.34) coinfections and lower rates of syphilis (0% vs. 21.9%, p < 0.05), and had more frequently received first-line ART including protease inhibitors (PIs) than patients without TF (70% vs. 30%, p < 0.05). Interestingly, infection with non-B variants reduced the risk of TDR to nucleoside reverse transcriptase inhibitors and increased the risk to PIs. CONCLUSION: HIV-1 non-B-infected patients in Spain had a particular epidemiological and clinical profile that should be considered during their clinical management

INTRODUCCIÓN: La prevalencia de variantes no-B del VIH-1 está aumentando en España, mostrando un incremento de las mutaciones de resistencia transmitidas (TDR) desde 2002. Este estudio muestra las características de los pacientes infectados por variantes no-B de la cohorte de infectados por VIH sin tratamiento antirretroviral de la Red de Investigación sobre VIH/SIDA (CoRIS). MÉTODOS: De 670 individuos en CoRIS con secuencias pol recogidas entre 2004 y 2008, se seleccionaron los pacientes infectados por variantes no-B. Se analizaron los datos epidemiológicos, clínicos y virológicos desde su inclusión hasta octubre de 2011, considerando la existencia de fracaso terapéutico (FT). RESULTADOS: Los 82 pacientes infectados por variantes no-B entre 2004 y 2008 fueron principalmente mujeres, inmigrantes, infectados por variantes recombinantes y transmisión heterosexual. Presentaron una tasa intermedia de TDR (9,4%) y elevada frecuencia de FT (25,6%), pérdidas de seguimiento (35%), coinfecciones (32,9%) y recuento basal de CD4+ ≥350 células/mm3 (61,8%). Los pacientes no-B con FT vs. sin FT mostraron mayor porcentaje de transmisión heterosexual (85,7% vs. 69,5%, p < 0,05), coinfecciones por tuberculosis (30,8% vs. 9,1%, p = 0,10), hepatitis C (23,8% vs. 13,9%, p = 0,34) y menores tasas de sífilis (0% vs. 21,9%, p < 0,05). Además recibieron con mayor frecuencia tratamiento de primera línea con inhibidores de la proteasa (IP) (70% vs. 30%, p < 0,05). La infección con variantes no-B redujo el riesgo de TDR a inhibidores de la transcriptasa inversa análogos de nucleósido y aumentó el riesgo a IP. CONCLUSIÓN: Los pacientes infectados por variantes no-B del VIH-1 en España presentan un perfil epidemiológico-clínico característico que deberá ser considerado durante su seguimiento

Deep analysis of HIV-1 natural variability across HIV-1 variants at residues associated with integrase inhibitor (INI) resistance in INI-naive individuals.

OBJECTIVES: We evaluated variant-associated variability at positions related to resistance to the integrase (IN) inhibitors (INIs) raltegravir, elvitegravir and dolutegravir using HIV-1 IN sequences from naive individuals retrieved from GenBank. METHODS: We evaluated the frequency of major, secondary and rare amino acid changes associated with INI resistance (INI-R) in 6706 sequences from 3791 INI-naive individuals carrying a large panel of different HIV-1 variants retrieved from GenBank, including four groups: M (6663), O (24), N (15) and P (4). HIV-1 group M sequences included 4599 sequences from the nine group M subtypes and 2064 recombinants ascribed to 54 circulating recombinant forms (CRFs). RESULTS: Primary INI-R mutations were rare in INI-naive participants and only present at a low rate in subtypes B, C and D and recombinants CRF01_AE and CRF14_BG, ranging from one to five per variant. Three secondary INI-R changes appeared with variable frequency in INI-naive individuals carrying specific HIV-1 variants: L74M in CRF43_02G (33.3%); T97A in group P (50%), J (33.3%), CRF18_cpx (20%) and F2 (11.5%); and G163RK in CRF44_BF (100%), CRF46_BF (66.7%), CRF17_BF (28.6%), F1 (21.7%), CRF12_BF (16.7%) and CRF29_BF (12.5%). Rare mutations were absent. CONCLUSIONS: Natural variability in INI-R positions across HIV-1 variants should be studied as they may facilitate or delay the emergence of INI-R viruses.

Clinical, epidemiological and treatment failure data among HIV-1 non-B-infected patients in the Spanish AIDS Research Network Cohort.

INTRODUCTION: The prevalence of HIV-1 non-B variants is increasing in Spain, showing a higher number of transmitted drug resistance mutations (TDR) since 2002. This study presents the features of non-B-infected patients enrolled in the cohort of antiretroviral treatment (ART) naïve HIV-infected patients included in the Research Network on HIV/AIDS (CoRIS). METHODS: The study includes a selected group of HIV-1 non-B-infected subjects from 670 subjects with pol sequences collected from 2004 to 2008 in the CoRIS cohort. Epidemiological-clinical-virological data were analyzed since cohort entry until October 2011, considering the presence or absence of treatment failure (TF). RESULTS: Eighty two non-B infected subjects with known HIV-1 variants were selected from 2004 to 2008 in the CoRIS cohort, being mainly female, immigrants, infected by recombinant viruses, and by heterosexual route. They had an intermediate TDR rate (9.4%), a high rate of TF (25.6%), of losses to follow-up (35%), of coinfections (32.9%), and baseline CD4+ counts ≥350cells/mm(3) (61.8%). Non-B subjects with TF showed higher rates of heterosexual infection (85.7% vs. 69.5%, p<0.05), tuberculosis (30.8% vs. 9.1%, p=0.10) and hepatitis C (23.8% vs. 13.9%, p=0.34) coinfections and lower rates of syphilis (0% vs. 21.9%, p<0.05), and had more frequently received first-line ART including protease inhibitors (PIs) than patients without TF (70% vs. 30%, p<0.05). Interestingly, infection with non-B variants reduced the risk of TDR to nucleoside reverse transcriptase inhibitors and increased the risk to PIs. CONCLUSION: HIV-1 non-B-infected patients in Spain had a particular epidemiological and clinical profile that should be considered during their clinical management.

New findings in cleavage sites variability across groups, subtypes and recombinants of human immunodeficiency virus type 1.

BACKGROUND: Polymorphisms at cleavage sites (CS) can influence Gag and Pol proteins processing by the viral protease (PR), restore viral fitness and influence the virological outcome of specific antiretroviral drugs. However, data of HIV-1 variant-associated CS variability is scarce. METHODS: In this descriptive research, we examine the effect of HIV-1 variants on CS conservation using all 9,028 gag and 3,906 pol HIV-1 sequences deposited in GenBank, focusing on the 110 residues (10 per site) involved at 11 CS: P17/P24, P24/P2, P2/P7, P7/P1, P1/P6 (gag) , NC/TFP, TFP/P6 (pol), P6 (pol) /PR, PR/RT(p51), RT(p51)/RT(p66) and RT(p66)/IN. CS consensus amino acid sequences across HIV-1 groups (M, O, N, P), group M 9 subtypes and 51 circulating recombinant forms (CRF) were inferred from our alignments and compared to the HIV-1 consensus-of-consensuses sequence provided by GenBank. RESULTS: In all HIV-1 variants, the most conserved CS were PR/RT(p51), RT(p51)/RT(p66), P24/P2 and RT(p66)/IN and the least P2/P7 and P6 (pol) /PR. Conservation was significantly lower in subtypes vs. recombinants in P2/P7 and TFP/P6 (pol) and higher in P17/P24. We found a significantly higher conservation rate among Group M vs. non-M Groups HIV-1. The late processing sites at Gag (P7/P1) and GagPol precursors (PR/RT(p51)) presented a significantly higher conservation vs. the first CS (P2/P7) in the 4 HIV-1 groups. Here we show 52 highly conserved residues across HIV-1 variants in 11 CS and the amino acid consensus sequence in each HIV-1 group and HIV-1 group M variant for each 11 CS. CONCLUSIONS: This is the first study to describe the CS conservation level across all HIV-1 variants and 11 sites in one of the largest available sequence HIV-1 dataset. These results could help other researchers for the future design of both novel antiretroviral agents acting as maturation inhibitors as well as for vaccine targeting CS.