Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection.

OBJECTIVE: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS: Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.

Caracterización clínica y epidemiológica de pacientes con bacteriemia en la Unidad de Cuidados Intensivos de Medicina Interna y Cirugía. Hospital Roosevelt-Guatemala / Clinical and epidemiological characterization of patients with bacteremia in the Intensive Care Unit of Internal Medicine and Surgery. Roosevelt Hospital-Guatemala

Antecedentes: La bacteriemia constituye un problema de salud prioritario debido al obstáculo que impone al proceso curativo de los pacientes, involucrando al personal y a los sistemas de salud. Objetivo: Caracterizar clínica y epidemiológicamente pacientes con bacteriemia. Materiales y Métodos: Se realizó una revisión retrospectiva de pacientes con hemocultivos positivo del año 2013, en el Intensivo médico-quirúrgico, del Hospital Roosevelt, con instrumento estandarizado, que incluyó: datos demográficos, morbilidades, comorbilidades, registro de morbilidad y mortalidad. Se calcularon intervalos de confianza al 95% y odds ratio (OR). Resultados: De 47 expedientes y 87 hemocultivos, 55% fueron femeninos, con predominio de edad de 30-49 años, en su mayoría, amas de casa. El 49%, presentó una o más condiciones médicas asociadas. La mayoría de casos de bacteriemia fueron asociados a cuidados de salud, de origen secundario. El principal foco infeccioso fue respiratorio. Los principales microorganismos aislados fueron A. baumannii, K. pneumoniae y S. haemolyticus. Los procedimientos invasivos más frecuentes fueron uso de catéter venoso central y periférico. La tasa de letalidad al día 14 fue del 30%. Conclusiones: Se observó predominio de bacteriemias secundarias, asociadas a los cuidados de la salud, cuyos principales microorganismos aislados coinciden con literatura internacional. La mayor mortalidad fue observada en el sexo femenino.(AU)

Background: Bacteremia known as a major public health problem, because of the limitation it causes to the healing process among patients, involving both health care workers, and health system.Objectives: Characterize the clinical and epidemiological profile among patients with bacteremia.Materials and methods: A retrospective review was made, including positive blood culture patients, admitted to the medical and surgical Intensive Care Unit during 2013, with a standardized instrument which included: demographical data, morbidities and co-morbidities, including a morbidity and morta-lity. The statistics included 95% confidence intervals and odds ratio (OR).Results: Of 47 clinical files, 87 blood cultures, 55% were females. The mostly affected age group was the one within 30-49 years, mainly housewives. 49% presented one or more than one associated con-dition. Most cases of bacteremia were secondary, nosocomial and health care associated. The main origin was the respiratory tract. Main microorganisms isolated were A. baumannii, K. pneumoniae and S. haemolyticus. The most frequent invasive dispositive was central and peripheral venous catheteri-zation. The mortality rate at day 14 was 30%.Conclusions: A predominance of secondary bacteremia, health care associated was observed, who-se main isolated microorganisms agree with international literature. The highest mortality rate was observed in the female sex (AU)

Perfil de resistencia del VIH-1 a anti-retrovirales en pacientes con fallo virològico: Hospital Roosevelt-Guatemala 2008-2012 / Patterns of HIV-1 resistance to antiretroviral drugs in patients with virologic failure: Roosevelt Hospital, Guatemala 2008-2012

Objective: To assess the secondary resistance patterns of HIV-1to Anti-Retroviral Agents drugs (ART) in patients with virological failure in the main HIV care center in Guatemala. Methods: Using the Stanford HIV Database,HIV pol sequences were analyzed to obtain resistance patterns in patients with first-failure to ART or multiple-failures (2 or more regimens failed), from 2008 to 2012. Proportions and odds ratio (OR) with 95% confidence intervals (95%CI) were calculated. Results: 83% (43) in the first-failure and 75% (30) in multiple-failures had resistance. The highest frequency (70%)of resistance was found in the non-nucleoside-inhibitors ART family. 44% (42) showed resistance to two ART families and 4% (4) to the three families. First-failure patients had higher risk of nucleoside-inhibitor resistance (OR:3.0, 95%CI 1.29-6.98) and multidrug resistance (OR:4.94, 95%CI 1.98-12.32). Most frequent mutations were: M184V, K103N and K65R (71, 50 and 22%, respectively). 70% of patients with first-failure were resistant to at least one of the drugs used as second ART in Guatemala (ABC, ddI or AZT). Conclusions: The high level of HIV-1 resistance to ART observed, suggest the need to amend the current second line regimen treatments in Guatemala and the importance of viral genotyping in all patients with first-failure to ART.

Objetivo: Evaluar el perfil de resistencia secundaria del VIH-1 a anti-retrovirales (ARV) en pacientes con fallo virológico en la clínica de atención integral más grande de Guatemala. Métodos: Uso de Stanford HIV Database para análisis de secuencias pol para perfiles de resistencia de VIH en pacientes con fallo virológico al primer esquema ARV o fallo múltiple (dos o más esquemas ARV fallidos), entre los años 2008 y 2012. Determinación de proporciones y análisis de riesgo. Resultados: Evidencia de resistencia de 83% (n: 43) en primer fallo y 75% (n: 30) en fallo múltiple. La mayor frecuencia de resistencia se presentó en los inhibidores-no-nucleosídicos (70%). Cuarenta y cuatro por ciento (n: 42) evidenció resistencia a dos familias de ARV y 4% (n: 4) a las tres familias. Pacientes con primer fallo tuvieron más riesgo de resistencia a inhibidores-nucleosídicos (OR: 3,0; IC 95% 1,29-6,98) y más riesgo de multi-resistencia (OR: 4,94; IC 95% 1,98-12,32). Mutaciones más frecuentes fueron: M184V, K103N y K65R (71, 50 y 22%, respectivamente). Setenta por ciento de los pacientes con primer fallo presentaron resistencia a al menos uno de los medicamentos utilizado como segunda línea en Guatemala (ABC/ddI/AZT). Conclusiones: El alto nivel de resistencia del VIH-1 a los ARV observada, sugiere la necesidad de modificar el actual esquema terapéutico de rescate en Guatemala y la importancia de realizar genotipificación viral en todos los pacientes con fallo al primer esquema.

[Patterns of HIV-1 resistance to antiretroviral drugs in patients with virologic failure: Roosevelt Hospital, Guatemala 2008-2012]. / Perfil de resistencia del VIH-1 a anti-retrovirales en pacientes con fallo virològico: Hospital Roosevelt-Guatemala 2008-2012.

OBJECTIVE: To assess the secondary resistance patterns of HIV-1to Anti-Retroviral Agents drugs (ART) in patients with virological failure in the main HIV care center in Guatemala. METHODS: Using the Stanford HIV Database,HIV pol sequences were analyzed to obtain resistance patterns in patients with first-failure to ART or multiple-failures (2 or more regimens failed), from 2008 to 2012. Proportions and odds ratio (OR) with 95% confidence intervals (95%CI) were calculated. RESULTS: 83% (43) in the first-failure and 75% (30) in multiple-failures had resistance. The highest frequency (70%)of resistance was found in the non-nucleoside-inhibitors ART family. 44% (42) showed resistance to two ART families and 4% (4) to the three families. First-failure patients had higher risk of nucleoside-inhibitor resistance (OR:3.0, 95%CI 1.29-6.98) and multidrug resistance (OR:4.94, 95%CI 1.98-12.32). Most frequent mutations were: M184V, K103N and K65R (71, 50 and 22%, respectively). 70% of patients with first-failure were resistant to at least one of the drugs used as second ART in Guatemala (ABC, ddI or AZT). CONCLUSIONS: The high level of HIV-1 resistance to ART observed, suggest the need to amend the current second line regimen treatments in Guatemala and the importance of viral genotyping in all patients with first-failure to ART.

Prevalence and patterns of HIV transmitted drug resistance in Guatemala / Prevalencia y patrones de farmacorresistencia transmitida del VIH en Guatemala

Objective. To assess human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) in Guatemala. Methods. One hundred forty-five antiretroviral treatment-naïve patients referred to the Roosevelt Hospital in Guatemala City were enrolled from October 2010 to March 2011. Plasma HIV pol sequences were obtained and TDR was assessed with the Stanford algorithm and the World Health Organization (WHO) TDR surveillance mutation list. Results. HIV subtype B was highly prevalent in Guatemala (96.6%, 140/145), and a 2.8% (4/145) prevalence of BF1 recombinants and 0.7% (1/145) prevalence of subtype C viruses were found. TDR prevalence for the study period was 8.3% (12/145) with the Stanford database algorithm (score > 15) and the WHO TDR surveillance mutation list. Most TDR cases were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (83.3%, 10/12); a low prevalence of nucleoside reverse transcriptase inhibitors and protease inhibitors was observed in the cohort (< 1% for both families). Low selection of antiretroviral drug resistance mutations was found, except for NNRTI-associated mutations. Major NNRTI mutations such as K101E, K103N, and E138K showed higher frequencies than expected in ART-naïve populations. Higher literacy was associated with a greater risk of TDR (odds ratio 4.14, P = 0.0264). Conclusions. This study represents one of the first efforts to describe HIV diversity and TDR prevalence and trends in Guatemala. TDR prevalence in Guatemala was at the intermediate level. Most TDR cases were associated with NNRTIs. Further and continuous TDR surveillance is necessary to gain more in-depth knowledge about TDR spread and trends in Guatemala and to optimize treatment outcomes in the country.

Objetivo. Evaluar la diversidad del virus de la inmunodeficiencia humana (VIH) y la prevalencia de la farmacorresistencia transmitida en Guatemala. Métodos. Entre octubre del 2010 y marzo del 2011 se incluyeron en el estudio 145 pacientes no tratados anteriormente con antirretrovirales, derivados al Hospital Roosevelt en la Ciudad de Guatemala. Se obtuvieron las secuencias pol a partir del VIH plasmático y se evaluó la farmacorresistencia transmitida con el algoritmo de Stanford y la lista de mutaciones para la vigilancia de la farmacorresistencia transmitida de la Organización Mundial de la Salud (OMS). Resultados. El subtipo B del VIH fue sumamente prevalente en Guatemala (96,6%, 140/145), y se encontró una prevalencia de formas recombinantes BF1 de 2,8% (4/145) y una prevalencia del subtipo C del virus de 0,7% (1/145). La prevalencia de la farmacorresistencia transmitida durante el período de estudio fue de 8,3% (12/145) según el algoritmo de la base de datos de Stanford (puntuación > 15) y la lista de mutaciones para la vigilancia de la farmacorresistencia transmitida de la OMS. En la mayoría de los casos, la farmacorresistencia transmitida se asoció con los inhibidores de la transcriptasa inversa no análogos de nucleósidos (ITINN) (83,3%, 10/12); en la cohorte se observó una baja prevalencia asociada con los inhibidores de la transcriptasa inversa análogos de nucleósidos y con los inhibidores de la proteasa (< 1% para ambas familias de fármacos). Se encontró una baja selección de mutaciones causantes de farmacorresistencia debidas a los antirretrovirales, excepto en las mutaciones asociadas a los ITINN. Las mutaciones importantes relacionadas con los ITINN, como K101E, K103N y E138K, mostraron frecuencias más elevadas que las esperadas en las poblaciones vírgenes de tratamiento antirretroviral. En las personas con un nivel de escolaridad más elevado se encontró un mayor riesgo de farmacorresistencia transmitida (razón de posibilidades 4,14; P = 0,0264). Conclusiones. Este estudio representa uno de los primeros intentos de describir la diversidad del VIH, y la prevalencia de la farmacorresistencia transmitida y sus tendencias en Guatemala. La prevalencia de la farmacorresistencia transmitida en Guatemala presentó un nivel intermedio y en la mayoría de los casos se asoció con los ITINN. Se necesita una vigilancia más intensa y sostenida de la farmacorresistencia transmitida para conocer más exhaustivamente su grado de diseminación y sus tendencias en Guatemala, al igual que para optimizar los resultados del tratamiento antirretroviral en el país.

Prevalence and patterns of HIV transmitted drug resistance in Guatemala.

OBJECTIVE: To assess human immunodeficiency virus (HIV) diversity and the prevalence of transmitted drug resistance (TDR) in Guatemala. METHODS: One hundred forty-five antiretroviral treatment-naïve patients referred to the Roosevelt Hospital in Guatemala City were enrolled from October 2010 to March 2011. Plasma HIV pol sequences were obtained and TDR was assessed with the Stanford algorithm and the World Health Organization (WHO) TDR surveillance mutation list. RESULTS: HIV subtype B was highly prevalent in Guatemala (96.6%, 140/145), and a 2.8% (4/145) prevalence of BF1 recombinants and 0.7% (1/145) prevalence of subtype C viruses were found. TDR prevalence for the study period was 8.3% (12/145) with the Stanford database algorithm (score > 15) and the WHO TDR surveillance mutation list. Most TDR cases were associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) (83.3%, 10/12); a low prevalence of nucleoside reverse transcriptase inhibitors and protease inhibitors was observed in the cohort (< 1% for both families). Low selection of antiretroviral drug resistance mutations was found, except for NNRTI-associated mutations. Major NNRTI mutations such as K101E, K103N, and E138K showed higher frequencies than expected in ART-naïve populations. Higher literacy was associated with a greater risk of TDR (odds ratio 4.14, P = 0.0264). CONCLUSIONS: This study represents one of the first efforts to describe HIV diversity and TDR prevalence and trends in Guatemala. TDR prevalence in Guatemala was at the intermediate level. Most TDR cases were associated with NNRTIs. Further and continuous TDR surveillance is necessary to gain more indepth knowledge about TDR spread and trends in Guatemala and to optimize treatment outcomes in the country.