Eficácia da ivermectina e atazanavir no tempo de recuperação dos sintomas de covid-19: uma coorte prospectiva / Effectiveness of ivermectin and atazanavir on time to resolution from covid-19 symptoms: a prospective cohort / Eficacia de ivermectina y atazanavir en el tiempo hasta lá resolución de los síntomas de covid-19: una cohorte prospectiva

Objetivo: avaliar a eficácia da Ivermectina e do Atazanavir em comparação com placebo no tempo de resolução dos sintomas e no tempo de duração da doença por COVID-19. Método: estudo observacional, de coorte prospectivo, longitudinal, descritivo e analítico com pacientes sintomáticos ambulatoriais, acompanhados por 06 meses em duas Unidades Básicas de Saúde para atendimento de COVID-19 em Teresina- Piauí, Brasil, no período de novembro a abril de 2021 identificados por amostragem aleatória 1:1:1. Foram realizados exames Reverse transcription polymerase chain reaction (RT-PCR) para confirmação laboratorial da suspeita de infecção pelo novo coronavírus e avaliação sociodemográfica e clínica. Resultados: dos 87 pacientes randomizados, 62,1% (n=54) eram do sexo masculino, com média de idade de 35,1 anos, possuíam companheira (53,9%), baixa renda (50,6%), eutróficos (40,7%) e sem comorbidades de saúde (78,2%). Não houve diferença entre o tempo médio para resolução dos sintomas, que foi de 21 dias (IQR, 8-30) no grupo atazanavir, 30 dias (IQR, 5-90) no grupo ivermectina em comparação com 14 dias (IQR, 9-21) no grupo controle. No dia 180, houve resolução dos sintomas em 100% no grupo placebo, 93,9% no grupo atazanavir e 95% no grupo ivermectina. A duração mediana da doença foi de 08 dias em todos os braços do estudo. Conclusão: o tratamento com atazanavir (6 dias) e ivermectina (3 dias) não reduziu o tempo de resolução dos sintomas e nem o tempo de duração da doença entre os pacientes ambulatoriais com COVID-19 leve em comparação com o grupo placebo. Os resultados não suportam o uso de ivermectina e atazanavir para tratamento de COVID-19 leve a moderado.

Objective: to evaluate the effectiveness of Ivermectin and Atazanavir compared to placebo in the time to resolution of symptoms and duration of illness due to COVID-19. Method: observational, prospective, longitudinal, descriptive and analytical cohort study with symptomatic outpatients, followed for 06 months in two Basic Health Units for COVID-19 care in Teresina-Piauí, Brazil, from November to April 2021 identified by 1:1:1 random sampling. Reverse transcription polymerase chain reaction (RT-PCR) tests were performed for laboratory confirmation of suspected infection with the new coronavirus and sociodemographic and clinical evaluation. Results: of the 87 randomized patients, 62.1% (n=54) were male, with a mean age of 35.1 years, had a partner (53.9%), low income (50.6%), eutrophic (40.7%) and without health comorbidities (78.2%). There was no difference between the median time to resolution of symptoms, which was 21 days (IQR, 8-30) in the atazanavir group, 30 days (IQR, 5- 90) in the ivermectin group compared with 14 days (IQR, 9- 21) in the control group. At day 180, there was resolution of symptoms in 100% in the placebo group, 93.9% in the atazanavir group, and 95% in the ivermectin group. The median duration of illness was 8 days in all study arms. Conclusion: Treatment with atazanavir (6 days) and ivermectin (3 days) did not reduce the time to symptom resolution or the duration of illness among outpatients with mild COVID-19 compared to the placebo group. The results do not support the use of ivermectin and atazanavir for the treatment of mild to moderate COVID-19.

Objetivo: evaluar la efectividad de Ivermectina y Atazanavir en comparación con placebo en el tiempo de resolución de los síntomas y duración de la enfermedad por COVID-19. Método: estudio de cohorte observacional, prospectivo, longitudinal, descriptivo y analítico con pacientes ambulatorios sintomáticos, seguidos durante 06 meses en dos Unidades Básicas de Salud para atención de COVID-19 en Teresina-Piauí, Brasil, de noviembre a abril de 2021 identificados por 1:1:1 muestreo aleatorio. Se realizaron pruebas de reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR) para confirmación de laboratorio de sospecha de infección por el nuevo coronavirus y evaluación sociodemográfica y clínica. Resultados: de los 87 pacientes aleatorizados, 62,1% (n=54) eran del sexo masculino, con una edad media de 35,1 años, tenían pareja (53,9%), bajos ingresos (50,6%), eutróficos (40,7%) y sin comorbilidades de salud (78,2%). No hubo diferencia entre la mediana de tiempo hasta la resolución de los síntomas, que fue de 21 días (RIC, 8-30) en el grupo de atazanavir, 30 días (RIC, 5- 90) en el grupo de ivermectina en comparación con 14 días (RIC, 9 - 21) en el grupo control. En el día 180, hubo una resolución de los síntomas del 100 % en el grupo de placebo, del 93,9 % en el grupo de atazanavir y del 95 % en el grupo de ivermectina. La mediana de duración de la enfermedad fue de 8 días en todos los brazos del estudio. Conclusión: El tratamiento con atazanavir (6 días) e ivermectina (3 días) no redujo el tiempo de resolución de los síntomas ni la duración de la enfermedad entre los pacientes ambulatorios con COVID-19 leve en comparación con el grupo placebo. Los resultados no respaldan el uso de ivermectina y atazanavir para el tratamiento de la COVID-19 de leve a moderada.

Biterapia con atazanavir/ritonavir más raltegravir versus terapia triple en segunda línea: Ensayo ARTE / ATV/r+RAL (DT) after failure with NNRTI

Antecedentes: La terapia dual ha surgido como un nuevo concepto para el tratamiento del VIH. Este estudio tenía como objetivo comparar un régimen dual basado en ATV/r + RAL (TD) frente a estándar de tres drogas con ATV/r + TDF/FTC (TT) luego del fracaso de un primer esquema ba-sado en INNTR.ClinicalTrials.gov, Número: NCT01829802.Método: Estudio piloto abierto, multicéntrico y aleatoriza-do. Resultado primario: proporción de sujetos con ARN del VIH-1 menor a 50 copias/mL en semana 48 (S48). Resulta-dos secundarios: discontinuaciones asociadas a eventos adversos (EA), tiempo transcurrido hasta la supresión viral, desarrollo de mutaciones de resistencia a la integrasa y proteasa, cambio en recuento de CD4. Resultados: De los 57 participantes seleccionados, 34 fue-ron asignados aleatoriamente para recibir: TD (n: 18) o TT (n: 16). En semana 48, 67% (n: 12/18) en TD tuvo respues-ta virológica y 88% (n: 14/16) en rama según el análisis FDA, intención de tratamiento/expuestos (p = NS) y 73% (TD) y 93% (TT) según análisis por protocolo (p = NS). El cambio de CD4 entre basal - S48: +119 y +52 células/µL en DT y TT, respectivamente. Cuatro participantes en TD y uno en TT presentaron fracaso virológico en la semana 48. Un participante desarrolló una mutación de resistencia a integrasa (155H).Conclusión: ATV/r+RAL como terapia dual de segunda línea mostró una tendencia al fracaso virológico más frecuente, en comparación con TT, aunque el estudio piloto no tenía potencia para demostrar esta diferencia. Este estudio está registrado en ClinicalTrials.gov, Número: NCT01829802

Background: Dual therapy has emerged as a novel concept for HIV treatment. This study was aimed at comparing a nucleoside-sparing dual regimen consisting of ATV/r + RAL (DT) vs standard therapy of ATV/r + TDF/FTC (TT) among individuals failing first NNRTI-containing treatment.Methods: Randomized multicenter open-label pilot study. Primary outcome: proportion of subjects with plasma HIV-1 RNA below the limit of detection (<50 copies/mL) at 48 weeks (W48). Secondary outcomes: proportion of discontinuation due to adverse events (AEs), time until viral suppression, time until loss of virological response, development of integrase resistance mutations, and absolute change in CD4 counts. The primary outcome was analyzed using the FDA snapshot analysis.Results: Out of 57 participants screened, 34 were randomized to receive: DT (n: 18) or TT (n: 16). At W48, virological response was achieved in 67% (n: 12/18) of participants receiving DT and 88% (n: 14/16) receiving TT by FDA snapshot analysis (p = NS) and 73% and 93% by per-protocol analysis (p = NS). CD4 cell count median change from baseline to W48 was +119 and + 52 cell/µL in DT and TT, respectively. Four participants receiving DT and one TT presented virological failure at W48, with low pVL. One participant developed an integrase resistance mutation (155H) and suppressed later on TT.Conclusion: ATV/r+RAL as second-line therapy showed a trend to more frequent virological failure, compared to TT, although the study was unpowered to prove this difference. No major differences were seen in tolerance or toxicity.This study is registered with ClinicalTrials.gov, Number: NCT01829802

Uso de Ivermectina e Atazanavir no tratamento da Covid-19: uma revisão de escopo / Use of Ivermectin and Atazanavir in the treatment of Covid-19: a scoping review / Uso de Ivermectina y Atazanavir en el tratamiento de Covid-19: una revisión de alcance

Objetivo: Examinar e mapear as evidências científicas sobre a eficácia do uso de ivermectina e atazanavir no tratamento de COVID-19. Metodologia: Scoping Review, baseado nos procedimentos recomendados pelo Instituto Joanna Briggs. Estabeleceu-se a pergunta norteadora: "Quais são as evidências científicas sobre o uso de ivermectina e atazanavir no tratamento de pacientes com sintomas leves de COVID-19?". Foram realizadas buscas em seis bases de dados nacionais e internacionais, sobre trabalhos publicados até dezembro de 2022. Dos 357 estudos encontrados, 22 foram selecionados para leitura na íntegra, resultando em uma amostra final de 11 estudos analisados. Resultados: As 11 publicações analisadas foram publicadas de 2020 a 2022 durante período pandêmico, de âmbito nacional e internacional com delineamento de estudos experimentais, do tipo ensaio clínico com randomização. Apenas 03 estudos (25%) testaram o atazanavir como intervenção conjugada a outras drogas, não evidenciando melhorias significativas em relação ao seu uso. Já no tratamento com Ivermectina, dos oito (75%) estudos que a testaram, apenas três (37,5%) recomendaram seu uso e cinco (62,5%) não suportam seu uso para tratamento de COVID-19 leve. O tempo de resolução dos sintomas variou de 8 a 10 dias nos braços tratados com ivermectina e em média 07 dias no tratamento com atazanavir. Não se detectou eventos adversos graves relacionados ao uso das duas drogas. Conclusão: As evidências que recomendavam o uso de ivermectina datam do início do período pandêmico, 2020, mas posteriormente, com a realização de ensaios clínicos robustos e controlados, novas evidências não suportam o uso de ivermectina e atazanavir no tratamento de COVID-19 leve mostrando que não houve diferença no tempo de resolução dos sintomas, na taxa de mortalidade, taxa de internação na UTI e tempo de hospitalização.

Objective: To examine and map the scientific evidence on the effectiveness of using ivermectin and atazanavir in the treatment of COVID-19. Methodology: Scoping Review, based on the procedures recommended by the Joanna Briggs Institute. The guiding question was established, "What is the scientific evidence on the use of ivermectin and atazanavir in the treatment of patients with mild symptoms of COVID-19?" Searches were conducted in six national and international databases on papers published until December 2022. Of the 357 studies found, 22 were selected for reading in full, resulting in a final sample of 11 studies analyzed. Results: The 11 publications analyzed were published from 2020 to 2022 during pandemic period, of national and international scope with experimental study design, of clinical trial type with randomization. Only 03 studies (25%) tested atazanavir as a combined intervention with other drugs, showing no significant improvements in relation to its use. As for the treatment with Ivermectin, of the eight (75%) studies that tested it, only three (37.5%) recommended its use and five (62.5%) did not support its use for treating mild COVID-19. The time to symptom resolution ranged from 8 to 10 days in the ivermectin-treated arms and on average 07 days in the atazanavir treatment. No serious adverse events related to the use of the two drugs were detected. Conclusion: evidence recommending the use of ivermectin dates back to the beginning of the pandemic period, 2020, but subsequently, with robust controlled clinical trials, new evidence does not support the use of ivermectin and atazanavir in the treatment of mild COVID-19 showing that there was no difference in time to symptom resolution, mortality rate, ICU admission rate, and length of hospital stay.

Objetivo: Examinar y mapear la evidencia científica sobre la eficacia del uso de ivermectina y atazanavir en el tratamiento de COVID-19. Metodología: Scoping Review, basada en los procedimientos recomendados por el Instituto Joanna Briggs. La pregunta guía era: "¿Cuál es la evidencia científica sobre el uso de ivermectina y atazanavir en el tratamiento de pacientes con síntomas leves de COVID-19? Se realizaron búsquedas en seis bases de datos nacionales e internacionales, en artículos publicados hasta diciembre de 2022. De los 357 estudios encontrados, se seleccionaron 22 para su lectura completa, lo que dio lugar a una muestra final de 11 estudios analizados. Resultados: Las 11 publicaciones analizadas fueron publicadas entre 2020 y 2022 durante el periodo pandémico, de ámbito nacional e internacional con diseño de estudio experimental, de tipo ensayo clínico con aleatorización. Apenas 03 estudios (25%) probaron el atazanavir como intervención combinada con otras drogas, sin evidenciar mejoras significativas en relación con su uso. En cuanto al tratamiento con Ivermectina, de los ocho (75%) estudios que la probaron, sólo tres (37,5%) recomendaron su uso y cinco (62,5%) no apoyaron su uso para tratar la COVID-19 leve. El tiempo transcurrido hasta la resolución de los síntomas osciló entre 8 y 10 días en los brazos tratados con ivermectina y una media de 07 días en el tratamiento con atazanavir. No se detectaron acontecimientos adversos graves relacionados con el uso de los dos fármacos. Conclusión: las pruebas que recomiendan el uso de ivermectina se remontan al inicio del periodo pandémico, 2020, pero posteriormente, con ensayos clínicos controlados sólidos, las nuevas pruebas no apoyan el uso de ivermectina y atazanavir en el tratamiento de la COVID-19 leve, lo que demuestra que no hubo diferencias en el tiempo hasta la resolución de los síntomas, la tasa de mortalidad, la tasa de ingreso en la UCI y la duración de la estancia hospitalaria.

Atazanavir para a COVID-19: revisão sistemática rápida / Atazanavir for COVID-19: rapid systematic review

CONTEXTO: Esta foi uma revisão rápida desenvolvida durante a epidemia da COVID-19 no Brasil no intuito de informar cientificamente, e de modo imparcial, a tomada de decisão em saúde. OBJETIVOS: Identificar, avaliar sistematicamente e sumarizar as melhores evidências científicas disponíveis sobre a eficácia e a segurança do uso do atazanavir para COVID-19. MÉTODOS: Revisão sistemática rápida (rapid review methodology). RESULTADOS: Foram realizadas buscas sistemáticas nas principais bases de dados, as buscas foram realizadas no dia 13 de abril de 2020 e atualizadas no dia 28 de abril de 2020. Após o processo de seleção, não foi identificado nenhum estudo clínico realizado com o atazanavir para o tratamento de pacientes com COVID-19. Também não há estudos em andamento. Os estudos disponíveis foram realizados in vitro e apresentam resultados contraditórios. Em um dos estudos os autores relataram que não foi observada atividade antiviral do atazanavir contra a SARS CoV-2. Em outro estudo, o atazanavir sozinho e associado ao ritonavir apresentou inibição da replicação viral de SARS-CoV-2 em diferentes linhagens celulares, e a associação de ritonavir ao atazanavir demostrou ser ainda mais potente na inibição da replicação de SARS-CoV-2 comparado com atazanavir sozinho e com cloroquina. A ação inibitória de atazanavir isolado e associado ao ritonavir também foi comprovada em células epiteliais pulmonares humanas. CONCLUSÃO: Apesar dos resultados divergentes dos estudos in vitro, o atazanavir é um medicamento em potencial a ser avaliado em ensaios clínicos quanto a eficácia no tratamento da COVID-19. Até o momento, o uso de atazanavir no tratamento da COVID-19 permanece não comprovado e depende de testes clínicos para que haja avanço no reconhecimento de sua eficácia.(AU)

Comparative study of adverse effect profile of first line drugs Zidovudine (ZDV) + Lamivudine (3TC) + Nevirapine (NVP) Vs Tenofovir (TDF) + Lamivudine (3TC) + Atazanavir (ATV) + Ritonovir (RTV) in HIV/AIDS patients

Background: The biggest threat to mankind from the health perspective is probably the virus Human Immunodeficiency Virus (HIV) responsible for a serious disease known as Acquired Immune Deficiency Syndrome (AIDS). To compare the adverse effect profile of two antiretroviral regimens i.e, Zidovudine (ZDV) + Lamivudine (3TC) + Nevirapine (NVP) [regimen A] Vs Tenofovir (TDF) + Lamivudine (3TC) + Atazanavir(ATV) + Ritonavir (RTV) [regimen B] by clinical and biochemical methods.Methods: This prospective, observational study was carried out in 200 HIV positive patients receiving first line and second-line antiretroviral therapy (ART) at ART centre, GGH, Vijayawada. Out of 200 patients, 100 patients received regimen A [(ZDV) + (3TC) + (NVP)] and 100 patients were treated with regimen B [(TDF) + (3TC) + (ATV) + (RTV)]. The collected data has been analysed and presented.Results: Out of 200 patients, 110 patients developed ADRs. In this 110, 38 patients received regimen A and 18 patients received regimen B and had CD4 + count <250 cells/mm3. In the remaining 54 patients, 20 patients received regimen A and 34 patients received regimen B who had CD4+ count >250 cells/ mm3.Conclusions: The ADRs were most common in those patients whose CD4+ count is less than 250cells/cu mm. Though the patients on second line showed significant increase in CD4+count, number of patients with ADRs were also more with regimen B. Though atazanavir containing regimen is more efficacious than zidovudine containing regimen, but regimen B produces more serious adverse effects. So, second line drugs are reserved for treatment failures to first line, drug resistance and for those not tolerating first line drugs.

Monomorphic ventricular tachycardia due to protease inhibitor intoxication by atazanavir

Atazanavir is a protease inhibitor approved for use in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus infection. Atazanavir and other protease inhibitors can sometimes induce corrected QT prolongation and ventricular arrhythmia. A 40-year-old man with no comorbidities, except human immunodeficiency virus 1 infection, presented with palpitations 3 days after an overdose of 150 caps of atazanavir, with suicidal intent. His initial electrocardiogram showed monomorphic ventricular tachycardia, and hyperbilirubinemia was observed in his initial blood test. Immediately after magnesium sulfate infusion, his ventricular tachycardia was converted into junctional bradycardia with prolonged corrected QT. After 3 days of close observation in the intensive care unit, the corrected QT prolongation and hyperbilirubinemia were normalized.

Development and validation of a stability-indicating RP–HPLC method for estimation of atazanavir sulfate in bulk / 药物分析学报

A stability-indicating reverse phase–high performance liquid chromatography (RP–HPLC) method was developed and validated for the determination of atazanavir sulfate in tablet dosage forms using C18 column Phenomenix (250 mm×4.6 mm, 5μm) with a mobile phase consisting of 900 mL of HPLC grade methanol and 100 mL of water of HPLC grade. The pH was adjusted to 3.55 with acetic acid. The mobile phase was sonicated for 10 min and filtered through a 0.45μm membrane filter at a flow rate of 0.5 mL/min. The detection was carried out at 249 nm and retention time of atazanavir sulfate was found to be 8.323 min. Linearity was observed from 10 to 90μg/mL (coefficient of determination R2 was 0.999) with equation, y=23.427x+37.732. Atazanavir sulfate was subjected to stress conditions including acidic, alkaline, oxidation, photolysis and thermal degradation, and the results showed that it was more sensitive towards acidic degradation. The method was validated as per ICH guidelines.

Estratégia de proteção de patentes farmacêuticas: o caso do atazanavir / The strategy of pharmaceutical patent protection: the case of atazanavir / Estrategia de protección de patentes farmacéuticas: el caso de atazanavir

O alto custo dos medicamentos antirretrovirais (ARVs) justifica estudos sobre estratégias de patenteamento farmacêutico vis-à-vis à política pública brasileira de acesso universal aos ARVs. A análise da evolução das tendências tecnológicas através do estudo de patentes fornece também uma visão dos envolvidos no desenvolvimento de uma tecnologia. Para traçar o perfil de patenteamento do antirretroviral atazanavir, no Brasil e no mundo, foi realizado um estudo na base de dados Thomson Reuters Integrity que identificou o desenvolvimento, produção e comercialização desse produto. Foram identificados 49 documentos de patentes, tendo a proteção dessa tecnologia se iniciado em 1996, com a empresa Novartis e seu licenciado,a Bristol, que reivindicaram proteção para a molécula. Prossegue até 2013, com proteção de invenções incrementais, originárias na China. O estudo possibilitou discutir a importância do sistema de patentes na promoção da inovação, e evidenciar tipos diversos de proteção para um produto e tecnologias relacionadas...

The high costs of antiretroviral drugs (ARVs) justifies studies on pharmaceutical patenting strategiesvis-à-vis the Brazilian public policy of universal access to ARVs. The analysis of the evolution oftechnology trends through patent study also provides an overview of those involved in the developmentof a technology. To trace the patenting profile of atazanavir antiretroviral in Brazil and in the world,a study was conducted using Thomson Reuters Integrity database and such study identified thedevelopment, production and marketing of this product. 49 patent documents were identified, havingbeen started the protection of this technology in 1996 with Novartis and its licensee Bristol, whichclaimed protection for the molecule. It remains until 2013, with protection of incremental inventionsoriginating in China. The study has allowed to discuss the importance of the patent system to promotinginnovation, and to highlight different types of protection for a product and related technologies...

El alto costo de los medicamentos antirretrovirales (ARVs) justifica estudios sobre estrategias de protecciónde patentes farmacéuticas vis-à-vis la política brasileña de acceso universal a los ARVs. El análisis de laevolución de las tendencias tecnológicas a través del estudio de las patentes posibilita una visión de losdiferentes actores responsables por el desarrollo de la tecnologia. Para analizar el perfil de patentamientodel antirretroviral atazanavir en Brasil y en el mundo se realizó un estudio através de la base de datosde Thomson Reuters Integrity a fin de identificar el desarrollo, la producción y comercialización delproducto. Fueron identificados 49 documentos de patentes y los resultados muestran que la protección dela tecnologia comienza en 1996 con Novartis y el detentor de su licencia, Bristol, las cuales reivindicaronprotección para la molécula. que continúa hasta 2013, con documentos originarios de China, que provienende invenciones incrementales. El estudio posibilitó discutir la importancia del sistema de patentes parafomentar la innovación y permitir diferentes tipos de protección para un producto y tecnologias relacionadas...

Atazanavir-Induced Severe Episodes of Kidney Stones in an HIV-1-Infected Subject Characterized by a CYP3A Poor Metabolizer Phenotype.

Background: Atazanavir, an antiretroviral drug of the protease inhibitor class, is coadministered with ritonavir to inhibit atazanavir metabolism and decrease pharmacokinetic variability. Atazanavir is metabolised mainly by CYP3A4/5 enzymes. High CYP3A intersubject variability has been documented in most cases on a genetic basis. The CYP3A5*3 allele affects splicing defect and protein truncation. Recently a new intronic variant, CYP3A4*22, was found associated with reduced CYP3A4 activity. To assess whether an altered CYP3A activity impairs the metabolism of atazanavir, we investigated the two functional polymorphisms. To the best of our knowledge, this is the first case report showing that overexposure to ATV is associated with CYP3A poor phenotype and nephrolithiasis. Further study is needed in order to confirm this interesting observation. Case Presentation: We describe the case of a 43 year-old HIV-1-infected man treated with atazanavir/ritonavir plus lamivudine who experienced early and recurrent severe episodes of kidney stones. Atazanavir plasma trough concentrations showed a value higher than the normal range, thus we investigated the two polymorphisms that are known to affect CYP3A4/5 activity. This analysis revealed that our patient was a CYP3A poor metabolizer since he carried CYP3A4*1/*22 and CYP3A5*3/*3 genotypes. Conclusion: We suggest that screening of CYP3A functional variants is an appropriate approach, helping in treatment choice and potential dosage adjustment of protease inhibitors.

Related factors to atazanavir plasma levels in a cohort of HIV positive individuals with undetectable viral load

OBJECTIVE: To evaluate the factors associated with plasma concentrations of atazanavir (ATV) in a cohort of well-controlled HIV infected subjects (undetectable viremia). Design: Cross-sectional study where 69 subjects were consecutively enrolled between April and November, 2011. METHODS: Patients had to be on atazanavir for at least six months, undetectable viral load for a period equal to or longer than 12 months, T CD4+ lymphocyte count higher than 200 cells/mm³, and aged between 18 years and 70 years old. Exclusion criteria were pregnancy, any neurologic disease, active opportunistic disease, hepatitis or cancer. Atazanavir plasma levels were measured by ultra-performance liquid chromatography. RESULTS AND DISCUSSION: Overall, 54 patients (mean age of 47 years and 50% women) were included in the analysis. Those without ritonavir (unboosted atazanavir) had statistically lower plasma concentrations than those with ritonavir boosted atazanavir (p = 0.001) and total and indirect bilirubin were statistically associated with plasma concentration of atazanavir (r = 0.32 and r = 0.33 respectively; p < 0.05 in both cases). no statistical association was found among gender, ethnicity, age, weight, body mass index (BMI), lipid profile, and the plasma concentration of atazanavir. CONCLUSION: in summary, as expected, concomitant ritonavir use was the only factor associated with atazanavir plasma levels. prospective studies with a larger sample size might help to observe an association of atazanavir concentrations to other characteristics such as body weight, since the p-value showed to be close to significance (p = 0.068).

Lipid Profile Changes after Switch to Atazanavir from other Protease Inhibitor-based Combined Antiretroviral Treatment in HIV-infected Korean

Dyslipidemia, one of the major disadvantages of use of protease inhibitor (PI), is a risk factor for cardiovascular disease in HIV-infected patients receiving antiretroviral treatment. Little is known about the effect of a switch from another PI to unboosted atazanavir (ATV) on the lipid profile. The aim of this study was to evaluate changes in the lipid profile after switching from another PI to either unboosted or boosted ATV in HIV-infected Koreans. We retrospectively collected data on the serum lipid profile at the time of the switch (week 0), and weeks 12 and 24 after the switch, as well as clinical characteristics at week 0 in a total of 27 patients. Triglyceride (TG) showed a significant decrease at weeks 12 and 24 in all patients (196 vs. 174 mg/dL, P=0.048 and 196 vs. 150 mg/dL, P=0.021, respectively). However, these effects were only observed in the unboosted ATV group (N=14; 239 vs. 125 mg/dL, P=0.017 and 239 vs. 87 mg/dL, P=0.021, respectively). For total cholesterol, only the unboosted ATV group at 24 weeks showed a significant decrease (184 vs. 158 mg/dL, P=0.031). No significant changes were observed in LDL- and HDL-cholesterol at weeks 12 and 24 in both the unboosted and boosted ATV groups. These results suggest that changing to unboosted ATV from another PI may ameliorate high TG and total cholesterol in HIV-infected Koreans.

Effect of Ritonavir-boosting on Atazanavir Discontinuation due to Jaundice in HIV-infected Koreans

BACKGROUND: Data regarding differences of intolerance between a ritonavir-unboosted and a ritonavir-boosted atazanavir regimen in HIV-infected Koreans is limited. MATERIALS AND METHODS: A review was conducted of the incidence of severe hyperbilirubinemia (serum total bilirubin >3.1 mg/dL) and discontinuation of atazanavir in HIV-infected patients who had received an atazanavir-containing regimen at Seoul National University Hospital from 2005 to 2009. Patients with active liver disease were excluded from the study. RESULTS: Of a total of 335 patients receiving an atazanavir-containing regimen, 145 (43.3%) received treatment with a ritonavir-boosted regimen. The cumulative incidence of severe hyperbilirubinemia at three months was 40.5% in patients receiving a ritonavir-boosted atazanavir regimen and 21.4% in patients receiving an un-boosted atazanavir regimen (P<0.001). The cumulative incidence of severe hyperbilirubinemia at 12 months was 58.5% in patients receiving a ritonavir-boosted regimen and 41.3% in those receiving an un-boosted regimen (P=0.008). The proportion of drug discontinuation due to jaundice during the 12-month period was 11.7% in patients receiving a ritonavir-boosted regimen and 5.3% in those receiving an un-boosted regimen (P=0.035). CONCLUSIONS: Occurrence of severe hyperbilirubinemia and discontinuation of atazanavir due to jaundice was significantly more common in HIV-infected Koreans who received a ritonavir-boosted atazanavir regimen than in those who received a ritonavir-un-boosted atazanavir regimen.

Incidence of Atazanavir-associated Hyperbilirubinemia in Korean HIV Patients: 30 Months Follow-up Results in a Population with Low UDP-glucuronosyltransferase1A1*28 Allele Frequency

Hyperbilirubinemia is frequently observed in Caucasian HIV patients treated with atazanavir. UDP-glucuronosyltransferase 1A1 polymorphism, UGT1A1*28, which is associated with atazanavir-induced hyperbilirubinemia, is less common in Asians than in Caucasians. However, little is known about the incidence of atazanavir-associated hyperbilirubinemia in Asian populations. Our objective was to investigate the incidence of and tolerability of atazanavir-associated hyperbilirubinemia in Korean HIV patients. The prevalence and cumulative incidence of atazanavir-associated hyperbilirubinemia and UGT1A1*28 allele frequency was investigated in 190 Korean HIV-infected patients treated with atazanavir 400 mg per day. The UGT1A1*28 were examined by direct sequencing of DNA from peripheral whole blood. The UGT1A1*28 allele frequency was 11%. The cumulative incidence of any grade of hyperbilirubinemia was 77%, 89%, 98%, and 100%, at 3, 12, 24, and 30 months, respectively. The cumulative incidence of severe (grade 3-4) hyperbilirubinemia was 21%, 41%, 66%, and 75%, at 3, 12, 24, and 30 months, respectively. However, the point prevalence of severe hyperbilirubinemia did not increase with time and remained around 25%. Our data suggest that atazanavir-associated hyperbilirubinemia is common but transient in a population with low UGT1A1*28 allele frequency.

Two Cases of Multidrug-Resistant Human Immunodeficiency Virus Infection Treated with Atazanavir and Lopinavir/Ritonavir Combination Therapy

The combination of atazanavir (ATV) and lopinavir/ritonavir (LPV/RTV) with nucleoside reverse transcriptase inhibitors (NRTI) has been used as a salvage regimen for human immunodeficiency virus (HIV)-positive patients. In this paper, we discuss two cases of HIV-positive patients who had long histories of virological failure following a heavy treatment of antiretroviral drugs, but then achieved virological suppression with double-boosted protease inhibitor (PI) regimens. In patients with multiple genotypic resistance to PIs and NRTIs, virological suppression can be achieved with a combination of ATV plus LPV/RTV with an NRTI backbone. The two cases in this report suggest that a combination of ATV plus LPV/RTV could be a useful salvage regimen for the subset of HIV-positive patients with limited treatment options.