Evaluación comparativa de perfiles de disolución del medicamento genérico lamivudina tableta 150 mg comercializado en Perú frente al innovador Epivir / Comparative evaluation of dissolution profiles of the generic drug lamivudine 150 mg tablet marketed in Peru vs. the innovative Epivir

RESUMEN La lamivudina es uno de los medicamentos más prescritos en el mundo, se utiliza para tratar la inmunodeficiencia humana y la hepatitis B. El objetivo del estudio fue evaluar los atributos de calidad y comparar los perfiles de disolución de dos lotes (A y B) del medicamento genérico lamivudina 150 mg tabletas con el medicamento innovador Epivir 150 mg tabletas. Se realizó un estudio analítico, experimental y de corte transversal, se usó un método espectrofotométrico a una longitud de onda de máxima absorción (λ) correspondiente a 270 nm, para medir el porcentaje de fármaco disuelto. El estudio evaluó identificación, contenido, disolución y uniformidad de masas. Se usó el aparato 2 USP (Paleta) 75 rpm, 900 mL de medio de disolución (37 ± 0,5 °C) a en tres medios de disolución: pH 1,2; 4,5 y 6,8. Se retiraron muestras de 5 mL a los 5, 10, 15, 20 y 30 min. Se encontró que ambos lotes de lamivudina genérico (A y B) presentan el mismo perfil cinético de disolución que el medicamento innovador. Ambas formulaciones cumplen con el criterio de medicamentos de disolución muy rápida (85% disuelto en 15 min), y de disolución rápida (85% disuelto en 30 min). Por lo tanto, no fue necesario calcular el factor de similitud. Se concluye que los medicamentos genéricos A y B son equivalentes in vitro con el medicamento innovador Epivir.

ABSTRACT Lamivudine is one of the most prescribed drugs in the world, and is used to treat human immunodeficiency and hepatitis B. This study aimed to evaluate the quality attributes and compare the dissolution profiles of two batches (A and B) of generic lamivudine 150 mg tablets with the innovator drug Epivir 150 mg tablets. We conducted an analytical, experimental, cross-sectional study, and used a spectrophotometric method at a wavelength of maximum absorption (λ) corresponding to 270 nm, to measure the percentage of dissolved drug. The study evaluated identification, content, dissolution and mass uniformity. Apparatus 2 USP (Paddle) 75 rpm, 900 mL of dissolution medium (37 ± 0.5 °C) was used in three dissolution media: pH 1.2; 4.5 and 6.8. Samples of 5 mL were obtained at 5, 10, 15, 20 and 30 min. Both batches of generic lamivudine (A and B) were found to have the same dissolution kinetic profile as the innovator drug. Both formulations met the criteria of very fast dissolving (85% dissolved in 15 min), and fast dissolving (85% dissolved in 30 min) drugs. Therefore, it was not necessary to calculate the similarity factor. We concluded that generic drugs A and B are in vitro equivalents to the innovator drug Epivir.

Hepatitis B y C en personas con VIH del Instituto para el Desarrollo Humano / Hepatitis B and C in People

INTRODUCCIÓN: la coinfección del VIH con la hepatitis B o C es causa de patología hepática crónica, con diversas seroprevalencias en diferentes regiones del mundo. OBJETIVO: conocer la seroprevalencia de hepatitis B y C en personas con VIH que acuden a consulta en el Instituto para el Desarrollo Humano, Cochabamba-Bolivia, gestión 2017-2018. MATERIALES Y MÉTODOS: estudio descriptivo, prospectivo-transversal, cuantitativo, no experimental. Se analizaron los resultados serológicos de los marcadores: antígeno de superficie del virus hepatitis B, anticuerpo anti-core del virus de hepatitis B, anticuerpo contra el virus hepatitis C; historial de vacuna para hepatitis B y esquema de tratamiento antirretroviral, de 195 personas con VIH en el Instituto para el Desarrollo Humano, se realizó análisis bivariado para la obtención de datos. RESULTADOS: la seroprevalencia obtenida para hepatitis B es de 7,7% y hepatitis C de 0,5%; la coinfección entre VIH y hepatitis B es de 80% con esquema antirretroviral tenofovir/lamivudina. El grupo poblacional homosexual tiene un riesgo de 5,5 veces más de tener la co-infección de VIH y hepatitis B con un valor de p de 0,006; con relación a la inmunización para hepatitis B solo el 9,2% de los pacientes cuentan con el esquema completo. CONCLUSIÓN: es imperativo ofertar las pruebas para hepatitis B y C a todas las personas con VIH; haciendo énfasis en los grupos más vulnerables homosexuales; es importante el abastecimiento de dosis para la inmunización completa contra la hepatitis B en todos los servicios de salud públicos del país.

INTRODUCTION: HIV co-infection with hepatitis B or C is the cause of chronic liver disease, with various seroprevalences in different regions of the world. OBJECTIVE: To know the seroprevalence of hepatitis B and C in people with HIV who come for consultation at the Institute for Human Development, Cochabamba-Bolivia, management 2017-2018. MATERIALS AND METHODS: descriptive, prospective-cross-sectional, quantitative, non-experimental study. The serological results of the markers were analyzed: Hepatitis B virus surface antigen, Hepatitis B virus anti-core antibody, Hepatitis C virus antibody; Hepatitis B vaccine history and antiretroviral treatment scheme of 195 people with HIV at the Institute for Human Development, bivariate analysis was performed to obtain data. RESULTS: the seroprevalence obtained for hepatitis B is 7.7% and hepatitis C 0.5%; coinfection between HIV and hepatitis B is 80% with the antiretroviral regimen tenofovir / lamivudine. The homosexual population group hasa 5.5 times risk of having HIV and hepatitis B co-infection with a p value of 0.006; Regarding immunization for hepatitis B, only 9.2% of patients have the complete scheme. CONCLUSION: it is imperative to offer hepatitis B and C testing to all people with HIV; emphasizing the most vulnerable groups (homosexuals); The provision of doses for complete immunization against hepatitis B in all public health services in the country is important.

Abacavir/lamivudine + unboosted atazanavir in routine clinical practice: Twelve years experience. / Abacavir/lamivudina + atazanavir no potenciado en la práctica clínica diaria: doce años de experiencia.

OBJECTIVE: To describe the experience using the combination abacavir, lamivudine plus non-boosted atazanavir (ABC/3TC+ATV) in a group of pretreated patients. PATIENTS AND METHODS: We performed a retrospective observational study to describe baseline characteristics and the evolution of patients who had received or were treating with ABC/3TC+ATV, from November 2004 and June 15th 2015, in the clinical setting. RESULTS: Overall, 236 patients were included in the study. Median age (IQR) was 45 (42-50) years and 69% were male. The main reasons for using this combination were previous toxicity in 130 patients (56%), simplification in 60 (20%) and virologic failure in 29 (14%). Previous treatment was based in boosted protease inhibitor in 115 patients (48.7%), 3 analogs in 56 (28%) and non-analogous based in 19 (8.1%). Median treatment length was 2.2 years (IQR0.8-5.3). A total of 66 (28%) patients continue receiving ABC/3TC+ATV (median time 5.7, IQR2.2-8.3), treatment was changed in 170 patients (72%) (median time 1.6 years, IQR0.7-3.6), and 22 (9.3%) patients were lost. Virological failure was assessed in 30 patients. CONCLUSION: In selected patients, ABC/3TC+ATV is a durable and attractive therapeutic alternative.

Zidovudine/Lamivudine vs. Abacavir/Lamivudine vs. Tenofovir/Emtricitabine in fixed-dose combinations as initial treatment for HIV patients: a systematic review and network meta-analysis / Zidovudina/Lamivudina vs Abacavir/Lamivudina vs Tenofovir/Emtricitabina en combinaciones de dosis fija como tratamiento inicial en pacientes con VIH: revisión sistemática y metanálisis en red

Abstract Introduction: Initial treatment of the HIV is based on the use of three drugs, two of which are nucleoside analog reverse-transcriptase inhibitors. There are three combinations of these drugs which have been approved by different guidelines, each with divergent results in terms of efficacy and safety. Objective: To compare the efficacy and safety of these three combinations. Methods: Systematic review and network meta-analysis of randomized clinical trials comparing fixed doses of Tenofovir Disoproxil Fumarate / Emtricitabine (TDF/FTC), Abacavir / Lamivudine (ABC/3TC) and Zidovudine / Lamivudine (ZDV/3TC). Results: Seven clinical trials met the eligibility criteria. The results suggested higher efficacy with TDF/FTC vs. ABC/3TC at 96 weeks and vs. ZDV/3TC at 48 weeks. However, there is clinical and statistical heterogeneity. Subgroup analysis were performed by third drug and by level of viral load prior to treatment, and found no differences in virological control. Network meta-analysis could only be carried out with TDF/FTC vs. ZDV/3TC, and the proportion of patients with virological response, with no differences at 48 weeks nor at 96 weeks. Direct comparisons showed an increased risk of bone marrow suppression of ZDV/3TC vs. TDF/FTC and of ABC/3TC hypersensitivity reactions vs. ZDV/3TC Conclusions: The results did not show differences in effectiveness among the interventions. However, due to the heterogeneity of the third drug and the follow-up time between the included studies, this result is not definitive. The results raise the need for further studies to help improve treatment recommendations in patients infected with HIV.

Resumen Introducción: El tratamiento inicial de la infección por VIH se basa en el uso de tres medicamentos, dos de ellos inhibidores de transcriptasa reversa análogos de nucleósido. Existen tres combinaciones de estos medicamentos aprobadas por diferentes guías, con resultados divergentes en cuanto a eficacia y seguridad. Objetivo: Comparar la eficacia y seguridad de las 3 combinaciones Métodos: Revisión sistemática y metanálisis en red de ensayos clínicos con asignación aleatoria comparando dosis fijas de Tenofovir Disoproxil Fumarato/Emtricitabina (TDF/FTC), Abacavir/Lamivudina (ABC/3TC) y Zidovudina/Lamivudina (ZDV/3TC). Resultados: Siete ensayos clínicos cumplieron los criterios de elegibilidad. Los resultados sugirieron mayor eficacia con TDF/FTC vs ABC/3TC a 96 semanas y vs. ZDV/3TC a 48 semanas. Sin embargo, existe heterogeneidad clínica y estadística. Se realizó análisis de subgrupos por tercer medicamento y por nivel de carga viral previa al tratamiento, sin encontrar diferencias en control virológico. Se pudo realizar metanálisis en red con TDF/FTC vs ZDV/3TC y proporción de pacientes con respuesta virológica, sin diferencias a las 48 semanas ni 96 semanas. Las comparaciones directas evidenciaron mayor riesgo de supresión de médula ósea de ZDV/3TC vs TDF/FTC y de reacciones de hipersensibilidad de ABC/3TC vs ZDV/3TC. Conclusión: Los resultados no demostraron diferencias en efectividad entre las intervenciones; sin embargo, debido a heterogeneidad en cuanto al tercer medicamento y el tiempo de seguimiento entre los estudios incluidos, dicho resultado no es definitivo. Los resultados plantean la necesidad de realizar nuevos estudios que ayuden a mejorar las recomendaciones de tratamiento en los pacientes infectados por el VIH.

Hipersensibilidade a lamivudina em paciente infectada pelo HIV: relato de caso / Lamivudine's hypersensitivity in an HIV infected patient: case report

Importância do problema: Relatar um caso de hipersensibilidade à lamivudina, droga considerada segura e antirretroviral indicado como de primeira linha para início de tratamento para pacientes infectados pelo HIV. Comentários: É relatado o caso de paciente infectada pelo HIV que evoluiu com farmacodermia associada à terapia antirretroviral (TARV) utilizando tenofovir, lamivudina e efavirenz. Inicialmente, a hipersensibilidade foi atribuída ao efavirenz, pela maior incidência de eventos desta natureza com este medicamento e este foi substituído por fosamprenavir/ ritonavir. Apesar da substituição, paciente desenvolveu síndrome de Stevens-Johnson. Foi hospitalizada e iniciou novo esquema, com introdução de droga a droga, com atazanavir/ritonavir, seguido de zidovudina e lamivudina, desenvolvendo manifestação de eritema multiforme após a última droga, sendo esta considerada a responsá- vel pela hipersensibilidade. (AU)

Relevance: To report a case of hypersensitivity to lamivudine, a medicine that is considered safe and is indicated as part of the initial therapy for HIV infected patients. Comments: It is reported the evolution of an HIV patient who developed a drug eruption due to the following antirretroviral therapy: tenofovir, lamivudine and efavirenz. It initially was attributed to efavirenz, due to its higher incidence in these adverse reactions and it was replaced by fosamprenavir/ritonavir. In spite of the replacement, the patient developed Stevens-Johnson's Syndrome. She was hospitalized and began a new therapy with atazanavir/ritonavir, followed by zidovudine and lamivudine and presented a drug reaction with the last one, which was considered to be the responsible for the hypersensitivity. (AU)

Desenvolvimento e caracterização de nanopartículas de poli (n-butil cianoacrilato) contendo a associação lamivudina e zidovudina / Development and characterization of poly (n- butyl cyanoacrylate) nanoparticles containing the combination of lamivudine and zidovudine

A zidovudina (AZT), fármaco antirretroviral utilizado no tratamento da AIDS, apresenta biodisponibilidade oral em torno de 60% e seu uso prolongado pode ocasionar efeitos tóxicos e tolerância ao tratamento. A lamivudina (3TC), apesar de demonstrar menor citotoxicidade e menor resistência viral, é considerada também menos potente. A associação entre os dois fármacos é recomendável em função da boa resposta terapêutica e maior adesão ao tratamento. As nanopartículas são uma alternativa para melhorar a biodisponibilidade e o transporte de fármacos sobretudo através da BHE. Nesse sentido, as nanopartículas poliméricas de poli (n-butil cianoacrilato) (PBCA) apresentam grande potencial para melhoria das características farmacêuticas, além de possibilitar resultados terapêuticos mais eficazes por meio da modificação de sua superfície, direcionando o fármaco ao sítio alvo. Diante do exposto, foram desenvolvidas nanopartículas de PBCA contendo a associação lamivudina e zidovudina (3TC/AZT) revestidas com polissorbato 80 (Ps80). As nanopartículas obtidas foram caracterizadas e apresentaram resultados coerentes aos encontrados na literatura. Após a encapsulação dos fármacos e o revestimento com Ps80, notou-se um aumento no diâmetro médio e o potencial Zeta foi próximo de zero. Esses resultados juntamente com a análise de SAXS comprovam o revestimento das nanopartículas de PBCA. Os dados de DSC e TG/DTG mostram que a encapsulação foi eficiente para a estabilização térmica dos fármacos. Foi desenvolvido e validado o método analítico por CLAE, a fim de determinar a eficiência de encapsulação. A validação do método analítico para quantificação simultânea do 3TC e AZT, tanto nas nanopartículas de PBCA quanto nas nanopartículas revestidas, apresentou linearidade, especificidade, precisão e exatidão adequadas de acordo com as normativas. A porcentagem de encapsulação dos fármacos foi igual a 44,45% e 30,44%. As nanopartículas de PBCA e PBCAPs80, em concentrações abaixo de 100 µg/mL, apresentaram viabilidade celular superior a 70% em células Caco-2, comprovando que o sistema apresenta baixa citotoxicidade, o que representa uma alternativa promissora para a encapsulação de fármacos antirretrovirais e consequente progresso no tratamento da AIDS

Zidovudine (AZT), which is an anti-retroviral drug used in the treatment of AIDS, has oral bioavailability around 60% and its prolonged use can cause toxic effects and tolerance to the treatment. Lamivudine (3TC), although it has lower cytotoxicity and lower viral resistance, is also considered less potent. The association between these two drugs is recommended based on the good therapeutic response and greater adherence to treatment. Nanoparticles are an alternative to improve the bioavailability and the transport of drugs, particularly through the BBB. Thus, the polymeric nanoparticles of poly (n-butyl cyanoacrylate) (PBCA) have great potential for improving the pharmaceutical characteristics, besides enabling more effective therapeutic results through the modification of its surface, directing the drug to the target site. That being said, PBCA nanoparticles were developed containing the association of lamivudine and zidovudine (3TC/AZT) coated with polysorbate 80 (Ps80). Nanoparticles obtained were characterized and presented coherent results when compared to those found in the literature. After the encapsulation of pharmaceuticals and Ps80 coating, it was noted an increase in the average diameter and Zeta potential was close to zero. These results along with the SAXS analysis proved the coating of the PBCA nanoparticles. The data of DSC and TG/DTG show that encapsulation was efficient for thermal stabilization of pharmaceuticals. An analytical method by HPLC was developed and validated to determine the efficiency of encapsulation. The validation of the analytical method for simultaneous quantification of 3TC and AZT, in both the PBCA nanoparticles and coated nanoparticles, presented as in linearity, specificity, precision and accuracy according to the regulations. The percentage of drug encapsulation was equal to 44.45% and 30.44%. The nanoparticles of PBCA and PBCA-Ps80, at concentrations below 100 µg/ml, presented cell viability greater than 70% in Caco-2 cells, proving that the system has low cytotoxicity, which represents a promising alternative for the encapsulation of antiretroviral drugs and consequent progress in AIDS treatment

Hipopotasémia asociada a antiretrovirales: informe de un caso y revisión de literatura / Hypokalemia associated with antiretroviral drugs: A case report and review

Se comunica el caso de un paciente de 10 años de edad con diagnóstico de VIH e hipopotasémia severa, quien realiza tratamiento actual con antiretrovirales del tipo de los inhibidores de la transcriptasa inversa análogos de los nucleótidos (Lamivudina/Zidovudina). Se revisa el caso y se hace una revisión de la literatura.

We describe a 10 year old HIV patient under anti-retroviral treatment (Lamivudina/Zidovudina), who developed severe hipokalemia. For the importance of this complication update the issue.

[Strategies for avoiding hepatitis B infection recurrence following liver transplantation]. / Estrategias para evitar la recidiva viral B después del trasplante hepático.

Hepatitis B is currently an excellent indication for liver transplantation due to the highly effective strategies of prophylaxis and treatment for recurrent hepatitis B infection. The combined administration of low-dose hepatitis B hyperimmune gamma globulin and a nucleoside/nucleotide analogue with a high genetic barrier to resistance, such as entecavir (except for patients with lamivudine resistance) or tenofovir, represents the standard for the prophylaxis of recurrent hepatitis B infection and is used in most centers. The drawbacks of long-term administration of hyperimmune gamma globulin have led to research on regimens in which this agent is withdrawn after a certain amount of time in combination treatment, a strategy that appears to be safe in patients with undetectable viremia at the time of liver transplantation if the patients adhere to the treatment. In recent years, there has also been research into regimens of gamma-globulin-free prophylaxis, based only on the administration of oral antiviral drugs, which appear to be safe if antivirals with a high genetic barrier to resistance are used. Hepatitis B prophylaxis should be maintained indefinitely; therefore, the total withdrawal of prophylaxis is not an accepted strategy at present in daily clinical practice if not in the context of a clinical trial.

Relato de caso: clareamento do HBsAG durante tratamento com lamivudina em paciente com cirrose hepática / Case report: HBsAg during the whitening treatment with lamivudine in patients with liver cirrhosis

O principal objetivo do tratamento da Hepatite B (HBV) é a erradiação viral, reduzindo a atividade necroinflamatória e as complicações do curso crônico da doença como o hepatocarcinoma e a descompensação da cirrose. Dentre os tratamentos disponíveis, a lamivudina, apresenta boas taxas de resposta terapêutica com melhora histológica, queda do HBV DNA, normalização das transaminases e soroconversão do HBeAG. Porém, assim como outras drogas, dificilmente atinge a soroconversão do HBeAG. Outro problema associado ao uso da droga são os altos índice de resistência com o tratamento prolongado. Dessa forma, discutiremos a eficácia da lamivudina em meio aos tratamentos atuais através de uma revisão da literatura

Evaluación de la respuesta y seguridada diferentes esquemas de tratamiento antirretroviral en Colombia / Response assessment and safety of different schemes of Anti-HIV Agents in Colombia / Avaliação da resposta e segurança a diferentes esquemas de tratamento antirretroviral em Colombia

Introducción: establecer variables asociadas a falla terapéutica, adherencia al tratamiento, cambio de esquema y efectos indeseables asociados al tratamiento de VIH/SIDA.Métodos: estudio de corte transversal realizado en población de pacientes condiagnóstico de VIH/SIDA en tratamiento antirretroviral de 19 ciudades colombianas afiliados al Sistema General de Seguridad Social en Salud. Se evaluaron variables socio-demográficas, esquemas terapéuticos, tiempo desde inicio de la terapia y cambio de esquema, reporte de falta de adherencia, falla terapéutica y efectos indeseables. Se hicieron análisis bivariados y multivariados. Resultados: se hallaron 510 pacientes; el tratamiento antirretroviral sufriómodificaciones al primer esquema en 56,4% de casos. Se reportó: falta de adherencia en 38,8%, falla terapéutica en 26,5% de pacientes; las reacciones adversas más frecuentes fueron: dislipidemia (14,9%), intolerancia gástrica (9,2%) y anemia (7,1%). El régimen de tratamiento Lamivudina/Zidovudina + Efavirenz se asoció con menor riesgo de cambio de esquema (p<0,001), de falla terapéutica (p<0,001) y de intolerancia (p<0,001). El fracaso terapéutico se asoció con antecedentes de neumocistosis, tomar 7 píldoras al día, repartidas en 3 a 4 dosis diarias, en tratamiento para diferentes comorbilidades, con falta de adherencia y efectos indeseables asociados a los antirretrovirales. Conclusiones: la identificación de los esquemas de tratamiento asociados con peortolerabilidad por su riesgo de afectar la adherencia al manejo del VIH, con mástabletas diarias y consumidos varias veces al día, permite orientar la selección de medicamentos que garanticen mayor adherencia y tolerabilidad.

Introduction: estimate variables associated with treatment failure, treatment adherence, schema change and adverse reactions associated with the treatment of HIV/AIDS.Methods: cross-sectional study conducted in a population of patients with HIV/ AIDS antiretroviral treatment in 19 cities of Colombia affiliates at Social Security System in Health. We assessed socio-demographic variables, treatment regimens, and time from start of therapy and schema change, report non-adherence, treatment failure and adverse reactions. Were used bivariate and multivariate analysis.Results: we found 510 patients, antiretroviral therapy was modified to the first scheme in 56.4% of cases, nonadherence in 38.8%, treatment failure in 26.5% of patients, and the most common adverse reactions were: dyslipidemia (14.9%), gastric intolerance (9.2%) and anaemia (7.1%). The treatment regimen Lamivudine / Zidovudine + Efavirenz was associated with lower risk of schema change (p <0.001), treatment failure (p <0.001) and intolerance (p <0.001). Treatment failure was associated with a history of pneumocystosis, taking 7 pills a day, divided into 3-4 daily doses, in treatment for different comorbidities, lack of adherence and adverse effects associated with antiretrovirals.Conclusions: the identification of treatment regimens associated with poorer tolerability for their risk of affecting adherence to HIV management, with more tablets daily and consumed several times a day can guide the selection of drugs to ensure greater adherence and tolerability.

Introdução: estabelecer variavéis associadas à falha terapêutica, aderência ao tratamento, mudança de esquema e efeitos indesejaveis associados ao tratamento de VIH/SIDA.Métodos: estudo de corte transversal realizado em grupos de pacientes com diagnóstico de VIH/SIDA em tratamento antirretroviral de 19 cidades colombianas filiados ao Sistema Geral de Segurança Social em Saúde. Avaliaram-se variavéis socio-demográficas, esquemas terapêuticos, tempo desde o inicio da terapia e mudança de esquema, anotação sobre falta de aderência, falha terapêutica e efeitos indesejaveis. Foram feitas análises bivariados y multivariados.Resultados: acharam-se 510 pacientes, e o tratamento antirretroviral sofreu modificações ao primeiro esquema em 56,4% dos casos, se reportou: falta de aderência em 38,8%, falha terapêutica em 26,5% dos pacientes; as reações adversas mais frequentes foram: dislipidemia (14,9%), intolerência gástrica (9,2%) e anemia (7,1%). O regime de tratamento Lamivudina/Zidovudina + Efavirenz se associou com menor risco de mudança de esquema (p<0,001), de falha terapêutica (p<0,001) e de intolerância (p<0,001). O fracasso terapêutico se associou com antecedentes de neumocistosis, tomar 7 comprimidos por dia, distribuido em 3 a 4 doses diárias, em tratamento para diferentes comorbilidades, com falta de aderência e efeitos indesejados associados aos antirretroviraies.Conclusões: a identificação dos esquemas de tratamento associados com pior tolerância pelo risco de afetar a aderência ao tratamento do VIH, com mais comprimidos diários e consumidos várias vezes ao dia, permite orientar a seleção de medicamentos que garantam maior aderência e tolerabilidade.

Análise morfológica e fisiológica dos fígados e rins de ratas prenhes e seus fetos tratados pela associação zidovudina, lamivudina e ritonavir durante toda a prenhez / Morphological and physiological analysis of livers and kidneys of pregnant rats and their fetuses treated by the association of zidovudine, lamivudine and ritonavir for the whole period of pregnancy

OBJETIVO: avaliar os efeitos da administração da associação zidovudina-lamivudina-ritonavir nos fígados e rins de ratas prenhes e seus conceptos do ponto de vista morfológico e fisiológico. MÉTODOS: 40 ratas albinas prenhes foram aleatoriamente divididas em 4 grupos: 1 controle (Ctrl: controle de veículo) e 3 experimentais (Exp1x, Exp3x e Exp9x). Estes últimos foram tratados por solução oral de zidovudina/lamivudina/ritonavir (Exp1x: 10/5/20 mg/kg; Exp3x: 30/15/60 mg/kg; Exp9x: 90/45/180 mg/kg). As drogas e o veículo foram administrados por gavagem, desde o 1º até o 20º dia de prenhez. No último dia do experimento, todos os animais foram anestesiados e sangue foi retirado da cavidade cardíaca para avaliação sérica das enzimas aspartato aminotransferase (AST) e alanina aminotransferase (ALT), por método calorimétrico, bem como da ureia, determinada por método cinético-enzimático, e creatinina, por método cinético-colorimétrico. Em seguida, fragmentos dos fígados e rins maternos e fetais foram coletados, fixados em formol a 10 por cento e processados segundo os métodos histológicos para inclusão em parafina. Cortes com 5 µm de espessura foram corados pela hematoxilina-eosina (HE) e analisados por microscopia de luz. Na leitura das lâminas, considerou-se o padrão de normalidade para fígado e rins, tais como: hepatócitos, espaço porta íntegros e veias hepáticas bem definidas. Nos rins, a presença de corpúsculos renais, túbulos contorcidos e alças de Henle típicos. Nos fígados fetais considerou-se, ainda, a morfologia das células da linhagem eritrocitária nas diferentes fases do desenvolvimento, bem como os megacariócitos. Quando houve alteração da coloração padrão estabelecida para as estruturas hepáticas e renais, alteração na morfologia de núcleos, rompimento de limites de alguma organela citoplasmática, presença de congestão vascular, tudo isso foi entendido como provavelmente provocado pelas drogas em sua(s) dose(s) de aplicação. A avaliação estatística foi realizada por análise de variância (ANOVA), completada pelo teste de Tukey-Kramer (p<0,05). RESULTADOS: os fígados maternos dos grupos Ctrl, Exp1x e Exp3x mostraram hepatócitos típicos, espaço porta íntegros e veias hepáticas com aspecto normal. No fígado materno do grupo Exp9x, foram encontrados hepatócitos com sinais de atrofia e apoptose (eosinofilia citoplasmática e núcleos picnóticos). Além disso, identificou-se vasodilatação dos capilares sinusoides (congestão). Os rins maternos dos grupos Ctrl e Exp1x apresentaram-se normais, com corpúsculos renais, túbulos contorcidos e alças de Henle típicos. Já nos grupos Exp3x e Exp9x, foram encontrados congestão vascular, glomérulos pequenos ricos em células contendo núcleos hipercromáticos, sendo mais intensos no Exp9x. Com relação aos fígados e rins fetais, não foram observadas alterações morfológicas ou fisiológicas nos grupos estudados. Encontrou-se aumento significante nos níveis da AST (305,70±55,80; p<0,05) e da creatinina (0,50±0,09; p<0,05) no grupo Exp9x. CONCLUSÕES: nossos resultados evidenciam que a administração da associação zidovudina/lamivudina/ritonavir a ratas prenhes em altas doses causa alterações morfológicas e funcionais nos fígados e rins maternos. Não houve alterações nem morfológicas nem fisiológicas nos fígados e rins fetais.

PURPOSE: to evaluate the effect of administration of three different doses of the zidovudine/lamivudine/ritonavir combination on the liver and kidneys of pregnant rats and their concepts from a morphological and physiological standpoint. METHODS: 40 pregnant EPM-1 Wistar rats were randomly divided into 4 groups: 1 control (Ctrl: drug vehicle control, n=10) and 3 experimental groups: Exp1x, Exp3x and Exp9x. An oral solution of the zidovudine/lamivudine/ritonavir combination was administered to the experimental groups from the day 0 to day 20 of pregnancy: Exp1x=10/5/20 mg/kg; Exp3x=30/15/60 mg/kg; Exp9x=90/45/180 mg/kg. On the 20th pregnancy day the rats were anesthetized and blood was taken directly from the ventricular chambers for further biochemical determinations: aspartate-(AST) and alanine-(ALT) aminotransferases (Calorimetric method), urea nitrogen (BUN) by an enzymatic-kinetic method, and creatinine by a kinetic-calorimetric method. Maternal and fetal liver and kidney samples were taken, fixed in 10 percent formaldehyde and processed histologically for paraffin embedding. Five µm-thick fragments of maternal and fetal livers and kidneys were stained with hematoxilyn-eosin, being analyzed by light microscopy. To interpret the results, the well-known pattern of normality for livers and kidneys was considered on the basis of the following structures: hepatocytes, portal structure, hepatic veins, renal corpuscles, renal tubules and loop of Henle. Regarding the fetal livers, we also considered the erythrocytes in their different stages of development as well as the megacariocytes. If there was a change in the established staining pattern for liver and kidney structures, changes in nuclear morphology, rupture of some cytoplasmic organelles, and presence of vascular congestion, this was considered to be due to the drug doses. Results were submitted to analysis of variance (ANOVA) and to the Tukey-Kramer multiple comparisons test (p<0.05). RESULTS: no morphological changes were observed in the maternal livers of the Ctrl, Exp1x and Exp3x groups. In the maternal liver of the Exp9x group, hepatocytes showed signs of atrophy and apoptosis (eosinophilic cytoplasm and pycnotic nuclei) and marked sinusoid capillary vasodilation (congestion) was observed. The maternal kidneys of the Ctrl and Exp1x groups were normal, with renal corpuscles, convoluted tubules and typical loops of Henle. In contrast, the Exp3x and Exp9x groups showed vascular congestion and small glomeruli rich in cells containing hyperchromatic nuclei which were more intense in Exp9x. Regarding the fetal organs, no morphological or physiological changes were observed. A significant increase of AST (305.70±55.80, p<0.05) and creatinine (0.50±0.09, p<0.05) was observed in group Exp9x. CONCLUSIONS: our results show that the administration of the zidovudine, lamivudine and ritonavir combination to pregnant rats at high doses caused morphological and physiological changes in the maternal liver and kidneys. On the other hand, there were no changes in fetal organs.

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo / Genotipagem do vírus da hepatite B de pacientes crônicos com resistência ao tratamento com lamivudina na Cidade de Ribeirão Preto, Estado de São Paulo

INTRODUCTION: Lamivudine is a nucleoside analogue that is used clinically for treating chronic hepatitis B infection. However, the main problem with prolonged use of lamivudine is the development of viral resistance to the treatment. Mutations in the YMDD motif of the hepatitis B virus DNA polymerase gene have been associated with resistance to drug therapy. So far, there have not been many studies in Brazil reporting on genotype-dependent development of resistance to lamivudine. Thus, the aim of the present study was to determine the possible correlation between a certain genotype and increased development of resistance to lamivudine among chronic hepatitis B patients. METHODS: HBV DNA in samples from 50 patients under lamivudine treatment was amplified by means of conventional PCR. Samples were collected at Hospital das Clínicas, FMRP-USP. The products were then sequenced and phylogenetic analysis was performed. RESULTS: Phylogenetic analysis revealed that 29 (58 percent) patients were infected with genotype D, 20 (40 percent) with genotype A and one (2 percent) with genotype F. Mutations in the YMDD motif occurred in 20 percent of the patients with genotype A and 27.6 percent of the patients with genotype D. CONCLUSIONS: Despite the small number of samples, our results indicated that mutations in the YMDD motif were 1.38 times more frequent in genotype D than in genotype A.

INTRODUÇÃO: Lamivudina é um análogo de nucleosídeo clinicamente utilizado para o tratamento da infecção crônica pela hepatite B. Entretanto, o principal problema do uso prolongado da lamivudina é o desenvolvimento de resistência viral ao tratamento. Mutações no motivo YMDD no gene da DNA polimerase do vírus da hepatite B estão associados com a resistência a terapia medicamentosa. Até o presente momento, não há muitos estudos no Brasil que descrevem o desenvolvimento genótipo-dependente da resistência à lamivudina. Assim, o intuito do trabalho aqui descrito foi determinar a possível correlação entre um determinado genótipo e o desenvolvimento aumentado da resistência à lamivudina em pacientes com hepatite B crônica. MÉTODOS: O HBV DNA foi amplificado por PCR convencional a partir de 50 amostras coletadas de pacientes submetidos ao tratamento com lamivudina no Hospital das Clínicas- FMRP- USP. Posteriormente, os produtos foram seqüenciados e a análise filogenética foi realizada. RESULTADOS: A análise filogenética mostrou que 29 (58 por cento) pacientes foram infectados com o genótipo D, 20 (40 por cento) com o genótipo A e 1 (2 por cento) com o genótipo F. Mutações no motivo YMDD ocorreu em 20 por cento dos pacientes com genótipo A e 27,6 por cento em pacientes do genótipo D. CONCLUSÕES: Apesar do baixo número de amostras, nossos resultados indicaram que mutações no motivo YMDD são 1,38 X mais frequentes no genótipo D em relação ao genótipo A.

Revisão sistemática da eficácia do interferon alfa (convencional, peguilado) e lamivudina para o tratamento da hepatite crônica B: [revisão] / Efficacy of interferon (conventional, pegylated) and lamivudine for treatment of chronic hepatitis B: a systematic review: [review]

A hepatite crônica B constitui um grave problema de saúde pública e vem demonstrando crescentes gastos com financiamento de medicamentos de dispensação em caráter excepcional e de alto custo no Sistema Único de Saúde (SUS). O objetivo do estudo foi comparar a eficácia do interferon (convencional; peguilado - PEG2a) e lamivudina (LAM) para o tratamento da hepatite crônica B, pelo método de revisão sistemática selecionando ensaios clínicos randomizados e controlados identificados nas bases PubMed e LILACS. As medidas de resultado consideradas foram resposta virológica, soroconversão, resposta bioquímica, resposta histológica e efeitos adversos. Foram selecionados 35 artigos. A presença ou ausência do HBeAg e os níveis de alanina amino transferase (ALT) no pré-tratamento demonstraram papel fundamental na indicação terapêutica inicial. O tratamento com interferons convencionais permite a inativação da doença por longos períodos de tempo, podendo resultar em soroconversão HBsAg. O PEG 2a demonstrou eficácia superior ao interferon e LAM e efeitos colaterais semelhantes ao interferon. A LAM apresenta vantagem de ser sensível para os pacientes HBeAg negativo e apresenta como maior desvantagem o desenvolvimento de resistência.

Chronic hepatitis B is considered a major public health problem, and its treatment entails increasing health budget expenses with high-cost drugs covered by Unified National Health System. The objective of this study was to compare the efficacy of interferon (conventional; pegylated - PEG2a) and lamivudine (LAM) for the treatment of chronic hepatitis B through a systematic review, selecting randomized, controlled clinical trials identified in PubMed and LILACS. Target outcomes were virological, biochemical, and histological response, seroconversion, and adverse effects. The review selected 35 articles. Presence or absence of HBeAg and pre-treatment alanine aminotransferase (ALT) levels were considered important factors in the initial therapeutic indication. Treatment with conventional interferon enables lasting disease inactivation and can result in HBsAg seroconversion. PEG2a showed better efficacy than interferon and LAM and similar side effects to interferon. LAM presents advantages such as its sensitivity in the HbeAg-negative phenotype, while its main disadvantage is the development of resistance.

Infección hepática crónica por el virus de la hepatitis B: unarevisión con énfasis en los aspectos terapéuticos / Chronic hepatitis B virus infection: a review with emphasis on therapy

Se calcula que 400 millones de personas en todo el mundo están infectadas crónicamente con el virus de la hepatitis B (VHB). Colombia ha pasado a tener una prevalencia baja con un 2% de la población positiva para el antígeno de superficie de este virus (HBsAg); sin embargo, la prevalencia varía entre las distintas regiones. Los portadores de VHB tienen mayor riesgo de desarrollar hepatitis crónica, cirrosis hepática (CH), falla hepática y carcinoma hepatocelular (CHC). El tratamiento de la infección crónica por el VHB busca frenar por completo la replicación viral e inducir la remisión del daño hepático antes de que se desarrolle CH o CHC. Actualmente la terapia farmacológica se hace, entre otros medicamentos, con interferón pegilado alfa 2a, lamivudina, adefovir y entecavir. Los pacientes con hepatitis aguda no necesitan tratamiento, aquellos con falla hepática fulminante se deben evaluar para trasplante y el tratamiento de la infección crónica se debe elegir según la gravedad y características de la enfermedad. El seguimiento de los pacientes con infección aguda por el VHB se debe hacer cada 1-3 meses para detectar la progresión hacia hepatitis crónica; para ese propósito se miden los niveles de aminotransferasas, bilirrubinas, tiempo de protrombina, albúmina sérica, alfa-fetoproteína y ADN VHB; también se hacen recuento de plaquetas, biopsia hepática, ultrasonido abdominal y endoscopia digestiva superior. A los pacientes en tratamiento con interferón pegilado se les deben medir cada seis meses el antígeno e (HBeAg), su correspondiente anticuerpo (anti-HBe) y el ADN VHB. En quienes reciben lamivudina, adefovir, entecavir u otros antivirales, estas mediciones se hacen cada 3-6 meses. Se están estudiando otros fármacos tales como: emtricitabine, clevudine, tenofovir, telmivudina y beta L nucleósidos. Las estrategias inmunomoduladoras incluyen el uso de citoquinas y la vacunación.

Despite vaccination campaigns around the world and the resolution of the disease in immunocompetent adults, it is estimated that 400 million people worldwide are chronically infected with the hepatitis B virus (HBV). The prevalence rate of this disease in the Colombian population is low, though variable among regions: only 2% are positive in tests for the surface antigen of this virus (HBsAg). Carriers of HBV have a higher risk of developing chronic hepatitis, cirrhosis (HC), liver failure and hepatocellular carcinoma (HCC). The aims of treatment for chronic HBV infection are to completely control viral replication and to induce remission of liver damage before HC or HCC may develop. Nowadays, pharmacological therapy of HBV infection is done, among others, with pegylated interferon alfa 2a, lamivudine, adefovir, and entecavir. Patients with acute hepatitis do not need to be treated, those with acute liver failure should be evaluated for transplantation, and therapy for chronic infection should be chosen according to the degree of severity and the characteristics of their disease. Patients with acute HBV infection should be monitored every 1 to 3 months in order to detect the progression toward chronic hepatitis; for that purpose the levels of aminotransferases, bilirubin, prothrombin time, serum albumin, alfa-fetoprotein and HBV DNA are determined, and platelet count, liver biopsy, abdominal ultrasonography and upper digestive endoscopy are carried out. In patients being treated with alfa 2ª pegylated interferon HBeAg, anti-HBe and HBV DNA must be measured every 6 months. These measurements should be made every 3 to 6 months in patients who use lamivudine, adefovir, entecavir or other antivirals. Other drugs with immunomodulatory or antiviral properties are being studied. The new antiviral agents include: emtricitabine, clevudine, tenofovir, telmivudine and beta L nucleosides. Immunomodulatory strategies include the use of cytokines and vaccination.

Impacto de la disminución de la carga viral en el tratamiento de la hepatitis B en pacientes pediátricos

El objetivo de este trabajo es comprobar la eficacia del tratamiento para Hepatitis B con Lamivudina como monoterapia durante 6 meses y posteriormente combinado con Interferon convencional o Pegilado durante 6 meses más, y comparar si hay diferencias entre los dos esquemas de tratamiento. Materiales y métodos: se incluyeron 15 pacientes con Hepatitis B crónica. 8/15 recibieron lamivudina + interferon convencional y 7/15 recibieron lamivudina + interferon pegilado. Se realizó ADNHBV a los 6 meses de tratamiento (antes de empezar tratamiento con interferon) y 6 meses posterior a terminarlo. Resultados: 15 pacientes en edades entre 2 y 15 años fueron incluidos. No fue estadísticamente significativo al comparar las edades y el sexo entre los grupos. Las aminotransferasas pretratamiento y postratmiento variaron significativamente. No hubo veriación significativa en la negativización del ADNVHB durante y posterior al tratamiento, en los 2 grupos. 12/15 negativizaron ADNVHB y AgHBe; 3/12 presentan AgHbs positivo. Conclusión: la disminución de la carga viral con lamivudina mejora la respuesta al tratamiento coninterferon en pacientes pediátricos.

The objective of this study is to determine the effectiveness of treatment for Hepatitis B with Lamivudine as monotherapy for 6 months followed with conventional or pegylated interferon therapy for another 6 months, and compare whether there are differences between the two treatment modalities. Materials and methods: 15 patients with chronic Hepatitis B were included. 8 / 15 received conventional interferon and lamivudine and 7 / 15 received lamivudine + pegylated interferon. ADNHBV was performed at 6 months of treatment (before starting treatment with interferon) and 6 months after completion. Results: 15 patients with ages between 2 and 15 years were included. There was not statistically significanse when comparing the age and gender between the groups. Aminotransferases pretreatment and postreatment varied significantly. There was no significant variation between both groups in regard to ADNVHB negativization during and after treatment. 12/15 had ADNVHB and eAgHB negativization; 3 / 12 were HBsAg positive. Conclusion: the decrease in viral load with lamivudine improves the response to treatment with interferon in pediatric patients.

Hepatitis crónica por el virus B embarazo y prevención de la transmisión perinatal: pregnancy and prevention of perinatal transmission / HBV chronic hepatitis

La probabilidad de evolucionar a hepatopatía crónica posterior a una infección por el virus B depende de la edad el 80 al 90% de los niños expuestos el primer año de vida desarrollarán la enfermedad. Se debe incluir la serología para el virus B en los exámenes de rutina del control prenatal. La inmunoprofilaxis pasiva y activa previene la infección perinatal del virus B. En las mujeres embarazadas portadoras de infección crónica por virus B con alta carga viral se documenta un 20-30% de transmisión al niño recién nacido. Las madres con alta carga viral deben ser tratadas con lamiduvina posterior a la semana 28 de gestación. El niño de madre con alta carga viral debe recibir dos dosis de HBIg y el esquema de vacunación. El niño de madre positiva con carga viral baja debe recibir dosis única de HBIg y esquema de vacunación completa. Se debe de realizar control serológico de anticuerpo y antígeno de superficie en el niño entre los 9 -15 meses de edad. La lactancia no está contraindicada.

The probability to evolve to chronic liver disease post HBV infection depends on the age. Between 80 to 90% of children exposed in their first year of life will develop this disease.The serology for HBV must be included in the routine tests of perinatal control. The active and passive immunoprophylaxis prevents the perinatal infection of HBV. It has been documented that pregnant women carrying the HBV chronic infection with high viral burden have a 2030% transmission to the new born child. Those mothers with high viral burden must be treated with lamiduvine after the 28th gestation week. The child of a mother with high viral burden must receive two unique dosages of HBIg and a complete vaccination scheme. Antibody and surface antigen serologic control must be done to the child between 9-15 months of age. Lactancy is not contraindicated.

Lamivudina / Lamivudine

La lamivudina produce una inhibición intensa de la replicación del VHB y bloquea de forma competitiva la actividad ADN-polimerasa; está indicada en pacientes con Hepatitis B crónica y evidencia de replicación viral; se administra por vía oral en una única dosis de 100 mg por día, con una duración mínima recomendada por un año; se tolera bien y el tratamiento a largo plazo se asocia a la aparición de mutaciones resistentes que limitan su beneficio.

lamivudine produces an intense inhibition of HBV replication and competitively blocks DNA-Polymerase activity. It is indicated in patients with chronic hepatitis B and with evidence of viral replication. It is administered orally with a single dose of 100 mg per day and a minimum recommended term of a year. It is well tolerated and long-term treatment is related to the appearance of resistant mutations that limit its benefit.

Manejo cirrosis descompensada / Handling decompensated cirrhosis

Todos los pacientes con cirrosis y ADN HBV detectable deben recibir tratamiento antiviral. Se debe iniciar tratamiento con lamiduvina o adefovir dipivoxil. El interferón alfa, en cualquier presentación, está contraindicado. Se debe realizar monitoreo constante (cada 3 meses) de niveles de ADN HBV en los pacientes con lamiduvina para detectar resistencia a la droga. Cuando reaparece el ADN HBV o aumenta el mismo en 1 log10, se debe pensar que se está desarrollando resistencia contra lamiduvina. En caso de resistencia se debe iniciar tratamiento con adefovir dipivoxil. Los pacientes con adefovir dipivoxil deben tener monitoreo constante (cada 3 meses) de su función renal.

All cirrhotic patients and detectable DNA HBV must take antiviral treatment. Treatment should start with lamivudine or adenofir dipivoxil. Alpha interferon in any presentation is contraindicated. Constant monitoring (every 3 moths) of DNA HBV levels of patients with lamiduvine must be carried aout to detect drug resistance. When DNA HBV reappers or increases itself in 1 log10, it is believed that resistance against lamiduvine is being developed. In case of resistance, treatment with adenofir dipivoxil should be srted (every 3 months) of their renal function.

Avaliação das características físico-químicas, farmacocinéticas e da biodisponibilidade relativa de comprimidos contendo associação de lamivudina 150 mg e zidovudina 300 mg / Assessment of physicochemical, pharmacokinetic and relative bioavailability characteristics of tablets containing combination lamivudine 150 mg and zidovudine 300 mg

Lamivudina (3TC) e zidovudina (ZDV) são inibidores nucleosídeos da transcriptase reversa utilizados na terapêutica anti-HIV. Para avaliar a equivalência farmacêutica entre um medicamento teste contendo esta associação e o referência, foi desenvolvido um método para determinação cromatográfica simultânea de 3TC e ZDV em comprimidos. O método empregou coluna C8 Shim-pack® (150 x 4,6 mm, 5 um), pré-coluna C18 Phenomenex® (50 x 4,6 mm 5 um), água e metanol 60:40 (v:v) como fase móvel e detecção a 266nm. Este mostrou-se específico, com linearidade entre 45 a 5000 ng/mL, precisão demonstrada por CV por cento inferior a 5 por cento, exatidão entre 90,0 e 110,0 por cento com recuperação superior a 90 por cento para ambos os fármacos...

Lamivudine (3TC) and zidovudine (ZDV) are the nucleoside reverse transcriptase inhibitors, They are used in combinations of antiretroviral therapy. The switchability between one test product and reference could be proved if they are pharmaceutically equivalents and bioequivalents. This research beginning with development and validation of chromatographic method to 3TC and ZDV simultaneous determination in tablet. The HPLC system were used to assay and 266nm wavelength ultraviolet detector. Separation was performed using a C8 column (150 x 4,6 mm, 5 µm) Shim-pack®protected by a C18 column (50 x 4,6 mm, 5 µm) Phenomenex®. The mobile phase is composed of water and methanol 60:40 (v:v). This method was successfully applied to simultaneous determination to 3TC and ZDV without interference. It was validated over the range of 45 a 5000 ng/mL for both drugs with accurate from 90 to 110% and precision with variation lower than 5%. Extraction recoveries of the analytes were higher than 90%. The mean dissolution data about 3TC and ZDV were above than 85% in 30 minutes of dissolution test. The relative bioavailability between Biovir® (brand-name product) and Lamivudina + Zidovudina 150 + 300 mg (test product), was conducted for one direct quantitative, open and crossover study. The serial plasma sample of 3TC and ZDV collected after oral administration of brand-name product and test product, were analyzed using a validated high-performance liquid chromatography assay with UV detection in wavelength of 270 nm. The double liquid-liquid extraction was realized with additions of amonio acetat. A CLC-C8 (M) column (150 x 4,6 mm 5 µm) Shim-pack®and C18 column (50 x 4,6mm 5 µm) Phenomenex®, was eluted with two mobile phase in a linear gradient system at a flow-rate...