RESUMEN
This study aimed to assess the formation of nevirapine (NVP) co-amorphs systems (CAM) with different co-formers (lamivudine-3TC, citric acid-CAc, and urea) through combined screening techniques as computational and thermal studies, solubility studies; in addition to develop and characterize suitable NVP-CAM. NVP-CAM were obtained using the quench-cooling method, and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier Transform Infrared Spectroscopy (FTIR), and polarized light microscopy (PLM), in addition to in vitro dissolution in pH 6.8. The screening results indicated intermolecular interactions occurring between NVP and 3TC; NVP and CAc, where shifts in the melting temperature of NVP were verified. The presence of CAc impacted the NVP equilibrium solubility, due to hydrogen bonds. DSC thermograms evidenced the reduction and shifting of the endothermic peaks of NVP in the presence of its co-formers, suggesting partial miscibility of the compounds. Amorphization was proven by XRD and PLM assays. In vitro dissolution study exhibited a significant increase in solubility and dissolution efficiency of NVP-CAM compared to free NVP. Combined use of screening studies was useful for the development of stable and amorphous NVP-CAM, with increased NVP solubility, making CAM promising systems for combined antiretroviral therapy.
Asunto(s)
Rastreo Diferencial de Calorimetría , Química Farmacéutica , Nevirapina , Solubilidad , Difracción de Rayos X , Nevirapina/química , Rastreo Diferencial de Calorimetría/métodos , Difracción de Rayos X/métodos , Química Farmacéutica/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Composición de Medicamentos/métodos , Lamivudine/química , Enlace de Hidrógeno , Fármacos Anti-VIH/químicaRESUMEN
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. Motivation for the study. To evaluate the quality of antiretroviral drugs used in the treatment of HIV dispensed in the HAART Program of the Ministry of Health of Peru. Main findings. Two batches of generic lamivudine drugs were found to achieve a dissolution rate greater than 85% at 15 min, being equivalent in vitro to the reference product Epivir. Implications. There is a need to apply the current regulations regarding equivalence between drugs by the regulatory authority prior to their authorization and to include dissolution profile tests as a requirement in public drug purchases, especially in national strategies (HIV, TB, etc.), in order to ensure quality products for the population.
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. Motivación para realizar el estudio. Evaluar la calidad de los medicamentos antirretrovirales usados en el tratamiento del VIH dispensados en el Programa TARGA del Ministerio de Salud de Perú. Principales hallazgos. Se encontró que dos lotes de medicamentos genéricos de lamivudina alcanzaron un porcentaje de disolución mayor del 85% a los 15 min, siendo equivalentes in vitro al producto de referencia Epivir. Implicancias. Existe la necesidad de aplicar la normatividad vigente respecto a equivalencia entre fármacos por parte de la autoridad regulatoria previo a su autorización e incluir ensayos de perfil de disolución como requisito en las compras públicas de medicamentos, especialmente en las estrategias nacionales (VIH, TBC, etc.), con la finalidad de asegurar productos de calidad para la población.
Asunto(s)
Medicamentos Genéricos , Lamivudine , Solubilidad , Comprimidos , Lamivudine/química , Medicamentos Genéricos/química , Medicamentos Genéricos/normas , Perú , Estudios TransversalesRESUMEN
BACKGROUND: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. METHODS: HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. RESULTS: In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. CONCLUSIONS: Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.
Asunto(s)
Fármacos Anti-VIH , Desoxiadenosinas , Infecciones por VIH , VIH-1 , Humanos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , VIH-1/genética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Mutación , Transcriptasa Inversa del VIH/genética , Farmacorresistencia Viral/genética , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
Perinatally HIV-infected infants can be infected with a drug-resistant virus or select for drug resistance by exposure to sub-therapeutic levels of maternal antiretroviral drugs present in breastmilk or from sub-therapeutic infant prophylaxis. We report a case of dolutegravir resistance detected in a treatment-naive perinatally HIV-infected infant whose mother was receiving tenofovir/lamivudine/dolutegravir. This case was detected during a national survey of HIV drug resistance in Haiti amongst infants testing positive for HIV through the national early infant diagnosis program between April 2020 and March 2021. This unique case underscores the need for prompt management of high viral loads in pregnant and breastfeeding women and supports HIV drug resistance surveillance efforts targeted at antiretroviral therapy-naive infants born to mothers in low-and middle-income countries.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Embarazo , Lactante , Femenino , Humanos , Lamivudine/uso terapéutico , Tenofovir/uso terapéutico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Madres , Fármacos Anti-VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Oxazinas/uso terapéuticoRESUMEN
BACKGROUND: Unreported HIV antiretroviral (ARV) drug usage by blood donors compromises the ability to detect evidence of HIV infection in blood screening tests and represents a risk for blood transfusion safety. Our objective was to determine the frequency of undeclared ARV drug use by blood donors with altered HIV markers. STUDY DESIGN AND METHODS: This was a retrospective cross-sectional analysis of donations that were tested for HIV antibody (ab), antigen (ag), and RNA by chemiluminescent immunoassay and nucleic acid screening tests. Positive samples were retested and were subjected to ARV drug testing by high-performance liquid chromatography-tandem mass spectrometry. RESULTS: Of 345,252 blood donations, 361 (0.1%) were positive on initial testing. Samples from 296 (81.9%) of these donations were available for further analysis. The presence of HIV ab/ag and/or RNA was confirmed in 83 (28.0%) of these samples. All 296 bloods were subjected to ARV testing. The ARV drug lamivudine, at 11.3 and 6.7 ng/mL, was detected in 2 of 83 (2.4%) donations that were HIV positive. Other drugs were not detected. CONCLUSION: Unreported ARV usage was identified in two candidates for blood donation. More intensive efforts to educate donors about disclosure and to investigate the extent of this phenomenon in Brazil are needed.
Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , Lamivudine/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/diagnóstico , Donantes de Sangre , Estudios Retrospectivos , Estudios Transversales , Anticuerpos Anti-VIH , Antirretrovirales/uso terapéutico , ARNRESUMEN
BACKGROUND: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. METHODS: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. RESULTS: One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. CONCLUSIONS: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.
Asunto(s)
Infecciones por VIH , Inhibidores de la Transcriptasa Inversa , Humanos , Brasil , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Lamivudine/farmacología , Lamivudine/uso terapéutico , Mutación , Antirretrovirales , Tenofovir , Insuficiencia del Tratamiento , Infecciones por VIH/tratamiento farmacológicoRESUMEN
BACKGROUND: Two-Drug Regimens (2DR) have proven effective in clinical trials but real-world data, especially in resource-limited settings, is limited. OBJECTIVES: To evaluate viral suppression of lamivudine-based 2DR, with dolutegravir or ritonavir-boosted protease inhibitor (lopinavir/r, atazanavir/r or darunavir/r), among all cases regardless of selection criteria. PATIENTS AND METHODS: A retrospective study, conducted in an HIV clinic in the metropolitan area of São Paulo, Brazil. Per-protocol failure was defined as viremia above 200 copies/mL at outcome. Intention-To-Treat-Exposed (ITT-E) failure was considered for those who initiated 2DR but subsequently had either (i) Delay over 30 days in Antiretroviral Treatment (ART) dispensation, (ii) ART changed or (iii) Viremia > 200 copies/mL in the last observation using 2DR. RESULTS: Out of 278 patients initiating 2DR, 99.6% had viremia below 200 copies/mL at last observation, 97.8% below 50 copies/mL. Lamivudine resistance, either documented (M184V) or presumed (viremia > 200 copies/mL over a month using 3TC) was present in 11% of cases that showed lower suppression rates (97%), but with no significant hazard ratio to fail per ITT-E (1.24, p = 0.78). Decreased kidney function, present in 18 cases, showed of 4.69 hazard ratio (p = 0.02) per ITT-E for failure (3/18). As per protocol analysis, three failures occurred, none with renal dysfunction. CONCLUSIONS: The 2DR is feasible, with robust suppression rates, even when 3TC resistance or renal dysfunction is present, and close monitoring of these cases may guarantee long-term suppression.
Asunto(s)
Fármacos Anti-VIH , Antiinfecciosos , Infecciones por VIH , Inhibidores de la Proteasa del VIH , Enfermedades Renales , Humanos , Lamivudine/uso terapéutico , Lamivudine/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Estudios Retrospectivos , Viremia/tratamiento farmacológico , Brasil , Inhibidores de la Proteasa del VIH/uso terapéutico , Quimioterapia Combinada , Antiinfecciosos/farmacología , Enfermedades Renales/tratamiento farmacológico , Carga ViralRESUMEN
In Argentina, transgender women (TGW) have a high HIV prevalence (34%). However, this population shows lower levels of adherence, retention in HIV care and viral suppression than cisgender patients. The World Health Organization (WHO) recommends the transition to dolutegravir (DTG)-based regimens to reduce adverse events and improve adherence and retention. The purpose of this study was to determine retention, adherence and viral suppression in naïve TGW starting a DTG-based first-line antiretroviral treatment (ART) and to identify clinical and psychosocial factors associated with retention. We designed a prospective, open-label, single-arm trial among ART-naïve HIV positive TGW (Clinical Trial Number: NCT03033836). Participants were followed at weeks 4, 8, 12, 24, 36 and 48, in a trans-affirmative HIV care service that included peer navigators, between December, 2015 and May, 2019. Retention was defined as the proportion of TGW retained at week 48 and adherence was self-reported. Viral suppression at <50 copies/mL was evaluated using snapshot algorithm and as per protocol analysis. Of 75 TGW screened, 61 were enrolled. At baseline, median age was 28 y/o., HIV-1-RNA (pVL) 46,908 copies/mL and CD4+ T-cell count 383 cells/mm3. At week 48, 77% were retained and 72% had viral suppression (97% per protocol). The regimen was well tolerated and participants reported high adherence (about 95%). Eleven of the fourteen TGW who discontinued or were lost to follow-up had undetectable pVL at their last visit. Older age was associated with better retention. DTG-based treatment delivered by a trans-competent team in a trans-affirmative service was safe and well tolerated by TGW and associated with high retention, high adherence and high viral suppression at 48 weeks among those being retained.
Asunto(s)
Infecciones por VIH , Personas Transgénero , Adulto , Femenino , Humanos , Antirretrovirales/uso terapéutico , Argentina/epidemiología , Emtricitabina/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Lamivudine/efectos adversos , Estudios Prospectivos , Piridonas/uso terapéutico , Tenofovir/efectos adversosRESUMEN
Introduction: Prevention strategies are key to combating the epidemic of infections such as HIV and syphilis. The epidemiological scenario of Porto Alegre/RS for these infections shows the need for greater efforts in the area of prevention, seeking to characterize both the population that uses these strategies and the services involved in the care of exposed people. Objective: This study aimed to characterize the clinical and epidemiological profile of patients who received post-exposure prophylaxis (PEP) to HIV treated in a public hospital in Porto Alegre/RS. Methods: This is a retrospective, research, descriptive study based on the Clinical Protocol and Therapeutic Guidelines for PEP, updated in 2018 by the Ministry of Health. Prophylaxis request forms and medical records of patients treated were analyzed. Results: The population consisted of 87 women who received PEP from January to September 2019. There was a predominance of women aged between 20 and 29 years old (55.2%). The most frequent sexual exposure was consensual (69.0%) followed by sexual assault (31.0%). Porto Alegre was the place of residence of most patients (73.6%). The most frequently used therapeutic regimen was the combination of atazanavir, ritonavir, and tenofovir plus lamivudine. On the first visit, 8.0% of the patients showed reactive results for the treponemal syphilis test. Only 23.0% and 14.9% of patients returned for anti-HIV tests in the first and third months after exposure, respectively, and the results were non-reactive. Only 19 patients (21.8%) attended the consultations between 0 and 28 days after PEP. Conclusion: It was identified that a considerable percentage of women already had reactive serology for syphilis, most women did not return for follow-up within 28 and 90 days after the first consultation, more than half of the women were aged between 20 and 29 years old, and the most frequent sexual exposure was consensual. In this sense, efforts are needed, such as adequate counseling, adoption of interventions such as sending messages by cell phone, telephone calls, and preparation of educational materials, seeking to improve adherence to treatment and follow-up in the service, which is important given the scenario of epidemiology in Porto Alegre.Keywords: HIV. Sexually transmitted diseases. Post-exposure prophylaxis. Disease prevention
Introdução: Estratégias de prevenção são fundamentais para o combate à epidemia de infecções como o vírus da imunodeficiência humana (HIV) e sífilis. O cenário epidemiológico de Porto Alegre/RS para essas infecções mostra a necessidade de maiores esforços na área de prevenção, buscando caracterizar tanto a população que utiliza essas estratégias quanto os serviços envolvidos no atendimento das pessoas expostas. Objetivo: Caracterizar o perfil clínico-epidemiológico das pacientes que receberam a profilaxia pós-exposição (PEP) ao HIV atendidas em um hospital público de Porto Alegre/RS. Métodos: Trata-se de um estudo retrospectivo, documental, descritivo e baseado no Protocolo Clínico e Diretrizes Terapêuticas para PEP, atualizado em 2021 pelo Ministério da Saúde. Foram analisados os formulários de solicitação da profilaxia e prontuários das pacientes atendidas. Resultados: A população foi composta de 87 mulheres que receberam a PEP no período de janeiro a setembro de 2019. Predominaram mulheres com idades entre 20 e 29 anos (55,2%). A exposição sexual mais frequente foi a consentida (69,0%), seguida pela violência sexual (31,0%). Porto Alegre foi o local de residência da maioria das pacientes (73,6%). O esquema terapêutico utilizado com maior frequência foi a combinação com atazanavir, ritonavir e tenofovir associado à lamivudina. No primeiro atendimento, 8,0% das pacientes demonstraram resultados reagentes para o teste treponêmico de sífilis. Retornaram para a realização dos testes anti-HIV no primeiro e terceiro mês após a exposição apenas 23,0 e 14,9% das pacientes, respectivamente, e os resultados foram não reagentes. Apenas 19 delas (21,8%) compareceram às consultas entre zero e 28 dias posteriores à PEP. Conclusão: Foi identificado que um percentual considerável de mulheres já apresentava sorologia reagente para sífilis, a maioria das mulheres não retornou para o seguimento no período de 28 e 90 dias após o primeiro atendimento, mais da metade delas tinha idade entre 20 e 29 anos e a exposição sexual mais frequente foi a consentida. Nesse sentido, são necessários esforços como aconselhamento adequado, adoção de intervenções como o envio de mensagens pelo celular, ligações telefônicas e elaboração de materiais educativos, buscando a melhoria da adesão ao tratamento e do acompanhamento no serviço, o que é importante diante do cenário epidemiológico de Porto Alegre.Palavras-chave: HIV. Infecções sexualmente transmissíveis. Profilaxia pós-exposição. Prevenção
Asunto(s)
Humanos , Femenino , Adulto , Adulto Joven , Infecciones por VIH/prevención & control , Fármacos Anti-VIH/administración & dosificación , Profilaxis Posexposición/estadística & datos numéricos , Estudios Retrospectivos , Ritonavir/administración & dosificación , Lamivudine/administración & dosificación , Quimioterapia Combinada , Tenofovir/administración & dosificación , Sulfato de Atazanavir/administración & dosificaciónRESUMEN
OBJECTIVES: The inadequacy of resistance monitoring in Latin America leads to circulation of HIV strains with drug resistance mutations (DRMs), compromising ART effectiveness. This study describes the DRM prevalence in HIV-infected paediatric patients in Panama. METHODS: During 2018-19, plasma was collected from 76 HIV-infected children/adolescents (5 ART-naive, 71 treated) in Panama for HIV-1 DRM pol analysis, predicted antiretroviral (ARV) susceptibility by Stanford, and HIV-1 variant phylogenetic characterization. RESULTS: HIV-1 pol sequences were recovered from 67 (88.2%) of 76 children/adolescents (median age 12 years), carrying 65 subtype B, 1 subtype G and 1 unique recombinant URF_A1B. Five were ART-naive and 62 ART-treated under virological failure (viraemia >50 copies/mL) with previous exposure to NRTIs, (100%), NNRTIs (45.2%), PIs (95.2%) and integrase strand transfer inhibitors (INSTIs, 17.7%). Among the treated patients, 34 (54.8%) carried resistant strains, with major DRMs to one (40.3%), two (9.7%) or three (4.8%) ARV families. Most of them harboured DRMs to NRTIs (58.5%) or NNRTIs (39%), but also major DRMs to PIs (4.9%) and INSTIs (6.5%). We also found dual-class NRTIâ+âNNRTI (12.2%) and NNRTIâ+âPI (2.6%) resistance. Two naive subjects carried viruses with DRMs to NRTIs and NRTIâ+âNNRTI, respectively. Sequenced viruses presented high/intermediate resistance mainly to emtricitabine/lamivudine (48.9% each) and efavirenz/nevirapine (33.3% each). Most participants were susceptible to PIs (91.3%) and INSTIs (88.1%). CONCLUSIONS: The high DRM prevalence to NRTIs and NNRTIs observed among treated HIV-infected children/adolescents in Panama justifies the need for routine resistance monitoring for optimal rescue therapy selection in this vulnerable population.
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Fármacos Anti-VIH , Infecciones por VIH , Humanos , Niño , Adolescente , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Filogenia , Farmacorresistencia Viral/genética , Lamivudine/uso terapéutico , Antirretrovirales/uso terapéutico , Mutación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , GenotipoRESUMEN
OBJECTIVES: We assessed real-world weight change and pregnancy outcomes among pregnant women living with HIV who used integrase strand transferase inhibitor (INSTI)-based combined antiretroviral therapy (cART). METHODS: In a retrospective cohort study from 2014 to 2021 for prevention of perinatal HIV infection, we evaluated changes in weight from the first prenatal visit to near delivery for two groups. The categories of change were: low (< 0.18 kg/week), normal (0.18-0.59 kg/week), and high (> 0.59 kg/week). The backbones were lamivudine + tenofovir disoproxil or lamivudine + zidovudine. The comparison groups were women with body mass index (BMI) < 25 kg/m2 versus BMI ≥ 25 kg/m2 and INSTI-naïve versus INSTI-experienced. Continuous variables were analysed with a Kruskal-Wallis test and count or categorical data with χ2 tests. RESULTS: We enrolled 198 pregnant women. At study entry, 74 had BMI < 25 kg/m2 and 124 had BMI ≥ 25 kg/m2 . Excess gestational weight gain was more frequent among women who were INSTI-naïve among both BMI groups (< 25 and ≥ 25). However, the proportion of participants per weight change category was only significantly different between INSTI-naïve women with baseline BMI < 25 kg/m2 and INSTI-experienced women with BMI < 25 kg/m2 . In particular, INSTI-naïve women with BMI < 25 kg/m2 had significantly higher rates of excess gestational weight gain (31.6%) compared with participants with BMI < 25 kg/m2 who conceived while on INSTIs (11.8%, p = 0.004). Rates of unfavourable pregnancy outcomes were low and did not differ significantly between groups. CONCLUSIONS: INSTI-naïve participants with BMI < 25 kg/m2 gained more weight during pregnancy than participants with BMI ≥ 25 kg/m2 who conceived while using INSTIs. Rates of adverse pregnancy outcomes did not differ between the groups.
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Fármacos Anti-VIH , Ganancia de Peso Gestacional , Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , Humanos , Femenino , Embarazo , Masculino , Infecciones por VIH/tratamiento farmacológico , Lamivudine/uso terapéutico , Mujeres Embarazadas , Estudios Retrospectivos , Fármacos Anti-VIH/uso terapéutico , Aumento de Peso , Inhibidores de Integrasa VIH/uso terapéutico , Resultado del EmbarazoRESUMEN
Levels of adherence to antiretroviral therapy (ART) can affect the likelihood of viral suppression differentially among ART regimens. In this prospective cohort conducted in Belo Horizonte, Brazil, we included 354 individuals who initiated ART containing tenofovir disoproxil fumarate/lamivudine/efavirenz in fixed-dose combination (TDF/3TC/EFV) or tenofovir disoproxil fumarate/lamivudine associated with dolutegravir (TDF/3TC + DTG). Viral suppression (viral load <50 copies/mL) was evaluated within six months of follow-up at different adherence levels and by therapeutic regimen. Adherence was measured by the Proportion of Days Covered (PDC) and classified into low (≤84%), intermediate (85-89%) or high (≥90%). The association between viral suppression, adherence levels, and other explanatory variables was analyzed using chi-square and multivariable logistic regression. Viral suppression was achieved by 76.0% of individuals and was more frequent among those who achieved higher levels of adherence (high adherence: 79.3%, intermediate: 71.4% and low: 45.2%), those on TDF/3TC + DTG, and those who had viral load ≤100,000 copies/mL at the onset of treatment (p < 0.05). Moreover, individuals on TDF/3TC + DTG had an approximately 90% probability of achieving viral suppression at intermediate adherence levels. These results add new insights on the possibility of lower adherence levels for contemporary antiretroviral regimens currently used as first-line therapy worldwide.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Lamivudine/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Brasil , Fármacos Anti-VIH/uso terapéutico , Estudios de Cohortes , Estudios Prospectivos , Antirretrovirales/uso terapéutico , Tenofovir/uso terapéutico , Benzoxazinas/uso terapéuticoRESUMEN
Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.
Asunto(s)
Comprimidos/análisis , Zidovudina/agonistas , VIH/patogenicidad , Lamivudine/agonistas , Pacientes/clasificación , Gestión de la Calidad Total/organización & administración , Honorarios y Precios/estadística & datos numéricos , Laboratorios/clasificación , Materiales Manufacturados/provisión & distribuciónRESUMEN
Several hepatitis B virus (HBV)-related factors, including the viral load, genotype, and genomic mutations, have been linked to the development of liver diseases. Therefore, in this study we aimed to investigate the influence of HBV genetic variability during acute and chronic infection phases. A real-time nested PCR was used to detect HBV DNA in all samples (acute, n = 22; chronic, n = 49). All samples were sequenced for phylogenetic and mutation analyses. Genotype A, sub-genotype A1, was the most common genotype in the study population. A total of 190 mutations were found in the pre-S/S gene area and the acute profile revealed a greater number of nucleotide mutations (p < 0.05). However, both profiles contained nucleotide mutations linked to immune escape and an increased risk of hepatocellular carcinomas (acute, A7T; chronic, A7Q). Furthermore, 17 amino acid substitutions were identified in the viral polymerase region, including the drug resistance mutations lamivudine and entecavir (rtL180M), with statistically significant differences between the mutant and wild type strains. Owing to the natural occurrence of these mutations, it is important to screen for resistance mutations before beginning therapy.
Asunto(s)
Hepatitis B Crónica , Hepatitis B , Proteína S/genética , Brasil/epidemiología , ADN Viral/genética , Farmacorresistencia Viral/genética , Genotipo , Virus de la Hepatitis B/genética , Humanos , Lamivudine/uso terapéutico , Mutación , Nucleótidos , FilogeniaRESUMEN
BACKGROUND: The World Health Organization (WHO) 2019 antiretroviral treatment guidelines recommend use of optimal treatment regimens in all populations. Dolutegravir-based regimens are the preferred first-line and second-line treatment in infants and children with HIV 4 weeks of age and above. There is an urgent need for optimal pediatric formulations of dolutegravir as single-entity (SE) and fixed-dose combination (FDC) to ensure correct dosing and adherence for swallowing and palatability. This article outlines the chronology of dolutegravir pediatric formulation development as granules and conventional and dispersible tablets in a total of 5 pharmacokinetic studies evaluating the relative bioavailability of dolutegravir SE and FDC formulations in healthy adults. METHODS: The relative bioavailability studies were 2-part, Phase I, open-label, randomized studies in healthy adults. Dolutegravir SE study compared conventional dolutegravir 50 and 25 mg with equivalent conventional 10-mg and dispersible 5-mg tablets, respectively. Subsequently, dolutegravir FDC study compared adult FDC of abacavir/dolutegravir/lamivudine and adult FDC of dolutegravir/lamivudine with their respective pediatric FDC formulations, taken as dispersion immediately or swallowed whole. RESULTS: As observed in previous studies, dolutegravir administered as dispersion (granules/dispersible tablets) showed relatively higher bioavailability compared with conventional tablets. The bioavailability of dolutegravir dispersible tablets (both SE and FDC) was approximately 1.6-fold higher when compared with conventional tablets. In addition, the bioavailability of abacavir/lamivudine was not impacted by dispersible formulation. CONCLUSIONS: These studies demonstrate the successful development of pediatric dolutegravir-containing formulations as SE and FDC that permit pediatric dosing in line with WHO recommendations.
Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Oxazinas/administración & dosificación , Piperazinas/administración & dosificación , Piridonas/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Fármacos Anti-VIH/farmacocinética , Disponibilidad Biológica , Didesoxinucleósidos , Combinación de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Lamivudine , Persona de Mediana Edad , Oxazinas/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Comprimidos/administración & dosificación , Adulto JovenRESUMEN
OBJECTIVE: To assess efficacy and safety of dolutegravir (DTG) + lamivudine (3TC) vs. DTG + tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in treatment-naive adults with HIV-1 in the prespecified 144-week secondary analyses of GEMINI-1 and GEMINI-2. DESIGN: Identical, multicenter, phase III, randomized, non-inferiority studies (double-blind through 96âweeks). METHODS: Participants with HIV-1 RNA ≤500â000âcopies/ml and no major viral resistance mutations to nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, or protease inhibitors were randomized 1:1 to once-daily DTG + 3TC or DTG + TDF/FTC. RESULTS: At week 144, DTG + 3TC (Nâ=â716) was noninferior to DTG + TDF/FTC (Nâ=â717) in proportion of participants achieving HIV-1 RNA <50âcopies/ml (Snapshot algorithm) in the pooled analysis (82% vs. 84%, respectively; adjusted treatment difference [95% confidence interval (CI)], -1.8% [-5.8, 2.1]), GEMINI-1 (-3.6% [-9.4, 2.1]), and GEMINI-2 (0.0% [-5.3, 5.3]). Twelve DTG + 3TC participants and nine DTG + TDF/FTC participants met protocol-defined confirmed virologic withdrawal (CVW) criteria; none developed treatment-emergent resistance. One DTG + 3TC participant who did not meet CVW criteria developed M184V at week 132 and R263R/K at week 144, conferring a 1.8-fold change in susceptibility to DTG; non-adherence to therapy was reported. Significantly fewer drug-related adverse events occurred with DTG + 3TC vs. DTG + TDF/FTC (20% vs. 27%; relative risk [95% CI], 0.76 [0.63-0.92]). Renal and bone biomarker changes favored DTG + 3TC. CONCLUSIONS: Three-year durable efficacy, long-term tolerability, and high barrier to resistance support first-line use of DTG + 3TC for HIV-1 treatment (see Supplemental Digital Content 1, http://links.lww.com/QAD/C297; video abstract).
Asunto(s)
Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada/efectos adversos , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos , Humanos , Lamivudine/uso terapéutico , Oxazinas , Piperazinas , Piridonas/uso terapéutico , Resultado del TratamientoRESUMEN
Nucleoside/nucleotide analogs such as tenofovir, have been used as long-term therapy for the treatment of hepatitis B and side effects such as the reduction in bone mineral density have been associated with their use. To determine the relationships between bone, hormonal, biochemical, and mineral parameters in patients with hepatitis B treated with nucleoside/nucleotide antiviral. A cross-sectional study was conducted with 81 adult patients with chronic hepatitis B infection. Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density. Biochemical analyses were performed for osteocalcin, deoxypyridinoline, parathyroid hormone, vitamin D, IGF-1, TSH, testosterone, estradiol, FSH, transaminases, urea, creatinine, calcium, serum and urinary phosphorus, magnesium, and FGF-23, body composition was performed by DXA. Participants, both gender, were divided according to the use of antiretrovirals: Group1: 27 inactive virus carriers without medication; Group2: 27 patients using tenofovir; and Group3: 27 patients using lamivudine or entecavir. DXA readings diagnosed osteopenia in the lumbar spine for 7.4% of individuals in Group1, 15% in Group2, and 3.7% in Group3. For all groups, we observed normal values in bone formation markers, osteocalcin levels as well as parathyroid hormone, insulin growth factor 1, and FGF-23. In all groups, we found increased levels of urinary deoxypyridinoline, a bone resorption marker. Increased levels in the bone resorption markers indicated a high resorptive activity of bone tissue. These data suggested high resorption activity of bone tissue in hepatitis B virus-infected patients independent of the use of antiretrovirals.
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Antirretrovirales/uso terapéutico , Resorción Ósea/complicaciones , Resorción Ósea/metabolismo , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Osteoclastos/metabolismo , Absorciometría de Fotón , Adulto , Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Resorción Ósea/diagnóstico por imagen , Resorción Ósea/virología , Estudios Transversales , Femenino , Cuello Femoral/diagnóstico por imagen , Cuello Femoral/metabolismo , Cuello Femoral/virología , Factor-23 de Crecimiento de Fibroblastos , Guanina/análogos & derivados , Guanina/uso terapéutico , Virus de la Hepatitis B/efectos de los fármacos , Cadera/diagnóstico por imagen , Cadera/virología , Humanos , Lamivudine/uso terapéutico , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/metabolismo , Vértebras Lumbares/virología , Masculino , Persona de Mediana Edad , Osteoclastos/efectos de los fármacos , Osteoclastos/virología , Tenofovir/uso terapéuticoAsunto(s)
Humanos , Virus de la Hepatitis B/efectos de los fármacos , Lamivudine/administración & dosificación , Tenofovir/uso terapéutico , Hepatitis B/tratamiento farmacológico , Enfermedades Renales/complicaciones , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Análisis Costo-Beneficio/economíaRESUMEN
OBJECTIVES: To assess the risk of adverse diagnoses and laboratory abnormalities associated with a 300 or 150âmg daily dose of lamivudine (3TC) initiated by people with HIV (PWH) with an estimated glomerular filtration rate (eGFR) between at least 30 and 49âml/min perâ1.73 m2 or less. DESIGN: Longitudinal study based on electronic health records of 539 PWH with eGFR between at least 30 and 49âml/min perâ1.73 m2 or less from the Observational Pharmaco-Epidemiology Research and Analysis (OPERA) cohort. METHODS: Common unintended effects of 3TC were evaluated as composite outcomes. We estimated the incidence (univariate Poisson regression) and association between dose and incident composite outcomes (multivariate Poisson regression) among PWH without the relevant diagnoses or laboratory abnormalities at 3TC initiation. RESULTS: PWH initiating 150âmg 3TC had higher HIV RNA, lower eGFR, and more comorbidities than those initiating 300âmg 3TC. The prevalence of relevant diagnoses and laboratory abnormalities was similar in both groups. The most common lab abnormality was low hemoglobin. There was no statistically significant difference in incident adverse diagnoses/severe lab abnormalities with 300âmg versus 150âmg [incidence rate ratio (IRR): 1.51; 95% confidence interval (CI) 0.59--3.92). However, a statistically significant association was observed when gastrointestinal symptoms/moderate lab abnormalities were included in the outcome (IRR: 3.07, 95% CI 1.12--8.40). CONCLUSION: As 3TC is a well tolerated drug with a wide therapeutic window, dose adjustment may be unnecessary among PWH with eGFR between at least 30 and 49âml/min per 1.73 m2 or less. Clinical judgement is key when weighing the risks and benefits of 3TC dose adjustment for PWH experiencing gastrointestinal symptoms or moderate lab abnormalities.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/efectos adversos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Riñón , Lamivudine/efectos adversos , Estudios LongitudinalesRESUMEN
OBJECTIVES: To assess the effect of protease inhibitor (PI)-based dual therapy on CD4/CD8 ratio during the first year of therapy in antiretroviral therapy (ART)-naïve patients using data from randomized controlled clinical trials. METHODS: We pooled data from the GARDEL and ANDES studies, both randomized controlled clinical trials that recruited ART-naïve people living with HIV and randomly assigned them to receive PI-based dual therapy (DT) or triple therapy (TT) aiming to compare viral efficacy. We compared median CD4/CD8 ratios and the proportion of patients with CD4/CD8 ratio > 1 at 48 weeks after ART initiation in both treatment arms using the Mann-Whitney U-test and the χ2 test. We performed subgroup analysis for patients > 50 years old, with baseline CD4 counts ≤ 200 cells/µL, viral load > 100 000 HIV RNA copies/mL, and ritonavir-boosted lopinavir-based therapy. RESULTS: We analysed data from 571 patients: 292 on DT and 279 on TT. No differences were observed in CD4/CD8 ratio (0.632 vs. 0.617, P = 0.729) or in the proportion of patients with CD4/CD8 ratio > 1 (17.9% vs. 19.3%, P = 0.678) 48 weeks after ART initiation. Subgroup analysis showed no further differences. CONCLUSION: The impact of PI-based DT regimens on the CD4/CD8 ratio during the first year of treatment for ART-naïve patients is similar to that of TT.