Immunovirological treatment outcomes after 2 years of antiretroviral therapy in children living with the human immune deficiency virus in Lagos Nigeria

Background/objective: The World Health Organization (WHO) recommends routine assessment of antiretroviral treatment outcomes to detect treatment failure early and prevent the development of drug resistance. The aim of this study was to describe treatment outcomes of antiretroviral therapy (ART) over 2 years in children living with the human immune deficiency virus enrolled in the paediatric HIV clinic at the Lagos UniversityTeaching Hospital (LUTH). Materials and methods: This was a retrospective study of antiretroviral treatment outcomes in 278 children receiving antiretroviral therapy at the paediatric HIV clinic of LUTH. Demographic, clinical and laboratory data were retrospectively collected from clinical records of pediatric patients who received antiretroviral therapy for 2 years ( from November 2015 to December 2017) . Virological failure was defined as viral load > 400 copies/ml and immunological failure was defined as a CD4 count <100 cells/mm3 or CD4 % <15% after receiving antiretroviral agents for 12 months. Data was analysed using graph pad prism version 5.0.Results: After 12 months on antiretroviral therapy (ART), 101 (36%) had virological failure while 14 (5%) and 36 (13%) failed immunologically [CD4 count <100 cells/mn3 and CD4 <15% respectively]. Virological blips were observed at 24 months in 6.1% of patients while immunovirological discordance occurred in 30% of patients (poor virological clearance despite good immunological recovery) . High baseline viral load (>5000 copies/ml), poor adherence (<95%) and low baseline CD4 counts (101-249 cells/mn3) were significantly associated with virological failure, while low baseline CD4 counts (<350 cells/mn3) and poor adherence (<95%) were significantly associated with immunologic failure.Conclusion: The treatment outcomes observed in this study are similar to those reported in earlier studies. At 1 and 2 years of antiretroviral therapy , there was immune restoration however 101 (36%) and 87 (31%) respectively had virological failure despite good adherence to therapy and good Immunological restoration. This calls for early initiation and switch to second and third line drugs

Transmisión vertical del virus de la inmunodeficiencia humana en mujeres usuarias del Centro Hospitalario Pereira Rossell; Uruguay, 2012-2014. Resultados de la aplicación del protocolo zidovudina - nevirapina en niños uruguayos / Vertical transmission of the HIV in women who are users of the Pereira Rossell Hospital Center, Uruguay 2012-2014. Results of the application of the Zidovudine ­ Nevirapine combined protocol in Uruguayan children / Transmissão vertical do Vírus da Imunodeficiência Humana em mulheres usuárias do Centro Hospitalário Pereira Roussel; Uruguai 2012-2014. Resultados da aplicação do protocolo Zidovudina - Nevirapina em crianças uruguaias

Introducción: el embarazo controlado y la supresión del amamantamiento son estrategias para disminuir la transmisión vertical (TMI) del virus de inmunodeficiencia humana (VIH). La profilaxis al neonato con zidovudina o zidovudina con nevirapina se utiliza según el riesgo de TMI. Objetivo: describir la TMI entre los años 2012 y 2014 en el Centro Hospitalario Pereira Rossell (CHPR), su relación con la carga viral materna y el cumplimiento de la recomendación AZT-NVP al neonato. Material y método: estudio descriptivo en el Centro de Referencia Obstétrico - Pediátrico VIH-Sida desde 1° de setiembre de 2012 al 31de diciembre 2014. Se incluyeron los recién nacidos de mujeres con carga viral detectable o indetectable al momento del parto. Se registró la administración de zidovudina-nevirapina. Se determinó la transmisión vertical. Resultados: se incluyeron 162 mujeres, 86 con carga viral detectable o desconocida y 76 indetectable. Las primeras tuvieron 88 hijos y las segundas 76. La TMI global fue de 4,9%; 9% en el primer grupo y 0% en el segundo. Se registró asociación entre TMI y CV materna (p <0,05). La administración de AZT-NVP se indicó en 46,5% de los niños. De los ocho niños infectados, la TMI fue intraútero en cinco. En los tres restantes, dos recibieron AZT y otro ninguna profilaxis. Discusión y conclusiones: la mitad de las mujeres no controló bien su embarazo. La TMI promedio fue de 4,9%. De los ocho infectados, cinco fueron intraútero; solo un diagnóstico y tratamiento precoces lo hubiesen evitado. El protocolo AZT-NVP no se utiliza en forma adecuada. Quizá su aplicación en los tres niños restantes hubiera evitado la infección.

Introduction: controlled pregnancy and interruption of breastfeeding are strategies used to reduce vertical transmission of the immunodeficiency virus (HIV). Neonates are subject to prophylactic treatment of zidovudine or combination therapy with zidovudine and nevirapine based on the mother-to-child transmission risk. Objective: to describe mother-to-child transmission from 2012 to 2014 at the Pereira Rossell Hospital Center, its relationship with the maternal viral load and the observation of the AZT-NVP prophylactic treatment recommended for neonates. Method: descriptive study, at the Obstetric Pediatrix HIV-Aids Reference Center from September 1, 2012 until December, 31, 2014. The newborns to mother with detectable or undetectable viral loads at the time of delivery. Administration of zidovudine-nevirapine was recorded. Vertical transmission was defined. Results: 162 women were included in the study, 86 of them with a detectable or unknown viral load and 76 women with a detectable load. The first group gave birth to 88 children and the second one to 76. Global mother-to-child transmission rate was 4.9%, 9% in the first group and 0% in the second one. The association between mother-to-child transmission and maternal load was recorded (P<0.05). Administration of AZT-NVP was indicated in 45.5% of children. Intrauterine mother-to child transmission was 5 for the 8 infected children. As to the other three children: 2 received AZT and another one received no prophylactic therapy. Discussion and conclusions: fifty per cent of the women's pregnancies were not dully controlled. Average mother-to-child transmission was 4.9%. Out of the 8 infected cases, 5 happened in the uterus, only an early diagnosis and treatment would have prevented it from happening. The AZT-NVP protocol is not applied in the right way. Its application on the other 3 children may have avoided the infection.

Introdução: o controle da gravidez e a supressão do aleitamento materno são estratégias para diminuir a transmissão vertical (TMI) do Vírus da Imunodeficiência Humana (VIH). No neonato, a profilaxia com zidovudina ou zidovudina com nevirapina é utilizada de acordo com o risco de TMI. Objetivo: descrever a TMI no período 2012-2014 no CHPR, sua relação com a carga viral materna e o cumprimento da recomendação AZT-NVP no neonato. Material e métodos: estudo descritivo, realizado no Centro de Referencia Obstétrico- Pediátrico VIH-Sida no período 1° de setembro de 2012 ­ 31 de dezembro de 2014. Foram incluídos os recém-nascidos de mulheres com carga viral (CV) detectável ou indetectável no momento do parto. A administração de zidovudina ­ nevirapina e a transmissão vertical foram registradas. Resultados: foram incluídas 162 mulheres, 86 com carga viral detectável ou desconhecida e 76 indetectável. As primeiras tiveram 88 filhos e as segundas 76. A TMI global foi de 4,9%, 9% no primeiro grupo e 0% no segundo. A associação entre TMI e CV materna (P<0.05) foi registrada. A administração de AZT-NVP foi indicada em 46.5% das crianças. Nas 8 crianças infectadas, a TMI foi intrauterina em 5 . Nas 3 restantes, duas receberam AZT e a restante não recebeu nenhum tipo de profilaxia. Discussão e conclusões: a metade das mulheres não controlou sua gravidez adequadamente. A TMI média foi de 4.9%. Das 8 infectadas, 5 foram intrauterinas; somente o diagnóstico e tratamento precoces poderiam ter evitado. O protocolo AZT-NVP, não foi utilizado de forma adequada. É possível que sua aplicação nas 3 crianças restantes tivesse evitado a infecção.

Nanopreparations for better drug delivery

Nanomedicines are a recent development to face medical and pharmaceutical challenges because nanoparticles have unique properties. They are very small in size and are easy to handle. One more advantage is that they are not harmful for the human body. Poorly soluble drugs have serious problems with their delivery and dosage forms. Formulation strategies by means of nanocarrier systems, such as polymeric micelles, can resolve the trouble. Micelles from PEG-diacyllipids, e.g. PEG-PE, are of special attention. On the other hand, the layer-by-layer [LbL] technique can be useful to set up stable nanocolloids of low solubility. In some cases, the use of nanopreparations is the only way to fulfill medical requirements. Thus, for the blood group CT imaging, one has to prepare long-circulating contrast-loaded nanoparticles. In other cases, poor stability of potential drugs creates a problem, such as with siRNA, and the use of nanocarriers may present a solution e.g. Polymeric micelles having a hydrophobic derivative of siRNA. We will discuss the preparation, properties, and anti-cancer activity of drug-loaded PEG-PE micelles and LbL nanoparticles and other [approaches] for making "undeliverable" substances deliverable. Injectable, implantable, topical delivery of active compounds, oral drug delivery system and many other methods have been improved by nanotechnology

Comparison of antioxidant effects of kolaviron and vitamin C interventions on testicular structures following nevirapine administration in Sprague-Dawley rats / Comparación de los efectos antioxidantes en la intervención con kolaviron y vitamina C sobre las estructuras testiculares después de la administración de nevirapina en ratas Sprague-Dawley

Testicular toxicity has been implicated in highly active anti-retroviral therapy (HAART) treatment. Hence there is need to identify an effective antioxidant product that can alleviate testicular necrosis due to HAART administration. Forty eight adult male Sprague-Dawley rats were used in this study. The animals were divided into eight (8) groups: A-H (n= 6). Group A animals received normal saline as the control; Group B was given Nevirapine (Nv); Group C was given Kolaviron (Kv); Group D was given vitamin C; Group E was given Nv and Kv; Group F was given Nv and Vitamin C; Group G was given Nv for 56 d and Kv for 28 d serving as a withdrawal group; Group H was given corn oil. Nv, Kv and Vit. C were given at 1.54, 200 and 250 (mg·kg)/bw respectively while all administrations were through oral gavage. The body weights were taken every other day. Thereafter, they were anaesthetized with halothane. The testes were excised, weighed, fixed in Bouin's fluid and stained with H&E while the epididymes removed for semen fluid analyses. The results showed a significant (P<0.05) decrease in sperm motility in group E (Nevirapine + kolaviron) when compared with group F (Nevirapine + Vitamin C) while Sperm count was not significantly different (P>0.05) across the groups. The testicular histoarchitectural studies revealed indistinct spermatogonia, necrotic interstititial endocrine cells in the altered interstitial space, fragmented spermatids, atrophy of mature spermatocytes, degenerated germ cells, obliterated seminiferous tubules lumen, undifferentiated spermatogonia and cellular debris in the somniferous tubules lumen of nevirapine administered group but normal across the other groups. In the testis, there were no significant reduction in SOD, Catalase and GPx activities but a significant decrease in GST activity (P<0.001) when group E was compared with group F. In conclusion, vitamin C presents a better remediation in nevirapine induced spermiotoxicity compared to kolaviron in Sprague-Dawley rats.

La toxicidad testicular ha sido implicada en la terapia antirretroviral altamente activa (TARAA). Por lo tanto existe la necesidad de identificar un producto antioxidante eficaz que pueda aliviar la necrosis testicular en la administración de la TARAA. Cuarenta y ocho ratas macho Sprague-Dawley adultas fueron utilizadas. Los animales se dividieron en ocho (8) grupos: AH (n= 6). Grupo A, animales recibieron solución salina normal como el control; Grupo B, recibió Nevirapina (Nv); Grupo C, recibió Kolaviron (Kv); Grupo D, recibió vitamina C; Grupo E, recibió Nv y Kv; Grupo F, recibió Nv y vitamina C; Grupo G, recibió Nv durante 56 d y Kv por 28 d como un grupo de retirada; Grupo H, recibió aceite de maíz. Nv, Kv y Vit. C se administraron en dosis de 1, 54, 200 y 250 (mg · kg) de peso corporal respectivamente; todas las administraciones fueron por sonda oral. Los pesos corporales se tomaron cada dos días. A partir de ese momento los animales fueron anestesiados con halotano. Los testículos fueron extirpados, pesados y fijados en solución de Bouin y teñidos con H&E, mientras que el epidídimo se retiró para analizar el semen. Los resultados mostraron un descenso (p<0,05) en la motilidad de los espermatozoides en el grupo E (Nevirapina + Kolaviron) en comparación con el grupo F (Nevirapina + vitamina C), mientras que el recuento espermático no mostró diferencias significativas (P>0,05) entre los grupos. El estudio de la histoarquitectura testicular reveló espermatogonias indiferenciadas, con células intersticiales necróticas en el espacio intersticial y espermátidas fragmentadas. Además, en el grupo que recibió Nevirapina mostró espermatocitos maduros atrofiados, degeneración de células germinales, lumen de los túbulos seminíferos obliterados, espermatogonias indiferenciadas y restos celulares en el lumen de los tubulos seminíferos. En el resto de los grupos los resultados fueron normales. En el testículo hubo una reducción significativa en las actividades de la superóxido dismutasa, catalasa y glutatión peroxidasa, pero una disminución significativa en la actividad glutatión S-transferasa (P <0,001) al comparar los grupo E y F.

Seroconversión frente a primovacunación reforzada contra hepatitis B en niños con cáncer / Seroconversion in response to a reinforced primary hepatitis B vaccination in children with cancer

Introducción: La respuesta inmune a los antígenos de las vacunas está disminuida en los niños con cáncer. El objetivo de este estudio fue evaluar la seroconversión frente a vacuna ADN recombinante contra hepatitis B al momento del inicio de la quimioterapia y/o remisión en niños con cáncer. Pacientes y método: Estudio prospectivo, bicéntrico, controlado, no aleatorizado de niños con diagnóstico reciente de cáncer pareados con niños sanos. Los casos fueron vacunados a tiempo 0, 1 y 6 meses, a dosis de 20 y 40 μg si eran < ó > 10 años, respectivamente, con vacuna ADN recombinante contra hepatitis B, en el momento del diagnóstico en el caso de los tumores sólidos y luego de la remisión en el caso de los tumores hematológicos. El grupo control recibió el mismo esquema, con dosis de 10 o 20 μg respectivamente. Se midieron anticuerpos séricos anti-HBs a los 2, 8 y 12 meses posvacunación. Seroconversión se definió como títulos anti-HBs > 10 mUI/ml al octavo mes. Resultados: Un total de 78 niños con cáncer y 25 controles fueron evaluados con títulos anti-HBs al octavo mes. La tasa de seroconversión fue de 26,9%, en niños con cáncer, sin diferencia por edad, género ni tipo de tumor (p = 0,13; 0,29; y 0,44, respectivamente), y de 100% en el grupo control (p < 0,0001, comparado con los niños con cáncer). En el seguimiento a los 12 meses solo el 31,9% de los niños con cáncer presentaba títulos anti-HBs > 10 mUI/ml. Conclusiones: La vacunación contra hepatitis B con vacuna ADN recombinante, con esquema reforzado de 3 dosis, en el momento del inicio de la quimioterapia y/o remisión provee una respuesta inmune insuficiente en la mayoría de los niños con cáncer. En esta población debieran evaluarse vacunas de tercera generación, con adyuvantes más inmunogénicos, esquemas reforzados a los 0, 1, 2 y 6 meses, medición de títulos de anticuerpos al octavo y duodécimo mes, eventual uso de refuerzos y reevaluación de inmunogenicidad si correspondiese.

Introduction: Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. Patients and method: Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 μg if < or > than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 μg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. Results: A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P < .0001 compared with the cancer group. At month 12 of follow up, just 31.9% of children with cancer achieved anti-HBs antibodies > 10 mIU/ml. Conclusions: Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12 h to evaluate the need for further booster doses.

Analysis on HIV suppression effect after initiating antiretroviral treatment and related factors among AIDS patients in Henan province during 2008 and 2013 / 中华预防医学杂志

<p><b>OBJECTIVE</b>To compare the HIV suppression rate after initiating antiretroviral treatment(ART) among AIDS patients at different immunological levels and to analyze the related factors.</p><p><b>METHODS</b>Data on AIDS patients initially starting antiretroviral therapy during 2008 and 2013 were collected from Chinese HIV/AIDS integrated control system. All the participants were divided into early treatment group(baseline CD4(+)T cell counts between 351/µl and 500/µl) and conventional treatment group(baseline CD4(+)T cell counts ≤ 350/µl). The rates of comprehensive virologic suppression at different time nodes after the initiation of ART were analyzed accordingly. Unconditional logistic regression model was adopted to examine the factors associated with the failure of viral suppression after 6 months after initiation of ART.</p><p><b>RESULTS</b>A total of 16 103 cases were selected, among which, 1 581 cases were early treatment group, and 14 522 cases were conventional treatment group. A total of 9 428 cases were males, 6 675 cases were females, and the sex ratio was 1.41: 1. The age was 47.2 ± 11.7, and 71.55% (11 522/16 103) of cases were married or cohabiting, 57.22% (9 214/16 103) were transmitted by blood. 81.26% (13 086/16 103) were cures in the township or village treatment institution, and 77.17% (12 426/16 103) received the ART regimen as Stavudine(D4T) or Zidovudine(AZT)+Lamivudine(3TC)+Nevirapine(NVP) or Efevirenz(EFV). After 0.5, 1, 2, 3, 4, 5 and 6 years after the initiation of ART, the rates of virologic suppression in the conventional treatment cohort were 72.6% (3 008/4 144), 73.9% (4 758/6 443), 74.1% (3 641/4 915), 74.9% (2 819/3 766), 76.1% (1 729/2 272) and 78.2% (492/629), respectively. While the rates of viral suppression in the early treatment cohort at the same time nodes were 65.5% (315/481), 65.4% (448/685), 68.8% (223/324), 66.0% (155/235), 71.4% (110/154) and 61% (30/49), respectively, and the differences between the two groups were significant (P < 0.05) except at the fourth year. Non-conditional logistic regression analysis showed that in the conventional treatment group, factors associated with low HIV suppression rate were male (OR = 1.23, 95%CI:1.07-1.42) , longer time interval from confirmed HIV infection to received ART (OR = 1.26, 95%CI:1.16-1.36) , using D4T/AZT+ DDI +NVP/EFV as initial treatment regimen (OR = 3.00, 95%CI:2.26-3.98) and nearly missing doses for 7 days at treatment of six months (OR = 1.97, 95%CI:1.22-3.18) and factors associated with high HIV suppression rate were infected through homosexual transmission route (OR = 0.57, 95%CI:0.35-0.90) and treated in the county level medical institution or above (OR = 0.61, 95%CI:0.50-0.75) . Among early treatment group, cases who received treatment at county level medical institution or above had high HIV suppression rate (OR = 0.43, 95%CI:0.23-0.80) and objects with longer time interval from confirmed HIV infection to receive ART had low HIV suppression rate (OR = 1.43, 95%CI:1.09-1.88).</p><p><b>CONCLUSION</b>The viral suppression efficacy among AIDS patients with different baseline immunologic levels after treatment was similarly satisfactory. AIDS cases who received ART at county level medical institution or above had better viral suppression effect and patients with longer time interval from confirmation to treatment had poor HIV suppression effect.</p>

Survival analysis of AIDS patients of 15 years or above years old after initiation antiretroviral treatment in Henan province during 2005 to 2014 / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the survival rate of AIDS patients after receiving antiretroviral therapy(ART) in Henan province and to determine factors associated with survival status.</p><p><b>METHODS</b>Database of AIDS patients receiving ART were downloaded from China Information System for Disease Preventioin and Control-AIDS, retrospective study method was conducted to analyze the information.</p><p><b>INCLUSION CRITERIA</b>initially received national free ART during January, 2005 to December, 2014; aged 15 years or above; and with relatively complete baseline information and follow-up information. The accumulated survival rate of AIDS patients was calculated by life table method and the influencing factors were analyzed by Cox proportional hazard model.</p><p><b>RESULTS</b>Total 30 376 AIDS patients were enrolled in this study. During the follow-up period, a total of 3 927 cases died from HIV/AIDS related diseases. The mortality of all patients was 3.2/100 person year. After 1, 5, 10 years after the initiation of ART, the rates of accumulate survival rate were 93.7%, 85.3%, and 78.4%, respectively. Stepwise regression was used to conduct the time multiple factors analysis, the results showed that man (HR=1.28, 95%CI: 1.20-1.37), older age (HR=1.20, 95% CI: 1.16-1.24), others marital status except marrage or cohabitation (HR=1.20,95% CI: 1.12-1.29), more number of symptoms (HR=1.11, 95%CI: 1.07-1.14), initial treatment were main stavudine (D4T) or zidovudine (AZT)+ didanosine(DDI)+ nevirapine (NVP) or efevirenz (EFV) (HR=1.12, 95% CI: 1.04-1.20), missing drug in the past 7 days (HR=18.36,95%CI: 17.08-19.74) among AIDS patients had high mortality risk, homosexuality sexual transmission (HR=0.59, 95% CI: 0.40-0.87), higher baseline count of CD4(+)T lymphocyte (relative to 0-200 cells/µl group, HR (95%CI) were 0.57 (0.53-0.62), 0.43(0.37-0.49), 0.33 (0.27-0.40) in 201-350 cells/µl group, 351-500 cells/µl group, and ≥501 cells/µl group, respectively), higher educations (HR=0.89, 95% CI: 0.83-0.95) had low mortality risk.</p><p><b>CONCLUSION</b>Survival rate was higher after initial antiretroviral treatment among AIDS patients in Henan province. AIDS patient will have shorter survival time after antiviral treatment under one or more following conditions: higher age, male, initial treatment with D4T or AZT + DDI + NVP or EFV, lower baseline CD4 (+) T lymphocyte count, ever missed antiviral drugs in past 7 days of latest follow-up.</p>

Avaliação do perfil de reconstituição imunológica de indivíduos HIV/TB submetidos a tratamento para tuberculose e terapia antirretroviral altamente ativa (haart) incluindo efavirenz / Profile assessment of immune reconstitution in HIV individuals / tb undergoing treatment for tuberculosis and highly active antiretroviral therapy (haart) including efavirenz

Mycobacterium tuberculosis (Mtb) e o vírus da imunodeficiência humana (HIV-1) são dois patógenos intracelulares que manipulam o sistema imune para gerar infecções persistentes. Ambas as infecções causam imunossupressão e ativação imune e, com a introdução da terapia antirretroviral altamente ativa (HAART), eventos como a síndrome da reconstituição imune (IRIS) podem ocorrer.Este estudo teve como objetivo avaliar os mecanismos de reconstituição imunológica de indivíduos com tuberculose (TB) e aids, em resposta aos respectivos tratamentos, analisando as subpopulações de células T, bem como os marcadores de ativação imunológica, o perfil de citocinas anti e pró-inflamatórias e a resposta aos antígenos de Mtb durante seis meses após a introdução da HAART. Estes parâmetros foram também avaliados de acordo com o status de imunossupressão dos pacientes no início do tratamento (células TCD4+ <200 ou ≥200 céls/mm3) e pelo desenvolvimento ou não da IRIS.Os pacientes incluídos neste estudo apresentaram restauração imune, com ganho de células TCD4+, redução da carga viral e da ativação imune, após a introdução da HAART...

Mycobacterium tuberculosis (Mtb) and human immunodeficiency vírus (HIV)are two intracellular pathogens that manipulate the immune system in order to generate persistent infections. Both infections cause immunosuppression and immune activationand, under Highly Active Antiretroviral Therapy (HAART), events like immunere constitution syndrome (IRIS) may occur. The objective of this study was to evaluate the immune reconstitution mechanisms among individual with tuberculosis (TB) andaids, in response to treatment to both diseases, based on the analyses of the T cellsubsets, immune activation markers, anti and pro-inflammatory cytokine profiles andresponses to Mtb antigens along six months after the introduction of HAART. These parameters were also evaluated according to the patients immunosuppression status atbaseline (CD4+<200 or greater than or equal to 200 cells/mm3) and the development or not of IRIS.The patients included in this study presented immune restoration, with gain ofCD4+T cells and reduction of viral load and immune activation after introduction of HAART...

Toxic epidermal necrolysis induced by lamotrigine treatment in a child / 소아과

Toxic epidermal necrolysis is an unpredictable and severe adverse drug reaction. In toxic epidermal necrolysis, epidermal damage appears to result from keratinocyte apoptosis. This condition is triggered by many factors, principally drugs such as antiepileptic medications, antibiotics (particularly sulfonamide), nonsteroidal anti-inflammatory drugs, allopurinol, and nevirapine. Lamotrigine has been reported potentially cause serious cutaneous reactions, and concomitant use of valproic acid with lamotrigine significantly increases this risk. We describe a case of an 11-year-old girl with tic and major depressive disorders who developed toxic epidermal necrolysis after treatment with lamotrigine, and who was diagnosed both clinically and pathologically. Children are more susceptible to lamotrigine-induced rash than adults, and risk of serious rash can be lessened by strict adherence to dosing guidelines. Unfortunately, in our case, the patient was administered a higher dose than the required regimen. Therefore, clinicians should strictly adhere to the dose regimen when using lamotrigine, especially in children.

HIV e Tuberculose: interacções farmacológicas entre nevirapina (ou efavirenz) e rifampicina/isoniazida em indivíduos infectados pelo HIV e com tuberculose activa (Maputo, Moçambique, entre 2007 e 2011) / HIV and Tuberculosis: drug interactions between nevirapine (or efavirenz) and rifampicin / isoniazid in HIV-infected individuals and with active tuberculosis (Maputo, Mozambique, between 2007 and 2011)

O presente trabalho se constitui de dois estudos clínicos realizados em Maputo, Moçambique, dos quais participaram 570 pacientes com infecção pelo HIV e tuberculose. Seus objetivos principais foram: a) determinar os parâmetros farmacocinéticos da rifampicina e da isoniazida na ausência e na presença da terapia antirretroviral (TARV) e b) comparar as concentrações plasmáticas da nevirapina e do efavirenz em vigência do tratamento para a tuberculose e após a sua descontinuação. Os dois estudos foram parte do ensaio clínicoANRS12146-CARINEMO, cujo objetivo foi comparar a eficácia e tolerância da terapia antirretroviral com base em nevirapina ou efavirenz quando coadministrada com a terapia padrão antituberculose. O tratamento para tuberculose foi composto por doses diárias de rifampicina e isoniazida, durante 6 meses, associadas a pirazinamida e etambutol nos dois primeiros meses. A TARV foi iniciada entre 4 e 6 semanas do tratamento para a tuberculose e os pacientes foram randomizados para receber nevirapina sem dose escalonada (200 mg duas vezes ao dia) ou efavirenz (600 mg dose única diária), ambos combinados com lamivudina e estavudina...

This work is composed of two clinical studies in Maputo, Mozambique, from which participated in 570 patients with co-infection with HIV and tuberculosis. Its main objectives were: a) determine the pharmacokinetic parameters of rifampicin and isoniazid in the absence and presence of antiretroviral therapy (ART) and b) compare the plasma concentrations of nevirapine and efavirenz in effectiveness of treatment for tuberculosis and after their discontinuation . The two studies were of the clínicoANRS12146-CARINEMO trial whose aim was to compare the efficacy and tolerability of antiretroviral therapy based on nevirapine or efavirenz when co-administered with the standard antituberculous therapy. The treatment for tuberculosis was composed of daily doses of rifampicin and isoniazid for 6 months, pyrazinamide and ethambutol associated with the first two months. The ART was initiated between 4 and 6 weeks of treatment for tuberculosis and patients were randomized to receive nevirapine without scaled dose (200 mg twice daily) or efavirenz (600 mg once daily), both in combination with lamivudine and stavudine...

Mechanism and action characteristics studies of a quinoxalinone compound against HIV-1 replication / 药学学报

This study is to investigate the mechanism and action characteristics of 6-chloro-3-methyl-4-(2-methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1 H)-one (XU07011) against HIV-1 replication. XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses' infectious assay. Time of addition was used to test HIV-1 reverse transcription process. RNA-dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method. Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics. The results showed that XU07011 inhibited HIV-1 replication with IC50 of (0.057 +/- 0.01) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA-dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x L(-1). The compound showed no effect on RNase H activity. XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains. This study could provide a theoretical basis for novel anti-HIV reagents development.

Optimization of human immunodeficiency virus type one replication assay using single cycle replicable virions

HIV virions with replication capacity are needed for HIV researches, like investigating for new anti HIV agents. Here HIV-1 replication assay was optimized with HIV-1 single cycle replicable [SCR] virions to improve biological safety condition. pSPAX2, pmzNL4-3 and pMD2G plasmids were co-transfected to the HEK293T by using polyfect reagent to produce the SCR HIV-1 virions. Virions were quantified using capture ELISA P24. Different MOI of SCR virions were used for infecting of Target cells [HEK] and the load of the supernatant P24 was monitored days after infection. Single cycle replication assay [SCRA] was developed using kinetic studies data. The P24 load of the infected cells supernatant has linear relation to the beginning infectious MOI. 24 hours post infection with HIV-1 SCR virions the viral particle production was detectable. The highest load of P24 in infected cells supernatant was detected 48 hours after infection. Using this developed method, the 50 and 95 percent inhibitory concentration of [IC[95] and IC[50]] Indinavir and Nevirapine were calculated as 25nM and 50nM. In this study, using SCR HIV-1 virions the SCRA was developed. SCR HIV-1 virions are replicable only for one cycle and this improves the safety of developed assays. The accuracy of assay was examined by quantifying the anti HIV-1 potential of two commercial anti-AIDS drugs and the calculated activity for test agents was equal to previously known amounts

Approaches to Effectively Documenting Prior Single Dose Nevirapine Exposure among Women in Africa

Background: Single dose nevirapine (sdNVP) is widely used in resource-limited settings for the prevention of mother to child transmission of HIV; but can result in NVP resistance that negatively impacts the subsequent efficacy of maternal antiretroviral therapy (ART). It is important to determine prior sdNVP exposure status to help guide treatment decisions; but systematic data on approaches to documenting previous sdNVP ingestion are lacking. Aim: With the growing body of evidence of the effects of sdNVP exposure on subsequent choices of ART; we aim to highlight some of the practical challenges that exist in documenting prior sdNVP exposure or lack thereof. Materials and Methods: ACTG A5208 Optimized Combination Therapy after Nevirapine Exposure (OCTANE) is a randomized treatment trial of protease inhibitor vs. NVP-based ART that enrolled 745 HIV-infected women in 7 African countries. Documentation of previous exposure to sdNVP (or lack thereof) was collected prospectively and intensively; as were locally-available sources of such data. Results: All 243 women who were exposed to sdNVP recalled having taken sdNVP; written documentation of sdNVP exposure was found for 73 and an additional 20 identified having ingested a NVP tablet when the tablet was shown to them. Among 502 women not exposed to sdNVP; only 10 (2) had written documentation of lack of sdNVP exposure. NVP resistance was detected in 33 (13.8) of sdNVP-exposed and 1 of non-exposed women. Conclusion: Maternal self-report of prior sdNVP exposure was corroborated by supporting evidence in the majority of women participating in the trial

12-hydroxy nevirapine as a possible cause of nevirapine induced skin rashes

Nevirapine [NVP] is the first non-nucleoside reverse transcriptase inhibitor approved by the U.S. Food and Drug Administration [FDA] for use in combination therapy of HIV-1 infection. The favorable pharmacokinetic profile of NVP permits a simplified dosage and inexpensive regimen to prevent perinatal transmission, more especially in developing countries. Greater than 80% of administered NVP dose is transformed to glucuronidated conjugates of hydroxylated metabolites that are excreted in urine and only a small fraction of the dose [2.7%] was urinary excreted as the parent compound NVP. Adverse effects, mainly hypersensitivity skin reactions and hepatotoxicity, have emerged from NVP and hampered its use. Maculopapular rash and several cases of Stevens-Johnson syndrome have been reported in 17% of patients treated with NVP. 12-hydroxynevirapine has been proposed as a factor in nevirapine hepatocarcinogenicity and skin rashes. This work was conducted to explore the proposition that 12-hydroxy-NVP is the ultimate toxic metabolite responsible for the NVP induced side effects. Primary culture of skin fibroblasts of small female Brown Norway rats was utilized in this study, where the third and the fourth passaged cells were used. NVP, 12-hydroxy-NVP as well as 12-chloro-NVP [as surrogate for 12-hydroxy-NVP] were utilized for exploring the expression profiles of some genes as well as the cytotoxic potential of each of them. Also, the stability of 12-hydroxy and 12-chloro NVP in vitro was determined. Results showed that both of NVP and 12-hydroxy-NVP are free from any cytotoxic potential while 12-chloro-NVP exhibited cytotoxic effect in the third and the fourth passaged population. Each of NVP, 12-hydroxy-NVP or 12chloro-NVP caused some what similar gene expression profile. The stability study showed clear transformation of 12-chloro-NVP to more stable metabolite which is 12-hydroxy-NVP. As a conclusion obtained from the present work is that the main metabolite of NVP which is 12-hydroxy-NVP may not be the ultimate toxic metabolite responsible for NVP induced side effect. It is possible to propose that; 12-hydroxy-NVP may be further converted to ultra short lived ultimate toxic metabolite responsible for the adverse side effects. This suggested proposal need to be verified by more extensive and advanced works

HIV and pregnancy: Maternal and neonatal evolution / HIV y embarazo: Evolución materna y neonatal

Data regarding epidemiological aspects, antiretroviral drug safety, and outcomes of HIV-infected pregnant women and their newborns are limited in Argentina. We underwent a retrospective analysis of registries of HIV-infected pregnant women assisted at Helios Salud, Buenos Aires, Argentina (1997-2006). Variables associated with preterm delivery and neonatal complications were analyzed by univariate and logistic regression analyses. A total of 204 mother-child binomium were included. Maternal age (median): 29 years; 32.5% without prior diagnosis of HIV-infection. Baseline median CD4 T-cell count: 417 cell/μl; 98% received antiretroviral drugs during pregnancy [2 nucleoside analogs plus either nevirapine (55%) or a protease inhibitor (32%)]. Overall incidence of toxicity was 12.5%: rash (8%), anemia (3.5%) and hepatotoxicity (1%). Rash was associated with exposure to nevirapine. Eighty one percent and 50% reached HIV-viral loads <1000 and <50 copies/ml at the end of pregnancy, respectively. Twenty six percent had obstetric complications and 16% had preterm delivery. Of the newborns, 1.6% had congenital defects and 9% had neonatal complications. Overall neonatal mortality was 1% and perinatal transmission was 0.7%. Protease inhibitor use and obstetric complications were associated to preterm delivery while obstetric complications were associated with neonatal complications. In our population, hepatotoxicity was low despite frequent use of nevirapine. Protease inhibitor use was associated to preterm delivery. A favorable virological response and a low rate of perinatal transmission was observed, what supports the consensus that antiretroviral therapy benefits during pregnancy outweigh risks of maternal and neonatal adverse events.

La información sobre aspectos epidemiológicos, seguridad de drogas antirretrovirales y evolución de mujeres embarazadas HIV positivas y sus hijos es limitada en la Argentina. Realizamos un análisis retrospectivo de registros de embarazadas HIV positivas asistidas en Helios Salud, Buenos Aires, Argentina (1997-2006). Las variables asociadas con parto prematuro y complicaciones neonatales se estudiaron mediante análisis univariado y regresión logística. Estudiamos 204 binomios madre-hijo. Edad materna (mediana): 29 años, 32.5% sin diagnóstico previo de HIV. Recuento de linfocitos T CD4+ (mediana): 417 células/μl. El 98% recibió tratamiento antirretroviral durante el embarazo [dos análogos de nucleósidos más nevirapina (55%) o un inhibidor de proteasa (32%)]. La incidencia global de toxicidad fue 12.5%: erupción cutánea (8%), anemia (3.5%) y hepatotoxicidad (1%). La exposición a nevirapina se asoció con rash. El 81% y 50% alcanzaron cargas virales <1000 y <50 copias/ml preparto, respectivamente. Cesárea programada: 68%; complicaciones obstétricas: 26%; parto prematuro: 16%. De los neonatos, 1.6% presentaron defectos congénitos y el 9% complicaciones neonatales. La mortalidad neonatal fue 1% y la transmisión vertical: 0.7%. Las complicaciones obstétricas y el uso de inhibidores de proteasa se asociaron a parto prematuro; las complicaciones obstétricas se asociaron con complicaciones neonatales. La tasa de hepatotoxicidad fue baja a pesar de la utilización frecuente de nevirapina; el uso de inhibidores de proteasa se asoció a parto prematuro. Se observó una respuesta virológica favorable y una baja tasa de transmisión vertical, lo que apoya el consenso de que el beneficio de las drogas antirretrovirales durante el embarazo supera el riesgo de efectos adversos maternos y neonatales.

Detection of HIV drug resistance mutations in pregnant women receiving single dose Nevirapine in south India.

Background: Single dose of Nevirapine to prevent mother to child transmission of HIV is the commonest preventive regimen in resource-limited countries. Objectives: The objective of this study was to detect drug-resistant virus after single dose of Nevirapine (sdNVP) provided to delivering HIV seropositive (HIV+ve) women and to evaluate the time taken for its decay. Results: Of the 36 consenting HIV+ve pregnant women enrolled into the study, the mean hemoglobin and total lymphocyte counts were 10.8 g/dl and 1843 cells/mm 3 , respectively. Mean CD4 counts in 64% of women was 363 cells/mm 3 and mean viral load for 16/36 women was 28,143 copies/ml of plasma. Nevirapine-resistance mutations were detected in 28% of women at delivery; using OLA (Oligonucleotide Ligation Assay). K103N mutations were seen in 19.4% of women while the Y181C mutation was seen in 5%. Both the mutations were detected in 2.7% of women. Sequential blood samples collected at delivery, 7-10 days, 6 weeks, 4 months, 6 months and one year postpartum showed that 81% of K103N mutations and 66.7% of Y181C mutations were detected at 6 weeks postpartum . Wild-type virus had replaced the mutants by one year postpartum in all women except one. Conclusion : These observations are relevant for future treatment with antiretroviral therapy in these women for their HIV disease.

Detección de hipotiroidismo en un programa de atención de VIH/SIDA en un hospital de Bogotá, Colombia / Mass screening for hypothyroidism in a cohort of HIV infected patients in a Bogotá hospital, Colombia

Objetivos: Evaluar la frecuencia de alteración tiroidea y los factores asociados en los pacientes con VIH/SIDA de un hospital universitario en Colombia. Pacientes y Métodos: Estudio tipo corte transversal de pacientes con VIH/SIDA durante el periodo de 2007 a 2008. Se registró niveles hormonales, inmunológicos, carga viral y tratamiento anti-retroviral. Resultados: En 636 pacientes la prevalencia de hipotiroidismo (TSH > 4,6 μUI/mL) fue de 15,5 por ciento (100/636). El análisis independiente demostró relación significativa para el uso de nevirapina (RR 1,6; IC 95 por ciento 1,1 - 2,3) y estavudina (RR 1,5; IC 95 por cientoo 1 - 2,3). Conclusiones: La prevalencia de hipotiroidismo fue alta y se relacionó con el uso de nevirapina.

Introduction: The objective of this study was to evaluate the frequency of thyroid function alterations and its associated factors in a group of patients from a university hospital in Colombia. Methods: From June 2007 through June 2008, 636 HIV patients were followed in order to assess the relation of thyroid function with the use of HAART. Results: The overall prevalence of hypothyroidism (TSH > 4.6 μUI/mL) was 15.5 percent (100/636). The association of hypothyroidism in the independent analysis showed significant relation only for the use of nevirapine (RR 1.6; CI 95 percent 1.1- 2.34) and stavudine (RR 1.5; CI 95 percent, 1 - 2.3). Conclusions: The prevalence of hypothyroidism was surprisingly high among the studied population.

Emergence of drug resistant mutations after single dose nevirapine exposure in HIV-1 infected pregnant women in south India.

Background & objectives: Resistance to nevirapine (NVP) has been described with single dose preventive regimens in other populations. Our aim was to study the pattern and prevalence of HIV drug resistance (DR) at baseline (during pregnancy) and after delivery among antenatal women exposed to single dose NVP for prevention of parent to child transmission (PPTCT). Methods: HIV-infected, ART-naive primigravidae between 18-25 years of age, attending government antenatal clinics in Chennai, Vellore or Madurai were recruited. Drug resistance testing was carried out during pregnancy and after Sd-NVP treatment (one month after delivery) by Viroseq sequencing. HIV-1 testing by DNA PCR was done in newborns at 30 days. Results: Thirty one women were enrolled but only twenty six plasma specimens were analyzable (24 paired and two postnatal only). No major mutations were observed in any drug class at baseline though many polymorphisms were observed in both the reverse transcriptase and protease genes. Mutations to non-nucleoside reverse transcriptase inhibitors (NNRTI) were observed post-delivery in 33 per cent of women who were treated with Sd-NVP. None of the infants were HIV-positive. Interpretation & conclusions: Among pregnant ART-naïve women, baseline HIV drug resistance was not observed. A high rate of development of NNRTI class resistance among women treated with single-dose NVP was observed. Our results emphasize the need to implement more effective PPTCT regimens, minimizing emergence of drug resistance and thereby preserving long-term treatment options for HIV-infected women in India.

Comparison of HPLC & spectrophotometric methods for estimation of antiretroviral drug content in pharmaceutical products.

Background & objectives: Simple and reliable methods to estimate drugs in pharmaceutical products are needed. In most cases, antiretroviral drug estimations are performed using a HPLC method, requiring expensive equipment and trained technicians. A relatively simple and accurate method to estimate antiretroviral drugs in pharmaceutical preparations is by spectrophotometric method, which is cheap and simple to use as compared to HPLC. We undertook this study to standardise methods for estimation of nevirapine (NVP), lamivudine (3TC) and stavudine (d4T) in single tablets/capsules by HPLC and spectrophotometry and to compare the content of these drugs determined by both these methods. Methods: Twenty tablets/capsules of NVP, 3TC and d4T each were analysed for their drug content by HPLC and spectrophotometric methods. Suitably diluted drug solutions were run on HPLC fitted with a C18 column using UV detection at ambient temperature. The absorbance of the diluted drug solutions were read in a spectrophotometer at 300, 285 and 270 nm for NVP, 3TC and d4T respectively. Pure powders of the drugs were used to prepare calibration standards of known drug concentrations, which was set up with each assay. Results: The inter-day variation (%) of standards for NVP, 3TC and d4T ranged from 2.5 to 6.7, 2.1 to 7.7 and 6.2 to 7.7, respectively by HPLC. The corresponding values by spectrophotometric method were 2.7 to 4.7, 4.2 to 7.2 and 3.8 to 6.0. The per cent variation between the HPLC and spectrophotometric methods ranged from 0.45 to 4.49 per cent, 0 to 4.98 per cent and 0.35 to 8.73 per cent for NVP, 3TC and d4T, respectively. Conclusions: The contents of NVP, 3TC and d4T in the tablets estimated by HPLC and spectrophotometric methods were similar, and the variation in the amount of these drugs estimated by HPLC and spectrophotometric methods was below 10 per cent. This suggests that the spectrophotometric method is as accurate as the HPLC method for estimation of NVP, 3TC and d4T in tablet/capsule. Hence laboratories that do not have HPLC equipment can also undertake these drug estimations using spectrophotometer.

Adverse drug reactions to antiretroviral therapy in AIDS patients at a tertiary care hospital in India: A prospective observational study.

Objectives: To identify the adverse drug reactions (ADRs) to antiretroviral therapy (ART) and to assess their impact on treatment compliance in patients with HIV/AIDS. Materials and Methods: Two hundred and thirty-five (235) AIDS patients who received ART were monitored for ADRs over a period of 6 months. The incidence and nature of ADRs occurring with different ART regimens were recorded. We also assessed the severity, causality as well as the impact of ADRs on the patients' compliance. Results: Of 235 patients receiving ART, 90.6% patients experienced ADRs. A total of 618 ADRs involving various systems were observed. A majority were related to gastrointestinal (42.39%) and central nervous (25.57%) system. 23.1% ADRs were severe in intensity. Severe ADRs occurred in 41 out of 235 (17.4%) patients necessitating drug withdrawal. A majority of the patients (87.8%) who complained of severe ADRs received combination of stavudine, lamivudine and nevirapine. Causality assessment revealed 6.63% ADRs were probable and 93.3% ADRs were possible. Non-compliance due to ADRs was observed in 28.9% patients. Conclusions: Myriad ADRs are associated with ART which leads to poor patient compliance. With the increasing access to ART in India, it is prudent that antiretroviral drugs are used judicially with regular monitoring of ADRs.