Nuevos y viejos anti-retrovirales en pediatría: Nuevas dosis, presentaciones y asociaciones / New and “old” antiretroviral drugs in Pediatrics: New doses, formulations and associations

De los 25 anti-retrovirales disponibles en el mercado, sólo 16 están autorizados en la edad pediátrica. Los antiretrovirales, pertenecientes a las tres primeras familias, usados desde hace dos décadas, continúan vigentes y son parte importante de la terapia anti-retroviral en niños naïve. Se describen las dosis, presentaciones y asociaciones actuales de estos fármacos en la edad pediátrica y además se comentan las nuevas co-formulaciones que permitirán disminuir el número de dosis, mejorar la tolerancia y por lo tanto conseguir mejor adherencia de los pacientes pediátricos.

Of the 25 antiretroviral drugs available in the market, only 16 are allowed for prescription in the pediatric patients. The antiretroviral, pertaining to the first three families, used for two decades, remain valid and are important components of antiretroviral therapy in naive children. We describe doses, presentations and current associations for these drugs in children, and also discuss new co-formulations that will reduce the number of doses, improve tolerance and therefore achieve better adherence of pediatric patients.

Efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine (GPO-vir) in advanced HIV infection.

OBJECTIVES: To assess the efficacy and safety of generic fixed-dose combination of stavudine, lamivudine and nevirapine; GPO-vir in advanced HIV infection. MATERIAL AND METHOD: Open-label combined prospective and retrospective study involving 102 HIV infected patients with baseline CD4 cell count < 100 cells/mm3. All patients received GPO-vir for 48 weeks. The CD4 cell count and plasma viral load (pVL) was measured at 48 weeks. RESULTS: The median baseline CD4 cell count and pVL were 13 cells/mm3 and 363,500 copies/ml, respectively. At 48 weeks, the median CD4 cell count increased to 191 cells/mm3 and 63.7% in intention-to treat and 82.3% in on-treatment analysis had pVL < 50 copies/ml. There was no significant difference in pVL between patients with baseline pVL > 100,000 or < or = 100,000 copies/ml (p = 0.312). The incidence of hepatotoxicity, rash and peripheral neuropathy was 4.9%, 14.7% and 6.9%, respectively. CONCLUSION: GPO-vir was well tolerated and effective in increasing CD4 cell count and suppressing plasma viremia in advanced HIV infection during the 48 weeks follow-up period.

Virological and immunological responses of efavirenz-based HAART regimen initiated in HIV-infected patients at CD4 < 100 versus CD4 > or = 100 cells/mm3.

OBJECTIVE: To compare virological and immunological responsiveness of efavirenz (EFV)-based highly active anti retroviral therapy (HAART) between patients with baseline CD4 < 100 and CD4 > or = 100 cells/mm3. MATERIAL AND METHOD: A prospective cohort study in antiretroviral-naive HIV-infected patients was conducted between February and April 2002. Donated HAART regimen, consisting of stavudine, didanosine, and EFV was initiated. The primary outcome was time to undetectable HIV RNA, < 50 copies/mL. Patients were followed up every 12 weeks until 48 weeks (the end of the study). RESULTS: Forty-six patients were included, 21 patients for CD4 < 100 cells/mm3 and 25 patients for CD4 > or = 100 cells/mm3. Median CD4 cell counts of these corresponding groups were 26.5 and 177 cells/mm3. Patients' characteristics were similar between the two groups except CD4. The probability of undetectable HIV RNA at 12, 24, 36, and 48 weeks were 57.1% (95% CI, 37.7-78.1%), 76.2% (95% CI, 56.9-91.3%), 80.9% (95% CI, 62.3-94.0%), and 90.5% (95% CI, 68.9-99.1%) for the former group; and 64.0% (95% CI, 45.8-81.8%), 92.0% (95% CI, 77.5-98.6%), 96.0% (95% CI, 83.0-99.7%), and 96.0%.(95% CI, 83.0-99.7%) for the latter group. Median time to undetectable HIV RNA was 12 weeks for both groups. Median CD4 change at 48 weeks was 171 and 132 cells/mm3, respectively (p = 0.232). The adverse events were similar between the two groups. CONCLUSION: Initiation of EFV-based HAART regimen in HIV-infected patients at CD4 < 100 and > or = 100 cells/ mm3 gains similar immunological and virological response.

Future implications: compliance and failure with antiretroviral treatment.

HIV management is currently in an era of effective, potent antiretroviral therapy. Modern drug discovery and development have transformed HIV-1 disease into a treatable, chronic infectious disease. Complete suppression of viral replication is critical for long-term durability of antiretroviral therapy. Partial suppression, even at very low levels, is likely to lead to virologic failure and ultimately to the appearance of drug resistance. The relationship between adherence and resistance to HIV antiretroviral therapy is more complex than to state 'non-adherence increases the risk of drug resistance.' In many patients who fail to respond to initial therapy, the primary reason for failure is their inability to take the prescribed drug regimen or nonadherence.

Foscarnet Effects on the Rat Pregnancy Outcome / Efectos del Foscarnet Sobre la Rata Preñada

There are few long-term data on which to base decisions of drug management of HIV infection in pregnancy. The determination of safe medications must take into consideration the need for certain drugs and the possibility of inadvertent fetal exposure because of unplanned pregnancies. The aim of this study was to evaluate the effects of foscarnet on the entire period of rat pregnancy. Female pregnant rats were randomly assigned to four treatment groups (n = 10): one control (C) ­ treated with the drug vehicle (bidestilled water) and three experimental groups (E1, E2 and E3) ­ treated with 180, 360 or 720 mg/Kg of foscarnet, respectively. Rats were treated by gavage once daily. The treatment period extended from the first until the 20th day of pregnancy. Body weights were recorded weekly along this period. At term, the rats were sacrificed, the implantation sites and the number of fetuses and resorptions were recorded. The fetuses were evaluated for externally visible abnormalities under a stereomicroscope. No differences in body weights among the groups were observed; however, foscarnet-treated rats showed reduced fetal and placental weights. The incidence 137of resorptions and major malformations (shortening of limbs) in the E3 group was significantly raised. Foscarnet treatment during the entire period of rat pregnancy can produce definite toxic effects, mainly on the placental and fetal compartments.

Foscarnet es un inhibidor de la transcriptasis reversa del HIV que actúa en la síntesis del DNA. En este trabajo evaluamos los efectos crónicos del foscarnet durante la preñez de la rata albina. Ratas preñadas fueron distribuidas aleatoriamente en cuatro grupos (n = 10 para cada grupo): uno control (C), tratadas con agua bidestilada, y tres experimentales (E1, E2 y E3), tratadas con 180, 360 o 720 mg/Kg al día de foscarnet. El fármaco y el vehículo (siempre 1 ml) fueron administrados una vez al día desde el día 0 hasta el día 20 de la gestación. Las ratas fueron pesadas semanalmente y sacrificadas al término de la preñez. No se observaron alteraciones significativas en cuanto al incremento de peso corporal entre los grupos. Sin embargo, las ratas tratadas con foscarnet (especialmente las de los grupos E2 y E3) presentaron reducciones del peso promedio de los fetos y de las respectivas placentas. La incidencia de reabsorciones y malformaciones (acortamiento de miembros) fue significativa en el grupo E3. Se concluye que la administración de foscarnet durante toda la preñez de la rata puede producir efectos tóxicos definidos, especialmente en los compartimientos placentario y fetal.

Aplastic anemia in an HIV infected child.

Hematologic manifestations of HIV in children are common and include anemia, neutropenia, lymphocytopenia, thrombocytopenia that may occur due to many reasons. However, aplastic anemia due to HIV infection is rare and even more so in children. Though anemia is seen with advanced disease and associated with poor prognosis it is treated with various therapeutic modalities. Our patient with aplastic anemia due to HIV infection responded to antiretroviral therapy.

Therapeutic Effect of Adefovir Dipivoxil on Recurrent or de novo Infection of Hepatitis B Virus after Liver Transplantation: A Preliminary Report / 대한소화기학회지

BACKGROUND/AIMS: Anti-viral therapy using hepatitis B immune globulin and lamivudine could not prevent HBV recurrence after liver transplantation (LT) completely. Adefovir dipivoxil is a acyclic nucleotide phosphate analogue and known to have potent anti-HBV effect. In this study, we analyzed the therapeutic effect of adefovir for recurrent or de novo HBV infection after LT. METHODS: From December 2002 to October 2004, adefovir was administered in 12 post-LT patients of HBV infection (11 recurrent and 1 de novo infection). In these patients, lamivudine and other combined therapies were used before the introduction of adefovir. Thereafter, adefovir combined with lamivudine was administered to all patients. RESULTS: The duration of adefovir administration was 5.5-18 (median, 15.5) months. The median values of serum AST and ALT levels were significantly reduced from 86+/-80 IU/L and 140+/-103 IU/L, respectively before the adefovir administration to 42+/-19 IU/L and 38+/-33 IU/L after 2 months of administration. This trend of improved liver function persisted throughout the follow-up period. HBeAg seroconversion was achieved in 4 of 10 patients (40%) and HBsAg seroconversion was observed in 1 of 10 patients (10%). HBV DNA levels have decreased to undetectable levels by hybridization assay in 6 of 7 patients within the first 2 months of therapy. Nephrotoxicity and hypophosphatemia were not found in all of these patients. CONCLUSIONS: Based on this preliminary result, adefovir dipivoxil seems to be an effective and safe antiviral agent leading to viral inhibition and clinical improvement in post-LT patients with recurrent or de novo HBV infection.

The efficacy of combined zidovudine and lamivudine compared with that of combined zidovudine, lamivudine and nelfinavir in asymptomatic and early symptomatic HIV-infected children.

In this 6-month prospective study, we compared the efficacy of two treatment regimens: double-drug therapy with zidovudine (ZDV) and lamivudine (3TC) and triple-drug therapy with ZDV plus 3TC plus nelfinavir (NFV), in the treatment of asymptomatic and early symptomatic HIV-infected children. Twenty-five children were enrolled in this study and were divided into 2 groups: group A, consisting of 13 children who were given ZDV+3TC; group B, consisting of 12 children who were given ZDV+3TC+NFV. Serial determinations of weight, CD4-cell count, HIV RNA or plasma viral load (VL) and complete blood counts (CBC), liver function tests (LFT), blood urea nitrogen (BUN) tests, creatinine and serum amylase tests were performed at study entry and at 1, 3 and 6 months. The side-effects of drugs were recorded. Over the 6-month period, the median weight increase in group B (24%) was higher than in group A (2%). The median CD4-cell count increase from baseline in group B (94.5%) was better than in group A (9.4%). The reduction of VL below baseline in group B (1.2 log10; 20.8%) was also better than in group A (0.72 log10; 13.8%). However, these differences were not statistically significant (p>0.05). Both combination regimens could not completely suppress HIV RNA below detectable limits (<400 copies/ml). Both groups tolerated the regimens well; no side-effects or toxicities occurred. The efficacy levels of triple-drug therapy (ZDV+3TC+NFV) and double-drug therapy (ZDV+3TC) were not different. There were no side-effects and no deaths during the 6-month study period.

A randomized, open-label, comparative trial of BID and TID dosing of saquinavir enhanced oral formulation as part of a triple therapy for advanced AIDS patients.

OBJECTIVE: To compare the efficacy and safety of 1,400 mg BID and 1,200 mg TID of saquinavir soft gel given with zidovudine and lamivudine in antiretroviral-naïve, advanced AIDS patients. METHOD: A randomized, open-label study conducted at a university hospital. RESULTS: Forty cases were enrolled in the study, 20 cases in each group. The mean CD4 cell count was 29 cells/mm3. The mean log10 HIV-1 RNA was 5.27 copies/mL. Using an on-treatment analysis, the reduction in plasma log10HIV-1 RNA of BID and TID groups was not statistically significant at -2.44 vs -2.60 copies/mL (-0.16, 95% CI -0.63 to 0.30; p= 0.48). The mean increase in CD4 cell counts was not statistically significant at +144 and +159 cells/mm3 (11, 95% CI -75 to 97; p=0.79). CONCLUSION: The preliminary data suggests that in antiretroviral-naïve, advanced AIDS patients, 1,400 mg BID of saquinavir soft gel given with two nucleoside analogues might be as effective as the standard 1,200 mg TID.

Tratamiento antirretroviral / Antiretroviral therapy

En el presente trabajo se analizan los beneficios y limitaciones de la terapia antirretroviral de alta eficacia (HAART). Los objetivos de esta terapia son reducir la carga viral plasmática lo máximo posible y durante el mayor tiempo posible. Esto implica alcanzar niveles de carga viral no detectables con técnicas ultrasensibles. Se evalúan los resultados obtenidos con los principales esquemas de tratamiento asi como sus indicaciones y efectos adversos.

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.

Terapeútica actual del compromiso neurológico primario por VIH / Current therapeutics of primary neurological: involvement by HIV

En la infección por el virus de la inmunodeficiencia humana (VIH), la afección del sistema nervioso central (SNC) es muy común. El compromiso neurológico observado con mayor frecuencia es el complejo cognoscitivo motor, también llamado demencia asociada al SIDA. Este es provocado directamente por la infección del VIH y la respuesta secundaria del sistema inmune, específicamente del sistema monocito-macrofágico. Revisamos la patogénesis y presentamos las posibilidades terapéuticas actuales en el manejo de esta compleja enfermedad, dividiéndola en terapia antirretroviral, control de la inflamación asociada a la infección y fármacos protectores del SNC. El pilar fundamental del tratamiento son las drogas antirretrovirales. Dentro de éstas, la zidovudina (AZT) ha demostrado hasta ahora la mayor efectividad. Actualmente se emplean terapias combinadas, utilizando inhibidores de la transcriptasa reversa e inhibidores de proteasas. Dentro de estas asociaciones, la terapia triasociada es la de elección, ya que permite cambiar la condición de la enfermedad, desde un problema mortal, al de una situación crónica controlable. Se revisa la terapéutica enfocada a frenar la reacción inflamatoria nociva, producida por macrófagos y microglia infectados y las drogas utilizadas en la protección del sistema nervioso central