No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

ABSTRACT Lopinavir-ritonavir is frequently prescribed to HIV-1-infected women during pregnancy. Decreased lopinavir exposure has been reported during pregnancy, but the clinical significance of this reduction is uncertain. This analysis aimed to evaluate the need for lopinavir dose adjustment during pregnancy. We conducted a population pharmacokinetic analysis of lopinavir and ritonavir concentrations collected from 84 pregnant and 595 nonpregnant treatment-naive and -experienced HIV-1-infected subjects enrolled in six clinical studies. Lopinavir-ritonavir doses in the studies ranged between 400/100 and 600/150 mg twice daily. In addition, linear mixed-effect analysis was used to compare the area under the concentration-time curve from 0 to 12 h (AUC 0–12 ) and concentration prior to dosing ( C predose ) in pregnant women and nonpregnant subjects. The relationship between lopinavir exposure and virologic suppression in pregnant women and nonpregnant subjects was evaluated. Population pharmacokinetic analysis estimated 17% higher lopinavir clearance in pregnant women than in nonpregnant subjects. Lopinavir clearance values postpartum were 26.4% and 37.1% lower than in nonpregnant subjects and pregnant women, respectively. As the tablet formulation was estimated to be 20% more bioavailable than the capsule formulation, no statistically significant differences between lopinavir exposure in pregnant women receiving the tablet formulation and nonpregnant subjects receiving the capsule formulation were identified. In the range of lopinavir AUC 0–12 or C predose values observed in the third trimester, there was no correlation between lopinavir exposure and viral load or proportion of subjects with virologic suppression. Similar efficacy was observed between pregnant women and nonpregnant subjects receiving lopinavir-ritonavir at 400/100 mg twice daily. The pharmacokinetic and pharmacodynamic results support the use of a lopinavir-ritonavir 400/100-mg twice-daily dose during pregnancy

H1N1pdm09 Adjuvanted Vaccination in HIV-Infected Adults: A Randomized Trial of Two Single versus Two Double Doses

Since human immunodeficiency virus (HIV)-infected individuals are at increased risk of severe disease from pandemic influenza A (H1N1pdm09), vaccination was recommended as a prevention strategy. The aim of the present study was to evaluate the safety, immunogenicity and persistence of the immune response after vaccination against pandemic influenza A (H1N1pdm09) with an adjuvanted vaccine in human immunodeficiency virus (HIV)-infected adults using two single and two double doses.Open label, randomized trial to evaluate the immune response following H1N1pdm09 vaccination in HIV-infected participants compared to HIV-negative controls (NCT01155037). HIV-infected participants were randomized to receive 2 single (3.75 µg hemagglutinin) or 2 double (7.5 µg hemagglutinin) doses of the vaccine, 21 days apart. Controls received one dose of the vaccine. The primary endpoint was seroconversion as measured by hemagglutination inhibition assay. Two hundred fifty six HIV-infected participants (129 and 127 randomized to single and double doses, respectively) and 71 HIV-negative controls were enrolled. Among HIV-infected participants, seroconversion increased from 46.7% and 51.7% after the first dose to 77.2% and 83.8% after the second dose of the vaccine using single and double doses, respectively. Participants aged >40 years showed higher seroconversion compared to younger participants. Seroconversion among HIV-infected women and those with nadir CD4<200 cells/mm(3) was significantly higher with double doses. Persistence of protective antibodies six months after vaccination was achieved by 80% and 89.9% of the HIV-infected participants who received single and double doses, respectively.Our results support the recommendation of two double doses of adjuvanted H1N1pdm09 vaccine for HIV-infected individuals, particularly women, and those aged >40 years or with nadir CD4<200 cells/mm(3), to achieve antibody levels that are both higher and more sustained.ClinicalTrials.gov NCT01155037

Farmacocinética da co-formulação Lopinavir/ritonavir em forma de comprimidos, em dosagem padrão e dosagem aumentada, em gestantes portadoras do HIV

Made available in DSpace on 2014-08-11T12:39:29Z (GMT). No. of bitstreams: 4 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) marilia_oliveira_ipec_dout_2012.pdf: 2996736 bytes, checksum: f7004296a25067ba239182bc45af24e7 (MD5) 69282.pdf.txt: 258706 bytes, checksum: 11d919c86b7699b17405769f4c936f23 (MD5) 69282.pdf.jpg: 1438 bytes, checksum: 51e59c52b79e442b1ee1e65062e4d93b (MD5) Previous issue date: 2014-05-06Fundação Oswaldo Cruz. Instituto Nacional de Infectologia, Rio de Janeiro,RJ, BrasilO uso de antirretrovirais (ARV) durante a gravidez é essencial para a prevenção da transmissão vertical do HIV, porém o impacto das alterações fisiológicas inerentes à gestação sobre a farmacocinética desses medicamentos e as possíveis implicações na eficácia e segurança dos esquemas profiláticos é pouco conhecido. O Lopinavir/r (LPV/r) é recomendado para uso nessa situação, mas a dose mais adequada para grávidas é controversa. O objetivo deste estudo é descrever a farmacocinética do LPV e do ritonavir(RTV) durante a gestação, comparando a dose padrão (dois comprimidos de 12/12 horas) com dose aumentada (três comprimidos de 12/12 horas) de LPV/r. Foi realizado estudo aberto, prospectivo, incluindo 60 voluntárias com infecção pelo HIV a partir de 14 semanas de gestação, selecionadas aleatoriamente (1:1) para receber uma das duas doses de LPV/r durante a gravidez, continuando a usar a dose padrão até seis semanas após o parto. Foram colhidas amostras de sangue nos segundo e terceiro trimestres da gravidez e no pós parto, além de sangue de cordão e materno no momento do parto, para avaliação da passagem transplacentáriados ARV A análise farmacocinética foi realizada por método de cromatografia líquida de alta performance (HPLC), com detecção por espectrometria de massa sequencial após ionização por electrospray de íons positivos (ESI-MS/MS). As pacientes que receberam dose padrão de LPV/r e que tiveram adesão ao tratamento apresentaram concentração mínima de LPV em média de 4,4, 4,3 e 6,1 mcg/mL nos segundo e terceiro trimestres da gravidez e no pós-parto, respectivamente, enquanto que as do grupo de dose aumentada tiveram valores de 7,9, 6,9 e 9,2 mcg/mL nos mesmos momentos. Apesar de a exposição ao LPV ter sido significativamente maior no segundo grupo, a dose padrão foi suficiente para fornecer níveis terapêuticos de LPV para vírus selvagem (1 mcg/mL) em todas as mulheres com adesão ao tratamento, exceto uma no terceiro trimestre da gravidez. Não atingiram níveis terapêuticos para vírus resistentes 50%, 37,5% e 25% das voluntárias em uso de dose padrão nos segundo e terceiro trimestres da gravidez e no pós-parto, respectivamente, enquanto que essa proporção foi de 0%, 15% e 0% no grupo de dose aumentada nos mesmos momentos. Após 12 semanas de tratamento e no pós parto todas as pacientes com adesão ao tratamento tinham carga viral do HIV indetectável e nenhum dos bebês que pôde ser avaliado (49/54) foi infectado. A dose padrão de LPV/r foi adequada para uso durante a gestação, sendo importante assegurar adesão ao tratamento e podendo-se considerar o uso de dose aumentada em casos de suspeita ou diagnóstico de infecçao por HIV com mutações de resistênciaAntiretrovirals (ARV) use during pregnancy is critical for the prevention of HIV vertical transmission, however the impact of physiological alte rations inherent to pregnancy on the pharmacokinetic of these drugs, and the possible implications on the effectiveness and safety of t he prophylactic regimen are unknown. Lopinavir/r (LPV/r) use is recommended in this circumstance, but the appropriate dose for pregnant women is cont roversial. The objective of this study is to describe the pharmacokinet ic of LPV and ritonavir (RTV) during pregnancy, comparing the standard dose regimen (two tablets bid ) with LPV/r increased dose (three tablets bid ). An open, prospective study was conducted, including 60 volunteers with HIV in fection from 14 weeks of pregnancy, randomly selected (1: 1) to receive one of the two doses of LPV/r during pregnancy, and using the standard dose up to six weeks after childbirth. Blood samples were drawn in the second and third trimesters of the pregnancy, and after childbirth, in addition to umbilical cord and maternal blood at labor, for evaluation of ARV transplacental tr ansmission. The pharmacokinetic analysis was performed by high performance liquid chromatography (HPLC), with spectrometry detection of sequential mass after ionization by positive ions electrospray (ESI-MS/MS). Patients who received LPV/r standard dose and that had good adherence to the treat ment presented LPV minimum concentration of 4.4, 4.3 and 6.1 mcg/mL, in the sec ond and third pregnancy trimesters and in the after-childbirth, respectively, whereas those of the group of increased dose had values of 7.9, 6.9 and 9.2 mcg/mL in the same time periods. Although LPV exposition has been significantly incr eased in the second group, the standard dose was enough to yield therapeutical levels of LPV to wild type virus (1 mcg/mL) in all women with treatment adherence, except one in the third pregnancy trimester. Fifty percent, 37.5% , and 25% of the volunteers have not achieved therapeutical levels for re sistant viruses using the standard dose during second and third trimesters of t he pregnancy and in the after-childbirth, respectively, whereas this ratio was of 0%, 15%, and 0% in the group of increased dose in the same time points. After 12 weeks of tr eatment and in the after childbirth, all the patients wit h good adherence to the treatment had undetectable HIV viral load and none of the babies who could be evaluated (49/54) was infected. T he standard dose of LPV/r was appropriate for use during pregnancy, and it is important to assure good treatment adherence, and to be able to consider the use of an increased dose when there are suspected cases or diagnosis of HIV infe ction with resistance mutations

Aging with HIV: a practical review

The worldwide elderly population is expected to grow by an additional 694 million people by 2025. By that time, there will be approximately two billion elderly people in the world, most of whom (80%) will be living in developing countries. Based on recent estimates, this population will number over 40 million in 2030 in Brazil and a consequent increase in governmental spending for this population can be expected. Since highly active antiretroviral therapy became available in the mid-1990s, the life expectancy of people living with HIV has increased significantly. Approximately 12 million life years were added to the world between 1996 and 2008 as a consequence of wider access to highly active antiretroviral therapy. In Brazil, the incidence of AIDS among the population aged >50 years doubled between 1996 and 2006. The development of antiretroviral therapy has allowed individuals diagnosed at a younger age to live longer, which partially explains the aging tendency associated with the HIV/AIDS epidemic. It is estimated that by 2015, subjects aged >50 years will represent 50% of the people living with HIV undergoing clinical treatment. This scenario presents some challenges, including the fact that the diagnosis of HIV tends to be delayed in older patients compared to younger patients because the symptoms of HIV can be confused with those of other common diseases among the elderly and also because healthcare professionals do not consider this population to be at high risk for HIV infection. In regard to the individuals diagnosed with HIV, a further challenge is presented by the morbidity normally associated with aging. Finally, the elderly also exhibit higher susceptibility to the toxic effects and pharmacological interactions of medications. The present article reviews the literature regarding the profile of HIV infection among individuals aged >50 years focusing on practical features related to the clinical approach and long-term follow-up of this population