MSc (Med), Population-Based Field Epidemiology,School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Good and quality social support has been positively associated with mental health and researchers and clinicians are increasingly recognising the important protective role it plays in people living with HIV/AIDS (PLWA). We investigated whether the mental health (depression) of patients receiving antiretroviral treatment (ART) in a public-sector treatment programme in the rural district of Umkhanyakude, KwaZulu-Natal, South Africa is influenced by social support and strategies to cope with HIV infection. Depression was assessed in a cross-section of 272 patients (mean age 38 years, age range 20-67 years) with the General Health Questionnaire 12 (GHQ12). A GHQ12 score of 4 or higher indicated mental health pathology (depression), while lower scores indicated normal mental health. We regressed depression on sex, age, marital status, education, household wealth, social support (instrumental and emotional social support), and 6 strategies to cope with HIV infection. Holding the other variables constant, “instrumental social support” was a significant predictor of mental health pathology (OR = 0.65 P<0.001, 95% CI 0.52 - 0.81). Using “avoidance of people” as a strategy to cope with HIV increased the odds of depression almost threefold (OR = 2.79 P=0.006, 95% CI 1.34 - 5.82), “trying to keep it from bothering” one reduced it by a factor two (OR = 0.45 P=0.068, 95% CI 0.20 - 1.06). 33% of patients were depressed indicating that depression is very common in patients on ART in rural South Africa. In addition to drug treatment, interventions improving instrumental social support and changes in the strategies to cope with HIV infection may be effective in reducing this disease burden among ART patients.

Introducció i objectius: Als països desenvolupats, la majoria de fills de mare VIH, estan exposats in utero, intrapart i postpart a antiretrovirals (ARV). Múltiples publicacions, sovint subjectes a biaixos metodològics, han relacionat l’exposició a ARV amb hiperlactacidèmia (fins i tot simptomàtica) i acidosi làctica en aquests nens. Objectius: Determinació de la incidència d’hiperlactacidèmia, acidosi làctica i manifestacions neurològiques associades en fills de mare VIH i fills de mare VHC durant el primer any de vida. Determinació dels paràmetres associats a la presència d’hiperlactacidèmia a ambdós grups, i la seva relació amb la presència de manifestacions neurològiques i del neurodesenvolupament. Pacients i mètodes: estudi clínic comparatiu de cohorts prospectives amb una mostra de 40 pacients per grup (320 mostres sanguínies) inclosos consecutivament des d’octubre de 2004 fins a octubre de 2007. Es va realitzar determinació conjunta de pH, àcid làctic i alanina als 1, 3, 6 i 12 mesos de vida. Es va definir com a hiperlactacidèmia patològica: valors de lactat >2,1 mmol/L i alanina >435 micromols/L. Resultats: 79 pacients (39 a la cohort exposada i 40 a la no exposada). Les característiques demogràfiques maternes van ser similars a ambdós grups. Un 89,7 % de les gestants del grup exposat va rebre TARGA durant la gestació i 10,3% monoteràpia amb AZT. Un 54% presentaven una càrrega viral (CV) indetectable prèvia al part i el 20% un recompte de CD4+ <350/mm3. Trenta-un nounats van rebre monoteràpia amb AZT i 8 tractament combinat. Tretze pacients (5 exposats i 8 no exposats) van presentar algun tipus de trastorn neurològic i 4 (5,1%) (1 exposat i 3 no) alteracions del neurodesenvolupament, sense diferències entre grups (p: 0,34). Es va detectar hiperlactacidèmia patològica en un 56,4% (IC95% 39,6-72,2) i un 57,5% (IC95% 40,9-73,0) respectivament (p: 0,92), sent més freqüent de manera significativa en els pacients prematurs (p< 0,05). No es va constatar acidosi làctica en cap cas. No es van associar la presència d’hiperlactacidèmia patològica: ús de TARGA durant la gestació, tipus d’ARV, diagnòstic de SIDA a les gestants, xifra de CD4, CV o presa de ARV al període neonatal. La presència d’hiperlactacidèmia no es va associar a alteracions neurològiques ni a alteracions del neurodesenvolupament. Conclusions: no es demostra una associació entre l’ús d’ARV in utero, intrapart i/o postpart i l’aparició d’hiperlactacidèmia. Només la prematuritat es va associar a una major incidència d’hiperlactacidèmia. A més, no es demostra l’associació entre aquesta i l’aparició de simptomatologia neurològica. / Introduction and aims: In developed countries, most children born of HIV-positive mothers are exposed to antiretroviral (ARV) agents prenatally, during birth, and postnatally. Various studies, some affected by methodological bias, have related ARV exposure in these children to elevated lactic acid levels in blood (sometimes symptomatic) and lactic acidosis. Aims: To determine the incidence of hyperlactatemia, lactic acidosis, and associated neurologic manifestations in children of HIV-infected mothers and HCV-infected mothers during the first year of life. To investigate parameters associated with the presence of hyperlactatemia in both groups, and its relationship with neurologic manifestations and neurodevelopmental delay. Patients and methods: Prospective comparative cohort study with 40 patients per group (320 blood samples) consecutively included from October 2004 to October 2007. pH, lactic acid, and alpha-alanine levels were determined at 1, 3, 6, and 12 months of life in all cases. The definition of pathological hyperlactatemia was based on a lactic acid value >2.1 mmol/L and alpha-alanine >435 μmol/L. Results. A total of 79 patients were studied (39 in the ARV-exposed cohort, 40 in the non-exposed cohort). The maternal demographic characteristics were similar in the 2 groups. In the exposed group, 89.7% of pregnant mothers were receiving HAART and 10.3% monotherapy with AZT; 54% had an undetectable viral load before delivery and 20% a CD4+ count <350/mm3. Thirty-one neonates received AZT monotherapy and 8 combined therapy. Twelve patients (5 exposed and 7 non-exposed) presented some type of neurologic abnormality and 4 (5.1%) (1 exposed and 3 non-exposed) presented neurodevelopment alterations, with no significant differences between groups (p=0.34). Pathological hyperlactatemia was seen in 56.4% (95% CI, 39.6-72.2) and 57.5% (95% CI, 40.9-73.0) of patients, respectively (p=0.92), with significantly more cases in premature patients (p<0.05). There were no cases of lactic acidosis. The following variables were not associated with pathologic hyperlactatemia: HAART use during pregnancy, type of ARV, AIDS diagnosis in the mother, CD4 count, viral load, or ARV therapy in the neonatal period. Hyperlactatemia was not associated with neurologic or neurodevelopment abnormalities. Conclusions: ARV use in the prenatal period, during delivery, and/or postnatally was not associated with the development of hyperlactatemia in our study. Only premature status was related to a higher incidence of this condition, Furthermore, there was no association between hyperlactatemia and the development of neurologic symptoms.

HIV and AIDS which was discovered in the 1980s is causing havoc in many developing countries and Sub-Saharan continent is the hardest hit. Pratt (2008:8) highlights that “the number of people living with the disease is concentrated in the industrially developing world, mostly in those resource deprived countries least able to afford the care of HIV-infected people”. Zimbabwe is one of the SADC countries with the highest statistics of HIV and AIDS. Women account for the largest number of people infected by the pandemic and this could be as a result of the social and cultural norms which oppress women and their position in society. Antiretrovirals (ARV’s) are the life-long drugs given to HIV-infected people to slow the progression of the disease. There are different types of ARV regimens. Zimbabwe introduced the ART roll-out in 2004, however the ART users face multiple obstacles in accessing ARVs. The study targets women because they are a vulnerable group in society, specifically in Zimbabwe. Women have been subjected to stigma, discrimination, violence, humiliation, degradation and psychological torture when they are identified as being HIV positive. Some are neglected and deserted by their partners and families after disclosure, as a result many are too scared to disclose their status to families. The country’s political and economic situation has a major impact on the HIV positive women’s access to ARV treatment. This is compounded with the social and cultural norms and values of the people. The focus of this study is on the challenges experienced by HIV positive women with regard to accessing ARV treatment in Zimbabwe. This study strived to understand the challenges HIV positive women encounter in adhering and accessing to ARV treatment. The goal was to explore the challenges experienced by HIV positive women with regard to accessing ARV treatment in Zimbabwe. The research question of the study was: What are the challenges experienced by HIV positive women with regard to accessing ARV treatment in Zimbabwe? This study used a qualitative approach with a collective case study research design. The population for this study was the African women from Zimbabwe who were infected with HIV and AIDS. Non-probability purposive sampling was utilised in this study to select the sample of 10 women who were living with HIV and AIDS in Masvingo District, Zimbabwe and who were accessing ART. Specific criteria for sampling was used to select clients of two NGO’s in Masvingo district of Zimbabwe: Batanai HIV and AIDS Service Organisation and the Reformed Church in Zimbabwe Community Based AIDS Program. Semi-structured one-to-one interviews were used to collect data. The researcher sought permission of the participants to voice record their interviews and the researcher transcribed them personally. The data gathered was analysed and theme and sub-themes were generated from the data. The research findings were presented thereafter by providing a profile of research participants followed by thematic analysis of the themes and sub-themes from the transcriptions. Literature control and verbatim quotes were used to support these themes and sub-themes. The following are the themes from this study: Theme One- Information regarding HIV and AIDS, Theme Two- Information on ARV treatment, Theme Three- Societal and HIV positive women’s views on HIV and AIDS, Theme Four- Experiences of being an HIV positive woman and Theme Five- Needs identified by HIV positive women. The conclusions of this study reflect that HIV positive women experience some challenges in adhering and accessing ARV treatment. Disclosure, stigma and discrimination, traditional and faith healer’s diagnosis of HIV and AIDS, access to medication for Opportunistic Infections, food shortage, distance to ARV sites, the availability and change of ARV regimens were amongst some of the factors which made access to ARV treatment a challenge. Recommendations from this study can be used by HIV and AIDS stakeholders to understand the challenges and experiences by HIV positive women better. The social workers can also use the recommendations to find ways to make their services known to the communities and also improve their intervention and support to these women. / Dissertation (MSW (Health Care))--University of Pretoria, 2014. / lk2014 / Social Work and Criminology / MSW (Health Care) / Unrestricted

This researched aimed to explore the effects of the Human Immunodeficiency Virus (HIV) upon the visuospatial abilities of HIV-positive adolescents on antiretroviral treatment in South Africa. The literature suggests that the neurology responsible for visuospatial abilities (specifically various white-matter tracts in the brain) is very susceptible to the damaging effect that HIV has on the brain. The research sample consisted of vertically transmitted HIV-positive adolescents, on first line antiretroviral treatment, with a HIV-negative control group comparable on age and SES. The results indicated that there is a significant difference in the visuospatial abilities between adolescents with and without HIV. The expressions of these deficits were displayed differently between males and females, highlighting a differing developmental neurology, and the effect of HIV upon it. The viral strength and health of the immune system were also examined as variables and illuminated interesting results. Overall, the research illustrates the negative effect that HIV has upon developing neurology and the subsequent effects on visuospatial abilities.

South Africa and the province of KwaZulu-Natal (KZN) has one of the greatest HIV burdens in the world with an estimated 5.7 mHIion people living with HIV/AIDS. One of the interventions that the government introduced to address this situation was the provision of antiretroviral treatment (ART) to those individuals that are eligible for HIV treatment in order to reduce the morbidity and mortality. Despite widespread availability of ART in KZN, children do not access ART to the extent that adults do, and therefore continue to die because of HIV and AIDS. This qualitative study explored the psychosocial and health system factors that influence paediatric access to ART in KZN from parents and caregivers perspectives. The ecological theory and the social cognitive theory was used to formulate an interview schedule used in conducting the in-depth interviews with adults (parents or guardians) who were bringing their children for ARTservices and those attending these services themselves and not their children at Edendale and King Edward Hospitals in KZN. Purposive sampling was used to select clients for interviews and thematic was done in accordance with the aims and objectives of the study. A total of 42 participants were interviewed in this study. The low uptake of child ART was found to be influenced by several psychosocial and economic factors such as the poor knowledge about ART, stigma and disclosure associated with HIV, extent of support provided by parents/caregivers, parent's own ART was a determinant for bringing children for ART, use of traditional / alternative medicines, disintegrated families, especially the issue of multiple caregivers, complexity of paediatric ART, poor referrals of children from community institutions, unsatisfactory service at clinics, and some health policy and legislation with respect to health care for HIV-infected children that had an unintended effect of restricting child access to ART as well as poverty related Issues. Improving knowledge and self-efficacy related to ART, prevention of mother to child transmission ofHIV, re-training of health workers on child issues and addressing stigma and discrimination and other psychosocial and institutional problems and logistics could help to improve the low paediatric uptake of ART. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2009.

Made available in DSpace on 2014-06-11T19:23:06Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-16Bitstream added on 2014-06-13T19:49:49Z : No. of bitstreams: 1 munhoz_lsr_me_botfm.pdf: 9483369 bytes, checksum: 914df7a3c919410ceb93de705a530cd4 (MD5) / Ministério da Saúde / Os antirretrovirais (ARVs) interferem nas enzimas virais resultando na inibição da replicação do HIV. O uso combinado destas drogas tem demonstrado grande eficácia no controle da progressão da infecção pelo HIV e aumento da sobrevida do paciente. Entretanto estes benefícios podem ser comprometidos pelo desenvolvimento de resistência às drogas, consequência da emergência de mutações nas enzimas virais, representando um grande obstáculo para o sucesso do tratamento de pacientes infectados pelo HIV-1. Os testes de resistência, principalmente de genotipagem do HIV-1, permitem a orientação de novos esquemas, possibilitando o retorno da supressão viral. Este estudo teve como objetivo avaliar o perfil de mutações e a resistência genotípica aos Inibidores da Transcriptase Reversa análogos de Nucleosídeos (ITRN), Inibidores da Transcriptase Reversa Não-análogos de Nucleosídeos (ITRNN) e Inibidores da Protease (IP) em pacientes com falha terapêutica submetidos ao exame de genotipagem, realizado no Laboratório de Rotinas Diagnósticas em Biologia Molecular do Hemocentro da FMB - UNESP ponto executor da RENAGENO (Rede Nacional de Genotipagem do HIV-1). Foram analisadas sequências genômicas da região pol do HIV-1 provenientes de todos os pacientes com exame de genotipagem realizados durante os anos de 2008 e 2009. Dois grupos distintos foram formados: grupo “Adulto” (idade ≥ 18 anos), com 386 indivíduos, e grupo “Pediátrico” (<18 anos), com 45 pacientes, totalizando 431 pacientes. A genotipagem foi realizada pelo kit comercial Trugene HIV-1 Genotyping Kit (Siemens Healthcare Diagnostics). As sequências obtidas foram submetidas ao Algoritmo de Interpretação de Resistência Genotípica da Universidade de Stanford (HIVdb) e a subtipagem foi realizado pelo REGA HIV-1 Subtyping Tool e pelo programa RIP 3.0. O subtipo B foi o mais frequente nos dois grupos estudados... / Antiretrovirals (ARV) interfere with viral enzymes resulting in the inhibition of HIV replication. The use of antiretroviral combinations has demonstrated highly effectiveness in controlling of the progression of HIV infection and increased of the patients’ survival. However these benefits can be compromised by the development of drug resistance, as consequence of the mutations emergence in viral enzymes, representing a major obstacle to successful treatment of HIV-1 patients infected. Resistance tests, mainly HIV-1 genotyping, allow the orientation of new schemes, enabling the return of viral suppression. This study aimed to evaluate the profile of mutations and genotypic resistance to the Nucleoside Reverse Transcriptase Inhibitors (NRTI), Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) and Protease Inhibitors (PI) in the patients in therapeutic failure submitted to the genotyping test, performed in Diagnostic Routine Laboratory in Molecular Biology at the Blood Center of FMB – UNESP, part of RENAGENO (National Network of HIV-1 Genotyping). HIV-1 pol region genomic sequences from all patients with genotype test performed during the years 2008 and 2009 were analyzed. The patients were separated in two distinct groups: “Adult group” (age ≥ 18 years), with 386 individuals, and “Pediatric group” (<18 years), with 45 patients, in a total of 431 patients. Genotyping was performed by Trugene HIV-1 Genotyping Kit (Siemens Healthcare Diagnostics). The sequences obtained were submitted to the Genotypic Resistance Interpretation Algorithm of Stanford University (HIVdb) and the subtyping was performed by REGA HIV-1 Subtyping Tool and by RIP 3.0 program. Subtype B was the most frequent in both groups followed by hybrid forms B and F (BF or FB) and subtype F1. Resistance mutations were found in 97.15% of patients in the adult group... (Complete abstract click electronic access below)

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Mgr. Lenka Ťupová Supervisor: doc. PharmDr. Martina Čečková, Ph.D. Title of doctoral thesis: Interactions of selected antiretroviral drugs and methylmercury with placental membrane transporters. Pregnant women are especially in developed countries exposed to high amount of various xenobiotic including environmental pollutants and drugs. Antiretroviral therapy (ART) is administered to HIV positive pregnant women for the purpose of prevention of HIV mother- to-child-transmission. Pharmacokinetics of many antiretrovirals is limited or enhanced by activity of ATP-binding cassette (ABC) or Solute carrier's transporters, of which many are expressed also in placental tissue. ART therapy usually consists of combination of 3 - 4 antiretroviral drugs, thereby leading to higher risk for development of drug-drug interactions on ABC and SLC transporters. In this study we described influence of non-nucleoside reverse transcriptase inhibitors etravirin and rilpivirin on BCRP- and MDR1-mediated transport of tenofovir disoproxil fumarate (TDF) and/or abacavir. Etravirin showed potent inhibition of BCRP transporter significantly changing transport of both, TDF and abacavir, across monolayers of MDCKII-BCRP...

This research was motivated by the urgent need for global health institutions like the World Health Organization and UNITAID to adopt an informed, market based approach to engaging with the research and development pipeline for drugs that treat children infected with the HIV virus. As the market size for these products declines over the next decade, the usual incentives for pharmaceutical and biotech companies to invest in the development of new drugs and new formulations of existing drugs is likely to dwindle. Innovated solutions are needed if a business case is to be made that addresses this important public health need. The objectives of the research include firstly, describing the public health need for research and development into paediatric Antiretroviral drugs; secondly describing the various stakeholders and their interests; and finally exploring and indentifying potential collaborative / partnership opportunities that can be employed to address the existing public health need while satisfying the various stakeholder interests at play.

Thesis (MScMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which makes them highly susceptible for opportunistic infections, requiring additional treatment. Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A great potential for drug-drug interactions (DDIs) between fluconazole and antiretrovirals (ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common metabolic pathways. The outcome may result in the development of adverse drug reactions or drug resistance and treatment failure. Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients diagnosed with cryptococcal meningitis or oropharyngeal candidiasis. Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region. Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse sampling design was used and corresponding ARV serum concentrations were determined by established HPLC and GC methods. Fluconazole serum concentrations were determined by a newly developed HPLC method. Patient characteristics, concomitant medications, clinical test data and ARV serum concentrations were included in a NONMEM generated, onecompartment, open pharmacometric model with first order elimination to detect any drugdrug interactions between fluconazole and the studied ARVs. The secondary outcome was to establish which patient characteristics influence ARV pharmacokinetics. Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67 nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz clearance was correlated with race and concomitant use of rifampicin. No significant covariates were established in the nevirapine model. In the lopinavir model, concomitant use of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin were identified as significant covariates. Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in clearance), which has not been previously described in the South African context. Although gender was not a significant covariate in the nevirapine model, female patients tended to have higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different effects on CYP isoenzymes. The exact contributing factor of each drug in the ultimate decrease in lopinavir clearance (46.4%) can therefore not be established. Conclusions: Given the limitations of the sample size in the present study, no statistical significant effect of fluconazole on the pharmacokinetics of the investigated ARVs could be demonstrated. A retrospective analysis of the data showed various co-factors that influence the pharmacokinetics of the investigated ARVs. This data needs to be confirmed in a prospective study as the identified covariates are appropriate in the management of HIVinfected patients in the South African context. / AFRIKAANSE OPSOMMING: Agtergrond: HIV-positief pasiënte het ‘n aansienlike verswakte immuunstelsel, wat hul hoogs vatbaar tot opportunistiese infeksies maak, en dus, addisionele behandeling benodig. Cryptococcal meningitis en orofaringeale kandidiase word met orale flukonasool behandel. As gevolg van middeling in algemene metaboliese paaie is daar ‘n groot moontlikheid van middel-middel interaksies tussen flukonasool en die antiretrovirale (ARV) middels, efavirenz, nevirapine, en lopinavir/ritonavir. Die uitkomste hiervan mag tot die ontwikkeling van nadelige middel-middel interaksies of middelweerstandigheid en mislukte behandeling lei. Doel: Die primêre doel van hierdie tesis was om die effek van flukonasool op die farmakokinetika van efavirenz, nevirapine en lopinavir/ritonavir in HIV geïnfekteerde pasiënte met gediagnoseerde cryptococcal meningitis en orofaringeale kandidiase te evalueer. Metodes: Die studie was met 80 HIV-positief, behandeling-ervare volwassenes (≥18 jaar) onderneem. Voorafgenoemde was in drie verskillende buitepasiëntklinieke in die Wes-Kaap behandel. Pasiënte was volgens ARV regimen en die gebruik van flukonasool, of dan nie, verder verdeel. ‘n Beperkte steekproef ontwerp was gebruik, en ooreenstemmende ARV serum konsentrasies is deurgevestigde HPLC en GC metodes vasgestel. Flukonasool serum konsentrasies was deur ‘n nuutontwikkelde HPLC metode vasgestel. Pasiëntkenmerke, gepaardgaande medikasie, kliniesetoets data en ARV serum konsentrasies was by ‘n NONMEM genereerde, een-kompartement, oop farmakometriese model met eerste orde eliminasie ingesluit om enige middel interaksies tussen flukonasool en die bestudeerde ARVs op te tel. Die sekondêre uitkomste was om vas te stel watter pasiënt kenmerke ARV farmakokinetika beïnvloed. Resultate:Uit 80 buitepasïente was ‘n totaal van 276 ARV serum monsters (137 efavirenz, 67 nevirapine en 72 lopinavir) vir farmakokinetiese evaluasie gekollekteer. Efavirenz opruiming was met ras gekorreleer asook gepaardgaande gebruik van rifampisien. Geen betekenisvolle ko-variante was in die nevirapine model vasgestel nie. In die lopinavir model het die gepaardgaande gebruik van clotrimazole en die anti-tuberkulose kombinasie isoniazied, pyrazinamied en rifampisien, lopinavir opruiming verminder. Bespreking: In hierdie studie is geen betekenisvolle effekte van flukanosool op die farmakokinetika van enige van die bestudeerde ARVs waargeneem nie. Afwisselende efavirenz plasma konsentrasies in verskillende etniese populasies mag aan verskille in geenuitdrukking, veral CYP2B6, toegeskryf word. Kleurling pasïente het betekenisvolle verlaagde efavirenz serum konsentrasies getoon (56.8% verlaging in opruiming). Hierdie bevinding is nog nooit voorheen in die Suid-Afrikaanse konteks beskryf nie. Alhoewel geslag nie ‘n beduidende ko-variant in die nevirapine model was nie, het vroulike pasïente geneig om hoer nevirapine serum konsentrasies te hê. TB behandeling, in alle pasïente wat lopinavir ontvang het, het uit die volgende kombinasie bestaan: isoniazied, pyrazinamied en rifampisien, elk met hul eie effekte op CYP isoensieme. Die presiese bydra van elke middel in die uiteindelike verlaging (46.4%) in lopinavir opruiming kan dus nie vasgestel word nie. Gevolgtrekking: Gegewe die beperkings van die steekproef in die huidige studie, kon geen statistiese beduidende effek van flukonazool op die farmakokinetika van die betrokke ARVs gedemonstreer word nie. ‘n Retrospektiewe analise van die data het gewys dat verskeidene ko-faktore die farmakokinetika van die betrokke ARVs beïnvloed. Hierdie data moet in ‘n prospektiewe studie bevestig word omdat die geidentifiseerde covariates die bestuur van MIV-positiewe pasiente in die Suid-Afrikaanse konteks te verbeter.

HIV protease inhibitors are an important component of Highly Active Antiretroviral Therapy used to treat HIV infected pregnant women. They have a low placental transfer and are highly plasma protein bound. The purpose of this thesis was to characterize the factors limiting placental passage and fetal exposure to lopinavir. These factors include lopinavir plasma protein binding and uptake, cellular binding, and efflux of lopinavir in the placental trophoblast cells. First, we determined the unbound fraction of lopinavir in cord blood and characterized the binding of lopinavir to α1-acid glycoprotein (AAG) and human serum albumin (HSA), and displacement by ritonavir. Serum was obtained from cord blood from placentae obtained after cesarean section of healthy non-HIV infected women (n=4). The unbound fraction of lopinavir in serum obtained from this cord blood was 0.02 ± 0.01. The unbound fraction of lopinavir in separately obtained maternal serum samples (n=4) was 0.009 ± 0.001, which was not significantly different from that observed with cord serum samples. Varying concentrations of lopinavir, AAG, and HSA in buffer solutions were then used to characterize the lopinavir binding. The data were fit to obtain the number of binding sites (N) and equilibrium dissociation constant (KD). Binding of lopinavir to AAG (7-23 µM) was saturable with KD of 5.0 ± 1.1 µM and N of 1.2 ± 0.2. At low HSA concentrations (15-152 µM), lopinavir binding KD was 24.3 ± 8.7 µM and N was 1.1 ± 0.4; however at 758 µM, lopinavir binding was essentially unsaturable. Additionally, lopinavir binding to AAG and HSA was not sensitive to ritonavir within the range of therapeutic concentrations. Next, we examined lopinavir uptake, binding and efflux using the BeWo human trophoblast cell culture model. BeWo cells were treated with 3H-lopinavir in the absence or presence of inhibitors of ATP- Binding Cassette transporters. The radioactivity was then measured in the buffer and the cells after incubating for different time intervals and at two temperatures. Verapamil (100µM) stimulated apparent efflux of 3H lopinavir by two fold, possibly due to ABCC2. In addition, this efflux process was 75% inhibited by reduced temperature (4°C). Ritonavir (10 µM) also stimulated 3H-lopinavir efflux, whereas GF120918 (1 µM) had no effect. Reduced temperature (4°C), verapamil (100 µM) or ritonavir (10 µM) individually did not significantly affect the binding of 3H-lopinavir to cell homogenates. However, slight but significant binding displacement by verapamil at 4°C was observed. 3H lopinavir uptake was not sensitive to verapamil, bromosulfophthalein, taurocholate or to reduced temperature suggesting uptake involves diffusion rather than Organic Anion Transporting Polypeptide transporters. The results suggested that interplay between cellular binding and ABC efflux transporters, in addition to simple diffusion, determines the extent of 3H-lopinavir distribution into BeWo cells.