Cette thèse présente nos travaux sur la prévention, le dépistage, le diagnostic précoce, et traitement du cancer broncho-pulmonaire (CBP) chez les personnes vivant avec le VIH (PVVIH). La finalité de cette synthèse est d’améliorer la prise en charge des PVVIH atteint de ce cancer, mais aussi de développer des axes de recherche après une évaluation rigoureuse de la bibliographie. Nos recherches soulignent tout d’abord que la prise en charge thérapeutique des PVVIH atteintes d’un CBP doit être identique à celle de la population générale, l’infection par le VIH ne constituant finalement qu’une comorbidité supplémentaire. Toutefois, une spécificité de la prise en charge de ce cancer chez les PVVIH est la survenue de complications potentiellement létales secondaires aux interactions et effets toxiques additifs entre les antirétroviraux et les médicaments cytotoxiques. Ce danger nécessite une bonne coordination des équipes oncologiques et infectiologiques, probablement par le biais de réunions de concertation pluridisciplinaires spécifiques, ainsi qu’une bonne connaissance des pharmacocinétiques et pharmacodynamies des produits administrés.Notre étude ANRS EP48 HIV CHEST, qui était une étude transversale multicentrique, a inclus 442 PVVIH à risque de développer un CBP, en raison (principalement) d’un tabagisme > 20 paquets-années, un âge > 40 ans, ainsi qu’un nadir en lymphocytes TCD4 < 350 cellules/ µl. Cette étude a rempli son objectif principal, qui était de démontrer la faisabilité du dépistage du CBP chez les PVVIH en France par TDM thoracique. Le diagnostic d’un nombre important de CBP de stades localisés, et donc guérissables, apporte probablement un bénéfice essentiel aux patients inclus. Le fait qu’aucune complication grave n’ait été engendrée par les explorations diagnostiques, et que la prévalence de nodules significatifs soit dans l’intervalle des résultats d’études en population générale, sont des éléments rassurants. Nos travaux, ainsi que d’autres données de la littérature de prévalence de ce cancer en fonction des âges, font apparaître que l’âge limite de dépistage par TDM faible dose pourrait être de 45 ans chez les PVVIH. Comme en population générale, l’apport du TDM thoracique ne se limite pas au diagnostic de CBP. Il permet d’augmenter l’efficacité du diagnostic précoce de comorbidités ayant un impact sur la qualité de vie et/ou la survie par : 1) le diagnostic des tassements vertébraux, pour la majorité asymptomatique, en rapport avec une prévalence élevée de l’ostéoporose fracturaire dans cette population, 2) l’évaluation de l’emphysème et de la bronchiolite du fumeur, 3) une estimation des calcifications coronaires, qui est associée aux événements cardio-vasculaires. Ce travail a également pour intérêt d’illustrer l’épidémiologie des complications actuelles des PVVIH sous traitement antirétroviral efficace et exposées à une intoxication tabagique. La BPCO, l’emphysème, le CBP, l’athérosclérose coronaire ont une prévalence élevée dans cette population et sont des enjeux importants de santé. Cette épidémiologie rapproche la population des PVVIH de la population générale mais avec des particularités liées, aux antécédents de déficit immunitaire et de traitements antirétroviraux toxiques, et à la prévalence plus élevée des comportements à risque. Pour certaines complications cependant (emphysème, bronchiolite, score calcique), l’absence d’association avec les variables immuno-virologiques souligne la primauté des facteurs comportementaux dans la survenue de ces complications. Ainsi, l’ensemble de ces travaux qui s’articulent principalement autour de l’étude ANRS EP48 HIV CHEST souligne que la réduction des risques liée aux facteurs d’exposition (tabagisme surtout, et probablement cannabis) est une priorité chez les PVVIH à l’ère des combinaisons antirétrovirales. / This thesis is an analysis of our on-going or published works on the theme of prevention, early diagnosis, screening, and treatment of subjects living with HIV with lung cancer. The ultimate objective of this work is to improve care and prevention of lung cancer in people living with HIV (PLWHIV), and to promote research in lung cancer in this population. Our work underscores that lung cancer treatment in PLWHIV should be identical to treatments administered for lung cancer in the general population. HIV is an additional comorbidity to be taken into account, but never a contraindication for optimal therapy. However, there exist specificities in management of PLWHIV with lung cancer, including the propensity for drug-to-drug interactions and additive toxicity between cytotoxic compounds for chemotherapy and antiretroviral therapy, with potentially lethal effects. Managing these toxicities implies optimal cooperation between oncologists and specialists in HIV, as well as good knowledge of pharmacokinetics and pharmacodynamics of these different compounds.The ANRS EP48 HIV CHEST Study in a cross-sectional, multicentre study, which included 442 subjects at lung cancer risk, primarily due to their age (> 40 years), smoking hazard (> 20 pack-years), as well as a CD4 cell nadir count < 350 cells/µl. This study showed feasibility of lung cancer screening with chest Computed Tomography (CT) in PLWHIV. The early diagnosis of localized lung cancers, potentially curable, suggests clinical benefits for most participants with cancer. Also, the facts that no serious adverse events occurred with invasive diagnostic procedures and that the prevalence of positive nodules was in the range of those found in lung cancer screening studies in the general population are reassuring. Also, our work, combined with data from previous epidemiological studies, support a lower age limit for screening lung cancer with chest CT in PLWHIV at risk than in the general population, starting as early as 45 years. As in the general population, the impact of lung cancer screening with chest CT is not limited to the diagnosis of early stage lung cancers. The diagnosis of other morbidities, such as vertebral fractures, generally asymptomatic, emphysema, bronchiolitis, and coronary calcifications, have a probable positive impact on quality of life and a benefit in survival if managed adequately. Our works also illustrate the epidemiology of complications in PLWHIV under antiretroviral therapy and exposed to smoking hazards. Chronic obstructive pulmonary diseases, emphysema, lung cancer, coronary atherosclerosis have high prevalence in this subpopulation of PLWHIV. The epidemiology of these emerging morbidities is close to the epidemiology in the smoking general population, but specificities exist, due to the presence of chronic immunodeficiency, antiretroviral toxicities, and an increased prevalence of behavioural risks in PLWHIV in comparison with the general population. However, some complications are not associated with HIV-related and immunological factors, such as prevalence of emphysema, coronary calcifications, and bronchiolitis, underscoring the major impact of behavioural hazards in the occurrence of these complications.Taken together, our work highlights the importance of reducing health hazards in PLWHIV, primarily smoking and probably cannabis, to reduce the emergence of these new life-threatening morbidities in the era of highly active antiretroviral therapy.

Magister Public Health - MPH / Background: Namibia is one of the Southern African countries hardest hit by the HIV epidemic, with an estimated one out of every five people infected (MoHSS, 2004). Approximately 80,000 of the infected population currently require antiretroviral treatment (ART). In order to prevent the progression of the HIV infection to AIDS, patients are required to take antiretroviral medicines lifelong. This lifelong use exposes patients to toxicities of these medicines and the only available options of managing the toxicities of ARVs are to treat the toxicity or substitute or switch the offending medicines. Aim: The current study aimed to describe the extent and reasons for substituting and switching HAART at the Katutura Intermediate Hospital in Windhoek, Namibia. Methodology: A descriptive retrospective case series study, in which medical records were reviewed to determine the extent and reasons for substituting and switching HAART was conducted. Random sampling was used to draw a sample of 500 from 3477 adult HAART patients who commenced treatment between 1 January 2002 and 31 December 2006. A prepiloted data collection tool was used to collect the data. The following information was collected: baseline CD4 count, weight, initial ARVs, first and second ARV substitutions, ART switch and the reasons for substituting ARVs or switching ART during the indicated period. Epi Info version 6 was used to analyse frequencies, means and medians of all important variables in the data set. Results: The sample was made up of 500 HAART patients; 60% were females. The median age of the sample was 34 years (Inter-quartile range (IQR) 30 – 40) and the median CD4 cell count was 153 cells/mm3 (IQR 96 – 212) at initiation of therapy. The median time on treatment before first substitution was 28 months (IQR 24 – 34), whereas the median time before second substitution was 10 months (IQR 6 – 15) from the time of the first substitution. The median time before switching was 31 months (IQR 24 - 39). A total of 31% of the study subjects underwent a substitution once, whereas 1.8% underwent a second substitution. Only six (1.2%) patients switched to a second line treatment after the modification of the treatment. The most commonly recorded reason for the first substitution was toxicity (19%). As in other studies, stavudine (D4T), nevirapine (NVP) and efavirenz (EFV) were the ARVs associated with most of the recorded toxicities. High viral load (50%) was the most reported reason for switching. In almost half of the substitution cases the reasons for substitution were not stated, and in a third of the switch cases the reasons for switching were not stated. Conclusion: The rate of substitution at 31% was similar to that found in other resource poor settings, however, the rate of switching (1.2%) was much lower than was found in similar settings. The main reason stated for substituting antiretrovirals was “toxicity”. / South Africa

Magister Public Health - MPH / The study aimed to assess the level of adherence and to identify the barriers to adherence and the motivations for good adherence to antiretroviral therapy, amongst women who commenced treatment while pregnant at research clinics in Molepolole, Mochudi, Lobatse and Gaborone. / South Africa

Philosophiae Doctor - PhD / The HIV/AIDS pandemic has been a torment to the African developmental agenda, especially the Southern African Development Countries (SADC), for the past two decades. The disease and condition tends to affect the productive age groups. Children have also not been spared from the severe effects associated with the disease. The advent of antiretroviral treatment (ART) has brought a great relief to governments and patients in these regions. More people living with HIV/AIDS have experienced a boost in their survival prospects and hence their contribution to national developmental projects. Survival analysis methods are usually used in biostatistics, epidemiological modelling and clinical research to model time to event data. The most interesting aspect of this analysis comes when survival models are used to determine risk factors for the survival of patients undergoing some treatment or living with a certain disease condition. The purpose of this thesis was to determine prognostic risk factors for patients' survival whilst on ART. The study sought to highlight the risk factors that impact the survival time negatively at different survival time points. The study utilized a sample of paediatric and adult datasets from Namibia and Zimbabwe respectively. The paediatric dataset from Katutura hospital (Namibia) comprised of the adolescents and children on ART, whilst the adult dataset from Bulawayo hospital (Zimbabwe) comprised of those patients on ART in the 15 years and above age categories. All datasets used in this thesis were based on retrospective cohorts followed for some period of time. Different methods to reduce errors in parameter estimation were employed to the datasets. The proportional hazards, Bayesian proportional hazards and the censored quantile regression models were utilized in this study. The results from the proportional hazards model show that most of the variables considered were not signifcant overall. The Bayesian proportional hazards model shows us that all the considered factors had different risk profiles at the different quartiles of the survival times. This highlights that by using the proportional hazards models, we only get a fixed constant effect of the risk factors, yet in reality, the effect of risk factors differs at different survival time points. This picture was strongly highlighted by the censored quantile regression model which indicated that some variables were significant in the early periods of initiation whilst they did not significantly affect survival time at any other points in the survival time distribution. The censored quantile regression models clearly demonstrate that there are significant insights gained on the dynamics of how different prognostic risk factors affect patient survival time across the survival time distribution compared to when we use proportional hazards and Bayesian propotional hazards models. However, the advantages of using the proportional hazards framework, due to the estimation of hazard rates as well as it's application in the competing risk framework are still unassailable. The hazard rate estimation under the censored quantile regression framework is an area that is still under development and the computational aspects are yet to be incorporated into the mainstream statistical softwares. This study concludes that, with the current literature and computational support, using both model frameworks to ascertain the dynamic effects of different prognostic risk factors for survival in people living with HIV/AIDS and on ART would give the researchers more insights. These insights will then help public health policy makers to draft relevant targeted policies aimed at improving these patients' survival time on treatment.

Approximately 33.4 million people are living with HIV/AIDS. Of those, 97% live in low and middle income countries, with 22.4 million in sub-Saharan Africa. Only 42% of the people who require anti-retrovirals (ARVs) in low to middle income countries are receiving anti-retroviral therapy (ART). There is a need to develop novel and cost effective methods for producing antiretroviral drugs. Stavudine and azidothymidine (AZT) were identified as potential targets because they could both be produced through a common intermediate – 5 methyluridine (5-MU). It has been established that the biocatalytic production of 5-methyluridine is possible through a reaction known as transglycosylation, in a process which has not previously been demonstrated as commercially viable. A selection of biocatalysts were expressed either in recombinant E. coli strains or in the wild type organisms, purified and then screened for their ability to produce 5-MU. A combination of Bacillus halodurans purine nucleoside phosphorylase 1 (BHPNP1) and E. coli uridine phosphorylase (EcUP) gave the highest 5-MU yield (80%). This result represents the first combination of free enzymes from different organisms, giving high yields of 5-MU under high substrate conditions. Both enzymes were purified and successfully characterised. The established pH optimum was pH 7.0 for both enzymes. Temperature optima and stability data for BHPNP1 (70 C and t1/2 at 60 C of 20.8 h) indicated that the biocatalytic step was operating within the capabilities of this enzyme and would operate well at elevated temperatures (up to 60 C). Conversely, the temperature optimum and stability data for EcUP (optimum of 40 C and t1/2 at 60 C of 9.9 h) indicated that the enzyme remained active at 40 C for the duration of a 25 h biotransformation, but at 60 C would only be operating at 20% of its optimum activity and would lose activity rapidly. BHPNP1 and EcUP were used in a bench scale (650 ml) transglycosylation for the production of 5-MU. A 5-MU yield of 79.1% was obtained at this scale with a reactor productivity of 1.37 g.l-1.h-1. Iterative saturation mutagenesis was used to rapidly evolve EcUP for improved thermostability. A moderately high throughput colorimetric method was developed for screening the mutants based on the release of p-nitrophenol upon phosphorolysis of a pyrimidine nucleoside analogue. By screening under 20 000 clones the mutant UPL8 was isolated. The mutant enzyme showed an optimum temperature of 60 C and improved stability at 60 C (t1/2 = 17.3 h). The increase in stability of UPL8 is due to only 2 mutations (Lys235Arg, Gln236Ala). These mutations may have caused an increase in stability due to interactions with other structural units in the protein, stabilization of the entrance to the binding pocket, or by decreasing the flexibility of the α-helix at the N-terminus. Transglycosylation experiments showed that the mutant enzyme UPL8 is a superior catalyst for the production of 5-MU. A 300% increase in reactor productivity was noted when free enzyme preparations of UPL8 was combined with BHPNP1 at 1.5% m.m-1 substrate loading. The high yield of 5-MU (75-80% mol.mol-1) was maintained at 9% m.m-1 substrate loading. A commercially viable productivity of 31 g.l-1.h-1 was thus realised. Further optimisation of the process could produce still higher productivities. Future work in directed evolution of nucleoside phosphorylases is envisaged for improved stability and enhanced substrate range for application to other commercially relevant transglycosylation reactions.

The Human Immunodeficiency Virus (HIV) and Acquired Immuno Deficiency Syndrome (AIDS) epidemic has had massive detrimental impacts on rural communities across Africa including in Zimbabwe. In response to the HIV and AIDS epidemic, the government of Zimbabwe has developed and adopted comprehensive programmes to address HIV and AIDS prevention, care and support. One of the critical components of these programmes relates specifically to treatment of the HIV infected given that HIV and AIDS is increasingly seen as a manageable threatening disease. However the success and effectiveness of the treatment regimen (involving antiretroviral drugs or ARVs) is dependent heavily on complete adherence to the rigid and complex regimens. It is against this background that this thesis studies a particular rural community in Zimbabwe called Chivanhu (in Masvingo Province) in terms of the relationship between rural livelihoods and HIV and AIDS (particularly HIV treatment and treatment adherence). Unlike other rural communities (notably in communal areas), Chivanhu is an informal and unstable community with a turbulent history. Most rural studies of HIV and AIDS in Zimbabwe and elsewhere in the region have focused on well-established and stable communities in which agricultural production is still of some significance. In such communities, the impact of HIV and AIDS on livelihoods is severe but, in more informal settlements, the vulnerability of households to the epidemic (and challenges pertaining to treatment adherence) is even more pronounced. Using a rural livelihoods framework, this thesis seeks to identify, understand and analyse the conditions which shape levels of adherence to HIV and AIDS in the informalsettlement of Chivanhu in Zimbabwe.

Despite the current interventions to avert contagions and AIDS-related deaths, sub-Saharan Africa is still the region most severely affected by the HIV/AIDS pandemic, where clade C is the dominant circulating HIV-1 strain. The pol-encoded HIV-1 protease enzyme has been extensively exploited as a drug target. Protease inhibitors have been engineered within the framework of clade B, the commonest in America, Europe and Australia. Recent studies have attested the existence of sequence and catalytic disparities between clades B and C proteases that could upset drug susceptibilities. Emergence of drug-resistant associated mutations and combinatorial explosions due to recombination thwarts the attempt to stabilize the current highly active antiretroviral therapy (HAART) baseline. The project aimed at identifying the structural and molecular mechanisms hired by mutants to affect the efficacies of both FDA approved and Rhodes University (RU)-synthesized inhibitors, in order to define how current and or future drugs ought to be modified or synthesized with the intent of combating drug resistance. The rationale involved the generation of homology models of the HIV-1 sequences from the South African infants failing treatment with two protease inhibitors: lopinavir and ritonavir (as monitored by alterations in surrogate markers: CD4 cell count decline and viral load upsurge). Consistent with previous studies, we established nine polymorphisms: 12S, 15V, 19I, 36I, 41K, 63P, 69K, 89M, and 93L, linked to subtype C wild-type; some of which are associated with protease treatment in clade B. Even though we predicted two occurrence patterns of M46I, I54V and V82A mutations as V82A→I54V→M46I and I54V→V82A→M46V, other possibilities might exist. Mutations either caused a protracted or contracted active site cleft, which enforced differential drug responses. The in silico docking indicated susceptibility discordances between clades B and C in certain polymorphisms and non-polymorphisms. The RU-synthesized ligands displayed varied efficacies that were below those of the FDA approved protease inhibitors. The flaps underwent a wide range of structural motions to accommodate and stabilize the ligands. Computational analyses unravelled the need for these potential drugs to be restructured by (de novo) drug engineers to improve their binding fits, affinities, energies and interactions with multiple key protease residues in order to target resilient HIV-1 assemblages. Accumulating evidences on contrasting drug-choice interpretations from the Stanford HIVdb should act as an impetus for the customization of a HIVdb for the sub-Saharan subcontinent.

Pharmacological interventions to treat Human Immunodeficiency Virus (HIV) with antiretrovirals (ARVs), have dramatically improved the survival rates of HIV positive children maturing into adulthood. However, HIV-associated neurocognitive decline still persists in the era of ARVs. Within the framework of brain plasticity, a number of researchers have begun to assess the feasibility of cognitive rehabilitation therapy as a complement to ARVs to reverse neurocognitive decline as a result of HIV (e.g., Becker et al., 2012). Only one study has been conducted in South Africa, by Zondo & Mulder (2014), assessing the efficacy of cognitive rehabilitation in a paediatric sample. The current research builds on the above mentioned study by implementing an experimental approach to examine the effect of cognitive rehabilitation in a sample of both HIV positive and HIV negative children. Five HIV positive and six HIV negative children were assigned to either an experimental or control group. The experimental group underwent two months of cognitive rehabilitation therapy remediating sustained attention, whereas the control group took part in placebo activities. Sustained attention measures were taken before and after the intervention training sessions, using a sustained attention subtest from the Test of Everyday Attention for Children (TEA-CH). A Mann Whitney U Test revealed that the experimental group (Mdn=38.50) did not differ significantly from the control group (Mdn = 37.00) after the cognitive rehabilitation intervention, U=12.00, z= -.55, p= .66, r= -.17. But a Wilcoxon Signed Rank Test found that there was a significant improvement from pretest scores (Mdn=31.00) to posttest scores (Mdn=38.00) following the rehabilitation for HIV positive participants in the sample, T=15.00, z = -2.02, p= .04, r= -.90. This raises the possibility that cognitive rehabilitation could be used as a low cost intervention in underdeveloped contexts

Despite good intentions and commitment from health providers, it is difficult for HIV positive pregnant women to access Prevention of Mother to Child Transmission of HIV (PMTCT) services (Skinner et al 2005:115). The aim of this research was to find out the extent to which socio-economic and cultural factors influence access to and utilization of PMTCT services. It appeared that despite having a legal plan and framework to ensure that PMTCT services are available and free, the realities confronting HIV positive women in South Africa as suggested by the literature contradicted this objective. Inevitably, these contradictions were identified as some of the main factors contributing to lack of access and inadequate utilization of PMTCT services. These factors were identified through a review of fifteen studies selected based on their relevance to the research aim. The findings were presented according to the following themes: Functioning of clinics, adherence to ART, uptake of VCT and infant feeding practices. According to research evidence, the major socio-cultural factors influencing access and utilization of PMTCT services include fear of stigma and discrimination which are related to cultural norms and practices. The socio-economic factors include transport costs, lack of food, medicines and formula milk which are all related to poverty and unemployment. The research also found that health system constraints such as long waiting times in clinics, stock-outs of formula milk, medicines and test kits influenced the utilization of PMTCT services by HIV positive women.

En 2004, l’Organisation Mondiale de la Santé (OMS) recommandait dans les pays à ressources limitées, l’utilisation de la multithérapie antirétrovirale (MARV) chez les femmes enceintes éligibles au traitement antirétroviral pour leur propre santé. Le but visé était de réduire de manière plus significative encore le taux de transmission de la mère à l’enfant du VIH (TME) parmi les femmes à haut risque. Cependant, très peu de données étaient alors disponibles en Afrique sub-saharienne sur les bénéfices de la MARV en termes de réduction du TME, y compris pendant l’allaitement, et les risques de survenue d’effets indésirables graves (EIG) chez les femmes enceintes ainsi que sur d’éventuelles issues défavorables des grossesses (fausse couche, prématurité, mort-né et petit poids de naissance). De plus, en Afrique sub-saharienne, le régime de première ligne chez les femmes enceintes infectées par le VIH comprend presque toujours la lamivudine (3TC) et la névirapine (NVP), deux molécules antirétrovirales utilisées jusqu’à présent en régimes courts dans la PTME. La survenue de mutations de résistance à ces molécules après une telle utilisation pourrait donc compromettre le succès au traitement de première ligne dans le cadre d’une MARV. Nous avons étudié ces différentes questions à Abidjan (Côte d’Ivoire) pour notre thèse avec les données du programme MTCT-Plus de prise en charge familiale avec comme porte d’entrée la femme enceinte infectée par le VIH, programme mis en place en juillet 2003. Cinq études ont ainsi été réalisées pour notre thèse. La première étude a porté sur la réponse virologique et/ou immunologique à 12 mois puis à 36 mois après l'initiation d’un régime antirétroviral de première ligne chez les femmes préalablement exposées à la névirapine monodose (NVPmd) et/ou au 3TC pour la PTME. Les délais médians entre l’exposition au 3TC ou à la NVP et l’initiation du traitement étaient respectivement de 22 mois et de 15 mois. Après 12 mois de MARV, 19,2% des femmes étaient en échec virologique et 11,1% des femmes étaient en échec immunologique. La survenue de mutations de résistance au 3TC après une exposition à ces ARV administrés dans le cadre d’un régime court de PTME était associée à une mauvaise réponse virologique à 12 mois de MARV, mais pas à une mauvaise immunologique à 12 et 36 mois. La survenue de résistance à la NVP après une exposition à la NVPmd n’était pas plus associée à une mauvaise réponse virologique à 12 mois qu’à une mauvaise réponse immunologique à 12 et 36 mois. La deuxième étude a porté sur l’estimation du taux de TME en fonction du type de recommandations de l’OMS qui était en vigueur. Le taux de TME à 12 mois était de 3,3% chez les femmes éligibles qui ont reçu une MARV (1,9% pour la transmission postnatale) et de 7,5% chez les femmes non éligibles ayant reçu un régime court d’antirétroviraux pour la PTME (3,5% pour la transmission postnatale). La troisième étude a porté sur l’estimation de l’incidence des effets indésirables graves (grade ¾), spécialement de l’hépatotoxicité et/ou du rash cutané, en fonction des CD4 et de l’initiation ou non d’une MARV contenant la NVP au cours de la grossesse. Durant un suivi médian de 25 mois, l’incidence des EIG était de 19,5 pour 100 femme-années. La probabilité de survenue d’hépatotoxicité et/ou de rash cutané à 24 mois n’était pas différente entre les femmes ayant des CD4 > 250 cellules/mm3 et celles ayant des CD4 = 250 cellules/mm3 (8,3% vs 9,9%, p = 0,75). De même, la probabilité de survenue d’hépatotoxicité et/ou de rash cutané à trois mois (durée médiane de grossesse) n’était pas différente entre les femmes initiant la MARV durant la grossesse et celles l’initiant en dehors de la grossesse (5,3% vs 7,5%, p = 0,35). / In 2004, the World Health Organization (WHO) began recommending Highly Active Antiretroviral Therapy (HAART) for pregnant women who were eligible for antiretroviral treatment in resource-limited settings. The aim of this recommendation was to significantly reduce the rate of mother-to-child transmission (MTCT), which remained high despite the use of short-course regimens for the prevention of MTCT (PMTCT). However, very little sub-Saharan Africa data were available on the benefits in reducing MTCT, including while breastfeeding, and the risks of occurrence of severe adverse events (SAEs) and adverse pregnancy outcomes associated with HAART. Moreover, the first regimen recommended for HIV-infected pregnant women in sub-Saharan Africa almost always included lamivudine (3TC) and nevirapine (NVP), two drugs used also for short-course PMTCT regimens. Thus, the relevant clinical question is whether the occurrence of viral resistance mutations, which could arise after using these drugs for PMTCT, might have an impact on the success of a future first-line regimen. We conducted five studies on pregnancy and HAART use in Abidjan, Côte d'Ivoire, using data from the MTCT-Plus program, which was established in July 2003 as a multi-country family-centered program provides HIV care and treatment to pregnant and postpartum women and their families. The first study evaluated the 12 and 36-month virologic and/or immunologic response of NVP and 3TC-based HAART in women previously exposed to these drugs for PMTCT. The median intervals between exposure to 3TC or NVP and HAART initiation were 22 months and 15 months, respectively. After 12 months of HAART, 19.2% of women experienced virologic failure and 11.1% experienced immunologic failure. Resistance to 3TC tested at week 4 after delivery was associated with virologic failure at 12 months; but not immunologic failure at 12 and 36-month. Resistance to NVP tested at week 4 after delivery was not associated with virologic failure at 12 months or immunologic failure at 12 and 36-months. The second study assessed the efficacy of the WHO-recommended two-tiered PMTCT strategy. The MTCT rate 12 months was 3.3% among eligible women who received HAART (postnatal transmission, 1.9%) and 7.5% among non-eligible women who received short-course regimen for PMTCT (postnatal transmission, 3.5%). The third study estimated the incidence of SAEs (grade ¾), especially hepatotoxicity and/or skin rash, according to CD4 and initiation of NVP–based HAART during pregnancy. The incidence of SAEs was 19.5 per 100 woman-years after a median follow-up of 25 months. The probability of hepatotoxicity or rash 24 months after HAART initiation was similar in women with CD4 cell counts >250 cells/mm3 and =250 cells/mm3 (8.3% vs. 9.9%; log-rank test: p=0.75). Similarly, the probability of hepatotoxicity or rash 3 months after HAART initiation (median duration of pregnancy) was similar in women who initiated HAART during pregnancy and those who did not (5.3% vs. 7.5%; log-rank test, p=0.35).