Thesis (MPH) -- University of Limpopo (Medunsa Campus), 2011. / Background Available and affordable second-line antiretroviral treatment regimens are a key component of universal access to treatment and its continuation. However, providing second-line ART is affected by a number of factors including infrastructure, skills and cod competency of available personnel, cost and availability of second-line drugs. Like first-line antiretroviral agents, second-line drugs have also inherent toxicities. While these have been described in adults, few studies reported this in children. Hence, the need to conduct this study. The aim of the study was to characterize the adverse effects on second-line antiretroviral therapy among HIV infected adults and adolescents and children treated at Mildmay Uganda (MUg). Method This was a cross-sectional study based on the review of patients' records. Data was extracted from client medical charts of patients on second-line antiretroviral treatment regimens treated at Mildmay Uganda Centre from January 2000 to December 2008. Results In total, 247 cases, the majority (90.7%) of the study participants were aged 13 years and above, female (53.0%), and single (68.0%). With regard to reasons that led to the second-line regimen, the main reason for switching was treatment failure (83%), followed by toxicity (5.7%), and other reasons such as the onset of Kaposi Sarcoma disease, maintaining regimen after transfer, and nevirapine pre-exposure. Overall, 55 out of 247 patients suffered from one or more adverse effects, a prevalence of 22.3%. The mean number of adverse drug reactions (ADR) was 1.3 per patient. Of the 55 who experienced adverse effects, 76.4% experienced one type of adverse effect. The three most common adverse effects were gastro-intestinal, followed by hematological and peripheral neuropathy. Based on age, while adults experienced a broad range of adverse 11 drug reactions including metabolic and hepatic ADRs besides the three cited above; children experienced two types only, gastrointestinal, and hematological ADRs. Hematological ADRs were significantly more prevalent in children than adults (66.7% versus 21.4%); they were also more prevalent in females than males (30.8% versus 15.2%). In contrast, while metabolic ADRs were equally distributed, peripheral neuropathy was more prevalent in males than females (30.3% versus 20.5%). Based on the number of ADRs experienced, more males than females (19.8% versus 14.5%) experienced one type of adverse effect whereas more females than males (6.1% versus 4.3%) experienced two to three adverse drug reactions to second-line regimens. Clinically, the didanosine-based regimens were the most associated with ADRs in both children and adults. In Children, the regimen, ABC/DDI/LPV/R, was responsible of 66.7% of ADRs documented; while in adults it was involved in 60.3% of ADRs. Similarly, TDF-, zidovudine-, and stavudine-based regimens were also involved respectively in 52.9%, 17.8%, and 14.7% of ADRs. Based on gender, didanosine-containing regimen, with either TDF or stavudine with lopinavir/r were responsible of 66.7% of ADRs reported in males; while TDF-based regimen with lamivudine or FTC were involved in 21.1% of ADRs also in males. In females, didanosine-, TDF-, zidovudine-, and stavudine-based regimens were also involved respectively in 57.9%, 36.9%, 23.7%, and 7.9% of ADRs. The regimen, TDF/DDI/LPV/R, was also the most associated with the occurrence of ADRs in females as it was in males. Moreover, although no difference was found among patients whose bodyweights increased significantly and those whose did not, patients whose CD4 counts increased significantly experienced more ADRs than those whose had not (8.8% versus 1.3%, p= 0.03). Conclusion Overall, second-line regimens seem to be well tolerated as the overall prevalence of adverse effects was 22.37%. The didanosine-containing regimens were most associated with the occurrence of ADRs. Hematological ADRs were more prevalent in children than 12 adults; and more in females than males. In contrast, while metabolic ADRs were equally distributed, peripheral neuropathy was more prevalent in males than females. These findings emphasize the need to individualize treatment based on the characteristics of the patient.

Thesis (M Med (Family Medicine)) -- University of Limpopo, 2010. / Depression commonly Occurs in chronic diseases such as HIV-AIDS and "Depression makes chronic disease worse: WHO", depression is expected to become the second-leading cause of disease burden by the year 2020, after heart disease. Depression can exacerbate chronic disease (WHO, 2007, Kerr L.K. & Kerr L.D., 2001). From the University of New Mexico Health Sciences Center (2009), it has been confirmed that depression is very common in people living with HIV/AIDS and the rate of depression among them was estimated as high as 60%. This was previously confirmed by Moosa and Jeenah (2007).' In Tanzania life events were found to be part in the aetiology of depression and that the rates had increased in recent years (Mbatia et aI., 2009).The authors recommend the strengthening of training of primary health care workers to detect depression and provide pharmacological and psychological treatment. The South African Journal of Psychiatry, states that depression in the world is exceedingly common in the general population. The lifetime prevalence rates are between nine to 20%. In chronic diseases the rate of depression is between 15 to 360/0,which is high. (Moosa & Jeenah, 2007). Untreated depression can lead to missing medication doses and lower the patient's quality of life (aidsinfonet.org, 2009). It has also been established that depression is linked to poor Highly Anti¬retroviral Therapy (HAART) adherence (Kacanek D., Jacobson D.L., Spiegelman D., Wanke c., Isaac R. & Wilson LB., 2010). Primary care based aualitv improvement programs for depression have shown to improve the quality of care, satisfaction with care and health outcomes, functioning, economic productivity and household wealth at reasonable cost (WHO 2010, Kumar & Encinosa W., 2009, Hoberg M.A. et aI., 2008). Study setting The study was conducted in the Rustenburg district of North West province. The comprehensive management of HIV/AIDS is part of the district health system that is implemented in this province. Voluntary Counselling and Testing (VCT) is offered to patients at the clinics or health centre (Primary Health care facilities). A positive rapid test, done in the clinic or health centre, is followed by collection of blood for confirmation, using a second rapid test and two Enzyme linked immuno sorbent assay (ELISA) and assessing CD4 levels at the h.ospital's laboratory. Patients with two rapid tests and two ELISA positives, and a CD4 of less than 200 or clinical stage three, according to revised World Health Organisation (WHO) clinical staging of HIV/AIDS (J.G. Barlett, J.E. Gallant & F.M. Conradie, 2008) are referred to wellness clinic / Job Shimankana Tabane (JST) hospital, for initiation of Anti¬Retroviral Therapy (ART). Once stable on treatment for more than six months, patients are referred down to the nearest clinic or health centre for follow up. Why is the study necessary? As a medical officer at one of the down referral primary health care facilities, the researcher encountered patients who were on antiretroviral therapy, that frequently presented with symptoms consistent with depression but these patients were not aware of the depression. x The researcher became concerned about the lack of identification of depression among adult patients on antiretroviral therapy for human immunodeficiency virus (HIV) in my district, with subsequent lack of appropriate management. After conducting an informal enquiry from some of the patients about symptoms that could be attributed to depression, the researcher became convinced that most of the patients were depressed, although they were not aware of it. The magnitude of the problem had not been explored in Rustenburg before. This is when the researcher decided to conduct a study on screening for depression amongst adult patients on antiretroviral therapy for human immunodeficiency virus in my district. The result of this study will inform the development of protocols used in the provision of comprehensive care to these patients. Methodoloav A descriptive cross-sectional study was conducted amongst adult patients on antiretroviral therapy for Human Immunodeficiency Virus (HIV) who attended one clinic and two health centres, all three accredited in terms of HIV management, in Rustenburg district (South Africa) during December 2009. A hundred and seventeen (117) adult patients, who consulted three Health Centres and agreed to participate in the study were sequentially selected for inclusion in the study. A questionnaire, adapted from the World Health Organization's (WHOs), Zung self-rating depression score by a trained nurse, was used to evaluate depression among the participants. Descriptive analysis of the data was done. The Medical Research, Ethics and Publications Committee (MREC) of the University of Limpopo/ Medunsa campus approved the intended study (Registration Number: MREC/M/29/2009). Results Amongst the 117 participants 81(69.2 %) had mild depression, 2 (1.7%) had moderate depression, 1(0.9 %) had severe depression and 33 (28.2%) did not have depression. Depression was equally common amongst males and females, 77.1% for males and 69.5% for females. Depression was most common on patients taking a regimen that contains efavirens, lamivudine and stavudine. Conclusion Depression is common among adult patients on antlretroviral therapy for Human Immunodeficiency Virus (HIV) attending primary health care facilities in Rustcenburg District. Most of the patients are mildly depressed, as demonstrated by this study research.

Thesis (MPH)--University of Limpopo, 2013. / Statistics from Pigg’s Peak Hospital, in Swaziland, continue to show an improvement in the uptake of HIV testing among TB patients, as well as a very high rate of HIV co-infection among the TB patients. The unit’s reports also show a low uptake of antiretroviral therapy among the HIV co-infected TB patients, and high death rates. Most of these deaths occur among HIV co-infected TB patients who have not yet initiated ART despite being on TB treatment. Anecdotal evidence suggests that there is reluctance and refusal by a considerable proportion of TB/HIV co-infected patients to take TB treatment and ART concurrently, and that they prefer to commence ART after completing TB treatment. No study has ever been conducted in Swaziland to determine the reasons for refusal of ART initiation prior to the completion of TB treatment among HIV co-infected TB patients. Aim The aim of this study was to explore the reasons for refusing antiretroviral therapy among HIV co-infected tuberculosis patients, prior to the completion of tuberculosis treatment, at Pigg’s Peak Hospital, in Swaziland. Methods A qualitative descriptive study was conducted in order to generate information on the subjects’ experiences and views on the concurrent taking of tuberculosis and antiretroviral medicines. A sample of nineteen HIV co-infected TB patients was purposefully selected to answer the research question. Results The most common reasons given by the respondents for refusing ART initiation during TB therapy were their un-readiness for ART, especially because ART must be taken for life, the perception that one was still in good health, the fear of adverse outcomes being precipitated by combining ART with TB medicines, a preference of traditional medicines, and health systems-related problems. Other reasons were: a lack of food, substance abuse, a fear of the increased pill burden, a denial of the HIV-positive status, and problems related to treatment supporters. Conclusion In TB/HIV co-infection care settings, comprehensive Pre-ART counseling must be integrated with interventions that address the specific barriers to ART initiation faced by clients; to improve the acceptability of ART initiation during TB therapy to these HIV/TB co-infected patients.

Thesis (MSc(Med)(Pharmacy)) -- University of Limpopo, 2010. / SUMMARY Introduction: The Human Immunodeficiency Virus (HIV) pandemic has become a global "monster" and much effort and funds have been channelled by various stake holders to change the deadly course of this threatening disease. Adherence has been identified as a critical element in optimal treatment of the disease with antiretroviral (ARV) medicines. A literature review was conducted on relevant facets of the HI virus, Acquired Immune Deficiency Syndrome (AIDS), disease prevention and treatment with ARVs, treatment obstacles, the importance of a sustained adherence level of at least 95% and the treatment interventions to promote medication adherence. Objectives: The objectives of this study were to evaluate the e-MuM electronic monitoring system (electronic microprocessor, reminder unit [a specialised wristwatch] and software program) for practicality, impact and effectiveness on ARV adherence, to test the ease of use for the patient and pharmacist, to get feedback from patients and clinic staff and finally to make recommendations concerning possible adaptations and the ideal use of the e¬MuM system. Method: The design was a four phase, prospective, randomised experimental, longitudinal study, conducted at the Tshepang Clinic of the Dr George Mukhari Hospital in Garankuwa using 210 volunteer patients.. After signing a consent form, patients were randomized into test and control groups, balanced according to gender and time on treatment. At the end of the baseline phase (only written adherence data collection), both groups were given their stavudine tablets in an electronic monitoring (e-MuM) container (from the end of the second month). The test group received interventions in the form of a alarm watch reminder unit (end of Phase 1), followed by visual (based on e-MuM generated graphs) and verbal feedback (end of Phases 2, 3 and 4). Other adherence tools used to evaluate and compare adherence in this study included a self-assessment questionnaire for gathering quantitative and qualitative data, visual analogue scale (VAS), 2-day and 7-day recall, tablet counts and the biological markers of the patients at the start and end of the study Results: There was no statistically significant difference between demographic data of the two groups at any point during the study. The mean time on treatment of the test group patients increased relative to baseline by the end of the study, which follows a reported trend that patients who have been on treatment for longer, tend to remain in studies. The e-MuM system revealed a large scattering of adherence results in both groups. Medication taken within an hour of the correct time was regarded as "strict" adherence and that taken at any time on the correct day as "lenient" adherence. The most significant increase in mean strict adherence was from Phase 2 to Phase 4 (after two verbal and visual feedback sessions). The adherence increase for the test group was 18.8% and 14.3% for the control group. The mean strict adherence level was 36.1 % for the test group and 29.8% for the control group for the full period. The mean lenient adherence for the full period was 45.5% for the test group and for the control group it was 36.6%. The difference between the two groups in adherence increase over time, did not reach the statistically significant level of P<0.05. One of the difficulties in the study data interpretation of the self-reported adherence was due to patieilts' decanting habits. Patients were asked to state whether and how often they removed their tablets from the original container into another container (decanting). Decanting habit options included daily, weekly, no decanting and unspecified decanting habits. Patients' decanting habits varied greatly. From decanting data available for a total of 209 patients, a majority (145) reported at least two different types of decanting habits for the study period, while five patients reported every decanting habit. Patients statements on their decanting habits were compared with the data recorded by the e-MuM system, but did not correlate at an individual level and were found not reliable enough to permit adjustment of the adherence levels that were calculated by the e-MuM system. Although self-assessment adherence measures exhibited a high degree of correlation, this was in stark contrast with the data obtained from the e-MuM. The mean adherence according to the Visual Analogue Scale (VAS) for the test group and control group was 87.7% and 88.4% respectively. Some of the study participants (11%) marked their adherence out of bounds on the 10cm solid line used for VAS. Despite frequent explanations from staff, some patients were not able to understand the abstract nature of the VAS. This observation may be related to patient educational level, as the majority of study participants (82%) had an incomplete secondary education or lower. In addition, clinic staff and data collectors commented that patients did not want to admit to being non¬ adherent. The mean stated adherence with the 7-day recall was 93.6% for the test group and 92.8% for the control group patients. The 2-day recall was omitted at the end of Phase 2. Adherence measured with tablet counts could not be used as it was only available in 60% of visits by test group patients and 64% of control group patients, as a result of patients not returning their remaining tablets at follow-up visits. Although positive tendencies in biological markers (CD4 and viral load [VL]) were evident towards the end of the study, differences between the groups did not reach statistical significance. The mean increase in CD4 count in the test group over the full period was 76.2 cells/mm3 and the number of patients in the test group with VL < 400 copies/ml increased from 72% to 89%. The mean increase in CD4 count in the control group was 72.2 cells/mm3 and the number of patients with VL < 400 copies/ml increased from 65% to 75%. Conclusion: The results of the study illustrated that the e-MuM system could be integrated in a normal clinic routine but additional staff and facilities (hardware) would be needed. The e-MuM system could be particularly helpful with new or suspected non¬ adherent patients. The disadvantage of the electronic monitoring system is its ability to monitor only one drug per container. It could be used with a fixed combination single tablet regimen. Patients were positive about the reminder unit as a tool to improve adherence. Doctors had mixed opinions of the usefulness of feedback graphs in monitoring adherence. Some patients disagreed with feedback results and this may reflect the anomalies caused by the range of decanting habits. The test group reached higher average rates of adherence than the control group, as jUdged bye-MuM recorded events, but differences were not statistically significant. The e¬ MuM data do not reflect adherence as such, merely container opening patterns, which makes it difficult to interpret results. In focus groups, patients and staff expressed their views about the use of the e-MuM system. No difficulty in the ease of use was reported by patients or staff. Notwithstanding this, a large portion of patients did decant tablets for various reasons, which made calculation of true adherence rates very difficult. A group of patients suggested routine use of the e-MuM system, to keep them conscious of their medication regimen while staff suggested limited use for new patients and non-adherent patients. The size of the container was the biggest obstacle according to patients and clinic staff and a small, more portable container was suggested. The sturdiness of the e-MuM lid with the microprocessor used for the study was questionable. Recommendations: Based on the results of this study, suggestions to increase adherence and utilise the e-MuM system are offered. The ideal medication dosage interval for patients, whose adherence patterns are being monitored electronically, would be once daily. For the e-MuM system to be practical, the device (container with embedded micro chip) has to be small, portable and sturdy. Patients will have to be educated to take every dose directly from the e-MuM container. For optimal e-MuM data interpretation, patient medication taking behaviour, including decanting of tablets must be accurately identified. A trained, dedicated, sensitive person has to interpret data and give feedback to patients.

The thesis work entails a bench-to-bedside translational research approach to the development of pediatric fixed dose combination of zidovudine/lamivudine/nevirapine (60/30/50mg) orally disintegrating tablets. A simple and cost-effective, direct compression method was used. Preformulation studies that included analytical and bio-analytical assay development, excipient selection and characterization of drug-excipient interaction for initial formulation were conducted. Response surface methodology was utilized to optimize the formulation in terms of disintegration time and crushing strength. Stable ODT tablet was developed with desired friability (&lt; 1%), reasonable crushing strength, disintegration time (&lt; 30sec) and other quality attributes such as potency and dissolution. An open label randomized two-way cross-over bioequivalence of the product (with approved IRBs), conducted in 24 healthy adult volunteers, indicated the product to be bioequivalent with the innovators. 90% C.I of the point estimates of PK parameters evaluated were in the range of 80-125% as specified by FDA. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Pharmaceutics / MS; / Thesis;

No description available.

This thesis assesses factors associated with a number of short and long-term outcomes in HIV-infected patients receiving antiretroviral treatment in Asia. Analyses in this thesis were based on two cohorts of HIV-infected patients; The Treat Asia HIV Observational Database (TAHOD), a multi-centre prospective observational cohort from countries in Asia-Pacific region, and the HIV Netherlands Australia Thailand (HIV-NAT) collaboration cohort, a cohort of patients treated with antiretroviral treatments at HIV-NAT in Bangkok, Thailand. We examined factors associated with time to immunological failure endpoints, such as CD4≤ 200 cells/??L, CD4≤ 100 cells/ ??L, and CD4 return to baseline, and with the virological failure endpoint, detectable viral load defined as a value greater than 500 copies/mL. Multivariate Cox proportional hazard models were used. Results showed that CD4 count at baseline and changes in CD4 strongly predicted immunological failure. For virological failure, detectable viral load at baseline was the strongest predictor. As a step to developing simplified monitoring strategies, in which patients with a low risk of failure could have their monitoring CD4 count and viral load tests deferred, we developed predictive models for each immunological and virological failure endpoint. Models were developed on the HIV-NAT cohort, and validated on the independent TAHOD cohort. For predictive models, the complementary log-log transformation for each endpoint was fitted appropriate to the interval censored nature of the data. To assess goodness-of-fit, cut-offs were defined for the predicted risks that separated patients from low risk to high risk. Overall, the observed versus expected failures from HIV-NAT data agreed quite well across all endpoints, probably reflecting that the HIV-NAT database was the data we built the models upon. Not only did these models fit the HIV-NAT database well, they also discriminated patients from low to high risk groups. When we validated models with TAHOD data, the observed and expected failures agreed well only in the model for CD4 count return to baseline. For most of the endpoints, the predictive models overestimated the number of failures, with predicted values larger than observed. However, the proportions of failures were lowest in the low risk group and highest in the high risk group, indicating that our models did discriminate between patients at high and low risk, and that the predictive models might still be of use for the purpose of simplified monitoring strategies. With CD4 count and viral load monitoring tests now comprising a large component of the cost of HIV treatment in resource limited settings, we developed and assessed a simplified monitoring strategy that aimed to reduce the numbers of monitoring tests performed. The predictive models developed earlier were used to calculate the probabilities of failure in TAHOD patients. We assumed that patients would have their CD4 and viral load assessments annually, at baseline and at one year, predicted risk of failure at ensuing clinical visits, week 12, 24 and 36. For patients at low predicted risk of failure at ensuing clinical visits, we assessed the effect of deferring monitoring tests, both in terms of blood tests avoided, and in terms of delaying detection of failure in some patients. A number of levels for the predicted risk of failure that lead to deferral of testing were evaluated. The results suggested that predicted probabilities of failure of 10% - 20% gave the best results across all failure endpoints. These cut-offs could save a median of 598 (51.6%) (range 37 (2.6%)_-1,218 (81.9%) ) blood tests over the first year of treatment, but would fail to detect 29 (18%) (range 10 (7.4%) - 128 (39.3%) ) failures. The median time from failure to detection in those patients who did fail and had deferred monitoring tests was 28 weeks. Rates of antiretroviral treatment change in TAHOD were examined. We identified patterns and factors associated with the rate of treatment change. Median time to the first treatment change was 3.2 years. Factors predicting rate of treatment change in TAHOD were treatment combination, being on second or third combination, number of drugs available in each site and being an injecting drug user. The overall rate of treatment change in TAHOD was 29 per 1OO-person-year. Around 30% of patients stopped their treatment due to adverse events. These rates of treatment change are lower than have been seen in patients in western countries. This may be due to patients in developing countries having access to fewer antiretroviral drugs than patients in developed countries.

The spectrum of drugs used in HIV-infected patients has dramatically changed since triple antiretroviral combinations were introduced, albeit at the expense of some severe adverse events, in 1996. Long term complications of antiretroviral drug exposure, such as HIV lipodystrophy, as well as organ-specific disease of heart and bone are, therefore, a critical issue when designing antiretroviral regimens. Because it is difficult to predict the occurrence of lipodystrophy, and because there is no therapeutic agents able to combat lipodystrophy once established, avoidance of thymidine nucleoside analogues remains the most useful strategy to prevent and treat lipoatrophy; although this approach can worsen dyslipidaemia. Metabolic syndrome can and should be assessed as it predicts type 2 diabetes as well as cardiovascular events in HIV-infected individuals. Ongoing HIV replication is a risk factor for serious non-AIDS events including cardiovascular disease, as well as for AIDS. Therefore, HIV RNA suppression is imperative in all patients requiring antiretroviral therapy. Finally, HIV-infected adults on antiretroviral therapy, particularly in those receiving a boosted protease inhibitor, have a high prevalence of low bone mineral density. The estimation of fracture risk with the WHO FRAXTM tool deserves further validation in HIV-infected adults.

This thesis assesses factors associated with a number of short and long-term outcomes in HIV-infected patients receiving antiretroviral treatment in Asia. Analyses in this thesis were based on two cohorts of HIV-infected patients; The Treat Asia HIV Observational Database (TAHOD), a multi-centre prospective observational cohort from countries in Asia-Pacific region, and the HIV Netherlands Australia Thailand (HIV-NAT) collaboration cohort, a cohort of patients treated with antiretroviral treatments at HIV-NAT in Bangkok, Thailand. We examined factors associated with time to immunological failure endpoints, such as CD4≤ 200 cells/??L, CD4≤ 100 cells/ ??L, and CD4 return to baseline, and with the virological failure endpoint, detectable viral load defined as a value greater than 500 copies/mL. Multivariate Cox proportional hazard models were used. Results showed that CD4 count at baseline and changes in CD4 strongly predicted immunological failure. For virological failure, detectable viral load at baseline was the strongest predictor. As a step to developing simplified monitoring strategies, in which patients with a low risk of failure could have their monitoring CD4 count and viral load tests deferred, we developed predictive models for each immunological and virological failure endpoint. Models were developed on the HIV-NAT cohort, and validated on the independent TAHOD cohort. For predictive models, the complementary log-log transformation for each endpoint was fitted appropriate to the interval censored nature of the data. To assess goodness-of-fit, cut-offs were defined for the predicted risks that separated patients from low risk to high risk. Overall, the observed versus expected failures from HIV-NAT data agreed quite well across all endpoints, probably reflecting that the HIV-NAT database was the data we built the models upon. Not only did these models fit the HIV-NAT database well, they also discriminated patients from low to high risk groups. When we validated models with TAHOD data, the observed and expected failures agreed well only in the model for CD4 count return to baseline. For most of the endpoints, the predictive models overestimated the number of failures, with predicted values larger than observed. However, the proportions of failures were lowest in the low risk group and highest in the high risk group, indicating that our models did discriminate between patients at high and low risk, and that the predictive models might still be of use for the purpose of simplified monitoring strategies. With CD4 count and viral load monitoring tests now comprising a large component of the cost of HIV treatment in resource limited settings, we developed and assessed a simplified monitoring strategy that aimed to reduce the numbers of monitoring tests performed. The predictive models developed earlier were used to calculate the probabilities of failure in TAHOD patients. We assumed that patients would have their CD4 and viral load assessments annually, at baseline and at one year, predicted risk of failure at ensuing clinical visits, week 12, 24 and 36. For patients at low predicted risk of failure at ensuing clinical visits, we assessed the effect of deferring monitoring tests, both in terms of blood tests avoided, and in terms of delaying detection of failure in some patients. A number of levels for the predicted risk of failure that lead to deferral of testing were evaluated. The results suggested that predicted probabilities of failure of 10% - 20% gave the best results across all failure endpoints. These cut-offs could save a median of 598 (51.6%) (range 37 (2.6%)_-1,218 (81.9%) ) blood tests over the first year of treatment, but would fail to detect 29 (18%) (range 10 (7.4%) - 128 (39.3%) ) failures. The median time from failure to detection in those patients who did fail and had deferred monitoring tests was 28 weeks. Rates of antiretroviral treatment change in TAHOD were examined. We identified patterns and factors associated with the rate of treatment change. Median time to the first treatment change was 3.2 years. Factors predicting rate of treatment change in TAHOD were treatment combination, being on second or third combination, number of drugs available in each site and being an injecting drug user. The overall rate of treatment change in TAHOD was 29 per 1OO-person-year. Around 30% of patients stopped their treatment due to adverse events. These rates of treatment change are lower than have been seen in patients in western countries. This may be due to patients in developing countries having access to fewer antiretroviral drugs than patients in developed countries.

This thesis assesses factors associated with a number of short and long-term outcomes in HIV-infected patients receiving antiretroviral treatment in Asia. Analyses in this thesis were based on two cohorts of HIV-infected patients; The Treat Asia HIV Observational Database (TAHOD), a multi-centre prospective observational cohort from countries in Asia-Pacific region, and the HIV Netherlands Australia Thailand (HIV-NAT) collaboration cohort, a cohort of patients treated with antiretroviral treatments at HIV-NAT in Bangkok, Thailand. We examined factors associated with time to immunological failure endpoints, such as CD4≤ 200 cells/??L, CD4≤ 100 cells/ ??L, and CD4 return to baseline, and with the virological failure endpoint, detectable viral load defined as a value greater than 500 copies/mL. Multivariate Cox proportional hazard models were used. Results showed that CD4 count at baseline and changes in CD4 strongly predicted immunological failure. For virological failure, detectable viral load at baseline was the strongest predictor. As a step to developing simplified monitoring strategies, in which patients with a low risk of failure could have their monitoring CD4 count and viral load tests deferred, we developed predictive models for each immunological and virological failure endpoint. Models were developed on the HIV-NAT cohort, and validated on the independent TAHOD cohort. For predictive models, the complementary log-log transformation for each endpoint was fitted appropriate to the interval censored nature of the data. To assess goodness-of-fit, cut-offs were defined for the predicted risks that separated patients from low risk to high risk. Overall, the observed versus expected failures from HIV-NAT data agreed quite well across all endpoints, probably reflecting that the HIV-NAT database was the data we built the models upon. Not only did these models fit the HIV-NAT database well, they also discriminated patients from low to high risk groups. When we validated models with TAHOD data, the observed and expected failures agreed well only in the model for CD4 count return to baseline. For most of the endpoints, the predictive models overestimated the number of failures, with predicted values larger than observed. However, the proportions of failures were lowest in the low risk group and highest in the high risk group, indicating that our models did discriminate between patients at high and low risk, and that the predictive models might still be of use for the purpose of simplified monitoring strategies. With CD4 count and viral load monitoring tests now comprising a large component of the cost of HIV treatment in resource limited settings, we developed and assessed a simplified monitoring strategy that aimed to reduce the numbers of monitoring tests performed. The predictive models developed earlier were used to calculate the probabilities of failure in TAHOD patients. We assumed that patients would have their CD4 and viral load assessments annually, at baseline and at one year, predicted risk of failure at ensuing clinical visits, week 12, 24 and 36. For patients at low predicted risk of failure at ensuing clinical visits, we assessed the effect of deferring monitoring tests, both in terms of blood tests avoided, and in terms of delaying detection of failure in some patients. A number of levels for the predicted risk of failure that lead to deferral of testing were evaluated. The results suggested that predicted probabilities of failure of 10% - 20% gave the best results across all failure endpoints. These cut-offs could save a median of 598 (51.6%) (range 37 (2.6%)_-1,218 (81.9%) ) blood tests over the first year of treatment, but would fail to detect 29 (18%) (range 10 (7.4%) - 128 (39.3%) ) failures. The median time from failure to detection in those patients who did fail and had deferred monitoring tests was 28 weeks. Rates of antiretroviral treatment change in TAHOD were examined. We identified patterns and factors associated with the rate of treatment change. Median time to the first treatment change was 3.2 years. Factors predicting rate of treatment change in TAHOD were treatment combination, being on second or third combination, number of drugs available in each site and being an injecting drug user. The overall rate of treatment change in TAHOD was 29 per 1OO-person-year. Around 30% of patients stopped their treatment due to adverse events. These rates of treatment change are lower than have been seen in patients in western countries. This may be due to patients in developing countries having access to fewer antiretroviral drugs than patients in developed countries.