Joseph Sempa

Evaluating the cost-effectiveness of combination antiretroviral therapy for the prevention of mother-to-child transmission of HIV in Uganda

Introduction The mother-to-child transmission of human immunodeficiency virus (HIV) poses a substantial risk in sub-Saharan Africa. (1) There are approximately 12 million HIV-positive women of childbearing age in sub-Saharan Africa (2) who every year account for an estimated 1.4 million pregnancies at risk of mother-to-child transmission. (3) In Uganda, a country with the second highest fertility rate in the world (6.7 children per woman), approximately 91000 infants are born annually to HIV-positive women. Only 51.6% of these women receive any intervention for the prevention of mother-to-child transmission (PMTCT), although the corresponding target coverage set by the General Assembly of the United Nations is 80%) (2,4,5) In 2009, mother-to-child transmission accounted for approximately 24% of the 110 000 new HIV infections that occurred in Uganda. (2,4) Of the Ugandan women who received any antiretroviral drug for PMTCT in 2009, 58% received single-dose nevirapine, 25% received dual therapy with zidovudine and lamivudine and the remaining 17% received combination antiretroviral therapy (ART). (4) In the PMTCT guidelines that were published by the World Health Organization (WHO) in 2010, two programmatic options (A and B) are outlined. In Option B, all pregnant women found to have fewer than 350 CD4+ T-lymphocytes per [mm.sup.3] are offered lifelong ART from week 14 of gestation. For women with higher CD4+ cell counts, it is recommended that ART be discontinued at the end of breastfeeding. (6) In 2011, Uganda adopted Option B, and all Ugandan health facilities are expected to follow this protocol once adequate resources are made available. (7) No published studies have evaluated the cost-effectiveness of lifelong ART for PMTCT. In the present study, mathematical models were used to evaluate: (i) the cost-effectiveness of ART for PMTCT in Uganda relative to that of other antiretroviral strategies for PMTCT; (ii) the implications of lifelong ART for eligible women from the standpoint of health economics; and (iii) the cost-effectiveness of increasing access to ART for PMTCT. Methods We developed a decision-based analytical model from the perspective of the Ugandan national health system. Four PMTCT alternatives (ART, single-dose nevirapine, dual therapy or no treatment) were evaluated at the decision point. The model included one chance event node that was populated according to estimates of the transmission risk associated with each PMTCT alternative. The only clinical outcome included in the model was mother-to-child transmission of HIV. Estimates of the disability-adjusted life years (DALYs) associated with one case of mother-to-child transmission were based on the HIV-attributable reduction in life expectancy plus standard disability weights for HIV infection and acquired immunodeficiency syndrome (AIDS). Estimates of the treatment costs for single-dose nevirapine and dual therapy included only the costs of drug acquisition; any potential costs for physician visits or laboratory examinations were excluded. For ART, however, we included both the costs of drug acquisition and the costs associated with regular physician and laboratory follow-ups. In the comparison of ART with no treatment, we assumed that incremental resources (e.g. overhead and capital costs needed to provide extra healthcare facilities and equipment) would be required to make ART available to the currently untreated populations. Based on the differences in the probability of mother-to-child transmission with each treatment alternative, we calculated the treatment-related cost offsets arising from the need to provide health-care services to fewer HIV-positive infants in the future. Two mathematical models (1a and 1b) were explored in an initial analysis and two more (2a and 2b) were investigated in a second analysis. In Model 1a we evaluated the cost-effectiveness of an 18-month course of ART (relative to that of single-dose nevirapine or dual therapy for 7 weeks in women who already have access to drugs for PMTCT). …

Evaluation of WHO Criteria for Viral Failure in Patients on Antiretroviral Treatment in Resource-Limited Settings

Our objective was to evaluate outcomes in patients with sustained viral suppression compared to those with episodes of viremia. Methods. In a prospective cohort of patients started on ART in Uganda and followed for 48 months, patients were categorized according to viral load (VL): (1) sustained-suppression: (VL ≤1,000 copies/mL) (2) VL 1,001–10,000, or (3) VL >10,000. Results. Fifty-Three (11.2%) and 84 (17.8%) patients had a first episode of intermediate and high viremia, respectively. Patients with sustained suppression had better CD4+ T cell count increases over time compared to viremic patients (P < .001). The majority of patients with viremia achieved viral suppression when the measurement was repeated. Only 39.6% of patients with intermediate and 19.1% with high viremia eventually needed to be switched to second line (P = .008). Conclusions. The use of at least one repeat measurement rather than a single VL measurement could avert from 60% to 80% of unnecessary switches.

Prevalence of HIV-Associated Metabolic Abnormalities among Patients Taking First-Line Antiretroviral Therapy in Uganda.

Introduction. While the introduction of highly active antiretroviral therapy decreased HIV-related morbidity and mortality rates in the sub-Saharan Africa, a subsequent increase in metabolic abnormalities has been observed. We sought to determine the prevalence of HIV-associated metabolic abnormalities among patients on first-line antiretroviral therapy (ART) in an ART clinic in Kampala, Uganda. Methods. Four hundred forty-two consecutive patients on first-line ART for at least 12 months were screened for eligibility in a cross-sectional study, and 423 were enrolled. Pre-ART patient characteristics were abstracted from medical charts, examinations included anthropometric measurement and physical assessment for lipodystrophy. Results. The prevalence of hyperglycemia and dyslipidemia was 16.3% (69/423) and 81.5% (345/423), respectively. Prevalence of dyslipidemia between stavudine- and zidovudine-based regimens (91% versus 72%; P < 0.001). Being on stavudine (aOR 4.79, 95%, 2.45–9.38) and peak body weight (aOR 1.44, 95% CI 1.05–1.97) were independent risk factors for dylipidemia. Stavudine (aOR 0.50, 95% CI  0.27–0.93) use was associated with lower risk for hyperglycemia while, and older age (aOR 1.31, 95% CI 1.11–1.56) and having a family history of DM (aOR 2.18, 95% CI 1.10–4.34) were independent risk factors for hyperglycemia. Conclusions. HIV-associated metabolic complications were prevalent among patients on thymidine analogue-containing ART regimens. Screening for lipid and glucose abnormalities should be considered in ART patients because of cardiovascular risks.

Outcomes in a Cohort of Patients Started on Antiretroviral Treatment and Followed up for a Decade in an Urban Clinic in Uganda

Background Short-medium term studies from sub-Saharan Africa show that, despite high early mortality, substantial loss to program, and high rates toxicity, patients on antiretroviral treatment have achieved outcomes comparable to those in developed settings. However, these studies were unable to account for long term outcomes of patients as they stayed longer on treatment. Objectives We aim to describe ten years outcomes of one of the first cohort of HIV positive patients started on antiretroviral treatment (ART) in Sub-Saharan Africa. Methods We report 10-years outcomes including mortality, retention, CD4-count response, virological outcomes, ART regimens change from a prospective cohort of 559 patients initiating ART and followed up for 10 years Uganda. Results Of 559 patients, 69.1% were female, median age (IQR) was 38 (33–44) years, median CD4-count (IQR) 98 (21–163) cell/μL; 74% were started on stavudine, lamivudine and nevirapine, 26% on zidovudine, lamivudine and efavirenz. After 10 years 361 (65%) patients were still in the study; 127 (22.7%) had died; 30 (5%) were lost to follow-up; 27 (5%) transferred; 18 (3%) withdrew consent. The probability of death was high in the first year (0.15, 95%, CI 0.12–0.18). The median CD4 count increased from 98 to 589 cell/μL (IQR: 450–739 cell/μL) with a median increase of 357 cells/μL (IQR: 128–600 cells/μL); 7.4% never attained initial viral suppression and of those who did 31.7% experienced viral failure. Three hundred and two patients had at least one drug substitution while on first line after a median of 40 months; 66 (11.9%) of the patients were switched to a second line PI-based regimen due to confirmed treatment failure. Conclusions Despite the high rate of early mortality due to advanced disease at presentation the outcomes from this cohort are encouraging, particularly the remarkable and incremental immune-recovery and a satisfactory rate of virologic suppression.

Mortality and immunological recovery among older adults on antiretroviral therapy at a large urban HIV clinic in Kampala, Uganda

Background:We describe older (>50 years) HIV-infected adults after antiretroviral therapy (ART) initiation, evaluating immunological recovery by age category, considering individual trajectories based on the pretreatment CD4. We also describe mortality on ART and its risk factors by age category including the contribution of poor immunological recovery at a large urban clinic in Kampala, Uganda. Methods:We performed a cohort analysis of adult (>18 years) HIV-infected patients who initiated ART between January 1, 2004 and January 3, 2012. Immunological response was evaluated using mixed-effects linear regression. We described mortality using Kaplan–Meier survival methods analyzing for risk factors of mortality using multivariate Weibull survival regression stratified by age category. Results:Among 9806 individuals who initiated ART, mean age was 37 years (SD: 8.8), average follow-up 5.7 years (SD: 1.7), and median baseline CD4 was 115 cells per cubic millimeter (interquartile range: 42–184). Adults younger than 50 years had on average a higher CD4 increase of 45 cells per cubic millimeter (95% confidence interval: 17 to 72; P = 0.001) compared with counterparts aged 60 years and older. Mortality was highest among older adults compared with younger counterparts. Only CD4 count <100 cells per cubic millimeter after 1 year on ART and a CD4 count less than baseline were associated with a statistically significant higher rate of death among older adults. Conclusions:Older adults had a slower immunological response, which was associated with mortality, but this mortality was not typically associated with opportunistic infections. Future steps would require more evaluation of possible causes of death among these older individuals if survival on ART is to be further improved.

Is CD4 Monitoring Needed Among Ugandan Clients Achieving a Virologic and Immunologic Response to Treatment

It is unclear whether ongoing CD4 monitoring is needed following immunologic and virologic response to antiretroviral therapy (ART). We investigated the proportion of clients who achieved a virologic and immunologic response and then had a subsequent CD4 count <200 cells/μL despite continued virologic suppression. Included in this analysis were clients receiving ART through the Rakai Health Sciences Program between June 2004-May 2013 who achieved a CD4 ≥200 cells/μL and VL ≤400 copies/mL and who had three sets of CD4 and VL measurements (defined as a sequence) within a 390 day period. A CD4 decline was defined as any drop in CD4 count to <200 cells/μL during a period of viral suppression. A total of 1553 clients were included, 68% females, mean age of 35.5 years (SD 8.3), median baseline CD4 count 183 cells/μL (IQR 106-224). 43 (2.8%) clients developed CD4 declines, the majority, 32/43 (74%), among individuals whose initial CD4 was <300 cells/μL. Of the 43 clients with CD4 declines, 24 had an additional CD4 measurement and 20/24 (83%) achieved a CD4 ≥200 cell/μL on their next measurement (median 285 cells/μL; IQR 220-365). CD4 declines were significantly greater among those with lower CD4 at sequence initiation [adjusted hazard ratio (AHR) 4.3 (95% CI 2.1, 9.0) CD4 200-249 versus ≥350 cells/μL]. Clients who achieved an immunologic and virologic response to ART were unlikely to experience a subsequent CD4 count decline to <200 cells/μL, and among those experiencing a decline, the majority were transient in nature. Thus, ongoing CD4 monitoring could be omitted.

Operational implementation of LED fluorescence microscopy in screening tuberculosis suspects in an urban HIV clinic in Uganda.

Background Light emitting diode (LED) fluorescence microscopy (FM) is an affordable, technology targeted for use in resource-limited settings and recommended for widespread roll-out by the World Health Organization (WHO). We sought to compare the operational performance of three LED FM methods compared to light microscopy in a cohort of HIV-positive tuberculosis (TB) suspects at an urban clinic in a high TB burden country. Methods Two spot specimens collected from TB suspects were included in the study. Smears were stained using auramine O method and read after blinding by three LED-based FM methods by trained laboratory technicians in the Infectious Diseases Institutelaboratory. Leftover portions of the refrigerated sputum specimens were transported to the FIND Tuberculosis Research Laboratory for Ziehl Neelsen (ZN) smear preparation and reading by experienced technologist as well as liquid and solid culture. Results 174 of 627 (27.8%) specimens collected yielded one or more positive mycobacterial cultures. 94.3% (164/174) were M. tuberculosis complex. LED FM was between 7.3–11.0% more sensitive compared to ZN microscopy. Of the 592 specimens examined by all microscopy methods, there was no significant difference in sensitivity between the three LED FM methods. The specificity of the LED FM methods was between 6.1% and 7.7% lower than ZN microscopy (P<0.001), although exclusion of the single poor reader resulted in over 98% specificity for all FM methods. Conclusions Laboratory technicians in routine settings can be trained to use FM which is more sensitive than ZN microscopy. Despite rigorous proficiency testing, there were operator-dependent accuracy issues which highlight the critical need for intensive quality assurance procedures during LED FM implementation. The low sensitivity of FM for HIV-positive individuals particularly those with low CD4 T cell counts, will limit the number of additional patients found by LED FM in countries with high rates of HIV co-infection.

Evaluation of in-house PCR for diagnosis of smear-negative pulmonary tuberculosis in Kampala, Uganda

BackgroundNucleic acid amplification tests (NAATs) have offered hope for rapid diagnosis of tuberculosis (TB). However, their efficiency with smear-negative samples has not been widely studied in low income settings. Here, we evaluated in-house PCR assay for diagnosis of smear-negative TB using Lowenstein-Jensen (LJ) culture as the baseline test. Two hundred and five pulmonary TB (PTB) suspects with smear-negative sputum samples, admitted on a short stay emergency ward at Mulago Hospital in Kampala, Uganda, were enrolled. Two smear-negative sputum samples were obtained from each PTB suspect and processed simultaneously for identification of MTBC using in-house PCR and LJ culture.ResultsSeventy two PTB suspects (35%, 72/205) were LJ culture positive while 128 (62.4%, 128/205) were PCR-positive. The sensitivity and specificity of in-house PCR for diagnosis of smear-negative PTB were 75% (95% CI 62.6-85.0) and 35.9% (95% CI 27.2-45.3), respectively. The positive and negative predictive values were 39% (95% CI 30.4-48.2) and 72.4% (95% CI 59.1-83.3), respectively, while the positive and negative likelihood ratios were 1.17 (95% CI 0.96-1.42) and 0.70 (95% CI 0.43-1.14), respectively. One hundred and seventeen LJ culture-negative suspects (75 PCR-positive and 42 PCR-negative) were enrolled for follow-up at 2 months. Of the PCR-positive suspects, 45 (60%, 45/75) were still alive, of whom 29 (64.4%, 29/45) returned for the follow-up visit; 15 (20%, 15/75) suspects died while another 15 (20%, 15/75) were lost to follow-up. Of the 42 PCR-negative suspects, 22 (52.4%, 22/42) were still alive, of whom 16 (72.7%, 16/22) returned for follow-up; 11 (26.2%, 11/42) died while nine (21.4%, 9/42) were lost to follow-up. Overall, more PCR-positive suspects were diagnosed with PTB during follow-up visits but the difference was not statistically significant (27.6%, 8/29 vs. 25%, 4/16, p = 0.9239). Furthermore, mortality was higher for the PCR-negative suspects but the difference was also not statistically significant (26.2% vs. 20% p = 0.7094).ConclusionIn-house PCR correlates poorly with LJ culture for diagnosis of smear-negative PTB. Therefore, in-house PCR may not be adopted as an alternative to LJ culture.

Cost-effectiveness of early initiation of first-line combination antiretroviral therapy in Uganda

BackgroundUgandan national guidelines recommend initiation of combination antiretroviral therapy (cART) at CD4+ T cell (CD4) count below 350 cell/μl, but the implementation of this is limited due to availability of medication. However, cART initiation at higher CD4 count increases survival, albeit at higher lifetime treatment cost. This analysis evaluates the cost-effectiveness of initiating cART at a CD4 count between 250–350 cell/μl (early) versus <250 cell/μl (delayed).MethodsLife expectancy of cART-treated patients, conditional on baseline CD4 count, was modeled based on published literature. First-line cART costs

Among Patients with Sustained Viral Suppression in a Resource-Limited Setting, CD4 Gains Are Continuous Although Gender-Based Differences Occur

192 annually, with an additional