Dolutegravir or Darunavir in Combination with Zidovudine or Tenofovir to Treat HIV.

BACKGROUND: The World Health Organization recommends dolutegravir with two nucleoside reverse-transcriptase inhibitors (NRTIs) for second-line treatment of human immunodeficiency virus type 1 (HIV-1) infection. Evidence is limited for the efficacy of this regimen when NRTIs are predicted to lack activity because of drug resistance, as well as for the recommended switch of an NRTI from tenofovir to zidovudine. METHODS: In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points). RESULTS: We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, -1.5 percentage points; 95% confidence interval [CI], -6.7 to 3.7; P = 0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, -2.6 to 7.9; P = 0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison. CONCLUSIONS: Dolutegravir in combination with NRTIs was effective in treating patients with HIV-1 infection, including those with extensive NRTI resistance in whom no NRTIs were predicted to have activity. Tenofovir was noninferior to zidovudine as second-line therapy. (Funded by Janssen; NADIA ClinicalTrials.gov number, NCT03988452.).

Plasmodium falciparum genetic diversity and multiplicity of infection based on msp-1, msp-2, glurp and microsatellite genetic markers in sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: In sub-Saharan Africa (SSA), Plasmodium falciparum causes most of the malaria cases. Despite its crucial roles in disease severity and drug resistance, comprehensive data on Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) are sparse in SSA. This study summarizes available information on genetic diversity and MOI, focusing on key markers (msp-1, msp-2, glurp, and microsatellites). The systematic review aimed to evaluate their influence on malaria transmission dynamics and offer insights for enhancing malaria control measures in SSA. METHODS: The review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Two reviewers conducted article screening, assessed the risk of bias (RoB), and performed data abstraction. Meta-analysis was performed using the random-effects model in STATA version 17. RESULTS: The review included 52 articles: 39 cross-sectional studies and 13 Randomized Controlled Trial (RCT)/cohort studies, involving 11,640 genotyped parasite isolates from 23 SSA countries. The overall pooled mean expected heterozygosity was 0.65 (95% CI: 0.51-0.78). Regionally, values varied: East (0.58), Central (0.84), Southern (0.74), and West Africa (0.69). Overall pooled allele frequencies of msp-1 alleles K1, MAD20, and RO33 were 61%, 44%, and 40%, respectively, while msp-2 I/C 3D7 and FC27 alleles were 61% and 55%. Central Africa reported higher frequencies (K1: 74%, MAD20: 51%, RO33: 48%) than East Africa (K1: 46%, MAD20: 42%, RO33: 31%). For msp-2, East Africa had 60% and 55% for I/C 3D7 and FC27 alleles, while West Africa had 62% and 50%, respectively. The pooled allele frequency for glurp was 66%. The overall pooled mean MOI was 2.09 (95% CI: 1.88-2.30), with regional variations: East (2.05), Central (2.37), Southern (2.16), and West Africa (1.96). The overall prevalence of polyclonal Plasmodium falciparum infections was 63% (95% CI: 56-70), with regional prevalences as follows: East (62%), West (61%), Central (65%), and South Africa (71%). CONCLUSION: The study shows substantial regional variation in Plasmodium falciparum parasite genetic diversity and MOI in SSA. These findings suggest a need for malaria control strategies and surveillance efforts considering regional-specific factors underlying Plasmodium falciparum infection.

Blood glucose outcomes of anti-retroviral therapy naïve Ugandan people with HIV with pre-diabetes mellitus initiated on dolutegravir for 48 weeks.

BACKGROUND: The Uganda ministry of Health recommends frequent blood glucose monitoring for the first six months on dolutegravir, in people with HIV (PWH) having pre-diabetes mellitus (pre-DM). We sought to determine if indeed PWH with pre-diabetes started on dolutegravir had worse blood glucose outcomes at 48 weeks compared to those with normal blood glucose. METHODS: In this matched cohort study, we compared 44 PWH with pre-DM and 88 PWH with normal blood glucose at baseline. The primary outcome was change in mean fasting blood glucose (FBG) from baseline to week 48 and 2-hour blood glucose (2hBG) from baseline to week 36 compared between the two groups. RESULTS: There was significant increase in FBG in PWH with normal blood glucose (mean change in FBG(FBG): 3.9 mg/dl, 95% confidence interval (95% CI): (2.2, 5.7), p value (p) = < 0.0001) and decrease in those with pre-DM (FBG: -6.1 mg/dl, 95%CI (-9.1, -3.2), p = < 0.0001) at 48 weeks. 2hBG was significantly lower than at baseline in both groups with the magnitude of reduction larger in those with pre-DM at 12 weeks (adjusted differences in mean drop in 2hBG (a2hBG): -19.69 mg/dl, 95%CI (-30.19, -9.19), p = < 0.0001) and 36 weeks (a2hBG: -19.97 mg/dl, 95%CI (-30.56, -9.39), p = < 0.0001). CONCLUSION: We demonstrated that Ugandan ART naïve PWH with pre-diabetes at enrollment have consistent improvement in both fasting blood glucose and glucose tolerance over 48 weeks on dolutegravir. Intensified blood glucose monitoring of these patients in the first six months of dolutegravir may be unnecessary.

Dyslipidemia among adult people living with HIV on dolutegravir - based antiretroviral therapy at a private tertiary hospital in Kampala, Uganda: burden and determinants.

BACKGROUND: Understanding the burden of dyslipidemia and its associated factors among adult people living with HIV on dolutegravir (DTG) based anti-retroviral therapy (ART) is critical to provide clinical guidance and risk reduction strategies in our setting. METHODS: We conducted a cross-sectional study on adult people living with HIV on DTG based ART between July and August 2022 at Mengo Hospital, a private not for profit missionary hospital owned by the Church of Uganda. Dyslipidemia was defined as: Total cholesterol (TC) ≥ 5.2 mmol/l, or high-density lipoprotein (HDL) < 1 mmol/l for men and < 1.3 mmol/l for women, or triglycerides (TG) ≥ 1.7 mmol/l, and low-density lipoprotein (LDL) ≥ 3.4 mmol/l. A participant was considered to have dyslipidemia if they had any of the lipid profile parameters in the above ranges. Socio-demographic information, clinical data and behavioral characteristics were collected. Fasting lipid profile and fasting blood glucose levels were also measured. Bivariate and multivariate analyses were done using a generalized linear model regression of the Poisson family with a log link (modified Poisson) using robust standard errors since the prevalence of dyslipidemia was more than 10%. Adjusted prevalence ratios (PR) were reported with their 95% confidence intervals (CI). A p-value of less than 0.05 was considered statistically significant. RESULTS: A total of 341 participants were included. The prevalence of dyslipidemia was 78.0%, (95%CI:73.3-82.1). The highest prevalence was for low HDL (72.1%, 95%CI 67.1-76.7) followed by high TG (20.2%, 95%CI: 16.3-24.9), high TC (12.0%, 95%CI: 9.0-15.9) and high LDL (6.5%, 95%CI: 4.3-9.6). Female sex (aPR:1.55, 95%CI: 1.32-1.84, p < 0.001) and previous use of protease inhibitor (PI) based ART regimen (aPR:1.26, 95%CI: 1.04-1.53, p = 0.018) were significantly associated with dyslipidemia. CONCLUSION: We demonstrate that the prevalence of dyslipidemia is very high as it was present in more than three quarters of the study participants. Female sex and previous use of PI based ART regimen were significantly associated with dyslipidemia. Management of dyslipidemia should be integrated in the HIV treatment package and we recommend further inquiry into the temporal relationship between dyslipidemia and DTG among ART patients, if any.

Prevalence of overweight and obesity among adolescents living with HIV after dolutegravir - based antiretroviral therapy start in Kampala, Uganda.

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is currently the preferred first-line treatment for persons living with HIV (PLHIV) including children and adolescents in many low- and middle-income countries including Uganda. However, there are concerns about excessive weight gain associated with DTG especially in adults. There remains paucity of current information on weight-related outcomes among adolescents on DTG. We determined the prevalence of excessive weight gain and associated factors among adolescents living with HIV (ALHIV) receiving DTG-based ART in Kampala, Uganda. METHODS: Cross-sectional study involving ALHIV aged 10-19 years on DTG-based ART for at least one year were recruited from public health facilities in Kampala between February and May 2022. Excessive weight gain was defined as becoming overweight or obese per body mass index (BMI) norms while on DTG-based ART for at least one year. Demographic, clinical and laboratory data were collected using interviewer-administered questionnaires and data extracted from medical records. At enrolment, blood pressure and anthropometry were measured and blood was drawn for blood glucose and lipid profile. Data was summarised using descriptive statistics and logistic regression was performed to determine the associated factors. RESULTS: We enrolled 165 ALHIV with a median age of 14 years (IQR 12-16). Eighty (48.5%) were female. The median duration on ART and DTG was 8 years (IQR 7-11) and 2 years (IQR 1-3) respectively. At DTG initiation, the majority of participants (152/165, 92.1%) were ART-experienced, and had normal BMI (160/165, 97%). Overall, 12/165 (7.3%) adolescents (95% CI: 4.2-12.4) had excessive weight gain. No factors were significantly associated with excessive weight gain after DTG start in ALHIV. However, all ALHIV with excessive weight gain were females. CONCLUSION: Our study found a prevalence of 7.3% of overweight and obesity in ALHIV after initiating DTG. We did not find any factor significantly associated with excessive weight gain in ALHIV on DTG. Nonetheless, we recommend ongoing routine monitoring of anthropometry and metabolic markers in ALHIV as DTG use increases globally, to determine the exact magnitude of excessive weight gain and to identify those at risk of becoming overweight or obese while taking the medication.

Same-Day Antiretroviral Therapy Initiation as a Predictor of Loss to Follow-up and Viral Suppression Among People With Human Immunodeficiency Virus in Sub-Saharan Africa.

BACKGROUND: Treat-All guidelines recommend initiation of antiretroviral therapy (ART) for all people with HIV (PWH) on the day of diagnosis when possible, yet uncertainty exists about the impact of same-day ART initiation on subsequent care engagement. We examined the association of same-day ART initiation with loss to follow-up and viral suppression among patients in 11 sub-Saharan African countries. METHODS: We included ART-naive adult PWH from sites participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium who enrolled in care after Treat-All implementation and prior to January 2019. We used multivariable Cox regression to estimate the association between same-day ART initiation and loss to follow-up and Poisson regression to estimate the association between same-day ART initiation and 6-month viral suppression. RESULTS: Among 29 017 patients from 63 sites, 18 584 (64.0%) initiated ART on the day of enrollment. Same-day ART initiation was less likely among those with advanced HIV disease versus early-stage disease. Loss to follow-up was significantly lower among those initiating ART ≥1 day of enrollment, compared with same-day ART initiators (20.6% vs 27.7%; adjusted hazard ratio: .66; 95% CI .57-.76). No difference in viral suppression was observed by time to ART initiation (adjusted rate ratio: 1.00; 95% CI: .98-1.02). CONCLUSIONS: Patients initiating ART on the day of enrollment were more frequently lost to follow-up than those initiating later but were equally likely to be virally suppressed. Our findings support recent World Health Organization recommendations for providing tailored counseling and support to patients who accept an offer of same-day ART.

Survival and predictors of mortality after completion of TB treatment among people living with HIV: a 5-year analytical cohort.

BACKGROUND: After completion of TB treatment patients may remain at risk of co-morbidity and mortality. We determined the survival and predictors of all-cause mortality after completing TB treatment among ART-experienced patients. METHODS: This was a retrospective cohort analysis of all ART experienced patients who completed TB treatment at a specialist HIV clinic in Uganda, between 2009 and 2014. The patients were followed for five years after TB treatment. We determined the cumulative probability of death, and predictors of mortality using Kaplan-Meier methods and Cox proportional hazard models, respectively. RESULTS: A total 1,287 patients completed TB treatment between 2009 and 2014, of which 1,111 were included in the analysis. At TB treatment completion, the median age was 36 years (IQR: 31-42), 563 (50.7%) were males, and median CD4 cell count was 235 cells/mL (IQR: 139-366). The person-time at risk was 4410.60 person-years. The all-cause mortality rate was 15.42 (95% CI: 12.14-19.59) per 1000 person-years. The probability of death at five years was 6.9% (95%CI: 5.5- 8.8). In the multivariable analysis, CD4 count < 200 cells/mL was a predictor of all-cause mortality (aHR = 1.81, 95%CI:1.06-3.11, p = 0.03) alongside history of retreatment (aHR = 2.12, 95%CI: 1.16-3.85, p = 0.01). CONCLUSION: Survival post TB treatment in ART experienced PLHIV is reasonably good. Most deaths occur within two years after TB treatment completion. Patients with a low CD4 count and those with a history of retreatment have an increased risk of mortality which underscores the need for TB prophylaxis, detailed assessment, and close monitoring after completion of TB treatment.

Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? a case report.

Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization due to its favorable side effect profile, high efficacy and genetic barrier to resistance.Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, DTG as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes.Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated.We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on DTG. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.

Risk factors for unsuppressed viral load after intensive adherence counseling among HIV infected persons in Kampala, Uganda: a nested case-control study.

BACKGROUND: Intensive adherence counseling (IAC) is the global standard of care for people living with human immunodeficiency virus (PLHIV) who have unsuppressed VL after ≥ 6 months of first-line anti-retroviral therapy (ART). We investigated whether the number of IAC sessions is associated with suppressed VL among PLHIV in Kampala, Uganda. METHODS: We conducted a nested case-control study among PLHIV with unsuppressed VL after ≥ 3 IAC sessions (cases) and a 2:1 random sample of PLHIV with suppressed VL after ≥ 3 IAC sessions (controls). Unsuppressed VL was defined as VL ≥ 1000 copies/ml. We performed multivariable logistic regression to identify factors that differed significantly between cases and controls. RESULTS: Demographic and clinical characteristics were similar among the 16 cases and 32 controls including mean age, sex, baseline CD4 count, VL before IAC, and WHO clinical stage. Only the number of IAC sessions differed significantly between cases and controls in unadjusted (p = 0.012) and adjusted (p = 0.016) analyses. Each unit increase in IAC session was associated with unsuppressed VL (Adjusted odds ratio 5.09; 95% CI 1.35-19.10). CONCLUSIONS: VL remained unsuppressed despite increasing IAC frequency. The fidelity to standardized IAC protocol besides drug resistance testing among PLHIV with unsuppressed VL before IAC commencement should be examined.

Dolutegravir use over 48 weeks is not associated with worsening insulin resistance and pancreatic beta cell function in a cohort of HIV-infected Ugandan adults.

BACKGROUND: The Uganda Ministry of Health issued restrictive guidelines on the use of dolutegravir (DTG) in persons stratified to have a heightened risk of diabetes mellitus. This followed multiple reports of persons with HIV (PWH) presenting with accelerated hyperglycemia after a few weeks to months of exposure to DTG. Having demonstrated a low incidence of diabetes mellitus and improving blood glucose trajectories in a cohort of ART naïve Ugandan PWH on DTG, we sought to determine whether the observed improvement in blood glucose did not mask background compensated insulin resistance. METHODS: In this analysis, 63 patients underwent serial oral glucose tolerance tests over 48 weeks. Using fasting serum insulin and glucose, we calculated insulin resistance and pancreatic beta cell function by homeostatic modelling (HOMA IR and HOMA%ß respectively). Absolute mean changes between baseline and post-baseline blood glucose, pancreatic beta cell function and insulin resistance were computed by subtracting each post-baseline value from the baseline value and compared using student t-test. Multiple linear regression models were used to determine the factors associated with changes in pancreatic beta cell function and insulin resistance. RESULTS: Of the 63 participants, 37 (58%) were female. Median age was 31 (IQR: 28-37). Despite a trend towards an initial increase in both HOMA IR and HOMA%ß at 12 weeks followed by a decline through 36 weeks to 48 weeks, the HOMA IR and HOMA%ß at 48 weeks were not significantly different from baseline i.e. (difference in mean HOMA IR from baseline: 0.14, 95%CI: -0.46, 0.733, p = 0.648) and (difference in mean HOMA %ß from baseline: 6.7, 95%CI: -13.4, 26.8, p = 0.506) respectively. CONCLUSION: We demonstrated insignificant changes in both insulin resistance and pancreatic beta cell function in clinically stable young adult Ugandan PWH on dolutegravir for 48 weeks. We add to the body of evidence demonstrating glucose metabolic safety of dolutegravir in ART naïve patients. Ugandan guidelines should reconsider restricting DTG initiation in ART naive adults at high risk for diabetes.

Serum E-selectin and endothelial cell-specific Molecule-1 levels among people living with HIV on long term ART in Uganda: a pilot cross-sectional study.

BACKGROUND: Prolonged exposure to HIV and anti-retroviral therapy (ART) has been linked with endothelial cell activation which subsequently predisposes people living with HIV (PLWH) to cardiovascular diseases. Serum biomarkers of endothelial cell activation such as E-Selectin and endothelial cell-specific molecule-1 (ESM-1) could aid in early detection of PLWH at a risk of cardiovascular diseases. However, there is a paucity of data on these biomarkers like E-selectin and endothelial cell-specific molecule-1 (ESM-1) among PLWH on long term ART (≥ 10 years) in Uganda. The aim of this study is to determine the serum levels of these biomarkers in this population. METHODS: This was a cross-sectional study where we randomly sampled 73 stored serum samples of PLWH who were enrolled in the Infectious Diseases Institute (IDI) ART long term (ALT cohort). We measured serum levels of E-selectin and ESM-1 by ELISA. Data was summarized using median and interquartile range. Inferential statistics were performed to determine predictors of elevated levels of E-selectin. RESULTS: Of the 73 samples analyzed, 38 (52.1%) were from female participants. The mean age was 54 ± 9.0 years. Twenty participants (27.4%) had a history of smoking while 52 (71.2%) had a history of alcohol intake. Twenty-five (34.3%) of the participants were overweight whereas 4 (5.6%) were obese. Fifty-four (74%) had an undetectable viral load (≤ 0 copies/ml) and the mean duration of ART at the time of sampling (2014/2015) was 10.4 ± 0.4 years. While serum levels of ESM-1 were not detectable in any of our samples, the median E-selectin levels was 147.6 µm/L ranging from 8.44 µm/L and 1,979.36 µm/L. Sixty-seven participants (91.8%) had elevated levels of E-selectin (> 39 µm/L). CD4 count > 500 cells/µl compared to lower counts was a predictor of elevated levels of E-Selectin (adjusted Odd Ratio 12.5, 95% CI (1.03 - 149.95, p < 0.05). CONCLUSIONS: The majority (91.8%) of PLWH on long term ART had elevated levels of E-selectin. Having high CD4 count (> 500 cells/µl) was predictive of elevated levels of E-Selectin. Future work should longitudinally assess the trend of levels of E-selectin and ESM-1 while assessing for cardiovascular diseases endpoint.

Blood glucose trajectories and incidence of diabetes mellitus in Ugandan people living with HIV initiated on dolutegravir.

BACKGROUND: Following reports of anti-retroviral therapy (ART) experienced Ugandan people living with HIV (PLHIV) presenting with diabetic ketoacidosis weeks to months following a switch to dolutegravir (DTG), the Uganda Ministry of Health recommended withholding DTG in both ART naïve and experienced PLHIV with diabetes mellitus (T2DM), as well as 3-monthly blood glucose monitoring for patients with T2DM risk factors. We sought to determine if the risk of T2DM is indeed heightened in nondiabetic ART naïve Ugandan PLHIV over the first 48 weeks on DTG. METHODS: Between January and October 2021, 243 PLHIV without T2DM were initiated on DTG based ART for 48 weeks. Two-hour oral glucose tolerance tests (2-h OGTT) were performed at baseline, 12, and 36 weeks; fasting blood glucose (FBG) was measured at 24 and 48 weeks. The primary outcome was the incidence of T2DM. Secondary outcomes included: incidence of pre-Diabetes Mellitus (pre-DM), median change in FBG from baseline to week 48 and 2-h blood glucose (2hBG) from baseline to week 36. Linear regression models were used to determine adjusted differences in FBG and 2hBG from baseline to weeks 48 and 36 respectively. RESULTS: The incidence of T2DM was 4 cases per 1000 PY (1/243) and pre-DM, 240 cases per 1000 person years (PY) (54/243). There was a significant increase in FBG from baseline to week 48 [median change from baseline (FBG): 3.6 mg/dl, interquartile range (IQR): - 3.6, 7.2, p-value (p) = 0.005] and significant reduction in 2hBG (2hBG: - 7.26 mg/dl, IQR: - 21.6, 14.4, p = 0.024) at week 36. A high CD4 count and increased waist circumference were associated with 2hBG increase at week 36. CONCLUSION: We demonstrated a low incidence of T2DM in Ugandan ART-naïve patients receiving DTG. We also demonstrated that longitudinal changes in BG were independent of conventional risk factors of T2DM in the first 48 weeks of therapy. Restricting the use of dolutegravir in Ugandan ART naïve patients perceived to be high risk for diabetes mellitus may be unwarranted.

Relating CYP2B6 genotype and efavirenz resistance among post-partum women living with HIV with high viremia in Uganda: a nested cross-sectional study.

BACKGROUND: We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV who started on antiretroviral therapy during pregnancy and with high viremia during post-partum. METHODS: This was a cross-sectional study of women with viral loads greater than 1000 copies/ml who were at least 6 weeks postpartum. Sanger sequencing was used to detect resistant mutations, as well as host genotyping, and efavirenz resistance was compared among the metabolizer genotypes. RESULTS: Over the course of one year (July 2017-July 2018), 322 women were screened, with 110 (34.2%) having viral loads of 1000 copies/ml and 62 having whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. Efavirenz resistance according to metabolizer genotype was; 47% in slow, 34% in extensive and 28% in intermediate metabolizers, but the difference was not statistically significant due to the small sample size. CONCLUSIONS: There was no statistically significant difference in EFV resistance between EFV metabolizer genotypes in women who started antiretroviral therapy during pregnancy and had high viremia in the postpartum period. However, a numerical trend was discovered, which calls for confirmation in a large, well-designed, statistically powered study.

Disparities in Dolutegravir Uptake Affecting Females of Reproductive Age With HIV in Low- and Middle-Income Countries After Initial Concerns About Teratogenicity : An Observational Study.

BACKGROUND: The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. OBJECTIVE: To describe dolutegravir uptake and disparities by sex and age group in LMICs. DESIGN: Observational cohort study. SETTING: 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. PATIENTS: 134 672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. MEASUREMENTS: Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). RESULTS: Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. LIMITATION: Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. CONCLUSION: Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. PRIMARY FUNDING SOURCE: National Institutes of Health.

Factors associated with uptake of contraceptives among HIV positive women on dolutegravir based anti-retroviral treatment-a cross sectional survey in urban Uganda.

BACKGROUND: In May 2018, following the preliminary results of a study in Botswana that reported congenital anomalies in babies born to HIV-positive women taking dolutegravir drug, the WHO issued a teratogenicity alert. However, there are scarce data on the impact of this guidance on contraceptive uptake among women taking dolutegravir. We assessed the uptake of contraceptives in HIV-positive women of reproductive age on dolutegravir regimens. METHODS: We conducted a cross-sectional survey from April 2019 to July 2019 in five government health facilities in central Uganda, where dolutegravir-based regimens were offered as the preferred first-line antiretroviral treatment. We randomly selected 359 non-pregnant women aged 15-49 years taking dolutegravir-based regimens and interviewed them using semi-structured interviewer-administered questionnaires. We collected data on demographics, contraceptive use, individual, social, and health system factors. We described patients' characteristics using descriptive statistics and assessed factors associated with contraceptive uptake using a modified Poisson regression model. RESULTS: A total of 359 women were included in the study. The mean age was 37 years (standard deviation = 6.8) and overall contraceptive uptake was 38.4%. The most utilized method was injectable method at 58.4% followed by condoms (15%), intrauterine device (10.7%), pills (6.4%), implants (5.4%), and sterilization (0.7%). Predictors for contraceptive uptake were parity of 3-4 children (Adjusted Prevalence Ratio (APR) = 1.48, 95% confidence interval (CI): 1.14, 1.92) in reference to those with 1-2 children. There was reduced contraceptive uptake in women of the age range 40-49 years (APR = 0.45, CI: 0.21-0.94) compared to those aged 15-24 years. Unemployed women were less likely to use contraceptives (APR: 0.6, CI: 0.42- 0.94) than the formally employed. Contraceptive uptake was lower among women who did not discuss family planning with their partners (APR = 0.39, CI: 0.29-0.52) than those who discussed family planning with their partners and women who did not receive family planning counseling (APR = 0.56, CI: 0.34-0.92) than those who received family planning counselling. CONCLUSION: We observed a low-level uptake of contraceptives, with injectables as the most used method. Family planning counseling and partner discussion on family planning were associated with contraceptive uptake among the women who used dolutegravir-based regimens. There is a need for more strategies to integrate FP services and increase male involvement in HIV care programs.

Patient and health system level barriers to and facilitators for tuberculosis treatment initiation in Uganda: a qualitative study.

BACKGROUND: The WHO END TB strategy targets to place at least 90% of all patients diagnosed with Tuberculosis (TB) on appropriate treatment. In Uganda, approximately 20% of patients diagnosed with TB are not initiated on TB treatment. We sought to identify the patient and health system level barriers to and facilitators for TB treatment initiation in Uganda. METHODS: We conducted the study at ten public health facilities (three primary care, four district and three tertiary referral hospitals). We carried out in-depth interviews with patients diagnosed with TB and key informant interviews with health managers. In addition, we held focus group discussions with healthcare workers involved in TB care. Data collection and thematic analysis of transcripts was informed by the Capability, Opportunity, Motivation and Behavior (COM-B) model. We identified relevant intervention functions using the Behavior Change Wheel. RESULTS: We interviewed 79 respondents (31 patients, 10 health managers and 38 healthcare workers). Common barriers at the health facility level included; lack of knowledge about the proportion of patients not initiated on TB treatment (psychological capability); difficulty accessing sputum results from the laboratory as well as difficulty tracing patients due to inadequate recording of patient addresses (physical opportunity). At the patient level, notable barriers included long turnaround time for sputum results and lack of transport funds to return to health facilities (physical opportunity); limited TB knowledge (psychological capability) and stigma (social opportunity). The most important facilitators identified were quick access to sputum test results either on the date of first visit (same-day diagnosis) or on the date of first return and availability of TB treatment (physical opportunity). We identified education, restructuring of the service environment to improve sputum results turnaround time and enablement to improve communication of test results as relevant intervention functions to alleviate these barriers to and enhance facilitators for TB treatment initiation. CONCLUSION: We found that barriers to treatment initiation existed at both the patient and health facility-level across all levels of the (Capability, Opportunity and Motivation) model. The intervention functions identified here should be tested for feasibility.

Willingness to pay for an mHealth anti-retroviral therapy adherence and information tool: Transitioning to sustainability, Call for life randomised study experience in Uganda.

INTRODUCTION: Evidence shows benefit of digital technology for people living with human immunodeficiency virus on antiretroviral therapy adherence and retention in care, however, scalability and sustainability have scarcely been evaluated. We assessed participants' willingness to pay a fee for mHealth "Call for life Uganda" support, a mobile-phone based tool with the objective to assess sustainability and scalability. METHODS: "Call for Life study", approved by Makerere University, School of Public Health research & ethics committee, at 2 sites in Uganda, evaluated a MoTech based software "CONNECT FOR LIFE™" mHealth tool termed "Call for life Uganda". It provides short messages service or Interactive Voice Response functionalities, with a web-based interface, allows a computer to interact with humans through use of voice and tones input via keypad. Participants were randomized at 1:1 ratio to Standard of Care or standard of care plus Call for life Uganda. This sends pill reminders, visit reminders, voice messages and self-reported symptom support. At study visits 18 and 24 months, through mixed method approach we assessed mHealth sustainability and scalability. Participants were interviewed on desire to have or continue adherence support and willingness to pay a nominal fee for tool. We computed proportions willing to pay (± 95% confidence interval), stratified by study arm and predictors of willingness to continue and to pay using multivariate logistic regression model backed up by themes from qualitative interviews. RESULTS: 95% of participants were willing to continue using C4LU with 77.8% willing to pay for the service. Persons receiving care at the peri-urban clinic (OR 3.12, 95% CI 1.43-9.11.86) and those with exposure to the C4LU intervention (OR 4.2, 95% CI 1.55-11.84) were more likely to continue and pay for the service. Qualitative interviews revealed mixed feelings regarding amounts to pay, those willing to pay, argued that since they have been paying for personal phone calls/messages, they should not fail to pay for Call for life. CONCLUSIONS: Payment for the service offers opportunities to scale up and sustain mHealth interventions which may not be priorities for government funding. A co-pay model could be acceptable to PLHIV to access mHealth services in low resource settings. Clinical Trial Number NCT02953080.

Adoption of evidence-informed guidelines in prescribing protease inhibitors for HIV-Tuberculosis co-infected patients on rifampicin and effects on HIV treatment outcomes in Uganda.

BACKGROUND: We aimed to determine how emerging evidence over the past decade informed how Ugandan HIV clinicians prescribed protease inhibitors (PIs) in HIV patients on rifampicin-based tuberculosis (TB) treatment and how this affected HIV treatment outcomes. METHODS: We reviewed clinical records of HIV patients aged 13 years and above, treated with rifampicin-based TB treatment while on PIs between1st-January -2013 and 30th-September-2018 from twelve public HIV clinics in Uganda. Appropriate PI prescription during rifampicin-based TB treatment was defined as; prescribing doubled dose lopinavir/ritonavir- (LPV/r 800/200 mg twice daily) and inappropriate PI prescription as prescribing standard dose LPV/r or atazanavir/ritonavir (ATV/r). RESULTS: Of the 602 patients who were on both PIs and rifampicin, 103 patients (17.1% (95% CI: 14.3-20.34)) received an appropriate PI prescription. There were no significant differences in the two-year mortality (4.8 vs. 5.7%, P = 0.318), loss to follow up (23.8 vs. 18.9%, P = 0.318) and one-year post TB treatment virologic failure rates (31.6 vs. 30.7%, P = 0.471) between patients that had an appropriate PI prescription and those that did not. However, more patients on double dose LPV/r had missed anti-retroviral therapy (ART) days (35.9 vs 21%, P = 0.001). CONCLUSION: We conclude that despite availability of clinical evidence, double dosing LPV/r in patients receiving rifampicin-based TB treatment is low in Uganda's public HIV clinics but this does not seem to affect patient survival and viral suppression.

Heme oxygenase-1 and neopterin plasma/serum levels and their role in diagnosing active and latent TB among HIV/TB co-infected patients: a cross sectional study.

BACKGROUND: Tuberculosis (TB) diagnosis in the context of HIV co-infection remains challenging. Heme oxygenase 1 (HO-1) and neopterin have been validated as potential biomarkers for TB diagnosis. Latent TB infection (LTBI) is diagnosed using tuberculin skin test (TST) and interferon gamma release assays (T-Spot and QuantiFERON TB gold tests, respectively). However, these tests have shown challenges and yet diagnosing LTBI is important for the overall control of TB. This study was conducted to determine the levels of H0-1 and neopterin, and their role in the diagnosis of TB among individuals enrolled in the Community Health and Social Network of Tuberculosis (COHSONET) study and the Kampala TB Drug Resistance Survey (KDRS). METHODS: This was a nested cross-sectional study. Plasma and serum samples collected from 140 patients at Mulago National Referral Hospital, Kampala Uganda were used. M.tb culture was performed on sputum to confirm active TB(ATB) and QuantiFERON TB gold test to confirm latent TB infection (LTBI). ELISAs were performed to determine the levels of HO-1 and neopterin. Data analysis was done using t-test and Receiver Operating Characteristic curves to determine the diagnostic accuracy. RESULTS: HO-1 levels among active tuberculosis (ATB)/HIV-infected patients and LTBI/HIV-infected patients were 10.7 ng/ml (IQR: 7.3-12.7 ng/ml) and 7.5 ng/ml (IQR: 5.4-14.1 ng/ml) respectively. Neopterin levels among ATB/HIV-positive patients and LTBI/HIV-positive patients were 11.7 ng/ml (IQR: 5.2.4 ng/ml) and 8.8 ng/ml (IQR: 2.4-19.8 ng/ml), respectively. HO-1 showed a sensitivity of 58.57% and a specificity of 67.14% with area under the curve (AUC) of 0.57 when used to discriminate between ATB and LTB. Neopterin showed an AUC of 0.62 with a sensitivity of 57.14% and a specificity of 60.0% when used to distinguish ATB from LTB. CONCLUSION: There was no in significant difference in HO-1 concentration levels of ATB individuals compared to LTB individuals. There was a significant difference in neopterin concentrations levels of ATB individuals compared to latently infected individuals. Findings from this study, show that HO-1 and neopterin have poor ability to distinguish between ATB and LTB.

Spectrum of antibiotic resistance in UTI caused by Escherichia coli among HIV-infected patients in Uganda: a cross-sectional study.

BACKGROUND: Antimicrobial drug resistance is one of the top ten threats to global health according to the World Health Organization. Urinary tract infections (UTIs) are among the most common bacterial infections and main reason for antibiotic prescription. The incidence of UTIs appears to be high among people living with HIV. We sought to determine the most common UTI pathogens among HIV infected patients and evaluate their susceptibility towards antibiotics. METHODS: We performed a cross-sectional study among HIV-infected patients aged ≥ 18 years presenting at an HIV care specialized clinic with symptoms suggestive of a urethritis. Urine cultures were subjected to antibiotic susceptibility testing according to Clinical Laboratory Standards Institute. The data was analyzed using STATA, we performed Pearson's Chi-square and Fisher's exact tests to compare differences between proportions. RESULTS: Out of the 200 patients, 123 (62%) were female. The median age was 41.9 years (IQR 34.7-49.3). Only 32 (16%) urine cultures showed bacterial growth. Escherichia coli was the most commonly isolated uropathogen (72%), followed by Klebsiella pneumoniae (9%). E. coli was completely resistant to cotrimoxazole and ampicillin; resistance to ciprofloxacin and ceftriaxone was 44% and 35% respectively; 9% to gentamicin; no resistance detected to nitrofurantoin and imipenem. CONCLUSIONS: Our findings are congruent with the Uganda national clinical guidelines which recommends nitrofurantoin as the first line antibiotic for uncomplicated UTI. Significant ciprofloxacin and ceftriaxone resistance was detected. In the era of emerging antibiotic resistance, understanding the local susceptibilities among sub-populations such as HIV infected patients is crucial. Further investigation is needed to address reasons for the low bacterial growth rate observed in the urine cultures.