Browsing by Author "Musaazi, Joseph"
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Item Antiretroviral concentration measurements as an additional tool to manage virologic failure in resource limited settings: a case control study(AIDS research and therapy, 2019) Buzibye, Allan; Musaazi, Joseph; Braun, Amrei von; Nanzigu, Sarah; Sekaggya‑Wiltshire, Christine; Kambugu, Andrew; Fehr, Jan; Lamorde, Mohammed; Gutteck, Ursula; Muller, Daniel; Sowinski, Stefanie; Reynolds, Steven J.; Castelnuovo, BarbaraSeveral studies demonstrate a correlation between sub-therapeutic concentrations of antiretroviral drugs and virologic failure. We examined the sensitivity, specificity and predictive values of sub-therapeutic drug levels in predicting viralogic failure. Methods: This was a case control study with cases being samples of participants with virologic failure, and controls samples of participants with virologic suppression. We analyzed samples obtained from participants that had been on antiretroviral treatment (ART) for at least 6 months. Virologic failure was defined as HIV-RNA viral load ≥ 1000 copies/ ml. Sub-therapeutic drug levels were defined according to published reference cutoffs. The diagnostic validity of drug levels for virologic failure was assessed using plasma viral loads as a gold standard. Results: Sub-therapeutic ART concentrations explained only 38.2% of virologic failure with a probability of experiencing virologic failure of 0.66 in a patient with low drug levels versus 0.25 for participants with measurements within or above the normal range. Approximately 90% of participants with ART concentrations above the lower clinical cut off did not have virologic failure. Conclusions: These results support prior indication for therapeutic drug monitoring in cases of suspected virologic failure.Item Baseline Xpert MTB/RIF ct values predict sputum conversion during the intensive phase of anti-TB treatment in HIV infected patients in Kampala, Uganda: a retrospective study(BMC Infectious Diseases, 2021) Namugenyi, Juliet; Musaazi, Joseph; Katamba, Achilles; Kalyango, Joan; Sendaula, Emmanuel; Kambugu, Andrew; Fehr, Jan; Castelnouvo, Barbara; Manabe, Yukari C.; Ssengooba, Willy; Sekaggya-Wiltshire, ChristineIn resource-limited settings, sputum smear conversion is used to document treatment response. Many People living with HIV (PLHIV) are smear-negative at baseline. The Xpert MTB/RIF test can indirectly measure bacterial load through cycle threshold (ct) values. This study aimed to determine if baseline Xpert MTB/RIF could predict time to culture negativity in PLHIV with newly diagnosed TB. Methods: A subset of 138 PLHIV from the ‘SOUTH’ study on outcomes related to TB and antiretroviral drug concentrations were included. Bacterial load was estimated by Mycobacterium Growth Indicator Tubes (MGIT) culture time-to-positivity (TTP) and Lowenstein Jensen (LJ) colony counts. Changes in TTP and colony counts were analyzed with Poisson Generalised Estimating Equations (GEE) and multilevel ordered logistic regression models, respectively, while time to culture negativity analysed with Cox proportional hazard models. ROC curves were used to explore the accuracy of the ct value in predicting culture negativity. Results: A total of 81 patients (58.7%) were males, median age 34 (IQR 29 ̶ 40) years, median CD4 cell count of 180 (IQR 68 ̶345) cells/μL and 77.5% were ART naive. The median baseline ct value was 25.1 (IQR 21.0 ̶ 30.1). A unit Increase in the ct value was associated with a 5% (IRR = 1.05 95% CI 1.04 ̶ 1.06) and 3% (IRR = 1.03 95% CI 1.03 ̶ 1.04) increase in TTP at week 2 and 4 respectively. With LJ culture, a patient’s colony grade was reduced by 0.86 times (0R = 0.86 95% CI 0.74 ̶ 0.97) at week 2 and 0.84 times (OR = 0.84 95% CI 0.79 ̶ 0.95 P = 0.002) at week 4 for every unit increase in the baseline ct value. There was a 3% higher likelihood of earlier conversion to negativity for every unit increase in the ct value. A ct cut point ≥28 best predicted culture negativity at week 4 with a sensitivity of 91. 7% & specificity 53.7% while a cut point ≥23 best predicted culture negativity at week 8. Conclusion: Baseline Xpert MTB/RIF ct values predict sputum conversion in PLHIV on anti-TB treatment. Surrogate biomarkers for sputum conversion in PLHIV are still a research priority.Item Boosted Lopinavir vs Boosted Atazanavir in Patients Failing a NNRTI first line Regimen in an Urban Clinic in Kampala(Journal of the International AIDS Society, 2014) Laker, Eva; Mambule, Ivan; Nalwanga, Damalie; Musaazi, Joseph; Kiragga, Agnes; Parkes-Ratanshi, RosalindIn 2011 Uganda recommended boosted atazanavir (ATV/r) as the preferred PI for second line due to once daily dosing, replacing aluvia (LPV/r) [1,2]. The evidence was based on the BMS O45 trial, of LPV/r vs ATV/r was performed in a highincome setting, on patients with prior PI use and resistance testing [2,3]. There are no RCTs or observational studies comparing use of ATV/r with LPV/r in patients failing NNRTI first line antiretroviral therapy in sub-Saharan Africa [3,4]. The Infectious Diseases Institute (IDI) has a large second line cohort (1838). This aims to compare clinical, immunologic and virologic response of LPV/r versus ATV/r at IDI. Retrospective cohort analysis on routinely collected data of patients switched to second line with NRTI backbones TDF/3TC or FTC, AZT/3TC, ABC/3TC from January 2009 to December 2013. Students T-tests and Chi-square tests were used in this analysis. A total of 1286 (73.5% female) patients were switched to LPV/r 991 (77%) and ATV/r 295 (23%) (pB0.001). NRTI backbones were 760 on TDF/3TC (66.8% LPV/r vs 33.2% on ATV/r), 504 on AZT/3TC (93.3% vs 6.7%), and 22 on ABC/3TC (59% vs 41%). Median (IQR) time on first line for LPV/r was 21 (144) months and for ATV/r was 41 months (2268). Median CD4 (IQR) at switch to LPV/r was 181 cells/uL (66424) and to ATV/r was 122 (57238) (p50.001). A total of 366 patients had CD4 done at six months after switch and the mean (IQR) CD4 increase was 153 (54241) for LPV/r versus 116 (52171) for ATV/r (p0.232). Additionally, 304 had a CD4 at 12 months and the means were 172 (45272) for LPV/r vs 179 (60271) for ATV/r (p0.426). There was no significant difference in the mean increment by NRTI backbone or by stratifying to viral load (VL) at time of switch to VL B100,000 and ]100,000. Median (IQR) VL at switch was 61,000 (13,0002,030,000) LPV/r and 51,000 (14,000_151,000) ATV/r. 269 had a VL done in the first 12 months and 178/250 (71.2%) on LPV/r versus 16/19 (84.2%) on ATV/r were undetectable (p0.228). 259 (26%) LPV/r versus 33(11%) ATV/r had ]1 opportunistic infections on second line (pB0.001). This is an observational study based on our experience at IDI. Like elsewhere in Africa, there is no routine viral load testing, making it difficult to get sensitive analysis of data on ART efficacy within routine clinical practice. Nevertheless, this observational study is reassuring in terms of efficacy of both ATV/r and LPV/r for patients failing first line therapy in our setting.Item Burden of Fungal Asthma in Africa: A Systematic Review and Meta-Analysis(PloS one, 2019) Kwizera, Richard; Musaazi, Joseph; Meya, David B.; Worodria, William; Bwanga, Freddie; Kajumbula, Henry; Fowler, Stephen J.; Kirenga, Bruce J.; Gore, Robin; Denning, David W.Asthma is one of the neglected diseases in Africa with a high prevalence. Allergic fungal diseases have been reported to complicate asthma progression and treatment outcomes. However, data about fungal asthma and its associated complications are limited in Africa. We aimed to estimate the burden of fungal asthma among adults and children in Africa using a systematic review.We first engaged the Institute for Health Metrics and Evaluation (IHME) to highlight the trend in morbidity and mortality attributed to asthma in Africa. We then searched PubMed, HINARI and Google Scholar for all studies of any design focusing on fungal asthma in any African country. Languages were restricted to English and French, but not year of publication. We estimated the weighted prevalence of allergic fungal infections among asthmatics with a 95% CI and pooled the results using a random effects model. This study is registered with PROSPERO, number CRD42019117319.The IHME data showed that there has been a gradual increase in morbidity and mortality due to asthma in African adults with a prevalence of 4%. Our search retrieved 5233 citations. We retained 20 studies that met our selection criteria. These were from 13 African countries published between 1967 and 2018. There were eight cross-sectional studies and twelve review articles. The average asthma prevalence in Africa was 6% from these studies. The prevalence of fungal sensitisation was relatively high (3–52%) in the asthmatic population with an average of 28% and a pooled estimate of 23.3%, mostly due to Aspergillus species. Prevalence of Allergic bronchopulmonary apsergillosis was estimated at 1.6–21.2%. Diagnosis of fungal allergy was mostly made by skin prick tests. There was no data on the use of medication to manage fungal asthma. None of the studies evaluated the association between fungal allergy and asthma severity. Data were lacking in children.There is a high prevalence of fungal sensitization among Africans with asthma. Fungal asthma is a significant problem in Africa but there remains a paucity of data on the epidemiology and associated complications. There is urgent need for national epidemiological studies to estimate the actual burden of fungal asthma in Africa.Item Cohort profile of a study on outcomes related to tuberculosis and antiretroviral drug concentrations in Uganda: design, methods and patient characteristics of the SOUTH study(BMJ open, 2017) Sekaggya-Wiltshire, Christine; Castelnuovo, Barbara; Braun, Amrei von; Musaazi, Joseph; Muller, Daniel; Buzibye, Allan; Gutteck, Ursula; Henning, Lars; Ledergerber, Bruno; Corti, Natascia; Lamorde, Mohammed; Fehr, Jan; Kambugu, AndrewTuberculosis (TB) is a leading cause of death among people living with HIV in sub-Saharan Africa. Several factors influence the efficacy of TB treatment by leading to suboptimal drug concentrations and subsequently affecting treatment outcome. The aim of this cohort is to determine the association between anti-TB drug concentrations and TB treatment outcomes. Participants Patients diagnosed with new pulmonary TB at the integrated TB-HIV outpatient clinic in Kampala, Uganda, were enrolled into the study and started on firstline anti-TB treatment. Findings to date Between April 2013 and April 2015, the cohort enrolled 268 patients coinfected with TB/HIV ; 57.8% are male with a median age of 34 years (IQR 29–40). The median time between the diagnosis of HIV and the diagnosis of TB is 2 months (IQR 0–22.5). The majority of the patients are antiretroviral therapy naive (75.4%). Our population is severely immunosuppressed with a median CD4 cell count at enrolment of 163 cells/μL (IQR 46–298). Ninety-nine per cent of the patients had a diagnosis of pulmonary TB confirmed by sputum microscopy, Xpert/RIF or culture and 203 (75.7%) have completed TB treatment with 5099 aliquots of blood collected for pharmacokinetic analysis. Future plans This cohort provides a large database of well-characterised patients coinfected with TB/HIV which will facilitate the description of the association between serum drug concentrations and TB treatment outcomes as well as provide a research platform for future substudies including evaluation of virological outcomes.Item Community-based directly observed therapy is effective and results in better treatment outcomes for patients with multi-drug resistant tuberculosis in Uganda(BioMed Central, 2023-11) Makabayi-Mugabe, Rita; Musaazi, Joseph; Zawedde-Muyanja, Stella; Kizito, Enock; Fatta, Katherine; Namwanje-Kaweesi, Hellen; Turyahabwe, Stavia; Nkolo, AbelAbstract Background Health facility-based directly observed therapy (HF DOT) is the main strategy for the management of patients with drug-resistant tuberculosis (DR TB) in Uganda, however, this still yields sub-optimal treatment out‑ comes. We set out to assess the efectiveness of community-based directly observed therapy (CB DOT) for the treat‑ ment of DR TB in Uganda. Methods Using a previously developed patient-centered model for CB DOT, we assigned community health workers (CHWs) as primary caregivers to patients diagnosed with DR TB. CHWs administered daily DOT to patients in their homes. Once a month, patients received travel vouchers to attend clinic visits for treatment monitoring. We assessed the efectiveness of this model using a quasi-experimental pre and post-study. From December 2020 to March 2022, we enrolled adult DR-TB patients on the CB DOT model. We collected retrospective data from patients who had received care using the HF DOT model during the year before the study started. The adjusted efect of CB DOT ver‑ sus HF DOT on DR TB treatment success was estimated using modifed Poisson regression model with robust cluster variance estimator. Results We analyzed data from 264 DR TB patients (152 HF DOT, 112 CB DOT). The majority were males (67.8%) with a median age of 36 years (IQR 29 to 44 years). Baseline characteristics were similar across the comparison groups, except for educational level, regimen type, and organizational unit with age being borderline. The treatment suc‑ cess rate in the CB DOT group was 12% higher than that in the HF DOT (adjusted prevalence ratio (aPR)= 1.12 [95%CI 1.01, 1.24], P-value=0.03). Males were less likely to achieve treatment success compared to their female counterparts (aPR=0.87 [95% CI 0.78, 0.98], P-value=0.02). A total of 126 (47.7%) of 264 patients reported at least one adverse event. The HF DOT group had a higher proportion of patients with at least one adverse event compared to the CB DOT group (90/152 [59.2%] versus 36/112 [32.1], P-value<0.01). The model was acceptable among patients (93.6%) and health workers (94.1%). Conclusions CB DOT for DR-TB care is efective and results in better treatment outcomes than HF DOT. The costefectiveness of this model of care should be further evaluated.Item Decreased Dolutegravir and Efavirenz Concentrations With Preserved Virological Suppression in Patients With Tuberculosis and Human Immunodeficiency Virus Receiving High-Dose Rifampicin(Clinical Infectious Diseases, 2022) Sekaggya-Wiltshire, Christine; Nabisere, Ruth; Musaazi, Joseph; Otaalo, Brian; Aber, Florence; Alinaitwe, Lucy; Nampala, Juliet; Najjemba, Letisha; Buzibye, Allan; Omali, Denis; Gausi, Kamunkhwala; Kengo, Allan; Lamorde, Mohammed; Aarnoutse, Rob; Denti, Paolo; Dooley, Kelly E.; Sloan, Derek J.Higher doses of rifampicin may improve treatment outcomes and reduce the duration of tuberculosis (TB) therapy. However, drug–drug interactions with antiretroviral therapy (ART) and safety in people with human immunodeficiency virus (HIV) have not been evaluated. Methods. This was a randomized, open-label trial where newly diagnosed TB patients were randomized to higher (35 mg/kg) or standard (10 mg/kg) daily-dose rifampicin. ART treatment–naive patients were randomized to dolutegravir- or efavirenz-based ART. At week 6, trough dolutegravir or mid-dose efavirenz plasma concentrations were assayed. HIV viral load was measured at week 24. Results. Among 128 patients randomized, the median CD4 count was 191 cells/mm3. The geometric mean ratio (GMR) for trough dolutegravir concentrations on higher- vs standard-dose rifampicin was 0.57 (95% confidence interval [CI], .34–.97; P =.039) and the GMR for mid-dose efavirenz was 0.63 (95% CI, .38–1.07; P= .083). There was no significant difference in attainment of targets for dolutegravir trough or efavirenz mid-dose concentrations between rifampicin doses. The incidence of HIV treatment failure at week 24 was similar between rifampicin doses (14.9% vs 14.0%, P= .901), as was the incidence of drug-related grade 3–4 adverse events (9.8% vs 6%). At week 8, fewer patients remained sputum culture positive on higherdose rifampicin (18.6% vs 37.0%, P =.063). Conclusions. Compared with standard-dose rifampicin, high-dose rifampicin reduced dolutegravir and efavirenz exposures, but HIV suppression was similar across treatment arms. Higher-dose rifampicin was well tolerated among people with HIV and associated with a trend toward faster sputum culture conversion.Item Delayed Sputum Culture Conversion in Tuberculosis– Human Immunodeficiency Virus–Coinfected Patients With Low Isoniazid and Rifampicin Concentrations(Clinical Infectious Diseases, 2018) Sekaggya-Wiltshire, Christine; Braun, Amrei von; Lamorde, Mohammed; Ledergerber, Bruno; Buzibye, Allan; Henning, Lars; Musaazi, Joseph; Gutteck, Ursula; Denti, Paolo; Kock, Miné de; Jetter, Alexander; Byakika-Kibwika, Pauline; Eberhard, Nadia; Matovu, Joshua; Joloba, Moses; Muller, Daniel; Manabe, Yukari C.; Kamya, Moses R.; Corti, Natascia; Kambugu, Andrew; Castelnuovo, Barbara; Fehr2, Jan S.The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods. We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results. We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37–.77; P = .001) or by the end of follow-up (0.61; .44–.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion. Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission.Item Efficacy and Safety of Dolutegravir or Darunavir in Combination with Lamivudine plus either Zidovudine or Tenofovir for second-line Treatment of HIV Infection (NADIA): week 96 results from a Prospective, Multicentre, Open-label, Factorial, Randomised, Non-inferiority trial(The Lancet HIV, 2022) Paton, Nicholas I.; Musaazi, Joseph; Kityo, Cissy; Walimbwa, Stephen; Hoppe, Anne; Balyegisawa, Apolo; Mirembe, Grace; Lugemwa, Abbas; Ategeka, Gilbert; Mugerwa, Henry; Kambugu, AndrewWHO guidelines recommend dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) for second-line HIV therapy, with NRTI switching from first-line tenofovir to zidovudine. We aimed to examine whether dolutegravir is non-inferior to darunavir, the best-in-class protease inhibitor drug, and whether maintaining tenofovir in second-line therapy is non-inferior to switching to zidovudine. In this prospective, multicentre, open-label, factorial, randomised, non-inferiority trial (NADIA), participants with confirmed HIV first-line treatment failure (HIV-1 RNA ≥1000 copies per mL) were recruited at seven clinical sites in Kenya, Uganda, and Zimbabwe. Following a 2 × 2 factorial design and stratified by site and screening HIV-1 RNA concentration, participants were randomly assigned (1:1:1:1) to receive a 96-week regimen containing either dolutegravir (50 mg once daily) or ritonavir-boosted darunavir (800 mg of darunavir plus 100 mg of ritonavir once daily) in combination with either tenofovir (300 mg once daily) plus lamivudine (300 mg once daily) or zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily). The NRTI drugs allocated by randomisation were administered orally in fixed-dose combination pills; other drugs were administered orally as separate pills. The previously reported primary outcome was the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 48 weeks. Here, we report the main secondary outcome: the proportion of participants with a plasma HIV-1 RNA concentration of less than 400 copies per mL at 96 weeks (non-inferiority margin 12%). We analysed this outcome and safety outcomes in the intention-to-treat population, which excluded only those who were randomly assigned in error and withdrawn before receiving trial drugs. This study was registered at ClinicalTrials.gov, NCT03988452, and is complete.Item Elevated Aspergillus-specific antibody levels among HIV infected Ugandans with pulmonary tuberculosis(BMC Pulmonary Medicine, 2017) Kwizera, Richard; Parkes-Ratanshi, Rosalind; Wiltshire, Christine Sekaggya; Musaazi, Joseph; Castelnuovo, Barbara; Kambugu, Andrew; Denning, David W.The incidence of tuberculosis (TB) is high among human immunodeficiency virus (HIV) infected Ugandans. Recent evidence suggests that Chronic Pulmonary Aspergillosis and Aspergillus sensitisation might be responsible for significant mortality in patients treated for tuberculosis in Uganda. We retrieved and tested paired serum aliquots for 101 HIV-TB co-infected patients at the beginning and week 24 of TB treatment. We tested samples for Aspergillus-specific immunoglobulin G (IgG) and immunoglobulin E (IgE) using ImmunoCAP®; and Aspergillus-specific IgG and total serum IgE using Immulite® immunoassays. We compared antibody levels between baseline and week 24, relating them to selected baseline characteristics.10% of the patients had elevated Aspergillus-specific IgE (Aspergillus sensitization) and Aspergillus-specific IgG antibodies were elevated in 9% of the patients at the end of TB treatment. There was a significant fall in the Aspergillus-specific IgG antibody levels between baseline and week 24 (P = 0.02). Patients with cluster of differentiation 4 (CD4) T-cell count <100 cells/μl and those who were not on anti-retroviral therapy at baseline had more elevated Aspergillus-specific IgG antibodies (P = 0.01, P = 0.03). The ImmunoCAP® Aspergillus-specific IgG antibody titres were higher at week 24 than baseline with more positives at week 24; even though the difference in means was small. However, this difference was statistically significant (P = 0.02). Pulmonary infiltrates were the commonest x-ray abnormality and only 5% of the patients had pulmonary cavities on chest x-ray at week 24.These results suggest that Aspergillus infection may complicate active pulmonary TB and further studies including fungal culture and thoracic imaging may now be indicated to measure the prevalence of pulmonary aspergillosis complicating tuberculosis.Item Estimating the effect of pretreatment loss to follow up on TB associated mortality at public health facilities in Uganda(PLoS ONE, 2020) Zawedde-Muyanja, Stella; Musaazi, Joseph; Manabe, Yukari C.; Katamba, Achilles; Nankabirwa, Joaniter I.; Castelnuovo, Barbara; Cattamanchi, AdithyaTuberculosis (TB) mortality estimates derived only from cohorts of patients initiated on TB treatment do not consider outcomes of patients with pretreatment loss to follow-up (LFU). We aimed to assess the effect of pretreatment LFU on TB-associated mortality in the six months following TB diagnosis at public health facilities in Uganda. Methods At ten public health facilities, we retrospectively reviewed treatment data for all patients with a positive Xpert®MTB/RIF test result from January to June 2018. Pretreatment LFU was defined as not initiating TB treatment within two weeks of a positive test. We traced patients with pretreatment LFU to ascertain their vital status. We performed Kaplan Meier survival analysis to compare the cumulative incidence of mortality, six months after diagnosis among patients who did and did not experience pretreatment LFU. We also determined the health facility level estimates of TB associated mortality before and after incorporating deaths prior to treatment initiation among patients who experienced pretreatment LFU. Results Of 510 patients with positive test, 100 (19.6%) experienced pretreatment LFU. Of these, we ascertained the vital status of 49 patients. In the six months following TB diagnosis, mortality was higher among patients who experienced pretreatment LFU 48.1/1000py vs 22.9/ 1000py. Hazard ratio [HR] 3.18, 95% confidence interval [CI] (1.61–6.30). After incorporating deaths prior to treatment initation among patients who experienced pretreatment LFU, health facility level estimates of TB associated mortality increased from 8.4% (95% CI 6.1%- 11.6%) to 10.2% (95% CI 7.7%-13.4%). Conclusion Patients with confirmed TB who experience pretreatment LFU have high mortality within the first six months. Efforts should be made to prioritise linkage to treatment for this group of patients. Deaths that occur prior to treatment initation should be included when reporting TB mortality in order to more accurately reflect the health impact of TB.Item Feasibility of a multifaceted intervention to improve treatment initiation among patients diagnosed with TB using Xpert MTB/RIF testing in Uganda(PLoS ONE, 2022) Zawedde-Muyanja, Stella; Musaazi, Joseph; Castelnuovo, Barbara; Cattamanchi, Adithya; Katamba, Achilles; Manabe, Yukari C.One in five patients diagnosed with TB in Uganda are not initiated on TB treatment within two weeks of diagnosis. We evaluated a multifaceted intervention for improving TB treatment initiation among patients diagnosed with TB using Xpert® MTB/RIF testing in Uganda. Methods This was a pre-post interventional study at one tertiary referral hospital. The intervention was informed by the COM-B model and included; i) medical education sessions to improve healthcare worker knowledge about the magnitude and consequences of pretreatment loss to follow-up; ii) modified laboratory request forms to improve recording of patient contact information; and iii) re-designed workflow processes to improve timeliness of sputum testing and results dissemination. TB diagnostic process and outcome data were collected and compared from the period before (June to August 2019) and after (October to December 2019) intervention initiation. Results In September 2019, four CME sessions were held at the hospital and were attended by 58 healthcare workers. During the study period, 1242 patients were evaluated by Xpert® MTB/ RIF testing at the hospital (679 pre and 557 post intervention). Median turnaround time for sputum test results improved from 12 hours (IQR 4–46) in the pre-intervention period to 4 hours (IQR 3–6) in the post-intervention period. The proportion of patients started on treatment within two weeks of diagnosis improved from 59% (40/68) to 89% (49/55) (difference 30%, 95% CI 14%-43%, p<0.01) while the proportion of patients receiving a same-day diagnosis increased from 7.4% (5/68) to 25% (14/55) (difference 17.6%, 95% CI 3.9%- 32.7%, p<0.01). Conclusion The multifaceted intervention was feasible and resulted in a higher proportion of patients initiating TB treatment within two weeks of diagnosis.Item Low Antituberculosis Drug Concentrations in HIV-Tuberculosis- Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?(Antimicrob Agents Chemother, 2019) Sekaggya-Wiltshire, Christine; Chirehwa, Maxwell; Musaazi, Joseph; Braun, Amrei von; Buzibye, Allan; Muller, Daniel; Gutteck, Ursula; Motta, Ilaria; Calcagno, Andrea; Fehr, Jan S.; Kambugu, Andrew; Castelnuovo, Barbara; Lamorde, Mohammed; Denti, PaoloAntituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing 55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)Item Low isoniazid and rifampicin concentrations in TB/HIV co-infected patients in Uganda(Journal of the International AIDS Society, 2014) Sekaggya Wiltshire, Christine; Lamorde, Mohammed; Scherrer, Alexandra; Musaazi, Joseph; Corti, Natascia; Allan, Buzibye; Nakijoba, Rita; Nalwanga, Damalie; Henning, Lars; Von Braun, Amrei; Okware, Solome; Kambugu, Andrew; Fehr, Jan; Castelnuovo, BarbaraThere is limited data available on exposure to anti-tuberculosis (TB) drugs in this region. Peloquin has described reference ranges [1] however some studies have demonstrated that patients actually achieve concentrations below these ranges [2]. There is limited data about exposure to anti-TB drugs in the HIV/TB co-infected population in Sub-Saharan Africa. Our objective is to describe the concentration of anti-TB drug levels in a well characterized prospective cohort of adult patients starting treatment for pulmonary TB. Methods: This study is an ongoing study carried out in the TB/HIV integrated clinic at the Infectious Diseases Institute in Kampala, Uganda. Sputum culture and microscopy was done for all patients. We performed pharmacokinetic blood sampling of anti-TB drugs for 1 hour, 2 hours and 4 hours post dose at 2 weeks, 8 weeks and 24 weeks after initiation of anti-TB treatment using ultraviolet high-performance liquid chromatography (UV-HPLC). We described the maximum concentration (Cmax) of isoniazid (H), rifampicin (R), ethambutol (E) and pyrazinamide (Z) and compare them with the values observed by Peloquin et al. referenced in other studies. Results: We started 113 HIV infected adults on a fixed dose combination of HREZ. The median age of our population was 33 years, of which 52% were male with a median BMI of 19 kg/m2 and a median CD4 cell count of 142 cells/mL. In 90% of the participants, the diagnosis of TB was based on microscopy and or cultures. The boxplot graph shows the median Cmax and IQR of H and R. Levels of H were found to be below the reference ranges (3 6 mg/mL) in 54/77(70.1%), 38/59(64.4%) and 15/24(62.5%) participants at weeks 2, 8 and 24. Rif levels were also found to be below the reference ranges (8 24 mg/mL) in 41/66(62.1%), 26/48(54.2%) and 8/10(8%) participants at weeks 2, 8 and 24, respectively. The mean Cmax of E and Z were within the reference range at week 2 and 8; mean Cmax of 3.29SD2.1 mg/mL and 4.09SD3.1 mg/mL for E and 41.69SD13.1 mg/mL and 42.69SD16.4 mg/mL for Z. Conclusion: We observed lower concentrations of isoniazid and rifampicin in our study population of HIV/TB co-infected patients. The implications of these findings are not yet clear.We therefore need to correlate our findings with the response to TB treatment.Item Relationship between socioeconomic status and risk of sexually transmitted infections in Uganda: Multilevel analysis of a nationally representative survey(International journal of STD & AIDS, 2019) Anguzu, Godwin; Flynn, Andrew; Musaazi, Joseph; Kasirye, Ronnie; Atuhaire, Leonard K.; Kiragga, Agnes N.; Kabagenyi, Allen; Mujugira, AndrewSocioeconomic status (SES) appears to have positive and negative associations with sexually transmitted infection (STI) risk in resource-limited settings, but few studies have evaluated nationally representative data.We assessed multiple SES measures and their effect on STI risk. We conducted a secondary analysis of data from the Uganda Demographic and Health Survey (UDHS 2011). The primary outcome (STI risk) was self-reported STIs and/or symptoms in the prior 12 months. We examined associations between multiple SES measures and STI risk using a mixed-effects Poisson regression model. The results showed that of the 9256 sexually active individuals, 7428 women and 1828 men were included in the analysis. At an individual level, middle wealth quintile and disposable income were associated with STI risk, whereas being in the richest wealth quintile was protective. Residence in wealthier regions (adjusted incidence rate ratio [aIRR] 3.92, 3.62, and 2.75, for Central, Western, and Eastern regions; p<0.01) was associated with increased STI risk. Regional level analysis revealed stochastic variability of STI risk across geographical region (variance 0.03; p¼0.01). The bilateral association between SES and STI risk underscores the need for multi-sectoral interventions to address the upstream effects of poverty on STI risk and downstream effects of STIs on health and economic productivity.Item Relationship between socioeconomic status and risk of sexually transmitted infections in Uganda: Multilevel analysis of a nationally representative survey(International journal of STD & AIDS, 2019) Anguzu, Godwin; Flynn, Andrew; Musaazi, Joseph; Kasirye, Ronnie; Atuhaire, Leonard K.; Kiragga, Agnes N.; Kabagenyi, Allen; Mujugira, AndrewSocioeconomic status (SES) appears to have positive and negative associations with sexually transmitted infection (STI) risk in resource-limited settings, but few studies have evaluated nationally representative data. We assessed multiple SES measures and their effect on STI risk. We conducted a secondary analysis of data from the Uganda Demographic and Health Survey (UDHS 2011). The primary outcome (STI risk) was self-reported STIs and/or symptoms in the prior 12 months. We examined associations between multiple SES measures and STI risk using a mixed-effects Poisson regression model. The results showed that of the 9256 sexually active individuals, 7428 women and 1828 men were included in the analysis. At an individual level, middle wealth quintile and disposable income were associated with STI risk, whereas being in the richest wealth quintile was protective. Residence in wealthier regions (adjusted incidence rate ratio [aIRR] 3.92, 3.62, and 2.75, for Central, Western, and Eastern regions; p < 0.01) was associated with increased STI risk. Regional level analysis revealed stochastic variability of STI risk across geographical region (variance 0.03; p = 0.01). The bilateral association between SES and STI risk underscores the need for multi-sectoral interventions to address the upstream effects of poverty on STI risk and downstream effects of STIs on health and economic productivity.Item Safety and efficacy of hydroxychloroquine for treatment of non‑severe COVID‑19 among adults in Uganda: a randomized open label phase II clinical trial(BMC Infectious Diseases, 2021) Byakika‑Kibwika, Pauline; Sekaggya‑Wiltshire, Christine; Semakula, Jerome Roy; Nakibuuka, Jane; Musaazi, Joseph; Kayima, James; Sendagire, Cornelius; Meya, David; Kirenga, Bruce; Nanzigu, Sarah; Kwizera, Arthur; Nakwagala, Fred; Kisuule, Ivan; Wayengera, Misaki; Mwebesa, Henry G.; Kamya, Moses R.; Bazeyo, WilliamSeveral repurposed drugs such as hydroxychloroquine (HCQ) have been investigated for treatment of COVID-19, but none was confirmed to be efficacious. While in vitro studies have demonstrated antiviral properties of HCQ, data from clinical trials were conflicting regarding its benefit for COVID-19 treatment. Drugs that limit viral replication may be beneficial in the earlier course of the disease thus slowing progression to severe and critical illness. Design: We conducted a randomized open label Phase II clinical trial from October–December 2020. Methods: Patients diagnosed with COVID-19 using RT-PCR were included in the study if they were 18 years and above and had a diagnosis of COVID-19 made in the last 3 days. Patients were randomized in blocks, to receive either HCQ 400 mg twice a day for the first day followed by 200 mg twice daily for the next 4 days plus standard of care (SOC) treatment or SOC treatment alone. SARS COV-2 viral load (CT values) from RT-PCR testing of samples collected using nasal/orapharyngeal swabs was performed at baseline, day 2, 4, 6, 8 and 10. The primary outcome was median time from randomization to SARS COV-2 viral clearance by day 6.