NRU :: Browsing by Author "Lamorde, Mohammed"

Browsing by Author "Lamorde, Mohammed"

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A Cross-Cutting Approach to Surveillance and Laboratory Capacity as a Platform to Improve Health Security in Uganda
(Health security, 2018) Lamorde, Mohammed; Mpimbaza, Arthur; Walwema, Richard; Kamya, Moses; Kajumbula, Henry; Sserwanga, Asadu; Namuganga, Jane Frances
Global health security depends on effective surveillance for infectious diseases. In Uganda, resources are inadequate to support collection and reporting of data necessary for an effective and responsive surveillance system. We used a cross-cutting approach to improve surveillance and laboratory capacity in Uganda by leveraging an existing pediatric inpatient malaria sentinel surveillance system to collect data on expanded causes of illness, facilitate development of real-time surveillance, and provide data on antimicrobial resistance. Capacity for blood culture collection was established, along with options for serologic testing for select zoonotic conditions, including arboviral infection, brucellosis, and leptospirosis. Detailed demographic, clinical, and laboratory data for all admissions were captured through a web-based system accessible at participating hospitals, laboratories, and the Uganda Public Health Emergency Operations Center. Between July 2016 and December 2017, the expanded system was activated in pediatric wards of 6 regional government hospitals. During that time, patient data were collected from 30,500 pediatric admissions, half of whom were febrile but lacked evidence of malaria. More than 5,000 blood cultures were performed; 4% yielded bacterial pathogens, and another 4% yielded likely contaminants. Several WHO antimicrobial resistance priority pathogens were identified, some with multidrug-resistant phenotypes, including Acinetobacter spp., Citrobacter spp., Escherichia coli, Staphylococcus aureus, and typhoidal and nontyphoidal Salmonella spp. Leptospirosis and arboviral infections (alphaviruses and flaviviruses) were documented. The lessons learned and early results from the development of this multisectoral surveillance system provide the knowledge, infrastructure, and workforce capacity to serve as a foundation to enhance the capacity to detect, report, and rapidly respond to wide-ranging public health concerns in Uganda. Fever may be the initial or sole symptom of many infectious diseases, including some with outbreak potential.1,2 Although clinical practice in many malaria-endemic areas has been to presumptively treat febrile patients for malaria, improved access to malaria diagnostics in recent years has revealed that a substantial proportion of acutely ill, febrile patients in sub-Saharan Africa do not have malaria.3-5 Yet, many countries lack resources and capacity for accurate diagnosis of most infectious conditions. Rapid response to diverse and emerging public health threats is severely challenged by lack of appropriate laboratory capacity and timely surveillance networks.6 These gaps foster antimicrobial and antimalarial resistance, limit evidence-based care and policy to improve population health, and hinder the ability to detect outbreaks early. Uganda, an inland East African country with a rapidly growing population estimated at 43 million people in 2017, has made progress in recent decades to improve life expectancy, reduce poverty and food insecurity, and expand access to immunizations and clean water.7 Yet, as with many African countries, Uganda faces diverse health challenges in a weak health infrastructure that limits the rapid detection and confirmation of infections with epidemic potential. In the past 2 decades, Uganda has experienced outbreaks of emerging and reemerging infectious diseases including Ebola, Marburg, Crimean-Congo hemorrhagic fever, Rift Valley fever, yellow fever, hepatitis E, cholera, typhoid fever, plague, and anthrax.8-16 Effective laboratory capacity and disease surveillance are critical to global health security and the basis for the 2005 International Health Regulations (IHR) signed by all World Health Organization (WHO) member states. IHR compliance has proven challenging for many low-income countries, including Uganda.17,18 The Global Health Security Agenda (GHSA), a multisectoral and multilateral partnership intended to support countries toward IHR compliance, launched officially in 2014 (www.ghsagenda.org). The government of Uganda and the US Centers for Disease Control and Prevention (CDC) jointly implemented a demonstration project a year earlier, in 2013. The pilot project improved specimen referral networks and information systems associated with outbreak response and created an emergency operations center; these activities set the stage for multiple GHSA activities in the country.19 Through GHSA-initiated partnerships, we introduced a cross-cutting surveillance approach to advance ability to detect unusual health events in Uganda. As conceived, this effort would provide comprehensive patient data and facilitate electronic systems infrastructure that could ultimately improve early detection of novel infections or outbreaks, define conditions causing human illness to inform appropriate and targeted laboratory capacity building efforts, and generate data for an antimicrobial resistance surveillance and intervention program in its infancy.
Aetiology of hospitalized fever and risk of death at Arua and Mubende tertiary care hospitals in Uganda from August 2019 to August 2020
(BMC infectious diseases, 2022) Blair, Paul W.; Kobba, Kenneth; Kakooza, Francis; Robinson, Matthew L.; Candia, Emmanuel; Mayito, Jonathan; Ndawula, Edgar C.; Kandathil, Abraham J.; Matovu, Alphonsus; Aniku, Gilbert; Manabe, Yukari C.; Lamorde, Mohammed
Epidemiology of febrile illness in Uganda is shifting due to increased HIV treatment access, emerging viruses, and increased surveillance. We investigated the aetiology and outcomes of acute febrile illness in adults presenting to hospital using a standardized testing algorithm of available assays in at Arua and Mubende tertiary care hospitals in Uganda. Methods We recruited adults with a ≥ 38.0 °C temperature or history of fever within 48 h of presentation from August 2019 to August 2020. Medical history, demographics, and vital signs were recorded. Testing performed included a complete blood count, renal and liver function, malaria smears, blood culture, and human immunodeficiency virus (HIV). When HIV positive, testing included cryptococcal antigen, CD4 count, and urine lateral flow lipoarabinomannan assay for tuberculosis. Participants were followed during hospitalization and at a 1-month visit. A Cox proportional hazard regression was performed to evaluate for baseline clinical features and risk of death. Results Of 132 participants, the median age was 33.5 years (IQR 24 to 46) and 58.3% (n = 77) were female. Overall, 73 (55.3%) of 132 had a positive microbiologic result. Among those living with HIV, 31 (68.9%) of 45 had at least one positive assay; 16 (35.6%) had malaria, 14 (31.1%) tuberculosis, and 4 (8.9%) cryptococcal antigenemia. The majority (65.9%) were HIV-negative; 42 (48.3%) of 87 had at least one diagnostic assay positive; 24 (27.6%) had positive malaria smears and 1 was Xpert MTB/RIF Ultra positive. Overall, 16 (12.1%) of 132 died; 9 (56.3%) of 16 were HIV-negative, 6 died after discharge. High respiratory rate (≥ 22 breaths per minute) (hazard ratio [HR] 8.05; 95% CI 1.81 to 35.69) and low (i.e., < 92%) oxygen saturation (HR 4.33; 95% CI 1.38 to 13.61) were identified to be associated with increased risk of death. Conclusion In those with hospitalized fever, malaria and tuberculosis were common causes of febrile illness, but most deaths were non-malarial, and most HIV-negative participants did not have a positive diagnostic result. Those with respiratory failure had a high risk of death.
An Individual Participant Data Population Pharmacokinetic Meta-analysis of Drug-Drug Interactions between Lumefantrine and Commonly Used Antiretroviral Treatment
(Antimicrobial agents and chemotherapy, 2020) Francis, Jose; Barnes, Karen I.; Workman, Lesley; Kredo, Tamara; Vestergaard, Lasse S.; Hoglund, Richard M.; Byakika-Kibwika, Pauline; Lamorde, Mohammed; Walimbwa, Stephen I.; Chijioke-Nwauche, Ifeyinwa; Sutherland, Colin J.; Merry, Concepta; Dentia, Paolo
Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavirritonavir- based antiretroviral therapy (ART), while it decreased by 47% with efavirenzbased ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations 200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.
An Interactive Voice Response Software to Improve the Quality of Life of People Living With HIV in Uganda: Randomized Controlled Trial
(JMIR mHealth and uHealth, 2021) Byonanebye, Dathan Mirembe; Nabaggala, Maria S.; Naggirinya, Agnes Bwanika; Lamorde, Mohammed; Oseku, Elizabeth; King, Rachel; Owarwo, Noela; Laker, Eva; Orama, Richard; Castelnuovo, Barbara; Kiragga, Agnes; Ratanshi, Rosalind Parkes
Following the successful scale-up of antiretroviral therapy (ART), the focus is now on ensuring good quality of life (QoL) and sustained viral suppression in people living with HIV. The access to mobile technology in the most burdened countries is increasing rapidly, and therefore, mobile health (mHealth) technologies could be leveraged to improve QoL in people living with HIV. However, data on the impact of mHealth tools on the QoL in people living with HIV are limited to the evaluation of SMS text messaging; these are infeasible in high-illiteracy settings.The primary and secondary outcomes were to determine the impact of interactive voice response (IVR) technology on Medical Outcomes Study HIV QoL scores and viral suppression at 12 months, respectively.Within the Call for Life study, ART-experienced and ART-naïve people living with HIV commencing ART were randomized (1:1 ratio) to the control (no IVR support) or intervention arm (daily adherence and pre-appointment reminders, health information tips, and option to report symptoms). The software evaluated was Call for Life Uganda, an IVR technology that is based on the Mobile Technology for Community Health open-source software. Eligibility criteria for participation included access to a phone, fluency in local languages, and provision of consent. The differences in differences (DIDs) were computed, adjusting for baseline HIV RNA and CD4.Overall, 600 participants (413 female, 68.8%) were enrolled and followed-up for 12 months. In the intervention arm of 300 participants, 298 (99.3%) opted for IVR and 2 (0.7%) chose SMS text messaging as the mode of receiving reminders and health tips. At 12 months, there was no overall difference in the QoL between the intervention and control arms (DID=0.0; P=.99) or HIV RNA (DID=0.01; P=.94). At 12 months, 124 of the 256 (48.4%) active participants had picked up at least 50% of the calls. In the active intervention participants, high users (received >75% of reminders) had overall higher QoL compared to low users (received <25% of reminders) (92.2 versus 87.8, P=.02). Similarly, high users also had higher QoL scores in the mental health domain (93.1 versus 86.8, P=.008) and better appointment keeping. Similarly, participants with moderate use (51%-75%) had better viral suppression at 12 months (80/94, 85% versus 11/19, 58%, P=.006).Overall, there was high uptake and acceptability of the IVR tool. While we found no overall difference in the QoL and viral suppression between study arms, people living with HIV with higher usage of the tool showed greater improvements in QoL, viral suppression, and appointment keeping. With the declining resources available to HIV programs and the increasing number of people living with HIV accessing ART, IVR technology could be used to support patient care. The tool may be helpful in situations where physical consultations are infeasible, including the current COVID epidemic.
An Observational Study in an Urban Ugandan Clinic comparing Virological Outcomes of Patients Switched from first-line Antiretroviral Regimens to Second-line Regimens containing Ritonavir-boosted Atazanavir or Ritonavir-boosted Lopinavir
(BMC Infectious Diseases, 2019) Laker, Eva Agnes Odongpiny; Nabaggala, Maria Sarah; Kaimal, Arvind; Nalwanga, Damalie; Abdu Musubire, Abdu Musubire; Kiragga, Agnes; Lamorde, Mohammed; Parkes- Ratanshi, Rosalind
The World Health Organisation approved boosted atazanavir as a preferred second line protease inhibitor in 2010. This is as an alternative to the current boosted lopinavir. Atazanavir has a lower genetic barrier than lopinavir. We compared the virological outcomes of patients during the roll out of routine viral load monitoring, who had switched to boosted second- line regimens of either atazanavir or lopinavir.
An open-label, randomized, single intravenous dosing study to investigate the effect of fixed dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR)
(Research Square, 2021) Walimbwa, Stephen Ian; Kaboggoza, Julian Paul; Waitt, Catriona; Byakika-Kibwika, Pauline; D'Avolio, Antonio; Lamorde, Mohammed
Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate /lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir.
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, Barbara
Several 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.
Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals
(Malaria Research and Treatment, 2011) Byakika-Kibwika, Pauline; Lamorde, Mohammed; Mayanja-Kizza, Harriet; Khoo, Saye; Merry, Concepta; Van geertruyden, Jean-Pierre Van geertruyden4
Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemetherlumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine aremetabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used forHIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed.
Assessment of parasite clearance following treatment of severe malaria with intravenous artesunate in Ugandan children enrolled in a randomized controlled clinical trial
(Malaria journal, 2018) Byakika‑Kibwika, Pauline; Nyakato, Patience; Lamorde, Mohammed; Kiragga, Agnes N.
Worldwide, malaria ranks as one of the most important causes of morbidity and mortality with 216 million cases and 445,000 deaths in 2016 alone, 90% of cases and deaths occur in Africa and 80% in sub-Saharan Africa Uganda is one of the heavy malaria burden countries where Plasmodium falciparum, which causes the most severe form of disease is the most prevalent [1]. Malaria is transmitted by the female Anopheles mosquito which injects sporozoites into the human host. Sporozoites undergo pre-erythrocytic and erythrocytic stages of multiplication causing erythrocyte rupture with release of merozoites and pro-inflammatory cytokines into circulation, which are responsible for the symptoms. Patients seek medical attention when they begin to experience symptoms of malaria.
Blood Culture Testing Outcomes among Non-Malarial Febrile Children at Antimicrobial Resistance Surveillance Sites in Uganda, 2017–2018
(Tropical medicine & infectious disease, 2018) Kisame, Rogers; Najjemba, Robinah; Griensven, Johan van; Kitutu, Freddy Eric; Takarinda, Kudakwashe; Thekkur, Pruthu; Delamou, Alexandre; Walwema, Richard; Kakooza, Francis; Mugerwa, Ibrahim; Sekamatte, Musa; Robert, Kimera; Katairo, Thomas; Opollo, Marc Sam; Otita, Morgan; Lamorde, Mohammed
Blood culture (BC) processes are critical to the utility of diagnostic testing, bloodstream infection (BSI) management, and antimicrobial resistance (AMR) surveillance. While Uganda has established BC guidelines, often laboratory practice does not meet the desired standards. This compromises pathogen recovery, reliability of antimicrobial susceptibility testing, and diagnostic test utility. This study assessed laboratory BC process outcomes among non-malarial febrile children below five years of age at five AMR surveillance sites in Uganda between 2017 and 2018. Secondary BC testing data was reviewed against established standards. Overall, 959 BC specimens were processed. Of these, 91% were from female patients, neonates, infants, and young children (1–48 months). A total of 37 AMR priority pathogens were identified; Staphylococcus aureus was predominant (54%), followed by Escherichia coli (19%). The diagnostic yield was low (4.9%). Only 6.3% of isolates were identified. AST was performed on 70% (18/26) of identified AMR priority isolates, and only 40% of these tests adhered to recommended standards. Interventions are needed to improve laboratory BC practices for effective patient management through targeted antimicrobial therapy and AMR surveillance in Uganda. Further research on process documentation, diagnostic yield, and a review of patient outcomes for all hospitalized febrile patients is needed.
Building clinical pharmacology laboratory capacity in low- and middle-income countries: Experience from Uganda
(African Journal of Laboratory Medicine, 2023) Omali, Denis; Buzibye, Allan; Kwizera, Richard; Byakika-Kibwika, Pauline; Namakula, Rhoda; Matovu, Joshua; Mbabazi, Olive; Mande, Emmanuel; Sekaggya-Wiltshire, Christine; Nakanjako, Damalie; Gutteck, Ursula; McAdam, Keith; Easterbrook, Philippa; Kambugu, Andrew; Fehr, Jan; Castelnuovo, Barbara; Manabe, Yukari C.; Lamorde, Mohammed; Mueller, Daniel; Merry, Concepta
Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. Intervention: Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. Lessons learnt: Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. Recommendations: Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.
Cardiac Conduction Safety during Coadministration of Artemether-Lumefantrine and Lopinavir/Ritonavir in HIV-Infected Ugandan Adults
(Chemotherapy research and practice, 2011) Byakika-Kibwika, Pauline; Lamorde, Mohammed; Lwabi, Peter; Nyakoojo, Wilson B.; Okaba-Kayom, Violet; Mayanja-Kizza, Harriet; Boffito, Marta; Katabira, Elly; Back, David; Khoo, Saye; Merry, Concepta
We aimed to assess cardiac conduction safety of coadministration of the CYP3A4 inhibitor lopinavir/ritonavir (LPV/r) and the CYP3A4 substrate artemether-lumefantrine (AL) in HIV-positive Ugandans. Methods. Open-label safety study of HIV positive adults administered single-dose AL (80/400 mg) alone or with LPV/r (400/100 mg). Cardiac function was monitored using continuous electrocardiograph (ECG). Results. Thirty-two patients were enrolled; 16 taking LPV/r -based ART and 16 ART naıve. All took single dose AL. No serious adverse events were observed. ECG parameters in milliseconds remained within normal limits. QTc measurements did not change significantly over 72 hours although were higher in LPV/r arm at 24 (424 versus 406; P = .02) and 72 hours (424 versus 408; P = .004) after AL intake. Conclusion. Coadministration of single dose of AL with LPV/r was safe; however, safety of six-dose AL regimen with LPV/r should be investigated.
Changes in Access to Alcohol-Based Hand Rub and Hand Hygiene Adherence among Healthcare Workers after a Hand Rub Production and Distribution Program in Rural Uganda before and during the COVID-19 Pandemic
(The American Journal of Tropical Medicine and Hygiene, 2024-09-18) Ishida, Kanako; Kesande, Maureen; Tusabe, Fred; Ocitti, Francis; Nanyondo, Judith; Isabirye, Herbert; Lamorde, Mohammed; Berendes, David
During the COVID-19 pandemic, the use of alcohol-based hand rubs (ABHRs) was critical for improving hand hygiene (HH) among healthcare workers (HCWs). Before and during the pandemic, we supported district-led production and district-wide distribution of ABHRs and one-time provision of portable handwashing stations to select healthcare facilities (HCFs) in five rural districts in Uganda. Comparison between baseline and follow-up assessments showed an overall increase in access to HH materials and HH adherence (HHA; handwashing with soap and water or use of ABHR) among HCWs. However, large differences in the changes in HH material coverage and HHA across districts may have been heavily influenced by the COVID-19 disease burden and its risk perception when the assessments were conducted. Using data collected at multiple time points before and during the pandemic across districts and estimating and controlling for pandemic effects in an exploratory multivariate analysis, the adjusted odds ratio of HHA in district HCFs was 4.6 (95% CI: 1.8–11.8) after (versus before) the ABHR intervention. This increase appeared to be primarily in larger HCFs, where the perceived need for ABHRs may have been greater. Additional strategies are needed to further increase HHA, especially in the smallest HCFs, among laboratory technicians and nurses and before patient contact. However, district-scale ABHR interventions seemed successful in ensuring the continued availability of HH materials.
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, Andrew
Tuberculosis (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.
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.
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.
Drug Interactions between Dolutegravir and Artemether- Lumefantrine or Artesunate-Amodiaquine
(Antimicrobial agents and chemotherapy, 2018) Walimbwa, Stephen I.; Lamorde, Mohammed; Waitt, Catriona; Kaboggoza, Julian; Else, Laura; Byakika-Kibwika, Pauline; Amara, Alieu; Gini, Joshua; Winterberg, Markus; Chiong, Justin; Tarning, Joel; Khoob, Saye H.
Across sub-Saharan Africa, patients with HIV on antiretrovirals often getmalaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemetherlumefantrine or artesunate-amodiaquine given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunateamodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h.
Drug–drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases: important considerations in the WHO 2020 Roadmap and London Declaration on Neglected Tropical Diseases
(Lippincott Williams & Wilkins, 2020) Sedena, Kay; Khooa, Saye; Backa, David; Prevattb, Natalie; Lamorde, Mohammed; Byakika-Kibwika, Pauline; Mayito, Jonathan; Ryan, Mairin; Merry, Concepta
TheWHO2020 Roadmap on neglected tropical diseases (NTDs) and the 2012 London Declaration on NTDs aim to ‘enable more than a billion people suffering from neglected tropical diseases to lead healthier and more productive lives’ and ‘chart a new course towards health and sustainability’. Two out of the five strategies for the prevention, control, elimination and eradication of NTDs set out in the WHO 2020 Roadmap involve sustaining and expanding existing drug donation programs to meet demand through to 2020. To this end, the governments of the US, UK and United Arab Emirates, theWorld Bank and the Bill and Melinda Gates Foundation along with 13 pharmaceutical companies, have announced the largest collaborative effort to date to combat NTDs.
Efavirenz- but not nevirapine-based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub-dermal contraceptive implant
(Journal of the International AIDS Society, 2014) Kimberly, Scarsi; Lamorde, Mohammed; Darin, Kristin; Dilly Penchala, Sujan; Else, Laura; Nakalema, Shadia; Byakika-Kibwika, Pauline; Khoo, Saye; Cohn, Susan; Merry, Concepta; Back, David
Sub-dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long-acting contraception, but their use among HIV-positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A-mediated drug-drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub-dermal implant over six months in HIV-positive Ugandan women on nevirapine (NVP)- or efavirenz (EFV)-based ART.
Factors Associated with Uptake of Contraceptives among HIV Positive Women on Dolutegravir based Anti-Retroviral Treatment at Health Centres of Kampala Capital City Authority. A cross sectional study in Uganda.
(BMC Women's Health, 2022) Mbabazi, Leah; Nabaggala, Mariah Sarah; Kiwanuka, Suzanne; Kiguli, Juliet; Okoboi, Stephen; Laker, Eva; Castelnuovo, Barbara; Lamorde, Mohammed; Kiconco, Arthur; Amperiize, Mathius
In May 2018, the World Health Organisation issued a teratogenicity alert for HIV positive women using dolutegravir (DTG) and emphasised increased integration of sexual and reproductive services into HIV care to meet contraceptive needs of HIV positive women. However, there are scarce data on the impact of this guidance on contraceptive uptake. Objective To investigate the uptake of contraceptives and the factors affecting the uptake of contraceptive services among the HIV positive women of reproductive age who use DTG. Methods A cross-sectional survey was conducted from April 2019 to July 2019, in five government clinics in central Uganda where DTG was offered as the preferred first-line antiretroviral treatment (ART) regimen. We randomly selected 359 non-pregnant women aged 15-49 years using DTG-based regimens. We used interviewer administered questionnaires to collect data on demographics, contraceptive use, social and health system factors. We defined contraceptive uptake as the proportion of women using any method of contraception divided by the total number of women on DTG during the review period. We described patients’ characteristics using descriptive statistics. Factors associated with contraceptive uptake were investigated using Poisson regression at multivariable analysis (STATA 14). Results Of the 359 participants, the mean age was 37(SD=6.8), half 50.7% had attained primary level of education and average monthly income <100,000Ushs. The overall level of Contraceptive uptake was 38.4%, modern contraceptive uptake was 37.6% and 96.4% of the participants had knowledge of contraceptives. The most utilised method was the injectable at 58.4% followed by condoms 15%, IUD 10.7%, pills 6.4%, implants 5.4%, and least used was sterilization at 0.7%. Predictor factors that increased likelihood of contraceptive uptake were; religion of others category AIRR=1.53(95% CI: 1.01, 2.29) and parity 3-4 children AIRR=1.48(95% CI: 1.14, 1.92). Reduced rates were observed for age 40-49 years AIRR=0.45(95% CI: 0.21, 0.94), unemployment AIRR 0.63(95% CI: 0.42, 0.94), not discussing FP with partner AIRR=0.39(95% CI: 0.29, 0.52) and not receiving FP counselling AIRR=2.86 (95% CI: 0.12, 0.73). Non-significant variables were facility, education level, marital status, sexual activity, experienced side effects of FP and knowledge on both contraceptives and DTG. Conclusion This study shows a low-level uptake of contraceptives and injectable was the most used method. It also indicated that FP counselling and partner discussion on FP increased contraceptive uptake. Therefore, more strategies should be put in place to increase male involvement in family planning programs and scale up the integration of family planning services into HIV care and management programs.

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