Pauline Byakika-Kibwika

Medicinal plants used by traditional medicine practitioners for the treatment of HIV/AIDS and related conditions in Uganda

INTRODUCTION AND OBJECTIVES In Uganda, there are over one million people with HIV/AIDS. When advanced, this disease is characterized by life-threatening opportunistic infections. As the formal health sector struggles to confront this epidemic, new medicines from traditional sources are needed to complement control efforts. This study was conducted to document herbal medicines used in the treatment of HIV/AIDS and related opportunistic infections, and to document the existing knowledge, attitudes and practices related to HIV/AIDS recognition, control and treatment in Sembabule, Kamuli, Kabale and Gulu districts in Uganda. METHODS In this study, 25 traditional medicine practitioners (TMPs) were interviewed using structured questionnaires. RESULTS The TMPs could recognize important signs and symptoms of HIV/AIDS and its associated opportunistic infections. The majority of practitioners treated patients who were already receiving allopathic medicines including antiretroviral drugs (ARVs) prescribed by allopathic practitioners. There were 103 species of medicinal plants identified in this survey. Priority plants identified include Aloe spp., Erythrina abyssinica, Sarcocephalus latifolius, Psorospermum febrifugum, Mangifera indica and Warburgia salutaris. There was low consensus among TMPs on the plants used. Decoctions of multiple plant species were commonly used except in Gulu where mono-preparations were common. Plant parts frequently used were leaves (33%), stem bark (23%) and root bark (18%). About 80% of preparations were administered orally in variable doses over varied time periods. The TMP had insufficient knowledge about packaging and preservation techniques. CONCLUSIONS Numerous medicinal plants for treatment of HIV/AIDS patients were identified in the four districts surveyed and the role of these plants in the management of opportunistic infections warrants further investigation as these plants may have a role in Ugandas public health approach to HIV/AIDS control.

Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults

Objectives Co-administration of artemether/lumefantrine with antiretroviral therapy has potential for pharmacokinetic drug interactions. We investigated drug–drug interactions between artemether/lumefantrine and efavirenz or nevirapine. Methods We performed a cross-over study in which HIV-infected adults received standard six-dose artemether/lumefantrine 80/480 mg before and at efavirenz or nevirapine steady state. Artemether, dihydroartemisinin, lumefantrine, efavirenz and nevirapine plasma concentrations were measured and compared. Results Efavirenz significantly reduced artemether maximum concentration (Cmax) and plasma AUC (median 29 versus 12 ng/mL, P < 0.01, and 119 versus 25 ng · h/mL, P < 0.01), dihydroartemisinin Cmax and AUC (median 120 versus 26 ng/mL, P < 0.01, and 341 versus 84 ng · h/mL, P < 0.01), and lumefantrine Cmax and AUC (median 8737 versus 6331 ng/mL, P = 0.03, and 280 370 versus 124 381 ng · h/mL, P < 0.01). Nevirapine significantly reduced artemether Cmax and AUC (median 28 versus 11 ng/mL, P < 0.01, and 123 versus 34 ng · h/mL, P < 0.01) and dihydroartemisinin Cmax and AUC (median 107 versus 59 ng/mL, P < 0.01, and 364 versus 228 ng · h/mL, P < 0.01). Lumefantrine Cmax and AUC were non-significantly reduced by nevirapine. Artemether/lumefantrine reduced nevirapine Cmax and AUC (median 8620 versus 4958 ng/mL, P < 0.01, and 66 329 versus 35 728 ng · h/mL, P < 0.01), but did not affect efavirenz exposure. Conclusions Co-administration of artemether/lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed.

Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults

Background Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and lumefantrine after administration of a single dose of 80/480 mg of artemether/lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. Methods A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and lumefantrine were measured. Results Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (Cmax) and area under the concentration–time curve (AUC) [median (range): 112 (20–362) versus 56 (17–236) ng/mL, P = 0.03; and 264 (92–1129) versus 151 (38–606) ng · h/mL, P < 0.01]. Dihydroartemisinin Cmax and AUC were not affected [66 (10–111) versus 73 (31–224) ng/mL, P = 0.55; and 213 (68–343) versus 175 (118–262) ng · h/mL P = 0.27]. Lumefantrine Cmax and AUC increased during co-administration [2532 (1071–5957) versus 7097 (2396–9462) ng/mL, P < 0.01; and 41 119 (12 850–125 200) versus 199 678 (71 205–251 015) ng · h/mL, P < 0.01]. Conclusions Co-administration of artemether/lumefantrine with lopinavir/ritonavir significantly increases lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

Unintended Pregnancies Observed With Combined Use of the Levonorgestrel Contraceptive Implant and Efavirenz-based Antiretroviral Therapy: A Three-Arm Pharmacokinetic Evaluation Over 48 Weeks

Women receiving efavirenz-based antiretroviral therapy plus a contraceptive implant had significantly lower levonorgestrel pharmacokinetics than women not receiving antiretroviral therapy. An unexpected high pregnancy rate (3/20, 15%) occurred in the efavirenz group, highlighting the clinical significance of this interaction.

Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications

AIM Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, lumefantrine, artemether and their respective metabolites desbutyl-lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir. METHOD Data from two clinical studies, investigating the influence of the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir on the pharmacokinetics of the antimalarial drugs lumefantrine, artemether and their respective metabolites, in HIV infected patients were pooled and analyzed using a non-linear mixed effects modelling approach. RESULTS Efavirenz and nevirapine significantly decreased the terminal exposure to lumefantrine (decrease of 69.9% and 25.2%, respectively) while lopinavir/ritonavir substantially increased the exposure (increase of 439%). All antiretroviral drugs decreased the total exposure to dihydroartemisinin (decrease of 71.7%, 41.3% and 59.7% for efavirenz, nevirapine and ritonavir/lopinavir, respectively). Simulations suggest that a substantially increased artemether-lumefantrine dose is required to achieve equivalent exposures when co-administered with efavirenz (250% increase) and nevirapine (75% increase). When co-administered with lopinavir/ritonavir it is unclear if the increased lumefantrine exposure compensates adequately for the reduced dihydroartemisinin exposure and thus whether dose adjustment is required. CONCLUSION There are substantial drug interactions between artemether-lumefantrine and efavirenz, nevirapine and ritonavir/lopinavir. Given the readily saturable absorption of lumefantrine, the dose adjustments predicted to be necessary will need to be evaluated prospectively in malaria-HIV co-infected patients.

Effect of Food on the Steady-State Pharmacokinetics of Tenofovir and Emtricitabine plus Efavirenz in Ugandan Adults

We investigated the effect of food on the steady-state pharmacokinetics of a proprietary fixed-dose combination (FDC) tablet containing tenofovir disoproxil fumarate (TDF)/emtricitabine/efavirenz. Fifteen Ugandan HIV-1 patients at steady-state dosing with TDF/emtricitabine/efavirenz were admitted for 24-hour intensive pharmacokinetic sampling after dosing in the fasting state. Blood sampling was repeated seven days later with TDF/emtricitabine/efavirenz administered with food (19 g fat). Drug concentrations in plasma were determined by liquid chromatography and tandem mass spectrometry. Geometric mean ratios (GMRs) and confidence intervals (CIs) of parameters were calculated (reference, fasting). For efavirenz, GMRs (90% CIs) for C max, AUC0−24, and C 24 were 1.47 (1.24–1.75), 1.13 (1.03–1.23), and 1.01 (0.91–1.11), respectively. Corresponding GMRs were 1.04 (0.84–1.27), 1.19 (1.10–1.29), and 0.99 (0.82–1.19) for tenofovir, 0.83 (0.76–0.92), 0.87 (0.78–0.97), and 0.91 (0.73–1.14) for emtricitabine. Stable patients may take the FDC without meal restrictions. The FDC should be taken without food by patients experiencing central nervous system toxicities.

Suboptimal Nevirapine Steady-state Pharmacokinetics During Intrapartum Compared With Postpartum in Hiv-1-seropositive Ugandan Women

Background: Conflicting data exist regarding the effect of pregnancy on steady-state nevirapine pharmacokinetics (PK), although steady-state nevirapine concentrations during pregnancy have never been characterized in sub-Saharan Africa. Methods: This was a longitudinal intensive PK study in Ugandan pregnant women receiving nevirapine-based antiretroviral therapy. Participants underwent intensive 12-hour PK sampling during the second trimester (T2; n = 4), third trimester (T3; n = 15) and 6 weeks postpartum (PP; n = 15). HIV-1 RNA was performed within 2 weeks of each visit. Nevirapine C12 above 3000 ng/mL was classified as optimal based on the suggested value for therapeutic drug monitoring. Results: The pharmacokinetics of nevirapine were influenced by pregnancy, demonstrated by a 20% reduction in the maximum concentration, minimum concentration (C12), and area under the curve between T3 and PP visits (P = 0.001, P = 0.011 and P = 0.005, respectively). Ten subjects (66.7%) had C12 values <3000 ng/mL during T3. Of these participants, 7 partcipants C12 concentrations increased to >3000 ng/mL during the PP visit. HIV-1 RNA were <1000 copies per milliliter at T3 and <400 copies per milliliter at PP in all patients. Conclusions: Nevirapine exposure was reduced in Ugandan women during their third trimester compared with the same women PP, however, HIV RNA remained <1000 copies per milliliter. The long-term impact of intermittent suboptimal nevirapine concentrations during pregnancy is unknown.

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.

The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the worlds population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug–drug interactions. Antiretrovirals pose a particularly high risk for potential drug–drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

Mentorship needs at academic institutions in resource-limited settings: a survey at makerere university college of health sciences

BackgroundMentoring is a core component of medical education and career success. There is increasing global emphasis on mentorship of young scientists in order to train and develop the next leaders in global health. However, mentoring efforts are challenged by the high clinical, research and administrative demands. We evaluated the status and nature of mentoring practices at Makerere University College of Health Sciences (MAKCHS).MethodsPre-tested, self-administered questionnaires were sent by email to all Fogarty alumni at the MAKCHS (mentors) and each of them was requested to complete and email back the questionnaire. In addition to training level and number of mentors, the questionnaires had open-ended questions covering themes such as; status of mentorship, challenges faced by mentors and strategies to improve and sustain mentorship within MAKCHS. Similarly, open-ended questionnaires were sent and received by email from all graduate students (mentees) registered with the Uganda Society for Health Scientists (USHS). Qualitative data from mentors and mentees was analyzed manually according to the pre-determined themes.ResultsTwenty- two out of 100 mentors responded (14 email and 8 hard copy responses). Up to 77% (17/22) of mentors had Masters-level training and only 18% (4/22) had doctorate-level training. About 40% of the mentors had ≥ two mentees while 27% had none. Qualitative results showed that mentors needed support in terms of training in mentoring skills and logistical/financial support to carry out successful mentorship. Junior scientists and students reported that mentorship is not yet institutionalized and it is currently occurring in an adhoc manner. There was lack of awareness of roles of mentors and mentees. The mentors mentioned the limited number of practicing mentors at the college and thus the need for training courses and guidelines for faculty members in regard to mentorship at academic institutions.ConclusionsBoth mentors and mentees were willing to improve mentorship practices at MAKCHS. There is need for institutional commitment to uphold and sustain the mentorship best practices. We recommend a collaborative approach by the stakeholders in global health promotion to build local capacity in mentoring African health professionals.

Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin

BACKGROUND rifampicin lowers nevirapine plasma concentrations by inducing cytochrome P450. However, few data are available on this interaction during the lead-in period of nevirapine treatment. METHODS eighteen HIV-1/tuberculosis co-infected adults receiving rifampicin daily as part of anti-tuberculosis therapy were evenly randomized to nevirapine initiation by dose escalation (NVP200) or nevirapine initiation at 200 mg twice daily (NVP400). Subjects underwent 12 h intensive pharmacokinetic sampling on Days 7, 14 and 21 of nevirapine treatment. A minimum effective concentration (MEC) of 3000 ng/mL was used to interpret nevirapine concentrations 12 h after dosing (C(12)). TRIAL REGISTRATION NUMBER NCT00617643 (www.clinicaltrials.gov). RESULTS day 7 geometric mean nevirapine C(12) [90% confidence interval (CI)] was 1504 (1127-2115) ng/mL and 3148 (2451-4687) ng/mL in the NVP200 and NVP400 arms, respectively (P < 0.01). Nevirapine C(12) on Days 14 and 21 was similar. On Day 21, nevirapine concentration in 64% of patients was below the MEC. On Day 7, geometric mean area under the curve (AUC(0-12)) was lower in the NVP200 arm, 25 223 (90% CI, 21 978-29 695) ng·h/mL versus 43 195 (35 607-57 035) ng·h/mL in the NVP400 arm (P  <  0.01). Similarly, on Day 14, nevirapine AUC(0-12) was lower in the NVP200 arm 23 668 (18 253-32 218) ng·h/mL versus the NVP400 arm 44 918 (36 264-62 769) ng·h/mL (P = 0.03). CONCLUSIONS in co-treated patients, nevirapine concentrations were below the MEC during initiation with dose escalation. Nevirapine initiation at the maintenance dose of 200 mg twice daily is preferred. Sub-therapeutic nevirapine concentrations were common at Day 21 with either regimen. Evaluation of higher nevirapine maintenance doses may be considered.