Browsing by Author "Khoo, Saye"

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    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.
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    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.
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    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.
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    Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults
    (Journal of antimicrobial chemotherapy, 2012) Byakika-Kibwika, Pauline; Lamorde, Mohammed; Okaba-Kayom, Violet; Mayanja-Kizza, Harriet; Katabira, Elly; Hanpithakpong, Warunee; Pakker, Nadine; Dorlo, Thomas P. C.; Tarning, Joel; Lindegardh, Niklas; Vries, Peter J. de; Back, David; Khoo, Saye; Merry, Concepta
    Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisininbased 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.
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    Nevirapine pharmacokinetics when initiated at 200 mg or 400 mg daily in HIV-1 and tuberculosis co-infected Ugandan adults on rifampicin
    (Journal of Antimicrobial Chemotherapy, 2011) Lamorde, Mohammed; Byakika-Kibwika, Pauline; Okaba-Kayom, Violet; Ryan, Mairin; Coakley, Peter; Boffito, Marta; Namakula, Rhoda; Kalemeera, Francis; Colebunders, Robert; Back, David; Khoo, Saye; Merry, Concepta
    In resource-poor countries, HIV and tuberculosis (TB) co-infection results in significant morbidity and mortality. Co-treatment is recommended by the WHO;1 however, drug interactions are common between anti-TB regimens containing rifampicin and antiretroviral drugs. In these settings, rifampicin is a key drug for TB treatment because alternative rifamycins are more expensive and usually not available in public TB control programmes. Similarly, for HIV treatment, only a limited number of antiretroviral drugs are routinely used. The problems arising from limited drug options are compounded by the wide use of fixed-dose combination (FDC) formulations for both diseases. When these formulations are used, drug substitutions are not possible and dose adjustments are usually difficult.
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    Relating CYP2B6 Genotype and EFV Resistance Among Women Living With HIV With High Viremia in Uganda: A Nested Cross-Sectional Study.
    (Research Square, 2021) Buzibye, Allan; Wools-Kaloustian, Kara; Olagunju, Adeniyi; Twinomuhwezi, Ellon; Yiannoutsos, Constantin; Owen, Andrew; Neary, Megan; Matovu, Joshua; Banturaki, Grace; Castelnuovo, Barbara; Lamorde, Mohammed; Khoo, Saye; Waitt, Catriona; Kiragga, Agnes
    We investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV started on anti-retroviral therapy during pregnancy and with high viremia during post-partum. Methods This was a cross sectional study. Women between 6-12 weeks post-partum with viral load >1000 copies/ml were eligible. Sanger sequencing to detect resistant mutations and host genotyping were performed. We categorized efavirenz metabolizer genotype according to the AIDS clinical trials group algorithm as slow, intermediate and extensive; and compared efavirenz resistance among the metabolizer genotypes. Results Over a one-year period (July 2017-July 2018), three hundred and thirty two women were screened of whom 112 (34.8%) had viral load ≥1000 copies/ml of whom 62 had whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. We observed a higher frequency of efavirenz resistance among slow metabolizers (47% versus 34% in extensive and 28% in intermediate, metabolizers) but due to low numbers, this was not statistically significant. Conclusions Our findings raise the possibility that CYP2B6 polymorphism may contribute to efavirenz drug resistance in women started on antiretroviral therapy during pregnancy and with high viremia in the post-partum period. If confirmed in a larger study, this would have important implications for all patients in sub- Saharan Africa receiving efavirenz and add further support to the changes in World Health Organization policy to switch away from efavirenz as first line antiretroviral therapy in countries with a high prevalence of CYP2B6 polymorphisms.
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    Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study)
    (PLoS Med, 2019) Waitt, Catriona; Orrell, Catherine; Walimbwa, Stephen; Singh, Yashna; Kintu, Kenneth; Simmons, Bryony; Kaboggoza, Julian; Sihlangu, Mary; Coombs, Julie- Anne; Malaba, Thoko; Byamugisha, Josaphat; Amara, Alieu; Gini, Joshua; Else, Laura; Heiburg, Christie; Hodel, Eva Maria; Reynolds, Helen; Mehta, Ushma; Byakika-Kibwika, Pauline; Hill, Andrew; Myer, Landon; Lamorde, Mohammed; Khoo, Saye
    The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). Methods and findings In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28–36 weeks of gestation, age 26 (19–42), weight 67kg (45–119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma.
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    Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults
    (Journal of Antimicrobial Chemotherapy, 2012) Byakika-Kibwika, Pauline; Lamorde, Mohammed; Mayito, Jonathan; Nabukeera, Lillian; Namakula, Rhoda; Mayanja-Kizza, Harriet; Katabira, Elly; Ntale, Muhammad; Pakker, Nadine; Ryan, Mairin; Hanpithakpong, Warunee; Tarning, Joel; Lindegardh, Niklas; Vries, Peter J. de; Khoo, Saye; Back, David
    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.
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    Steady-state pharmacokinetics of lopinavir plus ritonavir when administered under different meal conditions in HIV-infected Ugandan adults
    (Journal of acquired immune deficiency syndromes, 2012) Lamorde, Mohammed; Byakika-Kibwika, Pauline; Boffito, Marta; Nabukeera, Lillian; Mayito, Jonathan; Ogwal- Okeng, Jasper; Tjia, John; Back, David; Khoo, Saye; Ryan, Mairin; Merry, Concepta
    We investigated the effect of food on the steady-state pharmacokinetics of lopinavir and ritonavir in 12 Ugandan patients receiving lopinavir co-formulated with ritonavir (LPV/r) tablets using a cross-over design. Intensive pharmacokinetic sampling was performed seven days apart following LPV/r dosing under moderate fat, high fat and fasted meal conditions. Lopinavir and ritonavir concentrations were determined by liquid chromatography and tandem mass spectrometry. Compared to the fasted state, a high fat meal reduced lopinavir and ritonavir area under the curve (AUC) by 14% and 29%, respectively. With a moderate fat meal, AUC for both drugs was similar to the fasted state.
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    Suboptimal Nevirapine Steady-State Pharmacokinetics During Intrapartum Compared With Postpartum in HIV-1–Seropositive Ugandan Women
    (Journal of acquired immune deficiency syndromes, 2010) Lamorde, Mohammed; Byakika-Kibwika, Pauline; Okaba-Kayom, Violet; Flaherty, John P.; Boffito, Marta; Namakula, Rhoda; Ryan, Mairin; Nakabiito, Clemensia; Back, David J.; Khoo, Saye; Merry, Concepta; Scarsi, Kimberly K.
    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 RNAwas performed within 2weeks of each visit. Nevirapine C12 above 3000 ng/mLwas classified as optimal based on the suggested value for therapeutic drug monitoring.
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    Support, not blame: safe partner disclosure among women diagnosed with HIV late in pregnancy in South Africa and Uganda
    (BioMed Central Ltd, 2024-03) Twimukye, Adelline; Alhassan, Yussif; Ringwald, Beate; Malaba, Thokozile; Myer, Landon; Waitt, Catriona; Lamorde, Mohammed; Reynolds, Helen; Khoo, Saye; Taegtmeyer, Miriam
    Abstract HIV partner disclosure rates remain low among pregnant women living with HIV in many African countries despite potential benefits for women and their families. Partner disclosure can trigger negative responses like blame, violence, and separation. Women diagnosed with HIV late in pregnancy have limited time to prepare for partner disclosure. We sought to understand challenges around partner disclosure and non-disclosure faced by women diagnosed with HIV late in pregnancy in South Africa and Uganda and to explore pathways to safe partner disclosure. We conducted in-depth interviews and focus group discussions with pregnant women and lactating mothers living with HIV (n = 109), disaggregated by antenatal care (ANC) initiation before and after 20 weeks of gestation, male partners (n = 87), and health workers (n = 53). All participants were recruited from DolPHIN2 trial sites in Kampala (Uganda) and Gugulethu (South Africa). Topic guides explored barriers to partner disclosure, effects of non-disclosure, strategies for safe disclosure. Using the framework analysis approach, we coded and summarised data based on a socio-ecological model, topic guides, and emerging issues from the data. Data was analysed in NVivo software. Our findings illustrate pregnant women who initiate ANC late experience many difficulties which are compounded by the late HIV diagnosis. Various individual, interpersonal, community, and health system factors complicate partner disclosure among these women. They postpone or decide against partner disclosure mainly for own and baby's safety. Women experience stress and poor mental health because of non-disclosure while demonstrating agency and resilience. We found many similarities and some differences around preferred approaches to safe partner disclosure among female and male participants across countries. Women and male partners preferred healthcare workers to assist with disclosure by identifying the 'right' time to disclose, mentoring women to enhance their confidence and communication skills, and providing professional mediation for partner disclosure and couple testing. Increasing the number of counsellors and training them on safe partner disclosure was deemed necessary for strengthening local health services to improve safe partner disclosure. HIV diagnosis late in pregnancy amplifies existing difficulties among pregnant women. Late ANC initiation is an indicator for the likelihood that a pregnant woman is highly vulnerable and needs safeguarding. Respective health programmes should be prepared to offer women initiating ANC late in pregnancy additional support and referral to complementary programmes to achieve safe partner disclosure and good health.