Evaluation of cardiotoxicity and other adverse effects associated with concomitant administration of artemether/lumefantrine and atazanavir/ritonavir-based antiretroviral regimen in patients living with HIV.

The interplay of artemether-lumefantrine (AL) and atazanavir-ritonavir (ATVr) with Cytochrome P (CYP) 3A4 isoenzyme and QTc-interval may spawn clinically significant drug interactions when administered concomitantly. Cardiotoxicity and other adverse effects associated with interaction between AL and ATVr were evaluated in patients with HIV infection and malaria comorbidity. In a two-arm parallel study design, six doses of AL 80/480 mg were administered to 20 participants [control-arm (n = 10) and ATVr-arm (n = 10)], having uncomplicated Falciparum malaria, at intervals of 0, 8, 24, 36, 48 and 60 h respectively. Participants in the control arm took only AL while those in ATVr-arm took both AL and ATVr-based ART regimen. Electrocardiography, adverse events monitoring and blood tests were carried out for each of them at pre and post doses of AL. Data obtained were analyzed. QTc-interval was significantly increased in the ATVr-arm (0.4079 ± 0.008 to 0.4215 ± 0.007 s, p = 0.008) but not in the control-arm (0.4016 ± 0.018 to 0.4024 ± 0.014 s, p = 0.962). All values were, however, within normal range [0.36 - 0.44 / 0.46 s (male/female)]. General body weakness and chest pain were new adverse events reported, at post-dose of AL, in the ATVr-arm but not in the control-arm. There was no significant change (p > 0.05) in the plasma levels of creatinine, alanine aminotransferase, aspartate aminotransferase and hemoglobin at post-dose compared to pre-dose of AL in both arms of study. Concomitant administration of artemether-lumefantrine with atazanavir-ritonavir-based regimen is potentially cardiotoxic but not associated with clinically significant renal, blood nor liver toxicities. They must be used with caution.

Low prevalence of isoniazid preventive therapy uptake among HIV-infected patients attending tertiary health facility in Lagos, Southwest Nigeria.

INTRODUCTION: the burden of HIV and tuberculosis co-infection is a global public health challenge. Despite the benefit of isoniazid preventive therapy (IPT) in reducing the rate of co-infection, the uptake is generally limited in developing countries. This study aimed to determine the prevalence of IPT use and the factors affecting the uptake among HIV-infected patients attending our Teaching Hospital. METHODS: this cross-sectional survey involved 300 HIV-infected individuals attending the AIDS prevention initiatives in Nigeria clinic of the Lagos University Teaching Hospital. A self-designed and well-structured questionnaire was used to document the demographic data, patients' exposure to tuberculosis, and IPT uptake. Clinical data of eligible patients were also extracted from their case notes. The main outcome measure was the prevalence of IPT use and non-use. RESULTS: out of the respondents evaluated, (72.7%, n = 218) were females. Tuberculosis was the predominant comorbidity (15.7%, n = 47) and majority (53.0%, n = 159) had a CD4 count of < 500 cells/ml. Overall prevalence of IPT uptake was very low (7.1%, n = 18) among HIV-infected patients. Major factors affecting uptake were lack of awareness of benefit (44.4%, n = 8) and lack of fear of contracting tuberculosis (22.2%, n = 4). However, lack of awareness of IPT benefit was the only independent factor associated with poor IPT uptake (adjusted odds 1168.75, 95% confidence interval: 85.05-16060.33; p = 0.001). CONCLUSION: isoniazid preventive therapy uptake was found to be very low in this study. Increased awareness and policy implementation of IPT by the healthcare provider is necessary.

Evaluation of the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine in patients living with HIV in Lagos University Teaching Hospital, South-Western Nigeria.

PURPOSE: Atazanavir-ritonavir (ATVr)-based antiretroviral therapy and artemether-lumefantrine (AL) are commonly used drugs for the treatment of human immune deficiency virus (HIV) infection and malaria respectively. However, interaction of both drugs, with Cytochrome P 3A4 (CYP 3A4) isoenzyme, may spawn clinically significant pharmacokinetic interactions. This study evaluated the effects of atazanavir-ritonavir on the pharmacokinetics of lumefantrine. METHOD: In a case-control study, twenty participants having Plasmodium falciparum malaria were recruited and divided into two groups (ATVr-arm, n=10; and control-arm, n= 10). All the participants were administered six oral doses of AL 80-480 mg (Coartem). Thereafter, their blood samples were collected at different time intervals over seven days. The concentration of lumefantrine in each sample was quantified with high-performance liquid chromatography (HPLC) and used to determine its pharmacokinetic parameters which were compared between the test and control groups. RESULTS: ATVr increased the mean day 7 concentration of lumefantrine (ATVr 3847.09 ± 893.35 ng/mL, control 1374.53 ± 265.55 ng/mL, p = 0.016) and the area under its plasma concentration-time curve (ATVr 670529.57 ± 157172.93 ng.h/mL, control 447976.28 ± 80886.99 ng.h/mL, p = 0.224) by 179.88 % and 49.68 %, respectively, but decreased its mean maximum plasma drug concentration (Cmax) (ATVr 13725.70 ± 2658.44 ng/mL, control 15380.48 ± 2332.62 ng/mL, p = 0.645) by 10.76 %. CONCLUSION: ATVr increased drug exposure and day 7 plasma concentration of lumefantrine. AL is therefore considered effective for the treatment of malaria in patients taking ATVr-based regimen. However, the safety associated with the interaction requires further elucidation. TRIAL REGISTRATION: Clin ClinicalTrials.gov Identifier: NCT04531072, August 27, 2020. "Retrospectively registered".

Effect of nevirapine, efavirenz and lopinavir/ritonavir on the therapeutic concentration and toxicity of lumefantrine in people living with HIV at Lagos University Teaching Hospital, Nigeria.

Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.

Clinically Significant Drug-Drug Interaction in a Large Antiretroviral Treatment Centre in Lagos, Nigeria.

Background: An important cause of treatment failure to antiretroviral therapy (ART) is the potential interaction between the antiretroviral (ARV) drugs and co-prescribed drugs used concomitantly for the treatment of opportunistic infections and co-morbid ailments in HIV-infected patients. Objectives: The study evaluated potential clinically significant drug interactions (CSDIs) occurring between recommended ART regimens and their co-prescribed non-antiretroviral drugs (CPD) Method: This study was carried out in a large HIV treatment centre (APIN clinic) in a Nigerian teaching hospital, in Lagos Nigeria, caring for over 20,000 registered patients. Electronic Medical Records (EMR) of 500 patients  who received treatment between 2005 and 2015, were selected using systematic random sampling, reviewed retrospectively, and evaluated for potential CSDIs using Liverpool HIV Pharmacology Database and other similar databases.                                                                                                                                          Results:  Majority of patients, 421 (84%) were at risk of CSDIs, of  which  410, (82%) were moderate and frequently involved co-trimoxazole + zidovudine (or stavudine) /lamivudine (386, 77.2%) and NNRTIs or PIs + artemisinin-based combination therapies (ACTs) [296, 59.2%]. Age (p=0.131), sex (p=0.316) and baseline CD4+ cell counts (p>0.05) were not significantly associated with CSDIs. The interactions, however, were significantly associated with the development of antiretroviral treatment failure (p <0.001) which occurred in nearly a third (139; 27.8%) of the patients. Conclusion: There is a high prevalence of CSDIs between ART and CPDs most of which were categorized as moderate.  Further studies are required to evaluate the pharmacokinetic and clinical relevance of these interactions.