Clinical pharmacology considerations and drug-drug interactions with long-acting cabotegravir and rilpivirine relevant to sub-Saharan Africa.

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.

Off-label antibiotic use among paediatric in-patients: a mixed-method prospective study at a tertiary hospital in southwestern Uganda.

Background The off-label use of drugs to treat children is a global practice attributed to the traditional exclusion of children from clinical trials mainly due to practical and ethical reasons. Off-label drug use carries both benefits and risks, but data regarding this use pattern are scanty in sub-Saharan Africa. Objective To determine the incidence and predictors of off-label antibiotic use in children less than 5 years admitted at Mbarara Regional Referral Hospital (MRRH) in southwestern Uganda. Setting A prospective drug utilisation study was conducted among in-patients at the Paediatric Ward of MRRH from May to June 2019. Methods Clinical records and treatment notes of all children aged 0 to 59 months with at least one antibiotic prescription during the admission period were reviewed and included for data collection. Key informant interviews were conducted with physicians attending to patients in the Paediatric Ward. Main outcome measure Off-label use and potential predictors of off-label antibiotic use. Results Of 427 children admitted to the Paediatric Ward, 165 (38.6%) received 366 antibiotic prescriptions. However, 359 prescriptions belonging to 162 patients were analyzed. Off-label prescriptions occurred in 18.9% (95% CI: 14.9-23.0) of antibiotic prescriptions. Two categories of off-label prescriptions were found: off-label frequency of administration (n = 55, 80.9%), and off-label doses (n = 13, 19.1%). Ceftriaxone was the most common antibiotic prescribed at off-label doses, (n = 6, 8.8%) while ampicillin was the most common antibiotic prescribed with an off-label frequency of administration, (n = 39, 57.3%). Infants (1-23 months) received the majority (47.1%) of off-label antibiotic prescriptions; neonates (0-28 days) received 27.9%, and children (24-59 months) received 25% of the prescriptions. Controlling for sex and disease severity, age category remained significantly associated with off-label antibiotic use on multivariate analysis. Conclusion Off-label frequency of administration was the major category of off-label drug use, while off-label dose was the minor category. Age was a significant factor for off-label antibiotic prescription, with infants receiving the highest number of off-label prescriptions. Attending physicians identified several justifiable circumstances that warrant off-label antibiotic use and support emerging "well-founded" off-label uses of antibiotics in different paediatric age groups.

Variations in Trim5α and Cyclophilin A genes among HIV-1 elite controllers and non controllers in Uganda: a laboratory-based cross-sectional study.

BACKGROUND: Tripartite Motif Containing 5 alpha (TRIM5α), a restriction factor produced ubiquitously in cells and tissues of the body plays an important role in the immune response against HIV. TRIM5α targets the HIV capsid for proteosomal destruction. Cyclophilin A, an intracellular protein has also been reported to influence HIV infectivity in a cell-specific manner. Accordingly, variations in TRIM5α and Cyclophilin A genes have been documented to influence HIV-1 disease progression. However, these variations have not been documented among Elite controllers in Uganda and whether they play a role in viral suppression remains largely undocumented. Our study focused on identifying the variations in TRIM5α and Cyclophilin A genes among HIV-1 Elite controllers and non-controllers in Uganda. RESULTS: From the sequence analysis, the rs10838525 G > A mutation in exon 2 of TRIM5α was only found among elite controllers (30%) while the rs3824949 in the 5'UTR was seen among 25% of the non-controllers. In the Cyclophilin A promoter, rs6850 was seen among 62.5% of the non-controllers and only among 10% elite controllers. Furthermore, rs17860048 in the Cyclophillin A promoter was predominantly seen among elite controllers (30%) and 12.5% non-controllers. From gene expression analysis, we noted that the respective genes were generally elevated among elite controllers, however, this difference was not statistically significant (TRIM5α p = 0.6095; Cyclophilin A p = 0.6389). CONCLUSION: Variations in TRIM5α and Cyclophillin A promoter may influence HIV viral suppression. The rs10838525 SNP in TRIM5α may contribute to viral suppression among HIV-1 elite controllers. The rs6850 in the cyclophillin A gene may be responsible for HIV-1 rapid progression among HIV-1 non-controllers. These SNPs should be investigated mechanistically to determine their precise role in HIV-1 viral suppression.