Efavirenz side effects and other drug-drug interactions are common in Ugandan cohort
29 June 2018. Related: Conference reports, PK and drug interactions, Side effects, PK Workshop 19th 2018 Baltimore.
Drug-drug interactions and side effects, associated with currently-used first-line ART, are under-reported and managed in Uganda, according to findings presented at the 19th International Workshop on Clinical Pharmacology. 
Investigators from Makerere University and University of Liverpool are conducting an ongoing longitudinal study in adult outpatients taking current ART at three clinics in central Uganda.
In the study, trained pharmacy technicians take medication histories, including side effects. Drug-drug interaction (DDI) screening and side effect assessment is undertaken by pharmacists and clinicians using standardised tools.
The study enrolled 868 participants and this analysis described an initial 416 taking first-line regimens.
Most (72%) participants receiving first-line were on an efavirenz (EFV)-based regimen; 287 (69%) were women; median age was 35 years and time on ART was 36 months.
Of the 416 on first-line ART, 25.5% had at least one clinically significant DDI. People with clinically significant DDIs were more likely to report an adverse event: OR 1.86 (95% CI 1.16 to 2.98), p=0.0059. EFV was associated with reporting adverse events: OR 1.84 (95% CI 1.15 to 2.98), p=0.007. But EFV was not associated with DDIs: OR 0.76 (95% CI 0.46 to 1.27), p=0.265.
Of 252 total adverse events, 72.6% were probably or possibly related to EFV. Symptoms lasted for a median of 22 months (IQR 9–35.3). Of 123 evaluable reports, 83.7% of persistent nervous system/psychiatric disorder adverse events were not recorded in clinical notes.
Among 149 participants taking antimicrobials (antimalarials, antibiotics, antifungals, antivirals) 40.3% had a clinically significant DDI. These affected 14.4% of the 416 participants on first-line ART – accounting for approximately 40% of all clinically significant DDIs.
Of 37 women on first-line line ART who reported using hormonal contraceptives, nine experienced a DDI that put them at significant risk of contraceptive failure.
Prescribers were only aware of 3.5% of clinically significant DDIs (n=144). DDI checks provided new information in 56.1% of cases (n=214); prescribers changed participant management in 53.1% of cases (n=309); DDI checks saved time in 68% of cases (n=200) and added benefit in 72% (n=200).
The study investigators note that, compared to currently used first-line antiretrovirals, roll-out of newer ones with lower potential for DDIs and adverse events – such as dolutegravir (DTG) – might reduce the risk of contraceptive failure, antimicrobial treatment failure and microbial resistance as well as significant morbidity due to adverse drug reactions.
They suggest that people experiencing or at high risk of clinically significant DDIs or side effects should be prioritised for switching to DTG.
This analysis was conducted before the safety signal for neural tube defects with DTG was announced. It is an important reminder of some of the reasons why the drug was prioritised in the first place as part of an optimal ART regimen – including persistent central nervous system adverse events with EFV (often not picked up by providers) and lack of interaction between DTG and hormonal contraception.
These issues, alongside that of NNRTI resistance, need to be considered in order to make more nuanced recommendations for DTG than “no women less than 50 years old”. After all, women of reproductive age are frequently not pregnant or wish to have (more) children. The emphasis should be on filling the massive unmet need for contraception for HIV positive women in low- and middle-income countries.
We reported an earlier analysis from this study in which the authors pointed out that putting up with EFV side effects in low- vs high-income countries – where people switch more routinely – is exaggerated by a genetic polymorphism (G516T in CYP P450 2B6) that significantly increases drug levels of EFV (by reducing clearance rates) being more common in African compared with white populations. 
- Seden K et al. Medication safety issues associated with currently used first-line antiretroviral regimens in Uganda. 19th International Workshop on Clinical Pharmacology. Baltimore. 22–24 May 2018. Oral abstract 9.
- Collins S. High rates of undocumented efavirenz-related side effects in Uganda. HTB. 26 June 2017.