Table 2.
Examples of medicines that interact significantly with commonly used ART
| Drug | Antiretroviral | Interaction and management |
|---|---|---|
| Aluminium hydroxide/magnesium hydroxide | DTG | DTG forms insoluble complexes with metals (di- and tri-valent). Simultaneous coadministration of aluminium-containing antacids with DTG (50 mg once daily) decreased DTG Cmax, AUC and Ctrough by 72, 74 and 74%, respectively. Antacid should be taken a minimum of 2 hours after or 6 hours before dolutegravir. Avoid combination in the presence of integrase class resistance. |
| LPV/ATV/DRV + r | ATV solubility/absorption decreases as pH increases. ATV should be administered 2 hours before or 1 hour after antacids. | |
| RAL | Decreased RAL exposure. Do not coadminister. | |
| RPV | RPV plasma concentration decreases as the pH increases. Administer antacids 2 hours before or 4 hours after RPV. | |
| Amikacin/kanamycin/amphotericin B | TDF | Potential for additive nephrotoxicity. Avoid concurrent use if possible or monitor renal function weekly if concurrent use unavoidable. |
| Amlodipine | LPV/ATV/DRV + r | Amlodipine levels significantly increased by PIs. Both ATV and calcium channel blockers can prolong PR interval. Use with caution. If coadministration is indicated, consider a dose reduction for amlodipine of 50%. ECG monitoring is recommended. |
| Bedaquiline | EFV | Models predict that long-term use of EFV could decrease bedaquiline AUC by 50%. Also, additive risk of QT prolongation. Avoid combination. |
| ETR | No data available, but ETR may reduce bedaquiline exposure due to induction of CYP3A4. Avoid combination until more data available. | |
| LPV/ATV/DRV + r | A 2- to 3-fold increase in the exposure of bedaquiline is expected with LPV/r. No data for other PIs, but similar interaction expected. Clinical significance is unknown, monitor ECG and LFTs monthly. | |
| Calcium salts/ferrous salts | DTG | DTG forms insoluble complexes with metals (di- and trivalent). If taken with food, this interaction is not clinically relevant. Take DTG and supplement with food or take the calcium/iron supplement a minimum of 2 hours after or 6 hours before dolutegravir. |
| LPV/ATV/DRV + r | Calcium-containing products used as antacids may reduce plasma concentrations of ATV. Administer atazanavir 2 hours before or 1 hour after calcium-containing products used as antacids. | |
| RAL | RAL binds to divalent cations such as calcium/iron and forms a complex at the level of the gastrointestinal tract, which results in less raltegravir being absorbed. Separate doses by at least 4 hours. | |
| RPV | Calcium products used as antacids increase gastric pH and may lead to decreased RPV plasma concentrations. Administer antacid at least 2 hours before or 4 hours following RPV administration. | |
| Carbamazepine/phenobarbitone/phenytoin | DTG |
Carbamazepine: Coadministration of carbamazepine and DTG (50 mg once daily) decreased DTG Cmax, AUC and Cmin by 33, 49 and 73%, respectively. Use DTG 50 mg twice daily in treatment-naive or treatment-experienced patients but integrase inhibitor-naive. Avoid combination when integrase inhibitor resistance suspected. Phenobarbitone/phenytoin: Decreased DTG concentrations expected due to induction of UGT1A1 and CYP3A by phenobarbital/phenytoin. Avoid combination. Safer alternatives include lamotrigine and levetiracetam. |
| EFV | When EFV is administered concomitantly, there is a reduction in the plasma concentrations of both drugs. Avoid combination. Valproic acid (contraindicated in pregnancy and women of childbearing age), lamotrigine or levetiracetam can be used as an alternative. | |
| ETR | Reduced plasma concentrations of ETR. Avoid combination. Valproic acid (contraindicated in pregnancy and women of childbearing age), lamotrigine or levetiracetam can be used as an alternative. | |
| LPV/ATV/DRV + r | Coadministration may result in decreased concentrations of protease inhibitors. Also, PIs may increase the levels of carbamazepine and decrease phenytoin concentrations. Avoid combination. Valproic acid (contraindicated in pregnancy and women of childbearing age), lamotrigine (may require higher dose) or levetiracetam can be used as an alternative to carbamazepine. | |
| NVP | NVP may cause decreased carbamazepine plasma concentrations. Also, carbamazepine, phenytoin and phenobarbitone may lower NVP concentrations. Avoid combination. Valproic acid (contraindicated in pregnancy and women of childbearing age), lamotrigine or levetiracetam can be used as an alternative. | |
| RAL | Theoretically, RAL concentrations may be reduced via induction of glucuronidation. Consider therapeutic drug monitoring for RAL or monitor antiviral efficacy closely. | |
| RPV | Theoretically, RPV concentrations may be reduced via induction of CYP3A. Avoid combination. | |
| Cimetidine/ranitidine | LPV/ATV/DRV + r | No clinically significant interaction with LPV/DRV/r, but significantly reduces absorption of atazanavir. Atazanavir: management complicated and dependent on ARV regimen and dose of cimetidine/ranitidine. |
| RPV | Coadministration may decrease RPV concentrations due to decreased absorption. Use H2 antagonists that can be dosed once daily and take it at least 12 hours before or 4 hours after RPV. | |
| Contraceptives, oral | EFV | EFV did not change ethinylestradiol (EE) AUC, but significantly reduced exposure to the active metabolites of norgestimate. In another study, levonorgestrel levels were significantly reduced. Coadministration is expected to reduce contraceptive efficacy of desogestrel and EFV concentrations decreased by 22%. Use with caution. Avoid low-dose oral contraceptives (<35 mcg of EE). High-dose oral or injectable contraceptive or IUD are options. In addition, a barrier method must be used. |
| LPV/ATV/DRV + r | Ethinylestradiol (EE) AUC decreased by 42% and norethisterone concentration also decreased by LPV/r. Unboosted ATV may increase EE levels. ATV boosted with ritonavir decreased EE levels. DRV decreased EE AUC by 44%. Use with caution. LPV/ATV/DRV + r: Avoid low-dose OCs (<35 mcg of EE). High-dose oral or injectable contraceptive or IUD are options. In addition, a barrier method must be used. ATV (unboosted): use no more than 30 mcg EE. | |
| NVP | Ethinylestradiol and norethisterone AUCs are decreased by 29 and 18% respectively by NVP. Use with caution. Avoid low-dose OCs (<35 mcg of EE). High-dose oral or injectable contraceptive or IUD are options. In addition, a barrier method must be used. Subsequent research has demonstrated no significant difference in ovulation and pregnancy rates. | |
| Diazepam | EFV | Conflicting data on whether EFV is predicted to increase/decrease diazepam exposure. Avoid combination. Lorazepam, oxazepam or temazepam are safer alternatives. |
| ETR | Conflicting data on whether ETR is predicted to increase/decrease diazepam exposure. Alternatives to diazepam should be considered. Lorazepam, oxazepam or temazepam are safer alternatives. | |
| LPV/ATV/DRV + r | Unpredictable. Avoid combination. Lorazepam, oxazepam or temazepam are safer alternatives. | |
| NVP | Theoretically, NVP may reduce diazepam levels. Monitor for diazepam effects, and withdrawal symptoms when adding NVP to patient already on diazepam. | |
| Esomeprazole/lansoprazole/omeprazole | LPV/ATV/DRV + r | ATV: 75 and 94% decrease in AUC of ATV with omeprazole and lansoprazole, respectively. Coadministration of ATV and proton pump inhibitors is generally not recommended. If unavoidable, consider increasing ATV dose to 400 mg daily with ritonavir 100 mg daily and limiting the PPI dose to the equivalent of 20 mg omeprazole. |
| RPV | Decreased RPV concentrations due to reduced absorption of RPV as a result of an increase in gastric pH. Avoid combination. | |
| Etonogestrel | EFV | Coadministration decreases etonogestrel levels due to induction of CYP3A4. Increased risk of pregnancy has been reported. Contraindicated. |
| ETR | Coadministration is predicted to decrease etonogestrel levels due to induction of CYP3A4. Use another method of contraception. | |
| Fluticasone | LPV/ATV/DRV + r | Increased fluticasone levels possibly resulting in decreased plasma cortisol concentrations (e.g. Cushing’s syndrome, adrenal suppression). Avoid combination. Safer alternative is beclomethasone. |
| Itraconazole | EFV | Itraconazole effects decreased. In addition, increased risk of QT interval prolongation in some patients, for example, slow metabolisers of efavirenz. Avoid concurrent use. |
| ETR | ETR is predicted to decrease itraconazole concentrations, and itraconazole is expected to increase ETR plasma concentrations. Use with caution. | |
| LPV/ATV/DRV + r | Effects of both itraconazole and PIs may be increased. High doses of itraconazole (greater than 200 mg/day) are not recommended. Monitor for toxicity. Suggested alternative is fluconazole or terbinafine. | |
| NVP | Itraconazole levels reduced. Do not coadminister. | |
| RPV | Potential increase in RPV concentrations. Ketoconazole AUC decreased 24% by 150mg RPV. No dosage adjustment required. Monitor clinical effect of antifungal. | |
| TDF | Tenofovir-DF absorption may be increased via P-glycoprotein inhibition. Monitor renal function frequently, when using tenofovir-DF. | |
| Metformin | DTG | DTG increases metformin AUC by 79% (once daily) – 145% (twice daily). If concomitant use is needed, limit total daily dose of metformin to 1000 mg when starting metformin or DTG. Monitor renal function and blood glucose when starting and stopping. |
| Rifabutin | EFV | Decreased rifabutin effects. Increase rifabutin to 450 mg/day or 600 mg three times per week with concomitant EFV. |
| ETR | ETR AUC decreased by 37%. No dosage adjustment required, unless coadministered with a boosted PI. With boosted PI: caution and monitoring recommended and the US guidelines suggest ETR and rifabutin should not be coadministered with boosted DRV, LPV or saquinavir. | |
| LPV/ATV/DRV + r | Significantly increased rifabutin levels. Reduce rifabutin dose to 150 mg daily and monitor for adverse events such as neutropenia and uveitis. | |
| RPV | RPV AUC decreased by 42%. Increase RPV dose to 50 mg once daily. | |
| Rifampicin | DTG | Decreased DTG concentrations due to induction of UGT1A1 and CYP3A by rifampicin. If no integrase inhibitor mutations present, increase DTG dose to 50 mg twice daily. Avoid DTG if integrase inhibitor mutations present. |
| ETR | Decreased ETR concentrations. Contraindicated. | |
| LPV/ATV/DRV + r | Rifampicin reduces ATV, DRV and LPV levels. Increases in ALT/AST. Dosage adjustment required in resource-limited settings where rifabutin not readily available: Adults: The dose of LPV/r should be doubled slowly over 2 weeks (to 800/200 mg twice daily). Monitor ALT while increasing the dose at weekly intervals, and then monthly while on double dose. Children: Extra ritonavir should be added at a dose of 0.75 × the volume of the LPV/r dose. Avoid concurrent use with ATV/r and DRV/r as dose adjustment not established. Consider rifabutin 150mg daily as an alternative. | |
| NVP | Decreased NVP levels (AUC decreased by 58%). Switch to another ARV, if possible. If switch not possible, then consider monitoring trough NVP levels and adjusting dose accordingly. Monitor liver function closely. | |
| RAL | RAL AUC and minimum plasma concentration decreased by 40 and 61%, respectively. Although the manufacturer states that doubling of RAL dose to 800 mg twice daily can be considered, a clinical trial has shown that a dose adjustment may not be necessary. Monitor virological response closely. No data in children. | |
| RPV | RPV AUC decreased by 80%. Contraindicated. | |
| Simvastatin | EFV | EFV significantly reduces the concentrations of simvastatin. Patients should be closely monitored for antilipid activity and the simvastatin dose may need to be increased. |
| ETR | Decreased simvastatin exposure. Monitor response. Dose adjustments for simvastatin may be needed. | |
| LPV/ATV/DRV + r | Significantly increased simvastatin levels. Do not coadminister due to an increased risk of myopathy including rhabdomyolysis. Low-dose atorvastatin (max 10 mg/day) or pravastatin are alternatives. | |
| NVP | Potential for decreased concentrations of simvastatin due to enzyme induction by NVP. Patients should be closely monitored for antilipid activity, and the simvastatin dose may need to be increased. | |
| RAL | Additive risk of myopathy and rhabdomyolysis. Use with caution. |
This table has been compiled using: HIV-druginteractions.org. Liverpool HIV interactions. 2019. https://www.hiv-druginteractions.org. Accessed August–November 2018; Preston C, ed. Stockley’s Drug Interactions. 11th ed. Italy: Pharmaceutical Press; 2016; NCBI.nlm.nih.gov. Home – PubMed – NCBI. 2019. https://www.ncbi.nlm.nih.gov/pubmed. Accessed August–November 2018; Micromedexsolutions.com. DRUGDEX detailed drug information. 2019. http://www.micromedexsolutions.com. Accessed August–November 2018.
AUC, area under the curve; RAL, raltegravir; EFV, efavirenz; ETR, etravirine; LPV, lopinavir; ATV, atazanavir; DRV, darunavir; r, ritonavir; NVP, nevirapine; RPV, rilpivirine; DTG, dolutegravir; TDF, tenofovir;