- Three protease inhibitor (PI) combinations are recommended in southern Africa: lopinavir (LPV), atazanavir (ATV) or darunavir (DRV), each given with low-dose ritonavir (RTV; indicated as /r) for pharmacokinetic boosting.
- Ritonavir-boosted lopinavir (LPV/r) is the only PI combination that can be used with RIF-based TB treatment, but the dose of LPV/r must be doubled.
- ATV and DRV offer a better side-effect profile than LPV.
- DRV has the highest barrier to resistance of any drug in this class.
Overview of protease inhibitors
Protease inhibitors (PIs) are a class of agents that inhibit HIV’s protease enzyme, which is required to cleave HIV’s polyproteins into the final protein products that permit the production of infectious viral particles. Inhibition of this process results in immature, non-infectious virions.
Three PI combinations are recommended for use in southern Africa: lopinavir (LPV), atazanavir (ATV) and darunavir (DRV), each given with low-dose ritonavir (RTV; indicated as /r).
RTV is a PI in its own right, but is used principally as a pharmacokinetic ‘booster’. As a potent inhibitor of CYP3A4, its use results in higher drug levels and prolonged half-lives of its companion PI. This allows for lower or less frequent PI dosing, and decreases the chance of viral resistance developing. In rare situations, ATV is used without boosting in first-line therapy. However, this inhibition of CYP3A4, together with several other cytochrome P450 enzymes and P-glycoprotein, results in numerous drug-drug interactions with other medications. See Module 17.
|Common pitfall: Not using a drug interaction checker when prescribing PI-based ART with other medications. Clinically relevant drug-drug interactions are common with this class.|
All PIs may be associated with cardiac conduction abnormalities (especially PR interval prolongation). This seldom results in clinically significant effects, but caution should be taken when co-prescribing other drugs that cause delayed cardiac conduction, such as macrolides or bedaquiline. All PIs are, to some degree, associated with metabolic side-effects. Elevated triglycerides (TG) and elevated low-density lipoprotein cholesterol (LDL-C) are class effects, although these side-effects are more marked with LPV/r than with other PI combinations.31,32
Dosing and common ADRs of PIs are described in Table 6.
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|TABLE 6: Dosage and common adverse drug reactions of protease inhibitor drugs available in southern Africa.|
|Drug/combination||Recommended dosage||Common or severe ADR|
||Unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), dyslipidaemia (low potential), renal stones (rare), hepatitis (uncommon)|
||GI upset, dyslipidaemia, hepatitis|
||GI upset, rash, dyslipidaemia, hepatitis (uncommon)
Contains sulphonamide moiety (use with caution in patients with sulpha allergy)
ADR, adverse drug reaction; ATV/r, ritonavir-boosted atazanavir; DRV/r, ritonavir-boosted darunavir; EFV, efavirenz; GI, gastrointestinal; LPV/r, ritonavir-boosted lopinavir; PI, protease inhibitor.
†, Avoid the combination of ETR + ATV/r (due to drug interaction).
Individual protease inhibitors
Lopinavir (LPV) is co-formulated with ritonavir (LPV/r, e.g. Aluvia). In general, this twice-daily regimen has greater gastrointestinal (GI) side-effects than other PI combinations, and is associated with a worse metabolic profile. LPV is the only PI that can be used concurrently with RIF-based TB treatment; the LPV/r dose has to be doubled in this instance to 800 mg/200 mg twice daily until 2 weeks after RIF has been stopped (see Module 18).
|Common pitfall: Forgetting to double the dose of LPV/r when starting RIF-based TB treatment.|
Atazanavir (ATV) is generally better tolerated than LPV and can be taken once daily. It has important drug interactions with drugs that reduce stomach acidity, such as PPIs. ATV may cause an unconjugated hyperbilirubinaemia as a result of inhibition of the hepatic enzyme uridine-5-diphospho (UDP)-glucuronosyltransferase. Though the hyperbilirubinaemia is harmless and does not reflect a drug-induced liver injury (DILI), a minority of patients will become visibly jaundiced, and this may require switching ART regimens for cosmetic reasons.
|Common pitfall: Mistaking the unconjugated hyperbilirubinaemia sometimes seen with ATV use with a DILI. Conversely, it is equally important to note that ARVs can also cause a true DILI; therefore, a full liver function test (LFT) panel should be checked to distinguish between the two possibilities.|
Darunavir (DRV) has the highest barrier to resistance of any PI. Mutations selected by ATV or LPV can compromise DRV efficiency. For patients with mutations that confer any degree of resistance to DRV (e.g. I50V, L76V, I84V), the dose should be DRV/r 600 mg/100 mg twice daily. For patients without any DRV mutations, the drug can be taken at a dose of DRV/r 800 mg/100 mg once daily. There is evidence, however, that DRV/r 400 mg/100 mg once daily may be sufficient in this scenario, especially for patients with suppressed VLs at the time of the switch.33,34 Compared with twice-daily dosing, once-daily dosing offers the benefits of reduced pill burden and better side-effect profile. As with ATV, DRV cannot be co-prescribed with RIF-based TB treatment.
|Common pitfall: Prescribing ATV or DRV for patients receiving RIF-based TB treatment. LPV/r is the only PI combination that can be co-prescribed safely with RIF, but the dose of LPV/r must be adjusted as above.|