HIV protease inhibitors (PIs) inhibit HIV-1 and HIV-2 proteases and prevent cleavage of the gag-pol polyprotein during maturation of the newly formed viral particle. This results in the production of immature, non-infectious virus. There are currently seven licensed PIs: atazanavir (ATV), darunavir (DRV), fosamprenavir (FOS), lopinavir (coformulated with ritonavir [LPV/r]), ritonavir (RTV), saquinavir (SQV) and tipranavir (TPV). Whilst ritonavir is a protease inhibitor, it is not used for its antiretroviral activity; rather, it is used as a pharmaco-enhancer by exploiting its activity as an inhibitor of the cytochrome p-450 (3A4) enzyme to boost levels of concomitantly administered PIs. Similarly, cobicistat, a newer non-PI pharmaco-enhancer, is used to boost INSTIs and PIs. These actions of ritonavir and cobicistat may also lead to interactions with other medications that are metabolised by the cytochrome p-450 (3A4) system.
Guidelines on the dosing of PIs can be found in Table 4 and adverse effects are presented in Table 5. The usual dose of ritonavir for boosting protease inhibitors is 100 mg once daily or 100-200 mg twice daily, depending on the PI being boosted (referred to as PI/r). Furthermore, ritonavir boosting increases plasma levels of PIs to levels greatly above those required to inhibit viral replication, even in the setting of one or two PI mutations. This means that the development of PI resistance is much less likely to occur for a given level of adherence. [29] Third generation PIs include ritonavir-boosted darunavir and tipranavir, which are licensed for use in patients with multidrug resistant HIV.[30][31] Boosted darunavir is also licensed for use as once daily dosing in ART-naïve patients and treatment-experienced patients infected with a HIV that has no darunavir resistance mutations.[32] Of this antiretroviral class, only darunavir is recommended for treatment initiation, largely because of different adverse effects seen with other agents in this class, including: hyperlipidaemia, hyperglycaemia, fat maldistribution, diarrhoea and hepatotoxicity.
Table 4. Guidelines on PI dosing
|
Drug |
Dosing |
Food requirement |
Dose adjustment for renal impairment |
Dose adjustment for hepatic impairment |
|
Atazanavir (300 mg or 400 mg) |
ARV-naive people:
With TDF or in ARV-experienced people:
Co-formulated with cobicistat (ATV/c): · (ATV 300 mg + COBI 150mg) once daily |
Take with food; avoid antacids, H2 antagonists and proton pump inhibitors. Seek expert advice if unsure |
No, ATV/c not recommended for use with TDF if baseline CrCl < 70 mL/min. |
Not recommended if Child-Pugh class C. If Child-Pugh class B use ATV 300 mg qd (without ritonavir) |
|
Darunavir (600 mg or 800 mg) |
800 mg qd with RTV 100 mg qd or 600 mg bd with RTV 100 mg bd if DRV-associated mutations Co-formulated with cobicistat (DRV/c): DRV 800 mg + COBI 150 mg once daily. DRV/c is not recommended for patients with DRV-associated mutations. |
Take with food |
No. DRV/c not recommended for use with TDF if baseline CrCl < 70 mL/min. |
Not recommended if severe hepatic impairment |
|
Fosamprenavir (700 mg) |
1400 mg qd with RTV 100 mg qd for ART-naïve people 700 mg bd with RTV 100 mg bd for treatment experienced people |
Without RTV, take without regard to meals. With RTV, take with meals. |
No |
Complex. Seek expert advice. Dose reduction as Child-Pugh score increases |
|
Lopinavir/ ritonavir (200 mg/50 mg) |
400 mg/100 mg bd or 800 mg/ 200 mg qd (if < 3 lopinavir-associated drug resistance mutations) |
No |
No |
Use with caution |
|
saquinavir (500 mg) |
1g bd with RTV 100 mg bd |
Take within 2 hours of food |
No |
Use with caution: mild-mod impairment. Contraindicated in severe impairment |
|
Tipranavir (TPV) (250 mg) |
500 mg bd with RTV 200 mg bd |
Take with meals |
No |
Use with caution Contraindicated with Child-Pugh class B and C |
|
qd: once daily; bd: twice daily; ART: antiretroviral treatment; RTV: ritonavir; tenofovir DF: tenofovir disoproxil fumarate |
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Table 5. Adverse effects of PIs
|
Drug |
Adverse effect |
Potentially life-threatening adverse effect |
|
All PIs |
· Hyperglycaemia · Hyperlipidaemia · Fat maldistribution · Transaminase elevations / hepatotoxicity |
|
|
Atazanavir |
· Indirect hyperbilirubinaemia · Cholelithiasis · Nephrolithiasis · Renal insufficiency · Skin rash · Increase in serum creatinine (with COBI) |
Prolonged PR interval -1st degree symptomatic AV block in some patients; use with caution in patients with conduction defects or on medications that cause PR prolongation |
|
Darunavir * |
· Skin rash (10%) – due to sulfonamide moiety · Diarrhoea, · Nausea · Headache · Increase in serum creatinine (with COBI) |
SJS, toxic epidermal necrolysis, acute generalised exanthematous pustulosis and erythrema multiforme have been reported (rare) |
|
Fosamprenavir * |
· Skin rash (12-19%) – due to sulfonamide moiety · Diarrhoea · Nausea · Vomiting · Headache · Nephrolithiasis |
Possible increased bleeding episodes in patients with haemophilia |
|
Lopinavir/ritonavir |
· GI intolerance: nausea, vomiting, diarrhoea · Asthenia |
PR interval prolongation QT interval prolongation and torsades de pointes reported Pancreatitis Possible increased bleeding episodes in patients with haemophilia |
|
Ritonavir (boosting) |
· GI intolerance - nausea, vomiting, diarrhoea · Paresthesias -circumoral and extremities · Asthenia · Taste perversion |
Caution with drug-drug interactions for drugs with a narrow therapeutic index Possible increased bleeding episodes in patients with haemophilia |
|
Saquinavir * |
· GI intolerance - nausea, diarrhoea · Headache |
PR interval prolongation QT interval prolongation and torsades de pointes reported Pancreatitis Possible increased bleeding episodes in patients with haemophilia |
|
Tipranavir * |
· Skin rash (2–21%) - due to sulfonamide moiety |
Clinical hepatitis including hepatic decompensation has been reported, especially in patients with underlying liver disease Rare cases of fatal and non-fatal intracranial haemorrhages have been reported but most patients had underlying comorbidity including brain lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, alcoholism or medication with risk for bleeding Possible increased bleeding episodes in patients with haemophilia |
|
*can only be administered with boosting doses of ritonavir; SJS=Stevens-Johnson syndrome; AV: atrioventricular |
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