Darunavir (Prezista) is an antiretroviral drug from the class known as protease inhibitors. Protease inhibitors block the activity of the HIV protease enzyme that HIV uses to break up large viral proteins so that new HIV particles can be formed. Inhibiting this action slows HIV replication and delays damage to the immune system. For more information on how protease inhibitors work, see Protease inhibitors in the section Ways of attacking HIV.
Darunavir (formerly TMC114) was developed by the Belgian company Tibotec and designed to be active against HIV resistant to then-current 'first-generation' protease inhibitors. It was originally licensed in 2006 by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use and the US Food and Drug Administration for use in highly treatment-experienced people.
This recommendation was based on favourable results from the POWER study, a randomised comparison of darunavir/ritonavir with other ritonavir-boosted protease inhibitors in people with experience of all three classes of antiretroviral (ARV) drugs available at the time the study began. Participants in this study had relatively high levels of protease inhibitor resistance.
Following the results from the TITAN study in 2008, in which boosted darunavir showed a clear advantage in treatment-experienced people with less exposure to protease inhibitors, the EMA expanded its licence to include use by people with any prior ARV experience.
In 2008, the US approved darunavir’s use in ARV-naive individuals, based on data from the ARTEMIS study. Darunavir was approved for once-daily first-line use in Europe in February 2009.
Response to darunavir does not appear to vary according to previous protease inhibitors use. Analysis of resistance in clinical studies have indicated HIV would need to accumulate up to eleven different mutations in the protease enzyme to become resistant to darunavir.
Darunavir/ritonavir is recommended as a preferred third agent for use in combination with tenofovir and emtricitabine in first-line treatment in British HIV Association and US treatment guidelines.
Darunavir was initially licensed for treatment-experienced people on the basis of the POWER 1 and 2, phase IIb study results. In these studies, two different doses of boosted darunavir were compared with the effects of other protease inhibitors in treatment-experienced people. After a 24-week analysis, 600mg darunavir and 100mg ritonavir was selected as the optimal dose and all participants in the darunavir/ritonavir arm used that dosage.
Use of darunavir was approved at a dose of darunavir 600mg/ritonavir 100mg.[ref] [ref] Originally, darunavir's use in the EU was limited to highly-treated adults who had failed more than one regimen containing a protease inhibitor. In 2008, its licensing was expanded to include any antiretroviral (ARV)-experienced person.
In 2008, the US Food and Drug Administration expanded the indication for darunavir to include its use as first-line therapy, dosed once daily. The protease inhibitor was also given full approval for twice-daily use in all people with previous ARV experience. This approval was based on data from the ARTEMIS study.
In that study, results showed that people randomised to receive darunavir/ritonavir had a non-inferior virological response after 48 weeks as compared to those randomised to receive lopinavir/ritonavir (Kaletra). However, those who started treatment with a viral load over 100,000 copies/ml were significantly more likely to achieve a sustained undetectable viral load if they received darunavir/ritonavir.[ref]
Darunavir was licensed in the US for use in treatment-naive people dosed as two 400mg tablets once daily with a 100mg boosting dose of ritonavir. In late 2008, once-daily dosing of boosted darunavir was approved in the US, dosed at darunavir 800mg/ritonavir 100mg, for a first-line regimen.
Darunavir/ritonavir has been compared with atazanavir/ritonavir, raltegravir and dolutegravir in two clinical trials in previously untreated people.
In the ACTG 5257 study people treated with raltegravir were significantly more likely to have undetectable viral load after 96 weeks when compared to atazanavir/ritonavir or darunavir/ritonavir, but also more likely to develop resistance after virological failure.[ref]
In the FLAMINGO study a significantly higher proportion of people who received dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) had an undetectable viral load after 96 weeks compared to darunavir/ritonavir (80% vs 68%). The difference between arms was most pronounced in participants with high baseline viral load (> 100,000 copies/ml) (82% vs 52% response through week 96) and in people taking the tenofovir/emtricitabine backbone (79% vs 64%). Virologic non-response to treatment (dolutegravir 8%; darunavir/ritonavir 12%) and non-response due to other reasons (dolutegravir 12%; darunavir/ritonavir 21%) occurred less frequently with dolutegravir.[ref]
For ARV-experienced people, the TITAN study compared twice daily darunavir/ritonavir (600mg/100mg) with twice daily lopinavir/ritonavir capsules (at the previous 400mg/100mg formulation), plus an optimised background regimen selected by resistance testing.
After 48 weeks of treatment, intent-to-treat analysis showed that 77% of those randomised to receive darunavir had viral load below 400 copies/ml, compared with 68% of those randomised to receive lopinavir/ritonavir. This was statistically significant and darunavir/ritonavir was seen as having superiority over lopinavir/ritonavir in virologic suppression. A similar difference emerged when the proportion of people with viral load below 50 copies/ml at week 48 was compared.[ref] On the basis of this study, the drug was licensed for use in the EU for all ARV-experienced people.
Once-daily 800mg/100mg darunavir/ritonavir dosing is also suitable for some treatment-experienced people. The randomised, open-label ODIN trial found this once-daily dose to be as effective at suppressing viral load after 48 weeks as a 600mg twice-daily dose in treatment-experienced people who did not have resistance mutations to darunavir at the start of the trial. The once-daily dose was also less likely to cause lipid disturbances.[ref]
The open-label GRACE study found that 600/100mg darunavir/ritonavir twice daily, plus optimised background therapy, was equally effective in women and in men after 48 weeks. There was little difference in side-effects, except that women were somewhat more likely to report nausea.[ref]
A caution has been issued that 0.5% of people taking darunavir/ritonavir during its clinical development were diagnosed with drug-induced hepatitis. See the Side-effects section for more information on this topic.
Darunavir is licensed in both the European Union and the US for use in both treatment-naive and treatment-experienced people.
In November 2012, an 800mg tablet received US Food and Drug Administration approval, and was approved in Europe in January 2013. This dosage is approved for treatment-naive and treatment-experienced adults with no darunavir resistance, taken with 100mg of ritonavir. It enables people to take one darunavir pill once a day.
Darunavir 800mg is also approved for use with a 150mg boosting dose of cobicistat. A fixed-dose tablet containing darunavir and cobicistat is also available. See Rezolsta for further details.
Treatment-experienced people should take 600mg twice daily boosted with ritonavir 100mg. Treatment-experienced people without darunavir-associated resistance mutations and viral load below 100,000 copies/ml may take an 800mg dose once daily, boosted with cobicistat.
Darunavir should be taken with food.
Most drug-drug interaction studies used the twice-daily dose of boosted darunavir. Until more data are available, twice-daily dosing should be considered when darunavir is used with efavirenz, nevirapine, and etravirine in treatment-experienced people. However, in combination with raltegravir and maraviroc, once-daily dosing is an option. Neither lopinavir/ritonavir nor saquinavir is recommended for use with darunavir because of a significant decrease in darunavir serum concentration that occurs when these drugs are used together.
Common side-effects of darunavir include elevated lipids, diabetes, insomnia, headache, dizziness, peripheral neuropathy, diarrhoea, nausea, vomiting and abdominal pain. Rash, itching, tiredness and fatigue are also common.
A caution has been issued by the European Medicines Agency and the US Food and Drug Administration regarding hepatic issues concerning darunavir. About 0.5% of people taking darunavir/ritonavir during its clinical development were diagnosed with drug-induced hepatitis. People with pre-existing liver problems, including hepatitis B or hepatitis C infection, had a greater risk of developing such a complication. No adjustment in the dose of darunavir/ritonavir is recommended for people with mild or moderate liver problems, but the US product label now notes that the drug is not recommended for people with severe liver problems.
Liver function should be monitored in all people before treatment with darunavir/ritonavir is started, and monitoring of ALT/AST levels should be increased in people with pre-existing liver problems during the first few months of therapy with the drug. If an individual experiences a worsening of their liver function, or if they develop symptoms suggestive of drug-induced hepatitis (tiredness, weight loss, nausea, yellowing of the skin, dark urine, pain in the liver, or an enlarged liver) doctors are recommended to consider either interrupting or stopping treatment with darunavir/ritonavir.
A subanalysis of resistance in the 24-week pooled POWER 1, 2, and 3 data (using 600mg darunavir/100mg ritonavir dosed twice daily) in treatment-experienced people showed that darunavir has a high genetic barrier to resistance and that a large number of background darunavir mutations are required for resistance to develop.[ref]
Darunavir (Prezista) is broken down through the cytochrome 3A4 system in the liver.
People taking darunavir should not take the following drugs:
- Carbamazepine (Tegretol)
- Colchicine in people with renal or hepatic impairment
- Ergotamine tartrate (Cafergot / Migril)
- Hypericin (St John’s wort)
- Midazolam (Hypnovel)
- Phenytoin (Epanutin)
- Pimozide (Orap)
- Rifampicin (Rifadin / Rimactane)
- Simvastatin (Zocor)
The following drugs may require a dose adjustment in people taking darunavir, or may require darunavir’s dose to be altered. Until more data are available they should be used with darunavir cautiously:
- Atorvastatin (Lipitor)
- Ciclosporin (Neoral / Sandimmun)
- Efavirenz (Sustiva)
- Felodipine (Plendil)
- Fluticasone propionate (Flixotide)
- Indinavir (Crixivan)
- Itraconazole (Sporanox)
- Ketoconazole (Nizoral)
- Methadone hydrochloride (Methadose)
- Nicardipine hydrochloride (Cardene / Cardene SR)
- Nifedipine (Adalat / Adalat LA / Adalat Retard / Adipine MR / Adipine XL / Cardilate MR / Coracten SR / Coracten XL / Fortipine LA 40 / Hypolar Retard 20 / Nifedipress MR / Nifopress Retard / Slofedipine / Slofedipine XL / Tensipine MR)
- Paroxetine (Seroxat)
- Pravastatin sodium (Lipostat)
- Rifabutin (Mycobutin)
- Ritonavir-boosted lopinavir (Kaletra)
- Quinidine sulphate
- Sertraline (Lustral)
- Sildenafil (Viagra), a reduced dose is recommended. Sildenafil is contraindicated if used for treatment of pulmonary arterial hypertension.
- Sirolimus (Rapamune)
- Tacrolimus (Prograf)
- Tadalafil (Cialis), a reduced dose is recommended
- Trazodone hydrochloride (Molipaxin)
- Vardenafil (Levitra), a reduced dose is recommended
- Voriconazole (Vfend)
- Warfarin sodium.
Women using ethinylestradiol or norethidrone as hormonal contraception may experience reduced levels of the contraceptive if they take darunavir. Additional or alternative methods of contraception are recommended.
Darunavir should not be taken with the hepatitis C direct-acting antivirals elbasvir/grazoprevir (Zepatier), simeprevir (Olysio), paritaprevir, ombitasvir and dasabuvir (Viekirax). No dose adjustment of other direct-acting antivirals is necessary.
Darunavir is unsuitable for use in children below the age of 3. Dosing for children is determined by the child’s weight; the minimum weight required for treatment with darunavir/ritonavir is 10kg. Darunavir is available in liquid or tablet form and should be boosted with ritonavir tablets or liquid. Cobicistat is not recommended for use in children.
Darunavir/ritonavir should be used in pregnancy only if the benefits outweigh the risks. Lower blood levels of darunavir have been observed during pregnancy, implying a greater risk of treatment failure and subsequent drug resistance at this time.