Darunavir
Encyclopedia
Darunavir is a drug
used to treat HIV
infection. It is in the protease inhibitor
class. Prezista is an OARAC
recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Developed by pharmaceutical company Tibotec
, darunavir is named after Arun K. Ghosh, the chemist who discovered the molecule at the University of Illinois at Chicago
. It was approved by the Food and Drug Administration
(FDA) on June 23, 2006.
Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir
. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manufacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop in as little as a year of use, and effectively render the drugs useless.
Darunavir was designed to form robust interactions with the protease
enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.
Darunavir received much attention at the time of its release, as it represents an important treatment option for patients with drug-resistant HIV. Patient advocacy groups pressured developer Tibotec not to follow the previous trend of releasing new drugs at prices higher than existing drugs in the same class. Darunavir was priced to match other common PIs already in use, such as the fixed-dose combination drug lopinavir/ritonavir
. The drug costs around $9,000 for a one year supply.
(DHHS) recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.
Darunavir showed comparable efficacy to lopinavir/ritonavir at 96 weeks with a once-daily dosing in treatment-naïve patients. It was approved by the FDA for treatment-naive patients on October the 21st 2008.
Darunavir showed superiority to lopinavir/ritonavir
and other protease inhibitors
in the POWER trials. The POWER 1 and POWER 2 were designed for treatment-experienced patients, together with supportive data from the POWER 3 analysis. The patients eligible for these studies had experience with at least one protease inhibitor, one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI), and had one or more primary protease inhibitor mutations.
Darunavir also showed superior results to lopinavir
in the TITAN trials (pre-planned, secondary endpoint, week 48), which was designed for patients with less advanced HIV
disease compared to the POWER trials.
At 96 weeks, darunavir/ritonavir remained non-inferior to lopinavir/ritonavir.
/r
-naïve, HIV-1 infected adults with a viral load of greater than 1000 HIV-1 RNA
copies/mL.
Pre-planned secondary endpoint findings include:
Development of resistance also was studied. Findings include:
The efficacy results of POWER 1 and POWER 2 are confirmed by data from a large, non-randomized, open-label analysis known as POWER 3.
After 24 weeks:
, darunavir does not cure HIV infection or AIDS
, and does not prevent passing HIV to others.
In studies, darunavir was generally well tolerated. Mild to moderate rash was seen in 7% of patients. Some patients developed severe rash. In clinical studies, 0.3% of patients discontinued due to rash. The most common moderate to severe side effects associated with darunavir include diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%). Four percent of patients discontinued treatment due to adverse events. People who are allergic to darunavir or any of its ingredients, or ritonavir (Norvir) should not take darunavir.
There were few relevant drug-drug interactions with other medications commonly used in HIV patient populations, such as other antiretroviral medications, proton pump inhibitors, and H2 receptor antagonists. St. John's Wort may reduce its effectiveness by interaction with CYP3A
. Patients should talk to their healthcare provider about all the medicines they are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Before taking darunavir, patients should tell their healthcare provider if they have any medical conditions, including diabetes, liver problems, hemophilia, or allergy to sulfa medicines and should tell their doctor if they are pregnant or planning to become pregnant, or are nursing. Darunavir should be used with caution in patients with hepatic impairment.
High blood sugar, diabetes or worsening of diabetes, muscle pain, tenderness or weakness, and increased bleeding in people with hemophilia have been reported in patients taking protease inhibitor medicines like darunavir. Changes in body fat have been seen in some patients taking anti-HIV medicines, including loss of fat from legs, arms and face, increased fat in the abdomen and other internal organs, breast enlargement and fatty lumps on the back of the neck. The cause and long-term health effects of these conditions are not known at this time.
Clinical laboratory safety observed in the darunavir group was comparable to the control group. (Product Monograph, Darunavir)
Additional Studies Involving Darunavir
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
used to treat HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection. It is in the protease inhibitor
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
class. Prezista is an OARAC
OARAC
OARAC is the abbreviation for the Office of AIDS Research Advisory Council, which is developing guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents....
recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Developed by pharmaceutical company Tibotec
Tibotec
Tibotec is a pharmaceutical company with a focus on research and development for the treatment of infectious diseases such as HIV , and Hepatitis C...
, darunavir is named after Arun K. Ghosh, the chemist who discovered the molecule at the University of Illinois at Chicago
University of Illinois at Chicago
The University of Illinois at Chicago, or UIC, is a state-funded public research university located in Chicago, Illinois, United States. Its campus is in the Near West Side community area, near the Chicago Loop...
. It was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on June 23, 2006.
Darunavir is a second-generation protease inhibitor (PIs), designed specifically to overcome problems with the older agents in this class, such as indinavir
Indinavir
Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...
. Early PIs often have severe side effects and drug toxicities, require a high therapeutic dose, are costly to manufacture, and show a disturbing susceptibility to drug resistant mutations. Such mutations can develop in as little as a year of use, and effectively render the drugs useless.
Darunavir was designed to form robust interactions with the protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
enzyme from many strains of HIV, including strains from treatment-experienced patients with multiple resistance mutations to PIs.
Darunavir received much attention at the time of its release, as it represents an important treatment option for patients with drug-resistant HIV. Patient advocacy groups pressured developer Tibotec not to follow the previous trend of releasing new drugs at prices higher than existing drugs in the same class. Darunavir was priced to match other common PIs already in use, such as the fixed-dose combination drug lopinavir/ritonavir
Lopinavir/ritonavir
Lopinavir/ritonavir is a fixed dose combination drug for the treatment of HIV infection. It combines lopinavir with a sub-therapeutic dose of ritonavir into a fixed-dose pill....
. The drug costs around $9,000 for a one year supply.
Efficacy
Prezista is an OARACOARAC
OARAC is the abbreviation for the Office of AIDS Research Advisory Council, which is developing guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents....
(DHHS) recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents.
Darunavir showed comparable efficacy to lopinavir/ritonavir at 96 weeks with a once-daily dosing in treatment-naïve patients. It was approved by the FDA for treatment-naive patients on October the 21st 2008.
Darunavir showed superiority to lopinavir/ritonavir
Lopinavir/ritonavir
Lopinavir/ritonavir is a fixed dose combination drug for the treatment of HIV infection. It combines lopinavir with a sub-therapeutic dose of ritonavir into a fixed-dose pill....
and other protease inhibitors
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
in the POWER trials. The POWER 1 and POWER 2 were designed for treatment-experienced patients, together with supportive data from the POWER 3 analysis. The patients eligible for these studies had experience with at least one protease inhibitor, one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI), and had one or more primary protease inhibitor mutations.
Darunavir also showed superior results to lopinavir
Lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia ....
in the TITAN trials (pre-planned, secondary endpoint, week 48), which was designed for patients with less advanced HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
disease compared to the POWER trials.
ARTEMIS trial
ARTEMIS includes 689 treatment-naive participants with a baseline viral load of at least 5000 copies/mL who were randomly assigned to receive 800/100 mg once-daily darunavir/ritonavir or 800/200 mg lopinavir/ritonavir given once- or twice-daily.At 96 weeks, darunavir/ritonavir remained non-inferior to lopinavir/ritonavir.
- In an intent-to-treat analysis, significantly more patients in the darunavir/ritonavir arm achieved HIV RNA below 50 copies/mL compared with the lopinavir/ritonavir arm (79% vs. 71%; p = 0.012).
- Response rates in the darunavir/ritonavir arm were statistically superior to those in the lopinavir/ritonavir arm for patients with high baseline viral load and low baseline CD4 count.
- Among patients with baseline viral load below 100,000 copies/mL, 76% of patients in the darunavir/ritonavir arm and 63% in the lopinavir/ritonavir arm achieved HIV RNA below 50 copies/mL (p = 0.023).
- Once-daily darunavir/ritonavir was generally safe and well tolerated.
- Fewer patients in the darunavir/ritonavir arm discontinued treatment due to adverse events (4% vs. 9%).
- Patients taking darunavir/ritonavir were less likely to have moderate to severe (grade 2-4) treatment-related diarrhea (4% vs. 11%; p < 0.001).
- Grade 2-4 treatment-related rash occurred infrequently in both arms (3% with darunavir/ritonavir vs. 1% with lopinavir/ritonavir; p = 0.273).
- Patients taking darunavir/ritonavir had smaller average increases in triglycerides (0.1 vs. 0.8 mmol/L, or 12% vs. 50%) and total cholesterol (0.6 vs. 0.9 mmol/L, or 15% vs. 23%) (both p < 0.0001).
TITAN trial
Analysis of 595 treatment-experienced patients being lopinavirLopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia ....
/r
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
-naïve, HIV-1 infected adults with a viral load of greater than 1000 HIV-1 RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
copies/mL.
Pre-planned secondary endpoint findings include:
- 71 percent of patients in the darunavir/r arm reached an undetectable viral load (less than 50 copies/mL) vs. 60 percent of patients in the lopinavir/r arm, a statistically significant difference (pP-valueIn statistical significance testing, the p-value is the probability of obtaining a test statistic at least as extreme as the one that was actually observed, assuming that the null hypothesis is true. One often "rejects the null hypothesis" when the p-value is less than the significance level α ,...
= 0.005) - 77 percent of patients in the darunavir/r arm achieved at least a 1 log10 reduction in HIV RNA vs. 69 percent in the lopinavir/r arm, a statistically significant difference (p = 0.028)
- The median increase from baseline in CD4 cell count was similar between the darunavir/r and lopinavir/r arms (88 cells per cubic millimeter vs. 81 cells per cubic millimeter)
Development of resistance also was studied. Findings include:
- 10 percent of patients in the darunavir/r arm experienced virological failure vs. 22 percent of patients in the lopinavir/r arm
- Among patients experiencing virologic failure who had baseline and endpoint genotype data, 21 percent of patients in the darunavir/r arm developed primary PI resistance mutations vs. 36 percent of patients in the lopinavir/r arm, and 14 percent of patients in the darunavir/r arm developed primary NRTI resistance mutations vs. 27 percent of patients in the lopinavir/r arm
POWER 1 and POWER 2 trials
A pooled analysis of results from POWER 1 and POWER 2 demonstrated that after 24 weeks:- Significantly more treatment-experienced patients achieved a reduction in viral load at the 24-week primary endpoint with darunavir, compared with the investigator-selected PI (70% vs. 21%, respectively).
- Almost four times as many treatment-experienced patients (45%) have achieved an undetectable viral load with the darunavir containing regimen, compared with the investigator-selected PI arm (12%).
- In treatment-experienced patients, the darunavir containing regimen increases CD4 cell counts five times more than the investigator-selected PI arm (92 cells/mm3 vs. 17 cells/mm3, respectively) (Johnson & Johnson Press Release, 2006; Lazzarin, 2005)
The efficacy results of POWER 1 and POWER 2 are confirmed by data from a large, non-randomized, open-label analysis known as POWER 3.
After 24 weeks:
- 65 percent of patients achieved a reduction in viral load of 1 log10 or more, versus baseline.
- 40 percent of patients reached undetectable virus levels (less than 50 HIV RNA copies/mL). (Molina, 2005)
Pharmacoeconomic considerations
In the US and UK, healthcare costs were estimated to be lower with boosted darunavir than with investigator-selected control protease inhibitors in treatment-experienced patients.Safety
As other antiviralsAntiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
, darunavir does not cure HIV infection or AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
, and does not prevent passing HIV to others.
In studies, darunavir was generally well tolerated. Mild to moderate rash was seen in 7% of patients. Some patients developed severe rash. In clinical studies, 0.3% of patients discontinued due to rash. The most common moderate to severe side effects associated with darunavir include diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%). Four percent of patients discontinued treatment due to adverse events. People who are allergic to darunavir or any of its ingredients, or ritonavir (Norvir) should not take darunavir.
There were few relevant drug-drug interactions with other medications commonly used in HIV patient populations, such as other antiretroviral medications, proton pump inhibitors, and H2 receptor antagonists. St. John's Wort may reduce its effectiveness by interaction with CYP3A
CYP3A
Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene.The CYP3A locus includes all the known members of the 3A subfamily of the cytochrome P450 superfamily of genes. These genes encode monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of...
. Patients should talk to their healthcare provider about all the medicines they are taking or plan to take, including prescription and nonprescription medicines, vitamins, and herbal supplements.
Before taking darunavir, patients should tell their healthcare provider if they have any medical conditions, including diabetes, liver problems, hemophilia, or allergy to sulfa medicines and should tell their doctor if they are pregnant or planning to become pregnant, or are nursing. Darunavir should be used with caution in patients with hepatic impairment.
High blood sugar, diabetes or worsening of diabetes, muscle pain, tenderness or weakness, and increased bleeding in people with hemophilia have been reported in patients taking protease inhibitor medicines like darunavir. Changes in body fat have been seen in some patients taking anti-HIV medicines, including loss of fat from legs, arms and face, increased fat in the abdomen and other internal organs, breast enlargement and fatty lumps on the back of the neck. The cause and long-term health effects of these conditions are not known at this time.
Clinical laboratory safety observed in the darunavir group was comparable to the control group. (Product Monograph, Darunavir)
Dosing and administration
The recommended oral dose of darunavir tablets is 600 mg (two 300 mg tablets) twice daily (BID) taken with ritonavir 100 mg BID and with food. The drug can be taken with any type of food.Additional Studies Involving Darunavir
- TMC114-C211: Investigating a dose of 800 mg of the drug boosted with 100 mg of ritonavir once daily in treatment-naïve patients.
- TMC114-C214: Investigating a dose of 600 mg of the drug boosted with 100 mg of ritonavir twice daily in moderately treatment-experienced patients.
- DUET trial: The drug is being studied with TMC125, an investigational non-nucleoside reverse transcriptase inhibitor, in one of the few HIV clinical trials to involve two investigational HIV treatments in treatment-experienced patients. (Tibotec 2006)
External links
- Darunavir FAQFAQFrequently asked questions are listed questions and answers, all supposed to be commonly asked in some context, and pertaining to a particular topic. "FAQ" is usually pronounced as an initialism rather than an acronym, but an acronym form does exist. Since the acronym FAQ originated in textual...
at AIDSmeds.com - Drug information in PDF
- Arun Ghosh group
- Tibotec