Darunavir

Darunavir is an Office of AIDS Research Advisory Council (DHHS) recommended treatment option for adults and adolescents, regardless of whether they have received HIV treatment in the past.[8] In a study of patients that had never received HIV treatment, darunavir was as effective as lopinavir/ritonavir at 96 weeks with a once-daily dosing.[9] It was approved by the FDA on 21 October 2008 for people not previously treated for HIV.[10] As with other antiretrovirals, darunavir does not cure HIV/AIDS.[11]

It is indicated for the treatment of human immunodeficiency virus (HIV-1) infection in adults and children three years of age and older when co-administered with ritonavir, in combination with other antiretroviral agents.[3][12]

Darunavir is generally well tolerated by people. Rash is the most common side effect (7% of patients).[11] Other common side effects are diarrhea (2.3%), headache (3.8%), abdominal pain (2.3%), constipation (2.3%), and vomiting (1.5%).[11] Darunavir can also cause allergic reactions, and people allergic to ritonavir can also have a reaction to darunavir.[11]

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.[11] Changes in body fat have been seen in some patients taking medicines for HIV, 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.[11]

Darunavir is a nonpeptidic inhibitor of protease (PR) that lodges itself in the active site of PR through a number of hydrogen bonds.[13] It was developed to increase interactions with HIV-1 protease and to be more resistant against HIV-1 protease mutations. With a K_d (dissociation constant) of 4.5 x 10⁻¹² M, darunavir has a much stronger interaction with PR and its dissociation constant is 1/100 to 1/1000 of other protease inhibitors.[14] This strong interaction comes from increased hydrogen bonds between darunavir and the backbone of the PR active site (Figure 2). Darunavir's structure allows it to create more hydrogen bonds with the PR active site than most PIs that have been developed and approved by the FDA.[15] Furthermore, the backbone of HIV-1 protease maintains its spatial conformation in the presence of mutations.[16] Because darunavir interacts with this stable portion of the protease, the PR-PI interaction is less likely to be disrupted by a mutation.[15]

Figure 3. Ribbon structure of PR with darunavir in active site: Structures colored as in Fig. 1. with certain residues partaking in hydrogen bonding further highlighted. The catalytic aspartates, 25 and 25’, are in orange and the other interacting residues in green. Right image is a magnified view of the image on the left (PDB 4qdb).

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.[18]

Figure 2. Hydrogen bonds between darunavir and HIV-1 protease: The bonds with the red residues indicate hydrogen bonds that are also present between the PI saquinavir and HIV-1 protease. The hydrogen bonds with the blue residue are unique to darunavir.

Darunavir was approved for use in the United States in June 2006 and for use in the European Union in February 2007.[19][20][21][22][12]

The development of first-generation clinical inhibitors was founded on creating more protease-ligand interactions through hydrogen bonding and hydrophobic interactions.[13] The first HIV protease inhibitor approved by the FDA was saquinavir, which was designed to target wild-type HIV-1 protease.[23] However, this inhibitor is no longer effective due to resistance-causing mutations on the HIV-1 protease structure. The HIV genome has high plasticity, so has been able to become resistant to multiple HIV-1 protease inhibitors.[24] Since saquinavir, the FDA has approved several PIs, including darunavir.[21]

• Brecanavir

• Panel on Antiretroviral Guidelines for Adults and Adolescents (18 December 2019). "Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV" (PDF). Department of Health and Human Services. Archived from the original (PDF) on 13 August 2020. Retrieved 21 April 2020. Lay summary. {{cite web}}: Cite uses deprecated parameter |lay-url= (help)

• "Darunavir". Drug Information Portal. U.S. National Library of Medicine.