Darunavir

Antiretroviral medication

Darunavir (DRV), sold under the brand name Prezista among others, is an antiretroviral medication used to treat and prevent HIV/AIDS. It is often used with low doses of ritonavir or cobicistat to increase darunavir levels. Common side effects include diarrhea, nausea, abdominal pain, headache, rash and vomiting. It is of the protease inhibitor (PI) class and works by blocking HIV protease. It was approved by the Food and Drug Administration (FDA) in June 2006. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. The fixed dose combination medication darunavir/cobicistat (Prezcobix, Rezolsta) is available as a single pill.

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. 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. It was approved by the FDA on 21 October 2008 for people not previously treated for HIV. As with other antiretrovirals, darunavir does not cure HIV/AIDS. 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.

Darunavir is generally well tolerated by people. Rash is the most common side effect (7% of patients). It was developed to increase interactions with HIV 1 protease and to be more resistant against HIV 1 protease mutations. With a Kd (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. 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. Furthermore, the backbone of HIV 1 protease maintains its spatial conformation in the presence of mutations. Because darunavir interacts with this stable portion of the protease, the PR PI interaction is less likely to be disrupted by a mutation. Darunavir interacts with these catalytic aspartates and the backbone of the active site through hydrogen bonds, specifically binding to residues Asp25, Asp25’, Asp 29, Asp 30, Asp 30’, and Gly 27 (Figure 3). This interaction prevents viral replication, as it competitively inhibits the viral polypeptides from gaining access to the active site and strongly binds to the enzymatic portions of this protein.

Darunavir was approved for use in the United States in June 2006 and for use in the European Union in February 2007. 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. Since saquinavir, the FDA has approved several PIs, including darunavir.