Successful Salvage Therapy with Darunavir in HIV Patients Who Failed Several Ritonavir-boosted Protease Inhibitors

By Ronald Baker, PhD

A growing number of HIV patients have virus that is resistant to all or most of the available anti-HIV drugs, a situation that underscores the pressing need for the development of new drug classes capable of effectively and safely suppressing HIV infection.

Although use of the HIV protease inhibitors (PIs) has been enormously successful in the treatment of HIV, cross-resistance remains a problem within this drug class, and the number of baseline PI resistance mutations significantly impacts the degree of success of ritonavir-boosted PIs. For this reason, the development of new PIs with a higher genetic barrier to resistance is an important priority.

In June 2006, the US Food and Drug Administration (FDA) granted accelerated approval to the PI darunavir (Prezista) coadministered with ritonavir (Norvir) for treatment-experienced, adult HIV patients who are failing their current antiretroviral regimens. Darunavir (formerly known as TMC-114) is active against HIV strains resistant to currently available PIs.

In the present case study, published as a Research Letter in the July 13, 2006 issue of AIDS, Spanish researchers at Hospital Carlos III in Madrid evaluated the response to salvage therapy with ritonavir-boosted darunavir in four heavily antiretroviral drug-experienced patients.

All four patients had previously failed all current classes of anti-HIV drugs, including the sole available fusion inhibitor, enfuvirtide (Fuzeon, T-20), as well as two or more prior ritonavir-boosted PI regimens -- including, in one patient, ritonavir-boosted tipranavir (Aptivus), the most recently approved PI prior to darunavir.

Prior to salvage therapy with darunavir/ritonavir, the mean baseline plasma HIV RNA level was 24,560 copies/mL. The mean CD4 cell count was 146 cells/mm3, ranging from 33 to 425 cells/mm3.

All patients received the FDA-recommended dose of 600 mg darunavir (two 300 mg tablets) plus 100 mg ritonavir twice daily with food.

Three of the four patients experienced undetectable HIV RNA levels within 8 weeks after initiating darunavir/ritonavir, and each one experienced significant increases in their CD4 cell counts, ranging from 60% to 80% of baseline values.

As expected, all patients showed evidence of multiple drug resistance mutations, which conferred high-level resistance to most currently available antiretroviral agents. According to the authors, two patients showed genotypic and phenotypic resistance to all commercially available drugs, including enfuvirtide, "darunavir being the only potentially active drug within the salvage regimen."

"Of note," wrote the authors, "was the fact that all four patients harbored 10 or more PI-associated resistance mutations, including at least two primary changes." Only one patient was found to be susceptible to tipranavir/ritonavir. One patient was already failing on tipranavir/ritonavir before starting darunavir.

In spite of the high degree of baseline drug resistance, all of the individuals achieved viral loads below 50 HIV RNA copies/mL between 4 and 8 weeks after starting darunavir. In one patient, the virological and immunological response to darunavir was maintained during 48 weeks of follow-up.

The researchers noted that darunavir was well tolerated in all four patients. No serious adverse events were seen. One patient complained of nausea and vomiting during the initial week of treatment with the drug, "but these symptoms disappeared spontaneously thereafter," stated the authors.

In conclusion, the authors wrote, "All together, these results highlight the strong antiviral activity and good safety of darunavir, even when the drug was used as the unique active drug in salvage therapeutic interventions in heavily antiretroviral-experienced patients, including individuals who had failed enfuvirtide and tipranavir."

Suggested Further Reading

New Protease Inhibitor [darunavir] Approved for Treatment-experienced Patients

Patient Advocates Commend Pricing of New PI Darunavir

07/28/06

Reference
E Poveda, F Blanco, P García-Gascó, and others. Successful rescue therapy with darunavir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. [Research Letter] AIDS 20(11): 1558-1560. July 13, 2006.