Hypersensitivity and Desensitization to Darunavir in a Case of HIV Infection with Triple-Class Drug Resistance

Abstract

We report on a case of severe cutaneous reaction to darunavir/r and a successful desensitization protocol. The patient was a 41-year-old female, known to be HIV infected for 18 years and who had received several drug regiments in the past. As a consequence, her virus had triple-class mutations but was susceptible to darunavir/r. Her CD4 was 200 cells/mm³ and HIV viral load 56,000 copies/mL. Eight days after initiation of darunavir/r the patient developed a severe pruritic vesicular extended cutaneous allergic reaction which required cessation of all drugs. Due to the severity of the allergic reaction no rechallenge was done. After the patient's recovery, the virus was found to be susceptible only to maraviroc, raltegravir, and darunavir/r. Since darunavir/r was an essential component in treating this triple-class mutated virus, a desensitization protocol was applied successfully. Six months after desensitization, the patient is asymptomatic, compliant, and her HIV viral load remains at <20 copies/mL.

Antiretroviral therapy (ART) in HIV-infected individuals has changed the course of the disease from a lethal to a chronic, manageable condition. Antiretroviral therapy has improved over the years, with more potent and less toxic drugs. Patients who were infected for several years and were treated with old generation ART developed a series of adverse reactions such as neuropathy, lipodystrophy, anemia, cytopenia, central nervous system involvement, and triple-class ART resistance, in many cases due to noncompliance.

Darunavir, a protease inhibitor (PI) with high genetic barrier, is highly effective in patients who developed multidrug-resistant HIV, including cases resistant to older PIs. ¹ Darunavir contains a sulfonamide moiety and should be used with caution in patients with a known sulfonamide allergy. ²

One of the serious adverse events seen in patients undergoing ART is drug hypersensitivity reaction. Such an event may be a serious and sometimes even a life-threatening condition limiting the number of drugs available for the future management of the HIV-positive patient. Several antiretroviral drugs have been described to cause skin reactions. ^{3 –7} Amprenavir (APV) is a PI that most frequently produces adverse cutaneous reactions (in up to 28% of patients), ⁸ but mounting information is also accumulating concerning darunavir. Of note, information on darunavir is mostly from clinical trials due to the limited time that elapsed since its approval.

In a phase III clinical trial that randomized 604 patients treated with darunavir/ritonavir (darunavir/r) or lopinavir/ritonavir (LPV/r) plus an optimized background therapy, 16% of the patients who received darunavir/r developed a rash compared to only 7% in the other arm who received LPV/r. Two of the patients who received darunavir/r had a serious rash-related event requiring treatment cessation, whereas patients who received LPV/r did not develop any serious skin events. ⁹

Another large, open-label study that followed 327 HIV-positive patients treated with darunavir plus ritonavir for 24 weeks reported no serious (grade 3 or 4) skin-related events. ¹⁰

When pooled, 924 patients received darunavir/r in preapproval trials; 7% of whom reported rashes of severity, including rare cases of Stevens Johnson syndrome and erythema multiforme. ¹¹ In clinical trials, self-limiting, maculopapular rashes were generally of mild to moderate severity. Rashes of all grades, of uncertain causality, occurred in 7% of the patients. The rate of discontinuation of the drugs by the patients included in these clinical trials due to rash was 0.3%. ² In the TITAN clinical trial, rashes were reported in 16.1% of the darunavir/r users and in 6.7% of the LPV/r recipients. ⁹

We report a case of severe cutaneous reaction to darunavir/r and a successful desensitization protocol, as described previously. ^12,13 The patient was a 41-year-old female, known to be HIV infected for 18 years. Her drug history contained double nucleoside reverse transcriptase inhibitors (NRTIs; zidovudine [ZDV] and zalcitabine [ddC]), combinations of different NRTIs with indinavir (IDV) and later nelfinavir (NFV). As a consequence, her virus developed triple-class mutations but was susceptible to darunavir/r.

Her treatment options were very limited secondary to drug resistance and to severe adverse events including severe lipodystrophy, peripheral neuropathy, lactic acidosis secondary to NRTIs, severe cutaneous drug reaction secondary to efavirenz (EFV), and severe gastrointestinal manifestations secondary to LPV. The patient's HIV viral load (VL) was 56 000 copies/mL and her CD4 count dropped to 200 cells/mm³. Based on a drug-resistance test revealing 4 PI mutations (L63P, G73S, V77I, and L90M), darunavir/r was the only susceptible PI. A dose of 600/100 mg of darunavir/r twice daily (BID) was added to her previous backbone (didanosine [ddI] plus abacavir [ABC]).

Eight days after the initiation of darunavir/r, the patient developed a severe pruritic vesicular-extended cutaneous allergic reaction that required cessation of all drugs. No systemic symptoms were reported. The reaction faded away very slowly, even though antihistamines were added, and it took 4 weeks for her to recover completely. Due to the severity of the allergic reaction, no rechallenge was done.

After the patient recovered, the virus was found to be susceptible only to maraviroc, raltegravir, and darunavir/r.

Since darunavir/r was an essential component in treating this triple-class mutated virus and no other options were left, we decided to try a desensitization protocol, as described previously. ¹²

Twelve doses of darunavir were prepared by the local pharmacy, starting from 25 μg up to 300 mg, and each dose was given at 30-minute intervals. At the fourth dose, generalized pruritus appeared without rash, and antihistamines were added with a good response. The patient completed the protocol without further complications. The following day, the patient started a full-drug regimen comprising 600/100 mg darunavir/r BID, 150 mg maraviroc BID, and 400 mg raltegravir BID. Antihistamines were given for 1 week. No reaction recurred after cessation of the antihistamines.

After 2 months, her HIV VL dropped to <20 copies/mL and her CD4 count increased to 420 cells/mm³. Six months after desensitization, the patient became asymptomatic, compliant, and her VL was <20 copies/mL.

This case demonstrates that in a case of severe drug reaction to darunavir/r, a desensitization protocol may be useful, valid, and effective. This procedure is rather safe and may serve as a beneficial tool especially in cases such as that described previously, for whom the administration of certain drugs is highly important due to the multiple-drug mutations to several other drugs.