A drug normally used to treat asthma provided an effective treatment for antiretroviral-associated immune reconstitution inflammatory syndrome, investigators from one of London’s leading HIV treatment centres report in the January 30th edition of AIDS.
Doctors at the Royal Free Hospital in Hampstead, north London, treated an individual experiencing a recurrent immune reconstitution inflammatory syndrome with the leukotriene receptor antagonist, montelukast. This treatment lead to a rapid and sustained improvement in the patient’s condition. During therapy with montelukast the individual remained on antiretroviral therapy without experiencing any additional adverse effects, his viral load falling to undetectable levels and his CD4 cell count doubling.
Immune reconstitution inflammatory syndrome is a common syndrome that can occur in HIV-positive patients during the first few weeks of antiretroviral therapy. The exact causes and mechanisms involved in the development of the syndrome are not fully understood, but it is thought that it is related to changes in the immune system’s response to infections. Symptoms can be highly unpleasant and prolonged. Therapy often consists of steroids, but their side-effects necessitate their cautious use in HIV-positive individuals.
Three weeks after initiating a nucleoside-sparing antiretroviral regimen consisting of saquinavir (Invirase) and Kaletra (lopinavir/ritonavir), a 59 year-old Caucasian male presented to doctors at his HIV clinic with a one day history of hives (urticarial rash). The patient had previously taken potent anti-HIV therapy which had increased this CD4 cell count to 800 cells/mm3 from a nadir of only 36 cells/mm3. However, he discontinued this therapy (the investigators do not provide a reason), and after a five month treatment interruption, the patient’s CD4 cell count had fallen to 226 cells/mm3 and his viral load had risen to almost 35,000 copies/ml, prompting the reinitiation of HIV treatment. When the hives appeared, the patient’s CD4 cell count was essentially unchanged from the level at which he restarted HIV therapy, although his viral load had fallen to 221 copies/ml.
Blood tests indicated that the patient had elevated levels of C-reactive protein (79mg/l), an elevated white cell count (20.1 x 109/l - normal range, 3.0 – 10.0 x 109/l) and neutrophilia 14.7 x 109/l – normal range 1.5 – 7.4 x 10/sup>9/l). These tests were consistent with an inflammatory response. Further tests ruled out infection with syphilis, measles and rubella, and a screen for autoimmune disease was negative. The treating physicians initiated therapy with the antihistamines cetirizine and rantitidine.
Despite being adherent to this therapy, the patient’s condition deteriorated over the next two weeks. The rash worsened and he developed fevers, increasing malaise, diarrhoea and joint pain. Levels of C-reactive protein had increased (199mg/l) and the patient’s white cell count remained elevated.
Doctors made a presumptive diagnosis of immune reconstitution syndrome-associated urticarial vasculitis and initiated treatment with the oral steroid, prednisolone.
This treatment lasted a month and appeared to be successful - the patient’s symptoms resolved and blood tests monitoring inflammatory markers returned to normal.
However, two days after steroid therapy was completed, the rash returned, associated with a fever and rapid heartbeat. Blood tests once again indicated elevated white blood count and C-reactive protein.
Physicians continued therapy with antiretrovirals and also commenced treatment with a 10mg daily dose of montelukast. This drug is a leukotriene receptor antagonist and is used in the treatment of asthma.
An immediate improvement in the patient’s condition was observed and after five days his symptoms had disappeared and inflammatory markers had returned to normal. Treatment with montelukast was continued for three months causing no side-effects. At the end of this period, the patient’s viral load was below 50 copies/ml and his CD4 cell count doubled.
The investigators believe that the successful use of montelukast gives some clues about the causes of immune reconstitution inflammatory syndrome. They suggest that montelukast, “acting as a partial antagonist, attenuates an over-vigorous leukotriene-driven inflammatory response due to antiretroviral therapy without causing significant immunosuppression itself.”
They conclude, “montelukast may be useful in the treatment of [immune restoration inflammatory syndrome] and warrants further study.”
Lipman MCI et al. Successful drug treatment of immune reconstitution disease with the leukotriene receptor antagonist, montelukast: a clue to pathogenesis? AIDS 21: 383 – 384, 2007.