This article is more than 5 years old. Information may no longer be current.
Drug allergies in patients with HIV: What’s a doc to do?
HIV-positive patients are estimated to experience a drug-related rash 100 times more often than the general population. In a field with expanding but limited antiretroviral therapies, and even fewer options for effective prophylaxis against opportunistic infections, clinicians can find themselves struggling to manage these common and sometimes serious events. Reactions can range from mild rashes to reactions involving fevers with severe rash and internal organ involvement. Completely understanding the cause and predictive qualities of hypersensitivity reactions in HIV is still under research; however, we have some evidence to help clinicians prevent and manage drug reactions in this sensitive population.
Reactions to a common therapy
Trimethoprim-sulfamethoxazole is often cited as a culprit of cutaneous drug reactions, occurring 10 times more frequently in HIV-positive patients. Approximately 5% of the general population reports an allergy to TMP-SMX, whereas at least 60% of those with HIV have experienced a hypersensitivity reaction. This poses a problem for clinicians because TMP-SMX is the drug of choice for treatment of or prophylaxis against Pneumocystis carinii pneumonia (PCP). Skin testing to predict TMP-SMX hypersensitivity has proved ineffective. Classic hypersensitivity to TMP-SMX presents as a generalized maculopapular rash with fever and organ toxicity and resolves after discontinuation of the drug. Fortunately, severe or life-threatening reactions are rare, although it has been reported with similar frequency in HIV-positive and HIV-negative patients. The cause of increased hypersensitivity to TMP-SMX in HIV-positive patients is not fully understood, although possible explanations include complex metabolism to immunogenic metabolites, direct cytotoxicity, glutathione deficiency, and hyperactive immune response in the setting of HIV infection.
Kati Shihadeh
Rebecca Seymour
If a patient develops a reaction to TMP-SMX that requires discontinuation of therapy, clinicians are faced with the decision to rechallenge, desensitize or use alternative agents. Although glutathione deficiency may have a role in TMP-SMX reactions, a randomized, placebo-controlled trial failed to show reduced reactions in HIV-positive patients pre-treated with N-acetylcysteine taking TMP-SMX for PCP prophylaxis.
Rechallenging poses the threat of a severe reaction shortly after re-exposure to the offending agent and has not demonstrated great success. Desensitization protocols have demonstrated higher success rates than rechallenging and can be a safer option in patients with severe reactions. Protocols exist for rapid desensitization over hours in the hospitalized patient to ambulatory protocols that increase exposure over days, which provides flexibility for patients and providers. In severe reactions and rechallenge or desensitization failure, alternatives such as dapsone, atovaquone (Mepron, GlaxoSmithKline) and pentamidine (NebuPent, APP Pharmaceuticals) are recommended.
Patients with HIV are at risk for other drug reactions as well, particularly with antiretroviral therapy. Advancements in genetic testing allows identification of patients most likely to have a severe reaction to abacavir by the presence of HLA-B*5701, and rechallenging patients with a history of hypersensitivity to abacavir is contraindicated. Rash is the most common adverse effect of all non-nucleoside reverse-transcriptase inhibitors (NNRTIs), but nevirapine, in particular, has been implicated in severe hypersensitivity reactions. Risk for nevirapine reaction is greatest in the first 6 weeks of therapy and associated with female gender and high CD4 counts (women >250 cells/mm3 and men >400 cells/mm3). Although this association is best described in treatment-naive patients, recent evidence has suggested that viral loads actually play an important role in determining risk.
A study of 3,752 patients revealed that those with high CD4 counts but undetectable viral loads had similar hypersensitivity risk as treatment-naive patients with CD4 counts below the cutoffs, which suggested it may be safe to initiate nevirapine above the current CD4 cutoffs in patients without viremia. Still, the incidence of severe reaction with nevirapine is 1.5% to 6%, and the manufacturer strictly advises a 2-week lead-in of a lower dose and delaying titration upward in the presence of a rash. Providers can treat through a mild to moderate rash without constitutional symptoms or internal organ involvement, but therapy should be permanently discontinued otherwise.
Protease inhibitors cause of rash
Other classes of ART also have the potential to cause rash and hypersensitivity. Protease inhibitors are associated with rash as well. In patients without NNRTI-based ART and CD4 levels <50 cells/mcL, development of a rash with ritonavir (Norvir, AbbVie) or indinavir (Crixivan, Merck) was independently associated with female gender and lack of ART. This suggests that, similar to nevirapine, gender and viral loads may play a role in rash development and hypersensitivity risk. Raltegravir (Isentress, Merck) and a new integrase inhibitor, dolutegravir (Tivicay, ViiV Healthcare), have reported very few cases of rash and hypersensitivity, even in treatment-naive patients. These agents may be alternatives for patients intolerant to other ARTs due to rash or hypersensitivity reactions.
Reasons remain unclear
It is still unclear why this patient population is so prone to drug-related reactions. The answer, similar to most answers in medicine, is likely multifactorial. Altered metabolism affects the rate of inactivation and behavior of toxic metabolites while HIV-infected cells may be more sensitive to cytotoxicity — one hypothesis for TMP-SMX reactions. Another proposed mechanism is increased activity of the remaining immune system: T-cell activation via increased antigen presentation by major histocompatibility complex molecules or direct activation by parent drug or metabolites. The “danger signal” hypothesis endorses the idea that HIV-infection itself induces cytokine release and inflammatory signals — alerting the immune system to danger and promoting hyperactivity.
Further research into the mechanisms of hypersensitivity to commonly used medications in HIV-positive patients is vital to improving tolerability and adherence to therapy. Success in identifying genetic risk profiles or specific risk factors helps mitigate these burdensome and potentially dangerous reactions. Provider and patient awareness is key to managing adverse effects when they occur.
Coopman SA. N Engl J Med. 1993;328:1670-1674.
Florida M. HIV Med. 2004;5:1-10.
Koopmans PP. Pharm World Sci. 1998;20:253-257.
Phillips E. Curr Opin Allergy Clin Immunol. 2007;7:324-330.
Pirmohamed M. Curr Opin Allergy Clin Immunol. 2001;1:311-316.
Raffi F. Lancet Infect Dis. 2013;13:927-935.
Tilles SA. South Med J. 2001;94:817-824.
Walmsley SL. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;19:498-505.
Walmsley SL. N Engl J Med. 2013;369:1807-1818.
Wit FW. Clin Infect Dis. 2008;46:933-940.
Kati Shihadeh, PharmD, is a clinical pharmacy specialist – infectious diseases at Denver Health Medical Center, Denver. Shihadeh can be reached at katherine.shihadeh@dhha.org.
Disclosures: Seymour and Shihadeh report no relevant financial disclosures.