Drug hypersensitivity in HIV infection

Abstract

Purpose of review: Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS.

Recent findings: Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight.

Summary: IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

FIGURE 1.

Enhanced susceptibility to immune-mediated adverse drug reactions through the life-cycle of HIV/AIDS. Several potential mechanisms may explain the increased susceptibility to IM-ADRs through HIV/AIDS life cycle. Prior to infection, individuals or populations may carry specific HLA or other pharmacogenomic risk alleles to particular drugs. Host factors determining HIV control may influence the dynamics of immune dysregulation. Upon infection and as disease progresses, CD4⁺ T cells are depleted, with homeostatic expansion of CD8⁺ T cells, particularly functional memory CD8⁺ T cells. Marked immune hyperactivation characterized by excessive levels of inflammatory cytokines, such as type I interferons (IFN-α) and suppressive cytokines, IL-10 and changes in the expression levels of IFN-γ induced chemokines (IP-10). Another influence includes altered immunoregulatory pathways, which results in the lack of counterbalance against cytotoxic immune responses. Reactivation of comorbid herpes viral infections, such as CMV, EBV, of HHV6 and HHV8 may occur during worsening immunosuppression; viral reactivation has a known association with DRESS. HIV can alter redox balance and potentially increase the production and accumulation of toxic reactive metabolites. Overall, during chronic infection, uncontrolled immune activation, loss of CD4⁺ T cells and Tregs and unopposed CD8⁺ cytotoxic T-cell responses likely promotes the enhanced susceptibility to IM-ADRs in HIV/AIDS patients. The precise balance of these signals may determine the severity of these reactions in different stages of infection. ADME, absorption, distribution, metabolism and elimination; CMV, cytomegalovirus; DRESS, drug reaction with eosinophilia and systemic symptoms; EBV, Epstein–Barr virus; HHVs, human herpes viruses; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; IM-ADR, immune-mediated adverse drug reaction; IP-10, interferon gamma-induced protein 10; TB, tuberculosis; TH2, T-helper 2; TNF, tumor necrosis factor; Treg, regulatory T cells.