Drug hypersensitivity in HIV infection Peter, Jonny; Choshi, Phuti; Lehloenya, Rannakoe J
Current opinion in allergy and clinical immunology,
08/2019, Letnik:
19, Številka:
4
Journal Article
Odprti dostop
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.
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.
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.
Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are on a spectrum of cutaneous drug reactions characterized by pan-epidermal necrosis with SJS affecting < 10% of body surface area ...(BSA), TEN > 30%, and SJS/TEN overlap between 10 and 30%. Severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is a validated tool to predict mortality rates based on age, heart rate, BSA, malignancy and serum urea, bicarbonate, and glucose. Despite improved understanding, SJS/TEN mortality remains constant and therapeutic interventions are not universally accepted for a number of reasons, including rarity of SJS/TEN; inconsistent definition of cases, disease severity, and endpoints in studies; low efficacy of interventions; and variations in treatment protocols. Apart from mortality, none of the other endpoints used to evaluate interventions, including duration of hospitalization, is sufficiently standardized to be reproducible across cases and treatment centers. Some of the gaps in SJS/TEN research can be narrowed through international collaboration to harmonize research endpoints. A case is made for an urgent international collaborative effort to develop consensus on definitions of endpoints such as disease status, progression, cessation, and complete re-epithelialization in interventional studies. The deficiencies of using BSA as the sole determinant of SJS/TEN severity, excluding internal organ involvement and extension of skin necrosis beyond the epidermis, are discussed and the role these factors play on time to healing and mortality beyond the acute stage is highlighted. The potential role of artificial intelligence, biomarkers, and PET/CT scan with radiolabeled glucose as markers of disease status, activity, and therapeutic response is also discussed.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions with a higher incidence in HIV-infected persons. SJS/TEN are associated with skin and mucosal ...failure, predisposing to systemic bacterial infection (BSI), a major cause of death. There are limited data on risk factors associated with BSI and and mortality in HIV-infected people with SJS/TEN.
We conducted a retrospective study of patients admitted to a university hospital with SJS/TEN over a 3 year period. We evaluated their underlying illnesses, eliciting drugs, predictive value of bacterial skin cultures and other factors associated with mortality and BSI in a predominantly HIV-infected population by comparing characteristics of the patients who demised and those who survived.
We admitted 86 cases during the study period and 67/86(78%) were HIV-infected. Tuberculosis was the commonest co-morbidity, diagnosed in 12/86(14%) cases. Skin cultures correlated with BSI by the same organism in 7/64(11%) cases and 6/7 were Gram-negative. Two of the 8 cases of Gram-negative BSI had an associated Gram-negative skin culture, although not always the same organism. All 8 fatalities had >30% epidermal detachment, 7 were HIV-infected, 6 died of BSI and 6 had tuberculosis.
Having >30% epidermal detachment in SJS/TEN carries an increased risk of BSI and mortality. Tuberculosis and BSI are associated with higher risk of death in SJS/TEN. Our data suggests there may be an association between Gram-negative BSI and Gram-negative skin infection.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) form a spectrum of a rare and life-threatening cutaneous drug reaction. SJS/TEN in pregnancy poses largely unknown risk factors and ...outcomes for both the mother and foetus compared to the general population.
We conducted a study of consecutive pregnant women admitted to single tertiary referral centre in South Africa with SJS/TEN over a 3 year period. They were all managed by the same medical team using the same protocols. We evaluated their underlying illnesses, offending drugs and the course of pregnancy and outcomes to determine factors influencing maternal and foetal outcomes.
We identified twenty-two women who developed SJS/TEN while pregnant, all of them HIV-infected. Their median age was 29 years. The majority 16/22 (73%) had SJS, the milder variant of the disease affecting < 10% body surface area. Nevirapine was the offending drug in 21/22 (95%) cases. All 22 of the mothers survived with 3/22 (14%) developing postpartum sepsis. Pregnancy outcomes were known in 18/22 women and 9/18 (50%) babies were delivered by caesarean section. There were 2 foetal deaths at 21 and 31 weeks respectively and both were associated with post-partum sepsis. Postnatal complications occurred in 5 cases, 3 involving the respiratory system and the other two being low birth weight deliveries. Eight placentae and one foetus were sent for histology and none showed macroscopic or microscopic features of SJS/TEN. On follow-up, only 12/20 children were tested for HIV at 6 weeks post-delivery and none of them were HIV-infected. All had received prophylactic ARVs including nevirapine.
TEN, the severe form of the disease, was associated with poorer foetal outcomes. SJS/TEN-associated mortality is not increased in HIV-infected pregnant women. Maternal SJS/TEN does not seem to commonly manifest in the foetus.
Increased risk of tuberculosis (TB) associated with HIV-1 infection is primarily attributed to deficient T helper (Th)1 immune responses, but most people with active TB have robust Th1 responses, ...indicating that these are not sufficient to protect against disease. Recent findings suggest that favourable outcomes following Mycobacterium tuberculosis infection arise from finely balanced inflammatory and regulatory pathways, achieving pathogen control without immunopathology. We hypothesised that HIV-1 and antiretroviral therapy (ART) exert widespread changes to cell mediated immunity, which may compromise the optimal host protective response to TB and provide novel insights into the correlates of immune protection and pathogenesis. We sought to define these effects in patients with active TB by transcriptional profiling of tuberculin skin tests (TST) to make comprehensive molecular level assessments of in vivo human immune responses at the site of a standardised mycobacterial challenge. We showed that the TST transcriptome accurately reflects the molecular pathology at the site of human pulmonary TB, and used this approach to investigate immune dysregulation in HIV-1/TB co-infected patients with distinct clinical phenotypes associated with TST reactivity or anergy and unmasking TB immune reconstitution inflammatory syndrome (IRIS) after initiation of ART. HIV-1 infected patients with positive TSTs exhibited preserved Th1 responses but deficient immunoregulatory IL10-inducible responses. Those with clinically negative TSTs revealed profound anergy of innate as well as adaptive immune responses, except for preservation of type 1 interferon activity, implicated in impaired anti-mycobacterial immunity. Patients with unmasking TB IRIS showed recovery of Th1 immunity to normal levels, but exaggerated Th2-associated responses specifically. These mechanisms of immune dysregulation were localised to the tissue microenvironment and not evident in peripheral blood. TST molecular profiling categorised different mechanisms of immunological dysfunction in HIV-1 infection beyond the effects on CD4 T cells, each associated with increased risk of TB disease and amenable to host-directed therapies.
Recognizing Drug Hypersensitivity in Pigmented Skin Lehloenya, Rannakoe J; Phillips, Elizabeth J; Pasieka, Helena B ...
Immunology and allergy clinics of North America,
05/2022, Letnik:
42, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The imagery of pigmented skin is underrepresented in teaching materials such as textbooks, journals, and online references, and this has resulted in poorer diagnostic and management outcomes of skin ...pathology, including delayed cutaneous drug hypersensitivity reactions. In this review, we use clinical images to highlight factors that impact clinical presentations and sequelae of drug hypersensitivity reactions in pigmented skin compared with nonpigmented skin. We describe clinical features in some anatomic sites that aid diagnosis or are associated with more severe sequelae. Finally, we discuss strategies that may aid the diagnosis and management of these reactions in pigmented skin.
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and ...society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.
Photosensitive dermatoses are seen in 5% of HIV-infected persons. These include drug- and chemical-induced photoallergic and phototoxic reactions, chronic actinic dermatitis of HIV, photo lichenoid ...drug eruptions, and porphyria. Data on photodermatitis in HIV are limited to case reports and series. The pathogenesis is not completely understood and includes a th2 phenotype in HIV which results in impaired barrier function and resultant allergen sensitisation as well as immune dysregulation. The objective of this manuscript is to review the literature on the clinical phenotype, pathogenesis, role of photo and patch testing, outcomes, and treatment of photodermatitis in HIV in an African population.
Objective
To compare the cost of managing treatment‐limiting cutaneous adverse drug reactions (CADRs) to first‐line anti‐tuberculosis drugs to an alternative strategy of immediate treatment ...initiation using second‐line drugs in a South African setting.
Methods
Clinical and cost data were retrospectively collected from patients presenting with a first‐line anti‐tuberculosis therapy‐associated CADR. Costs (2016 US$) were estimated using an ingredient’s approach from a healthcare provider perspective. The per‐patient and total cost of drug rechallenge, the current management strategy for severe CADR, was calculated. Alternative strategies involving second‐line treatment were derived from literature and expert clinical advice.
Results
Drug rechallenge costs US $5831 (95% CI: 5134–6527) per patient. Hospitalisation accounted for 62% of this cost. Alternative CADR management strategies using regimens containing rifabutin, bedaquiline and/or delamanid cost 44%–55% less than drug rechallenge (US $2651–US $3276/patient). In univariate sensitivity analyses, drug rechallenge and alternative strategies were most sensitive to hospitalisation and tuberculosis drug costs, respectively.
Conclusion
Cutaneous adverse drug reactions to anti‐tuberculosis treatment represent a significant economic burden. An alternate strategy of outpatient‐initiated second‐line therapy is economically feasible but requires clinical validation to assess effectiveness.
Objectif
Comparer le coût de la prise ne charge des effets indésirables cutanés (EIC) limitant le traitement aux antituberculeux de première ligne à celui d'une stratégie alternative d'initiation immédiate du traitement par des médicaments de deuxième ligne dans un contexte sud‐africain.
Méthodes
Les données cliniques et les coûts ont été collectés rétrospectivement chez des patients présentant un EIC associé au traitement antituberculeux de première ligne. Les coûts (USD, 2016) ont été estimés en utilisant une approche d'ingrédient du point de vue d'un prestataire de soins de santé. Le coût par patient et le coût total du nouveau traitement, de la stratégie actuelle de prise en charge des cas d’EIC sévère, ont été calculés. Des stratégies alternatives impliquant un traitement de deuxième ligne ont été dérivées de la littérature et de conseils cliniques d'experts.
Résultats
Le coût du nouveau traitement était de 5.831 USD (IC95%: 5.134 ‐ 6.527) par patient. L'hospitalisation représentait 62% de ce coût. Les stratégies alternatives de prise en charge des EIC utilisant des schémas thérapeutiques contenant de la rifabutine, de la bédaquiline et/ou du delamanide coûtent de 44 % à 55 % moins cher que le nouveau traitement (2.651 USD – 3.276 USD/patient). Dans les analyses de sensibilité univariées, les stratégies de re‐traitement et les stratégies alternatives étaient plus sensibles aux coûts d'hospitalisation et de médicaments antituberculeux, respectivement.
Conclusion
Les EIC des antituberculeux représentent une charge économique importante. Une stratégie alternative de traitement de deuxième ligne mise en place chez des patients ambulatoires est économiquement réalisable mais nécessite une validation clinique pour évaluer l'efficacité.
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