Bictegravir-Induced Drug Reaction With Eosinophilia and Systemic Symptoms in a Patient With Acute Human Immunodeficiency Virus

Abstract

Although drug reaction with eosinophilia and systemic symptoms (DRESS) is associated with antiretrovirals, there are no published reports of bictegravir-induced DRESS. Bictegravir is recommended as first-line treatment for patients with human immunodeficiency virus (HIV). Recognition of DRESS, its skin manifestations, and potential complications is vital for appropriate care and management of acute HIV.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening condition characterized by severe skin exanthem, fever, atypical lymphocytosis, marked eosinophilia, and, less commonly, multiorgan involvement [1]. It is most often associated with antiepileptics, allopurinol, sulfonamides, and other antibiotics. However, there are very few cases in the literature of DRESS associated with antiretroviral therapy (ART) in people with human immunodeficiency virus (HIV) [2]. Anti-retroviral medications that have been implicated in probable cases of DRESS include abacavir, efavirenz, nevirapine, raltegravir, and tenofovir disoproxil fumarate [3–5]. However, none include bictegravir, one of the newest integrase inhibitors approved as part of a single-tablet regimen with emtricitabine and tenofovir alafenamide (Biktarvy) by the US Food and Drug Administration in 2018 [6]. Bictegravir is recommended as part of first-line therapy for patients newly diagnosed with HIV [7]. In this study, we present the case of a patient who developed bictegravir-induced DRESS syndrome.

CASE REPORT

A 51-year-old African American male with a past medical history of childhood asthma and intermittent cocaine use was admitted to the hospital reporting 2 weeks of diffuse generalized rash, myalgias, malaise, night sweats, sore throat, and generalized lymphadenopathy. He reported a recent history of unprotected penetrative anal and oral sexual intercourse with another man 3 months prior. He was diagnosed with acute HIV-1 on fourth-generation antigen/antibody screen and confirmatory testing with a baseline CD4 count of 560 cells/µL (CD4% 12) and HIV ribonucleic acid (RNA) of 70 892 copies/mL. His workup for opportunistic infections and other sexually transmitted infections including chlamydia, gonorrhea, herpes simplex virus, and varicella zoster virus (VZV) were negative. His syphilis testing was notable for a positive treponema pallidum antibody screen and negative nontreponemal antibody (negative rapid plasma reagin [RPR], titer 1:1). On the date of discharge, he was started on 1 oral fixed-dose combination tablet of bictegravir/emtricitabine/tenofovir alafenamide (50 mg/200 mg/25 mg) daily, which he was told he would be on indefinitely given his new HIV diagnosis. On the same day, he was started on a 7-day course of oral nystatin 500 000 units every 6 hours for oral candidiasis.

Ten days later, he presented to the outpatient HIV clinic for follow-up with a diffuse painful and pruritic erythematous morbilliform rash with areas of desquamation, blistering, and oropharyngeal erosions to his upper and lower lips, targetoid plaques on his palms and soles, as well as scrotal and bilateral lower extremity pitting edema (Figure 1). He reported full adherence to ART; however, he stopped taking nystatin 3 days after discharge and denied taking any other new medications or over-the-counter supplements.

Figure 1.

Clinical and pathologic presentation of the patient. Ten days after initiating bictegravir/emtricitabine/tenofovir alafenamide, the patient developed a papulosquamous eruption of deep brown and erythematous scaly papules (A), with areas of targetoid appearance and involvement of the face, hands, and feet (B). Punch biopsies taken from the left forearm and left thigh both demonstrated acanthosis with spongiosis, parakeratosis, and serum in addition to a perivascular infiltrate of lymphocytes with scattered eosinophils and occasional neutrophils ([C] hematoxylin and eosin, ×10).

He was readmitted to the hospital where he presented with an elevated white blood cell count (WBC) of 26 750 cells/µL with an absolute lymphocyte count of 9840 cells/µL (36.8%), an absolute eosinophil count of 7490 cells/mL (28.0%), normal creatinine, aspartate aminotransferase of 80 U/L, alanine aminotransferase of 148 U/L, and a normal bilirubin and alkaline phosphatase. Serologies for hepatitis A, B, and C virus were negative. Epstein-Barr virus (EBV), VZV, and monkeypox virus polymerase chain reaction (PCR) were also negative. Syphilis serology included a positive treponemal antibody and nonreactive RPR with a titer of 1:1. Human herpesvirus (HHV)-6 serology revealed a positive immunoglobulin (Ig)G and negative IgM, 1:10 and <1:20, respectively.

Bictegravir/emtricitabine/tenofovir alafenamide was stopped, and a punch biopsy of the left upper arm and left calf was obtained. On Day 2 of hospitalization, he had a temperature of 100.2°F and mild tachycardia without hypotension. Blood cultures obtained that day later grew methicillin-sensitive Staphylococcus aureus (MSSA). Intravenous cefazolin was started with rapid blood culture clearance on Day 4. Also, notably on Day 4, the patient's WBC was 27 570 cells/µL and his absolute lymphocyte count peaked at 11 880 cells/µL (43.1%). On hospital Day 5, his absolute eosinophil count peaked at 6670 cells/µL (26.1%), at which time his WBC was 25 600 cells/µL. A transthoracic echocardiogram was negative for endocarditis. His rash and pruritus gradually improved with topical steroids and cessation of ART. Further infectious disease testing was significant for negative cytomegalovirus (CMV) PCR, stool ova and parasites, and QuantiFERON gold. He was given 1 of 3 doses of intramuscular benzathine penicillin G 2.4 million units for late latent syphilis given no known prior history of treatment. His elevated transaminases gradually decreased after holding bictegravir/emtricitabine/tenofovir alafenamide, peaking on Day 5 of admission. Skin punch biopsy demonstrated acanthosis with spongiosis with perivascular infiltrate of eosinophils with final pathology consistent with drug eruption (Figure 1). He was discharged home on Day 11 on topical steroids, oral fluconazole, and a 4-week course of intravenous cefazolin for MSSA bacteremia. At the time of discharge, the patient's WBC was 15 430 cells/µL, his absolute lymphocyte count was 6890 cells/µL (44.7%), and his absolute eosinophil count was 1290 cells/µL (8.4%).

The patient was seen at an outpatient HIV clinic 1 week later with significant improvement of his symptoms and generalized rash. He was initiated on darunavir/cobicistat/emtricitabine/tenofovir alafenamide. Repeat laboratory studies 1 month after initiation of this new regimen showed a normal absolute eosinophil count and liver enzymes, undetectable HIV RNA and CD4 count 1277 cells/µL (CD4% 25).

Patient Consent Statement

We acknowledge that the patient's written consent was obtained. Institutional Review Board approval was not required for this case report.

DISCUSSION

Although DRESS has been reported in the literature as a result of the integrase inhibitor raltegravir, this is the first case reported in the literature of DRESS syndrome secondary to bictegravir to our knowledge. Our patient with acute HIV developed severe generalized rash, lymphocytosis, eosinophilia, and elevated liver enzymes with a confirmed biopsy consistent with DRESS after initiation of bictegravir/emtricitabine/tenofovir alafenamide. Given that his rash did not recur after initiation of a darunavir-based regimen also containing emtricitabine and tenofovir alafenamide, bictegravir was the most likely drug culprit in this case. In cases such as these, clinicians should be able to discern the rash associated with acute HIV and the development of DRESS due to initiation of ART.

The pathogenesis of DRESS involves a genetic predisposition with certain human leukocyte antigen haplotypes and genetic polymorphisms present in the host, followed by exposure to drug metabolites that leads to a T cell-mediated drug reaction. The incidence of DRESS ranges from 1 in 1000 to 1 in 10 000 drug exposures. The median time to symptoms after drug exposure is 2 to 8 weeks. However, our patient developed symptoms only approximately 10 days after exposure [2]. There is also emerging evidence that viral reactivation of EBV and/or HHV-6/HHV-7 may be another potential cause of DRESS, yet these were negative in our case except for positive HHV-6 IgG [1, 8].

Although DRESS can be diagnosed using a patch test, we did not perform this because there is not a standardized way to perform this type of testing. Some drugs do not lead to a positive patch test despite causing DRESS and, therefore, a negative test cannot be interpreted. Furthermore, patch testing can sometimes put a patient at risk of reactivating DRESS [9]. The most frequently used diagnostic criteria for DRESS are those in the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) score, which includes fever (>101.3°F or >38.5°C core body temperature or >100.4°F or >38°C axillary body temperature), lymphadenopathy in at least 2 different body areas, eosinophilia (>700 cells/µL or ≥10% if leukopenic), atypical lymphocytosis, skin rash, skin biopsy suggestive of DRESS, organ involvement, disease duration greater than 15 days, and exclusion of other causes (1 point assigned if 3 of the following tests are performed and are negative: hepatitis A, hepatitis B, hepatitis C, mycoplasma, chlamydia, antinuclear antibody, blood culture) [10]. Our patient met criteria for eosinophilia, atypical lymphocytosis, skin rash, biopsy suggestive of DRESS, organ involvement (transaminitis), and exclusion of other causes (hepatitis A, B, and C negative), giving him a score of 6, which meets criteria for definite DRESS.

Although the patient did develop MSSA bacteremia, this was likely due to superimposed bacterial skin and soft tissue infection, and it is unlikely that it was the primary cause of his presentation given the appearance of his skin rash and his skin biopsy findings. Of note, we also considered nystatin as another potential cause of DRESS in this case; however, there was a stronger temporal association between bictegravir/emtricitabine/tenofovir alafenamide and the patient's symptoms.

Another potential diagnosis we considered was immune reconstitution inflammatory syndrome associated with syphilis given the patient's positive syphilis serology and negative RPR titer. The prozone effect is a well characterized phenomenon in syphilis infection, in which an overwhelming antibody titer may lead to a false-negative result. However, our laboratory repeated syphilis testing and confirmed no prozone effect, and there were no spirochetes noted on biopsy. The eczematous pattern noted on the patient's biopsy is found in 40% of DRESS cases with perivascular infiltrate of lymphocytes and eosinophils found in 70% to 90% of cases [11].

Treatment of DRESS typically involves supportive treatment, topical corticosteroids, and cessation of the causative agent. Systemic corticosteroids can be considered in severe cases, but they were not indicated in our patient's case. In patients requiring systemic corticosteroids, it is important to be cognizant of the risk of relapse upon withdrawal of steroids. Other potential complications involving use of systemic corticosteroids to treat DRESS in immunocompromised patients include CMV reactivation and elevated risk of other viral and fungal infections [12].

CONCLUSIONS

In conclusion, we present a case of bictegravir-induced DRESS syndrome, which has not yet been reported in the medical literature. Although bictegravir and other integrase inhibitors are first-line ART for many patients, it is important for clinicians to consider the possibility of DRESS when initiation of these agents is followed by development of classic skin and systemic symptoms, which should prompt immediate diagnosis and treatment before significant complications arise.