Increased human immunodeficiency virus viral load with cerebral infarction due to varicella zoster virus vasculopathy on treatment with bictegravir/emtricitabine/tenofovir alafenamide suspension: a case report and literature review

Bictegravir (BIC) can be administered as a single-tablet regimen and in combination with emtricitabine (FTC) and tenofovir alafenamide (TAF). BIC/FTC/TAF is among the most frequently prescribed antiretroviral therapy (ART), given its simplicity, good safety profile, and high genetic barrier to resistance [1]. However, there are safety concerns regarding BIC/FTC/TAF therapy among patients unable to swallow an intact tablet, given the limited data on suspension formulations. BIC/FTC/TAF manufacturer’s labeling does not indicate whether the tablet could be converted to suspension [2].

Varicella-zoster virus (VZV) causes chickenpox. The virus then becomes latent in ganglionic neurons. With higher age or an immunocompromised host, the VZV reactivates to cause herpes zoster (shingles). VZV causes severe neurological complications—such as vasculopathy, meningoencephalitis, spinal encephalitis, myelopathy, and postherpetic neuralgia—in immunocompromised hosts, such as patients with Human Immunodeficiency Virus (HIV) [3]. In the case series of 30 patients [4], clinical characteristics and management for almost non-HIV-infected patients are shown; however, the risks factor and optimal therapy for patients with HIV remain unclear.

We present a patient with HIV and severe VZV vasculopathy who presented with increased HIV viral load and worsened clinical course after BIC/FTC/TAF suspension administration. We performed two literature reviews of the administration of BIC/TAF/3TC suspension and VZV vasculopathy in patients with HIV to collect more evidence.

A 55-year-old homosexual man with a history of type 2 diabetes mellitus presented with herpes zoster in the left anterior thoracic area 3 months before admission. Two weeks before admission, he was diagnosed with HIV and started on BIC/TAF/FTC. On admission day, he visited our hospital complaining of high fever, headache, and consciousness disorder. His vital signs were as follows: level of consciousness, E4V4M6 in the Glasgow Coma Scale; body temperature, 36.4 °C; blood pressure, 147/97 mmHg; heart rate, 109 min; respiratory rate, 26 min; oxygen saturation at room air, 99%. Physical examination revealed no neck rigidity, no oral lesion, clear bilateral auscultation, and no skin rash or raised patches. The laboratory test results were as follows: white blood cell count, 5200 μL (lymphocytes, 810 μL; CD4, 49 μL; CD4/8, 0.12); blood glucose level, 153 mg/dL; HIV viral load, 2.4 × 10⁵/mL; cryptococcal antigen, negative; and no ART-resistant HIV mutation. The cerebrospinal fluid (CSF) test findings were as follows: initial pressure, 15 cmH₂0; cell count, 124 μL (mononuclear cells: 88.7%); protein levels, 388 mg/dL; glucose levels, 87 mg/dL; VZV polymerase chain reaction, 9.4 × 10⁴ copies/mL; and cryptococcal antigen, negative. The CSF culture was negative. Contrast-enhanced magnetic resonance imaging (MRI) of the brain revealed cerebral infarctions in the subcortical areas (Fig. 1). He was diagnosed with cerebral infarction caused by VZV vasculopathy and was started on acyclovir (ACV) 10 mg/kg at 8 h intervals. On day 18 of hospitalization, MRI revealed worsening of the cerebral infarction (Fig. 1). There was a subsequent gradual deterioration of his swallowing function due to worsening neurological symptoms. A CSF lumbar puncture did not reveal a VZV load on day 38. He was started on tube feeding on day 45. Further, there was no BIC/TAF/FTC administration or gastrointestinal symptoms, including diarrhea. The HIV viral load decreased to 86 copies/mL on day 86 but increased to 390 copies/mL on day 99. No drug-resistance genes were detected. He was started on prednisone from day 57 (first 3 days 1 g/day, and thereafter 1 mg/kg). MRI revealed a temporal progression of the multiple cerebral infarctions (on days 48 and 62; Fig. 1). The patient was switched to Doltegravir/Abacavir/Lamivudine (DTG/ABC/3TC) on day 105. The findings of the MRI on day 117 indicated multiple cerebral infarctions progression cessation compared to the findings on day 83 (Fig. 1). On day 161, the HIV viral load was 52 copies/mL with 61 μL of CD4, and he was transferred to another hospital. The clinical course of our case is shown in Fig. 2.

This article presents a patient with HIV who had severe multiple cerebral infarction due to VZV vasculopathy and failed treatment with BIC/TAF/FTC suspension. Although the manufacturer’s labeling indicates the safety of BIC/TAF/FTC suspension [2], there are three reported cases of failed treatment, including our case [5, 6]. Two of these cases, including ours, did not use other ART regimens [6]. Unlike our case, the two cases showed viral mutations [5, 6] We switched to DTG/ABC/3TC because the randomized controlled trials have shown that DTG/ABC/3TC has no pharmacokinetic problems when administered in suspension form to healthy adults [7]. Although Tenofovir disoproxil fumarate suspension is not listed by the FDA, the safety serum concentration level has been reported [8]. However, the SOLUBIC study reported a decrease in plasma TAF levels (Area Under the Curve: AUC 86%, 90% confidence interval (CI) [82–91], C_max 70%, 95% CI [63–78]) [9]. In this study, bioequivalence was met if the 90% CIs of the AUC and Cmax were within 80–125% of the reference. We could not perform therapeutic drug monitoring due to limited facilities; however, the effectiveness of BIC/FTC/TAF suspension remains unclear; and safer ART suspensions are required to avoid difficulties in swallowing or tube administration.

In general, patients with herpes zoster are known to have significantly higher cerebral infarction within 1 year [10]. From our review, we propose that we need a careful follow-up of the neurological symptoms in patients with HIV who started ART after a recent history of VZV infection at under 200 μL in CD4 counts. Experts have recommended administering 14 days course of ACV with oral prednisone. The case series recommended a more effective treatment regimen of ACV + steroid than ACV [4]. In our review, ACV + steroid for neurologic deficits in patients with HIV were more improved or stabilized than ACV alone. We could not find the optimal duration of treatment in our review. This needs to be clarified in a further prospective study (Figs. 3, 4).

Patients with HIV with CD4 counts under 200 μL during or after treatment for herpes zoster should be followed carefully for neurological symptoms. DTG/ABC/3TC may be considered over BIC/TAF/FTC in the case of suspension administration.