Varicella zoster immune globulin (human) (VARIZIG) in immunocompromised patients: a subgroup analysis for safety and outcomes from a large, expanded-access program

Physician-identified, high-risk individuals who were exposed to varicella or herpes zoster were eligible for inclusion in the study. High-risk participants included immunocompromised children and adults, among others (e.g. preterm infants, in utero–exposed newborns, pregnant women). A full report of the study has been previously published [15]. This analysis focuses on the immunocompromised participants, providing an in-depth analysis of the subgroups within this heterogeneous population. The protocol did not specify what constituted an exposure to varicella or herpes zoster, and was left to the judgment of the investigator. The timing of administration post-exposure was defined based on information provided to the investigator by the participant or family member. Participants were excluded if they had known immunity to varicella, hypersensitivity to blood or blood products, hypersensitivity to any component of VARIZIG, a history of selective immunoglobulin A deficiency, evidence of current varicella or herpes zoster infection at study entry, or evidence of severe thrombocytopenia. Participants with previous varicella immunity who had received an HCT were considered non-immune and could receive VARIZIG per the guidelines established by the Advisory Committee on Immunization Practices [9].

This expanded-access program (NCT00338442) was open-label and took place in a real-world setting at 285 clinical study sites across the United States between March 2006 and April 2013. Study visits occurred at baseline (to determine eligibility, administer VARIZIG, and monitor participants after exposure), between days 1 to 4, between days 7 to 20, and between days 28 to 42. VARIZIG (125 IU/10 kg [up to 625 IU]) was administered once intramuscularly. Ideally, administration occurred as soon as possible after exposure, but administration could occur within 10 days of exposure. This study was conducted in accordance with the Good Clinical Practice Guideline as defined by the International Conference on Harmonisation, the Declaration of Helsinki, and all applicable federal and local regulations and institutional review board guidelines. The protocol and amendments, the informed consent form, and study-related materials were reviewed and approved by a central independent ethics committee (Western Institutional Review Board, Puyallup, WA, USA) before study initiation and throughout the conduct of the study. All patients (or their guardians) provided written informed consent.

Immunocompromised participants were grouped by age (children aged 18 years or younger and adults) and then stratified into five groups based on immunocompromising condition: “primary immunodeficiencies”, “oncologic immunodeficiencies”, “history of SOT”, “history of HCT”, and “other” immunodeficiencies. Data were analyzed using descriptive statistics.

There were 40 immunocompromised adults included in the study (Table 1). Of these, 10 individuals (25%) had oncologic immunodeficiencies, 6 (15%) had primary immunodeficiencies, 5 (13%) had a history of SOT, 6 (15%) had a history of HCT, and 13 (32%) had other or unspecified immunocompromising conditions. Most exposures occurred in the household (53%) or the healthcare setting (40%); this pattern held for each subgroup, although the distribution varied to some degree, with SOT recipients more commonly exposed in the hospital (80%), whereas individuals with primary immunodeficiencies were more commonly exposed in the household (83%). There was a relatively equivalent distribution of type of exposure, with 48% exposed to varicella, 38% exposed to herpes zoster, and 15% with an “unknown” or “not specified” exposure in the case report form.

There were 263 immunocompromised children included in the study (Table 2). One hundred fifty-two (58%) had oncologic immunodeficiencies, with acute lymphocytic leukemia (n = 63) as the most common diagnosis, followed by pre-B acute lymphocytic leukemia (n = 13) and neuroblastoma (n = 15); all other causes occurred in seven or fewer patients each. There were 36 (14%) children with a history of SOT, 17 (6%) children with a history of HCT, 13 (5%) children with primary immunodeficiencies, and 45 (17%) children with other causes of immunodeficiency. Exposure to varicella or herpes zoster most commonly occurred in the healthcare setting (39%), the household (33%), and school/daycare (21%). Seventy-two percent of children were exposed to varicella, with 16% exposed to herpes zoster and 12% unknown/not specified exposure noted in the case report form.

Of the immunocompromised adults, 80% received VARIZIG within 96 h of varicella or herpes zoster exposure (Table 1). Across subgroups, this pattern was similar, although in adult SOT patients, 60% received VARIZIG in the first 96 h. Overall, immunocompromised adults had a 6% incidence of varicella (Fig. 1a). Within subgroups, adults with oncologic immunodeficiencies had a 10% incidence of varicella and adults with other immunodeficiencies had a 9% incidence of varicella. No patients with primary immunodeficiencies, history of SOT, or history of developed varicella. Varicella outcome data were not available for four adults (two were in the primary immunodeficiency subgroup and two were in the other immunodeficiencies subgroup); these patients were excluded from incidence calculations. Timing of administration did not greatly impact the varicella incidence in adults (Fig. 1b). There were no varicella-related complications (> 100 lesions, pneumonia, or encephalitis) or hospitalizations in immunocompromised adults. Overall, four adults (10%) were treated prophylactically with antiviral therapy, with one patient in the oncologic immunodeficiency subgroup and three patients in the HCT subgroup; none of these patients developed varicella. Antiviral dosing regimens varied, with two patients dosed within the first 2 days of varicella or herpes zoster exposure for a duration of 3 weeks, and two patients were given antiviral therapy 7 days after varicella or herpes zoster exposure for unknown duration (i.e. treatment was still ongoing at study completion).

Ninety percent of immunocompromised children were administered VARIZIG within 96 h of varicella or herpes zoster exposure, this pattern was similar in all subgroups (Table 2). Overall, immunocompromised children had a 7% incidence of varicella (Fig. 1a). This incidence was similar in the subgroup of children with oncologic immunodeficiencies (5%), and children with a history of HCT (6%). Varicella incidence was greater in children with primary immunodeficiencies (15%) and children with a history of SOT (12%). Children with “other” immunocompromising conditions had a 3% incidence of varicella. Varicella outcome data were not available for 18 children (oncologic immunodeficiency, n = 4; SOT, n = 3; other, n = 11); these children were excluded from incidence calculations. When assessed by timing of VARIZIG administration, all cases of varicella occurred in patients who were administered VARIZIG within 96 h of varicella or herpes zoster exposure. Varicella infections were mild, with only two patients developing more than 100 lesions, and no cases of varicella-related pulmonary disease or encephalitis occurred. Most children with oncologic immunodeficiencies who developed varicella (6 of 8 children) and one child with history of SOT were hospitalized for varicella treatment; there were no varicella-related hospitalizations in children with primary immunodeficiencies, history of HCT, or children with other immunodeficiencies. Overall, 49 children (19%) were treated prophylactically with antiviral therapy, of whom 2 were in the primary immunodeficiency subgroup, 32 in the oncologic immunodeficiency group, 6 in the SOT group, 4 in the HCT group, and 5 in the “other” subgroup; none of these patients developed varicella. Antiviral therapy (acyclovir or valacyclovir) was most often dosed (orally or intravenously) in two different regimens: patients were either given antiviral therapy immediately (within 2 days) after exposure for a duration of 2 days to > 1 month, or patients were given antiviral therapy approximately 6 to 10 days after exposure, for a duration of 2 to 3 weeks. A small group of patients were already on antiviral therapy for underlying medical conditions. If patients who received prophylactic antiviral therapy are excluded from the analysis, varicella incidence is not markedly changed (overall pediatric population: 7.5% [16 of 214 participants], oncologic: 6.7% [8 of 120 participants], history of HCT: 7.7% [1 of 13 participants], SOT: 13.3% [4 of 30 participants], primary immunodeficiencies: 18.2% [2 of 11 participants], and other immunodeficiencies: 2.5% [1 of 40 participants].

Overall, 15 immunocompromised adults (38%) experienced 51 AEs, of which only one AE of nausea was considered related to VARIZIG (Table 3). Four adults (10%) experienced 10 serious AEs, none of which were considered related to VARIZIG. There was one death (respiratory failure in a patient with AIDS) in the immunocompromised adult group; this death was considered unrelated to varicella or VARIZIG.

In the group of immunocompromised children, 90 (34%) experienced 402 AEs, of which 53 (13%) were considered related to VARIZIG (Table 4). The most frequently occurring (in more than one participant) AEs that were considered related to VARIZIG were injection site pain (n = 5, 2%), headache (n = 2, 0.8%), and diarrhea (n = 2, 0.8%). There were 42 children (16%) who experienced 93 serious AEs, of which one (serum sickness) was considered related to VARIZIG. There were five deaths: three (caused by acute myeloid leukemia, intracranial hemorrhage, and neuroblastoma) occurred in the oncologic immunodeficiency group, one (caused by acute lymphoblastic leukemia complicated by pneumonia infection) occurred in the group with a history of HCT, and one (caused by congestive cardiac failure) occurred in the “other” immunocompromised group. None of these deaths were considered by the investigators to be related to varicella or VARIZIG.