Dose escalation of adalimumab as a strategy to overcome anti-drug antibodies: A case report of infantile-onset inflammatory bowel disease.

BACKGROUND: Treatment of infantile-onset inflammatory bowel disease (IO-IBD) is often challenging due to its aggressive disease course and failure of standard therapies with a need for biologics. Secondary loss of response is frequently caused by the production of anti-drug antibodies, a well-known problem in IBD patients on biologic treatment. We present a case of IO-IBD treated with therapeutic drug monitoring (TDM)-guided high-dose anti-tumor necrosis factor therapy, in which dose escalation monitoring was used as a strategy to overcome anti-drug antibodies. CASE SUMMARY: A 5-mo-old boy presented with a history of persistent hematochezia from the 10th d of life, as well as relapsing perianal abscess and growth failure. Hypoalbuminemia, anemia, and elevated inflammatory markers were also present. Endoscopic assessment revealed skip lesions with deep colic ulcerations, inflammatory anal sub-stenosis, and deep fissures with persistent abscess. A diagnosis of IO-IBD Crohn-like was made. The patient was initially treated with oral steroids and fistulotomy. After the perianal abscess healed, adalimumab (ADA) was administered with concomitant gradual tapering of steroids. Clinical and biochemical steroid-free remission was achieved with good trough levels. After 3 mo, antibodies to ADA (ATA) were found with undetectable trough levels; therefore, we optimized the therapy schedule, first administering 10 mg weekly and subsequently up to 20 mg weekly (2.8 mg/kg/dose). After 2 mo of high-dose treatment, ATA disappeared, with concomitant high trough levels and stable clinical and biochemical remission of the disease. CONCLUSION: TDM-guided high-dose ADA treatment as a monotherapy overcame ATA production. This strategy could be a good alternative to combination therapy, especially in very young patients.

Immunological profiles of HIV-positive recipients of liver transplant.

BACKGROUND: Scarce data are available about immune cell frequencies in HIV-positive recipients of liver transplant. Alterations in immune subsets can lead to persistent immune activation and disease progression or reduced HIV-specific responses. In liver transplantation, impaired immune tolerance can lead to organ rejection. METHODS: HIV-positive subjects with undetectable HIVRNA and CD4 > 100/mm3 were included. Control groups were non-transplanted HIV-positive patients with similar immunovirological parameters and healthy subjects. B cells (memory, transitional, and mature subsets), T cells (effector TH1, nonclassic TH1, TH17, TH1/17; T regulatory naïve and effector subsets and CD8+ T regulatory cells), and NK cells (CD56dim and CD56bright subsets) were analyzed by flow cytometry. RESULTS: A total of 56 patients, including 14 HIV-positive transplant recipients (HIV-LT), 14 HIV-positive controls, and 28 healthy controls were included. Median age of HIV-LT patients was 54.9 years with median time from transplant of 7.6 years. Eleven (79%) were HIV/HCV coinfected. Compared to nontransplanted patients, HIV-LT displayed significantly increased frequency of T CD8+ cells, lower percentage of T CD4+ cell, and lower number of nonclassic TH1, TH1/17 cells and naïve T CD4+ regulatory cells (Tregs). Healthy controls showed increased numbers of B cell subsets and decreased percentage of T effector subpopulations compared to HIV-LT. Compared to HIV-positive patients, healthy controls had higher B cells, NK cells, CD4+ T cells, naïve CD4+ Tregs but lower CD8+ T cells, effector Tregs, CD8+ Tregs, and all T effector cell subsets. CONCLUSIONS: Immune cell subpopulations potentially associated with HIV progression and organ rejection were detected in HIV-positive transplant recipients. We confirmed altered frequencies of B, T, and NK cell populations in HIV-positive liver transplant recipients compared to healthy controls. The imbalance among immune cell subsets deserves further studies to identify markers of transplant outcome and potential therapeutic targets.

Serological and T Cell Responses After Varicella Zoster Virus Vaccination in HIV-Positive Patients Undergoing Renal Dialysis.

Limited data on varicella zoster virus (VZV) vaccine responses are available in HIV-positive adults, especially among those with end-stage renal disease on dialysis or undergoing kidney transplantation (KT). Serological and T cell responses were analyzed using anti-VZV IgG titers, enzyme-linked immunosorbent assay and flow cytometric intracellular cytokine staining (ICS) in two HIV-positive kidney transplant candidates undergoing dialysis and receiving VZV immunization. The results were compared with two HIV-positive and two HIV-negative VZV-seropositive patients (two kidney transplant candidates and two kidney transplant recipients), and with one HIV-negative vaccinee. HIV-positive VZV-susceptible patients received two doses of VZV vaccine 12 weeks apart. No adverse events were reported. Serological data were indicative of immunological response in one patient and corresponded to T cell responses. The second patient showed only a transient increase in anti-VZV IgG titers, but reported positive CD4+ T cell responses that were maintained after KT. Positive T cell and serological responses were detected in both HIV-positive and HIV-negative controls. VZV vaccination appeared safe and effective in HIV-positive KT candidates. VZV-specific T cell immunity was detected among transplant candidates and after KT. The assessment of VZV-specific T cell immunity using flow cytometric ICS may be more reliable compared to serology in assessing responses to VZV vaccine in this group.

Antimicrobial resistance and treatment: an unmet clinical safety need.

INTRODUCTION: Infections due to multidrug-resistant (MDR) bacteria are burdened by high mortality rates. The development of new compounds to face the global threat of resistance is urgently needed. Combination regimens including "old" high-dose antimicrobials are currently limited by the risk of toxicity, resistance selection, and reduced efficacy. Following the Infectious Diseases Society of America call to develop 10 new antibacterials by 2020, new molecules are currently under development or have become available for use in clinical practice. AREAS COVERED: We have reviewed safety characteristics and tolerability of old antimicrobials that are currently employed in combination regimens as well as new antimicrobials, including beta-lactams/beta-lactamase inhibitors, new cephalosporins, quinolones, and aminoglycosides. EXPERT OPINION: The availability of new compounds that show in vitro efficacy against MDR represents a unique opportunity to face the threat of resistance and to optimize the current use of antimicrobials, potentially reducing toxicity. Agents that are potentially active against MDR Gram-negatives are ceftozolane/tazobactam, new carbapenems and cephalosporins, the combination of avibactam with ceftazidime, and plazomicin. Further data from clinical trials and post-marketing studies for drugs targeting MDR pathogens are crucial to confirm their efficacy and safety.