Research Spotlight

Haugh, I. M., A. K. Preston, D. N. Kivelevitch and A. M. Menter (2018). “Risankizumab: an anti-IL-23 antibody for the treatment of psoriasis.” Drug Des Devel Ther 12: 3879-3883.

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Risankizumab, a fully human IgG monoclonal antibody inhibitor of IL-23, is a therapeutic agent currently in late stage development for use in the treatment of moderate-to-severe plaque psoriasis. It is a biologic agent similar to guselkumab and tildrakizumab which targets IL-23 specifically, and has been primarily developed for use in moderate-to-severe psoriasis. USA-based pharmaceutical company Abbvie submitted it for a Biologics License Application to the US Food and Drug Administration (FDA) in April 2018. Risankizumab is the result of a collaboration between the German company Boehringer Ingelheim and Abbvie, which together are leading the future development and commercialization of risankizumab globally. The results from Phase I to Phase III clinical trials of risankizumab show it is highly effective and its FDA-approval in 2018 is likely. In this article we provide an independent expert opinion on the efficacy and safety of risankizumab in psoriasis based on a full review of the literature.

Gupta, A. K., S. G. Versteeg, W. Abramovits and K. D. Vincent (2018). “Ilumya(R) (Tildrakizumab): A Newly Approved Interluekin-23 Antagonist for the Treatment of Plaque Psoriasis.” Skinmed 16(5): 321-324.

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Ilumya is the second of probably three monoclonal antibodies against IL-23 to enter the market for plaque psoriasis treatment, and possibly for psoriatic arthritis. Studies comparing drugs in this class and with anti-IL-17 are underway. Tildrakizumab displayed higher treatment success rates in plaque psoriasis patients, with a long-lasting and expedient response with over 50% of tildrakizumab-treated patients reporting PGA scores of 0 or 1 by week 12. Administration of tildrakizumab (100 mg) at weeks 0 and 4, and every 12 weeks thereafter is recommended for the treatment of moderate-to-severe plaque psoriasis. Due to the impact of tildrakizumab on the IL-23, IL-17 and tumor necrosis factor (TNF) pathways, this IL-23 antagonist may also be a beneficial treatment for psoriatic arthritis and axial spondyloarthropathies. (Excerpt from text, p. 324; no abstract available.)

Goyal, A., K. Chatterjee, R. O. Mathew, M. S. Sidhu, S. Bangalore, P. A. McCullough and J. Rangaswami (2018). “In-Hospital Mortality and Major Adverse Cardiovascular Events after Kidney Transplantation in the United States.” Cardiorenal Med 9(1): 51-60.

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BACKGROUND: Kidney transplantation (KT) is the treatment of choice for end-stage kidney disease. Cardiovascular disease is a major determinant of morbidity and mortality in patients with KT. Temporal trends in perioperative cardiovascular outcomes after KT are understudied, especially in light of an aging KT waitlist population. METHODS: We performed a retrospective observational cohort study using the National Inpatient Sample for the years 2004-2013. All adult patients undergoing KT were identified using the appropriate International Classification of Diseases, 9th Revision, Clinical Modification codes. Demographic and hospital characteristics, discharge disposition, payer status, and major adverse cardiovascular events (MACEs) were summarized using summary statistics. Multivariate logistic regression was used to identify predictors of MACEs in the perioperative period of KT. RESULTS: A total of 147,431 KTs were performed between 2004 and 2013. The mean age at KT went up from 48.1 to 51.8 years from 2004 to 2013. Medicare was the primary payer for 59.6% of the KTs. Overall average perioperative mortality was 0.5%, median length of stay was 5 days, and 6.5% of patients experienced an MACE, 78% of which were heart failures (HFs). Important predictors of perioperative MACEs were age >/=65 years (OR = 2.14), Medicare as primary payer (OR = 1.51), diabetes (OR = 1.46), recreational drug use (OR = 1.72), pulmonary circulation disorders (OR = 3.28), and malnutrition (OR = 1.91). CONCLUSION: Despite increases in age at the time of KT, the absolute risk of perioperative MACEs has remained stable from 2004 to 2013. HF is a major component of postoperative MACEs in KT. Malnutrition and pulmonary hypertension are major nontraditional predictors of perioperative MACE outcomes.

Ford, E. S., A. S. Magaret, C. W. Spak, S. Selke, S. Kuntz, L. Corey and A. Wald (2018). “Increase in HSV shedding at initiation of antiretroviral therapy and decrease in shedding over time on antiretroviral therapy in HIV and HSV-2 infected persons.” Aids 32(17): 2525-2531.

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OBJECTIVES: HIV-infected persons with chronic herpesvirus infections may experience paradoxical worsening after initiation of antiretroviral therapy (ART), but the impact of longer term ART is unclear. We evaluated the relationships between genital herpes simplex virus (HSV) shedding and ART initiation and time on therapy in HIV and HSV-2-infected persons. DESIGN: Prospective observational study. METHODS: Rates of HSV shedding in 45 HIV and HSV-2-infected persons on or off ART were prospectively followed over up to three, noncontiguous, 60-day periods, during which participants performed daily genital swabs for HSV detection by real-time HSV DNA PCR and reported symptoms. Initiation or discontinuation of ART was at the discretion of participants’ healthcare providers. RESULTS: In all, 6425 daily genital swabs were obtained from 45 persons (38 men and seven women) during 105 swabbing sessions. During the three sessions, 67, 74, and 92% of persons were on ART. HSV was detected on 26.5% of days in men and 22.3% of days in women. The overall rates of genital HSV shedding were 19.4% of days in persons not on ART, 30.2% in persons within 90 days of ART initiation, and 23.3% in persons on ART for longer than 90 days. After initiation of ART, HSV shedding decreased by 2% per month, or 23% per year (RR 0.98/month on ART; P = 0.0003 in adjusted analysis). This finding was consistent after including consideration of HIV viral load and CD4 cell count. CONCLUSIONS: HSV shedding increased significantly shortly after ART initiation, but decreased with time on prolonged ART.

Flamar, A. L., H. Bonnabau, S. Zurawski, C. Lacabaratz, M. Montes, L. Richert, A. Wiedemann, L. Galmin, D. Weiss, A. Cristillo, L. Hudacik, A. Salazar, C. Peltekian, R. Thiebaut, G. Zurawski and Y. Levy (2018). “HIV-1 T cell epitopes targeted to Rhesus macaque CD40 and DCIR: A comparative study of prototype dendritic cell targeting therapeutic vaccine candidates.” PLoS One 13(11): e0207794.

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HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is stopped. HIV-1-infected individuals under this drug regimen have increased rates of cancers, cardiovascular diseases, and autoimmunity due to compromised immunity. A therapeutic vaccine boosting cellular immunity against HIV-1 is therefore desirable and, possibly combined with other immune modulating agents, could obviate the need for long-term drug therapies. An approach to elicit strong T cell-based immunity is to direct virus protein antigens specifically to dendritic cells (DCs), which are the key cell type for controlling immune responses. For eliciting therapeutic cellular immunity in HIV-1-infected individuals, we developed vaccines comprised of five T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol (HIV5pep) fused to monoclonal antibodies that bind either, the antigen presenting cell activating receptor CD40, or the endocytic dendritic cell immunoreceptor DCIR. The study aimed to demonstrate vaccine safety, establish efficacy for broad T cell responses in both primed and naive settings, and identify one candidate vaccine for human therapeutic development. The vaccines were administered to Rhesus macaques by intradermal injection with poly-ICLC adjuvant. The animals were either i) naive or, ii) previously primed with modified vaccinia Ankara vector (MVA) encoding HIV-1 Gag, Pol, and Nef (MVA GagPolNef). In the MVA-primed groups, both DC-targeting vaccinations boosted HIV5pep-specific blood CD4+ T cells producing multiple cytokines, but did not affect the MVA-elicited CD8+ T cell responses. In the naive groups, both DC-targeting vaccines elicited antigen-specific polyfunctional CD4+ and CD8+ T cell responses to multiple epitopes and these responses were unchanged by a subsequent MVA GagPolNef boost. In both settings, the T cell responses elicited via the CD40-targeting vaccine were more robust and were detectable in all the animals, favoring further development of the CD40-targeting vaccine for therapeutic vaccination of HIV-1-infected individuals.