Safety and efficacy of topical artesunate for the treatment of vulvar intraepithelial neoplasia 2/3.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of topical artesunate ointment for treatment of biopsy-confirmed Human papillomavirus (HPV)-associated Vulvar intraepithelial neoplasia (VIN) 2/3. METHODS: Participants were enrolled on a prospective, IRB-approved, dose-escalation phase I trial testing either 1, 2 or 3 treatment cycles (5 days), every other week, as applicable. Clinical assessments were completed prior to each dose cycle and included exam and review of adverse event (AE) diary cards. HPV testing and colposcopy was completed at 15 and 28 weeks. AEs were assessed according to CTCAE 4.0 criteria. Complete responders (CR) underwent biopsy of the treated site at the 28-weeks while partial (PR) and non (NR)-responders underwent surgical resection or biopsy and ablation. RESULTS: Fifteen patients consented to and began treatment. Per-protocol assessments were completed in 100% at 15- and 80% at 28-weeks. All patients completed prescribed cycles with no grade 3 or 4 AEs. Vulvovaginal burning/ was the most common AE occurring in 93.3%. AEs were grade 2 in 23.7% and included vulvovaginal pruritus (n = 3), swelling (n = 3) and candidiasis (n = 2). The highest ORR was in the 3-cycle group (88.9% with 55.6% CR). HPV-16 was detected either alone (46.7%) or with other subtypes (33.3%) in 80% of lesions and 5 of 8 (62.5%) with CR had complete viral clearance. CONCLUSIONS: Topical artesunate for treatment of high-grade VIN shows high tolerability, low toxicity and evidence for clinical response in this initial small series. The safety and observed responses support further study in a Phase II trial.

Ara h 2-specific IgE is superior to whole peanut extract-based serology or skin prick test for diagnosis of peanut allergy in infancy.

BACKGROUND: Screening of high-risk infants for peanut allergy (PA) before introduction is now recommended in the United States, but the optimal approach is not clear. OBJECTIVE: We sought to compare the diagnostic test characteristics of peanut skin prick test (SPT), peanut-specific IgE (sIgE), and sIgE to peanut components in a screening population of infants before known peanut exposure. METHODS: Infants aged 4 to 11 months with (1) no history of peanut ingestion, testing, or reaction and (2) (a) moderate-severe eczema, (b) history of food allergy, and/or (c) first-degree relative with a history of PA received peanut SPT, peanut-sIgE and component-IgE testing, and, depending on SPT wheal size, oral food challenge or observed feeding. Receiver-operator characteristic areas under the curve (AUCs) were compared, and diagnostic sensitivity and specificity were calculated. RESULTS: A total of 321 subjects completed the enrollment visit (median age, 7.2 months; 58% males), and 37 (11%) were found to have PA. Overall, Ara h 2-sIgE at a cutoff point of 0.1 kUa/L discriminated between allergic and nonallergic best (AUC, 0.96; sensitivity, 94%; specificity, 98%), compared with peanut-sIgE at 0.1 kUa/L (AUC, 0.89; sensitivity, 100%; specificity, 78%) or 0.35 kUa/L (AUC, 0.91; sensitivity, 97%; specificity, 86%), or SPT at wheal size 3 mm (AUC, 0.90; sensitivity, 92%; specificity, 88%) or 8 mm (AUC, 0.87; sensitivity, 73%; specificity, 99%). Ara h 1-sIgE and Ara h 3-sIgE did not add to prediction of PA when included in a model with Ara h 2-sIgE, and Ara h 8-sIgE discriminated poorly (AUC, 0.51). CONCLUSIONS: Measurement of only Ara h 2-sIgE should be considered if screening of high-risk infants is performed before peanut introduction.

Age and eczema severity, but not family history, are major risk factors for peanut allergy in infancy.

BACKGROUND: Whether to screen high-risk groups before early peanut introduction is controversial. OBJECTIVE: We sought to determine the risk of peanut allergy (PA) before peanut introduction for infants with (1) moderate-severe eczema, (2) another food allergy (FA), and/or (3) a first-degree relative with peanut allergy (FH). METHODS: Infants aged 4 to 11 months with no history of peanut ingestion, testing, or reaction and at least 1 of the above risk factors received peanut skin prick test and, depending on skin prick test wheal size, oral food challenge or observed feeding. RESULTS: A total of 321 subjects completed the enrollment visit (median age, 7.2 months; 58% males); 78 had eczema only, 11 FA only, 107 FH only, and 125 had multiple risk factors. Overall, 18% of 195 with eczema, 19% of 59 with FA, and 4% of 201 with FH had PA. Only 1% of 115 with FH and no eczema had PA. Among those with eczema, older age (odds ratio [OR], 1.3; 95% CI, 1.04-1.68 per month), higher SCORing Atopic Dermatitis score (OR, 1.19; 95% CI, 1.06-1.34 per 5 points), black (OR, 5.79; 95% CI, 1.92-17.4 compared with white), or Asian race (OR, 6.98; 95% CI, 1.92-25.44) and suspected or diagnosed other FA (OR, 3.98; 95% CI, 1.62-9.80) were associated with PA. CONCLUSIONS: PA is common in infants with moderate-severe eczema, whereas FH without eczema is not a major risk factor, suggesting screening only in those with significant eczema. Even within the first year of life, introduction at later ages is associated with a higher risk of PA among those with eczema, supporting introduction of peanut as early as possible.

A first-in-human proof-of-concept trial of intravaginal artesunate to treat cervical intraepithelial neoplasia 2/3 (CIN2/3).

OBJECTIVE: Most treatment options for cervical intraepithelial neoplasia 2/3 (CIN2/3) are either excisional or ablative, and require sequential visits to health care providers. Artesunate, a compound that is WHO-approved for treatment of acute malaria, also has cytotoxic effect on squamous cells transformed by HPV. We conducted a first-in-human Phase I dose-escalation study to assess the safety and efficacy of self-administered artesunate vaginal inserts in biopsy-confirmed CIN2/3. METHODS: Safety analyses were based on patients who received at least one dose, and were assessed by the severity, frequency, and duration of reported adverse events. Tolerability was assessed as the percentage of subjects able to complete their designated dosing regimen. Modified intention-to-treat analyses for efficacy and viral clearance were based on patients who received at least one dose for whom endpoint data were available. Efficacy was defined as histologic regression to CIN1 or less. Viral clearance was defined as absence of HPV genotoype (s) detected at baseline. RESULTS: A total of 28 patients received 1, 2, or 3 five-day treatment cycles at study weeks 0, 2, and 4, respectively, prior to a planned, standard-of-care resection at study week 15. Reported adverse events were mild, and self-limited. In the modified intention-to-treat analysis, histologic regression was observed in 19/28 (67.9%) subjects. Clearance of HPV genotypes detected at baseline occurred in 9 of the 19 (47.4%) subjects whose lesions underwent histologic regression. CONCLUSIONS: Self-administered vaginal artesunate inserts were safe and well-tolerated, at clinically effective doses to treat CIN2/3. These findings support proceeding with Phase II clinical studies.

Rates of New Peanut Allergy and Discontinuation Following Introduction in High-Risk Infants.

BACKGROUND: Peanut introduction guidelines recommend that infants with severe eczema and/or egg allergy consume 6 g of peanut protein weekly to prevent peanut allergy. Rates of new peanut allergy after introduction and adherence remain under study. OBJECTIVE: To determine compliance with peanut introduction guidelines, rates of new peanut allergy, and reasons for discontinuation of peanut consumption in a cohort of high-risk infants. METHODS: A prospective cohort of 4- to 11-month-old high-risk infants (defined as moderate-severe eczema or non-peanut food allergy or a first-degree relative with peanut allergy) with no prior peanut exposure who were determined to not be peanut allergic were recommended to introduce 6 g of peanut protein weekly. Participants were followed to 30 months with 2 in-person visits and monthly questionnaires. RESULTS: Two hundred seventy-seven infants were followed. At last follow-up, 245 (88%) were consuming some peanut protein with median weekly consumption of 3 g (interquartile range: 1-5 g). New peanut allergy developed in 6 (2%), with 2 of those cases consistent with food protein-induced enterocolitis syndrome. Fear of reaction in another household member was the most common reason for peanut discontinuation. Reactions to peanut after introduction in the index infant occurred in <2% of peanut-allergic siblings and in 20% of peanut-allergic parents. CONCLUSION: We found low rates of new peanut allergy and generally low rates of peanut discontinuation after introduction in our high-risk cohort. However, families of high-risk infants require significant support with introduction, especially those with another peanut-allergic member.

A phase I study of intra-anal artesunate (suppositories) to treat anal high-grade squamous intraepithelial lesions.

BACKGROUND: Ablation or surgical excision is the typical treatment of anal high-grade squamous intraepithelial lesions (HSIL). Recurrences are common due to the persistence of underlying human papillomavirus (HPV) infection. Additional well-tolerated and effective non-surgical options for HPV-associated anal disease are needed. METHODS: This 3+3 dose escalation Phase I clinical trial evaluated the safety and tolerability of artesunate suppositories in the treatment of patients with biopsy-proven HSIL. RESULTS: The maximal tolerated dose was 400 mg, administered in 3 cycles. All adverse events associated with the use 200- and 400-mg artesunate suppositories were Grade 1. At the 600-mg dose, patients experienced clinically significant nausea. CONCLUSION: Artesunate suppositories are a safe treatment option for anal HSIL.