Global Pharmacovigilance for Antiretroviral Drugs: Overcoming Contrasting Priorities

Jur Strobos and colleagues describe the deliberations of a recent multi-stakeholder meeting discussing the creation of a sustainable global pharmacovigilance system for antiretroviral drugs that would be applicable in resource limited settings

Single DermaVir Immunization: Dose-Dependent Expansion of Precursor/Memory T Cells against All HIV Antigens in HIV-1 Infected Individuals

BACKGROUND: The GIHU004 study was designed to evaluate the safety and immunogenicity of three doses of DermaVir immunization in HIV-infected subjects on fully suppressive combination antiretroviral therapy (cART). METHODOLOGY/PRINCIPAL FINDINGS: This first-in-human dose escalation study was conducted with three topical DermaVir doses targeted to epidermal Langerhans cells to express fifteen HIV antigens in draining lymph nodes: 0.1 mg DNA targeted to two, 0.4 mg and 0.8 mg DNA targeted to four lymph nodes. Particularly, in the medium dose cohort 0.1 mg DNA was targeted per draining lymph node via ∼8 million Langerhans cells located in 80 cm(2) epidermis area. The 28-days study with 48-week safety follow-up evaluated HIV-specific T cell responses against Gag p17, Gag p24 and Gag p15, Tat and Rev antigens. DermaVir-associated side effects were mild, transient and not dose-dependent. Boosting of HIV-specific effector CD4(+) and CD8(+) T cells expressing IFN-gamma and IL-2 was detected against several antigens in every subject of the medium dose cohort. The striking result was the dose-dependent expansion of HIV-specific precursor/memory T cells with high proliferation capacity. In low, medium and high dose cohorts this HIV-specific T cell population increased by 325-, 136,202 and 50,759 counts after 4 weeks, and by 3,899, 9,878 and 18,382 counts after one year, respectively, compared to baseline. CONCLUSIONS/SIGNIFICANCE: Single immunization with the DermaVir candidate therapeutic vaccine was safe and immunogenic in HIV-infected individuals. Based on the potent induction of Gag, Tat and Rev-specific memory T cells, especially in the medium dose cohort, we speculate that DermaVir boost T cell responses specific to all the 15 HIV antigens expressed from the single DNA. For durable immune reactivity repeated DermaVir immunization might be required since the frequency of DermaVir-boosted HIV-specific memory T cells decreased during the 48-week follow up. TRIAL REGISTRATION: ClinicalTrial.gov NCT00712530

Outcomes of Bedaquiline Treatment in Patients with Multidrug-Resistant Tuberculosis

Bedaquiline is recommended by the World Health Organization for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB). We pooled data from 5 cohorts of patients treated with bedaquiline in France, Georgia, Armenia, and South Africa and in a multicountry study. The rate of culture conversion to negative at 6 months (by the end of 6 months of treatment) was 78% (95% CI 73.5%–81.9%), and the treatment success rate was 65.8% (95% CI 59.9%–71.3%). Death rate was 11.7% (95% CI 7.0%–19.1%). Up to 91.1% (95% CI 82.2%–95.8%) of the patients experienced >1 adverse event, and 11.2% (95% CI 5.0%–23.2%) experienced a serious adverse event. Lung cavitations were consistently associated with unfavorable outcomes. The use of bedaquiline in MDR and XDR TB treatment regimens appears to be effective and safe across different settings, although the certainty of evidence was assessed as very low

A prospective patient registry to monitor safety, effectiveness, and utilisation of bedaquiline in patients with multidrug-resistant tuberculosis in South Korea

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) represents a major public health concern, with an ongoing need for new effective treatments. Bedaquiline is an oral diarylquinoline that has shown encouraging treatment success and culture conversion rates in MDR-TB. Methods A South Korean patient registry was set up across 19 centres between 2016 and 2018 for the prospective collection of data from patients with MDR-TB who received either a bedaquiline-containing or a non-bedaquiline-containing regimen. Treatment was at the physician’s discretion (bedaquiline use requiring approval by special committee) and was based on patient characteristics, disease status, and local treatment guidelines. Results The safety population included 172 patients (88 bedaquiline and 84 non-bedaquiline). The mean (standard deviation, SD) duration of follow-up was 24.3 (9.5) months. Mean (SD) durations of treatment were 5.4 (1.8) months in bedaquiline-treated patients and 15.7 (6.7) months in the non-bedaquiline group. Treatment success (cured and treatment completed according to WHO 2013 treatment outcome definitions) was achieved by 56.3% of bedaquiline-treated and 45.2% of non-bedaquiline-treated patients. Sputum culture conversion rates were 90.4% and 83.7% with and without bedaquiline, respectively. Diarrhoea and nausea were the most frequently reported treatment-emergent adverse events (TEAEs) in the bedaquiline group (27.3% [24/88] and 22.7% [20/88], respectively). The most frequent bedaquiline-related TEAEs were prolonged QT interval (10.2%; 9/88), and diarrhoea and nausea (9.1% each; 8/88). QT interval prolongation was reported in 19.3% (17/88) of bedaquiline-treated and 2.4% (2/84) of non-bedaquiline-treated patients, but bedaquiline was not discontinued for any patient for this reason. There were 13 (14.7%) and three (3.6%) deaths in the bedaquiline-treated and non-bedaquiline groups, respectively. Review of fatal cases revealed no unexpected safety findings, and no deaths were bedaquiline-related. The most common cause of death was worsening cancer (three patients). Patients in the bedaquiline group tended to have poorer baseline risk profiles than non-bedaquiline patients and were more likely to have relapsed or already failed second-line treatment. Interpretation of mortality data was complicated by high rates of loss to follow-up in both groups. Conclusions The South Korean registry findings support previous risk/benefit observations and the continued use of bedaquiline as part of combination therapy in patients with MDR-TB

Increase of HIV-specific memory/precursor T cells from baseline after a single DermaVir immunization.

*<p>Calculated from data of the 2 separate PBMC specimen obtained from every subjects at screening and at day 0, just before DermaVir immunization.</p>**<p>PHPC counts were calculated as follows: (Proliferation index) x (mean number of spots/million PBMC in wells from each pool of peptides - mean number of spots/million PBMC in wells with control medium). PHPC counts in response to Gag p17 pool, Gag p24 pool and Gag p15 pool were summed to calculate total Gag responses (denoted as Gag).</p>***<p>Gag+Tat+Rev responses were calculated by adding Gag, Rev and Tat responses together; it represents ∼25% of the total immunologic potential of DermaVir <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035416#pone.0035416-Somogyi1" target="_blank">[9]</a>.</p

HIV-specific ICC responses.

<p>Responders: at least 2 separate visits >baseline and/or response is ≥2% (net cytokine producing CD4 or CD8 T cells).</p

HIV-specific ELISPOT responses.

<p>ELISPOT SFU/10⁶ PBMC are the average of a duplicate or triplicate assay; Mocks were subtracted.</p>*<p>Cohort 1 samples were collected at week 24. Bold: ELISPOT responders: ≥10 fold above the response at baseline.</p

Kinetics of the HIV-specific PHPC responses.

<p>Long-lived HIV-specific precursor/memory T cells with high proliferative capacity prior and after a single DermaVir immunization in each HIV-infected individual on fully suppressive cART. 1^st raw: Low dose; 2^nd raw: Medium Dose; 3^rd raw: high dose DermaVir immunizations. Frequency of PHPC responses against Tat, Rev and the three Gag antigens are shown prior (Day 0) and after DermaVir immunization (day 7, day 14, day 28, and week 48). Every sample was assayed in duplicate or triplicate, and data are shown as PHPC counts/10⁶ PBMC.</p

Baseline data of study participants.

*<p>Cohort 1: Low dose DermaVir (0.1 mg DNA); Cohort 2: Medium dose DermaVir (0.4 mg DNA); Cohort 3: high dose DermaVir (0.8 mg DNA). All participants were Caucasian and was negative for ANA and anti-ds-DNA; F: Female; M: Male. CD4 in counts/mm³.</p

CD4⁺ and CD8⁺ T cell counts.

<p>CD4⁺ and CD8⁺ T cell counts.</p