Developing a Bayesian adaptive design for a phase I clinical trial: a case study for a novel HIV treatment.

The design of phase I studies is often challenging, because of limited evidence to inform study protocols. Adaptive designs are now well established in cancer but much less so in other clinical areas. A phase I study to assess the safety, pharmacokinetic profile and antiretroviral efficacy of C34-PEG4 -Chol, a novel peptide fusion inhibitor for the treatment of HIV infection, has been set up with Medical Research Council funding. During the study workup, Bayesian adaptive designs based on the continual reassessment method were compared with a more standard rule-based design, with the aim of choosing a design that would maximise the scientific information gained from the study. The process of specifying and evaluating the design options was time consuming and required the active involvement of all members of the trial's protocol development team. However, the effort was worthwhile as the originally proposed rule-based design has been replaced by a more efficient Bayesian adaptive design. While the outcome to be modelled, design details and evaluation criteria are trial specific, the principles behind their selection are general. This case study illustrates the steps required to establish a design in a novel context. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical Presentation of Mpox in People With and Without HIV in the United Kingdom During the 2022 Global Outbreak.

Early UK surveillance data revealed that people living with HIV were overrepresented among cases of monkeypox (mpox). However, it remains unknown whether mpox infection is more severe in people living with well-controlled HIV. All laboratory-confirmed mpox cases presenting between May and December 2022 to one London hospital service were identified via pathology reporting systems. We extracted demographic and clinical data to allow comparison of clinical presentation and severity of mpox among people with and without HIV. We identified 150 people with mpox (median age 36 years, 99.3% male, 92.7% reporting sex with other men). HIV status was available for 144 individuals, 58 (40.3%) of whom were HIV positive (only 3/58 had CD4 cell counts <200 cells/mm3 and 5/58 had HIV RNA >200 copies/mL). People with HIV had similar clinical presentations to those without HIV, including indicators of more widespread disease, such as extragenital lesions (74.1% vs. 64.0%, p = .20) and nondermatological symptoms (87.9% vs. 82.6%, p = .38). People with HIV also experienced a similar time from onset of symptoms to discharge from all inpatient or outpatient clinical follow-up (p = .63) and total time under follow-up (p = .88) compared with people without HIV. A similar proportion of people with HIV required review in the hospital emergency department (36.2% vs. 25.6%, p = .17) or admission to hospital (19.0% vs. 9.3%, p = .09). There were no recorded deaths. In this cohort of people with mpox, there was a high prevalence of HIV coinfection, the majority of which was well-controlled. We find no evidence that people with well-controlled HIV experienced more severe mpox infection.

Use of ß-D-glucan in diagnosis of suspected Pneumocystis jirovecii pneumonia in adults with HIV infection.

OBJECTIVES: An elevated serum (1-3)-ß-D-glucan (BDG) concentration has high sensitivity for a diagnosis of Pneumocystis pneumonia (PCP) in people with HIV (PWH). At the current manufacturer-recommended positive threshold of 80 pg/mL (Fungitell), specificity for PCP is variable and other diagnostic tests are required. We evaluated the utility of serum BDG for diagnosis of suspected PCP in PWH at three inner-London hospitals to determine BDG concentrations for diagnosis and exclusion of PCP. METHODS: From clinical case records, we abstracted demographic and clinical information and categorised patients as having confirmed or probable PCP, or an alternative diagnosis. We calculated sensitivity, specificity and positive predictive value (PPV) of serum BDG concentrations >400 pg/mL and negative predictive value (NPV) of BDG <80 pg/mL. RESULTS: 76 patients were included; 29 had laboratory-confirmed PCP, 17 had probable PCP and 30 had an alternative diagnosis. Serum BDG >400 pg/mL had a sensitivity of 83%, specificity of 97% and PPV 97% for diagnosis of PCP; BDG <80 pg/mL had 100% NPV for exclusion of PCP. CONCLUSIONS: In PWH with suspected PCP, BDG <80 pg/mL excludes a diagnosis of PCP, whereas BDG concentrations >400 pg/mL effectively confirm the diagnosis. Values 80-400 pg/mL should prompt additional diagnostic tests.

A first-in-human study of the novel HIV-fusion inhibitor C34-PEG4-Chol.

Long-acting injectable antiretroviral (LA-ARV) drugs with low toxicity profiles and propensity for drug-drug interactions are a goal for future ARV regimens. C34-PEG4-Chol is a novel cholesterol tagged LA HIV-fusion-inhibitor (FI). We assessed pre-clinical toxicology and first-in-human administration of C34-PEG4-Chol. Pre-clinical toxicology was conducted in 2 species. HIV-positive men were randomised to a single subcutaneous dose of C34-PEG4-Chol at incrementing doses or placebo. Detailed clinical (including injection site reaction (ISR) grading), plasma pharmacokinetic (time-to-minimum-effective-concentration (MEC, 25 ng/mL) and pharmacodynamic (plasma HIV RNA) parameters were assessed. In both mice and dogs, no-observed-adverse effect level (NOAEL) was observed at a 12 mg/kg/dose after two weeks. Of 5 men enrolled, 3 received active drug (10 mg, 10 mg and 20 mg). In 2 individuals grade 3 ISR occurred and the study was halted. Both ISR emerged within 12 hours of active drug dosing. No systemic toxicities were observed. The time-to-MEC was >72 and >96 hours after 10 and 20 mg dose, respectively, and mean change in HIV RNA was -0.9 log10 copies/mL. These human pharmacodynamic and pharmacokinetic data, although limited to 3 subjects, of C34-PEG-4-Chol suggest continuing evaluation of this agent as a LA-ARV. However, alternative administration routes must be explored.

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, MVA, and Env gp140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes.

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant-aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p = 0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccine-induced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen.

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study.

BACKGROUND: PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. METHODS: Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. RESULTS: Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported 'being deferred' as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. CONCLUSION: The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study.

Laboratory adverse events and discontinuation of therapy according to CD4(+) cell count at the start of antiretroviral therapy.

OBJECTIVE: Few data describe antiretroviral treatment (ART)-related adverse events when treatment is initiated at CD4(+) cell counts more than 350 cells/µl. We compared rates of laboratory-defined adverse events (LDAEs) according to CD4(+) cell count at ART initiation. DESIGN: Analysis of on-going cohort study. METHODS: ART-naive persons initiating ART from 2000 to 2010 were included. Chi-square, analysis of variance (ANOVA) and Kruskal-Wallis tests compared characteristics among those starting ART with a CD4(+) cell count of 350 or less, 351-499 and at least 500 cells/µl. Time-updated Poisson regression compared rates of LDAE in the three CD4(+) cell strata. Cox proportional hazard models compared risk of ART discontinuation. RESULTS: Nine thousand, four hundred and six individuals were included: median age 37 years, 61% white, 80% men, median viral load 4.8 log copies/ml. Four hundred and forty-seven (4.9%) and 1099 (11.7%) started ART with a CD4(+) cell count at least 500 and 351-499 cells/µl, respectively. One thousand, two hundred and eighty-three (13.6%) patients experienced at least one LDAE. The rate of LDAE did not differ between those starting ART with a CD4(+) cell count 351-499 and less than 350 cells/µl [relative rate 0.90, 95% confidence interval (CI) 0.74-1.09)], but an increased risk of ART discontinuation was observed (hazard ratio 1.58, 95% CI 1.10-2.27). Those starting ART at CD4(+) cell count at least 500 cells/µl had an increased rate of LDAE (relative rate 1.44, 95% CI 1.13-1.82) but were not more likely to discontinue ART (hazard ratio 1.15, 95% CI 0.64-2.09). CONCLUSION: This study demonstrates the need to consider ART-related toxicities when initiating therapy at CD4(+) cell counts at least 500 cells/µl. Whilst evidence from randomized controlled trials is awaited, the timing of ART initiation in terms of benefits and risks of ART remains an important question.