CROI 2015 Program and Abstracts

Abstract Listing

Poster Abstracts

Methods: We integrated the ingestible sensor (IS) with Rifamate and Rifinah, the combination dosage forms of isoniazid (INH) and rifampin (RIF), via over-encapsulation (OE) with Gelcaps. We performed dissolution testing on these. We conducted a randomized bioequivalence (BE) study in 12 patients with active TB during the continuation phase comparing ISRifamate to its native form. INH and RIF were assayed using validated HPLC methods, and the pharmacokinetic parameters were analyzed using non-compartmental methods (Phoenix/WinNonlin software). We measured the positive detection accuracy (PDA) of the WOT system using ISRifamate by comparing WOT ingestions recorded when doses were given under DOT (n=280) and evaluated WOT performance in comparison to DOT in 14 active TB patients. Results: Patients mean age was 41 yrs, 71%male. Dissolution of OE ISRifinah 100mg/300mg was 100% at 43-45 mins for RIF and INH, meeting USP requirements. Dissolution for OE ISRifamate (100mg/300mg) reached 85-90% at 120mins. In the PK analysis of OE ISRifamate versus native form, INH and RIF were bioequivalent using the population method ratio test (95% confidence level); median INH Cmax were 3.85 and 4.27 mcg/ml; median AUC0-12h were 13.34 and 12.50 mcg/ml for native and OE, respectively. Median RIF Cmax were 12.12 and 11.79 mcg/ml; median AUC0-12h were 45.19 and 43.76 mcg/ml for native and OE ISRifamate, respectively. PDA for WOT based on 280 simultaneous DOT ingestions was 98.7% (mean), 100% (median), range (94-100%). However, the total number of WOT observations versus the total numbers of DOT doses was 148% (mean), 142% (median), range (130-187). Patients found the system easy to use with 90% giving high comfort ratings; 1 transient skin rash was observed. Conclusions: Over–encapsulation with IS was safe and bioequivalent to standard drug. The PDA confirms WOT is highly accurate. WOT is delivered daily and confirmed more drug doses ingested than DOT overall. WOT represents a new paradigm in TB therapy monitoring.

TUESDAY, FEBRUARY 24, 2015 Session P-R4 Poster Session

Poster Hall

2:30 pm– 4:00 pm TB Adverse Events, Recurrence, and Mortality 829 Severe Adverse Events in Outpatient Drug-Resistant TB Treatment in South Africa Rebecca H. Berhanu 1 ; Kathryn Schnippel 2 ; Andrew Black 3 ; Erika Mohr 4 ; Busi Mncube 1 ; Ian Sanne 1 1 Health Economics and Epidemiology Research Organisation, Johannesburg, South Africa; 2 Right to Care, Johannesburg, South Africa; 3 Reproductive Health Institute, University of Witswatersrand, Johannesburg, South Africa; 4 Médecins Sans Frontières, Cape Town, South Africa Background: South Africa adopted a policy of decentralization of drug-resistant TB treatment to satellite and outpatient sites in 2011. Outcomes of treatment at these new sites are not yet known. We report on the occurrence of adverse events (AE) to treatment at two outpatient, decentralized, drug-resistant tuberculosis (DR-TB) treatment sites in Johannesburg, South Africa. Methods: Combined retrospective and prospective medical record review of the six-month intensive phase of treatment for patients (>18 years old) with DR-TB registered between May 2012 to December 2013. Patients who transferred out or were lost to follow-up during the study period were excluded. A standardized regimen of kanamycin, moxifloxacin, ethionamide and terizidone was used according to the South African national DR-TB guidelines. Results: All 217 patients had resistance to rifampicin; 41 (20%) were also resistant to isoniazid (MDR-TB). 179 (82%) of patients were co-infected with HIV with a median CD4 count of 114 cells/ μ l. 240 AEs were recorded in 118 (54%) patients: hearing loss (18% of patients), hypokalemia (5%), acute kidney injury (4%) peripheral neuropathy (6%) and vomiting (4%) were the most common. Severe AEs (grade 3 to 5) accounted for 73 (30%) of AEs and were reported in 38 (18%) patients. Severe AEs were more likely to occur in those 50 years or older [Odds ratio: 5.9, 95%CI: 1.5 – 23.4], in HIV co-infected with CD4 < 100 cells/ μ l [2.3, CI: 1.2-4.4] and in those diagnosed with DR-TB in an inpatient setting ([1.9, CI 1.1-3.4]. Acute kidney injury was more likely to occur in men [2.3, CI 0.9-5.6] and inpatients [2.8, CI 1.1-7.2]. 22 (10%) patients died during the intensive phase of treatment. No statistically significant differences were detected in AE incidence or severity according to HIV status [0.7, CI 0.3-1.5 and 1.6, CI 0.6-0.4].

Poster Abstracts

Conclusions: These results suggest that severe adverse events are being experienced by a significant proportion of patients managed at outpatient DR-TB treatment sites. The most common toxicities: hearing loss, hypokalemia, and acute kidney injury, are all related to aminoglycoside treatment. As treatment of drug-resistant TB is further decentralized, training of health care workers to identify and treat adverse events is critical to improving treatment outcomes.

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CROI 2015