Optimized Background Regimen Research Articles

Interim treatment outcomes in multidrug-resistant tuberculosis patients treated sequentially with bedaquiline and delamanid

ObjectivesThe objective of this study was to evaluate the efficacy and safety of the sequential use of bedaquiline (Bdq) and delamanid (Dlm) in patients with multidrug-resistant tuberculosis (MDR-TB) and limited treatment options. MethodsThis study evaluated 74 MDR-TB patients treated between March 2016 and December 2018 with Bdq followed by Dlm (n = 22), or vice versa (n= 52), combined with optimized background regimens. ResultsThe mean age of the participants was 49.0 ± 15.8 years. Fifty-one (68.9%) of the participants were male. Fluoroquinolone resistance was identified in 54 (72.9%) patients, including 20 (27.0%) with extensively drug-resistant TB. Of the 47 (63.5%) patients with positive cultures at the commencement of the first new drug, culture conversion occurred in 44 (93.6%). The interim treatment outcome after 12 months was favourable in 68/74 patients (91.9%). Twenty-four weeks of treatment were completed in 137 of 148 episodes of new drug use (92.3%). Regarding the 11 early discontinuation events, six patients stopped using a new drug due to adverse drug reactions that were not life-threatening, including one (1.4%) who stopped Bdq due to QT-prolongation. ConclusionsSequential use of the two new drugs appears to be an effective and safe option for MDR-TB patients with few treatment options.

Early treatment outcome of bedaquiline plus optimised background regimen in drug resistant tuberculosis patients

AimsBedaquiline (BDQ) has been recently approved for drug resistant tuberculosis with active drug safety monitoring under programmatic condition. The present study was conducted to evaluate safety, tolerability and efficacy of bedaquiline plus optimised background regimen. MethodsA prospective study was conducted on cohort of pre-extensively drug resistant (XDR) and XDR pulmonary TB patients. Eligible patients were closely monitored for cardiac safety, adverse events (AEs), clinical and microbiological improvement during BDQ (6 months) and post BDQ phase for twelve months. ResultsOf 127 patients enrolled, a significant increase in mean QTc interval was observed on 13th day and 3rd week as compared to baseline (p < 0.0001). Mean maximum increase of QTc was 37.92ms (95% CI, 14.1–61.74ms). Concomitant anti-TB medications, age, gender, low body mass index (BMI) had significant effect on QTc prolongation (p < 0.0001, p < 0.05). However, none of the patient required discontinuation of BDQ. Majority of AEs (86.3%) were non-serious and not preventable 108 (87.1%). The median time for sputum-culture conversion was 40.89 ± 3.5 days (95% CI, 34–48 days) and the treatment outcome was successful in 102 (80.3%) patients with negative sputum culture conversion. ConclusionsBedaquiline containing regimen achieved favourable outcome. Although, bedaquiline along with concomitant anti-TB medications has the potential to prolong QTc interval, the benefit certainly outweighs the risk. This calls for a through pre-treatment cardiovascular and biochemical evaluation as a preventive measure and appropriate selection of patients for safe use of BDQ and successful outcome.

Clinical and Economic Impact of Ibalizumab for People With Multidrug-Resistant HIV in the United States.

We projected the clinical outcomes, cost-effectiveness, and budget impact of ibalizumab plus an optimized background regimen (OBR) for people with multidrug-resistant (MDR) HIV in the United States. Using the Cost-Effectiveness of Preventing AIDS Complications microsimulation model and a health care sector perspective, we compared 2 treatment strategies for MDR HIV: (1) IBA + OBR-ibalizumab plus OBR and (2) OBR-OBR alone. Ibalizumab efficacy and cohort characteristics were from trial data: mean age 49 years, 85% male, and mean CD4 150/µL. Six-month viral suppression was 50% with IBA + OBR and 0% with OBR. The ibalizumab loading dose cost $10,500, and subsequent ibalizumab injections cost $8400/month; OBR cost $4500/month. Incremental cost-effectiveness ratios (ICERs) were calculated using discounted (3%/year) quality-adjusted life years (QALYs) and costs. ICERs ≤$100,000/QALY were considered cost-effective. We performed sensitivity analysis on key parameters and examined budget impact. In the base case, 5-year survival increased from 38% with OBR to 47% with IBA + OBR. Lifetime costs were $301,700/person with OBR and $661,800/person with IBA + OBR; the ICER for IBA + OBR compared with OBR was $260,900/QALY. IBA + OBR was not cost-effective even with 100% efficacy. IBA + OBR became cost-effective at base case efficacy if ibalizumab cost was reduced by ≥88%. For an estimated 12,000 people with MDR HIV in the United States, IBA + OBR increased care costs by $1.8 billion (1.5% of total treatment budget) over 5 years. For people with MDR HIV lacking other treatment options, ibalizumab will substantially increase survival when effective. Although adding ibalizumab to OBR is not cost-effective, the low number of eligible patients in the United States makes the budget impact relatively small.

Ibalizumab: A Review in Multidrug-Resistant HIV-1 Infection.

Ibalizumab (Trogarzo®; ibalizumab-uiyk) is the first monoclonal antibody to be approved for the treatment of HIV-1 infection. As a CD4-directed post-attachment inhibitor, ibalizumab blocks HIV-1 entry into CD4 cells while preserving normal immune function. Ibalizumab, in combination with other antiretroviral(s), is indicated in the USA for the treatment of heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen, and in the EU for the treatment of adults infected with multidrug-resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive antiviral regimen. In the pivotal phase III TMB-301 trial, ibalizumab significantly reduced the viral load 7days after being added to a failing antiretroviral regimen. Almost half of all patients achieved an undetectable viral load after 24weeks of treatment with ibalizumab plus an optimized background regimen, with virological suppression maintained over the longer term (up to 96weeks) in an expanded access protocol. The drug was generally well tolerated in clinical trials. Although additional studies and long-term post-marketing data are needed to fully determine its efficacy and safety, ibalizumab represents a valuable and much needed treatment option for patients with multidrug-resistant HIV-1 infection.

IMPACT-TB*: A Phase II Trial Assessing the Capacity of Low Dose Imatinib to Induce Myelopoiesis and Enhance Host Anti-Microbial Immunity Against Tuberculosis. *Imatinib Mesylate per Oral As a Clinical Therapeutic for TB

Background: With existing anti-tubercular therapies, treatment success rates for multi- and extensively-drug resistant tuberculosis (MDR-TB, XDR-TB) are dismal, highlighting the urgent need for new drugs. Ratios of myeloid to lymphoid cells are important predictors of TB disease susceptibility and vaccine efficacy. Imatinib mesylate (Gleevec), a cancer drug used in humans for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), is a potential "host- directed therapeutic (HDT)" for drug resistant TB infections and HIV/TB co-infections. Imatinib inhibits c-Abl tyrosine kinase (TK), which is dysregulated in CML, as well as related TKs (e.g. c-Kit). Imatinib facilitates clearance of Mycobacterium tuberculosis (Mtb), by disrupting the cellular mechanisms that Mtb uses for entry and survival in host cells. At doses 10-fold lower than those used for CML, imatinib also stimulates "emergency hematopoiesis," a host immune response to infection that mobilizes myeloid cell differentiation in the bone marrow and alters ratios of myeloid to lymphoid cells in the periphery towards protective levels, an effect suppressed by Mtb. Imatinib acts synergistically with antibiotics and is effective against antibiotic-resistant mycobacteria, and may be less likely to engender resistance compared to antibiotics. Preclinical data at low doses indicate efficacy of imatinib in a non-human primate (NHP) model of infection with TB or, alternatively, TB/SIV, which mimics poorly controlled TB or HIV/TB in humans. Study Design, Endpoints, and statistical design: We describe the design of two NIH-sponsored Phase II clinical trials in humans (NCT03891901). The first trial will comprise testing of 4 low doses of imatinib with or without antibiotics in 72 normal individuals in the United States. We will determine safety, immunological responses, and drug-drug interactions with standard of care antibiotics. The primary endpoints are to (i) identify the two best doses that induce myelopoiesis in humans, (ii) maximize bactericidal activity by immune cells ex vivo, and (iii) maximize safety. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals. The second trial will assess the safety and microbiologic efficacy of two doses of imatinib administered over 3 months in conjunction with optimized background antibiotic regimens versus the optimized background regimen alone. The trial will include 180 individuals with TB or HIV/TB in South Africa (60 per arm). The primary endpoints are (i) the time to sputum culture conversion, (ii) lung function by PET-CT and spirometry, and (iii) immunological parameters associated with myelopoieisis. Secondary endpoints include transcriptomics, proteomics, and measures of pathogen-specific immune responses. The trial is powered to detect a 2-fold increase in myelopoiesis across all imatinib doses relative to untreated individuals. The trial is statistically powered to distinguish at either dose an improvement over baseline treatment in time to sputum conversion or lung function or both. Major Inclusion/Exclusion Criteria: Phase II dosing trial: Normal volunteers, age 18 - 55 years. Phase II efficacy trial: Active antibiotic-sensitive tuberculosis with or without HIV. Pregnant women are excluded from both studies. Trial Status : The dosing trial has FDA and NIAID approval to begin and is currently undergoing registration with DAIDS prior to starting enrollment. Overall Goal: Data from these trials will provide a paradigm with which to further evaluate imatinib or other immunomodulatory HDTs as therapeutics for TB infection and HIV/TB co-infection. If successful, imatinib may shorten the time of treatment and limit development of antibiotic resistance, and may be useful against antibiotic resistant strains. This project is supported a grant from NIH/NIAID. Disclosures Waller: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents &amp; Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents &amp; Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. OffLabel Disclosure: Imatinib is known as a therapeutic for CML. Here, we will discuss our plans to develop imatinib as a host-directed-therapy to improve treatment of multi-drug-resistant tuberculosis

Study to Evaluate the Safety and Efficacy of GS-6207 in Combination With an Optimized Background Regimen in Heavily Treatment Experienced Participants Living With HIV-1 Infection With Multidrug Resistance

Study to Evaluate the Safety and Efficacy of GS-6207 in Combination With an Optimized Background Regimen in Heavily Treatment Experienced Participants Living With HIV-1 Infection With Multidrug Resistance

661. Ibalizumab Efficacy and Safety Through 48 Weeks of Treatment: Results of an Expanded Access Protocol (TMB-311)

BackgroundIbalizumab (IBA), a humanized monoclonal antibody, is the first CD4-directed post-attachment HIV-1 inhibitor. It was approved by the FDA in March 2018 based on results from the pivotal Phase 3 TMB-301 clinical study.The TMB-311 expanded access protocol Cohort 2 enrolled treatment-experienced patients with multidrug-resistant (MDR) HIV-1 infection to further evaluate the efficacy, safety and tolerability of IBA in combination with an optimized background regimen (OBR). Here, we report the results through 48 weeks of treatment in these patients.MethodsMajor eligibility criteria included HIV-1 viral load (VL) >1000 copies/mL, resistance to ≥1 antiretroviral (ARV) medication from three different ARV classes and full viral sensitivity to ≥1 ARV agent. Treatment started with IBA 2000 mg intravenously (IV) on Day 0 and then 800 mg IV (maintenance) every 2 weeks thereafter. OBR with ≥1 fully active agent also started at Day 0.ResultsCohort 2 enrolled 38 patients with a median age of 53 years, mostly male (87%) and white (53%). At Baseline, median VL was 4.7 log10 copies/mL, CD4 cell count was 26 cells/mm3 and overall susceptibility score of 1. A ≥0.5 log10 decrease in VL from Baseline was achieved in 28 of 37 patients (76%) at Day 7. Of 24 patients who completed the Week 24 visit, 11 (46%) had HIV-1 RNA levels <50 copies/mL. Of 17 patients with a VL assessment at Week 48, 8 (47%) achieved <50 copies/mL. Seven patients did not have a Week 48 endpoint because they withdrew from the study to receive commercial IBA. At both time points, the median change in VL from Baseline was -2.6 log10 copies/mL. The most frequently reported treatment-emergent adverse events (TEAEs) were diarrhea (24%), headache (21%), and nausea, cough, rash, and fatigue (16% each). No injection site reactions related to IBA were reported. Most events were mild; 9 patients reported Grade ≥3 TEAEs. Two events were fatal (sepsis and cardiac arrest); neither related to IBA. One event of immune reconstitution inflammatory syndrome was reported and considered possibly related to IBA.ConclusionResults from Cohort 2 patients of TMB-311 (IBA + OBR) demonstrate durable viral suppression in this difficult-to-treat patient population and with a safety profile consistent with pivotal Phase 3 study of IBA.Disclosures All authors: No reported disclosures.

2493. Real-World Utilization of Ibalizumab (IBA) Without an Optimized Background Regimen (OBT)

BackgroundIt is difficult to treat multidrug-resistant (MDR) human immunodeficiency virus (HIV). Trogarzo® (ibalizumab) a novel monoclonal antibody was approved in 2018 for heavily treatment-experienced HIV patients. Data support IBA use with at least one fully active agent, an OBR. Real-world IBA data are lacking. We report a successful case of reaching and maintaining suppression with IBA in a patient without an OBR.MethodsMutations were reviewed for the patient, Table 1, and evaluated for treatment. The patient is a 52- year old male, diagnosed in 1994, with MDR HIV secondary to non-adherence. Upon re-presenting to care, the patient was non-compliant with ART. Genotypic interpretation via the Stanford/ANRS algorithm was performed and interpreted, resulting in the addition of IBA intravenous administration every other week. IBA was obtained through patient assistance and costs were covered by the institution for infusion.ResultsEvaluation of the resistance profile indicated varying resistance to all available ART. More specifically, high-level resistance to all FDA-approved INSTIs, PIs, and low to high-level resistance to all NNRTIs and NRTIs. Table 2 outlines the ART history and viral load (VL) trends. The patient was initiated on daruanvir/ritonavir twice daily, etravirine twice daily, emtricitabine/tenofovir alafenamide and did not reach suppression. IBA was added off-label to a failing regimen. The patient reached VS (VL < 200 copies/mL) at Week 4 and has had an undetectable VL for 8 weeks. Notably his CD4 count has risen to 46, first detectable number since re-presenting to care.ConclusionWe describe a heavily treatment experienced patient with an MDR HIV virus who achieved an undetectable VL without an OBT and the addition of intravenous IBA. Fostemsavir, was utilized in IBA’s phase III trial for similar patients, however, it is not currently FDA-approved nor available. Further data are needed to ensure continued susceptibility to IBA without an OBT. This patient required high-level coordination to reach each visit and receive this therapy alongside his oral agents. We conclude, IBA has allowed this patient to reach and maintain VS. Disclosures All authors: No reported disclosures.

Increased dose of Dolutegravir as a Potential Rescue Therapy in Multi-Experienced Patients

The pilot Phase IIb VIKING study suggested that dolutegravir (DTG), an HIV integrase inhibitor (INI), is efficacious in INI-resistant patients at the 50 mg twice-daily dose. However, DTG response was most reduced in subjects carrying resistance-associated mutations at position G140 and Q148. These mutations can cause a 10-20-fold reduced susceptibility to DTG as well as a 96% lower odds of achieving HIV-1 RNA <50 copies/ml at week 24 if compared with those with no mutations at these positions. Five multi-experienced patients harbouring the mutation complex G140-Q148, resistant to at least three drug classes, and previously exposed to DTG 50 mg twice daily, were treated with an increased dose of DTG (100 mg twice daily) in association with an optimized background regimen (OBR) based on their individual viral genotyping assays. The blood concentration of DTG was measured in order to determine whether a solubility issue is related with this high dosage. Four out of five patients attained an HIV-1 RNA <50 copies/ml at week 48 and no relevant adverse events were detected. The measured DTG blood concentration was that expected for the administered dosage, ruling out any solubility concerns. For the first time 100 mg twice daily of DTG was administered to five multi-experienced patients harbouring the mutation complex G140-Q148. Although a small number of patients were tested, the results show a potential for a high-dose regimen of DTG as a rescue therapy in patients harbouring integrase strand transfer inhibitor resistant viruses.

Initial experience of bedaquiline implementation under the National TB Programme at NITRD, Delhi, India

BackgroundBedaquiline (BDQ) was approved for treatment of drug resistant TB (DR-TB) under Conditional Access Programme (CAP) of Revised National Tuberculosis Control Programme (RNTCP) and was also implemented in the National Institute of TB and Respiratory Diseases (NITRD). We present early efficacy and safety of BDQ containing regimens for DR-TB. ObjectiveTo ascertain the early efficacy and safety of Bedaquline containing regimens in treatment of DR-TB. MethodsBDQ containing regimens along with other drugs were designed as per WHO recommendations for DR-TB patients. They were followed up for sputum smear and culture conversion, adverse events during the treatment. ResultsA cohort of 290 DR-TB patients (Median age-29.77) were initiated on BDQ containing regimens. Of the available Sputum results, smear conversion was seen in 51% and 91% patients at the end of 1st week and 3rd month respectively. Similarly, 93% and 98% patients had culture conversion at the end of 3rd and 6th month respectively. 201 adverse events (AE) including 47 deaths were reported among 109 patients. QTc prolongation was seen in 29% patients but only 4 required discontinuation of BDQ. Lost to follow up of treatment was about 6%. ConclusionBedaquiline along with an optimized background regimen has shown early sputum conversion in larger number of difficult to treat patients having additional resistance of second line drugs along with INH and Rifampicin. The regimen is feasible in programmatic conditions and is relatively safe.

544. Pharmacokinetic Profile of Ibalizumab From a Phase 3 Trial

BackgroundIbalizumab (IBA) is a long-acting humanized monoclonal antibody that binds domain 2 of the CD4 receptor and blocks HIV-1 infection of host cells. TMB-301 was a 24-week, Phase 3 clinical trial conducted in 40 heavily treatment-experienced patients with multidrug-resistant (MDR) HIV-1 investigating the safety, efficacy and tolerability of IBA. Patients received a 2,000 mg IBA loading dose followed by 800 mg every 2 weeks by intravenous infusion plus an optimized background regimen. Viral load <50 and <200 HIV RNA copies/mL was achieved in 43% and 50% of patients, respectively, at Week 25. We determined the pharmacokinetic profile of IBA, i.e., serum concentrations, CD4 receptor occupancy (RO), and CD4 receptor density (RD), in these patients with MDR HIV-1.MethodsPre- and post-dose blood samples collected at various time points during trial were used to determine IBA serum concentrations, CD4 RO and RD at trough. IBA serum concentrations were measured using a validated ELISA. IBA bound to CD4+ T cells (RO) and cell surface CD4 levels (RD) were measured simultaneously by flow cytometry using the Molecules of Equivalent Soluble Fluorescence approach.ResultsThe maximum IBA serum concentrations were observed immediately after the end of the 2,000 mg infusion with mean (SD) of 567 (235) μg/mL. Steady state was reached at Week 4 after the loading dose. The mean IBA concentrations were >30 μg/mL throughout the dosing period. Both Cpeak and Ctrough (Day 7 and Week 25 IBA concentrations) were decreased with increased body weight. The median Ctrough in the high body weight group (≥85 kg) was 0.23 μg/mL. The mean RO was >85% throughout the dosing period. The 2,000 mg loading dose helped to reach >85% RO after the initial dose and maintain high levels of RO throughout the dosing period. Elevation in RO was generally associated with increased IBA serum concentrations; concentrations ≥0.13 μg/mL supported ≥85% CD4 RO. After IBA administration, down-modulation of surface CD4 receptors by up to 20% was observed. There was no apparent association between IBA serum concentration and RD probably due to high inter-individual variation.ConclusionDosing regimen of 2,000 mg loading dose followed by 800 mg every 2 weeks was sufficient to support high levels of RO and to maintain the drug concentration above the therapeutic level.Disclosures P. N. Kumar, TheraTechnologies: Consultant and Investigator, Consulting fee and Research grant. ViiV: Consultant, Investigator and Shareholder, Research grant and Speaker honorarium. Merck: Investigator and Shareholder, Research grant. Gilead: Consultant, Investigator and Shareholder, Consulting fee and Research grant. S. Weinheimer, TaiMed Biologics: Employee, Salary. Z. Cohen, Theratechnologies Inc.: Employee, Salary. C. Marsolais, Theratechnologies Inc.: Employee, Salary. K. L. Kuo, TaiMed Biologics Taiwan: Employee, Salary. S. Lewis, TaiMed Biologics: Employee, Salary.

Optimized Background Regimen for Treatment of Active Tuberculosis with the Next-Generation Benzothiazinone Macozinone (PBTZ169).

The efficacy of the standardized four-drug regimen (comprising isoniazid, rifampin, pyrazinamide, and ethambutol) for the treatment of tuberculosis (TB) is menaced by the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis Intensive efforts have been made to develop new antibiotics or to repurpose old drugs, and several of these are currently being evaluated in clinical trials for their antitubercular activity. Among the new candidate drugs is macozinone (MCZ), the piperazine-containing benzothiazinone PBTZ169, which is currently being evaluated in phase I/II clinical trials. Here, we determined the in vitro and in vivo activity of MCZ in combination with a range of anti-TB drugs in order to design a new regimen against active TB. Two-drug combinations with MCZ were tested against M. tuberculosis using checkerboard and CFU enumeration after drug exposure assays. MCZ was observed to have no interactions with all first- and second-line anti-TB drugs. At the MIC of each drug, MCZ with either bedaquiline (BDQ), clofazimine (CLO), delamanid (DMD), or sutezolid (STZ) reduced the bacterial burden by 2 logs compared to that achieved with the drugs alone, indicating synergism. MCZ also displayed synergism with clomiphene (CLM), a potential inhibitor of the undecaprenyl pyrophosphate synthase (UppS) in mycobacteria. For all the other drugs tested in combination with MCZ, no synergistic activity was observed. Neither antagonism nor increased cytotoxicity was found for most combinations, suggesting that MCZ could be added to different TB treatment regimens without any significant adverse effects.

Phase 3 Study of Ibalizumab for Multidrug-Resistant HIV-1

BackgroundIbalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of human immunodeficiency virus type 1 (HIV-1) by noncompetitive binding to CD4.MethodsIn this single-group, open-label, phase 3 study, we enrolled 40 adults with multidrug-resistant (MDR) HIV-1 infection in whom multiple antiretroviral therapies had failed. All the patients had a viral load of more than 1000 copies of HIV-1 RNA per milliliter. After a 7-day control period in which patients continued to receive their current therapy, a loading dose of 2000 mg of ibalizumab was infused; the viral load was quantified 7 days later. Through week 25 of the study, patients received 800 mg of ibalizumab every 14 days, combined with an individually optimized background regimen including at least one fully active agent. The primary end point was the proportion of patients with a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (day 7) to day 14.ResultsA total of 31 patients completed the study. The mean baseline viral load was 4.5 log10 copies per milliliter, and the mean CD4 count was 150 per microliter. Of the 40 patients in the intention-to-treat population, 33 (83%) had a decrease in viral load of at least 0.5 log10 copies per milliliter from baseline (P<0.001 for the comparison with the control period). The mean viral-load decrease was 1.1 log10 copies per milliliter. During the control period, 1 patient, who received the optimized background regimen prematurely, had a decrease in viral load of 0.5 log10 copies per milliliter. At week 25, patients who had received ibalizumab plus an optimized background regimen had a mean decrease of 1.6 log10 copies per milliliter from baseline; 43% of the patients had a viral load of less than 50 copies per milliliter, and 50% had a viral load of less than 200 copies per milliliter. Among 10 patients who had virologic failure or rebound, in vitro testing identified 9 who had a lower degree of susceptibility to ibalizumab than at baseline. The most common adverse event was diarrhea (in 20% of patients). Four patients died from causes related to underlying illnesses; 1 had a serious adverse event (the immune reconstitution inflammatory syndrome) that was deemed to be related to ibalizumab therapy.ConclusionsIn patients with MDR HIV-1 infection who had advanced disease and limited treatment options, ibalizumab had significant antiviral activity during a 25-week study. Evidence of the emergence of diminished ibalizumab susceptibility was observed in vitro in patients who had virologic failure. (Funded by the Orphan Products Clinical Trials Grants Program of the Food and Drug Administration and TaiMed Biologics; TMB-301 ClinicalTrials.gov number, NCT02475629.)

High Virologic Failure Rates with Maraviroc-Based Salvage Regimens Among Indian Patients: A Preliminary Analysis-Maraviroc Effectiveness in HIV-1 Subtype C.

Background:There is no information on the clinical effectiveness of Maraviroc (MVC) amongst People Living with HIV (PLHIV) in India infected with HIV-1 Subtype C viruses.Methods:We conducted a retrospective chart review of adult PLHIV on MVC based Antiretroviral (ARV) regimens for at least 6 months. Maraviroc was initiated amongst PLHIV with documented R5 tropic viruses (determined by in-house population sequencing of the V3 loop in triplicate and interpreted using the Geno2Pheno algorithm) in combination with an Optimized Background regimen (designed using genotypic resistance testing and past ARV history). Plasma viral loads (PVL) are performed 6 months post-initiation and annually thereafter. Primary outcome d. Median duration on MVC treatment was 1.8 years (range 1-2.9 years) while median duration of ART prior to switching to MVC was 13 years. Maraviroc was combined with Darunavir/ritonavir (DRV/r) (n=10), Atazanavir/r (ATV/r) (n=2) and Lopinavir/r (LPV/r) (n=1). All PLHIV were infected with HIV-1 Subtype C. Only 23.3% PLHIV achieved virologic suppression at 6 months and sustained it for 2.3 years. Median CD4 count change from baseline was +117 (n=13), +228 (n=10), +253 (n=9), and +331 (n=4) at 6, 12, 18 and 24 months respectively. Repeat tropism among patients with virologic failure demonstrated R5 virus.Conclusions:High rates of virologic failure was seen when MVC was used amongst treatment experienced PLHIV infected with HIV-1 Subtype C in India. was the proportion of PLHIV with virologic success (PVL<50 copies/ml) at last follow up visit.Results:Data on 13 PLHIV were analyze

An optimized background regimen design to evaluate the contribution of levofloxacin to multidrug-resistant tuberculosis treatment regimens: study protocol for a randomized controlled trial

BackgroundCurrent guidelines for treatment of multidrug-resistant tuberculosis (MDR-TB) are largely based on expert opinion and observational data. Fluoroquinolones remain an essential part of MDR-TB treatment, but the optimal dose of fluoroquinolones as part of the regimen has not been defined.Methods/designWe designed a randomized, blinded, phase II trial in MDR-TB patients comparing across levofloxacin doses of 11, 14, 17 and 20 mg/kg/day, all within an optimized background regimen. We assess pharmacokinetics, efficacy, safety and tolerability of regimens containing each of these doses. The primary efficacy outcome is time to culture conversion over the first 6 months of treatment. The study aims to determine the area under the curve (AUC) of the levofloxacin serum concentration in the 24 hours after dosing divided by the minimal inhibitory concentration of the patient’s Mycobacterium tuberculosis isolate that inhibits > 90% of organisms (AUC/MIC) that maximizes efficacy and the AUC that maximizes safety and tolerability in the context of an MDR-TB treatment regimen.DiscussionFluoroquinolones are an integral part of recommended MDR-TB regimens. Little is known about how to optimize dosing for efficacy while maintaining acceptable toxicity. This study will provide evidence to support revised dosing guidelines for the use of levofloxacin as part of combination regimens for treatment of MDR-TB. The novel methodology can be adapted to elucidate the effect of other single agents in multidrug antibiotic treatment regimens.Trial registrationClinicalTrials.gov, NCT01918397. Registered on 5 August 2013.

Interim outcomes of delamanid for the treatment of MDR- and XDR-TB in South Korea.

Delamanid is a new anti-TB drug, but few data exist on its use outside clinical trials. The purpose of this study was to evaluate the efficacy as well as the safety and tolerability of a delamanid-containing regimen for 24 weeks in the treatment of MDR- and XDR-TB. We performed a retrospective cohort study among patients with MDR/XDR-TB who were treated with a delamanid-containing regimen in seven hospitals in South Korea. A total of 32 patients with MDR-TB, of which 6 (18.8%) were XDR-TB, were included and all completed 24 weeks of delamanid treatment. Of 19 patients (59.4%) who had positive culture sputum at the initiation of delamanid treatment, the proportion of culture conversion at 8 weeks was 72.2% (13 of 18) in solid medium and 50.0% (7 of 14) in liquid medium. The proportion of culture conversion at 24 weeks was 94.4% (17 of 18) in solid medium and 92.9% (13 of 14) in liquid medium. The median time to culture conversion was 33 days (range = 5-81) using solid medium and 57 days (range = 8-96) using liquid medium. Of the 32 patients, there was no serious adverse event or death. Three patients developed a transient QTcF of > 500 ms. The use of delamanid combined with optimized background regimens has the potential to achieve high culture conversion rates at 24 weeks with an acceptable safety and tolerability profile in patients with MDR/XDR-TB.

Forty-eight-Week Safety and Efficacy On-Treatment Analysis of Ibalizumab in Patients with Multi-Drug Resistant HIV-1

BackgroundManagement of multi-drug-resistant (MDR) HIV-1 remains a challenge. The advent of antiretroviral (ARVs) with novel mechanisms of action are needed to expand therapeutic options for MDR patients. Ibalizumab (IBA) is a humanized monoclonal antibody with a unique binding specificity to the CD4 domain 2, allowing it to block viral entry into host cells without CD4 depletion. Patients completing the 24-week Phase 3 study (TMB-301) continued treatment in study TMB-311. Here, we report the durable efficacy and long-term safety of IBA with an optimized background regimen (OBR) through 48 weeks of treatment.MethodsTMB-301 was an open-label study investigating the antiviral activity and safety of IBA plus OBR in highly treatment-experienced patients with MDR HIV-1. Patients received an intravenous loading dose of 2,000mg followed by 800mg doses every 2 weeks for 24 weeks. 7 days after loading dose, an OBR was added with at least 1 additional sensitive agent throughout the study. Following completion of the 24-week TMB-301 study, patients continued to receive IBA at 800mg every 2 weeks under TMB-311 for up to 48 weeks. Safety and efficacy were assessed until 48 weeks.ResultsA total of 31 patients enrolled in TMB-301 completed the 24-week treatment period. Of 31 patients, 27 entered study TMB-311. These patients were highly resistant patients - 59% and 33% of patients had exhausted ≥3 and ≥4 ARV classes, respectively, and 7% of patients had HIV-1 resistant to all approved ARVs. IBA plus OBR was well tolerated. Of the 27 patients, 24 (89%) continued to receive treatment until Week 48. The three patients discontinued early due to non IBA-related reasons. No new or unexpected safety concerns emerged between Week 24 and 48. The potent suppression of viremia observed Week 24 was sustained through Week 48. Median viral load (VL) reduction from BL was 2.5 log10 at both Week 24 and 48. Of 27 patients (59%) 16 had VL <50 copies/ml and 17 (63%) patients had VL < 200 copies/ml. All 15 patients with VL < 50 copies/ml at Week 24 maintained viral suppression to Week 48.ConclusionIBA plus OBR continued to achieve high rates of virologic suppression through Week 48. The results support the durable efficacy and long-term safety of IBA in highly treatment-experienced MDR patients and offer a valuable treatment option for patients.Disclosures B. Emu, TaiMed Biologics: Employee and Shareholder, Salary; P. N. Kumar, TaiMed: Advisory Board and Investigator, Consulting fee and Grant recipient; G. Richmond, TaiMed: Investigator, Research support; S. Weinheimer, TaiMed: Employee, Salary; C. Marsolais, TaiMed: Commercial partner, Salary and Salary from Theratechnologies, commercial partner; S. Lewis, TaiMed: Employee, Salary and Salary from Theratechnologies, commercial partner

Second- and Third-line Antiretroviral Therapy for Children and Adolescents: A Scoping Review.

The World Health Organization identified a need for evidence to inform revision of second- and third-line antiretroviral therapy (ART) options in children failing ART. We performed an in-depth scoping review of all available literature on second-line and subsequent ART regimens in children younger than 18 years. We comprehensively searched, without language or date limitations, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov. The search retrieved 1982 records. Eighteen studies provided efficacy data: 1 randomized controlled trial, 7 phase II trials, 5 prospective and 5 retrospective cohorts. Five studies evaluated regimens in children failing first-line ART, 4 in children with multidrug resistance and 9 in children with variable treatment experience. Only 10/18 studies reported week 48 or month 12 outcomes. The overall proportion of children with virologic suppression defined by study at week 48 was 61.8%. Although the randomized controlled trial had low risk of bias, outcomes were similar between groups because of highly active optimized background regimens. All phase II and prospective studies were judged to have moderate to high risk of bias. No study compared currently recommended lopinavir-based second-line regimens for nonnucleoside reverse transcriptase inhibitor failures to other non-nonnucleoside reverse transcriptase inhibitor regimens head-to-head. We found no evidence comparing current World Health Organization-recommended second- and third-line ART regimens with regimens including drugs of interest: raltegravir, darunavir, etravirine and atazanavir. Randomized controlled trials or prospective cohort studies with comparator arms, and bridging studies, ideally conducted in resource-limited settings, are required to guide future recommendations.

Effectiveness and Risk Factors for Virological Outcome of Raltegravir-Based Therapy for Treatment-Experienced HIV-Infected Patients.

ObjectiveWe evaluated the effectiveness of a raltegravir (RAL)-containing regimen plus an optimized background regimen in HIV-1 highly treatment-experienced patients.DesignA retrospective cohort, multicentre study was conducted.MethodsAdult (>16 years old) HIV treatment-experience patients starting therapy with a RAL-containing regimen were included. Effectiveness was evaluated as the percentage of patients with an undetectable HIV-1 RNA viral load (<50 and <200 copies/mL) after 48 weeks, and changes in CD4+ cell counts. We evaluated the risk factors associated with treatment failure.ResultsOf the 107 patients in the cohort, 86% were men, the median age was 45 years [interquartile range (IQR) 40–52] and the median number of previous regimens was six (IQR 4–7). After 48 weeks of treatment, 73% (IQR 63–80%) of patients (n = 78) had a viral load of <50 copies/mL and 85% (IQR 77–90%) (n = 91) had <200 copies/mL. In a logistic regression model, risk factors associated with a virological outcome of HIV-1 RNA of <200 copies/mL were age >40 years [odds ratio (OR) 5.61; 95% confidence interval (CI) 1.61–18.84; P = 0.006] and use of tenofovir in the regimen (OR 0.16; 95% CI 0.03–0.80; P = 0.026).ConclusionsIn this Mexican cohort, RAL achieved high rates of virological suppression and an increase in CD4+ cell count in highly treatment-experienced patients infected with HIV-1. Age >40 years was associated with a good virological outcome, contrary to tenofovir use, which was associated with a poor virological outcome.

Effectiveness of etravirine-based therapy for treatment-experienced HIV-infected patients.

Treatment options are limited for HIV-1-infected individuals who have received extensive previous antiretroviral therapy. ETV has shown significant clinical benefits in treatment-experienced HIV-1+ patients with antiretroviral resistance. The aim of this study was to evaluate the effectiveness of ETV plus optimized background regimen in real-life conditions in a cohort of highly HIV-1 antiretroviral-experienced patients. Retrospective cohort of treatment-experienced HIV-1-infected adults with virological failure who started therapy with an ETV-containing regimen. The effectiveness was evaluated using HIV-1 RNA viral load and changes in CD4+ cell count after 48 weeks of treatment. Forty-two patients ≥ 16 years of age were included; 74% were men, and the median age was 45 years (IQR 41-53). All participants had prior non-nucleoside reverse transcriptase inhibitor use (55% nevirapine, 83%, efavirenz, and 28% both). Baseline median HIV-1 RNA viral load was 15,598 copies/mL (IQR 2651-84,175) and CD4+ cell count was 276 cells/mL (IQR 155-436). After 48 weeks of treatment, 90.5% (95% CI 78-96) of patients had HIV-1 RNA viral load < 200 copies/mL and 76% (95% CI 61-86) had < 50 copies/mL. CD4+ cell counts increased from baseline to 48 weeks of treatment to a median of 407 cells/mL (IQR 242-579); p < 0.001. Virological outcome was associated with virological failure at baseline HIV-1 RNA viral load ≥ 100,000 copies/mL (OR 7.6; 95% CI 1.2-44.80; p = 0.025). Our study provides clinically important evidence of the effectiveness and safety of ETV in highly antiretroviral-experienced HIV-1-infected patients.