Optimized Background Regimen Research Articles

Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.

Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor. In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24. Viral loads (VL) below the detection limit were achieved in 44% and 28% of patients in the 800 mg q2wk and 2,000 mg q4wk groups, respectively, at Week 24. Mean (standard deviation) VL (log10 copies/mL) decreased from Baseline (4.6(0.8), 800 mg q2wk; 4.7(0.7), 2,000 mg q4wk) to Week 2, with the reduction maintained through Week 24 (2.9(1.5), 800 mg q2wk; 3.2(1.4), 2,000 mg q4wk). Baseline CD4+ counts were 80.5 and 54.0 cells/μL in the 800 mg q2wk and 2,000 mg q4wk groups, respectively. Mean CD4+ T-cell count was increased at Week 24 in both groups. No serious adverse events were related to ibalizumab. In heavily treatment-experienced patients with HIV (PWH) at a more advanced baseline disease severity, clinically significant response rates at Week 24 were achieved with ibalizumab plus OBR. Ibalizumab's unique mechanism of action and lack of cross-resistance to other antiretroviral agents make it an important component of combination treatment regimens for PWH with limited treatment options.

US cost-utility model of lenacapavir plus optimized background regimen (OBR) vs fostemsavir plus OBR and ibalizumab plus OBR for people with HIV with multidrug resistance.

Heavily treatment-experienced (HTE) people with HIV (PWH) have limited treatment options owing to multidrug resistance (MDR). Lenacapavir (LEN) is indicated, in combination with other antiretrovirals, for the treatment of adults with MDR HIV-1 experiencing failure of their current antiretroviral regimen because of resistance, intolerance, or safety considerations. To evaluate the cost-utility of LEN in combination with an optimized background regimen (OBR) vs alternative recently approved treatments for HTE PWH, fostemsavir (FTR)+OBR and ibalizumab (IBA)+OBR, for the treatment of PWH with MDR, from a mixed US health care payer perspective. A Markov state-transition model with a lifetime time horizon was developed. Transition probabilities between viral load categories were based on individual participant data from the CAPELLA trial for LEN+OBR and on relative efficacy parameters obtained from indirect treatment comparisons for comparators. Health state utilities were sourced from the literature. Costs included drug acquisition costs, drug administration costs, disease management costs, adverse event costs, AIDS-related event costs, and treatment switching costs and were sourced from red book costs, Medicare and Medicaid fees, and the literature. Costs and outcomes were discounted at 3% annually. The model was used to estimate total and incremental costs, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. A deterministic and a probabilistic sensitivity analysis, as well as scenario analyses, were performed to address elements of uncertainty in the model and to explore the robustness of the results. Over a lifetime time horizon, LEN+OBR was associated with the highest absolute QALYs (9.41) and the greatest number of LYs (12.09) compared with FTR+OBR (QALYs: 8.75; LYs: 11.26) and IBA+OBR (QALYs: 8.36; LYs: 10.78). LEN+OBR was also associated with the lowest total lifetime costs of the 3 interventions (LEN+OBR: $1,441,122 [US dollars]; FTR+OBR: $1,504,986; IBA+OBR: $1,524,396) and therefore was dominant over both comparators in the base case. LEN+OBR remained dominant vs FTR+OBR and IBA+OBR across the range of scenarios tested and LEN+OBR had a 99% probability of being cost-effective compared with FTR+OBR and IBA+OBR in the probabilistic sensitivity analysis at a willingness-to-pay threshold of $50,000/QALY. This economic evaluation demonstrated that LEN+OBR provides meaningful increases in QALYs and LYs, and is dominant over a lifetime time horizon, compared with FTR+OBR and IBA+OBR for the treatment of PWH with MDR in the United States.

Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial.

Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. At Week 104, 44 of 71 participants (62%, 95% CI 50; 73) had HIV-1 RNA <50 copies/mL via US Food & Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; seven resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

Body Mass Index a Forecast of Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients.

Background Drug-resistant tuberculosisis a major health issue around the world. The time it takes to find a sputum-positive patient is a major risk factor for the spread of tuberculosis, and many things can indicate a longer time to culture conversion. Also, there is strong proof that poor nutrition is linked to infectious diseases. So, this study aimed to look into the link between a person's body mass index (BMI) and the change of a sputum culture within three months in people who have rifampicin-resistant (RR)/multidrug-resistant (MDR)-tuberculosis (TB) kept on a bedaquiline-based regimen. Materials and methods The Department of Respiratory Medicine at King George's Medical University, Lucknow, hosted an observational, analytical, prospective, single-center study from May 2020 to April 2021. The study included 105 people who had been identified with RR/MDR-TB and were on an optimized background regimen that included a bedaquiline-based regimen. The result we were interested in was sputum culture conversion within three months, and we looked at how BMI related to that outcome. Analytical analyses utilized Pearson's chi-square test for categorical variables and the t-test for continuous variables. Differences with a P-value of <0.05 were considered significant. SPSS software (version 18.0, IBM Corp., Armonk, NY, USA) was used for all analyses, with missing data not replaced or credited. Results A total of 105 people who met the inclusion and exclusion criteria were analyzed. The patients had a mean age of 33.34 years and were mostly male 61 (58%). Fifty-eight (58; 55%) patients lived in rural areas. Most patients had fever 77 (73%), cough 72 (69%), and weight loss 66 (63%). Sixty-nine (69; 66%) patients had a history of TB. Fifty-seven patients had a BMI of <18.5 kg/m2, and 48 patientshad with BMI of ≥18.5. At the end ofthe study, 75/105 patients converted their sputum culture. Of the 105 patients, 57 (54%) had a low BMI (less than 18.5 kg/m2). Among the 57 patients with a BMI of <18.5 kg/m2, only 28(46%) achieved sputum culture conversion after 3 months while 29 (60%) of 48 with BMI ≥18.5 achieved sputum culture conversion after 3 months.Among the patients with a BMI <18.5, 15/57 (26%) tested positive for sputum culture after three months. In patients with a BMI of ≥18.5, only 4/48 (8%) patients tested positive for sputum culture after three months. Conclusion Inpatientswithdrug-resistant tuberculosis, lowBMI (<18.5kg/m2)wasanindependentriskfactor forfailingtoconvert sputum cultureswithinthreemonths.

EE472 US Cost-Effectiveness of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multi-Drug Resistant HIV

Lenacapavir (LEN), a first-in-class multi-stage HIV capsid inhibitor, is indicated in combination with an optimized background regimen (OBR) for the treatment of HIV-1 in heavily treatment-experienced (HTE) adults with multi-drug resistant (MDR) HIV-1 failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. Historically, this population has had limited treatment options, leading to virologic failure and high risk of AIDS-related mortality. The health outcomes associated with LEN+OBR versus relevant comparators in this population were evaluated previously. This current analysis aimed to assess the cost-effectiveness of LEN+OBR.

Baseline glycated hemoglobin and potassium level correlated with pretreatment QT-corrected interval among patients with diabetic drug-resistant tuberculosis.

Bedaquiline is a core drug with an optimized background regimen for treating drug-resistant tuberculosis (DR-TB) patients. One of the adverse effects of bedaquiline is QT-corrected (QTc) interval prolongation. TB patients with diabetes mellitus (DM) are more likely to develop QTc interval prolongation during TB treatment than those without DM. This study aimed to correlate baseline electrolyte levels (potassium, calcium, and magnesium), thyroid-stimulating hormone (TSH), body mass index (BMI), blood glucose, glycated hemoglobin (HbA1c), and pretreatment QTc interval among patients with diabetic DR TB who received regimens containing bedaquiline. It was a prospective study with a cross-sectional design. Blood samples, BMI, and electrocardiogram were collected at baseline before starting the regimen for DR-TB. Pearson correlation was used to correlate between baseline electrolyte level, TSH, BMI, complete blood count, blood glucose, HbA1c, and pretreatment QTc interval. Seventy-two DR-TB patients met the inclusion criteria, half with DM. The blood glucose and HbA1c were significantly higher in patients with DM. Pretreatment QTc interval was similar between the two groups. Levels of calcium, magnesium, TSH, blood glucose, and BMI were not correlated with pretreatment QTc interval. There was a correlation between baseline potassium and HbA1c levels with pretreatment QTc interval (P < 0.05; r = 0.357 and r = -0.376, respectively). Baseline potassium level correlates with the pretreatment QTc interval in those without DM. Baseline HbA1c and potassium levels correlate with pretreatment QTc interval among DR-TB patients with DM. Our study indicates the importance of monitoring HbA1c and potassium levels during DR-TB therapy containing bedaquiline for early detection of QTc prolongation.

Indirect Treatment Comparisons of Lenacapavir Plus Optimized Background Regimen Versus Other Treatments for Multidrug-Resistant Human Immunodeficiency Virus

Background/AimsHeavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multidrug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the phase 2/3 CAPELLA study. This study aimed to compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR) + OBR, ibalizumab (IBA) + OBR, and OBR alone in terms of VS, CD4 cell count change from baseline, immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons. MethodsA systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for indirect treatment comparison analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons of LEN + OBR versus comparators were conducted. ResultsLEN + OBR had 6.57 times higher odds of VS at weeks 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). Change from baseline in CD4 cell count was similar across LEN + OBR, FTR + OBR, and IBA + OBR. ConclusionLEN + OBR has statistically significantly greater odds of VS at weeks 24 to 28 than its comparators and represents a novel treatment for people with MDR HIV.

1585. Efficacy and safety of long-acting subcutaneous lenacapavir in heavily treatment-experienced people with multi-drug resistant HIV: Week 52 results

Abstract Background Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development as a long-acting agent for treatment and prevention of HIV-1. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance. 36 participants were randomized (2:1) to add oral LEN or placebo to their failing regimen. At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (Q6M); those on placebo started the oral LEN lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, optimized background regimen (OBR) at D15. An additional 36 participants started OBR concurrent with LEN (oral lead-in → SC) in a non-randomized cohort. We report the Week (W) 52 efficacy and safety results from both cohorts. Results Of 72 participants enrolled, 25% were female, 38% Black, median age 52 years, 64% had CD4 &amp;lt; 200 cells/µL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 53% had OBR with 1 or no fully active agents. At W52, 78% (56/72) achieved VL&amp;lt; 50 c/mL and 82% (59/72) achieved VL&amp;lt; 200 c/mL via FDA Snapshot algorithm. CD4 count increased by a median 84 cells/µL (Q1 to Q3: 21 to 153) and the proportion of participants with CD4 count ≥200 cells/ul increased from 36% at baseline to 68% at W52. Ten participants had emergent LEN resistance (8 previously reported); 4 of 10 subsequently suppressed. The median (range) duration of follow up on LEN was 71 (13–111) weeks. One participant discontinued due to injection site nodule (Grade 1). The most common injection site reaction (ISR) was swelling (28% [20/72] and 17% [12/70] after the 1st and 2nd SC doses, respectively). Most ISRs were mild or moderate. The most common AEs (excluding injection site reactions) were nausea and diarrhea (14% each). Conclusion In HTE PWH, subcutaneous LEN was well tolerated and in combination with OBR led to high and sustained rate of virologic suppression at W52. These results support the potential role for LEN for treatment of multi-drug resistant HIV-1 infection. Disclosures Sorana Segal-Maurer, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|JANSSEN THERAPEUTICS: Honoraria|ViiV: Honoraria Benoit Trottier, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jason Brunetta, M.D., Gilead Canada: Advisor/Consultant|Gilead Canada: Honoraria|Gilead Canada: Conference Attendance Sponsorship|Viiv Canada: Advisor/Consultant Hui Wang, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Nicolas A. Margot, MA, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Martin S Rhee, MD, Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jean-Michel Molina, MD; PhD, GIlead: Board Member|GIlead: Grant/Research Support|Merck: Board Member|Merck: Expert Testimony|ViiV: Board Member.

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir.

Lenacapavir (LEN) is a first-in-class inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function in clinical development for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) harboring multidrug resistance (MDR) in combination with an optimized background regimen (OBR). Here we describe resistance analyses conducted in the pivotal phase 2/3 CAPELLA study. CAPELLA enrolled viremic HTE PWH with resistance to ≥3 of 4 of the main antiretroviral (ARV) classes and resistance to ≥2 ARV drugs per class. Baseline resistance analyses used commercial assays (HIV-1 protease, reverse transcriptase, integrase genotypic/phenotypic tests). Postbaseline resistance was evaluated in participants experiencing virologic failure. At baseline, 46% of participants had resistance to the 4 main ARV drug classes, with one-third of participants having exhausted all drugs from ≥3 of the 4 main ARV classes. Treatment with LEN + OBR for 26 weeks led to viral suppression in 81% of participants. Postbaseline resistance mutations to lenacapavir occurred in 8 participants (6 with M66I, 1 with K70H, 1 with Q67H + K70R) who were receiving unintended functional LEN monotherapy at the time of resistance selection. LEN added to OBR led to high efficacy in this HTE patient population with MDR but could select for resistance when used unintentionally as functional monotherapy.

EE233 LONG-TERM OUTCOMES OF LENACAPAVIR PLUS OPTIMIZED BACKGROUND REGIMEN VERSUS OTHER TREATMENTS FOR MULTI-DRUG RESISTANT HIV VIA A COST-EFFECTIVENESS MODEL

Achieving virologic suppression is particularly challenging for people with HIV (PWH) who are heavily treatment-experienced with multi-drug resistance (MDR). Lenacapavir (LEN), a first-in-class multi-stage HIV capsid inhibitor, in combination with an optimized background regimen (OBR), is under investigation for treating PWH with MDR failing current therapy due to resistance, intolerance, or safety considerations. The aim of this analysis was to explore the costs and benefits of LEN+OBR versus relevant comparators in this population.

Comparison of efficacy of bedaquiline and moxifloxacin in drug resistant pulmonary tuberculosis. A prospective observational study.

Drug-resistant tuberculosis remains a major public health concern in many countries. We compared the efficacy and safety of bedaquiline plus optimized background regimen (Bdq+OBR) with high dose moxifloxacin and optimized background regimen (Mfx(h)+OBR) for the treatment of patients with multidrug-resistant tuberculosis with additional resistance to fluoroquinolones. In this prospective observational study, newly diagnosed cases of multidrug-resistant tuberculosis with additional resistance to fluoroquinolone were enrolled. They received either Bdq+OBR or Mfx(h)+OBR and were followed up for six months. The sputum culture conversion rate at the end of six months and the time to culture conversion in each group were studied. The safety profile of both regimens was also studied. The sputum culture conversion was achieved in 41 patients (100%) in the Bdq+OBR group and 36 patients (87.8%) in the Mfx(h)+OBR group at the end of 6 months. The mean time to culture conversion was found to be 3.10±0.8 months in the Bdq+OBR group and 3.32±0.9 months in the Mfx(h)+OBR group. Mortality was 6.8% in the Bdq+OBR group and 10.8 % in the Mfx(h)+OBR group at 6 months. Raised serum lipase and dark discolouration of skin were significantly more common in the Bdq+OBR group while vomiting and ototoxicity were more common in the Mfx(h)+OBR group. Bdq+OBR was associated with higher success of sputum culture conversion at 6 months and faster sputum culture conversion rate as compared to the Mfx(h)+OBR.

Ibalizumab shows in-vitro activity against group A and group B HIV-2 clinical isolates.

Treatment of multidrug-resistant HIV-2 is an emerging issue, because of the rapid selection of mutations at time of virological failure and the low number of antiretrovirals active on HIV-2. The aim of this study was to determine the susceptibility of HIV-2 primary isolates to ibalizumab, a long-acting monoclonal antibody that binds to CD4 that is approved for the treatment of MDR HIV-1. In-vitro phenotypic susceptibility of 16 HIV-2 primary isolates was measured using a modified version of the ANRS peripheral blood mononuclear cells (PBMC) assay. Susceptibility to ibalizumab was assessed through 50% inhibitory concentrations and maximum percentage inhibitions (MPI), and gp105 was sequenced to look for determinants of reduced susceptibility. Ibalizumab inhibited viral replication of all 16 isolates, with a median IC 50 value of 0.027 μg/ml (range = 0.001-0.506 μg/ml), and a median MPI of 93%. Although two isolates presented higher IC 50 (above 0.1 μg/ml), they did not exhibit a loss of potential N-linked glycosylation sites in V5 loop, as reported in HIV-1 strains with reduced susceptibility. However, both presented shorter V1 and V2 loops than the HIV-2 reference strain. Ibalizumab inhibits HIV-2 replication, with IC 50 and MPI in the range of those reported for HIV-1. These in vitro data support the use of ibalizumab in patients with MDR HIV-2, in combination with an optimized background regimen.

Achieving virological control in pan-resistant HIV-1 infection: A case series.

SummaryBackgroundHIV-1 pan-resistance refers to a reduced susceptibility to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and integrase strand tranfer inhibitors. Although still anecdotal, its management remains a concern both for affected people living with HIV (PLWH) and for public health.MethodsWe described genotypic resistance testing (GRT) of three PLWH with a documented poor virological response to previous antiretroviral therapies, who started ibalizumab, an anti-CD4 monoclonal antibody, combined with an optimized background therapy. Both historical and most recent GRT on plasma RNA and peripheral blood mononuclear cell DNA were interpreted according to the Stanford HIVDb version 9.0 (last updated on 22 February, 2021). After the switch to a regimen including the monoclonal antibody, HIV-1 RNA has been quantified biweekly (PCR Cobas® HIV-1 test 6800 Systems, Roche Diagnostics). Follow-up was censored at data freezing (16 January, 2021).FindingsWe report findings from heavily treatment-experienced PLWH with a pan-resistant HIV-1 infection, who achieved virological control once introduced injections of ibalizumab, that is free from cross-resistance with all the antiretroviral drugs available and ensures patient adherence due to a close monitoring attributable to the route of administration, combined with recycled enfuvirtide and an optimized background regimen, selected on the basis of an accurate evaluation of resistance mutations.InterpretationIn these cases, this new approach has revealed to be a turning point in achieving virological control.FundingNone, this research was supported by internal funding.

Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.

The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored. To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India. Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described. Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period. Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

P6‐2: To study the efficacy and safety of bedaquiline plus optimized background regimen and high dose moxifloxacin plus optimized background regimen in drug resistant pulmonary tuberculosis‐A prospective observational study

P6‐2: To study the efficacy and safety of bedaquiline plus optimized background regimen and high dose moxifloxacin plus optimized background regimen in drug resistant pulmonary tuberculosis‐A prospective observational study

V3-Loop genotypes do not predict maraviroc susceptibility of CCR5-tropic virus or clinical response through week 48 in HIV-1-infected, treatment-experienced persons receiving optimized background regimens.

Viruses from 15 of 35 maraviroc-treated participants with virologic failure and CCR5-tropic (R5) virus in the MOTIVATE studies at Week 24 had reduced maraviroc susceptibility. On-treatment amino acid changes were observed in the viral envelope glycoprotein 120 third variable (V3)–loop stems and tips and differed between viruses. No amino acid change reliably predicted reduced susceptibility, indicating that resistance was genetic context–dependent. Through Week 24, poor adherence was associated with maraviroc-susceptible virologic failure, whereas reduced maraviroc susceptibility was associated with suboptimal background regimen activity, highlighting the importance of overall regimen activity and good adherence. Predictive values of pretreatment V3-loop sequences containing these Week 24 mutations or other variants present at >3% in pretreatment viruses of participants with virologic failure at Week 48 were retrospectively assessed. Week 48 clinical outcomes were evaluated for correlates with pretreatment V3-loop CCR5-tropic sequences from 704 participants (366 responders; 338 virologic failures [83 with R5 virus with maraviroc susceptibility assessment]). Seventy-five amino acid variants with >3% prevalence were identified among 23 V3-loop residues. Previously identified variants associated with resistance in individual isolates were represented, but none were associated reliably with virologic failure alone or in combination. Univariate analysis showed virologic-failure associations with variants 4L, 11R, and 19S (P < 0.05). However, 11R is a marker for CXCR4 tropism, whereas neither 4L nor 19S was reliably associated with reduced maraviroc susceptibility in R5 failure. These findings from a large study of V3-loop sequences confirm lack of correlation between V3-loop genotype and clinical outcome in participants treated with maraviroc.Clinical trial registration numbers (ClinicalTrials.gov): NCT00098306 and NCT00098722

1027. Long-Term Efficacy, Safety, and Durability of Ibalizumab-Based Regimens in Subgroup of TMB-202 Participants

BackgroundThird line antiretroviral regimens have been associated with suboptimal virologic suppression, due to drug cross-resistance and regimen complexity. Yet, in treatment-experienced (TE) HIV patients, ART durability is essential for preventing further resistance and decreasing HIV-associated morbidity and mortality. Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved to treat multi-drug resistant (MDR) HIV, may support regimen durability given its directly observed administration. We analyzed the safety, efficacy, and durability of response in 12 patients who started IBA in a Phase 2b study.MethodsIn TMB-202, 113 patients with MDR HIV received either 2000 mg IBA every 4 weeks (n=54) or 800 mg IBA every 2 weeks (n=59) for 24 weeks with an optimized background regimen (OBR). Of 96 patients who completed TMB-202, 56 transferred into an investigator-sponsored investigational new drug protocol and 12 later moved onto an expanded access protocol, TMB-311, where efficacy and safety were monitored until IBA was commercially available (approval 2018).ResultsBaseline median viral load (VL) and CD4 count for the 12 patients were 4.4 log10 copies/mL (c/mL) and 135 cells/mL, respectively. The median duration of HIV infection was 22 years (range 18-25). At the completion of TMB-202 11/12 achieved virologic suppression (VL < 200 c/mL) and 8/12 had VL < 50 c/mL. All 12 patients were suppressed (VL < 50 c/mL) at their last TMB-311 visit. Patients gained an average of 99 CD4 cells/mL relative to baseline. There were no treatment-emergent adverse events (TEAE) or therapy discontinuations related to IBA during follow-up. Two patients died from unrelated causes. Overall, the 12 patients remained on IBA for an average of 8.9 years (range 8-9.5), during which 8/12 did not require addition of new ARVs to their OBR to maintain suppression.Figure 1: duration of ibalizumab-based regimen is displayed for the 12 patients. Grey bars represent patients with no addition of new ARVs to OBR. Black bars represent patients with an addition to OBR. Asterisks represent addition of ritonavir only. ConclusionData from 12 patients who received IBA for an average of 9 years validate the long-term efficacy and safety of IBA in TE patients. Importantly, for most patients, the durability of virologic response was maintained with minimal adjustments to the OBR. Altogether, these data demonstrate the contribution of IBA towards durable viral suppression in TE HIV patients with limited therapeutic options.Disclosures William Towner, MD, Dynavax (Research Grant or Support)Gilead (Grant/Research Support)Merck (Research Grant or Support)Tai Med (Research Grant or Support)ViiV (Research Grant or Support) Edwin DeJesus, MD, Gilead Sciences (Advisor or Review Panel member) Colleen McGary, PhD, Theratechnologies (Employee) Mohammed Zogheib, PharmD, MPH, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

1008. Disease Severity Impact on Long-Term Virologic Response to Ibalizumab in Expanded Access Protocol (TMB-311)

BackgroundThe principal goal of antiretroviral therapy (ART) is durable suppression of HIV RNA. In treatment-experienced (TE) patients, ongoing viremia can lead to further accumulation of drug resistance, increased morbidity and mortality. ART efficacy often depends on HIV disease severity; therefore, we sought to assess its impact on long-term virologic suppression in patients treated with Ibalizumab (IBA), the first long-acting, post-attachment inhibitor approved for multi-drug resistant (MDR) HIV-1 treatment.MethodsIn TMB-301, a Phase 3 study, 40 TE patients with viral load (VL) >1000 copies/mL (c/mL) received an intravenous (IV) loading dose of IBA (2000mg) followed by maintenance doses (800mg IV) every 2 weeks combined with an optimized background regimen. Patients who completed TMB-301 in the US (n=27) continued to an expanded access protocol TMB-311. To determine the impact of baseline (BL) disease on long-term virologic response, we conducted an on-treatment analysis stratified by BL VL and CD4 count up to week 96. Differences in the proportion of suppressed (< 50 c/mL) individuals among the strata were assessed by Fisher’s exact test.ResultsMedian BL VL and CD4 count were 35,350 c/mL and 73 cells/mL, respectively. The number of patients in the VL strata were 11, 17 and 12 for VL < 10,000, 10,000-70,000, and >70,000 c/mL, respectively. There were 12, 10, 5 and 13 patients in the subgroups with CD4 count < 10, 10-100, >100-200 and >200 cells/µL. Population disease severity was reflected by four deaths (unrelated to study drug). Overall, the proportion of suppressed patients increased from 55% at week 24 (n=31) to 75% for patients remaining on treatment for 96 weeks (n=20). Median VL decrease was 2.9 log10 c/mL. Notably, no statistically significant differences were found across groups. Among patients with advanced HIV disease, 66.7% with CD4 count < 10 cells/mL and 71.4% with VL >70,000 c/mL at BL remained fully suppressed at week 96.ConclusionIn TE patients with advanced HIV disease, maximal viral suppression with IBA was observed regardless of BL CD4 or VL strata if patients remained on treatment. This demonstrates that TE patients across the spectrum of HIV disease, can achieve viral suppression by using drugs with a new mechanism of action.Disclosures Princy Kumar, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Jason Leider, MD, PhD, THERA (Speaker’s Bureau) Jihad Slim, MD, Abbvie (Speaker’s Bureau)Gilead (Speaker’s Bureau)Jansen (Speaker’s Bureau)Merck (Speaker’s Bureau)ViiV (Speaker’s Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Maurice Leonard, PhD, Theratechnologies Europe Ltd (Employee, Shareholder) R Brandon Cash, PharmD, Theratechnologies (Employee) Steven Weinheimer, PhD, TaiMed Biologics USA (Employee) Pedro Mesquita, PhD, Theratechnologies, Inc. (Employee)

Population Pharmacokinetic Analysis of Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

A population pharmacokinetic (PopPK) model of delamanid in patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) was developed using data from four delamanid clinical trials. The final PopPK data set contained 20,483 plasma samples from 744 patients with MDR-TB receiving an optimized background regimen (OBR). Delamanid PK was adequately described for all observed dosing regimens and subpopulations by a two-compartment model with first-order elimination and absorption, an absorption lag time, and decreased relative bioavailability with increasing dose. Relative bioavailabilities of 200-mg and higher doses (250 and 300 mg) were 76% and 58% of a 100-mg dose, respectively. Relative bioavailability was 26% higher after evening doses than morning doses and 9% higher in outpatient settings than inpatient settings. The rate of absorption was higher, and lag time was shorter, following a morning dose than an evening dose. Relative bioavailabilities in patients in Northeast Asian and Southeast Asian regions were 53% and 40% higher, respectively, than in patients in non-Asian regions. Apparent clearance was higher (to the power of -0.892) in patients with hypoalbuminemia (albumin levels of <3.4 g/dl). Coadministration of efavirenz in patients with HIV increased delamanid clearance by 35%. Delamanid exposure was not affected by age (18 to 64 years), mild or moderate renal impairment, anti-TB antibiotic resistance status, HIV status, or markers of hepatic dysfunction or by concomitant administration of OBR, lamivudine, tenofovir, pyridoxine, CYP3A4 inhibitors and inducers, or antacids. Model evaluation suggested reasonable model fit and predictive power, indicating that the model should prove reliable to derive PK metrics for subsequent PK/PD analyses.

Long-term virological effectiveness with darunavir/ritonavir-based salvage therapy in people living with HIV/AIDS from São Paulo, Brazil.

Even though darunavir/ritonavir (DRV/r) has high potency and a greater genetic barrier, there are few studies on the long-term effectiveness of DRV/r-based salvage therapy in people living with HIV (PLWH) in low and middle-income countries. This retrospective cohort study, from São Paulo, Brazil, included ART-experienced PLWH aged ≥18 years with virological failure (VF) who had started DRV/r plus an optimized background regimen (OBR) between 2008 and 2012. The proportion of patients with viral load (VL) <50 copies/mL, the improved mean CD4+ T cell count and the factors associated with VF during the 144-week follow-up were assessed. The study included 173 patients with the following characteristics [median (interquartile range)]: age 48 (42 -53) years; CD4+ T cell count, 229 (89 -376) cells/mm3; VL, 4.26 (3.70 -4.74) log10; 6 (4 -7) previous regimens; and 100 (38 -156) months of VF. After 144 weeks, 129 (75%) patients had VL< 50 copies/mL and a mean increase in the CD4+ T cell count of 190 cells/mm3. VL>100,000 copies/mL and poor adherence were associated with VF. DRV/r plus an OBR showed high long-term virological suppression and immunological recovery. VL>100,000 copies/mL and poor adherence were associated with VF at 144 weeks.