PI-containing Regimen Research Articles

MagnetisMM-30: A phase 1b, open-label study of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma (RRMM).

TPS7577 Background: Elranatamab (ELRA) is a humanized B-cell maturation antigen (BCMA)–CD3 bispecific antibody (BsAb). Single-agent ELRA induced deep and durable responses with a manageable safety profile in patients (pts) with RRMM enrolled in the phase 2 registrational MagnetisMM-3 study (NCT04649359; Lesokhin et al, Nat Med 2023). Iberdomide (IBER) is a novel CELMoD[TM] agent that induces enhanced antimyeloma tumoricidal and immunomodulatory activity in pts with RRMM (Lonial et al, Lancet Haematol 2022). While IBER in combination with ELRA has not been evaluated clinically, it may provide additional benefit to pts with RRMM based on the mechanisms of action of this novel combination. Methods: MagnetisMM-30 is a phase 1b, open-label, prospective study evaluating the safety, efficacy, and pharmacokinetics of ELRA in combination with IBER in pts with RRMM. The study has 2 parts: Part 1 for dose-escalation and Part 2, randomized for dose optimization. After 2 step-up priming doses of ELRA, pts will receive subcutaneous ELRA weekly with IBER given daily for 21 days of each 28-day cycle. After ≥6 months (cycles) of treatment, pts with a partial response or better for ≥2 months are eligible for reduced dosing frequency of ELRA. Once the 2 combination dose levels (dose levels A and B) are selected from Part 1 as the recommended phase 2 doses for ELRA and IBER, pts in Part 2 will be randomized 1:1 (stratified by the number of prior lines of therapy [LOTs; 1 vs >1]) to dose levels A and B. Key inclusion criteria are pts aged ≥18 years with a MM diagnosis per IMWG criteria, Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and bone marrow function, and disease relapsed or refractory to the last antimyeloma regimen per IMWG response criteria. Pts who received 2-4 or 1-3 prior LOTs, including ≥1 immunomodulatory drug (IMiD) and ≥1 proteasome inhibitor (PI), are eligible for Parts 1 and 2, respectively. All pts must have received ≥2 consecutive cycles of an IMiD-containing regimen and ≥2 consecutive cycles of a PI or PI-containing regimen. Key exclusion criteria are pts with stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior treatment with BCMA-directed or CD3 redirecting therapy or prior CELMoD agents (ie, IBER or mezigdomide). This study is ongoing; Part 1 and Part 2 will enroll approximately 27 and 60 pts, respectively. Study endpoints are listed in the table. Clinical trial information: NCT06215118 . [Table: see text]

ART-related medication errors in hospitalized people with HIV in the INSTI-era: analysis from 2 health systems in South Georgia, U.S.

ABSTRACT ART-related medication errors occur at high rates in hospitalized people with HIV (PWH), but few studies included modern regimens. As such, we evaluated ART-related medication errors in hospitalized PWH in an era where use of INSTI-based regimens dominate. This multi-center, retrospective cohort included PWH at least 18 years hospitalized in South Georgia, U.S. between March 2016 and March 2018. Of those eligible for inclusion, 400 were randomly selected and included. Three hundred sixty-three inpatient ART-related medication errors occurred in 203 patients during the study period due to incorrect scheduling (44%), an incorrect or incomplete regimen (27%), and drug–drug interactions (27%). Approximately 25% of errors persisted to discharge. Medication errors were more likely to occur in patients receiving NNRTI- or PI-containing multi-tablet regimens, whereas those receiving INSTI-containing multi-tablet regimens were less likely to experience a medication error. ART-related medication errors are less likely in patients receiving INSTI-containing multi-tablet regimens. Ensuring appropriate transition of ART throughout hospitalization remains an area in need of significant improvement.

Acid Ceramidase (ASAH1) Is a Key Mediator of Drug Resistance in Refractory Multiple Myeloma

Despite the growing armamentarium of treatments including proteasome inhibitors (PIs), immunomodulatory imides (IMiDs) and cellular and non-cellular immunotherapies MM remains incurable, due to the emergence of drug resistance that causes patient relapse. To develop therapies that significantly extend overall survival, a clearer understanding of the mechanisms driving drug-resistance is urgently required. Analysis of RNA-seq data derived from 672 MM Moffitt patients revealed that sphingolipid metabolism genes and in particular acid ceramidase (ASAH1), are significantly enriched in relapse MM (RMM). Further, high levels of ASAH1 in RMM patients predicted poorer overall survival when patients were treated with any PI-containing regimen (median overall survival 552 vs 1226 days). These findings were corroborated in the Multiple Myeloma Research Foundation CoMMpass dataset (IA17). Next, we queried potential mechanisms of treatment resistance using gene-set enrichment analysis (GSEA). ASAH1 High patients displayed upregulation of gene signatures involved in metabolism of lipids, sphingolipids and regulation of apoptosis. Further, PI-resistant cell lines (U266-PSR, RPMI8226-B25, and ANBL6-V10R) displayed elevated levels of ASAH1, and total and phosphorylated levels of anti-apoptotic proteins MCL-1 and BCL-2 compared to PI-sensitive parental cells (U266, RPMI8226 and ANBL6). Genetic (shRNA) and pharmacological (ceranib-2) inhibition of ASAH1 significantly decreased MM viability and reduced MCL-1/BCL-2 expression. Further, ASAH1 inhibition resensitized resistant MM cells to PI treatment. Importantly, we recapitulated our findings in CD138+ patient MM cells ex vivo (EMMA platform), with ceranib-2/PI treatment being synergistic in the majority (>75%) of patient samples tested. In vivo, ceranib-2 treatment limited PI-resistant U266-PSR MM tumor growth and extended overall survival of NSG mice. Further, ASAH1 depletion (shRNA) resensitized MM cells to PI treatment in vivo and loss of MCL-1 and BCL-2 expression was confirmed ex vivo. To understand the mechanism through which ASAH1 mediates PI-resistance we performed total and pSTY proteomic profiling (LC-MS/MS). Proteomic analyses revealed inhibition of the endogenous phosphatase PP2A inhibitor, I2PP2A as a candidate mechanism. Notably, I2PP2A was elevated in PMRC RMM patient samples, correlating with ASAH1 expression, and predicting poorer overall survival. In conclusion, in vitro, in vivo and patient ex vivo data demonstrate ASAH1 is a novel, clinically relevant and tractable target for the treatment of PI-resistant MM. Future studies to develop novel and potent ASAH1 inhibitors for the treatment resistant MM, in combination with current standard of care therapies are on-going and we believed warranted based on our emerging data.

Clonal Hematopoiesis Is More Common in People Living with HIV and May be Associated with Increased Prevalence of Cardiovascular Disease

Background: Cardiovascular disease (CVD) is more common in people living with HIV (PLWH) and may be related to abnormal immune activation. With aging, the expansion of mutated hematopoietic clones or clonal hematopoiesis (CH) has been associated with CVD events in the general population and is hypothesized to be driven by systemic inflammation. We investigated whether CH was more common in PLWH compared to those without HIV, whether the distribution of CH mutations differed by HIV status, and whether CH was associated with subclinical coronary atherosclerosis in PLWH.Methods: Study participants were selected from men in the Baltimore -Washington DC center of the Multicenter AIDS Cohort Study (MACS) who had had coronary CT angiography (CTA) as part of the MACS Cardiovascular Study 2. The MACS is a prospective study of the natural history of HIV infection in men who have sex with men, and includes both PLWH and HIV-uninfected men. Since the prevalence of CH increases with age, the oldest participants were preferentially included in this study. To detect CH, DNA extracted from viably frozen peripheral blood mononuclear cells or cell pellets was subjected to targeted, error-corrected, ultra-deep next generation sequencing (NGS) which included 70 genes frequently mutated in hematologic malignancies. CTA results and inflammatory biomarker levels were already available from MACS data.Results: The current analysis was a cross-sectional study involving 118 participants: 86 (72.9%) PLWH and 32 (27.1%) HIV-uninfected men (HIV-). The groups were well-balanced in terms of known major risk factors for CH such as age and smoking. The median age was 53 and 54 years for PLWH and HIV- men, respectively (p=0.147). Caucasians represented 37 (43.0%) of PLWH and 21 (65.6%) of HIV- men. Out of 86 PLWH, 72 (83.7%) were on antiretroviral therapy (ART) at the time of the assessment; 41 (47.7%) on a PI-containing regimen and 31 (36.0%) on an NNRTI-containing regimen. The HIV viral load was under 400 copies/mL in 77 (89.5%) of PLWH, and the median (IQR) CD4+ count was 585 (397, 745)/mL. The prevalence of coronary artery stenosis of 50% or more was 12 (14.3%) in PLWH and 5 (16.1%) in HIV- men (p = 0.774).Since the minimum size of the biologically relevant CH is unknown, we applied variant allele frequency (VAF) cut-offs of > 0.5% and > 1%. For both cutoffs, CH was significantly more frequent in PLWH than in HIV- men (p=0.012 and p=0.036, respectively) (Figure 1A). Mutations in epigenetic modifiers (DNMT3A, TET2) were the most common mutations among both PLWH and HIV- men. Interestingly, DNMT3A mutations were more frequent in PLWH (Figure 1B). For both VAF cut-offs, PLWH had significantly more somatic mutations than HIV-uninfected men (p = 0.043 and 0.033, respectively) (Figure 1C).Since inflammation-mediated complications of CH become more apparent in people with larger clones, we focused on CH with VAF > 1% in order to determine the clinical consequences of CH in PLWH. As CH is known to be a risk factor for accelerated CVD in the general population, we asked whether CH was also associated with subclinical atherosclerosis in PLWH. Coronary artery stenosis > 50% (moderate/severe) was significantly more frequent in PLWH with CH compared to PLWH without CH (p = 0.032) (Figure 1 D). This difference remained significant in multivariable logistic regression models that adjusted for the Framingham coronary heart disease 10-year risk (p=0.017) and for the Framingham hard coronary heart disease 10-year risk (p<0.01).Additionally, we examined the association of serum concentrations of several inflammatory markers such as CRP, IL-1b, IL-6, as well as white blood cell count, with the presence of CH in PLWH, but we found no significant associations.Conclusions: CH was more common in PLWH compared to HIV-uninfected men, and PLWH had more somatic mutations. Moreover, the presence of CH was significantly associated with the presence of coronary artery stenosis > 50% (moderate/severe) in PLWH, even after adjusting for known CVD risk factors. The results from our exploratory analysis may provide a potential explanation for increased CVD in PLWH. Larger studies are warranted to further delineate the etiology of increased CH in PLWH and its impact on accelerated CVD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No increased risk of Kaposi sarcoma relapse in patients with controlled HIV-1 infection after switching protease inhibitor-based antiretroviral therapy.

Our aim was to assess if switching from a protease inhibitors (PI)-based regimen to a PI-free one is associated with an increased risk of Kaposi Sarcoma (KS) relapse among patients living with HIV (PLHIV) with history of KS and controlled HIV replication. In a retrospective analysis of the prospectively collected Dat'AIDS database we selected patients who both had a past KS history and a HIV-1 viral load below 200 copies/mL while being PI-treated. We searched for KS relapses while persistent virological success was maintained for at least 6 months, whether patients kept taking the PI, or switched to PI-free regimen. Among the 216 patients with past KS event and a history of HIV-1 infection efficiently treated by a PI-based regimen, 148 patients (68.5%) later switched to a PI-sparing regimen. Their baseline characteristics were not different from non-switching patients. We described 7 cases of relapse (3.2% of the 216 patients). Five cases of relapse occurred in switching patients (3.4%). The remaining two relapses occurred in PI-treated patients (2.9%). At KS relapse, CD4 cell count was 459 cells/μL (range 225-560) for switching patients, compared with 362 and 136 cells/μL for the other two patients. In this large cohort of PLHIV with a history of KS and ART-controlled HIV replication, KS relapses were described in 3.2% of the patients, and were not more frequent when a PI-containing ART regimen has been switched to a PI-free regimen. Our results do not support a specific effect of PI on KS.

Timing, Dosage, and Adherence of Antiretroviral Therapy and Risk of Osteoporosis in Patients With Human Immunodeficiency Virus Infection in Taiwan: A Nested Case-Control Study.

The progression of acquired immunodeficiency syndrome is delayed in patients with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART). However, long-term ART is associated with adverse effects. Osteoporosis is one of the adverse effects and is a multifactorial systemic skeletal disease associated with bone fragility and an increased risk of fracture. We performed a longitudinal, comprehensive, nested case-control study to explore the effect of ART on the risk of osteoporosis in 104 osteoporotic and 416 non-osteoporotic patients with HIV infection at their average age about 29 years old in Taiwan. Patients with history of ART, current exposure to ART, higher cumulative defined daily doses (DDDs), or higher ART adherence were at a higher risk of osteoporosis (p < 0.05). Patients receiving nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-containing regimen (zidovudine-lamivudine combination, lamivudine-abacavir combination, and abacavir alone) and protease inhibitor (PI)-containing regimen (lopinavir-ritonavir combination, ritonavir, and atazanavir) had a higher risk of osteoporosis (p < 0.05). Especially, patients receiving high doses of the PIs lopinavir-ritonavir combination had an increased risk of osteoporosis (p < 0.05). In conclusion, history of ART, current exposure to ART, higher cumulative DDDs, and higher ART adherence were associated with an increased risk of osteoporosis. Furthermore, NRTI- and PI-containing regimens and high doses of PIs lopinavir-ritonavir combination may be associated with an increased risk of osteoporosis in patients with HIV infection in Taiwan.

Incidence and impact of low-level viremia among people living with HIV who received protease inhibitor- or dolutegravir-based antiretroviral therapy

ObjectivesThe impact of very low-level viremia (VLLV) and low-level viremia (LLV) are rarely investigated among people living with HIV (PLWH) receiving dolutegravir- vs protease inhibitor (PI)-based antiretroviral therapy (ART). MethodsVirally suppressed PLWH receiving long-term PI-containing ART were included in this study. The incidences of developing VLLV (plasma HIV RNA load (PVL) 20–49 copies/ml), LLV (PVL 50–999 copies/ml), and virological failure (any PVL ≥ 1000 copies/ml) were compared between those switched to dolutegravir-based ART and those remaining on PI-containing ART. ResultsA total of 183 PLWH were switched to dolutegravir-based regimens and 309 remained on PI-containing regimens. The incidences of VLLV and LLV were 26.5 and 13.2 per 100 person-years of follow-up in the dolutegravir group, respectively, and 17.1 and 7.0 per 100 person-years of follow-up in the PI group; there were no statistically significant differences after adjusting for confounders. The rate of virological failure was 1.3 per 100 person-years of follow-up in the dolutegravir group and 1.9 per 100 person-years of follow-up in the PI group (p = 0.32). Neither VLLV nor LLV was related to subsequent virological failure. ConclusionsAmong virally suppressed PLWH, the risk of developing VLLV or LLV were similar between those switched to dolutegravir-based therapy and those who continued PI-based therapy. VLLV and LLV were not associated with subsequent virological failure.

Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study

Effect of Prior Treatment with Proteasome Inhibitors on the Efficacy and Safety of Once-Weekly Selinexor, Bortezomib, and Dexamethasone in Comparison with Twice-Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Subgroup Analysis from the Boston Study

Efficacy of Proteasome Inhibitor-Based Maintenance Post Autologous Hematopoietic Cell Transplant in Multiple Myeloma: A Systematic Review and Meta-Analysis

Background Autologous hematopoietic cell transplantation (AHCT) followed by maintenance therapy is the current standard of care in the treatment of multiple myeloma (MM). Lenalidomide (Len) is most commonly utilized as maintenance therapy as it has been shown to improve both progression free survival (PFS) and overall survival (OS). However, long-term maintenance therapy with Len is associated with development of secondary primary malignancies (SPM). Proteasome-inhibitor (PI)-based maintenance strategies have been evaluated in several phase III trials and also appear to yield survival benefits in MM. Methods We performed a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019. We extracted data on clinical outcomes related to benefits (OS, PFS and deepening of hematologic response [DOHR]) and harms (SPM), independently by two authors. Our search strategy identified total of 2144 references. Three studies (5 manuscripts) were included in this systematic review (Figure 1). Results Median age for patients receiving PI maintenance after AHCT ranged from 25 to 65 years. All patients underwent an AHCT with melphalan 200mg/m2 prior to initiation of PI maintenance. Also, 70% of patients received a PI-containing induction regimen. 513 patients received bortezomib maintenance and 395 patients received ixazomib. The control arm in these studies was either placebo (n=261) or thalidomide (n=597). PI maintenance did not improve OS (n=2 studies, 1012 patients, hazard ratio [HR] 0.88, 95% CI 0.73-0.105, p=0.15) but improved PFS (HR 0.75, 95% CI 0.67-0.85, p= Conclusions The results of our systematic review show that PI-based maintenance following AHCT in MM leads to significant improvement in PFS and DOHR without an increase in development of SPM compared to placebo/non-PI maintenance. Prospective randomized phase III trials comparing Len to PI-based maintenance is an interesting question that remains unanswered.

Dual therapy combining raltegravir with etravirine maintains a high level of viral suppression over 96 weeks in long-term experienced HIV-infected individuals over 45 years on a PI-based regimen: results from the Phase II ANRS 163 ETRAL study.

Dual therapy combining integrase inhibitors and NNRTIs represents a promising regimen in ageing HIV-infected individuals with long exposure to nucleoside analogues and PIs. The ANRS 163 ETRAL trial (NCT02212379) was a 96 week, multicentre, single-arm study evaluating the efficacy and safety of raltegravir (400 mg twice daily)/etravirine (200 mg twice daily) in individuals >45 years, on a PI-containing regimen who were integrase inhibitor and etravirine naive. The primary endpoint was the proportion of participants with virological success, defined by the absence of virological failure up to week 48. Main secondary outcomes included evolution of metabolic parameters, CD4/CD8 count, bone mineral density and inflammatory markers. The study was designed to show an efficacy >90%, assuming a success rate ≥95%, with a power of 80% and a 5% type-1 error. One hundred and sixty-five participants (median age 52 years, duration of ART 16.9 years, viral suppression 6.9 years and CD4 count 700 cells/mm3) were enrolled. By ITT analysis, viral suppression was maintained in 99.4% of participants (95% CI = 95.6%-99.9%) at week 48 and 98.7% (95% CI = 95.0%-99.7%) at week 96. Two virological failures occurred (week 24 and week 64) without emergence of integrase inhibitor resistance. Eight participants discontinued raltegravir/etravirine for adverse events, leading to a strategy success rate of 95.1% (95% CI = 90.5%-97.5%) at week 48 and 92.7% (95% CI = 87.5%-95.8%) at week 96. Over 96 weeks, lipid fractions improved (P < 0.001), CD4/CD8 ratio increased, IFNγ-induced protein 10 (IP-10) decreased (-8.1%), soluble CD14 decreased (-27%, P < 0.001) bone mineral density improved and BMI increased. Raltegravir plus etravirine dual therapy demonstrated durable efficacy in virologically suppressed ageing patients.

Durability of INI-containing regimens after switching from PI-containing regimens: a single-centre cohort of drug-experienced HIV-infected subjects.

PurposeIntegrase inhibitor (INI)-containing regimens are increasingly replacing protease inhibitor(PI)-containing regimens in clinical practice. The aim of this study was to evaluate the determinants of the durability of INI-containing regimens after the switch.Patients and methodsWe retrospectively analysed all of the people with HIV infection attending the University of Milan’s Infectious Diseases Unit at Luigi Sacco Hospital who were switched from a PI- to an INI-containing regimen between April 2008 and March 2017. The probability of remaining on an INI-containing regimen was estimated using Kaplan-Meier curves, and the baseline clinical predictors of INI-containing regimen durability were assessed using a multivariable Cox proportional hazard regression model.ResultsThree hundred and twelve patients were included in the analysis. The median time of observation was 21 months (interquartile range 10–36 months). The main reasons for switching from a PI-containing regimen to an INI-containing regimen were toxicities (31.4%) and simplification (31.1%). Univariate analysis revealed no difference in the probability of INI discontinuation between the patients treated with raltegravir, dolutegravir or elvitegravir (p=0.060), but the multivariable Cox regression model showed that the patients treated with dolutegravir were at less risk of discontinuation than those treated with raltegravir (adjusted hazard ratio 0.49, 95% confidence interval 0.26–0.95; p=0.034).ConclusionSwitching from a PI- to an INI-containing regimen may be an option for patients under virological control. The patients switched to dolutegravir were less likely to discontinue the INI than those switched to raltegravir. Our findings support this therapeutic strategy and highlight the durability and efficacy of dolutegravir containing-regimens after switching from a PI-containing regimen.

New mechanisms of resistance in virological failure to protease inhibitors: selection of non-described protease, Gag and Gp41 mutations.

To further characterize HIV-1 viruses of patients experiencing unexplained virological failure (VF) on PI-containing regimens, ultradeep sequencing was performed on protease, gag and gp41 genes in patients failing a first-line treatment. All naive patients initiating an antiretroviral treatment based on boosted darunavir, atazanavir or lopinavir and experiencing VF without any transmitted drug resistance mutation detected by Sanger sequencing on protease and reverse transcriptase genes were selected. Ultradeep sequencing (IlluminaTM Nextera®) was performed on protease, gag and gp41 genes in plasma before initiation of treatment and at VF to identify emergent mutations. Among the 32 patients included in the study, emergent and previously undescribed mutations in the viral protease gene were identified in five patients at VF: 64M (1 CRF02_AG), 64M/70R with mutation 15V (2 CRF02_AG), 79A (1 CRF06_cpx) and 79A with mutation 15V (1 CRF02_AG). Two patients showed the emergence of R286K in the gag region, outside of cleavage sites (2 CRF02_AG). In the gp41 region, the V321I mutation emerged inside the cytoplasmic tail (1 subtype A and 1 subtype B). All these patients were treated with a darunavir/ritonavir-based regimen. In some cases of VF to PIs, we observed the emergence of protease, Gag or Gp41 mutations that had not previously been associated with VF or PI resistance. These mutations should be further studied, in particular the 15V/64M/70R pattern in the protease gene identified among CRF02_AG viruses.

Effectiveness of switching from protease inhibitors to dolutegravir in combination with nucleoside reverse transcriptase inhibitors as maintenance antiretroviral therapy among HIV-positive patients

Prolonged exposure to regimens containing protease inhibitors (PIs) as second-line therapy for human immunodeficiency virus (HIV) infection may have a negative impact on metabolic profiles and increase the risk of cardiovascular diseases. Real-world experience with dolutegravir (DTG)-based regimens as alternatives to PI-based regimens is limited in antiretroviral-experienced patients with previous failure or intolerance to first-line therapy. The current study included HIV-positive patients receiving PI-containing regimens with viral suppression for ≥6 months. Virological response and lipid profiles were compared between patients who were subsequently switched to DTG-based therapy plus nucleoside reverse transcriptase inhibitors (NRTIs) and those remaining on their PI-containing regimen at Week 48. In total, 189 patients were switched to DTG-based regimens and 313 remained on PI-containing regimens during the observation period. Patients in the DTG group were younger (mean age 40.0 years vs. 44.6 years) and were more likely to have a previous history of virological failure (44.4% vs. 19.5%) than those in the PI group. At Week 48, 1.1% of the DTG group and 3.8% of the PI group had virological non-response (HIV-RNA load >50 copies/mL) (difference, -2.7%, 95% CI -5.5% to 0.5%). The presence of M184V/I mutation and other NRTI resistance-associated mutations (RAMs) did not increase the risk of virological failure in either group. Patients switched to DTG-based therapy had statistically significant improvement of lipid profiles. Among virally suppressed HIV-positive patients, a switch to DTG-based therapy was non-inferior to continuation of PI-based therapy in virological effectiveness at Week 48, even in the presence of NRTI RAMs.

Factors Associated with Virological Rebound in HIV-Positive Sub-Saharan Migrants Living in France After Traveling Back to Their Native Country: ANRS-VIHVO 2006-2009 Study.

In France, around 25% of the estimated number of people living with HIV are migrants, of whom three quarters are from sub-Saharan Africa (SSA). Our objective was to determine factors associated with virological rebound (VR) at the occasion of a transient stay to the country of origin. HIV-positive migrants from SSA participating to the ANRS-VIHVO adherence study between 2006 and 2009, on effective ART with controlled pre-travel HIV-1 plasma viral load (VL), were included. Outcome was VR, defined as VL ≥ 50 copies/ml at the post-travel visit during the week following the return to France. Among 237 persons (61.6% female, median age 41years (IQR, 35-47), median time on ART 4.2years (IQR, 2.2-7.1), 27 (11.4%) experienced VR. The main purpose of the travel was to visit family and median time spent abroad was 5.3weeks (IQR, 4.1-8.8). The travel was extended longer than anticipated by at least 1week in 42 individuals (17.7%). In multivariable logistic model, risk factors for VR were male sex [adjusted OR (aOR) 5.1; 95% CI 1.6-16.2)], no employment in France (aOR 2.0; 1.2-3.5), self-reported non-adherence during the trip (aOR 14.9; 4.9-45.9) and PI-containing regimen (aOR 4.6; 1.2-17.6). In another analysis not including self-reported adherence, traveling during Ramadan while respecting the fast (aOR 3.3; 1.2-9.6) and extension of the stay (aOR 3.0; 1.1-7.8) were associated with VR. Virological rebound was partly explained by structural barriers to adherence such as extension of the travel and inadequate management of Ramadan fasting. Individuals' journeys should be carefully planned with health care providers.

Molecular Mechanism of Resistance in a Clinically Significant Double-Mutant Variant of HCV NS3/4A Protease

Despite significant progress in hepatitis C virus (HCV) protease inhibitor (PI) drug design, resistance remains a problem causing treatment failure. Double-substitution variants, notably Y56H/D168A, have emerged in patients who fail therapy with a PI-containing regimen. The resistance conferred by Asp168 substitutions has been well characterized and avoided in newer inhibitors. However, an additional mutation at Tyr56 confers resistance to even the most robust inhibitors. Here, we elucidate the molecular mechanisms of resistance for the Y56H/D168A variant against grazoprevir (and four analogs), paritaprevir, and danoprevir through inhibition assays, co-crystal structures, and molecular dynamics simulations. The PIs' susceptibility to Y56H/D168A varies, with those stacking on the catalytic His57 losing the most potency. For such inhibitors, the Y56H substitution disrupts favorable stacking interactions with the neighboring catalytic His57. This indirect mechanism of resistance threatens to cause multi-PI failure as all HCV PIs in clinical development rely on interactions with the catalytic triad.

Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens.

With the introduction of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy, persons living with HIV have a potent new treatment option. Recently, providers at our large treatment clinic noted weight gain in several patients who switched from efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). In this study, we evaluated weight change in patients with sustained virologic suppression who switched from EFV/TDF/FTC to an INSTI-containing regimen. We performed a retrospective observational cohort study among adults on EFV/TDF/FTC for at least 2 years who had virologic suppression. We assessed weight change over 18 months in patients who switched from EFV/TDF/FTC to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen versus those on EFV/TDF/FTC over the same period. In a subgroup analysis, we compared patients switched to DTG/ABC/3TC versus raltegravir- or elvitegravir-containing regimens. A total of 495 patients were included: 136 who switched from EFV/TDF/FTC to an INSTI-containing regimen and 34 switched to a PI-containing regimen. Patients switched to an INSTI-containing regimen gained an average of 2.9 kg at 18 months compared with 0.9 kg among those continued on EFV/TDF/FTC (P = 0.003), whereas those switched to a PI regimen gained 0.7 kg (P = 0.81). Among INSTI regimens, those switched to DTG/ABC/3TC gained the most weight at 18 months (5.3 kg, P = 0.001 compared with EFV/TDF/FTC). Adults living with HIV with viral suppression gained significantly more weight after switching from daily, fixed-dose EFV/TDF/FTC to an INSTI-based regimen compared with those remaining on EFV/TDF/FTC. This weight gain was greatest among patients switching to DTG/ABC/3TC.

Weight Gain After Switch from Efavirenz-Based to Integrase Inhibitor-Based Regimens

BackgroundIntegrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) offers persons living with HIV a potent new treatment option. Recently, local HIV clinicians noted weight gain in patients who switched from daily, fixed-dose efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to fixed-dose dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). To assess whether regimen switch was significantly associated with weight gain, we evaluated body weight over time among patients with sustained virologic suppression who switched from EFV/TDF/FTC to an INSTI-containing regimen, including DTG/ABC/3TC.MethodsWe analyzed data from adult patients on EFV/TDF/FTC for >=2 years with consistent plasma HIV-1 RNA <1000 copies/mL prior to date of switch (or date of sham switch for those who remained on EFV/TDF/FTC). All maintained HIV-1 RNA <1000 copies/mL for >=18 months post-switch. We assessed weight change over 18 months in patients switched to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen vs. those remaining on EFV/TDF/FTC over the same period. In a sub-group analysis, we compared patients switched to DTG/ABC/3TC vs. raltegravir- or elvitegravir-containing regimens. Linear mixed effects models assessed mean differences in weight over time, adjusting for baseline age, sex, race, CD4+ count and weight.ResultsAmong 495 patients, 136 switched to an INSTI-containing regimen, 34 switched to a PI-containing regimen, and 325 remained on EFV/TDF/FTC. Patients switched to an INSTI-containing regimen gained an average of 2.9 kilograms (kg) at 18 months compared with 0.9 kg among those continued on EFV/TDF/FTC (P = 0.003, Figure a), while those switched to a PI regimen gained 0.7 kg (P = 0.81, Figure b). Among INSTI regimens, those switched to DTG/ABC/3TC gained 5.3 kg at 18 months, which was more than raltegravir or elvitegravir regimens (P = 0.19, Figure c) and significantly more than those continued on EFV/TDF/FTC (P = 0.001, Figure d).ConclusionSwitching from daily, fixed-dose EFV/TDF/FTC to an INSTI-containing regimen among patients with virologic control was associated with weight gain at 18 months. This weight gain was particularly profound among those switching to DTG/ABC/3TC.Disclosures All authors: No reported disclosures.

Unraveling the structural basis of grazoprevir potency against clinically relevant substitutions in hepatitis C virus NS3/4A protease from genotype 1a

Grazoprevir is a potent pan-genotype and macrocyclic inhibitor of hepatitis C virus (HCV) NS3/4A protease and was developed for treating chronic HCV infection. In HCV genotype (GT) 1a, grazoprevir maintains potent activity against a majority of NS3 resistance-associated amino acid substitutions, including the highly prevalent and naturally occurring Q80K polymorphism that impacts simeprevir, another NS3/4A protease inhibitor. The basis for an unexpected difference in the clinical impact of some NS3 substitutions was investigated. Phenotypic analysis of resistance-associated substitutions identified in NS3 from GT1a-infected patients who failed therapy with grazoprevir (in combination with elbasvir, an inhibitor of HCV NS5A protein) showed that positions 56, 156, and 168 in NS3 were most impactful because they diminished protein-inhibitor interactions. Although an amino acid substitution from aspartic acid to alanine at position 168 (D168A) reduced the potency of grazoprevir, its combination with R155K unexpectedly nullified this effect. Molecular dynamics and free-energy surface studies indicated that Asp-168 is important in anchoring Arg-155 for ligand binding but is not critical for Lys-155 because of the inherent flexibility of its side chain. Moreover, modeling studies supported a strong direct cation-heterocycle interaction between the Lys-155 side chain of the double substitution, R155K/D168A, and the lone pair on the quinoxaline in grazoprevir. This unique interaction provides a structural basis for grazoprevir's higher potency than simeprevir, an inhibitor to which the double substitution confers a significant reduction in potency. Our findings are consistent with the detection of R155K/D168A in NS3 from virologic failures treated with simeprevir but not grazoprevir.

Impact of antiretroviral therapy on clinical outcomes in HIV + kidney transplant recipients: Review of 58 cases

Background: Antiretroviral therapy (ART) poses challenging drug-drug interactions with immunosuppressant agents in transplant recipients. We aimed to determine the impact of specific antiretroviral regimens in clinical outcomes of HIV + kidney transplant recipients. Methods: A single-center, retrospective cohort study was conducted at a large academic center. Subjects included 58 HIV - to HIV + adult, first-time kidney transplant patients. The main intervention was ART regimen used after transplantation. The main outcomes assessed at one- and three-years were: patient survival, death-censored graft survival, and biopsy-proven acute rejection; we also assessed serious infections within the first six months post-transplant. Results: Patient and graft survival at three years were both 90% for the entire cohort. Patients receiving protease inhibitor (PI)-containing regimens had lower patient survival at one and three years than patients receiving PI-sparing regimens: 85% vs. 100% ( p=0.06) and 82% vs. 100% ( p=0.03), respectively. Patients who received PI-containing regimens had twelve times higher odds of death at 3 years compared to patients who were not exposed to PIs (odds ratio, 12.05; 95% confidence interval, 1.31-1602; p=0.02). Three-year death-censored graft survival was lower in patients receiving PI vs. patients on PI-sparing regimens (82 vs 100%, p=0.03). Patients receiving integrase strand transfer inhibitors-containing regimens had higher 3-year graft survival. There were no differences in the incidence of acute rejection by ART regimen. Individuals receiving PIs had a higher incidence of serious infections compared to those on PI-sparing regimens (39 vs. 8%, p=0.01). Conclusions: PI-containing ART regimens are associated with adverse outcomes in HIV + kidney transplant recipients.

The Decline in HIV-1 Drug Resistance in Heavily Antiretroviral-Experienced Patients Is Associated with Optimized Prescriptions in a Treatment Roll-Out Program in Mexico.

A decrease in the rate of acquired antiretroviral (ARV) drug resistance (ADR) over time has been documented in high-income settings, but data on the determinants of this phenomenon are lacking. We tested the hypothesis that in heavily ARV-experienced patients in the Mexican ARV therapy (ART) roll-out program, the drop in ADR would be associated with changes in ARV drug usage. Genotypic resistance tests obtained from 974 HIV-infected patients with virological failure and at least 2 previously failed ARV regimens from throughout the country were analyzed for the presence of nucleos(t)ide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitor (PI) resistance-associated mutations (RAMs). Patients were divided into two groups according to their first ART start date: 488 patients initiated ART before mid-2003 (group 1) and 486 after mid-2003 (group 2). The rate of RAMs, median resistance score of several sentinel ARVs, and composition of ART drugs in patient's entire treatment history were compared between both groups. Patients in group 2 were less likely to have >3 thymidine analogue-associated mutations (TAMs) and >3 PI-mRAMs [adjusted odds ratio (aOR) = 0.37; 95% confidence interval (95% CI) = 0.25-0.54; p < .001 and aOR = 0.53; 95% CI = 0.36-0.77; p = .001, respectively] and had a significantly lower resistance score for zidovudine, tenofovir, ritonavir-boosted (r)-lopinavir, r-atazanavir, and r-darunavir than group 1 patients. A significantly lower proportion of patients in group 2 used monotherapy, bitherapy, thymidine analogue-containing regimens, nonboosted PI-containing regimens, and low resistance barrier PI-containing regimens. In Mexican ARV-experienced patients, the occurrence of TAM and PI-mRAM has significantly declined over time. This can be explained by treatment optimization in the national ART roll-out program in recent years.