Myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis that results in reduced blood counts. Although MDS can transform into leukemia, most of ...the morbidity experienced by these patients is due to chronically low blood counts. Conventional cytotoxic agents used to treat MDS have yielded some encouraging results but are characterized by many adverse effects in the predominantly elderly patient population. Targeted interventions aimed at reversing the bone marrow failure and increasing the peripheral blood counts would be advantageous in this cohort of patients. Studies have demonstrated over-activated signaling of myelo-suppressive cytokines such as TGF-β, TNF-α and Interferons in MDS hematopoietic stem cells. Targeting these signaling cascades could be potentially therapeutic in MDS. The p38 MAP kinase pathway, which is constitutively activated in MDS, is an example of cytokine stimulated kinase that promotes aberrant apoptosis of stem and progenitor cells in MDS. ARRY-614 and SCIO-469 are p38 MAPK inhibitors that have been used in clinical trials and have shown activity in a subset of MDS patients. TGF-β signaling has been therapeutically targeted by small molecule inhibitor of the TGF-β receptor kinase, LY-2157299, with encouraging preclinical results. Apart from TGF-β receptor kinase inhibition, members of TGF-β super family and BMP ligands have also been targeted by ligand trap compounds like Sotatercept (ACE-011) and ACE-536. The multikinase inhibitor, ON-01910.Na (Rigosertib) has demonstrated early signs of efficacy in reducing the percentage of leukemic blasts and is in advanced stages of clinical testing. Temsirolimus, Deforolimus and other mTOR inhibitors are being tested in clinical trials and have shown preclinical efficacy in CMML. EGF receptor inhibitors, Erlotinib and Gefitinib have shown efficacy in small trials that may be related to off target effects. Cell cycle regulator inhibitors such as Farnesyl transferase inhibitors (Tipifarnib, Lonafarnib) and MEK inhibitor (GSK1120212) have shown acceptable toxicity profiles in small studies and efforts are underway to select mutational subgroups of MDS and AML that may benefit from these inhibitors. Altogether, these studies show that targeting various signal transduction pathways that regulate hematopoiesis offers promising therapeutic potential in this disease. Future studies in combination with high resolution correlative studies will clarify the subgroup specific efficacies of these agents.
TPS9154
Background: The combination of platinum, pemetrexed, and pembrolizumab (CIT) has become the standard of care in 1L non–oncogene addicted NSCLC. Despite an initial improvement in response rate ...and survival, the 5-year survival of NSCLC remains approximately 20-30%, due to the emergence of primary and acquired resistance. Additionally, the presence of brain metastases occurs in ˜30-50% of NSCLC patients and confers a poor prognosis. Among the currently non-actionable mutations, STK11/LKB1 mutations (STK11m) are common (˜20%) in NSCLC. Recent evidence suggests that STK11m NSCLC patients have a minimal response to checkpoint inhibitors and to chemo-immunotherapy in the first line setting. STK11m tumors are characterized by an immune-suppressed phenotype which is highly associated with AXL signalling. BEM, a first-in-class, oral, selective AXL inhibitor, has demonstrated the ability to prevent chemoresistance, re-sensitize STK11m NSCLC tumors to pembrolizumab, and enhance efficacy of CIT in preclinical lung models. Moreover, following oral administration, BEM readily distributes in brain tumour tissue in recurrent glioblastoma patients, with a 25.9 mean ratio of drug concentration in brain tissue to plasma. Therefore, the addition of BEM to CIT has the potential to improve 1L treatment outcomes in NSCLC overall and particularly in STK11m tumors. Methods: This is an open-label, multi-center, phase 1b/2a study to assess the safety, tolerability, and preliminary anti-tumor activity of BEM + CIT as 1L treatment in patients with advanced (Stage IIIb/IIIc) or metastatic (Stage IV) non-squamous NSCLC without actionable mutations. Patients with stable brain metastases are eligible to participate. Phase 1b follows a 3+3 design and will explore CIT in combination with one of 3 BEM dose levels: Cohort 1 = 75mg; Cohort 2 = 100 mg; or Cohort 3 = 150 mg. BEM is administered orally once/day on Day 1 of each 21-day treatment cycle. After 4 cycles of CIT + BEM, maintenance with BEM + pemetrexed + pembrolizumab is administered for up to 2 years. An independent data safety monitoring board will assess the safety data at the end of the dose-limiting toxicity period (the first 21 days of treatment for each patient, i.e. cycle 1) of each cohort and will recommend the BEM dose for the phase 2a expansion. In the phase 2a, up to 40 patients harboring a STK11m (regardless of their co-mutational status), in the absence of driver mutations will be enrolled. The study will include extensive co-mutational analyses via next-generation sequencing to identify potential sub-groups of patients deriving particular benefit. The trial is open to patient enrolment in phase1b in the US; recruitment for phase 2a is planned to open in Q2 2023 in Europe and US. EudraCT 2019‐003806‐28/NA/124645. Clinical trial information: NCT05469178 .
Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
To investigate whether adding autologous tumor lysate-loaded ...dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
ClinicalTrials.gov Identifier: NCT00045968.
Abstract
BACKGROUND
Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor ...lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and
METHODS
Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results.
RESULTS
331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine.
CONCLUSION
Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.
Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal ...development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation. Gene bodies, intergenic regions, and CpG shores were preferentially demethylated during erythropoiesis. Epigenetic changes at transcription factor binding sites correlated significantly with changes in gene expression and were enriched for binding motifs for SCL, MYB, GATA, and other factors not previously implicated in erythropoiesis. Demethylation at gene promoters was associated with increased expression of genes, whereas epigenetic changes at gene bodies correlated inversely with gene expression. Important gene networks encoding erythrocyte membrane proteins, surface receptors, and heme synthesis proteins were found to be regulated by DNA methylation. Furthermore, integrative analysis enabled us to identify novel, potential regulatory areas of the genome as evident by epigenetic changes in a predicted PU.1 binding site in intron 1 of the GATA1 gene. This intronic site was found to be conserved across species and was validated to be a novel PU.1 binding site by quantitative ChIP in erythroid cells. Altogether, our study provides a comprehensive analysis of methylomic and transcriptomic changes during erythroid differentiation and demonstrates that human terminal erythropoiesis is surprisingly associated with hypomethylation of the genome.
Background: Not much is known about epigenomic changes during the differentiation of human stem cells into mature enucleated red cells.
Results: Methylome analysis during human erythropoiesis revealed that global hypomethylation occurs during this process and correlates with transcriptomic changes.
Conclusion: Integrative analysis also allowed us to identify novel regulatory areas of the genome.
Significance: Progressive functional hypomethylation during human erythroid differentiation changes the current paradigm.
Abstract 1827
Prior studies suggest that HIV+ patients have a higher prevalence of paraproteinemia. Paraproteinemia is a known risk factor for development of hematological malignancy (HM) in non HIV ...patients. However the pathogenesis of paraproteinemia and the additional risk conferred by it to development of HM in HIV remains unclear. We describe our findings from a large database of HIV+ patients in Montefiore Medical Center with and without paraprotein for differences in HIV status, comorbidities and incidence of HM.
Our de-identified patient database, Clinical Looking Glass, was used to identify all documented HIV+ patients who underwent at least one serum protein electrophoresis test (SPEP) after the HIV test between January 1st 2001 and December 31st 2011. Patients were classified into SPEP+ and SPEP-, and SPEP+ patients further stratified into distinct (D-SPEP) or faint/multiple/oligoclonal (F-SPEP) cases by visual assessment of gel electrophoresis. Laboratory data was reviewed for comorbidities and HIV status. Results of all biopsies undergone by each patient were reviewed to identify HM diagnoses.
A total of 17,961 HIV+ patients were identified of which 2,095 patients had at least one SPEP test. Of those tested, 21.2% were SPEP+ (D-SPEP: 4%; F- SPEP:17.2%). 3.3% had a missing result. IgG was the commonest subtype on immunofixation (85.4%). All 3 groups (SPEP-, D-SPEP and F-SPEP) had a similar median duration of HIV before testing for SPEP. Mean CD4+ value measured around the time of the SPEP test (3 months before or after) was significantly higher in the F-SPEP group compare to both other groups. Patients in the D-SPEP and F-SPEP groups were more likely to be seropositive for Hepatitis C and Rheumatoid Factor (RF) than those who were SPEP-.
A significantly higher proportion of patients were biopsied in the D-SPEP and F-SPEP groups than the SPEP-. Overall the incidence of HM in D-SPEP was significantly higher but when adjusted for patients who were biopsied, the higher incidence in D-SPEP did not reach statistical significance. 50–60% of HM were diagnosed within 6 months of the index SPEP; the D-SPEP group had the shortest time to diagnosis of HM after SPEP. The pattern of HM was different among the three groups with the D-SPEP patients mostly developing plasma cell dyscrasias, while the F-SPEP and SPEP- groups had a higher proportion of high grade B and T cell neoplasms. (Table 1).
To our knowledge this is the largest published sample of HIV+ patients tested for paraproteinemia. The higher prevalence of Hepatitis C in SPEP+ patients suggests its role in pathogenesis of paraproteinemia. The higher incidence of HM, especially plasma cell dyscrasias diagnosed close to the index SPEP in the D-SPEP group suggests that D-SPEP may reflect malignant clonal proliferation. In contrast, the F-SPEP group had a similar HM incidence to SPEP- and a higher CD4+ count than the other groups. These suggest that faint/oligoclonal paraproteins may require T cell mediated B cell activation to develop and maybe directed against viral antigens rather than reflect premalignant or malignant proliferation. Understanding antigen specificity of paraproteins may shed light on the risk of HM in HIV+ SPEP+ patients.Table 1Differences between HIV+ SPEP-, HIV+D-SPEP and HIV+F-SPEPCharacteristicHIV+SPEP- (n=1596)HIV+DSPEP+ (n=82)HIV+FSPEP+ (n=348)pAge (yrs)49.4 (SE:0.29)50.5 (SE:1.35)49.9 (SE:0.58)0.604Male (%)53.2%47.6%47.1%0.088Median HIV duration before SPEP (days)8908117600.554Mean CD4 for patients tested (/uL)264 (SE:7.41)295 (SE:32.41)329 (SE:17.88)0.001*Mean HIV viral load for patients tested (copies/ml)127310 (SE:15094)118218 (SE:31448)98378 (SE:27968)0.691Median follow up after SPEP test (days)65410477340.362Hepatitis C+ of total tested patients494 (36.3%)33 (50.8%)125 (41.8%)0.018*Hepatitis B+ of total patients tested96 (9.9%)7 (13.2%)29 (12.4%)0.441ANA +of total patients tested89 (13.7%)5 (18.5%)17 (11.3%)0.531RF + of total patients tested88 (22.7%)11 (45.8%)43 (39.8%)0.000*Patients with HM (% of total N)66 (4.1%)10 (12.2%)21 (6%)0.004*Number of patients s/p biopsy268 (16.8%)22 (26.8%)90 (25.9%)0.000*Number of patients with HM of those biopsied66 (24.8%)10 (45.5%)21 (23.3%)0.087Number of total HM diagnosed after index SPEP37 (56.1%)6 (60%)11 (52.4%)0.918Median time from SPEP test to HM diagnosis (d)56363290.016*
No relevant conflicts of interest to declare.
Abstract
BACKGROUND: Paraproteinemias occur in 1 to 3% of people over the age of 50 and progress to hematological malignancies (HM) at the rate of about 1% per year. In HIV+ patients a higher ...incidence of paraproteinemia has been reported however the rate of progression to HM remains unclear. We studied a large database comparing HIV+ and HIV- patients with paraproteinemia for incidence of HM.
METHODS: Patients tested for HIV who also had a serum protein electrophoresis test (SPEP) performed between January 1st 2001 and December 31st 2011 were identified using a medical database at a large tertiary care center. SPEP+ patients were stratified into distinct (D-SPEP) or faint/multiple/oligoclonal (F-SPEP) bands by an independent laboratory technician. Demographics, coinfections and biopsy data were reviewed.
RESULTS: 181,851 patients underwent a HIV test and 10,293 were HIV+. Significantly greater number of HIV+ patients (1381 of 10,293) compared to HIV- (6512 of 171,588) were tested for paraprotein (13.4% vs 3.8%, p<0.0001). Of those tested, the prevalence of SPEP positivity was higher in HIV+ (266 of 1381) versus HIV- (537 of 6512) (19.3% vs 8.2%, p<0.0001). HIV+ SPEP+ patients were more likely to have F-SPEP and light chain paraproteins compared to their HIV- counterparts. HIV+SPEP+ patients were significantly more likely to be tested and more likely to be positive for hepatitis B and C co infections.
HIV- SPEP+ patients were more likely to have a D-SPEP and IgA and IgM subtype paraproteins than HIV+ patients. HIV- patients also had a higher incidence of HM which persisted when adjusted for year of SPEP and duration of follow up (p<0.0001).
CONCLUSIONS: While a higher prevalence of paraproteinemia was noted in the HIV+, HM incidence was lower in the HIV+ compared to HIV-, suggesting that nonmalignant virus-dependent proliferation may lead to paraproteinemia in some HIV+ cases. Identification of HIV+SPEP+ cases with higher risk of HM will be clinically relevant.
Table 1.Comparison of HIV+SPEP+ and HIV- SPEP+ patientsCharacteristicHIV+ SPEP+ (n = 266)HIV- SPEP+ (n = 537)p value(Chi square/ Fishers exact/ t-test)Age at SPEP test (yrs)50 (SE: 0.54)59 (SE: 0.55)<0.0001*F-SPEP (n,%)234 (88%)342 (63.7%)<0.0001D-SPEP (n,%)32 (12%)195 (36.3%)<0.0001*IgG (n,%)209 (78.6%)372 (73.5%)0.136IgM (n,%)4 (1.5%)42 (8.3%)<0.0001*IgA (n,%)3 (1.1%)40 (7.9%)<0.0001*Light chain (n,%)24 (9%)23 (4.5%)0.013Hepatitis C positive by serology/ viral load of those tested113/246 (45.9%)78/412 (18.9%)<0.0001HBsAg/ Hepatitis B viral load positive of those tested22/241 (9.1%)4/254 (2.6%)0.012Follow up after SPEP test (months)23360.003HM (n,%)17 (6.5%)83 (16.1%)<0.0002HM+ of F-SPEP+12/234 (5.1%)34/342 (9.9%)0.042HM+ of D-SPEP+5/32 (15.6%)49/195 (25%)0.369
Citation Format: Erin Jou, Oleg Gligich, Alvita CY Chan, Diwakar Mohan, Uriel R. Felsen, Sabarish Ayyappan, Henny H. Billett, Edwin P. Hui, Anthony TC Chan, Radha Raghupathy. Progression of paraproteinemia in HIV-positive versus HIV-negative patients. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5594. doi:10.1158/1538-7445.AM2015-5594
An increasing incidence of hematological malignancies (HM) has been noted in HIV+ patients, however the risk factors remain unclear. We retrospectively explored our large database of HIV+ patients to ...assess the incidence and distribution of different HM and premalignant hematological disorders (PMD) in HIV+ patients and the HIV and non HIV related risk factors for development.
Patients over the age of 18 with a positive HIV test (western blot or detectable viral load) between Jan 1st 2001 and Dec 31st 2011 were identified using the medical center database Clinical Looking Glass. Data were collected regarding demographics, Hepatitis B, C status, paraproteinemia and HIV characteristics. Results of all biopsies performed for each patient, ICD9 and cancer registry diagnoses were reviewed for a diagnosis of hematological malignancy (HM). Data collection was censored as of April 1st 2013.
10,293 patients with a positive HIV test were identified with a median duration of follow up of 60 months (0-146 months) from the test date. 747 of these patients underwent a total of 948 biopsies for diagnosis of hematological disorders. 46 patients were excluded for an insufficient biopsy specimen. 255 of 10,293 patients (2.5%) were diagnosed with a HM or PMD. 241 patients had biopsy confirmation and 14 patients had ICD9 code/cancer registry data which were confirmed by chart review. Ten patients were diagnosed with HM when their HIV status was unknown and were excluded. 2 of the remaining 245 HM positive patients had two HM each, myeloma followed by extranodal NK/ T cell lymphoma and Castleman followed by DLBCL.
Mean age at diagnosis of the first HM/PHD was 46 years (SD:9.9). HM positive cases (n=245) in comparison to HM negative (n=9992) controls were more likely to be male (69% vs 57.6%, p<0.0001). More than 85% of patients in both groups were tested for hepatitis C and active hepatitis B with no difference in prevalence. HM positive cases were more often tested for paraprotein (OR:3.63, 95% CI: 2.78-4.75). Of those tested (n=1381), HM positive cases were more likely to have a discrete paraprotein. (OR: 2.79, 1.05-7.43) but no significant difference in prevalence of faint, oligoclonal or multiple paraprotein bands was detected. Binary logistic regression analysis of the paraproteinemia tested group showed increased odds of developing HM with male gender (OR:2.01, 1.27-3.19) and discrete (OR:3.25, 1.2-8.79), but not faint (OR: 1.4, 0.8-2.46) paraproteins.
The distribution of HM is noted in Table 1. High grade lymphomas accounted for 80.6% of HM, with DLBCL being the most frequent category. Of all HM, 43.5% occurred as non-nodal primaries The closest CD4 count within 6 months prior to HM diagnosis was obtained and median CD4 count compared. High grade lymphomas had a significantly lower median CD4 count close to HM diagnosis compare to low grade lymphomas and plasma cell dyscrasias. (150 vs 314 vs 281, p: 0.012)
Table 1Characteristics of patients with HIV related HMType of neoplasmSubtypes (n)Total Cases n(%)Discrete paraproteinFaint or multiple paraproteinsMedian CD4Plasma cell dyscrasiaMyeloma (5)7(2.9%)83.30%0%281Immature plasma cell tumour (2)High grade lymphomasDLBCL (106)199 (80.6%)0%18.80%150Burkitts (29)High grade B cell NHL (15)DLBCL/Burkitts overlap (3)Plasmablastic (8)Hodgkins (32)B cell large cell lymphoma (1)PEL (2)T cell NHL (2)Extranodal NK/ T cell (1)Low grade lymphomasCLL (1)11 (4.5%)0%0%314Follicular (2)MALT (6)Mycosis fungoides (2)Acute leukemiasAML (5)7(2.8%)98ALL (2)MDS/MPDMDS (1)4(1.6%)550CML (1)CMML (2)OtherMGUS (1)17 (6.8%)258MBUS (7)Atypical lymphoid proliferation (3)Castleman (6)
Our study suggests that in HIV related HM, male gender and discrete paraproteins are likely to be significant risk factors but oligoclonal or multiple paraproteins are not. No additional risk appeared to be conferred by concurrent viral illnesses. The relationship of CD4 count to HM development suggests the role of immune mechanisms in pathogenesis.
No relevant conflicts of interest to declare.
The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether ...co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (
n
= 229) and HM negative (
n
= 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5–4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2–8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.
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