Advances in antiretroviral therapy (ART) have decreased HIV-related morbidity and mortality and contributed to rapidly increasing numbers of older people living with HIV. Successful management of ART-related side effects (metabolic syndrome) and age-related comorbidities (frailty) are major challenges for patients and providers. Exercise has proven beneficial for younger HIV-infected patients, but we know little about which exercise regimens to recommend to the elderly. Our goal was to develop age-appropriate, evidence-based exercise recommendations for older HIV-infected adults (age > 50). We reviewed randomized controlled trials on the effects of physical exercise for: (a) HIV-infected young adults, (b) frail older adults, and (c) elderly individuals with metabolic syndrome. We recommend a combination of endurance and resistance exercises 3 times per week for at least 6 weeks to improve cardiovascular, metabolic, and muscle function. Further research is warranted to study the benefits and risks of physical exercise in older HIV-infected patients.

Objective assessment in human immunodeficiency virus (HIV)-related fatigue has been elusive because the biological mechanisms are not well characterized. We tried to identify low-abundance plasma proteins that correlate with self-reported fatigue intensity in people living with HIV. We used plasma samples from 32 patients with HIV with varying degrees of fatigue who were either treated with nucleoside reverse transcriptase inhibitors or treatment naïve. The plasma samples were enriched for low-abundance proteins and trypsinized. The peptides were analyzed using shotgun proteomics. Five targets correlated with severity of fatigue: apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB), histine-rich glycoprotein, alpha-1 B glycoprotein, and orosomucoid 2. These targets were selected based on total abundance and spectral count differences, and ApoA1 and ApoB were analyzed via Western blots to verify the mass spectrometry results. ApoA1 levels were higher in untreated patients, while ApoB results suggested a possible positive trend in treated patients. Further analysis is needed to identify additional low-abundance proteins and confirm already-identified proteins as potential fatigue biomarkers.

Poorly controlled HIV infection and antiretroviral therapy, especially the use of protease inhibitors, are among the causes that contribute to the development of cardiovascular disease in people living with HIV (PLWH). Poor lifestyle choices (smoking, lack of physical activity, poor diet) and individual factors such as high stress, physical or emotional trauma, depression, and so forth contribute to the overall risk of developing cardiovascular disease. The purpose of this review was to critically evaluate the more recent aerobic and resistance exercise studies and their impact on cardiovascular and metabolic risk factors in PLWH.

People living with HIV (PLWH) see their providers quarterly to go over their laboratory results and discuss problems with antiretroviral treatment (ART) regimens. Our purpose was to determine whether socially and economically marginalized PLWH were accurate in self-reporting their most recent CD4 count, viral load, and ART regimen, and whether demographic differences influenced self-reporting. We conducted a secondary data analysis based on results from (N = 200) PLWH. We found moderate agreement for CD4 count (k = .58), and viral load (k = .43), but only 43% were able to recall their ART regimens accurately. PLWH ≥ age 50 (k = .77) and those with health insurance coverage (k = .61) were more accurate to self-report CD4. Women were more accurate in reporting viral load than men (k = .53, p = .003 vs. k = .38). These findings suggest that PLWH need multiple modalities of education to relate CD4 counts, viral load, and ART regimens to their personal health understanding.

Idelalisib (Zydelig™), a first-in-class, selective, oral inhibitor of PI3Kδ, is approved for the treatment of chronic lymphocytic leukemia (CLL) in combination with rituximab and as monotherapy for patients with follicular lymphoma who have received at least 2 prior therapies. Despite remarkable clinical efficacy, complete responses are rare, highlighting the need to identify more effective therapies, including combinations of novel agents. GS-4059 (ONO-4059) is an investigational next generation BTK inhibitor with improved selectivity compared to ibrutinib. We report here on the results of the combination of idelalisib and GS-4059 in lymphoma cell lines. Methods: Growth inhibition was assessed using CellTiter-Glo™ Assay (Promega) after 72-96 h incubation with idelalisib and GS-4059. Synergy for anti-proliferative effects was assessed using the Bliss Model of Independence (Meletiadis et al., Med Mycol, 2005), using MacSynergy II (Prichard et al., MacSynergyTM II, Version 1.0, 1993) or the Chalice software (Horizon Discovery, Inc., Lehar et al., Nature Biotech, 2009). Lysates were analyzed by Simple Western (Protein Simple) or Western blot. Ibrutinib resistance was established by continuous passaging of a clonal isolate of TMD8 in the presence of 10-20 nM ibrutinib. Resistance mutations were identified by whole exon sequencing (WES, GeneWiz). Results: GS-4059 potently inhibited growth (EC50<26 nM) of 3 ABC-DLBCL cell lines (OCI-LY10, Ri-1, and TMD8) that were also sensitive to idelalisib (EC50<210 nM). The combination showed synergistic growth inhibition in OCI-LY10 and TMD8 and increased apoptosis above the level observed with single agents (Table 1). Idelalisib and GS-4059 synergistically inhibited growth in 2 MCL cell lines (Rec-1 and JMV-2). The combination was additive in the other lymphoma cell lines sensitive to these agents. Two mechanisms of resistance to BTK inhibitors were identified in TMD8: an inactivating mutation in the NF-kB inhibitor A20 (TNFAIP3 Q143*), and a BTK mutation (C481F). TMD8 cells with the BTK (C481F) mutation only were less sensitive to idelalisib (Emax = 14% at 1 uM vs. 86% in parental, Figure 1A). Addition of GS-4059 did not enhance growth inhibition in those clones. A20 mutant only TMD8 cells were resistant to GS-4059 (EC50>10 μM), but were sensitive to idelalisib, albeit less than parental (EC50 ≥ 4300 nM vs. 54 nM). Addition of 50 nM GS-4059 to idelalisib provided further growth inhibition, consistent with the presence of wild-type BTK, and increased the potency of idelalisib to a level comparable to parental TMD8 (EC50 ≥ 99 nM, n=5 clones, Figure 1B). Conclusion: Idelalisib and GS-4059 synergistically inhibited the growth of a subset of DLBCL and MCL cell lines. A20 mutation and loss-of -function was identified as a novel mechanism of resistance to BTK inhibitors. Idelalisib less potently inhibited the growth of A20 mutant TMD8 but the combination with GS-4059 provided additional benefit. TMD8 with a BTK-C481F mutation, were resistant to idelalisib and to the combination with GS-4059. These data suggest that the combination of idelalisib and GS-4059 may overcome some mechanisms of resistance to BTK. Table 1. Synergistic inhibition of ABC-DLBCL cell viability by GS-4059 and idelalisib GS-4059 (nM) EC50 of idelalisib (nM) when combined with GS-4059 TMD-8 OCI-LY-10 Ri-1 Pfeiffer 0 254 440 442 174 5 130 38 372 NTc 15 32 22 372 NT 45 24 5 372 174 EC50 shift (fold) 10.6 88 12 1 Synergy Score 65 65 0 0 Figure 1. Growth inhibition of ibrutinib resistant TMD8 with (A) BTK C481F mutation or (B) A20 Q143* mutation A. B. Figure 1. Growth inhibition of ibrutinib resistant TMD8 with (A) BTK C481F mutation or (B) A20 Q143* mutation. / A. / B. Figure 2. Figure 2. Disclosures Tannheimer: Gilead Sciences: Employment, Other: Share holder. Sorensen:Gilead Sciences: Employment, Other: Share holder. Yahiaoui:Gilead Sciences: Employment, Other: Share holder. Meadows:Gilead Sciences: Employment, Other: Share holder. Li:Gilead Sciences: Employment, Other: Share holder. Yue:Gilead Sciences: Employment, Other: Share holder. Tumas:Gilead Sciences: Employment, Equity Ownership. Queva:Gilead Sciences: Other: Share holder.