1.
What is the collective effect of aging and HIV on the gut microbiome?
Dillon, SM, Wilson, CC
Current opinion in HIV and AIDS. 2020;(2):94-100
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Abstract
PURPOSE OF REVIEW Aging and HIV share features of intestinal damage and alterations in the communities of enteric bacteria, termed dysbiosis. The purpose of this review is to highlight the various features of the gut microbiome in aging and in people with HIV (PWH) and to discuss how aging and HIV converge to impact the gut microbiome. The term microbiome reflects the combined genetic material of micro-organisms present including bacteria, viruses, bacteriophages, and fungi. To date, the majority of studies investigating the impact of aging and HIV on the gut microbiome have focused on bacteria, and therefore, for the purposes of this review, the term 'microbiome' is used to reflect enteric bacterial communities. RECENT FINDINGS Aging is associated with alterations in the gut bacterial microbiome. Although changes vary by the age of the population, lifestyle (diet, physical activity) and geographic location, the age-associated dysbiosis is typically characterized by an increase in facultative anaerobes with inflammatory properties and a decrease in obligate anaerobes that play critical roles in maintaining intestinal homeostasis and in regulating host immunity. PWH also have dysbiotic gut microbiomes, many features of which reflect those observed in elderly persons. In one study, the age effect on the gut microbiome differed based on HIV serostatus in older adults. SUMMARY HIV and age may interact to shape the gut microbiome. Future studies should investigate relationships between the gut microbiome and age-associated comorbidities in older PWH populations. Identifying these links will provide new avenues for treatments and interventions to improve the healthspan and lifespan of older PWH.
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Comparison of illumina and 454 deep sequencing in participants failing raltegravir-based antiretroviral therapy.
Li, JZ, Chapman, B, Charlebois, P, Hofmann, O, Weiner, B, Porter, AJ, Samuel, R, Vardhanabhuti, S, Zheng, L, Eron, J, et al
PloS one. 2014;(3):e90485
Abstract
BACKGROUND The impact of raltegravir-resistant HIV-1 minority variants (MVs) on raltegravir treatment failure is unknown. Illumina sequencing offers greater throughput than 454, but sequence analysis tools for viral sequencing are needed. We evaluated Illumina and 454 for the detection of HIV-1 raltegravir-resistant MVs. METHODS A5262 was a single-arm study of raltegravir and darunavir/ritonavir in treatment-naïve patients. Pre-treatment plasma was obtained from 5 participants with raltegravir resistance at the time of virologic failure. A control library was created by pooling integrase clones at predefined proportions. Multiplexed sequencing was performed with Illumina and 454 platforms at comparable costs. Illumina sequence analysis was performed with the novel snp-assess tool and 454 sequencing was analyzed with V-Phaser. RESULTS Illumina sequencing resulted in significantly higher sequence coverage and a 0.095% limit of detection. Illumina accurately detected all MVs in the control library at ≥0.5% and 7/10 MVs expected at 0.1%. 454 sequencing failed to detect any MVs at 0.1% with 5 false positive calls. For MVs detected in the patient samples by both 454 and Illumina, the correlation in the detected variant frequencies was high (R2 = 0.92, P<0.001). Illumina sequencing detected 2.4-fold greater nucleotide MVs and 2.9-fold greater amino acid MVs compared to 454. The only raltegravir-resistant MV detected was an E138K mutation in one participant by Illumina sequencing, but not by 454. CONCLUSIONS In participants of A5262 with raltegravir resistance at virologic failure, baseline raltegravir-resistant MVs were rarely detected. At comparable costs to 454 sequencing, Illumina demonstrated greater depth of coverage, increased sensitivity for detecting HIV MVs, and fewer false positive variant calls.
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Sevelamer does not decrease lipopolysaccharide or soluble CD14 levels but decreases soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol levels in individuals with untreated HIV infection.
Sandler, NG, Zhang, X, Bosch, RJ, Funderburg, NT, Choi, AI, Robinson, JK, Fine, DM, Coombs, RW, Jacobson, JM, Landay, AL, et al
The Journal of infectious diseases. 2014;(10):1549-54
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Abstract
UNLABELLED Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. CLINICAL TRIALS REGISTRATION NCT 01543958.
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Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262).
Taiwo, B, Zheng, L, Gallien, S, Matining, RM, Kuritzkes, DR, Wilson, CC, Berzins, BI, Acosta, EP, Bastow, B, Kim, PS, et al
AIDS (London, England). 2011;(17):2113-22
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Abstract
OBJECTIVE To explore darunavir/ritonavir (DRV/r) plus raltegravir (RAL) combination therapy in antiretroviral-naive patients. DESIGN Phase IIb, single-arm, open-label, multicenter study. METHODS One hundred and twelve antiretroviral-naive, HIV-1-infected patients received DRV/r 800/100 mg once daily and RAL 400 mg twice daily. Primary endpoint was virologic failure by week 24. Virologic failure was defined as confirmed viral load of 1000 copies/ml or more at week 12, or an increase of more than 0.5 log(10) copies/ml in viral load from week 4 to 12, or a confirmed viral load of more than 50 copies/ml at or after week 24. Protease and integrase genes were sequenced in patients experiencing virologic failure. RESULTS Virologic failure rate was 16% [95% confidence interval (CI) 10-24] by week 24 and 26% (95% CI 19-36) by week 48 in an intent-to-treat analysis. Viral load at virologic failure was 51-200 copies/ml in 17/28 failures. Adjusting for age and sex, virologic failure was associated with baseline viral load of more than 100,000 copies/ml [hazard ratio 3.76, 95% CI (1.52-9.31), P = 0.004] and lower CD4 cell count [0.77 per 100 cells/μl increase (95% CI 0.61-0.98), P = 0.037]. When trough RAL concentrations were included as a time-varying covariate in the analysis, virologic failure remained associated with baseline viral load more than 100,000 copies/ml [hazard ratio = 4.67 (95% CI 1.93-11.25), P < 0.001], whereas RAL level below detection limit in plasma at one or more previous visits was associated with increased hazard [hazard ratio = 3.42 (95% CI 1.41-8.26), P = 0.006]. All five participants with integrase mutations during virologic failure had baseline viral load more than 100,000 copies/ml. CONCLUSION DRV/r plus RAL was effective and well tolerated in most patients, but virologic failure and integrase resistance were common, particularly in patients with baseline viral load more than 100,000 copies/ml.