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1.  Incomplete Reversibility of Estimated Glomerular Filtration Rate Decline Following Tenofovir Disoproxil Fumarate Exposure 
Jose, Sophie | Hamzah, Lisa | Campbell, Lucy J. | Hill, Teresa | Fisher, Martin | Leen, Clifford | Gilson, Richard | Walsh, John | Nelson, Mark | Hay, Phillip | Johnson, Margaret | Chadwick, David | Nitsch, Dorothea | Jones, Rachael | Sabin, Caroline A. | Post, Frank A. | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Chadwick, David | Delpech, Valerie | Dunn, David | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hay, Phillip | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Orkin, Chloe | Palfreeman, Adrian | Phillips, Andrew | Pillay, Deenan | Post, Frank | Sabin, Caroline | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Hill, Teresa | Huntington, Susie | Josie, Sophie | Phillips, Andrew | Sabin, Caroline | Thornton, Alicia | Dunn, David | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Churchill, D. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Poulton, M. | Taylor, C. | Gleisner, Z. | Campbell, L. | Babiker, Abdel | Dunn, David | Glabay, Adam | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Gompels, M. | Allan, S. | Palfreeman, A. | Moore, A. | Chadwick, D. | Wakeman, K. | Kegg, Stephen | Main, Paul | Mitchell,  | Hunter,  | Sachikonye, Memory | Hay, Phillip | Dhillon, Mandip
The Journal of Infectious Diseases  2014;210(3):363-373.
Background. Tenofovir disoproxil fumarate (TDF) has been linked to renal impairment, but the extent to which this impairment is reversible is unclear. We aimed to investigate the reversibility of renal decline during TDF therapy.
Methods. Cox proportional hazards models assessed factors associated with discontinuing TDF in those with an exposure duration of >6 months. In those who discontinued TDF therapy, linear piecewise regression models estimated glomerular filtration rate (eGFR) slopes before initiation of, during, and after discontinuation of TDF therapy. Factors associated with not achieving eGFR recovery 6 months after discontinuing TDF were assessed using multivariable logistic regression.
Results. We observed declines in the eGFR during TDF exposure (mean slopes, −15.7 mL/minute/1.73 m2/year [95% confidence interval {CI}, −20.5 to −10.9] during the first 3 months and −3.1 mL/minute/1.73 m2/year [95% CI, −4.6 to −1.7] thereafter) and evidence of eGFR increases following discontinuation of TDF therapy (mean slopes, 12.5 mL/minute/1.73 m2/year [95% CI, 8.9–16.1] during the first 3 months and 0.8 mL/minute/1.73 m2/year [95% CI, .1–1.5] thereafter). Following TDF discontinuation, 38.6% of patients with a decline in the eGFR did not experience recovery. A higher eGFR at baseline, a lower eGFR after discontinuation of TDF therapy, and more-prolonged exposure to TDF were associated with an increased risk of incomplete recovery 6 months after discontinuation of TDF therapy.
Conclusions. This study shows that a decline in the eGFR during TDF therapy was not fully reversible in one third of patients and suggests that prolonged TDF exposure at a low eGFR should be avoided.
PMCID: PMC4091582  PMID: 24585896
tenofovir; highly active antiretroviral therapy; eGFR; eGFR slopes; renal function; kidney
2.  Late HIV diagnosis is a major risk factor for intensive care unit admission in HIV-positive patients: a single centre observational cohort study 
HIV positive patients are at risk of infectious and non-infectious complications that may necessitate intensive care unit (ICU) admission. While the characteristics of patients requiring ICU admission have been described previously, these studies did not include information on the denominator population from which these cases arose.
We conducted an observational cohort study of ICU admissions among 2751 HIV positive patients attending King’s College Hospital, South London, UK. Poisson regression models were used to identify factors associated with ICU admission.
The overall incidence rate of ICU admission was 1.0 [95% CI 0.8, 1.2] per 100 person-years of follow up, and particularly high early (during the first 3 months) following HIV diagnosis (12.4 [8.7, 17.3] per 100 person-years compared to 0.37 [0.27, 0.50] per 100 person-years thereafter; incidence rate ratio 33.5 [23.4, 48.1], p < 0.001). In time-updated analyses, AIDS and current CD4 cell counts of less than 200 cells/mm3 were associated with an increased incidence of ICU admission while receipt of combination antiretroviral therapy (cART) was associated with a reduced incidence of ICU admission. Late HIV diagnosis (initial CD4 cell count <350 or AIDS within 3 months of HIV diagnosis) applied to 81% of patients who were first diagnosed HIV positive during the study period and who required ICU admission. Late HIV diagnosis was significantly associated with ICU admission in the first 3 months following HIV diagnosis (adjusted incidence rate ratio 8.72, 95% CI 2.76, 27.5).
Late HIV diagnosis was a major risk factor for early ICU admission in our cohort. Earlier HIV diagnosis allowing cART initiation at CD4 cell counts of 350 cells/mm3 is likely to have a significant impact on the need for ICU care.
PMCID: PMC3553027  PMID: 23331544
ICU; Intensive care; HIV; Antiretroviral therapy; cART; Immunodeficiency; Late
3.  Total protein, albumin and low-molecular-weight protein excretion in HIV-positive patients 
BMC Nephrology  2012;13:85.
Chronic kidney disease is common in HIV positive patients and renal tubular dysfunction has been reported in those receiving combination antiretroviral therapy (cART). Tenofovir (TFV) in particular has been linked to severe renal tubular disease as well as proximal tubular dysfunction. Markedly elevated urinary concentrations of retinal-binding protein (RBP) have been reported in patients with severe renal tubular disease, and low-molecular-weight proteins (LMWP) such as RBP may be useful in clinical practice to assess renal tubular function in patients receiving TFV. We analysed 3 LMWP as well as protein and albumin in the urine of a sample of HIV positive patients.
In a cross-sectional fashion, total protein, albumin, RBP, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were quantified in random urine samples of 317 HIV positive outpatients and expressed as the ratio-to-creatinine (RBPCR, CCR and NGALCR). Exposure to cART was categorised as none, cART without TFV, and cART containing TFV and a non-nucleoside reverse-transcriptase-inhibitor (TFV/NNRTI) or TFV and a protease-inhibitor (TFV/PI).
Proteinuria was present in 10.4 % and microalbuminuria in 16.7 % of patients. Albumin accounted for approximately 10 % of total urinary protein. RBPCR was within the reference range in 95 % of patients while NGALCR was elevated in 67 % of patients. No overall differences in urine protein, albumin, and LMWP levels were observed among patients stratified by cART exposure, although a greater proportion of patients exposed to TFV/PI had RBPCR >38.8 μg/mmol (343 μg/g) (p = 0.003). In multivariate analyses, black ethnicity (OR 0.43, 95 % CI 0.24, 0.77) and eGFR <75 mL/min/1.73 m2 (OR 3.54, 95 % CI 1.61, 7.80) were independently associated with upper quartile (UQ) RBPCR. RBPCR correlated well to CCR (r2 = 0.71), but not to NGALCR, PCR or ACR.
In HIV positive patients, proteinuria was predominantly of tubular origin and microalbuminuria was common. RBPCR in patients without overt renal tubular disease was generally within the reference range, including those receiving TFV. RBP therefore appears a promising biomarker for monitoring renal tubular function in patients receiving TFV and for distinguishing patients with normal tubular function or mild tubular dysfunction from those with severe renal tubular disease or Fanconi syndrome.
PMCID: PMC3444380  PMID: 22883485
Proteinuria; Albuminuria; Retinol-binding protein; RBP; Cystatin C; Neutrophil gelatinase-associated lipocalin; NGAL; Tenofovir; HIV

Results 1-3 (3)