Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection

Figures & data

Figure 1. Study flow diagram.

Table 1. Biomarkers of endothelial activation

Author	Year	Biomarkers	Study design	Patient population and follow-up	Outcomes studied	Finding
Zangerle^43	1994	ICAM-1	Prospective	47 HIV-infected adults followed for mean 12.7 mo (range, 8–16 mo)	CD4 decline	• No association between ICAM-1 levels and CD4 count decline
Greenwood^44	1998	ICAM-1, VCAM-1	Prospective	25 HIV-infected adults with and without CMV retinitis followed for up to 19 mo	CMV retinitis	• No difference in ICAM-1 or VCAM-1 levels between patients with and without retinitis • No difference in ICAM-1 or VCAM-1 levels between active flares and quiescent periods
Renwick^45	2002	VEGF	Prospective	40 HIV-infected men followed in the Amsterdam Cohort Studies (follow-up time not reported)	Kaposi sarcoma	• No change in VEGF levels after HIV-1 or HHV-8 seroconversion • No difference in VEGF concentration in men who did or did not develop KS
Sipsas^31	2003	E-selectin, ICAM-1	Prospective	64 HIV-infected adults followed for median 46 mo (range, 2–78 mo)	Death	• Baseline levels of E-selectin and ICAM-1 higher in those who died • ICAM-1 associated with time to death, but not in multivariate analysis
van Vonderen^27	2009	ICAM-1, VCAM-1	Prospective	37 HIV-infected, ART-naïve men randomized to receive either AZT/3TC/LPV/r or NVP/LPV/r and followed for 24 mo	c-IMT, arterial stiffness	• Levels of VCAM-1 and ICAM-1 decreased in both groups during treatment • c-IMT increased and arterial stiffness decreased, with no difference between arms
Ford^29	2010	ICAM-1, VCAM-1	Nested case-control within prospective NIH cohort	52 HIV-infected adults with a CVD event (cases) and 102 matched controls followed for mean 8.9 and 8.4 y from ART initiation, respectively	CVD event (see text for details)	• Elevated VCAM-1 associated with CVD events, but association not significant in multivariable analysis
Gupta^25	2010	E-selectin, ICAM-1, VCAM-1	Prospective	9 HIV-infected adults not requiring ART, randomized to pentoxifylline or placebo, followed for 8 weeks	FMD, NTGMD	• Pentoxifylline reduced VCAM-1 levels and improved FMD over 8 weeks
Hileman^24	2010	ICAM-1, VCAM-1	Prospective	40 HIV-infected adults with virologic suppression on ART, randomized to salsalate or placebo, followed for 13 weeks	FMD	• Neither ICAM-1 nor VCAM-1 levels correlated with change in FMD • Change in FMD did not differ between arms
Francisci^32	2011	VCAM-1	Prospective, with retrospective case-control component	69 HIV-infected adults initiating ABC- or TDF-containing ART followed for 6–12 mo, 20 HIV-infected untreated controls, and 10 healthy controls	Finger arterial pulse wave amplitude, circulating endothelial cells	• HIV-infected adults had increased circulating endothelial cells and impaired tonometry • Endothelial function was worse in adults taking ABC than those taking TDF • VCAM-1 levels elevated in HIV infection, and decreased to a greater extent among adults treated with TDF
Musselwhite^30	2011	E-selectin, ICAM-1, ICAM-3, P-selectin, VCAM-1	Nested case-control within prospective NIH cohort	23 HIV-infected adults with VTE (cases) and 69 matched HIV-infected controls followed for median 6.9 and 7.2 y from ART initiation, respectively	VTE	• Increased P-selectin levels associated with VTE
Tungsiripat^26	2011	ICAM-1, VCAM-1	Prospective	71 HIV-infected adults with lipoatrophy on thymidine-sparing ART, randomized to rosiglitazone or placebo and followed for 48 weeks	c-IMT	• VCAM-1 levels decreased and c-IMT increased, with no difference between groups • Neither ICAM-1 nor VCAM-1 levels associated with c-IMT

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; AZT, zidovudine; c-IMT, carotid intima-media thickness; CMV, cytomegalovirus; CVD, cardiovascular disease; FMD, flow-mediated dilation; HIV, human immunodeficiency virus; KS, Kaposi sarcoma; LPV/r, boosted lopinavir; NIH, National Institutes of Health; NTGMD, nitroglycerin-mediated dilation; NVP, nevirapine; TDF, tenofovir; VEGF, vascular endothelial growth factor; VTE, venous thromboembolism

Table 2. Biomarkers of coagulation

Author	Year	Biomarkers	Study design	Patient population and follow-up	Primary outcome	Finding
Schved^36	1992	PAI-1, tPA, VWF	Prospective	85 HIV-infected adults, 65 of whom were followed prospectively for a median 22 mo	Death	• Higher PAI-1, tPA, and VWF in advanced disease • Increased VWF and tPA in non-survivors • tPA and CD4 count independently predicted death
Aukrust^34	2000	VWF	Prospective	43 HIV-infected adults followed for a median of 5 y (range, 3.8 to 6 y) and 19 healthy controls	Disease progression (see text for details)	• Marked rise in VWF associated with disease progression • Positive correlation between VWF levels and HIV-1 RNA
Hsue^46	2004	Fibrinogen	Prospective	148 HIV-infected adults followed for 12 mo, and 63 healthy controls	c-IMT, c-IMT progression	• Higher fibrinogen levels and c-IMT in HIV-infected adults • No association between fibrinogen and c-IMT or c-IMT progression
Kuller^10	2008	d-dimer, prothrombin fragment 1+2	Nested case control within the SMART study^47	499 HIV-infected adults randomized to drug conservation or viral suppression strategies followed for 1 mo, with nested case-control comparing 85 adults who died to 170 matched HIV-infected controls (follow-up time not reported)	All-cause mortality	• Higher levels of d-dimer at study entry associated with increased risk of all-cause mortality • d-dimer levels associated with HIV-1 RNA levels, with both higher in the drug conservation group
Rodger^28	2009	d-dimer, prothrombin fragment 1+2	Nested case control within the SMART study^47	91 HIV-infected adults with opportunistic infections (cases) and 182 HIV-infected controls (follow-up time not reported)	Opportunistic infection	• Neither baseline d-dimer nor prothrombin fragment 1+2 predicted opportunistic infections
van Vonderen^27	2009	PAI-1, VWF	Prospective	37 HIV-infected, ART-naïve men randomized to receive either AZT/3TC/LPV/r or NVP/LPV/r and followed for 24 mo	c-IMT, arterial stiffness	• VWF levels decreased in both groups during treatment • c-IMT increased and arterial stiffness decreased, with no difference between arms
Ford^29	2010	d-dimer, tissue factor	Nested case-control within prospective NIH cohort	52 HIV-infected adults with a CVD event (cases) and 102 matched controls followed for mean 8.9 and 8.4 y from ART initiation, respectively	CVD event (see reference for details)	• Elevated d-dimer and tissue factor associated with CVD events • Only d-dimer independently associated with CVD events in multivariable analysis
Hileman^24	2010	d-dimer, fibrinogen	Prospective	40 HIV-infected adults with virologic suppression on ART, randomized to salsalate or placebo, followed for 13 weeks	FMD	• Neither d-dimer nor fibrinogen levels correlated with change in FMD • Change in FMD did not differ between arms
Jong^33	2010	APCsr, d-dimer, endogenous thrombin potential, protein C, prothrombin, PT, PTT, thrombin-antithrombin complex, total and free protein S, VWF	Prospective	123 HIV-infected adults initiating ART followed for a median 7.2 mo (± 1.6 mo) and 71 healthy controls	DVT	• No asymptomatic DVT in 57 HIV-infected adults tested • All biomarkers of coagulation except APCsr improved after ART initiation • Persistent differences with uninfected controls
Musselwhite^30	2011	d-dimer, tissue factor, thrombomodulin, VWF	Nested case-control within NIH cohort	23 HIV-infected adults with VTE (cases) and 69 matched HIV-infected controls followed for median 6.9 and 7.2 y from ART initiation, respectively	VTE	• Increased d-dimer levels were associated with VTE
Tungsiripat^26	2011	VWF	Prospective	71 HIV-infected adults with lipoatrophy on thymidine-sparing regimens, randomized to rosiglitazone or placebo, followed for 48 weeks	c-IMT	• VWF levels decreased and c-IMT increased, with no difference between groups • VWF levels not associated with c-IMT
Justice^35	2012	D-dimer	Nested case control followed in VACS	1302 HIV-infected adults (follow-up time not reported)	Death	• D-dimer correlated with VACS Index, which was more predictive of mortality than any biomarker • Addition of D-dimer to the VACS Index improved classification by 7%

3TC, lamivudine; AIDS, acquired immunodeficiency syndrome; APCsr, activated protein C sensitivity ratio; ART, antiretroviral therapy; AZT, zidovudine; c-IMT, carotid intima-media thickness; DVT, deep venous thrombosis; FMD, flow-mediated dilation; HIV, human immunodeficiency virus; LPV/r, boosted lopinavir; NVP, nevirapine; PAI-1, plasminogen activator-inhibitor 1; PT, prothrombin time; PTT, partial thromboplastin time; tPA, tissue-type plasminogen activator; VACS, Veterans Aging Cohort Study; VTE, venous thromboembolism; von Willebrand Factor, VWF.

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