Table 2 A qualitative summary of the findings on platelet function in antiretroviral-treated individuals in the included studies (n = 30)

Aukrust [45]

1997

AZT+3TC (26%)

–

IDV (26%)

The serum RANTES levels were elevated in HIV-1 infected patients. In addition, the levels of RANTES directly correlated with CD4 counts and inversely correlated with plasma viral load. Notably, the serum RANTES levels were further increased following the initiation of IDV containing ART.

Baker [21]

2012

–

56% of patients NNRTI

29.1% of patients on PIs

The initiation of ART showed no significant reduction in the plasma levels of sCD62P and sCD40L. In addition, the basal sCD40L and sCD62P showed a direct correlation and inversely correlated with platelet counts.

Bordoni [43]

2020

All patients (100%) were on NRTIs

4.6% of patients on NNRTIs

72.1% of patients on PIs

The plasma RANTES levels were elevated in patients living with HIV. Moreover, these levels gradually increased despite the initiation of ART.

Corrales-medina [6]

2010

3TC (68%)

ABC (46%)

TDF (43%)

FTC (14%)

AZT (39%)

d4T (14%)

DDI (3%)

EFV (36%);

NVP (18%)

Lopinavir (18%)

NFV (7%)

IDV (7%)

ATV (7%)

FPV (7%)

There were no differences in the levels of CD62P expression in HIV-infected patients on treatment compared to uninfected controls. However, the levels of platelet-derived microparticles were elevated in HIV-infected patients on antiretroviral treatment when compared to uninfected controls. Moreover, the levels of platelet-derived microparticles and activated platelets were similar between patients living with HIV on PI-based therapy or ABC compared to those who were not on PIs or ABC.

Damien [7]

2013

None

46% of patients on NNRTIs

54% of patients on PIs (PI regime not reported)

The levels of platelet activation were elevated in HIV-infected patients compared to uninfected controls. Notably, the plasma levels of sCD62P in HIV-infected patients on antiretroviral treatment were 2-fold higher compared to treatment-naïve patients and 3-fold higher, compared to uninfected controls.

Davidson [46]

2013

ABC + 3TC (34%)

EFV (37%)

LPV/r (29%)

NNRTI administration was associated with elevated plasma sCD40L. EFV induces the release of sCD40L and also activates the glycogen synthase kinase 3 beta (GSK3β) in platelets.

De Luca [26]

2000

65% of patients on NRTIs

–

–

The baseline RANTES levels were compared between treatment-naïve HIV-infected patients, ART-treated and uninfected controls. Notably RANTES were produced at a higher level in the late-stage HIV infected followed by asymptomatic HIV-infected individuals. In addition, plasma RANTES levels were significantly reduced following treatment.

Donhauser [27]

2012

NR

NR

NR

The levels of sCD40L were elevated in HIV-infected patients when compared to uninfected controls. Notably, these levels were attenuated by successful antiretroviral therapy and were significantly lower when compared to treatment-naïve HIV-infected patients. However, the levels of sCD40L were not normalised following HAART.

Francisci [8]

2009

None

EFV (86%)

NVP (14%)

LPV/r (93%)

NFV (7%)

The levels of platelet activation were elevated in HIV-infected patients compared to uninfected controls. Notably, only the levels of sCD62P were elevated in patients infected with HIV. While the levels of sCD40L were similar between the HIV and control group. Interestingly, the levels of sCD62P remained persistently elevated post 24 months of antiretroviral therapy.

Guzmán-Fulgencio [28]

2011

95.9% of patients on NRTIs

78.5% of patients on NNRTIs

76.7% of patients on PIs

Patients living with HIV had significantly higher levels of sCD40L and sCD62P despite successful HAART. Notably, these showed no significant associations with the risk of cardiovascular events.

Kalayjian [24]

2010

d4T

DDI

3TC

EFV

NFV

LPV/r

The levels of sCD40L remained unchanged following HAART. In addition, higher baseline sCD40L were associated with the incidence of de novo AIDS-defining illness or mortality despite the initiation of HAART.

Kiebala [9]

2015

NR

NR

NR

The levels of sCD62P were elevated in HIV-infected patients compared to uninfected controls. These elevated levels persisted even during antiretroviral treatment. In, addition platelet activation is not dependent on IKKB signalling

Li [30]

2013

NR

NR

NR

A two-fold increase in sCD40L was reported in treatment-naïve HIV-infected elite controllers when compared to ART-treated or uninfected controls. While the levels of RANTES were lower in elite controllers when compared to treatment-naïve and uninfected controls. In addition, the levels of sCD40L and RANTES showed no correlation with the levels of HIV RNA levels.

Jenabian [23]

2014

NR

NR

NR

The levels of sCD40L were elevated chronically infected treatment-naïve HIV-infected patients compared to healthy controls. However, these were normalised following successful ART.

Kasang [25]

2012

NR

NR

NR

The levels of sCD40L were lower in HIV-infected patients on HAART compared to treatment naïve patients.

LandrØ [12]

2011

NR

NR

NR

Increased levels of sCD62P, sCD40L, RANTES and NAP-2 in HIV-infected patients compared to uninfected controls. These levels were persistently elevated post 24 months of antiretroviral therapy. In addition, the levels of NAP-2 were markedly significantly increased after the initiation of antiretroviral therapy.

De Larrañaga [29]

2006

NR

NR

70%

The levels of sCD62P were elevated in HIV patients on HAART

Mesquita [31]

2018

60%

40%

30%

Increased levels of platelet activation, mitochondrial dysfunction and apoptosis in virologically suppressed HIV-infected individuals. Moreover, HIV-infected patients had elevated levels of platelet exhaustion.

O’Brien [32]

2013

RAL (16%)

ABC (20%)

36% of patients were on NNRTIs

52% of patients were on PIs

The levels of sCD62P were comparable between HIV-infected patients and uninfected controls. Notably, the levels of urinary 11-dehydro-(TX) B2 were elevated in HIV-infected patients compared to uninfected controls. HIV-infected patients who were on antiretroviral therapy and were virally suppressed had elevated levels of activated platelets that were also hyper-reactive. In HIV-infected patients, platelets have a lower activation threshold and display dose-dependent hyper-reactivity. Moreover, Cyclo- oxygenase-1 reactivity remained higher in HIV-infected individuals compared to uninfected controls. Aspirin failed to inhibit arachidonic acid and thromboxane A2 mediated platelet activation.

O’Halloran [11]

2015

TDF/FTC

68% of patients were on NNRTIs

None

The levels of sCD62P, sCD40L and sGPVI were elevated in HIV-infected treatment-naïve patients compared to uninfected controls. All markers of platelet activation remained elevated following 3 months of antiretroviral therapy. However, these normalised post 12 months of antiretroviral therapy.

Pastori [33]

2015

3TC/AZT or FTC/TDF

64% of patients were on NNRTIs

36% of patients were on PIs

The levels of sCD40L and platelet oxidative stress were increased in HIV-infected patients compared to uninfected controls.

Quiros-Roldan [34]

2020

RAL (25%)

The levels of RANTES remained unchanged despite successful ART. Notably, the INSTIs (RAL, EVG and DTG) were associated with a 18–21% increase in RANTES whereas treatment with PI was associated with 32% decrease in serum RANTES levels although these were not statistically significant.

Rӧnsholt [35]

2013

NR

NR

NR

The levels of sCD62P were comparable between HIV-infected patients on antiretroviral therapy and uninfected controls.

Satchell [36]

2010

ABC (38%)

TDF (44%)

AZT (19%)

50% of patients were on NNRTIs

None

HIV-infected patients on treatment had decreased reactivity to TRAP, ADP and collagen. In treated HIV-infected patients, a decreased platelet response to TRAP was associated with a lower BMI, total LDL cholesterol and elevated CD8 count. While decreased platelet reactivity to ADP was associated with lower levels of hsCRP. Moreover, an increased platelet response to epinephrine in HIV-infected patients was associated with a lower CD4 count and increased CD8 count. Whereas a history of CVDs was associated with decreased response to epinephrine.

Singh [37]

2014

NR

NR

NR

The levels of platelet monocyte aggregates are elevated in patients with HIV and these persist despite successful ART

Sipsas [38]

2002

NR

NR

NR

The levels of sCD40L were two-fold higher in HIV-infected patients compared uninfected controls. In addition, these were threefold higher following 8–12 months of HAART.

Tunguputri [39]

2014

RAL (31.25%)

ABC (6%)

EFV; RPV or NVP

ABC 9%

RTV-boosted PI

(DRV, ATV or LPV)

ABC (3%)

Increased levels of platelet monocyte aggregates in HIV-infected patients persist despite effective ART. Notably, RAL-based regimen lowered platelet hyperactivity and platelet monocyte aggregates. While ABC-treated patients showed a trend of higher platelet reactivity.

Wolf [41]

2012

2.5% of patients were on NRTIs

NVP (10%)

EFV (10%)

RTV (5%)

IDV (5%)

SQV (37.5%)

The levels of platelet activation were higher in HIV-infected patients when compared to controls. The levels of sCD62P and sCD40L did not decrease during antiretroviral therapy.

Von Hentig [40]

2008

–

–

SQV/LPV/r (22%)

SQV/RTV (61%)

FPV (11%)

FPV/LPV/r (6%)

Short-term 4-week ART treatment with PIs enhanced the levels of CD40L and CD41 activity on platelets. Whereas CD62P levels were comparable after ART.

Wooten [22]

2013

NR

NR

NR

The plasma levels of RANTES were significantly elevated in patients with HIV on stable HAART for a duration of 6 months.