Table 2 Switch studies reporting the influence of therapy modification on biomarkers of cardiovascular disease

STRATEGY-

NNRTI

Randomized, open label switch study looking at the non inferiority of switching patients who were virologically suppressed on an NNRTI based regimen to co-formulated elvitegravir

439 patients. 266 out of 291 participants randomized to the switch group completed the study. 119 out of 143 participants assigned to the no-switch group completed the study

Fasting serum cholesterol; fasting serum HDL-C; fasting serum LDL-C; fasting serum triglyceride; CD4 cell count; HIV RNA;

48

At week 48 93% of participants in the switch group and 88% in the no-switch group maintained plasma viral load <50 copies/ml. No emergent resistances were observed among the two groups. Starting at week 4 increases of serum creatinine were observed among the switch group; increase was stable and non progressive through week 48. A small decrease in HDL-C was observed in the switch group.

[32]

STRATEGY PI

Multicenter randomised open-label trial investigating the non inferiority of switching to co-formuated elvitegravir in patients virologically suppressed on a PI based regimen

433 patients. 293 were included in the group switching to co-formulated elvitegravir and 140 remained on their existing regimen

Fasting serum COL; fasting serum HDL-C; fasting serum LDL-C; fasting serum TG; CD4 cell count; HIV RNA;

48

At week 48 3.8% of patients enrolled in the switch arm abd 87.1% of participants in the no-switch arm maintained a plasma HIV RNA <50 copies/ml. Starting at week 4 a stable non progressive increase in serum creatinine occurred among switch arm participants. A decrease in serum triglycerides was observed in the switch group.

[32]

SPIRAL Substudy

Changes in cardiovascular biomarkers in HIV-infectedpatients switching from ritonavir-boosted proteaseinhibitors to raltegravir

Of 273 patients initiating study drugs in the SPIRAL trial, 233 (119 RAL, 114 PI/r) remained on allocated therapy for 48 weeks and had sera available for the purpose of this substudy

hsCRP MCP-1 OPG IL-6 IL-10 TNF-a ICAM-1 VCAM-1 Selectin E Selectin P Adiponectin Insulin D-dimer

48

hsCRP (40%, P < 0.0001), MCP-1 (20%, P¼0.0003), osteoprotegerin (13%, P¼0.0024), IL-6 (46%,P < 0.0001), TNF-a (27%, P¼0.0011), insulin (26%, P < 0.0001), and D-dimer (8%, P¼0.0187) decreased in RAL relative to PI/r group, whereas IL-10 (þ1%, P¼0.7773), ICAM-1 (6%, P¼0.1255), VCAM-1(0%, P¼0.8671), E-selectin (9%, P¼0.2174), P-selectin (6%, P¼0.3865), and adiponectin (þ8%, P¼0.2028) remained unchanged

[34]

SPIRAL Substudy LDL

LDL subclasses and lipoprotein-phospholipase A2 activity in suppressed HIV-infected patients switching to raltegravir

81 (41 PI/r and 40 raltegravir) patients were evaluated

Total cholesterol, LDL-c, HDL-c,Triglycerides, TC/HDL-c,Non-HDL-c, Apo A-I, Apo B, ApoA-I/Apo B Lipoprotein PCSK9,LDL size, Cholesterol content in sdLDLLDL phenotype A, LDL phenotype intermediate, LDL phenotype B, Lp-PLA2 Total LDL-Lp-PLA2 Total HDL-Lp-PLA2 8 (4; 14.9) 8.7 (5.4; 17.2) 0.829Insulin, C-Peptide, HOMA index

48

TC, LDL-c, non-HDL-c, TC/HDL, triglyceride, Apo B, Apo A-I and Lp (a) decreased in raltegravir arm compared to PI/r arm. A shift from LDL phenotype B to the less atherogenic phenotype A was observed only in raltegravir arm.

[31]

SPIRAL-LIP substudy

To compare 48-week changes in body fat distribution and bone mineral density (BMD) - using Dual-energy X-ray absorptiometry and computed tomography scans - between patients switching from a ritonavir-boosted protease inhibitor (PI/r) to raltegravir (RAL) and patients continuing with PI/r.

86 patients were included and 74 patients (39 RAL, 35 PI/r) completed the substudy.

CT-scan:TAT (cm2) SAT (cm2) SAT (%) VAT (cm2) VAT (%)SAT/VATSAT, subcutaneous adipose tissue; TAT, total adipose tissue; VAT, visceral adipose tissue

48

Significant increases in median VAT and TAT were seen within the PI/r group.No significant changes in body fat were seen with RAL or between treatment groups.

[34]

ANRS 138 Substudy

To compare the effect of randomly switching virologically suppressed, treatment-experienced patient from enfuvirtide to raltegravir on biomarker levels

164 participants in the ANRS138 trial

IL-6 hsCRP Level D-dimer

24, 48

At week 24, a significant decrease from baseline was observed in the IS arm, compared with the DS arm, for IL-6 level (−30% vs +10%; P < .002), hsCRP level (−46% vs +15%; P < .0001), and D-dimer level (−40% vs +6%; P < .0001). At week 48, there was a reproducible decrease in levels of all biomarkers in the DS arm

[132]

na

We retrospectively identified from our electronic database all patients with HIV RNA < 50 copies/ml for >6 months on an NVP-containing regimen and no prior exposure to integrase strand transfer inhibitors who were switched to RAL plus NVP.

39 patients

Total cholesterol, HDL-cholesterol,LDL-cholesterol,Total cholesterol/HDL ratio,triglycerides

24, 48, 72

Median changes in serum lipids showed significant improvement at M6 for all paremeters except low-density lipoprotein-cholesterol in the whole population but lipid improvement was greater in the PI/r group

[133]

na

multi-centric retrospective study was conducted including HIV-1-positive patients on raltegravir/nevirapinedual regimens

77 patients switching from successful regimens

routine biochemical tests

48,96

In patients switching with lipid abnormalities [n = 52; 19 (36.5%) on statins, 3 on fibrates (5.7%), 4 on omega-3 fatty acids (7.7%)] triglycerides showed a significant decrease both at 48 and 96 weeks (−83 mg/dL with p = 0.004 and −51 mg/dL with p = 0.011, respectively), while total and LDL-cl were unchanged (p = 0.11 and p = 0.12, respectively).

[134]

STRIIVING

randomized open label,non inferiority trial

551 patients on aintegrase inhibitors pr protease inhibitor or nonucleoside reverse trascriptase inhibitor regimens with HIV-RNA < 50 copie/mL were included

TC, HDL-C, LDL C, TG,TC/ratio; hs-PCR,sCD1s,sCD163, IL-6, D-dimer, sVCAM, I-FABP

24

Significant declines of the levels of I-FABP and sCD14 was observed at 24 weeks

[135]