eFigure 1: Process of identification and selection of ... · eFigure 1: Process of identification and selection of studies for inclusion in the review . 2 eFigure 2: Publication bias

1

eFigure 1: Process of identification and selection of studies for inclusion in the review

2

eFigure 2: Publication bias in studies reporting incidence rate of diabetes mellitus in ART-experienced global HIV infected people

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eFigure 3: Publication bias in studies reporting cumulative incidence of diabetes mellitus in ART-experienced global HIV infected people

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eFigure 4: Publication bias in studies reporting incidence rate of prediabetes conditions in ART-experienced global HIV infected people

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eFigure 5: Publication bias in studies reporting cumulative incidence of prediabetes conditions in ART-experienced global HIV infected people

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eTable 1: Summary of study findings

Study ID Country Study period Selection criteria Study endpoint(s) Diagnostic criteria Duration of

FU

Age (years) Male

sex (%)

ART regimen Sample size; Total PYFU Cases Incidence rate, for

1000 PYFU (95%CI)

Cumulative

incidence, %

(95%CI)

NOS

score

Araujo et al, 2014 Spain December

2010/December

2011-

December 2013

HIV infected patients

aged 18+ years and

receiving ART

Rates and causes of

insulin resistance

and risk od DM

DM: fasting SG ≥126

mg/dl or reported use of

anti-diabetic medication

Median (after

insulinemia

determination)

35.2 (IQR

19.7-40.9)

months

Mean (IQR)

43.9 (39-49)

75 NNRTI, PI, or other

Cumulative time on

ART mean (IQR)

120.5 (48.6–188)

months

265; 770.8 PYFU DM: 22 DM: 2.9 (1.9-4.3) DM: 8.3 (5.5-12.2) 8

Bala et al, 2016 India January 2010-

January 2011

ART-naïve HIV positive

patients older than 12

years

Metabolic

complications after

initiation of ART

IFG:>100 and <126

g/dl;

DM:≥126 g/dl

1 year NM NM d4T-3TC-EFV; d4T-

3TC-NVP; AZT-3TC-

EFV; AZT-3TC-NVP

101 DM: 4

PDC: 18

DM: 4.0 (1.6-9.7)

PDC: 17.8 (11.6-

26.4)

6

Bastard et al, 2009

French Starting in

1997

HIV patient started on PIs

at inclusion

Incidence and risk

factors for new-onset

DM

DM: fasting SG≥126

mg/dl or 2-h OGTT SG

≥ 200mg/dl on two

occasions or

glycaemia gradually

increasing over these

values and/or

antidiabetic

treatment

9 years FU NM NM PI therapy 643; 4,449 PYFU 7

7

Bognounou et al,

2011

Burkina-

Faso

October 2005-

March 2009

HIV patients aged >18

years and taking ART

Incidence of

metabolic disorders

and cardiovascular

risk factors

DM: repeated

measurements of fasting

SG levels > 125 mg/dl

Mean 42

months

Mean 37 23 NNRTI, NRTI, PI;

cumulative duration of

exposure NM

100 DM: 4 DM: 4.0 (1.6-9.8) 5

Boulassel et al, 2006

Canada January 1996 -

May 2004

HIV-1 seropositive

patients initiating

HAART

Incidence of

metabolic

abnormalities after

initiation of HAART

HG: two or more SG

values ≥140 mg/dl or a

single random SG value

≥ 200 mg/dl

Median 3.7

years

Mean

Men 40 (SD

8.2; range

14–71)

Women 35

(SD 9.8 ;

range 16–

73)

75

PI, NNRTI, NRTI 988; 3,944 PYFU DM: 125 DM: 3.2 (2.7-3.8) DM: 12.7 (10.7-

14.9)

9

Brambilla et al,

2003

Italy NM

HIV-infected patients

followed-up for at least 3

months, with a stable

(without interruption)

antiretroviral

regimen (or no therapy)

for at least one month

before entry and

throughout the FU period

Incidence of DM DM: fasting SG > 126

mg/dl on two different

occasions

Median

(range) 289

(91-624) days

Median

(range) 37

(18-74)

68 AZT, ddI, 3TC, d4T,

NVP, SQR, RTV, IDV,

NFV ; duration of ART

median (range :

diabetics 371 (30-

1315) ; non-diabetics

603 (30-3655) days

1,011; 768 PYFU DM: 16 DM: 2.1 (1.3-4.3) DM: 1.6 (1.0-2.6) 6

Brown et al, 2005 USA April 1, 1999-

March 31, 2003

HIV-infected men who at

the baseline visit had a

fasting SG of 98 mg/dl or

less, no self-reported

Prevalence and

incidence of DM

DM: fasting SG ≥ 126

mg/dl, self-reported

diagnosis of

DM, or self-reported

Median (IQR)

2.3 (1.1-3.0)

Median

(IQR) 46

(42-51)

100 PI, NNRTI; duration of

HAART median

(IQR): 3.26 (2.63-3.81)

years

411; 505.8 PYFU DM: 24

PDC: 69

DM: 4.7 (3.2-7.0) DM: 5.8 (4.0-8.5)

PDC: 16.8 (13.5-

20.7)

9

8

history of DM, and no

self-reported

use of antidiabetic

medication

use of antidiabetic

medication

HG: fasting SG 100-125

mg/dl

Butt et al, 2004 USA 1992-2001 HIV positive veterans Incidence of DM DM: presence of ≥1

inpatient or ≥2

outpatient International

Classification of

Diseases-9 codes for

DM

NM Median: 44 100 HAART; duration NM 26988 DM: 9.5 (9.2-9.9) 6

Capeau et al, 2012 France 1997/1999-

2009

HIV infected patients

initiating PI containing

combined ART

Incidence and

determinants of

diabetes

DM: confirmed fasting

SG

at least 1.26 mg/dl or 2-

h OGTT glycaemia at

least

200 mg/dl, and/or if

initiation with

antidiabetic drugs

during FU

Median (IQR)

9.6 (5.1-10.7)

years

Median 37 78.5 IDV, d4T, ddL; no

NNRTI; duration NM

1,046; 7,846 PYFU DM: 111 DM: 1.4 (1.2-2.7) DM: 10.6 (8.9-

12.6)

8

Capiluppi et al,

2000

Italy NM Patients with primary

HIV-1 infection

Incidence of

metabolic disorders

NM Mean (range):

26 (15-36)

months

Mean 35 85 PI+NNRTI; mean

(range) 26 (15-36)

months of exposure to

PI therapy

37 DM: 0

PDC: 0

DM: 0 (0.0-9.4)

PDC: 0 (0.0-9.4)

5

9

De Wit et al, 2008 Europe,

USA,

Argentina

and

Australia

December

1999-January

2005

11 cohorts of HIV-

infected patient followed

in 212 clinics

Incidence of DM

and associated

factors

DM: either definite

diagnosis if fasting SG

> 7.0 mmol/l (126

mg/dl) on two

consecutive occasions

or possible diagnosis in

the

case of a physician-

reported date of

diabetes onset and

initiation of antidiabetic

therapy

NM Medain IQR

38 (33–44)

73.8

PI and/or NNRTI;

27.1% were ART naïve

at entry

32,437; 130,151 PYFU

DM: 744 DM: 0.6 (0.5-0.6) DM: 2.3 (2.1-2.5) 9

Dever et al, 2000 USA Sept 1996-Aug

1997

HIV-infected adult veterans Incidence of

hyperglycemia and

DM

Random glycemia ≥ 200

mg/dl on more than one

occasion and associated

symptoms of

hyperglycemia

12 months NM NM PI: IND, RTV, SQV 117 7 DM: 6.0 (2.9-11.8) 5

Dooko et al, 2014 USA NM HIV-infected adults with

CD4 count ≥ 300/mm3

initiating ART

Incidence of DM

and association with

inflammatory

markers

DM: the patient has

received a diagnosis of

diabetes requiring drug

treatment during FU

Mean 4.6

years

Mean (SD):

42.7 (9.4)

77.1 HAART 3,965; 16,748 PYFU DM: 137 DM: 0.8 (0.7-1.0) DM: 3.5 (2.9-4.1) 8

Galli et al, 2002 Italy NM HIV-1 infected patients

treated for at least 3

months with a

combination of 2 NRTIs

and naive of PIs

Risk of developing

body habitus

changes and

metabolic

abnormalities

HG: SG levels ≥ 110

mg/dl

Median

(range) 472

(105-503)

days

Median

(range) 34

(20-71)

54.3 D4T, 3TC, AZT; 245

patients ART naïve at

inclusion; duration

median (range) 747.5

(91-1400) days

335 PDC: 48 PDC: 14.3 (11.0-

18.5)

6

10

García-Benayas et

al, 2006

Spain September

2002-June

2003

HIV subjects who had

completed

12 months of an

unmodified ART regimen

based on

ddI, TDF, or ddI+TDF,

and had available glucose

levels during

the entire FU

Incidence of HG DM: repeated

measurements of fasting


HG: fasting SG levels >

110 mg/dl

Mean 12

months

NM 80.8 ddI and/or TDF; ART

duration: 27 ± 13

months

177 DM: 12

PDC: 34

DM: 6.8 (3.9-11.5)

PDC: 19.2 (14.1-

25.6)

7

Gomes et al, 2016 Dominican

Republic

September 1,

2007-May 31,

2013

Participants ≥18 years,

initiating ART <90 days prior

to study enrollment

Incidence of IFG, DM,

overweight and

obesity

IFG: FPG 100-125 mg/dl;

DM: FPG ≥ 126 mg/dl or


Median 34.8

months

median age

of 39 (33-

45)

43% NRTIs (d4T, 3TC, FTC,

AZT, TDF, or ABC) +1 PI

(LPV/RTV) or 1 NNRTI

(NVP or

EFV)

DM: 113

IFG: 91

DM:6

PDC: 46

DM: 5.3 (2.5-11.1)

PDC: 50.5 (40.5-

60.6)

8

Gutpa et al, 2011 India Nov 2007-Oct

2009

HIV-infected adults ≥ 18

years taking ART

Morphological and

metabolic

complications

associated with

combined ART

IFG: FPG 100-125 mg/dl

DM: FPG ≥ 126 mg/dl

Six months Mean age:

35.9 years

57 (84%) AZT /d4T + 3TC +

NVP/EFV

68 DM: 3

PDC: 6

DM: 4.4 (1.5-12.2)

PDC: 8.8 (4.1-17.9

5

Herrin et al, 2016 USA 01/01/2000-

30/09/2011

ART naïve, HIV-1 RNA

>500 copies/ mL in the

180 days prior to ART

Association between

weight gain and

incident DM after

initiation of ART

DM: HbA1c ≥6.5 % Median 4.9

(IQR 2.6-5.0)

years

Median 50

(43-56)

years

96.8 NNRTI, PI, triple

nucleoside

7,177; 17,780 PYFU DM: 357 DM: 2.0 (1.8-2.2) DM: 5.0 (4.5-5.5) 9

11

initiation

Isa et al, 2016 Nigeria 1 January

2011-31

December 2013

ART naïve HIV infected

patients

Incidence of T2DM

after initiation of

ART

DM : random plasma

glucose level of

≥11.1 mmol/L, fasting

plasma glucose of ≥7.0

mmol/L, or

self-reported use of

hypoglycemic agents

12 months 37.4 ± 9.7

years

35.1 3TC + AZT + NVP ;

3TC

/FTC + TDF + EFV ;

ATV/RTV

; LPV/RTV

2,452 DM: 130 DM: 5.3 (4.5-6.3) 8

Justman et al, 2003

USA 1994-1998

Non-pregnant HIV-

infected women

Association between

PI use and incidence

of DM

DM: based on reported

occurrence since the last

study visit of DM

specifically or any new

illness or by review

(every 6 months) of the

complete list of

medications

Median 2.91

years

Median 37

0 PI; NNRTI; NRTI;

probably started at

inclusion

1,541; 2,193 PYFU DM: 38 DM: 1.7 (1.3-2.4) DM: 2.5 (1.8-3.4) 8

Karamchand et al,

2016

South

Africa

January 2002-

December 2011


years, starting NNRTI-

based ART

Association between

efavirenz exposure

and incident DM

DM: initiation of

antidiabetic medication

Median 1.56

(IQR 0.71–

2.79) years

Median

38.14 (IQR

33.15-

44.26) years

35.92 NNRTI (EFV

containing ART; NVP

containing ART)

56,298; 113,297 PYFU DM:

1,500

DM: 1.3 (1.3-1.4) DM: 2.7 (2.5-2.8) 8

Ledergerber et al,

2007

Switzerland March 1st

2000-17 July

2006

HIV-1 infected

individuals aged ≥16

years with at least 2 study

New onset of DM DM: confirmed

plasma glucose level

cut-off values of 7.0

mmol/l (fasting)

Median 4.3

years

median

(IQR) 38

(34–44)

68.8 PI, NNRTI, NRTI;

27.2 % ART naïve at

inclusion; cumulative

6,513; 27,798 PYFU DM: 123 DM: 0.4 (0.4-0.5) DM: 1.9 (1.6-2.2) 9

12

visits and at least 1 year

of follow-up after 1

March 2000

and 11.1 mmol/l

(nonfasting)

duration of exposure

NM

Lichtenstein et al,

2015

USA 2002-2011 HIV infected adults with at

least two visits

Incidence of DM and

association with statin

use

At least one FPG>125

mg/dl or 2h-PG >200

mg/dl or anti-diabetic

medication for at least 30

continuous days

Median of 4.6

years

(interquartile

range: 1.8–9.0)

NM 3661

(78%)

NM 4692 355 DM: 7.6 (6.8-8.4) 8

Lo et al, 2009 Taiwan January 1993-

December 2007

HIV-infected patients

receiving combination

antiretroviral therapy who

made at least

two visits to the study site

and had FU for 1 year or

more after January 1993

Incidence and risk

factors for DM

DM: at least two

separate fasting SG

levels

above 126 mg/dl during

FU

Mean 4.6

years

Median

(IQR) 34

(28-40)

92.1

NRTI, NNRTI, PI;

duration of cumulative

ART NM

824; 3,829 PYFU DM: 50 DM: 1.3 (1.0-1.7) DM: 6.1 (4.6-7.9) 6

Magula et al, 2014 South

Africa

NM HIV adult subjects of

second-generation Zulu

descent

Eligible for ART

Prevalence,

incidence and

predictors of

dysglycemia

WHO definition for

DM, IGT and IFG using

OGTT and HbA1c

24 months NM NM ART duration 24

months

150; 219 PYFU DM: 53

PDC: 23

DM: 5.9 (3.5-9.9)

PDC: 10.0 (7.1-15.3)

DM: 8.7 (5.1-14.3)

PDC: 15.3 (10.4-

22.0)

8

Mehta et al, 2003 USA January 1996-

May 2002

Patients on their first

HAART regimen with at

least one random glucose

before and during ART

Prevalence and

incidence of HG

among HIV-infected

DM: either 2 random


or documentation of

Median (IQR)

8.9 (3.9-20.7)

months

Median

(IQR)

69.9 PI; NNRTI; PI+NNRTI 1,149; 1,808 PYFU DM: 47 DM: 2.6 (2.0-3.4) DM: 4.1 (3.1-5.4) 9

13

patients by HCV and

type of HAART

DM in the medical

record

HCV-: 35

(29-40)

HCV+: 39

(34-43)

Narciso et al, 2001

Italy May 1997-

April 2001

Patients diagnosed with

primary HIV infection

Morphologic and

metabolic disorders

in patients treated

with HAART since

primary

HIV infection

HG: at least one fasting

SG value >110 mg/dl

during FU

Median

(range) 19.0

(3-47) months

Median

(range) 31

(18-54)

85.4

IND-AZT-3TC; NEL-

AZT-3TC; IND-d4T-

3TC; EFV-AZT-3TC;

NVP-AZT-3TC

41 PDC: 0 0 (0.0-8.6) 6

Ndona et al, 2012 D R Congo 2004-2008 HIV infected patients Incidence and

predictors of type 2

diabetes

DM: fasting SG levels ≥

126 mg/dl measured on

two consecutive

occasion and/or 2H-

glucose post load

plasma glucose ≥ 200

mg/dl

NM Mean

43±9.2

42.9 Combination of d4T +

3TC, AZT + 3TC +

NVP, or EFV; Mean

duration on ART 25 ±

15 months

49 DM: 4 DM: 8.2 (3.2-19.2) 7

Palacios et al, 2003 Spain From January

1997 to

December 2001

HIV infected patient on

HAART

Risk factors for new

onset DM

DM was defined

according to

international criteria

(1998), they did not

specify

5 years Mean: 48.6

(33-67)

Not

reported

Not clearly reported.

But PI use reported

745 DM: 34

PDC: 71

DM: 4.6 (3.3-6.3)

PDC: 9.5 (7.6-

11.9)

8

14

Pinto Neto et al,

2013

Brazil January 2008-

May 2011

HIV-1 infected adults

(18+ years)visiting an

AIDS outpatient clinic

Cumulative

incidence of

dyslipidemia and

fasting glucose

impairment

IFG: fasting SG levels >

99mg/dl; DM: fasting


36 months Median 45

(IQR 37-52)

58.9 NRTI, NNRTI, PI;

duration 36 months

454 DM : 454

PDC :

141

DM : 3.7 (2.4-5.9)

PDC : 31.1 (27.0-

35.5)

8

Putcharoen et al, 2017 Thailand July 1, 1996-

April 30, 2015

HIV-infected adults > 18

years with at least 2 study

visits and a minimum of 1

year of FU on ART and

without DM

Incidence and factors

associated with

developing DM

Two consecutive FPG

>126 mg/dl or reporting


Median FU 9

(IQR 3.9-14.7)

Median age

at ART

initiation

32.2 (IQR

27.4-37.8)

years

1051

(60.1%)

NNRTI, PI 1,748; 16,274 PYFU DM: 123 DM: 7.6 (6.3-9.0) DM: 7.0 (5.9-8.3) 8

Rasmussen et al, 2012 Denmark 1 January 1996

to 1 January

2010

HIV-infected Danish-borned

individuals aged ≥ 16 years

Risk of DM in HIV-

infected individuals

compared

to that of the general

population

Medical report of anti-

diabetic medication

Median 8.0

(3.4–14.0)

Median 38.7

(32.2–46.6)

2,977

(84.1%)

NM 3,540; 28,342 PYFU 90 DM: 3.2 (2.6-3.9) DM: 2.5 (2.1-3.1) 9

Riyatenet al, 2015 Thailand January 2000-

December 2011

HIV-1 infected patients

aged ≥ 18 years and ART

naive

New-onset DM and

associated factors

DM: confirmed fasting

SG levels ≥ 126mg/dl or

random SG ≥ 200mg/dl

Median

(IQR): 6.9

(4.9-8.2) years

Median

(IQR) 32.5

(28.2-37.7)

24 PI, NNRTI, NRTI 1,594; 10,507 PYFU DM: 53 DM: 0.5 (0.4-0.7) DM: 3.3 (2.6-4.3) 8

Salehian et al, 2005 USA August 1999-

September

2002

HIV positive patients Prevalence and

incidence of DM

DM: fasting SG >126

mg/dl and/or any

random SG >200 mg/dl

at two different times

NM mean

36±2,5

years in non

PI users (18)

and 40±1

70 PI NNRTI

NRTI; ART

commenced before

inclusion mean (SD):

non PI users 2.25 (0.7);

101 DM: 4

PDC: 10

DM: 4.0 (1.6-9.7)

PDC: 9.9 (5.5-

17.3)

8

15

and/or use of any

antidiabetic medications

year among

PI users (83)

PI users 4.08 (0.37)

years

Spagnuo et al, 2017 Italy Jan 1991-Nov

2014

HIV-1 infected adults

starting ART; no DM and no

statins at inclusion

Evaluate the

associations of statin

use and exposure to

antiretroviral drugs

with the onset of type

2 DM

2 consecutive FPG ≥ 126

mg/dl or 2h-PG ≥ 200

mg/dl (after OGTT) or 2

fasting HbA1c ≥ 48

mmol/mol or anti-

diabetic prescription

9.8 years

(interquartile

range: 4.3–16.3

years)

median

duration of ART

was

10 years (IQR:

4–16 years)..

Median 47.2

years (IQR:

40.6–52.7

years)

4,828

(78%)

NRTIs (97%); PIs (79%);

NNRTI (61%); integrase

strand transfer inhibitors

(12%) and entry

inhibitors (9%)

235; 64149 PYFU 235 DM: 3.7 (3.2-4.2) DM: 3.8 (3.3-4.3) 8

Squillace et al, 2016 Italy 01/01/1997-

2013

HIV-positive naïve

patient

Incidence of DM

arising during

combination ART

DM: two consecutive

blood glucose values

of.126 mg/dL

(7 mmol/L), clinical

diagnosis of DM or start

of antidiabetic treatment

NM Median 38

(IQR 33-45)

years

73.7 NRTI, NNRTI, PI 3,546; 13,911 PYFU DM: 80 DM: 0.6 (0.5-0.7) DM: 2.3 (1.8-2.8) 8

Tien et al, 2007 USA October 2000-

March 2006

Incidence of DM HIV infected women

with no evidence of

DM at

enrollment

DM: either fasting SG

≥1.26 g/l, reporting

antidiabetic medication,

or reporting DM

diagnosis (with

subsequent

confirmation by fasting

NM median

(IQR) 39.2

(33.4-45.2)

0 PI, NRTI, NNRTI;

duration of ART NM

1,283; 3,326 PYFU DM: 91 DM: 2.7 (2.2-2.3) DM: 7.1 (5.8-8.6) 9

16

SG ≥1.26 g/l or reported

antidiabetic medication)

Tripathi et al, 2014 USA 1st January

1994-31st

December 2011

HIV infected adults 18+

years on combined ART

for at least 30 days

Incidence of DM DM: at least 2visit

claims with

International

Classification of

Diseases-9 codes for

Type 1 or Type 2

diabetes mellitus and/or

prescription of anti-

diabetic

medications including

insulin for at least 30

days

Median 70

months (IQR

23-105)

Median 39

(IQR 31-46)

56.8 PI or NNRTI or or

NRTIPI+NNRTI;

duration NM

5,478; 37,181 PYFU DM: 422 DM: 1.1 (1.0-1.2) DM: 7.7 (7.0-8.4) 9

Tsiodras et al, 2000 Boston,

USA

October 1,

1993-July 31,

1998

HIV-1 infected adults,

minimum of 6 months of

FU, measurement of SG

at least twice during the

FU period, and survival

until Nov 1997

Temporal trends in

SG and lipid levels,

and associated risk

factors after

initiation of PI

therapy

HG: 2 or more SG

values ≥ 140 mg/dl

during FU; DM: a

single random SG value

≥ 200 mg/dl

Mean (SD):

45 (12.9)

months

Mean (SD) :

36.8 (0.5)

77

PIs, NRTIs; ART was

commenced before

inclusion; duration NM

207; 858 PYFU DM: 23

PDG: 11

DM: 2.7 (1.8-4.0)

PDG: 1.3 (0.7-2.3)

DM: 10.4 (7.0-

15.1)

PDC: 5.0 (2.8-8.7)

9

Wand et al, 2007 Australia NM HIV infected individuals

initiating ART regimen

3-year incidence of,

and predictive

factors for metabolic

DM: fasting SG >7

mmol/l

or non-fasting SG >11.1

Median (IQR)

192 (165-215)

weeks

Mean (SD)

38.7 (10)

62.2

EFV, NFV 881; 820 PYFU DM: 41 DM: 5.0 (3.7-6.7) DM: 4.7 (3.4-6.3) 6

17

syndrome,

cardiovascular

disease and DM

mmol/l in the absence

of

symptoms of diabetes

Wong et al, 2017 USA, Canada Jan 1, 2000-Dec

31, 2013


years initiating ART

Estimate the rates of

first documented

occurrence of

hypertension, DM and

CKD

HbA1c≥6.5% and/or anti-

diabetic medication

Median follow-

up was 4.8

(IQR, 2.8–8.0)

years

NM 72463

(83.5%)

NM 86789; 476176 PYFU 5,881 DM: 12.4 (12.0-12.7) DM: 6.8 (6.6-6.9) 8

Wu et al, 2016 Taiwan 2004-2015 ART-naïve adults without

DM

Incidence of DM

among ART-naïve

HIV adults initiating

ART

DM: fasting glucose

≥126 mg/dL or HbA1C

≥6.5%.

NM NM NM DRV, TDF/3TC, d4T,

ddl

1432; 7632 PYFU 8

Zannou et al, 2009 Benin October 2004-

June 2005

16+ years old HIV

infected, Karmofsky

index > 70%, eligible to

start combination ART

according to WHO

criteria, and consenting to

participate in the study

Incidence of

lipodystrophy and

metabolic

abnormalities, and

associate factors

DM:

fasting SG at 1,26g/l

and above

Median (IQR)

23.2 ( 22.3-

23.7) months

Mean (SD)

38 (9.7)

40.5 NNRTI, NRTI, PI

79; 1,779.25 PYFU DM: 6 DM: 0.3 (0.2-0.7) DM: 7.6 (3.5-15.6) 6

Zhang et al, 2015 China November

2008-January

2010

ART-naïve HIV infected

patients between 18 and

65 years

Incidence of DM

and IFG

Fasting SG levels ≥7.0

mmol/l (126 mg/dl) for

DM, and

Mean 96

weeks

Median

(IQR) 34

(27-41)

74 ZDV+3TC+NVP;

d4T+3TC+NVP;

415; 457.35 PYFU DM: 12

PDC: 163

DM: 2.6 (1.5-4.5)

PDC: 35.6 (31.4-40.1)

DM: 2.9 (1.7-5.0)

PDC: 39.3 (34.7-

44.1)

8

18

between 5.6 and 6.9

mmol/l (101-125 mg/dl)

for IFG, on 2

separate measurements

3TC: lamivudine; ABC: abacavir; AZT: zidovudine; AIDS: acquired immunodeficiency syndrome; ATV : azatanavir ; ART: antiretroviral therapy; CI= confidence interval; DM= diabetes mellitus; d4T: stavudine; ddI: didanosine; DRV : darunavir ; EFV: efavirenz; FTC: emtricitabine; FU= follow-up;

HAART= highly active antiretroviral therapy; HbA1c: A1c glycated hemoglobin; HCV= Hepatitis C virus; HG: hyperglycemia; IFG: impaired fating glucose; IGT: impaired glucose tolerance; IND: indinavir; IQR= interquartile range; LPV : lopinavir ; NFV: nelfinavir; NM= not mentioned; NNRTI=

nonnucleoside reverse transcriptase inhibitor; NOS: Newcastle Ottawa Scale; NRTI= nucleoside reverse transcriptase inhibitors; NVP: nevirapine; OGTT; oral glucose tolerance test; PI= protease inhibitor; Prediabetes condition (PDC); PYFU= patient-years of follow-up; RTV : Ritonavir; RNA:

ribonucleic acid; SD= standard deviation; SG= serum glucose; SQR: Saquinavir ; TDF: tenofovir; WHO: World Health Organization

19

eTable 2: Global and regional incidence of diabetes mellitus among HIV-infected people on antiretroviral therapy

Regions #Studies #Total

PYFU

#Cases Estimate, by

1,000 PYFU

(95%CI)

I², % p-

heterogeneity

p-Egger p-

difference

Incidence rate < 0.001

Global 29 396,496 4,035 13.7 (11.4-16.3) 98.7 < 0.001 0.323 < 0.001*

Intercontinental 1 130,151 744 5.7 (5.3-6.1) - - NE

Africa 3 115,295 1,519 15.9 (4.4-33.9) 94.6 < 0.001 0.817

Americas 12 584,401 7,506 19.1 (15.9-22.6) 96.1 < 0.001 0.013

Europe 7 143,585 677 8.0 (5.4-11.2) 96.4 < 0.001 0.010

South-East Asia 2 26,781 176 6.5 (5.6-7.5) 99.4 < 0.001 NE

Western Pacific 4 12,739 131 19.0 (5.7-39.7) 97.2 < 0.001 0.143

Cumulative

incidence

#Sample

size

Estimate, %

(95%CI)

Global 41 158,456 6,754 4.9 (4.0-5.9) 98.9 < 0.001 0.899 < 0.001

Intercontinental 1 32,437 744 2.3 (2.1-2.5) - - NE < 0.001*

Africa 6 59,128 1,657 5.1 (3.0-7.8) 92.3 < 0.001 0.063

Americas 12 141,467 10,098 6.1 (5.1-7.2) 97.2 < 0.001 0.540

Europe 10 23,075 723 3.8 (2.5-5.2) 95.4 < 0.001 0.234

20

South-East Asia 4 3,511 183 4.6 (2.3-7.6) 87.5 < 0.001 0.842

Western Pacific 4 3,552 131 3.7 (2.0-6.0) 89.5 < 0.001 0.635

PYFU: Persons Year of Follow-Up; CI: Confidence interval

* After exclusion of the intercontinental cohort

21

eTable 3: Subgroup analyses of incidence and cumulative incidence rates of diabetes mellitus and prediabetes conditions

Coefficient, % (95%

confidence interval)

p value Adjusted coefficient, %

(95% confidence interval)

p value

Incidence rate of DM

Proportion of male -0.003 (-0.020; 0.010) 0.688

WHO regions -0.26 (-0.45; -0.07) 0.007 -0.24 (-0.45; -0.04) 0.021

Total persons year of follow-up 7 x 10-7 (-2.2 x 10-7; 1.7 x 10-6) 0.314

NOS score -0.31 (-0.72; 0.10) 0.140 -0.11 (-0.56; 0.33) 0.619

Diabetes diagnostic criteria .028 (-.005; 0.11) 0.497

Cumulative incidence of DM

Proportion of male 0.03 (-0.01;0.07) 0.191 0.064 (0.039; 0.090) < 0.001

WHO regions -0.51 (-1.30; 0.29) 0.213 -0.83 (-1.37; -0.29) 0.003

Sample size 4.44 x 10-6 (-4.10 x 10-5; 4.99 x

10-5

0.848

NOS score -0.61 (-1.67; 0.44) 0.253

Diabetes diagnostic criteria 0.023 (-0.014; 0.098) 0.676

Incidence rate of PDC*

22

Proportion of male NE

WHO regions 7.7 (-0.6; 16.0) 0.068

Total persons year of follow-up -0.023 (-0.12; -0.08) 0.650

NOS score -22.3 (-63.1; 18.5) 0.283

Pre-diabetes diagnostic criteria 12.8 (-12.8; 38.3) 0.327

Cumulative incidence of PDC

Proportion of male -0.47 (-1.04; 0.09) 0.101 -0.47 (-1.04; 0.09) 0.101

WHO regions 3.05 (-4.04; 10.13) 0.399

Sample size 0.0045 (-0.033; 0.0042) 0.823

NOS score 2.33 (-4.2; 8.9) 0.485

Pre-diabetes diagnostic criteria 3.44 (-3.44; 10.3) 0.327

23

eTable 4: Global and regional incidence of prediabetes conditions among HIV-infected people on antiretroviral therapy

Condition Regions #Studies #Total

PYFU

#Cases Estimate, by

PYFU (95%CI)

I², % p-

heterogeneity

p-egger

Incidence rate

Global 3 1,532 197 12.5 (0.0-42.3) 99.4 < 0.001 0.721

Africa 1 216.3 23 10.6 (7.1-15.3) - - -

Americas 1 858 11 1.3 (0.7-2.3) - - -

Western Pacific

Asia

1 457.53 163 35.6 (31.4-40.1) - - -

Cumulative

incidence

#Sample

size

Estimate, %

(95%CI)

Global 13 3,347 640 14.9 (9.1, 21.8) 96.0 < 0.001 0.703

Africa 1 150 23 15.3 (10.4-22.0) - - -

Americas 5 1,278 277 12.0 (3.4, 24.5) 96.9 < 0.001 0.959

Europe 5 1,335 153 7.7 (3.2-13.9) 89.0 < 0.001 0.710

South-East Asia 2 169 24 13.9 (9.0-19.6) 97.2 < 0.001 -

Western Pacific 1 415 163 39.3 (34.7-44.1) - - -

24

eTable 5: Summary of risk factors for conversion from normoglycemia to prediabetes or overt diabetes mellitus

Study, year Country Selection criteria Risk factors*

Bala et al, 2016 India ART-naïve HIV positive patients older than

12 years

NA

Bastard et al, 2009

NM HIV patient started on PIs at inclusion -Age (> 40 years)

-Markers of adiposity (body mass index > 25 kg/m², waist to hip

ratio ≥ 0.97 in men and 0.92 in women)

-Treatment with stavudine

Boulassel et al,

2006

Canada HIV-1 seropositive patients initiating

HAART

aHR (95%CI)

-Age (per 10 years) 1.6 (1.3-1.9)

-Baseline glucose 2.0 (1.7-2.4)

-PI-NNRTI users 11 (1.2-103)

Brambilla et al,

2003

Italy HIV-infected patients followed-up for at least

3 months, with a stable (without interruption)

antiretroviral regimen (or no therapy) for at

least one month before entry and throughout

the FU period

aHR (95%CI)

-Older age: 1.11 (1.06-1.16);

-Stavudine use: 16.0 (3.03-83.8);

-Indinavir use: 4.0 (1.26-12.7)

Brown et al, 2005 USA HIV-infected men who at the baseline visit

had a fasting SG of 98 mg/dl or less, no self-

aRR (95% CI)

-Body mass index (5-unit increment): 1.34 (0.91-1.96)

25


reported history of DM, and no self-reported

use of antidiabetic medication

-Age (5-unit increment): 1.31 (1.04-1.64)

-Ritonavir (inducing DM or hyperglycemia): 1.70 (1.08-2.68)

Butt et al, 2004 USA HIV positive veterans aHR (95% CI)

-Age (10-year increments): 1.44 (1.39-1.49)

-African-Americans compared to Caucasians: 1.35 (1.24-1.48)

-Hispanics compared to Caucasians: 1.63 (1.43-1.86)

-Care in HAART era 2.35: (2.01-2.75)

-Drug diagnosis: 0.88 (0.79-0.98)

-HCV*HAART era interaction 1.51 (1.13-2.01)

Capeau et al, 2012 France HIV infected patients initiating PI containing

combined ART

-Age

-BMI

-waist-to-hip ratio

-time-updated lipoatrophy

-Indinavir, stavudine, didanosine

De Wit et al, 2008 Europe,

USA,

Argentina

11 cohorts of HIV-infected patient followed

in 212 clinics

-Stavudine, zidovudine, didanosine, ritonavir, nevirapine

26


and

Australia

-Age, male sex, body mass index (25-30; > 30 Kg/m²), ethnicity

(black, other), risk group (heterosexual)

-Current smokers, year of entry in the cohort (1999-2000, 2001,

2002, 2003, 2004)

Dever et al, 2000 Boston,

USA

HIV-1 infected adults, minimum of 6 months

of FU, measurement of SG at least twice

during the FU period, and survival until Nov

1997

aIRR (95% CI)

-Age > 40 years: 4 (1.1-14.1)

-PI use: 5 (1.3-19.4)

-Pentamidine use: 16.8 (3.2-87.7)

Dooko et al, 2014 USA HIV-infected adults with CD4 count ≥

300/mm3 initiating ART

aHR (95%CI)

-Interleukine-6: 1.36 (1.07-1.72)

-Hypersensitive C reactive protein: 1.22 (1.05-1.41)

-Body mass index: 1.10 (1.06 - 1.14)

-Age (per 10 years): 1.43 (1.08 - 1.89)

-HBV or HCV co-infection: 2.04 (1.06 - 3.90)

-Use of lipid-lowering therapy: 2.20 (1.23 - 3.94)

-Non-smoking status: 0.54 (0.31 - 0.95)

27


Galli et al, 2002 Italy HIV-1 infected patients treated for at least 3

months with a combination of 2 NRTIs and

naive of PIs

aOR (95% CI)

-Age (>34 years): 2.61 (1.27-5.33)

García-Benayas et

al, 2006

Spain HIV subjects who had completed 12 months

of an unmodified ARV regimen based on

didanosine, tenofovir, or didanosine +

tenofovir, and had available glucose levels

during the entire FU

aOR (95% CI)

-Lower baseline weight: 0.70 (0.51-0.97)

-Didanosine + Tenofovir use: 465.1 (1.22-1.95*1011)

Gomes et al, 2016 Dominican

Republic

Participants ≥18 years, initiating ART <90

days prior to study enrollment

Dyslipidemia

Gutpa et al, 2011 Australia HIV infected individuals initiating ART

regimen

aHR (95% CI)

-Metabolic Syndrome at baseline: Adult Treatment Panel-III

4.34 (1.83-10.25); International Diabetes Federation 3.33

(1.35-8.17);

-Metabolic syndrome during follow-up: Adult Treatment Panel-

III: 4.89 (2.22-10.78); International Diabetes Federation: 4.84

(2.20-10.64)

-Body mass index 1.13 (1.04-1.22);

-Hip circumference 1.05 (1.02-1.09)

-Total cholesterol 1.37 (1.01-1.84)

28


Herrin et al, 2016 USA ART naïve, HIV-1 RNA >500 copies/ mL in

the 180 days prior to ART initiation

aHR (95%CI)

-Age, per 5 years: 1.16 (1.09, 1.23)

-Blacks compared to Caucasians: 1.69 (1.30, 2.20)

-Hispanic compared to Caucasians: 1.67 (1.03, 2.71)

-Overweight (body mass index between 25-30 mg/Kg²): 2.11

(1.61, 2.77)

-Obese (body mass index > 30 kg/m²): 3.40 (2.48, 4.65)

- HCV infection: 1.33 (1.04, 1.71)

- Weight gain, per 5 pounds: 1.13 (1.10, 1.17)

Isa et al, 2016 Nigeria ART naïve HIV infected patients aOR (95%CI)

-BMI ≥25 kg/m²: 7.5 (2.9–23.7)

Justman et al, 2003

USA Non-pregnant HIV-infected women aHR (95% CI)

-PI use: 3.99 (1.69-9.46)

-Older age (10-years difference): 2.04 (1.29-3.25);

-Obesity: 3.89 (1.41-10.74)

Karamchand et al,

2016

South

Africa

HIV-infected adults ≥ 19 years old, starting

NNRTI-based ART

aHR (95%CI)

29


-Efavirenz vs Nevirapine: 1.27 (1.10–1.47)

-Zidovudine: 1.35 (1.19–1.52)

-Stavudine: 1.60 (1.38–1.87)

-Exposure to other diabetogenic drugs: 1.53 (1.37–1.70)

- Age (reference 35-44 years old)

19-24 years old: 0.47 (0.27–0.81)

25-34 years old: 0.71 (0.62–0.82)

45-54 years old: 1.38 (1.21–1.56)

≥ 55 years old 1.64 (1.32–2.04)

-Male vs female 1.47 (1.32–1.64)

-Baseline body mass index (reference 25-30 kg/m²)

10-17 kg/m² : 0.33 (0.19–0.56)

18-24 kg/m² 0.61 (0.5-3–0.69)

> 35 kg/m² 1.58 (1.26–1.97)

-Baseline viral load 0-999 1.24 (1.05–1.47)

30


Ledergerber et al,

2007

Switzerland HIV-1 infected individuals aged ≥16 years

with at least 2 study visits and at least 1 year

of follow-up

aIRR (95% CI)

-Male: 2.54 (1.53-4.21);

-Age

40-49 years: 1.93: (1.22-3.05);

50-59 years 2.29: (1.30-4.09);

≥60 years 2.29: (1.30-4.09);

-Black compared to Caucasians: 2.10 (1.11-4.00);

-Asian compared to Caucasians: 2.10 (1.11-4.00)

-CDC stage C (vs A or B): 1.56 (1.04-2.35);

-Central obesity: 4.69 (3.14-7.00)

Lichtenstein et al,

2015

USA HIV infected adults with at least two visits Statin use, older age, Hispanic/Latino vs. non-Hispanic/Latino

white race ethnicity, non-Hispanic/Latino black vs. non-

Hispanic/Latino white race ethnicity, ARV-naive vs. ARV-

experienced, prevalent hepatitis C, and BMI ≥30 kg/m²

Lo et al, 2009 Taiwan HIV-infected patients receiving combination

antiretroviral therapy who made at least two

visits to the study site and had FU for 1 year

aOR (95%CI)

-A family history of DM: 2.6 (1.21-5.83);

-Exposure to zidovudine: 3.17 (1.16-8.66);

31


-Current exposure to PI: 2.53 (1.19-5.39)

Magula et al, 2014 South

Africa

HIV adult subjects eligible for antiretroviral

therapy (ART)

OR (95%CI)

-SBP: 1.05 (1.01-1.09) for DM

-SBP: OR 1.04 (1.0-1.07) for DM

-CD4 cell count: 0.98 (0.97-0.99) for IGT

-Visceral fat by CT scan: 1.02 (1.004-1.03) for IFG

Mehta et al, 2003 USA Patients on their first HAART regimen with at

least one random glucose before and during

ART

aRH (95% CI)

-PI use: 5.02 (1.39-18.2)

-HCV infection: 2.28 (1.23-4.22)

-Age: 1.04 (1.01-1.07)

-Baseline SG: 1.25 (1.15-1.36)

Ndona et al, 2012 D R Congo HIV infected patients aHR (95% CI)

-Change of nadir CD4 cell count: 1.003 (1.001-1.005);

-Religion (traditional vs new charismatic religion): 2.1 (1.1-4.2)

Palacios et al, 2003 Spain HIV infected patient on HAART -Obesity at the start of the follow-up for HIV

-Increase in the duration of treatment with PI

32


-Lipodystrophy

Petoumenos et al,

2012

Europe,

USA,

Argentina

and

Australia

11 cohorts of HIV-infected patients -Fasting glucose higher than 5.6 mmol/L

-Random glucose higher than 7.8 mmol/L

-Increasing BMI

-High triglycerides

-Increasing age per five years

-Increasing CD4 category

-Lipodystrophy

Pinto Neto et al,

2013

Brazil HIV-1 infected adults (18+ years) visiting an

AIDS outpatient clinic

-Age >50 years old

-HCV infection

Putcharoen et al,

2017

China ART-naïve HIV infected patients between 18

and 65 years

aHR (95% CI)

-Age: 1.03 (1.01-1.04)

-HBV coinfection: 1.59 (1.06-2.38)

-baseline fasting glucose: 1.28 (1.00- 1.63)

Rasmussen et al,

2012

Denmark HIV-infected Danish-borned individuals aged

≥ 16 years

Older age 60+, lipoatrophy

33


Riyatenet al, 2015 Thailand HIV-1 infected patients aged ≥ 18 years and

ART naive

aHR (95% CI)

-Age (≥30 years old): 2.7 (1.3-5.7)

-Triglycerides (≥140 mg/dl): 1.8 (1.0-3.1)

-BMI (≥25 kg/m²): 2.7 (1.5-4.7)

-Stavudine + Didanosine: 3.9 (1.7-9.0)

-Zidovudine + Lamuvinde + Efavirenz: 2.2 (1.2-3.8)

-Cumulative exposure to Zidovudine (≥1 year): 2.3 (1.2-4.2)

-Tenofovir + Lamivudine + Efavirenz: 0.1 (0.05-0.5)

-Cumulative exposure to TDF (≥ 1 year): 0.4 (0.2-0.9)

Spagnuolo et al,

2017

USA Incidence of DM aRH (95% CI)

-NRTI exposure (>3 years): 2.64 (1.11–6.32)

-Lamivudine use: (> 1 PYFU reporting use after index): 2.81

(1.33-5.95)

Wong et al, 2017 USA HIV infected adults 18+ years on combined

ART for at least 30 days

aHR (95%CI)

-Female sex: 1.32 (1.06-1.65)

-Age: 1.09 ((1.04-1.15)

34


-Pre-existing hypertension: 2.01 (1.59–2.55)

-Pre-existing dyslipidemia: 1.71 (1.29–2.26)

-Pre-existing obesity: 1.57 (1.15–2.13)

-PI exposure: 1.29 (1.04–1.61)

Wu et al, 2016 Italy HIV-positive naïve patients aRR (95%CI)

-Triglycerides/high density lipoprotein cholesterol ratio (per 10-

unit rise): 1.63 (1.32–2.01)

-Age (per 10 years): 1.44 (1.06–1.95)

-Body mass index: 30 kg/m2 vs. 25 kg/m2: 4.92 (2.42–10.00)

-Stavudine + Lamivudine vs Tenofovir + Emtricitabine: 6.31

(1.95– 20.40)

-Atazanavir/ritonavir vs. Efavirenz: 3.23 (1.30–7.98)

-Baseline cholesterol 201-239 mg/dL vs. ≤ 200 mg/dL: 2.49

(1.30–4.78)

Documents

eFigure 1: Process of identification and selection of ... · eFigure 1: Process of identification and selection of studies for inclusion in the review . 2 eFigure 2: Publication bias