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

Transcription

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

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

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

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

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

6 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 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 ) months Mean (IQR) 43.9 (39-49) 75 NNRTI, PI, or other Cumulative time on ART mean (IQR) ( ) months 265; PYFU DM: 22 DM: 2.9 ( ) DM: 8.3 ( ) 8 Bala et al, 2016 India January 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 ( ) PDC: 17.8 ( ) 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 6

7 Bognounou et al, 2011 Burkina- Faso October 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 NNRTI, NRTI, PI; cumulative duration of exposure NM 100 DM: 4 DM: 4.0 ( ) 5 Boulassel et al, 2006 Canada January 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 ( ) DM: 12.7 ( ) 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 ( ) ; non-diabetics 603 ( ) days 1,011; 768 PYFU DM: 16 DM: 2.1 ( ) DM: 1.6 ( ) 6 Brown et al, 2005 USA April 1, 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 ( ) Median (IQR) 46 (42-51) 100 PI, NNRTI; duration of HAART median (IQR): 3.26 ( ) years 411; PYFU DM: 24 PDC: 69 DM: 4.7 ( ) DM: 5.8 ( ) PDC: 16.8 ( ) 9 7

8 history of DM, and no self-reported use of antidiabetic medication use of antidiabetic medication HG: fasting SG mg/dl Butt et al, 2004 USA HIV positive veterans Incidence of DM DM: presence of 1 inpatient or 2 outpatient International Classification of Diseases-9 codes for DM NM Median: HAART; duration NM DM: 9.5 ( ) 6 Capeau et al, 2012 France 1997/ 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 Median (IQR) 9.6 ( ) years Median IDV, d4t, ddl; no NNRTI; duration NM 1,046; 7,846 PYFU DM: 111 DM: 1.4 ( ) DM: 10.6 ( ) mg/dl, and/or if initiation with antidiabetic drugs during FU Capiluppi et al, 2000 Italy NM Patients with primary HIV-1 infection Incidence of metabolic disorders NM Mean (range): 26 (15-36) months Mean PI+NNRTI; mean (range) 26 (15-36) months of exposure to PI therapy 37 DM: 0 PDC: 0 DM: 0 ( ) PDC: 0 ( ) 5 8

9 De Wit et al, 2008 Europe, USA, Argentina and Australia December 1999-January cohorts of HIVinfected 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 physicianreported 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 ( ) DM: 2.3 ( ) 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 DM: 6.0 ( ) 5 Dooko et al, 2014 USA NM HIV-infected adults with CD4 count 300/mm 3 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 ( ) DM: 3.5 ( ) 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 ( ) days Median (range) 34 (20-71) 54.3 D4T, 3TC, AZT; 245 patients ART naïve at inclusion; duration median (range) ( ) days 335 PDC: 48 PDC: 14.3 ( ) 6 9

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 Incidence of HG DM: repeated measurements of fasting SG levels > 125 mg/dl 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 ( ) PDC: 19.2 ( ) 7 ddi, TDF, or ddi+tdf, and had available glucose levels during the entire FU 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 mg/dl; DM: FPG 126 mg/dl or anti-diabetic medication 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 DM: 113 IFG: 91 DM:6 PDC: 46 DM: 5.3 ( ) PDC: 50.5 ( ) 8 EFV) 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 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 ( ) PDC: 8.8 ( Herrin et al, 2016 USA 01/01/ /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 ) years Median 50 (43-56) years 96.8 NNRTI, PI, triple nucleoside 7,177; 17,780 PYFU DM: 357 DM: 2.0 ( ) DM: 5.0 ( ) 9 10

11 initiation Isa et al, 2016 Nigeria 1 January 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 TC + AZT + NVP ; 3TC /FTC + TDF + EFV ; ATV/RTV ; LPV/RTV 2,452 DM: 130 DM: 5.3 ( ) 8 Justman et al, 2003 USA Non-pregnant HIVinfected 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 ( ) DM: 2.5 ( ) 8 Karamchand et al, 2016 South Africa January December 2011 HIV-infected adults 19 years, starting NNRTIbased ART Association between efavirenz exposure and incident DM DM: initiation of antidiabetic medication Median 1.56 (IQR ) years Median (IQR ) years NNRTI (EFV containing ART; NVP containing ART) 56,298; 113,297 PYFU DM: 1,500 DM: 1.3 ( ) DM: 2.7 ( ) 8 Ledergerber et al, 2007 Switzerland March 1st 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 ( ) DM: 1.9 ( ) 9 11

12 visits and at least 1 year of follow-up after 1 and 11.1 mmol/l (nonfasting) duration of exposure NM March 2000 Lichtenstein et al, 2015 USA 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: ) NM 3661 (78%) NM DM: 7.6 ( ) 8 Lo et al, 2009 Taiwan January 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 ( ) DM: 6.1 ( ) 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 ( ) PDC: 10.0 ( ) DM: 8.7 ( ) PDC: 15.3 ( ) 8 Mehta et al, 2003 USA January 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 SG levels > 200 mg/dl or documentation of Median (IQR) 8.9 ( ) months Median (IQR) 69.9 PI; NNRTI; PI+NNRTI 1,149; 1,808 PYFU DM: 47 DM: 2.6 ( ) DM: 4.1 ( ) 9 12

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 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 ( ) 6 Ndona et al, 2012 D R Congo HIV infected patients Incidence and predictors of type 2 diabetes DM: fasting SG levels 126 mg/dl measured on two consecutive occasion and/or 2Hglucose post load plasma glucose 200 mg/dl NM Mean 43± Combination of d4t + 3TC, AZT + 3TC + NVP, or EFV; Mean duration on ART 25 ± 15 months 49 DM: 4 DM: 8.2 ( ) 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 ( ) PDC: 9.5 ( ) 8 13

14 Pinto Neto et al, 2013 Brazil January 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 SG levels > 126 mg/dl 36 months Median 45 (IQR 37-52) 58.9 NRTI, NNRTI, PI; duration 36 months 454 DM : 454 PDC : 141 DM : 3.7 ( ) PDC : 31.1 ( ) 8 Putcharoen et al, 2017 Thailand July 1, 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 anti-diabetic medication Median FU 9 (IQR ) Median age at ART initiation 32.2 (IQR ) years 1051 (60.1%) NNRTI, PI 1,748; 16,274 PYFU DM: 123 DM: 7.6 ( ) DM: 7.0 ( ) 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 HIVinfected individuals compared Medical report of antidiabetic medication Median 8.0 ( ) Median 38.7 ( ) 2,977 (84.1%) NM 3,540; 28,342 PYFU 90 DM: 3.2 ( ) DM: 2.5 ( ) 9 to that of the general population Riyatenet al, 2015 Thailand January 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 ( ) years Median (IQR) 32.5 ( ) 24 PI, NNRTI, NRTI 1,594; 10,507 PYFU DM: 53 DM: 0.5 ( ) DM: 3.3 ( ) 8 Salehian et al, 2005 USA August 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 ( ) PDC: 9.9 ( ) 8 14

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 antidiabetic prescription 9.8 years (interquartile range: years) median duration of ART was Median 47.2 years (IQR: years) 4,828 (78%) NRTIs (97%); PIs (79%); NNRTI (61%); integrase strand transfer inhibitors (12%) and entry inhibitors (9%) 235; PYFU 235 DM: 3.7 ( ) DM: 3.8 ( ) 8 10 years (IQR: 4 16 years).. Squillace et al, 2016 Italy 01/01/ HIV-positive naïve patient Incidence of DM arising during combination ART DM: two consecutive blood glucose values of.126 mg/dl NM Median 38 (IQR 33-45) years 73.7 NRTI, NNRTI, PI 3,546; 13,911 PYFU DM: 80 DM: 0.6 ( ) DM: 2.3 ( ) 8 (7 mmol/l), clinical diagnosis of DM or start of antidiabetic treatment Tien et al, 2007 USA October 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 ( ) 0 PI, NRTI, NNRTI; duration of ART NM 1,283; 3,326 PYFU DM: 91 DM: 2.7 ( ) DM: 7.1 ( ) 9 15

16 SG 1.26 g/l or reported antidiabetic medication) Tripathi et al, 2014 USA 1 st January st 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 Median 70 months (IQR ) 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 ( ) DM: 7.7 ( ) 9 Classification of Diseases-9 codes for Type 1 or Type 2 diabetes mellitus and/or prescription of antidiabetic medications including insulin for at least 30 days 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 ( ) PDG: 1.3 ( ) DM: 10.4 ( ) PDC: 5.0 ( ) 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 ( ) weeks Mean (SD) 38.7 (10) 62.2 EFV, NFV 881; 820 PYFU DM: 41 DM: 5.0 ( ) DM: 4.7 ( ) 6 16

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 HIV-infected adults 18 years initiating ART Estimate the rates of first documented occurrence of hypertension, DM and CKD HbA1c 6.5% and/or antidiabetic medication Median followup was 4.8 (IQR, ) years NM (83.5%) NM 86789; PYFU 5,881 DM: 12.4 ( ) DM: 6.8 ( ) 8 Wu et al, 2016 Taiwan 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 June 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 ( ) months Mean (SD) 38 (9.7) 40.5 NNRTI, NRTI, PI 79; 1, PYFU DM: 6 DM: 0.3 ( ) DM: 7.6 ( ) 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; PYFU DM: 12 PDC: 163 DM: 2.6 ( ) PDC: 35.6 ( ) DM: 2.9 ( ) PDC: 39.3 ( ) 8 17

18 between 5.6 and 6.9 mmol/l ( 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 18

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 < Global ,496 4, ( ) 98.7 < < 0.001* Intercontinental 1 130, ( ) - - NE Africa 3 115,295 1, ( ) 94.6 < Americas ,401 7, ( ) 96.1 < Europe 7 143, ( ) 96.4 < South-East Asia 2 26, ( ) 99.4 < NE Western Pacific 4 12, ( ) 97.2 < Cumulative incidence #Sample size Estimate, % (95%CI) Global ,456 6, ( ) 98.9 < < Intercontinental 1 32, ( ) - - NE < 0.001* Africa 6 59,128 1, ( ) 92.3 < Americas ,467 10, ( ) 97.2 < Europe 10 23, ( ) 95.4 <

20 South-East Asia 4 3, ( ) 87.5 < Western Pacific 4 3, ( ) 89.5 < PYFU: Persons Year of Follow-Up; CI: Confidence interval * After exclusion of the intercontinental cohort 20

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 (-0.020; 0.010) WHO regions (-0.45; -0.07) (-0.45; -0.04) Total persons year of follow-up 7 x 10-7 (-2.2 x 10-7 ; 1.7 x 10-6 ) NOS score (-0.72; 0.10) (-0.56; 0.33) Diabetes diagnostic criteria.028 (-.005; 0.11) Cumulative incidence of DM Proportion of male 0.03 (-0.01;0.07) (0.039; 0.090) < WHO regions (-1.30; 0.29) (-1.37; -0.29) Sample size 4.44 x 10-6 (-4.10 x 10-5 ; 4.99 x NOS score (-1.67; 0.44) Diabetes diagnostic criteria (-0.014; 0.098) Incidence rate of PDC* 21

22 Proportion of male NE WHO regions 7.7 (-0.6; 16.0) Total persons year of follow-up (-0.12; -0.08) NOS score (-63.1; 18.5) Pre-diabetes diagnostic criteria 12.8 (-12.8; 38.3) Cumulative incidence of PDC Proportion of male (-1.04; 0.09) (-1.04; 0.09) WHO regions 3.05 (-4.04; 10.13) Sample size (-0.033; ) NOS score 2.33 (-4.2; 8.9) Pre-diabetes diagnostic criteria 3.44 (-3.44; 10.3)

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, ( ) 99.4 < Africa ( ) Americas ( ) Western Pacific Asia ( ) Cumulative incidence #Sample size Estimate, % (95%CI) Global 13 3, (9.1, 21.8) 96.0 < Africa ( ) Americas 5 1, (3.4, 24.5) 96.9 < Europe 5 1, ( ) 89.0 < South-East Asia ( ) 97.2 < Western Pacific ( )

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 ( ) -Baseline glucose 2.0 ( ) -PI-NNRTI users 11 ( ) 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 ( ); -Stavudine use: 16.0 ( ); -Indinavir use: 4.0 ( ) Brown et al, 2005 USA HIV-infected men who at the baseline visit had a fasting SG of 98 mg/dl or less, no selfarr (95% CI) -Body mass index (5-unit increment): 1.34 ( ) 24

25 Study, year Country Selection criteria Risk factors * reported history of DM, and no self-reported use of antidiabetic medication -Age (5-unit increment): 1.31 ( ) -Ritonavir (inducing DM or hyperglycemia): 1.70 ( ) Butt et al, 2004 USA HIV positive veterans ahr (95% CI) -Age (10-year increments): 1.44 ( ) -African-Americans compared to Caucasians: 1.35 ( ) -Hispanics compared to Caucasians: 1.63 ( ) -Care in HAART era 2.35: ( ) -Drug diagnosis: 0.88 ( ) -HCV*HAART era interaction 1.51 ( ) 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 25

26 Study, year Country Selection criteria Risk factors * 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 ( , 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 ( ) -PI use: 5 ( ) -Pentamidine use: 16.8 ( ) Dooko et al, 2014 USA HIV-infected adults with CD4 count 300/mm 3 initiating ART ahr (95%CI) -Interleukine-6: 1.36 ( ) -Hypersensitive C reactive protein: 1.22 ( ) -Body mass index: 1.10 ( ) -Age (per 10 years): 1.43 ( ) -HBV or HCV co-infection: 2.04 ( ) -Use of lipid-lowering therapy: 2.20 ( ) -Non-smoking status: 0.54 ( ) 26

27 Study, year Country Selection criteria Risk factors * 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 ( ) 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 ( ) -Didanosine + Tenofovir use: ( *10 11 ) 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 ( ); International Diabetes Federation 3.33 ( ); -Metabolic syndrome during follow-up: Adult Treatment Panel- III: 4.89 ( ); International Diabetes Federation: 4.84 ( ) -Body mass index 1.13 ( ); -Hip circumference 1.05 ( ) -Total cholesterol 1.37 ( ) 27

28 Study, year Country Selection criteria Risk factors * 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) Isa et al, 2016 Nigeria ART naïve HIV infected patients aor (95%CI) Justman et al, 2003 USA Non-pregnant HIV-infected women ahr (95% CI) -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 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) -BMI 25 kg/m²: 7.5 ( ) -PI use: 3.99 ( ) -Older age (10-years difference): 2.04 ( ); -Obesity: 3.89 ( ) Karamchand et al, 2016 South Africa HIV-infected adults 19 years old, starting NNRTI-based ART ahr (95%CI) 28

29 Study, year Country Selection criteria Risk factors * -Efavirenz vs Nevirapine: 1.27 ( ) -Zidovudine: 1.35 ( ) -Stavudine: 1.60 ( ) -Exposure to other diabetogenic drugs: 1.53 ( ) - Age (reference years old) years old: 0.47 ( ) years old: 0.71 ( ) years old: 1.38 ( ) 55 years old 1.64 ( ) -Male vs female 1.47 ( ) -Baseline body mass index (reference kg/m²) kg/m² : 0.33 ( ) kg/m² 0.61 ( ) > 35 kg/m² 1.58 ( ) -Baseline viral load ( ) 29

30 Study, year Country Selection criteria Risk factors * 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 ( ); -Age years: 1.93: ( ); years 2.29: ( ); 60 years 2.29: ( ); -Black compared to Caucasians: 2.10 ( ); -Asian compared to Caucasians: 2.10 ( ) -CDC stage C (vs A or B): 1.56 ( ); -Central obesity: 4.69 ( ) 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. ARVexperienced, 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 ( ); -Exposure to zidovudine: 3.17 ( ); 30

31 Study, year Country Selection criteria Risk factors * -Current exposure to PI: 2.53 ( ) Magula et al, 2014 South Africa HIV adult subjects eligible for antiretroviral therapy (ART) OR (95%CI) -SBP: 1.05 ( ) for DM -SBP: OR 1.04 ( ) for DM -CD4 cell count: 0.98 ( ) for IGT -Visceral fat by CT scan: 1.02 ( ) 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 ( ) -HCV infection: 2.28 ( ) -Age: 1.04 ( ) -Baseline SG: 1.25 ( ) Ndona et al, 2012 D R Congo HIV infected patients ahr (95% CI) -Change of nadir CD4 cell count: ( ); -Religion (traditional vs new charismatic religion): 2.1 ( ) 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 31

32 Study, year Country Selection criteria Risk factors * -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 ( ) -HBV coinfection: 1.59 ( ) -baseline fasting glucose: 1.28 ( ) Rasmussen et al, 2012 Denmark HIV-infected Danish-borned individuals aged 16 years Older age 60+, lipoatrophy 32

33 Study, year Country Selection criteria Risk factors * Riyatenet al, 2015 Thailand HIV-1 infected patients aged 18 years and ART naive ahr (95% CI) -Age ( 30 years old): 2.7 ( ) -Triglycerides ( 140 mg/dl): 1.8 ( ) -BMI ( 25 kg/m²): 2.7 ( ) -Stavudine + Didanosine: 3.9 ( ) -Zidovudine + Lamuvinde + Efavirenz: 2.2 ( ) -Cumulative exposure to Zidovudine ( 1 year): 2.3 ( ) -Tenofovir + Lamivudine + Efavirenz: 0.1 ( ) -Cumulative exposure to TDF ( 1 year): 0.4 ( ) Spagnuolo et al, 2017 USA Incidence of DM arh (95% CI) -NRTI exposure (>3 years): 2.64 ( ) -Lamivudine use: (> 1 PYFU reporting use after index): 2.81 ( ) 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 ( ) -Age: 1.09 (( ) 33

34 Study, year Country Selection criteria Risk factors * Wu et al, 2016 Italy HIV-positive naïve patients arr (95%CI) -Pre-existing hypertension: 2.01 ( ) -Pre-existing dyslipidemia: 1.71 ( ) -Pre-existing obesity: 1.57 ( ) -PI exposure: 1.29 ( ) -Triglycerides/high density lipoprotein cholesterol ratio (per 10- unit rise): 1.63 ( ) -Age (per 10 years): 1.44 ( ) -Body mass index: 30 kg/m 2 vs. 25 kg/m 2 : 4.92 ( ) -Stavudine + Lamivudine vs Tenofovir + Emtricitabine: 6.31 ( ) -Atazanavir/ritonavir vs. Efavirenz: 3.23 ( ) -Baseline cholesterol mg/dl vs. 200 mg/dl: 2.49 ( ) 34