lifestyle diseases in people living with hiv nombulelo magula nelson r mandela school of medicine...
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Lifestyle diseases in People living with HIV
Nombulelo MagulaNelson R Mandela School of Medicine
University of KwaZulu-Natal
• Exposure over many decades• Unhealthy diets• Smoking • Lack of exercise• Stress
• Major risk factors• High blood pressure• High blood cholesterol• Diabetes• obesity
Diseases of Lifestyle
Lifestyle diseases in 2005
• 2/3 deaths globally were attributable to CDL.
• 35 million deaths from CDL recorded were double the number of
deaths
• for all infectious diseases (HIV/AIDS, tuberculosis, malaria),
• maternal and perinatal conditions, and
• nutritional deficiencies combined.
• Approximately 4/5 CDL deaths occurred in low and middle-income
countries with the main ones being
• heart disease
• stroke
• cancer
• chronic respiratory diseases and
• diabetes
• Smoking is projected to kill 50% more people in 2015 than HIV/AIDS,
and
• Will be responsible for 10% of all deaths globally.
World’s largest ART program
IHD among top 3 causes of death in HIV infected population in
2030 in low income countries
Mathers C, Loncar D. Plos Med. 2006; 3:e442
To determine:•Prevalence•Incidence•Predictors
of diabetes and dysglycaemia in South African black patients.
Eligibility• Prospective designStudy group1. 2nd generation Zulu2. Age >18 years 3. ART naïve 4. Starting ART5. Informed consent
• Cross sectional designStudy group1. HIV infected2. 2nd generation Zulu3. Age > 18years 4. ART naïve 5. Informed consent
Controls1. Age, gender and ethnically matched HIV negative volunteers
Outcomes:
A. lipodystrophy development (by FRAM questionnaire
B. Development of:
i. Fat re-distribution (by CT scan and Dexa scan measures)
ii. Diabetes and dysglycaemia
iii. Dyslipidaemia
iv) Other metabolic changes
At 0, 3, 6, 12, 18 and 24 months
HIV+
Starting ART
Baseline, 3, 6, 12, 18 and 24 months;
1. ART outcomes
2. Examine incidence and determinants of lipodystrophyDiabetes and
dysglycaemia in HIV infected vs control (HIV-) group
Volunteers
group 3
HIV +
Starting ART
group 2
HIV +
Not starting ART
group 1
HIV negative
Participants presenting at KEH and VCT centers in Durban
Study Design Flow DiagramStep 2: Prospective
Step 1: Cross-sectional
Methods
• Outcomes• Diabetes• Impaired glucose
tolerance (IGT)• Impaired fasting glucose
(IFG)• Dysglycaemia=
Diabetes or IGT or IFG (Any disorder of glycaemia)
• History • Physical examination• Anthropometry
• Circumferences• Skin folds
• Oral glucose tolerance test• 0 hour plasma glucose (after
overnight fast) and • 2 hour plasma glucose (after
ingestion of 75g glucose monohydrate dissolved in 250 ml water
• HbA1c
• Laboratory tests• Fat distribution
• DXA scan• CT scan
WHO and ADA diagnostic criteria for diabetes and other disorders of glycaemia
Category WHO ADA
Diabetes
HbA1c > 6.5 % or > 6.5 % or
Plasma glucose (PG):
Fasting or > 7.0 mmol/l > 7.0 mmol/l
2-h post glucose load > 11.1 mmol/l > 11.1 mmol/l
Impaired Glucose tolerance (PG)
Fasting (if measured) and
<7.0 mmol/l
2-h post glucose load > 7.8 mmol/l 7.8 – 11.0 mmol/l
Impaired Fasting glucose (PG)
Fasting > 6.1 and < 7.0 mmol/l 5.6 – 6.9 mmol/l
and (if measured) 2-h post glucose load
<7.8 mmol/l
Study Enrolment Flow Chart
Screened, n=530 Not Eligible, n=204:Failure to return after
screening, n=120 Not second generation Zulu,
n=16 Consent refused, n=12 History of ART, n=20 Tuberculosis, n=27 Malignancy, n=3
Died before starting ART, n=1Pregnant, n=4
Wishes to fall pregnant, n=1
Eligible, n=326
Group 1 HIV negative
n=88
Group 2 HIV infected, not
starting ART n=88
Group 3 HIV infected, starting ART
n=150
Variable Group 1HIV - n=88
Group 2HIV + not starting ART, n=88
Group 3HIV + starting ART, n=150
p
Age (yr) 37.0 + 14.5
37.6 + 9.1 36.9 + 9.1 ns
Female 58 (65.9) 58 (65.9) 102 (68.0) Marital status (single) 61(69.3) 67 (79.8) 112(76.7) nsHigh school education 61(70.1) 63(74.1) 98(69.0)
ns
Employed 19 (30.2) 24(37.5) 59(41.3) nsTobacco smoking 18 (20.7) 18 (21.2) 24 (17.9) nsAlcohol 29 (34.1) 33 (38.8) 40 (27.0) 0.01Physical activity Occupational: moderate 32 (40.0) 26 (31.7) 37 (30.6)
ns
Leisure: moderate 9 (10.7) 10 (12.2) 15 (10.6) ns
Familial diabetes 17 (19.3) 18 (21.2) 36 (24.3) ns
Demographic characteristics at baseline*
* n (%) or Mean + SD
Clinical and laboratory characteristics at baseline
Variable Group 1HIV - n=88
Group 2HIV + not starting ART, n=88
Group 3HIV + starting ART, n=150
p
Systolic BP (mmHg) 118.9 + 21.8 115.66 + 17.2 112.1 + 16.8 0.02
Diastolic BP (mmHg) 72.9 + 12.5 72.36 + 11.2 70.9 + 10.7 ns
Body mass index(kg/m2) 29.1 + 7.9 28.6 + 7.8 26.4 + 6.2 0.01
Plasma glucose (mM)
0 – min 5.0 + 0.9 4.8 + 0.4 4.8 + 0.4 ns
120 – min 5.6 + 2.3 4.8 + 1.3 5.2 + 1.1 nsHbA1c (%) 3.97 + 0.7 3.95 + 0.6 3.98 + 0.7 ns
CD4 cell count, cells/mm3 - 404.5(343 - 531) 132(64 - 193) 0.0001
Log HIV RNA - 4.33 + 0.93 4.75 + 0.92 0.002
HIV negative HIV infected not starting
ART
HIV infected starting ART
0
2
4
6
8
10
12
4.9
0 0
3.7
2.42.96
0
1.20.7
8.6
3.7 3.7
WHO criteriaDiabetes IGT IFG Dysglycaemia
%
Prevalence of diabetes and dysglycaemia
HIV negative HIV infected not starting
ART
HIV infected starting ART
4.9
0 0
3.7
2.42.96
3.7 3.6 3.7
11.1
6.16.6
ADA criteria
****
**p<0.01 D group 3 vs. group 1
Multivariate analysis
Variable OR (95% CI) p
Systolic blood pressure 1.07 (1.02 to 1.12) 0.003
Serum triglyceride 4.5 (1.03 to 19.8) 0.04
Overall response rate of Group 3 (HIV infected and starting ART)
24 Months
Baseline
n =150
Not followed-up
n = 53
(35.0%)
Follow-up complete
n = 97
(64.7%)
Prospective - Step 2Antiretroviral treatment allocation*
*n(%)
Variable
All patients
n=150
Male
n=48
Female
n=102 p
Efavirenz 76 (50.7) 40 (83.3) 36 (35.3) <0.0001
Nevirapine 74 (49.3) 8 (16.7) 66(64.7) <0.0001
Lamivudine 150 (100.0) 48 (100.0) 102 (100.0) -
Tenofovir 150 (100.0) 48 (100.0) 102 (100.0) -
Baseline characteristics of Group 3 subjects: completed vs. not completed 24 month visit follow-up
Variable 24 month follow-up complete
n=9724 month follow-up
incompleten=53 p
Age 37.5 + 9.1 36.0 + 9.3 ns
Female 64 (65.98) 38 (71.7) ns
Marital Status: Single 71 (73.2) 41 (77.4) nsHigh school 64 (70.3) 34 (66.7) nsEmployed 47 (50.5) 12 (24) 0.002Body mass index 26.6 + 5.9 26.1 + 6.7 ns CD4 cell count(cells/mm3) 142 + 82.6 135.2 + 97.5 ns log HIV RNA load 4.7 + 1.0 4.9 + 0.8 ns Haemoglobin 11.3 + 1.9 10.8 + 2.1 ns Albumin 34.9 + 5.0 33.4 + 6.3 ns Efavirenz 49 (50.5) 27 (50.9) ns Nevirapine 48 (49.5) 26 (49.1) ns Tenofovir 97 (100.0) 53 (100.0) - Lamivudine 97 (100.0) 53 (100.0) -
Immunological and Virological response during 24 months follow up on ART
0 3 6 12 18 240
50
100
150
200
250
300
350
400
0
1
2
3
4
5
6
CD4 Cell Count HIV RNA Load
month
Cells
/mm
3
log
p < 0.0001
p < 0.0001
* OGTT criteria
Incidence of Diabetes Mellitus*during 24 months follow up on ART
n PYFU Incidence rate
5 221.9 (150) 2.3 (0.7 to 5.3)
n PYFU Incidence rate
16 211.6 (150) 7.6 (4.3 to 12.3)
Incidence of Dysglycaemia (Diabetes or IGT or IFG)* during 24 months follow up on ART
* OGTT criteria
Baseline characteristics : Group 3 (n:150)developed diabetes vs. not developed diabetes*
VariableDeveloped Diabetes
n=5
Not developed Diabetes n= 145
p
Age (yr) 39.8+6.1 36.8+9.3 0.5
Male 4 (80.0) 44 (30.3) 0.02
Efavirenz 5 (100.0) 71 (47.9) 0.02
BP (mmHg)
Systolic 126.8+17.4 111.4+16.6 0.04
Diastolic 84.8+12.1 70.3+10.4 0.003
BMI (kg/m2) 25.6+6.9 26.3+6.2 0.6
*by OGTT
Baseline characteristics :Group 3 (n:150):developed vs. not developed dysglycaemia
VariableDeveloped
dysglycaemia, n=16
Not developed dysglycaemia,
n=134p
Age 41.1+6.97 36.3+9.3 0.03
Male 9 (56.3) 37 (28.5) 0.03
Efavirenz 12 (75.0) 64(47.8) 0.04
Nevirapine 4 (25.0) 70(52.2) 0.04
BP (mmHg)
Systolic 124.2+19.2 110.6+15.97 0.002
Diastolic 77.8+11.7 70.2+10.5 0.01
World’s largest ART program
Prevalence of diabetes
HbA1c criteria
HIV negative: 1.2 %
HIV infected: 0%
Prevalence of diabetes
(glucose-based criteria)
HIV negative: 4.9%
HIV infected: 0%
Prevalence of dysglycaemia
HIV negative: 8.6%
HIV infected: 3.7%
World’s largest ART program
IR of dysglycaemia
7.6 per 100 PYFU
(95% CI [4.3 to 12.3])
IR of diabetes (glucose-based criteria)
2.3 per 100 PYFU (95% CI[0.7 to 5.3])
IR rate of diabetes (HbA1c criteria) 3.8 per 100 PYFU (95% CI [1.6 to 7.4])
Multivariate analysis
Diabetes Dysglycaemia
Variable HR (95% CI) pVisceral: subcutaneous fat
2.95 (1.25 to 6.96) 0.01Variable HR (95% CI) p
Systolic BP 1.04 (1.01 to 1.06) 0.002
Albumin 0.84 (0.8 to 0.9) 0.002
CD 4 cell count 0.988 (0.980 to 0.997) 0.01
Efavirenz 3.98 (1.29 to 14.8) 0.02
WIHS: 2.8*
D: A:D: 0.5*
SWISS: 4.4*
MACS: 4.7* D: A:D: 0.5*
D: A:D: 0.5*D: A:D: 0.5*
APROCO-COPILOTE:1.4*
Incidence rate studies of Diabetes or dysglycaemia in HIV infected patients on cART
*incidence rate/100 PYFU
KZN: 2.3*Justman,et.al. 2003De Wit,et.al. 2008Brown, et.al. 2005Ledergerber, et.al. 2007Capeau, et.al. 2012
Conclusion
• Prevalence of diabetes 0% prior to cART
• Incidence of diabetes and dysglycaemia on cART is high
• Monitoring for diabetes and dysglycaemia in patients on cART warranted
• Probably the first study reporting efavirenz as a predictive risk factor for incident dysglycaemia
• Alternative to Efavirenz as the backbone of cART needs to be considered
Clinical and laboratory characteristics at baseline
Variable Group 1HIV - n=88
Group 2HIV + not starting ART, n=88
Group 3HIV + starting ART, n=150
p
Systolic BP (mmHg) 118.9 + 21.8 115.66 + 17.2 112.1 + 16.8 0.02
Diastolic BP (mmHg) 72.9 + 12.5 72.36 + 11.2 70.9 + 10.7 ns
Body mass index(kg/m2) 29.1 + 7.9 28.6 + 7.8 26.4 + 6.2 0.01
Plasma glucose (mM)
0 – min 5.0 + 0.9 4.8 + 0.4 4.8 + 0.4 ns
120 – min 5.6 + 2.3 4.8 + 1.3 5.2 + 1.1 nsHbA1c (%) 3.97 + 0.7 3.95 + 0.6 3.98 + 0.7 ns
CD4 cell count, cells/mm3 - 404.5(343 - 531) 132(64 - 193) 0.0001
Log HIV RNA - 4.33 + 0.93 4.75 + 0.92 0.002
0 3 6 12 18 240
102030405060708090
weight (kg) BMI(kg/m2)
months
p<0.0001
p<0.0001
0 3 6 12 18 24405060708090
100110120130
Systolic BP Diastolic BP
months
mm
Hg
p<0.0001
p=0.05
Clinical characteristicsduring 24 months
follow-up on ART