Lifestyle diseases in People living with HIV Nombulelo Magula Nelson R Mandela School of Medicine University of KwaZulu-Natal

This is a reminder to all of us of the battle that we have fought against HIV disease. Although other parts of the world struggled against the virus, our battle was different for many reasons. As such, we now as a country carry the statistics that we do. While we were debating whether AIDS was caused by HIV or poverty, scores of people died. Across the atlantic, the disease was getting under control. The bigger challenge across the atlantic was the a different three letter word: the BMI. Amagama amathathu.

Diseases of Lifestyle Exposure over many decades Major risk factors Unhealthy diets Smoking Lack of exercise Stress Major risk factors High blood pressure High blood cholesterol Diabetes obesity

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 ART has resulted in a drastic reduction in mortality and morbidity due to AIDS related conditions, however, mortality due to non-AIDS conditions, in particular CVD, seems to be rising. IHD is predicted to be among the top 3 causes of death in the HIV infected population in 2030 in low income countries. Diabetes is an important risk factor for CVD, therefore we set out to determine Mathers C, Loncar D. Plos Med. 2006; 3:e442

of diabetes and dysglycaemia in South African black patients. To determine: Prevalence Incidence Predictors of diabetes and dysglycaemia in South African black patients. With this in mind we conducted a study to evaluate cardiovascular risk factors in our population

Setting

Eligibility Cross sectional design Study group HIV infected 2nd generation Zulu Age > 18years ART naïve Informed consent Controls 1. Age, gender and ethnically matched HIV negative volunteers Prospective design Study group 2nd generation Zulu Age >18 years ART naïve Starting ART Informed consent

Study Design Flow Diagram Step 1: Cross-sectional Step 2: Prospective 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   group 1 HIV negative   Volunteers group 2 HIV + Not starting ART HIV+ Starting ART Baseline, 3, 6, 12, 18 and 24 months; 1. ART outcomes 2. Examine incidence and determinants of lipodystrophy Participants presenting at KEH and VCT centers in Durban group 3 HIV + Starting ART   For the cross-sectional step of the study, Participants were categorized into three groups, HIV negative for group 1, HIV infected and not starting ART for group 2 and HIV infected and starting ART for group 3. In the prospective step, group three was followed up for 24 months after initiating ART and the outcome measured was diabetes and dysglycaemia Diabetes and dysglycaemia in HIV infected vs control (HIV-) group

Methods 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 Outcomes Diabetes Impaired glucose tolerance (IGT) Impaired fasting glucose (IFG) Dysglycaemia= Diabetes or IGT or IFG (Any disorder of glycaemia)

WHO and ADA diagnostic criteria for diabetes and other disorders of glycaemia Category WHO ADA Diabetes HbA1c > 6.5 % or Plasma glucose (PG): Fasting or > 7.0 mmol/l 2-h post glucose load > 11.1 mmol/l Impaired Glucose tolerance (PG) Fasting (if measured) and <7.0 mmol/l > 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) <7.8 mmol/l

Study Enrolment Flow Chart 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=1 Pregnant, n=4 Wishes to fall pregnant, n=1 Screened, n=530 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

Demographic characteristics at baseline* Variable Group 1 HIV - n=88 Group 2 HIV + not starting ART, Group 3 HIV + starting ART, n=150 p Age (yr) 37.0 + 14.5 37.6 + 9.1 36.9 + 9.1 ns Female 58 (65.9) 102 (68.0) Marital status (single) 61(69.3) 67 (79.8) 112(76.7) High school education 61(70.1) 63(74.1) 98(69.0) Employed 19 (30.2) 24(37.5) 59(41.3) Tobacco smoking 18 (20.7) 18 (21.2) 24 (17.9) Alcohol 29 (34.1) 33 (38.8) 40 (27.0) 0.01 Physical activity Occupational: moderate 32 (40.0) 26 (31.7) 37 (30.6) Leisure: moderate 9 (10.7) 10 (12.2) 15 (10.6) Familial diabetes 17 (19.3) 36 (24.3) * n (%) or Mean + SD

Clinical and laboratory characteristics at baseline Variable Group 1 HIV - n=88 Group 2 HIV + not starting ART, Group 3 HIV + 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 + 0.4 120 – min 5.6 + 2.3 4.8 + 1.3 5.2 + 1.1 HbA1c (%) 3.97 + 0.7 3.95 + 0.6 3.98 + 0.7 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

Prevalence of diabetes and dysglycaemia ** P<0.01 for diabetes, P NS for rest of categories **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) Baseline n =150   24 Months   Follow-up complete n = 97 (64.7%) Not followed-up n = 53 (35.0%) ch5

Prospective - Step 2 Antiretroviral treatment allocation* 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) Lamivudine 150 (100.0) 48 (100.0) 102 (100.0) - Tenofovir Ch5 tab1 *n(%)

24 month follow-up complete 24 month follow-up incomplete Baseline characteristics of Group 3 subjects: completed vs. not completed 24 month visit follow-up Variable 24 month follow-up complete n=97 24 month follow-up incomplete n=53 p Age 37.5 + 9.1 36.0 + 9.3 ns Female 64 (65.98) 38 (71.7) Marital Status: Single 71 (73.2) 41 (77.4) High school 64 (70.3) 34 (66.7) Employed 47 (50.5) 12 (24) 0.002 Body mass index 26.6 + 5.9 26.1 + 6.7 CD4 cell count(cells/mm3) 142 + 82.6 135.2 + 97.5 log HIV RNA load 4.7 + 1.0 4.9 + 0.8 Haemoglobin 11.3 + 1.9 10.8 + 2.1 Albumin 34.9 + 5.0 33.4 + 6.3 Efavirenz 49 (50.5) 27 (50.9) Nevirapine 48 (49.5) 26 (49.1) Tenofovir 97 (100.0) 53 (100.0) - Lamivudine Ch5 tab 1 -1

Immunological and Virological response during 24 months follow up on ART

Incidence of Diabetes Mellitus* during 24 months follow up on ART PYFU Incidence rate 5 221.9 (150) 2.3 (0.7 to 5.3) * OGTT criteria

Incidence of Dysglycaemia (Diabetes or IGT or IFG) Incidence of Dysglycaemia (Diabetes or IGT or IFG)* during 24 months follow up on ART n PYFU Incidence rate 16 211.6 (150) 7.6 (4.3 to 12.3) * OGTT criteria

Not developed Diabetes Baseline characteristics : Group 3 (n:150) developed diabetes vs. not developed diabetes* Variable Developed 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) 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

Developed dysglycaemia, n=16 Baseline characteristics :Group 3 (n:150): developed vs. not developed dysglycaemia Variable Developed dysglycaemia, n=16 Not developed dysglycaemia, n=134 p Age 41.1+6.97 36.3+9.3 0.03 Male 9 (56.3) 37 (28.5) Efavirenz 12 (75.0) 64(47.8) 0.04 Nevirapine 4 (25.0) 70(52.2) 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% (glucose-based criteria) HIV negative: 4.9% 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) p Visceral: subcutaneous fat 2.95 (1.25 to 6.96) 0.01 Variable HR (95% CI) p Systolic BP 1.04 (1.01 to 1.06) 0.002 Albumin 0.84 (0.8 to 0.9) CD 4 cell count 0.988 (0.980 to 0.997) 0.01 Efavirenz 3.98 (1.29 to 14.8) 0.02

SWISS: 4.4* WIHS: 2.8* APROCO-COPILOTE:1.4* MACS: 4.7* D: A:D: 0.5* KZN: 2.3* Justman,et.al. 2003 De Wit,et.al. 2008 Brown, et.al. 2005 Ledergerber, et.al. 2007 Capeau, et.al. 2012 *incidence rate/100 PYFU Incidence rate studies of Diabetes or dysglycaemia in HIV infected patients on cART

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 1 HIV - n=88 Group 2 HIV + not starting ART, Group 3 HIV + 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 + 0.4 120 – min 5.6 + 2.3 4.8 + 1.3 5.2 + 1.1 HbA1c (%) 3.97 + 0.7 3.95 + 0.6 3.98 + 0.7 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

Clinical characteristics during 24 months follow-up on ART