As antiretroviral therapy (ART) coverage in sub-Saharan African (SSA) populations continue to increase, [
Between May and August 2008, patients were enrolled for the study at the Adult Infectious Disease Clinic at the Infectious Diseases Institute (IDI) in Kampala, Uganda. We enrolled patients aged 18 years and above, on first line ART for at least 12 months with an adherence level by self-report of ≥95% and who gave informed consent. After fasting for at least 8 hours, blood was drawn for glucose, lipid profile and CD4 count. Persons were excluded if their ART had ever been switched or substituted, they were diabetic prior to ART initiation, had index dyslipidemias, or used lipid-lowering drugs, corticosteroids, or oral contraceptives pills. A trained research assistant obtained a medical history from the patient and abstracted clinical information from the patient’s chart including the date of ART start, pre-ART CD4 count, WHO clinical stage, body weight at ART start, current CD4 count, and peak body weight while on ART. A clinician, masked to the patient’s ART regimen, performed a physical examination and anthropometric measurements, including the determination of blood pressure (BP) and waist/hip circumferences. A patient was considered hypertensive, when the systolic blood pressure was ≥140 mmHg or diastolic BP was ≥90 mmHg on more than two occasions. All patients were assessed for evidence of subcutaneous fat loss or fat accumulation. Features suggestive of fat loss in the face included sunken eyes, prominent zygoma, sunken cheeks, and in the upper and lower limbs included prominent veins, subcutaneous fat wasting especially in the arms. Features of fat accumulation were the presence of excessive abdominal fat compared to peripheral fat (after excluding organomegaly and intra-abdominal masses as assessed by palpation), buffalo humps and lipomata on any part of the body.
CD4 cell count was done using BD FACSCalibur (Becton Dickinson, Mountain View, CA, USA). Serum lipid assays were batched and run by an automated enzyme-based chemistry analyzer (Konelab 30 system, Thermo Electron Corporation, Finland), with quality controls done at the beginning of each batched run. Ten duplicate samples from each batch were analyzed in a separate laboratory within the National Referral Hospital complex as an external quality check. Finger prick blood for glucose was done on an automated one touch analyzer (Lifescan. Inc, United Kingdom). Participants with fasting blood sugar ≥7 mM were asked to return for a repeat test to confirm diabetes mellitus (DM) at the next convenient date. Those confirmed with DM were referred to a specialist at the diabetic clinic for further management.
The international classification system recommended by the World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) for glucose and lipid profiles [
Lipid and glucose international classification recommended by the World Health Organization.
Classification | TC (mmol/L) | LDL (mmol/L) | HDL (mmol/L) | TG (mmol/L) | GLU (mmol/L) |
---|---|---|---|---|---|
Desirable |
|
|
|
|
|
Borderline | 5.17–6.18 | 3.36–4.11 | 0.91–1.53 | 2.26–4.50 | 6.11–6.94 |
High |
|
|
|
|
|
Low |
|
TC: total cholesterol; LDL: low-density lipoprotein; HDL: high-density lipoprotein; GLU: Glucose.
Data was cleaned and entered in Epidata version 3.1 and exported to STATA version 10.0 for analysis. At univariate level all variables were compared according to ART regimen (stavudine- or zidovudine-containing regimen). Categorical variables were compared using a Chi square test and a
At bivariate level, all predictor variables including ART regimen were compared with lipid and glucose levels: both were dichotomized into abnormal and normal levels. Study participants were categorized as having abnormal glucose levels if they had ≥6.11 mmol/L, while those who were classified as having abnormal lipid levels had either total cholesterol ≥5.17 mmol/L or ldl-cholesterol ≥3.36 mmol/L or hdl-cholesterol ≥1.53 mmol/L or triglycerides ≥2.26 mmol/L. Odds ratio was used as the measure of association, a 95% confidence interval (CI) was obtained, and a
Four hundred forty-two patients on ART were enrolled into the study between May–August, 2008. Nineteen patients had incomplete chart records and were excluded from the analysis. Of the 423 patients analyzed, 60% (255/423) were women. The median (IQR) age of the study participants was 39 years (34–44), and the median (IQR) initial CD4 counts was 90 cells/
Results presented in Table
Characteristics of patients initiated on stavudine- and zidovudine-based regimens.
Characteristics | Stavudine ( |
Zidovudine ( |
|
---|---|---|---|
Gender, male. |
72 (34.6) | 96 (44.6) | 0.035 |
Age, (5 years), median (IQR) | 38 (33–43) | 39 (34–46) | 0.131 |
ART duration (years), median (IQR) | 2.5 (1.8–2.9) | 2.7 (1.8–3.3) | 0.016 |
Initial CD4+ counts, median (IQR) | 94 (30.5–171) | 89 (38–166) | 0.888 |
Initial body weight (Kg), median (IQR) | 53.8 (48.3–61.5) | 54 (48–60) | 0.784 |
Peak body weight, median (IQR) | 63 (57–71) | 63 (57–68) | 0.387 |
BMI |
57 (27.4) | 56 (26.1) | 0.752 |
Systolic blood pressure (mmHg), median (IQR) | 120 (110–130) | 110 (110–120) |
|
Hypertension, |
33 (15.9) | 16 (7.4) | 0.007 |
CD4 at study enrolment |
175 (85.0) | 153 (72.5) | 0.002 |
Abnormal waist to hip ratio+ | 0.94 (0.88–0.99) | 0.91 (0.88–0.95) |
|
Family history of hypertension, |
90 (43.7) | 66 (30.7) | 0.006 |
Family history diabetes mellitus, |
42 (20.4) | 34 (15.8) | 0.223 |
Lipodystrophy, |
74 (35.8) | 14 (6.7) |
|
WHO stage III and IV, |
151 (72.6) | 166 (77.2) | 0.274 |
*Hypertension defined as systolic blood pressure
+Waist to hip ratio was categorized into abnormal if the value was
The overall prevalence of patients with dyslipidemia was 81.6% (345/423). The majority (60%, 253/423), had undesirable high-density lipoprotein C (HDL-C), defined as <1.53 mmol/L; 39% (165/423) had high total cholesterol (TC), 24% (100/423), high triglycerides (TG), and 20% (83/423) elevated low-density lipoprotein C (LDL-C) (Table
Prevalence of dyslipidemia and hyperglycemia in HIV-infected patients according to stavudine- and zidovudine-containing regimens.
Stavudine | Zidovudine | Total | ||
---|---|---|---|---|
Lipid abnormalities |
|
|
|
|
|
|
|
||
Total cholesterol | ||||
Borderline | 58 (27.9) | 48 (22.3) | 106 (25.1) | 0.018 |
High | 35 (16.8) | 24 (11.2) | 59 (14.0) | |
LDL-cholesterol | ||||
Borderline | 29 (13.9) | 17 (7.9) | 46 (10.9) | 0.013 |
High | 22 (10.6) | 15 (7.0) | 37 (44.6) | |
Triglycerides | ||||
Borderline | 40 (19.2) | 31 (14.4) | 71 (16.8) | 0.025 |
High | 19 (9.1) | 10 (4.7) | 29 (6.9) | |
HDL-cholesterol | ||||
Borderline | 147 (70.7) | 87 (40.5) | 234 (55.3) |
|
Low | 12 (5.8) | 7 (3.3) | 19 (4.5) | |
Dyslipidemia | ||||
Borderline | 190 (91.4) | 155 (72.1) | 345 (81.6) |
|
Overt | 46 (22.1) | 34 (15.8) | 80 (18.9) | |
Hyperglycemia | ||||
Borderline | 23 (11.1) | 38 (17.7) | 61 (14.4) | |
Overt | 6 (2.9) | 11 (5.1) | 17 (4.0) |
TC: total cholesterol; LDL: low-density lipoprotein; HDL: high-density lipoprotein.
The overall prevalence of hyperglycemia (defined as >6.11 mmol/L) was (69/423, 16.3%) of which 63.8% had borderline hyperglycemia, and 36.2% had overt diabetes mellitus (defined as >6.94 mmol/L). The proportion of patients with borderline hyperglycemia and overt diabetes mellitus on stavudine compared to AZT were similar (11%, 3% versus 18%, 5% resp.).
At bivariate analysis, use of stavudine (odds ratio (OR) 4.18, 95% CI 2.37–7.37,
Risk factors for borderline dyslipidemia.
Characteristics | Odds ratio | 95% CI |
|
Adjusted odds ratio | 95% CI |
|
---|---|---|---|---|---|---|
Male gender |
|
0.56–1.50 |
|
|||
Stavudine-based ART regimen |
|
2.37–7.37 |
|
4.79 | 2.45–9.38 |
|
Age |
|
0.89–1.19 |
|
|||
ART duration |
|
0.95–1.63 |
|
|||
Initial CD4 counts per 50 cells/ |
|
0.86–1.15 |
|
|||
ART start body weight |
|
0.90–1.05 |
|
|||
Peak body weight |
|
1.03–1.75 |
|
1.44 | 1.05–1.97 | 0.023 |
Enrolment BMI |
|
0.77–2.27 |
|
|||
Systolic blood pressure |
|
0.99–1.02 |
|
0.99 | 0.97–1.06 | 0.153 |
Enrolment CD4 count |
|
0.49–1.64 |
|
|||
Abnormal waist to hip ratio+ |
|
0.73–2.07 |
|
1.14 | 0.63–2.05 | 0.673 |
Family history of hypertension |
|
1.02–2.98 |
|
1.44 | 0.79–2.64 | 0.235 |
Family history of diabetes mellitus |
|
1.05–4.97 |
|
|||
Lipodystrophy |
|
1.28–5.99 |
|
1.60 | 0.61–4.21 | 0.338 |
WHO stage III and IV |
|
0.71–2.08 |
|
CI: confidence interval; ART: antiretroviral treatment; BMI: body mass index; WHO: World Health Organization.
+WHR defined abnormal if
Risk factors for borderline hyperglycemia.
Characteristics | Odds ratio | 95% CI |
|
Adjusted odds ratio | 95% CI |
|
---|---|---|---|---|---|---|
Male gender | 0.76 | 0.44–1.33 | 0.336 | 0.93 | 0.41–2.12 | 0.855 |
Stavudine-based ART regimen | 0.58 | 0.33–1.01 | 0.055 | 0.50 | 0.27–0.93 | 0.028 |
Age | 1.32* | 1.14–1.54 |
|
1.31 | 1.11–1.56 | 0.002 |
ART duration | 1.09 | 0.82–1.46 | 0.550 | |||
Initial CD4 counts per 50 cells/ |
0.94 | 0.80–1.11 | 0.463 | |||
ART start body weight | 1.00 | 0.97–1.03 | 0.95 | |||
Peak body weight |
1.00 | 0.92–1.09 | 0.957 | |||
Enrolment BMI |
1.00 | 1.00–1.02 | 0.213 | |||
Systolic blood pressure |
1.02 | 1.00– 1.03 | 0.05 | 1.01 | 0.90–1.03 | 0.146 |
Enrolment CD4 count |
1.06 | 0.55–2.05 | 0.86 | |||
Abnormal waist to hip ratio+ | 1.97 | 1.01–3.84 | 0.046 | 1.73 | 0.67–4.46 | 0.255 |
Family history of hypertension | 0.99 | 0.57–1.73 | 0.972 | |||
Family history of diabetes mellitus | 1.71 | 0.91–3.22 | 0.095 | 2.18 | 1.10–4.34 | 0.026 |
Lipodystrophy | 0.98 | 0.56–1.89 | 0.946 | |||
WHO stage III and IV | 1.00 | 0.54–1.85 | 0.991 |
CI: confidence interval; ART: antiretroviral treatment; BMI: body mass index; WHO: World Health Organization.
+WHR defined abnormal if
*Denote that age as a variable was supposed to be interpreted as a 5-year increase as interpreted in the text.
At multivariable analysis, the use of stavudine and peak body weight were independently associated with dyslipidemia (adjusted odds ratio (aOR) 4.79, 95% CI 2.45–9.38;
The use of stavudine had a protective effect on developing hyperglycemia (aOR 0.50, 95% CI 0.27–0.93;
Routine baseline fasting glucose and lipid profile are not usually measured in HIV-infected patients initiating ART in resource-limited settings like Uganda, due to cost. In this report, the overall prevalence of fasting dyslipidemia of 81.5% is the highest among published reports so far in SSA population. We observed a higher prevalence of dyslipidemia among patients on stavudine-containing regimens compared with zidovudine-containing regimen. The majority of these lipid abnormalities were due to borderline decreased levels of cardioprotective HDL-C in both categories of ART regimens. We observed a higher prevalence of an atherogenic lipid profile in patients on stavudine compared with zidovudine, TC (44.7% versus 33.7%), LDL-C (24.5% versus 14.9%), and TG (28.4% versus 19.1%), but AZT-based regimens also had notable rates of dyslipidemia. A similar study in an urban setting in Kenya among patients on stavudine-based regimens reported an overall prevalence of dyslipidemia of 63.1% [
Fasting hyperglycemia was observed in 14.4% of our patients (4% meeting the criteria of diabetes mellitus), with no significant differences between the ART regimens. This is a slightly lower prevalence than that reported from Rwanda (16%–18%) [
There were several differences observed between the patients initiated on stavudine- and zidovudine-containing regimens at enrollment. Patients on stavudine-containing regimens on average had a shorter duration of therapy compared to zidovudine, probably because of toxicities related to stavudine (peripheral neuropathy) [
Thymidine nucleosides, especially stavudine, are associated with mitochondrial toxicity and reduced clearance of free fatty acids and triglycerides, which is currently the most favored hypothesis to partly explain the atherogenic lipid profile and body fat redistribution in HIV-infected patients [
We identified two independent factors associated with dyslipidemia, being on a stavudine-containing regimen and a peak body weight of >65 kgs during ART. The majority of our patients were from an urban setting, and compared with individuals from rural communities, they are more likely to live a sedentary life, and to eat unhealthy diets which may be confounders in this study. Age and ART duration which have been reported in another study, [
The consequences of these HIV-associated metabolic disturbances in an African population are still unclear. However from DAD study in Europe and North American populations, a significant risk of cardiovascular morbidity was reported [
Although increased access to relatively cheaper generic fixed-drug combinations of ART have dramatically improved the outcome of patient with HIV infection in Africa, the problem of the increasing prevalence of dyslipidemia, hyperglycemia and body fat changes associated with the commonly available ART regimens should be addressed. Coupled with the adoption of western diets and sedentary lifestyle in our urban population, we are likely to see a steady rise in atherosclerotic diseases in patients on long-term ART. Mutimura and colleagues in Rwanda have shown in a clinical trial that simple but regular exercise can be beneficial in alleviating lipodystrophy and improving metabolic abnormalities, which can be adopted in an ART package of HIV-infected patients in RLS [
The authors have no conflict of interests to declare.
The authors wish to thank the Flemish Interuniversity Council, University Cooperation for Development for their financial contribution for the work. They also thank the Fogarty International Clinical Research Fellowship Program for the technical support and mentorship.