
 as antiretroviral therapy ( art ) coverage in sub - saharan african ( ssa ) populations continue to increase ,   deaths from hiv / aids has dramatically declined in the past decade . in ssa and other resource limited settings ( rls ) , where stavudine - containing art regimens have been extensively used , a wide range of disfiguring body fat changes and metabolic abnormalities have been reported [ 35 ] .
stavudine and zidovudine are both thymidine nucleoside analogues used in combination with lamivudine and either nevirapine or efavirenz as first - line therapy of hiv in most rls . after a recent who recommendation against use of stavudine - containing regimens
,   stavudine has been largely discontinued , but a large proportion of patients remain on zidovudine - containing regimens in uganda and other ssa due to cost considerations .
the mechanisms of these metabolic complications remain largely unclear , but several studies suggest that hiv itself , cytokine disregulation [ 7 , 8 ] , and the thymidine nucleosides - induced mitochondrial toxicity contribute to these abnormalities . epidemiological data on these metabolic abnormalities and risk of cardiovascular morbidity are still limited in ssa .
a few cross - sectional studies in the region have concentrated mainly on stavudine - containing regimens and little is reported on zidovudine - containing regimens [ 3 , 5 , 10 ] . in this study
we describe the metabolic abnormalities observed in patients on first - line art in an urban outpatient infectious diseases clinic in kampala , uganda on art for at least 12 months .
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 .
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 .
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 [ 1113 ] were used ( table 1 ) .
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 p value was obtained .
continuous variables were compared using a wilcoxon rank - sum test , a nonparametric test .   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 p value was used to show statistical significance .
variables with a p value < 0.20 , and those which had clinical significance were used in the multivariate model to identify factors associated with abnormal lipid and glucose levels .
the final model was tested for suitability in predicting the outcome using the hosmer - lemeshow test which a variant of chi square test and the model was deemed good if p < 0.05 .
the study was approved by makerere university department of medicine , faculty of medicine research and ethics board .
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 )
the median ( iqr ) age of the study participants was 39 years ( 3444 ) , and the median ( iqr ) initial cd4 counts was 90  cells/l ( 33168 ) .
two hundred and eight ( 49% ) were started on stavudine plus lamivudine plus nevirapine and 215 ( 51% ) on zidovudine plus lamivudine plus efavirenz ( n = 203 ) or nevirapine ( n = 12 ) .
results presented in table 2 show the characteristics of the patients initiated on stavudine- and zidovudine - based regimens . compared with the patients on zidovudine patients on stavudine
were more frequently male , had more often a family history of hypertension , had been on art for a shorter time , and had a higher median cd4 count at enrollment .
physician - assessed lipodystrophy was significantly higher in patients on stavudine with a greater median waist - to - hip ratio in the stavudine group .
patients on stavudine also had a higher median systolic blood pressure and overall hypertension .  
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 3 ) .
the proportion of patients with borderline and overt dyslipidemia on stavudine compared to azt was higher ( 91% , 22% versus 72% , 16% resp . ) .  
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 
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 2.377.37 , p < 0.001 ) , and lipodystrophy ( or 2.77 , 95% ci 1.285.99 , p = 0.01 ) were more likely to be associated with dyslipidemia compared to use the zidovudine ; a peak body weight > 65  kgs was also more likely to be associated with dyslipidemia ( or 1.35 , 95% ci 1.031.75 p = 0.027 ) ; family history of hypertension and diabetes mellitus increased the odds of being diagnosed with dyslipidemia ( or 1.75 , 95% ci 1.022.98 ;
p = 0.040 and or 2.29 , 95% ci 1.054.97 , p = 0.037 ) , respectively ( table 4 ) . factors that were associated with hyperglycemia at bivariate level were a 5-year increase in age ( or 1.32 , 95% ci 1.141.54 , p < 0.001 ) , and an abnormal waist - to - hip ratio ( or 1.97 , ci 1.013.84 , p = 0.046 ) ( table 5 ) . at multivariable analysis ,
the use of stavudine and peak body weight were independently associated with dyslipidemia ( adjusted odds ratio ( aor ) 4.79 , 95% ci 2.459.38 ; p < 0.001 and aor 1.44 , ci 1.051.97 ; p = 0.023 ) ( table 4 ) .
we repeated the analysis excluding patients with borderline lipid abnormalities and we found that the only factor independently associated with high lipid levels was obesity at enrollment ( aor 3.2 , 95% ci 1.228.27 ; p = 0.018 ) ( results not shown ) .
the use of stavudine had a protective effect on developing hyperglycemia ( aor 0.50 , 95% ci 0.270.93 ; p = 0.028 ) ; a 5-year increase in age increased the odds of developing hyperglycemia ( aor 1.31 , 95% ci 1.111.56 ; p = 0.002 ) and ; family history of diabetes mellitus increased the odds of having hyperglycemia ( aor 2.18 , 95% ci 1.104.34 ; p = 0.026 ) ( see table 5 ) .
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% . in a retrospective study in a rural setting in eastern uganda an even lower prevalence of dyslipidemia ( 1041% ) was noted but art regimens in the latter study were not constant during followup .  
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% )   and kenya ( 20.7% )   in patients on a stavudine regimen .   
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 )   and nevirapine ( liver toxicity and rash ) prompting early switch of therapy .
we found a higher prevalence of hypertension among patients on a stavudine - containing compared to a zidovudine - containing regimen ( 16% versus 7% ) .
moreover lipodystrophy was more prevalent in stavudine - based patients compared to zidovudine ( 35.8% versus 6.7% ) . in spite of lack of a uniform definition of lipodystrophy across the literature , our findings are similar to those observed in patients on stavudine - containing regimens in the region [ 5 , 16 ] .
previous studies have documented an association between art - associated lipodystrophy and hypertension but the explanation for this remains unclear .   
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 [ 79 ] .
in addition , interactions of nonnucleoside drug combinations on lipid metabolism may be significant in a setting where stavudine was most often given with nevirapine .
nevirapine was reported to have a more favorable lipoprotein profile ( causing elevation of the hdl - c ) compared with efavirenz .   
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 ,   were not significantly associated with dyslipidemia possibly because we only enrolled patients who were already on therapy for at least one year .
lipodystrophy was significantly associated with dyslipidemia at bivariate analysis , although it was not significant when adjusted for other factors .
age over 40 years was independently associated with hyperglycemia . however , at subanalysis when patients with borderline glucose levels were excluded , being overweight at assessment and obese at enrollment ( by bmi ) were independently associated with overt diabetes mellitus whereas higher median cd4 ( > 100  cells/l ) at initiation of art was protective ( data not shown ) .
again , aging and urban lifestyle are likely to play a significant role in the development of insulin resistance and diabetes mellitus in hiv - infected patients on art .  
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 .
the major limitations of this study are its cross - sectional design , nonrandomized treatment allocations and a subjective clinical assessment of lipodystrophy . allocation to fixed regimen occurred in rls in sub - saharan africa where the relative risk of thymidine analogues compared to nnrti could not be separated .
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 .
our study justifies the ministry of health action in uganda to phase out stavudine - use from first - line art drug list but our study shows that zidovudine contributes to metabolic abnormalities as well .
all hiv - infected patients on thymidine analogues should be screened for glucose and lipid abnormalities .
furthermore , prospective studies to evaluate long term effect of these metabolic disturbances on cardiovascular health are needed .
 
 introduction . while the introduction of highly active antiretroviral therapy decreased hiv - related morbidity and mortality rates in the sub - saharan africa , a subsequent increase in metabolic abnormalities has been observed . 
 we sought to determine the prevalence of hiv - associated metabolic abnormalities among patients on first - line antiretroviral therapy ( art ) in an art clinic in kampala , uganda . methods . 
 four hundred forty - two consecutive patients on first - line art for at least 12 months were screened for eligibility in a cross - sectional study , and 423 were enrolled . 
 pre - art patient characteristics were abstracted from medical charts , examinations included anthropometric measurement and physical assessment for lipodystrophy . 
 results . 
 the prevalence of hyperglycemia and dyslipidemia was 16.3% ( 69/423 ) and 81.5% ( 345/423 ) , respectively . 
 prevalence of dyslipidemia between stavudine- and zidovudine - based regimens ( 91% versus 72% ; p < 0.001 ) . 
 being on stavudine ( aor 4.79 , 95% , 2.459.38 ) and peak body weight ( aor 1.44 , 95% ci  1.051.97 ) were independent risk factors for dylipidemia . 
 stavudine ( aor 0.50 , 95% ci   0.270.93 ) use was associated with lower risk for hyperglycemia while , and older age ( aor 1.31 , 95% ci  1.111.56 ) and having a family history of dm ( aor 2.18 , 95% ci  1.104.34 ) were independent risk factors for hyperglycemia . 
 conclusions . 
 hiv - associated metabolic complications were prevalent among patients on thymidine analogue - containing art regimens . screening for lipid and glucose abnormalities should be considered in art patients because of cardiovascular risks . 
1. Introduction
2. Materials and Methods
3. Results
4. Discussion