adherence to antiretroviral therapy ( art ) is essential for maximal suppression of viral replication and avoidance of drug resistance . as such
, good adherence is believed to be a critical determinant of long - term survival among hiv - infected individuals . where availability of second - line or salvage antiretroviral drug regimens is limited
early studies in africa reported adherence levels as high or higher than those observed in developed countries .
however , measures used to assess adherence vary and many have not been validated in the context of rapid art scale - up . in this analysis
, we describe the impact of art adherence on immunologic response and survival in a large population of adults initiating art in lusaka , zambia .
we use the medication possession ratio  a simple metric that has been correlated with virologic outcomes in developed countries  to describe the adherence behaviour of our population .
in lusaka , zambia , a large - scale public sector hiv care and treatment program was established by the zambian ministry of health in april 2004 .
clinical care , patient tracking and outcomes monitoring for the lusaka program have been described elsewhere .
briefly , care has been standardized across all sites according to the zambian national guidelines for adult hiv treatment . in the first months of the program ,
art was initiated in individuals with either a cd4 cell count < 200 cells/l or who stage iii / iv .
since 2005 , the zambian guidelines have been revised , so that art eligibility for patients in who stage 3 requires a cd4 cell count 350 cells/l .
first - line drug regimens in zambia had comprised two nucleoside reverse transcriptase inhibitors ( lamivudine with either zidovudine or stavudine ) and one non - nucleoside reverse transcriptase inhibitor ( nnrti ; nevirapine or efavirenz ) . since july 2007 , however , the zambian ministry of health has incorporated combination tenofovir / emtricitabine as a first - line nucleoside reverse transcriptase inhibitor backbone for individuals newly initiating therapy ; those continuing therapy remain on their previous regimen except in cases of toxicity or treatment failure .
antiretroviral drugs provided are free of charge and dispensed by pharmacy technicians or nurses within the art clinic itself .
these individuals are authorized to collect a limited number of drug refills when the patient is unable to attend a pharmacy appointment .
medical information , including the number of pills dispensed and the date of next visit , is entered into an electronic patient tracking system .
patients on art who are > 10 days late for a scheduled appointment are followed up by community health workers at their homes .
we calculated adherence based on a variation of the commonly - reported medication possession ratio ( mpr ) .
we divided the number of days late for pharmacy refills by total days on therapy , and then subtracted that percentage from 100% .
the resulting figure represents the percentage of days a patient is known to have medication on hand and has been correlated with hiv virologic outcomes in africa . in the lusaka public sector , patients are provided a buffer stock of 3 days with each drug dispensation ; therefore , we began calculating lateness on the fourth day after a missed pharmacy appointment . since art is provided free charge by the zambian government , the 
patients were categorized as optimally adherent ( 95% ) , suboptimally adherent ( 8094% ) and poorly adherent ( < 80% ) .
owing to the high rates of early mortality in our setting and others like it , we excluded patients from this analysis who had been on therapy for < 12 months .
we reasoned that poor patient outcomes associated with adherence would likely manifest later in the course of treatment , after viral drug resistance and treatment failure had developed .
early death also introduces bias into the mpr measurement , since these patients do not have the same opportunity to fully demonstrate long - term adherence behaviours . for these reasons
, we considered only adherence behaviour during the first 12 months and evaluated outcomes after 12 months .
active if they attended their last scheduled clinical and/or pharmacy visit within 30 days of their appointment date .
 dead patients are so classified in the medical record after confirmation from family members , friends or community health workers . 
late patients are > 30 days overdue for their last scheduled clinical and/or pharmacy visit and can not be located via community health worker contact tracing . in survival analyses and rate calculations ,
inactive patients are censored as of the date they became inactive , and late patients are censored 30 days after their last scheduled visit .
we analysed programmatic data from treatment - nave adults ( > 15 years ) initiating art across 18 primary care sites in lusaka , zambia from april 1 , 2004 to september 30 , 2007 . to be included in the analysis , individuals had to be active for 12 months of follow - up , so that the mpr measure for adherence could be calculated .
those who had died , withdrew from the program or were lost to follow - up prior to 12 months were excluded . to compare demographic and clinical characteristics among members of the study population and those who were excluded , we analysed categorical variables using pearson 's chi - square test
. non - parametric wilcoxon rank - sum tests were used to compare continuous variables .
we used logistic regression to describe the association between these characteristics and adherence to therapy at 12 months . in this multivariable analysis
, we included all covariates associated with adherence at a p - value < 0.10 level .
log - rank tests were used to evaluate differences in survival among adherence categories using kaplan 
meier analysis ; cox proportional hazards models were used to assess the risk of death .
the proportional hazards assumption was confirmed via the kolmogorov - type supremum test ( p = 0.83 ) .
all factors associated in crude analysis with p - value < 0.10 , or that have been previously shown to be associated with mortality in our setting , were included in the multivariable analysis .
however , we excluded any such covariate if it was believed to be an intermediary step between the exposure and outcome .
( for example , we include enrollment cd4 lymphocyte count in the multivariable models but not later measures of cd4 ) . in all adjusted models ,
continuous covariates were categorized based on the conventions in the medical literature . finally , we compared clinical and immunologic outcomes ( i.e. cd4 count , weight , haemoglobin ) longitudinally according to mpr categories .
means and corresponding 95% cis at each time point were calculated ; trends were evaluated at each 6-month interval using separate student 's t - tests .
available patient data through november 1 , 2008 , the dataset freeze date , were considered in this report .
all analyses were performed using sas version 9.1 ( sas institute , cary , nc , usa ) , and were approved by the institutional review boards of the university of zambia ( lusaka , zambia ) and the university of alabama at birmingham ( birmingham , al , usa ) , and by the us centers for disease control and prevention ( atlanta , ga , usa ) .
from april 1 , 2004 to september 30 , 2007 , 37 039 art - nave adults ( > 15 years of age ) initiated treatment across 18 sites in lusaka , zambia .
of these , 27 115 ( 73.2% ) remained active in the program at or after 12 months and were thus included in the analysis .
a total of 9924 ( 26.8% ) were excluded from the analysis because they had left the program before reaching the 12 month threshold : 1133 withdrew from the program , 5114 were late for patient visits and 3677 had died ( crude mortality rate = 105.5/100 person - years , 95% ci : 102.1108.9 ) . a comparison of those included and excluded from the analysis is shown in table 1 . 

table 1characteristics of treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthsincluded in analysisexcluded from analysisnvaluenvaluepage , median years ( iqr)27 11535 ( 3041)992434 ( 2940)<0.001  1525271810.0%128512.9%<0.001  263512 15944.8%452645.6%  3645863631.8%288429.1%  4655287510.6%9019.1%  567272.7%3283.3%sex  female16 88962.3%556656.1%<0.001  male10 22637.7%435843.9%adherence supporter  no546920.2%328933.1%<0.001  yes21 64679.8%663566.9%cd4 lymphocyte count , median cells/l ( iqr)26 068132 ( 69198)9409110 ( 48191)<0.001  200 cells/l635824.4%212122.5%<0.001  50199 cells/l15 27458.6%485551.6% 
< 50 cells/l443617.0%243325.9%who stage  i or ii874132.5%233023.8%<0.001  iii15 78958.6%605761.8%  iv23988.9%142014.5%haemoglobin , median g / dl ( iqr)23 79610.9 ( 9.612.3)837010.2 ( 8.711.8)<0.001  8.0 g / dl21 99592.4%712285.1%<0.001  < 8.0
g / dl18017.6%124814.9%bmi , median kg / m ( iqr)24 25020.0 ( 18.122.3)835818.9 ( 16.921.2)<0.001  20 kg / m12 14750.1%307836.8%<0.001  1819 kg / m614825.4%201524.1%  1617
kg / m425817.6%193023.1%  < 16 kg / m16977.0%133516.0%tuberculosis co - infection at enrollment  no23 48886.6%856986.3%0.49  yes362713.4%135513.7%initial art regimen  d4 t + 3tc + nvp10 69939.7%469148.0%<0.001  zdv + 3tc + nvp12 99648.3%350135.8% 
d4 t + 3tc + efv15235.7%8758.9%  zdv + 3tc + efv10263.8%4234.3%  tdf + ftc + nvp2290.9%981.0%  tdf + ftc + efv4481.7%1942.0%adherence by mpr , median ( iqr)27 11597.9 ( 91.2100.0)9924100.0 ( 92.6100.0)<0.00l  95100%17 06062.9%705171.0%<0.00l  8094%768228.3%141214.2%  < 80%23738.8%146114.7%for those included in the analysis , adherence by mpr was based on behaviour within the first 12 months from art initation . for those excluded because they were not active at 12 months , mpr was based on time from art initiation to censor date .
art = antiretrovinal therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . characteristics of treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months for those included in the analysis , adherence by mpr was based on behaviour within the first 12 months from art initation . for those excluded because they were not active at 12 months , mpr was based on time from art initiation to censor date .
art = antiretrovinal therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . of the 27 115 included in this analysis , 1419 ( 5.2% ) withdrew from the program , 3067 ( 11.3% )
were late for their most recent scheduled visit , and 823 ( 3.0% ) were known to have died ( crude post-12 month mortality rate = 2.1/100 person - years , 95% ci : 2.0 , 2.3 ) after the initial 12-month period .
the median observation period was 15.7 [ interquartile range ( iqr ) = 7.526.4 ] months , from 12 months onward . of 27 115 patients , 17 060 ( 62.9% ) demonstrated optimal adherence , 7682 ( 28.3% ) had suboptimal adherence and 2373 ( 8.8% ) had poor adherence over the first 12 months on therapy ( figure 1 ) .
individuals with an mpr < 80% were more likely to have a higher median cd4 count at enrollment than those with optimal adherence .
when compared with those with optimal adherence , individuals in the 8094 and < 80% mpr were generally younger and were less likely to report adherence support ( i.e. adherence 
the proportion of individuals with tuberculosis at time of art initiation was lower among individuals with suboptimal adherence ( 12.2 vs 14.0% ; p < 0.001 ) when compared with those with optimal adherence .
the proportion of patients who withdrew from the program or were lost to follow - up after 12 months increased as adherence declined categorically ( table 2 ) . 

figure 1distribution of adherence to art over the first 12 months on treatment among adults surviving to at least 12 months in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data 
 table 2characteristics by adherence category for treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthsoptimal ( 95100%)sub - optimal ( 8094%)poor ( < 80%)nvaluenvaluepnvaluepage , median years ( iqr)17 06035 ( 3041)768234 ( 2941)0.03237333 ( 2840)<0.001  152516019.4%78210.2%0.1233514.1%<0.001  2635762044.7%345845.0%108145.6%  3645552532.4%244131.8%67028.2%  4655186310.9%78510.2%2279.6%  564512.6%2162.8%602.5%sex  female10
73062.9%468561.0%<0.01147462.1%0.46  male633037.1%299739.0%89937.9%adherence supporter reported at enrollment14 05782.4%594377.4%<0.001164669.4%<0.001cd4 lymphocyte count , median cells/l ( iqr)16 469132 ( 70196)7350129 ( 68198)0.592249139 ( 73207)<0.001  200 cells/l394323.9%180424.5%0.6061127.2%<0.01  50199 cells/l969958.9%429358.4%128257.0%  < 50 cells/l282717.2%125317.0%35615.8%who stage  i or ii553232.6%243632.0%0.1977332.9%0.81  iii995658.7%446758.7%136658.1%  iv14738.7%7139.4%2129.0%haemoglobin , median g / dl ( iqr)15 18610.9 ( 9.612.3)665710.9 ( 9.612.3)0.42195311.0 ( 9.512.4)0.49  8.0 g / dl14 06092.6%615492.4%0.71178191.2%0.03  < 8.0 g / dl11267.4%5037.6%1728.8%bmi , median kg / m ( iqr)15 35620.0 ( 18.122.3)684620.0 ( 18.022.2)0.34204819.9 ( 18.022.3)0.53  20 kg / m772550.3%341849.9%0.42100449.0%0.75  1819 kg / m390925.5%170324.9%53626.2%  1617
kg / m265317.3%124118.1%36417.8%  < 16 kg / m10697.0%4847.1%1447.0%tuberculosis co - infection at enrollment238214.0%93712.2%<0.00130813.0%0.19initial art regimen  d4 t + 3tc + nvp673139.7%304239.9%0.0792639.7%0.24  zdv + 3tc + nvp822248.5%365547.9%111947.9% 
d4 t + 3tc + efv9435.6%4405.8%1406.0%  zdv + 3tc + efv6283.7%2983.9%1004.3%  tdf + ftc + nvp1671.0%490.6%130.6%  tdf + ftc + efv2711.6%1411.8%361.5%lost to follow - up or withdrawn after 12 months229413.4%140418.3%<0.00178833.2%<0.001defined at 12 months of therapy as the percentage of time on therapy with art via pharmacy claims.based on comparisons to the optimal adherence category.art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . distribution of adherence to art over the first 12 months on treatment among adults surviving to at least 12 months in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data characteristics by adherence category for treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months defined at 12 months of therapy as the percentage of time on therapy with art via pharmacy claims . based on comparisons to the optimal adherence category .
art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
individuals who were > 35 years [ odds ratio ( or ) : 0.8 ; 95% ci : 0.70.9 ] or reported presence of an adherence 
buddy ( or : 0.5 ; 95%ci : 0.50.6 ) were less likely to have mpr < 80% . when compared with those with cd4 count
> 200 cells/l , those with lower baseline cd4 counts were less likely to be poorly adherent over the first 12 months : 50199 cells/l ( or : 0.9 , 95% ci = 0.81.0 ) and < 50 cells/l ( or : 0.8 , 95% ci : 0.70.9 ) .
baseline world health organization ( who ) clinical stage , haemoglobin , body mass index ( bmi ) and tuberculosis status were not predictive of poor adherence ( data not shown ) . in kaplan 
meier analysis , individuals with < 80% adherence had a significantly higher risk of death when compared with those in other adherence categories ( log rank p = 0.0001 ) .
in unadjusted proportional hazards regression , the relative hazard for death was 1.7 ( 95% ci : 1.42.1 ) among those with poor adherence , when compared with those with optimal adherence .
these findings remained virtually unchanged in a multivariable model controlling for sex , age , adherence support , baseline cd4 lymphocyte count , baseline who stage and initial regimen dispensed [ n = 25 836 ; adjusted hazard ratio ( ahr ) : 1.7 ; 95% ci : 1.42.2 ] .
baseline haemoglobin and bmi were not included in this initial multivariable model , since early versions of our patient tracking software did not routinely collect these data . in a separate model that included these two parameters ( n = 20 951 ) , the hazard for mortality associated with poor adherence did not change appreciably ( table 3 ) . 
 figure
2post-12-month mortality by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data .
the numbers shown at the bottom of the graph represent the number of patients active in each adherence category at 6-monthly intervals .
perfect survival in the first 12 months is a result of our study design . to be eligible for inclusion in this analysis , patients had to remain alive , active , and on art until at least 12 months 
 table 3factors associated with post-12-month mortality among treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthscrude hazard ratio ( 95% ci)adjusted hazard ratio ( 95% ci)adherence  optimal ( 95100%)1.01.0  suboptimal ( 8094%)1.0 ( 0.91.2)0.9 ( 0.81.1 )  poor ( < 80%)1.7 ( 1.42.1)1.7 ( 1.42.3)age  35 years1.01.0  > 35 years1.4 ( 1.21.6)1.4 ( 1.21.6)sex  female1.01.0  male1.4 ( 1.21.6)1.3 ( 1.11.5)adherence supporter  no1.01.0  yes0.7 ( 0.60.8)0.7 ( 0.60.9)cd4 count  200 cells/l1.01.0  50199 cells/l1.3 ( 1.01.5)1.2 ( 1.01.6 )  < 50 cells/l1.9 ( 1.52.3)1.5 ( 1.22.0)who stage  i or ii1.01.0  iii1.6 ( 1.41.9)1.4 ( 1.11.7 )  iv2.5 ( 2.03.2)2.0 ( 1.52.7)haemoglobin  8.0 g / dl1.01.0  < 8.0 g / dl2.0 ( 1.62.5)1.6 ( 1.22.0)bmi  16 kg / m1.01.0  < 16 kg / m2.2 ( 1.82.8)1.8 ( 1.42.2)initial art regimen  d4 t + 3tc + nvp1.01.0  zdv + 3tc + nvp0.7 ( 0.60.8)0.7 ( 0.60.9 )  d4 t + 3tc + efv1.1 ( 0.81.4)0.9 ( 0.71.3 )  zdv + 3tc + efv0.8 ( 0.51.1)0.8 ( 0.51.3)adherence defined by mpr.in adjusted models
, tenofovir - based regimens were not included due to relatively small number of patients who received these drugs ( n = 636 ) and deaths documented among this group ( n = 2).art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
post-12-month mortality by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data .
the numbers shown at the bottom of the graph represent the number of patients active in each adherence category at 6-monthly intervals .
perfect survival in the first 12 months is a result of our study design . to be eligible for inclusion in this analysis
, patients had to remain alive , active , and on art until at least 12 months factors associated with post-12-month mortality among treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months adherence defined by mpr . in adjusted models , tenofovir - based regimens were not included due to relatively small number of patients who received these drugs ( n = 636 ) and deaths documented among this group ( n = 2 ) .
art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
while trends in cd4 response , haemoglobin response and weight gain appeared similar for individuals in the optimal and suboptimal adherence categories , outcomes generally appeared worse among those with poor adherence ( figure 3 ) . when compared with individuals with 80% adherence , for example , those with poor adherence appeared to have an attenuated cd4 response at 18 months ( 185 vs 217 cells/l ; p < 0.001 ) , 24 months ( 213 vs 246 cells/l ; p < 0.001 ) , 30 months ( 226 vs 261 cells/l ; p < 0.001 ) and 36 months ( 245 vs 275 cells/l ; p < 0.01 ) .
those with < 80% mpr in their first 12 months also had attenuated increases in weight and haemoglobin at 18 months ( 5.0 vs 5.8 kg ; p < 0.001 and 1.7 vs 2.0 g / dl ; p
< 0.001 ) , 24 months ( 5.5 vs 6.0 kg ; p < 0.05 and 1.7 vs 2.0 g / dl ; p < 0.001 ) , 30 months ( 5.8 vs 6.3 kg ; p < 0.17 and 1.8 vs 2.1 g / dl ; p < 0.01 ) and 36 months ( 5.6 vs 6.4 kg ; p < 0.06 and 2.0 vs 2.1 g / dl ; p = 0.35 ) . 
 figure
3immunologic and clinical responses by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 , and remaining on art for > 12 months .
these include ( a ) cd4 lymphocyte count , ( b ) haemoglobin and ( c ) weight immunologic and clinical responses by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 , and remaining on art for > 12 months .
these include ( a ) cd4 lymphocyte count , ( b ) haemoglobin and ( c ) weight
from april 1 , 2004 to september 30 , 2007 , 37 039 art - nave adults ( > 15 years of age ) initiated treatment across 18 sites in lusaka , zambia .
of these , 27 115 ( 73.2% ) remained active in the program at or after 12 months and were thus included in the analysis .
a total of 9924 ( 26.8% ) were excluded from the analysis because they had left the program before reaching the 12 month threshold : 1133 withdrew from the program , 5114 were late for patient visits and 3677 had died ( crude mortality rate = 105.5/100 person - years , 95% ci : 102.1108.9 ) . a comparison of those included and excluded from the analysis is shown in table 1 . 

table 1characteristics of treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthsincluded in analysisexcluded from analysisnvaluenvaluepage , median years ( iqr)27 11535 ( 3041)992434 ( 2940)<0.001  1525271810.0%128512.9%<0.001  263512 15944.8%452645.6%  3645863631.8%288429.1%  4655287510.6%9019.1%  567272.7%3283.3%sex  female16 88962.3%556656.1%<0.001  male10 22637.7%435843.9%adherence supporter  no546920.2%328933.1%<0.001  yes21 64679.8%663566.9%cd4 lymphocyte count , median cells/l ( iqr)26 068132 ( 69198)9409110 ( 48191)<0.001  200 cells/l635824.4%212122.5%<0.001  50199 cells/l15 27458.6%485551.6% 
< 50 cells/l443617.0%243325.9%who stage  i or ii874132.5%233023.8%<0.001  iii15 78958.6%605761.8%  iv23988.9%142014.5%haemoglobin , median g / dl ( iqr)23 79610.9 ( 9.612.3)837010.2 ( 8.711.8)<0.001  8.0 g / dl21 99592.4%712285.1%<0.001  < 8.0
g / dl18017.6%124814.9%bmi , median kg / m ( iqr)24 25020.0 ( 18.122.3)835818.9 ( 16.921.2)<0.001  20 kg / m12 14750.1%307836.8%<0.001  1819 kg / m614825.4%201524.1%  1617
kg / m425817.6%193023.1%  < 16 kg / m16977.0%133516.0%tuberculosis co - infection at enrollment  no23 48886.6%856986.3%0.49  yes362713.4%135513.7%initial art regimen  d4 t + 3tc + nvp10 69939.7%469148.0%<0.001  zdv + 3tc + nvp12 99648.3%350135.8% 
d4 t + 3tc + efv15235.7%8758.9%  zdv + 3tc + efv10263.8%4234.3%  tdf + ftc + nvp2290.9%981.0%  tdf + ftc + efv4481.7%1942.0%adherence by mpr , median ( iqr)27 11597.9 ( 91.2100.0)9924100.0 ( 92.6100.0)<0.00l  95100%17 06062.9%705171.0%<0.00l  8094%768228.3%141214.2%  < 80%23738.8%146114.7%for those included in the analysis , adherence by mpr was based on behaviour within the first 12 months from art initation . for those excluded because they were not active at 12 months , mpr was based on time from art initiation to censor date .
art = antiretrovinal therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . characteristics of treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months for those included in the analysis , adherence by mpr was based on behaviour within the first 12 months from art initation . for those excluded because they were not active at 12 months , mpr was based on time from art initiation to censor date .
art = antiretrovinal therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . of the 27 115 included in this analysis , 1419 ( 5.2% ) withdrew from the program , 3067 ( 11.3% )
were late for their most recent scheduled visit , and 823 ( 3.0% ) were known to have died ( crude post-12 month mortality rate = 2.1/100 person - years , 95% ci : 2.0 , 2.3 ) after the initial 12-month period .
the median observation period was 15.7 [ interquartile range ( iqr ) = 7.526.4 ] months , from 12 months onward . of 27 115 patients , 17 060 ( 62.9% ) demonstrated optimal adherence , 7682 ( 28.3% ) had suboptimal adherence and 2373 ( 8.8% ) had poor adherence over the first 12 months on therapy ( figure 1 ) .
individuals with an mpr < 80% were more likely to have a higher median cd4 count at enrollment than those with optimal adherence .
when compared with those with optimal adherence , individuals in the 8094 and < 80% mpr were generally younger and were less likely to report adherence support ( i.e. adherence 
the proportion of individuals with tuberculosis at time of art initiation was lower among individuals with suboptimal adherence ( 12.2 vs 14.0% ; p < 0.001 ) when compared with those with optimal adherence .
the proportion of patients who withdrew from the program or were lost to follow - up after 12 months increased as adherence declined categorically ( table 2 ) . 

figure 1distribution of adherence to art over the first 12 months on treatment among adults surviving to at least 12 months in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data 
 table 2characteristics by adherence category for treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthsoptimal ( 95100%)sub - optimal ( 8094%)poor ( < 80%)nvaluenvaluepnvaluepage , median years ( iqr)17 06035 ( 3041)768234 ( 2941)0.03237333 ( 2840)<0.001  152516019.4%78210.2%0.1233514.1%<0.001  2635762044.7%345845.0%108145.6%  3645552532.4%244131.8%67028.2%  4655186310.9%78510.2%2279.6%  564512.6%2162.8%602.5%sex  female10
73062.9%468561.0%<0.01147462.1%0.46  male633037.1%299739.0%89937.9%adherence supporter reported at enrollment14 05782.4%594377.4%<0.001164669.4%<0.001cd4 lymphocyte count , median cells/l ( iqr)16 469132 ( 70196)7350129 ( 68198)0.592249139 ( 73207)<0.001  200 cells/l394323.9%180424.5%0.6061127.2%<0.01  50199 cells/l969958.9%429358.4%128257.0%  < 50 cells/l282717.2%125317.0%35615.8%who stage  i or ii553232.6%243632.0%0.1977332.9%0.81  iii995658.7%446758.7%136658.1%  iv14738.7%7139.4%2129.0%haemoglobin , median g / dl ( iqr)15 18610.9 ( 9.612.3)665710.9 ( 9.612.3)0.42195311.0 ( 9.512.4)0.49  8.0 g / dl14 06092.6%615492.4%0.71178191.2%0.03  < 8.0 g / dl11267.4%5037.6%1728.8%bmi , median kg / m ( iqr)15 35620.0 ( 18.122.3)684620.0 ( 18.022.2)0.34204819.9 ( 18.022.3)0.53  20 kg / m772550.3%341849.9%0.42100449.0%0.75  1819 kg / m390925.5%170324.9%53626.2%  1617
kg / m265317.3%124118.1%36417.8%  < 16 kg / m10697.0%4847.1%1447.0%tuberculosis co - infection at enrollment238214.0%93712.2%<0.00130813.0%0.19initial art regimen  d4 t + 3tc + nvp673139.7%304239.9%0.0792639.7%0.24  zdv + 3tc + nvp822248.5%365547.9%111947.9% 
d4 t + 3tc + efv9435.6%4405.8%1406.0%  zdv + 3tc + efv6283.7%2983.9%1004.3%  tdf + ftc + nvp1671.0%490.6%130.6%  tdf + ftc + efv2711.6%1411.8%361.5%lost to follow - up or withdrawn after 12 months229413.4%140418.3%<0.00178833.2%<0.001defined at 12 months of therapy as the percentage of time on therapy with art via pharmacy claims.based on comparisons to the optimal adherence category.art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz . distribution of adherence to art over the first 12 months on treatment among adults surviving to at least 12 months in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data characteristics by adherence category for treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months defined at 12 months of therapy as the percentage of time on therapy with art via pharmacy claims . based on comparisons to the optimal adherence category .
art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
individuals who were > 35 years [ odds ratio ( or ) : 0.8 ; 95% ci : 0.70.9 ] or reported presence of an adherence 
buddy ( or : 0.5 ; 95%ci : 0.50.6 ) were less likely to have mpr < 80% . when compared with those with cd4 count
> 200 cells/l , those with lower baseline cd4 counts were less likely to be poorly adherent over the first 12 months : 50199 cells/l ( or : 0.9 , 95% ci = 0.81.0 ) and < 50 cells/l ( or : 0.8 , 95% ci : 0.70.9 ) .
baseline world health organization ( who ) clinical stage , haemoglobin , body mass index ( bmi ) and tuberculosis status were not predictive of poor adherence ( data not shown ) .
in kaplan  meier analysis , individuals with < 80% adherence had a significantly higher risk of death when compared with those in other adherence categories ( log rank p = 0.0001 ) .
in unadjusted proportional hazards regression , the relative hazard for death was 1.7 ( 95% ci : 1.42.1 ) among those with poor adherence , when compared with those with optimal adherence .
these findings remained virtually unchanged in a multivariable model controlling for sex , age , adherence support , baseline cd4 lymphocyte count , baseline who stage and initial regimen dispensed [ n = 25 836 ; adjusted hazard ratio ( ahr ) : 1.7 ; 95% ci : 1.42.2 ] .
baseline haemoglobin and bmi were not included in this initial multivariable model , since early versions of our patient tracking software did not routinely collect these data . in a separate model that included these two parameters ( n = 20 951 ) , the hazard for mortality associated with poor adherence did not change appreciably ( table 3 ) . 
 figure
2post-12-month mortality by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data .
the numbers shown at the bottom of the graph represent the number of patients active in each adherence category at 6-monthly intervals .
perfect survival in the first 12 months is a result of our study design . to be eligible for inclusion in this analysis
, patients had to remain alive , active , and on art until at least 12 months 
 table 3factors associated with post-12-month mortality among treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 monthscrude hazard ratio ( 95% ci)adjusted hazard ratio ( 95% ci)adherence  optimal ( 95100%)1.01.0  suboptimal ( 8094%)1.0 ( 0.91.2)0.9 ( 0.81.1 )  poor ( < 80%)1.7 ( 1.42.1)1.7 ( 1.42.3)age  35 years1.01.0  > 35 years1.4 ( 1.21.6)1.4 ( 1.21.6)sex  female1.01.0  male1.4 ( 1.21.6)1.3 ( 1.11.5)adherence supporter  no1.01.0  yes0.7 ( 0.60.8)0.7 ( 0.60.9)cd4 count  200 cells/l1.01.0  50199 cells/l1.3 ( 1.01.5)1.2 ( 1.01.6 )  < 50 cells/l1.9 ( 1.52.3)1.5 ( 1.22.0)who stage  i or ii1.01.0  iii1.6 ( 1.41.9)1.4 ( 1.11.7 )  iv2.5 ( 2.03.2)2.0 ( 1.52.7)haemoglobin  8.0 g / dl1.01.0  < 8.0 g / dl2.0 ( 1.62.5)1.6 ( 1.22.0)bmi  16 kg / m1.01.0  < 16 kg / m2.2 ( 1.82.8)1.8 ( 1.42.2)initial art regimen  d4 t + 3tc + nvp1.01.0  zdv + 3tc + nvp0.7 ( 0.60.8)0.7 ( 0.60.9 )  d4 t + 3tc + efv1.1 ( 0.81.4)0.9 ( 0.71.3 )  zdv + 3tc + efv0.8 ( 0.51.1)0.8 ( 0.51.3)adherence defined by mpr.in adjusted models , tenofovir - based regimens were not included due to relatively small number of patients who received these drugs ( n = 636 ) and deaths documented among this group ( n = 2).art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
post-12-month mortality by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 .
adherence was measured by the number of days a patient had antiretroviral drugs available according to pharmacy refill data .
the numbers shown at the bottom of the graph represent the number of patients active in each adherence category at 6-monthly intervals .
perfect survival in the first 12 months is a result of our study design . to be eligible for inclusion in this analysis
, patients had to remain alive , active , and on art until at least 12 months factors associated with post-12-month mortality among treatment - nave adults initiating art in lusaka , zambia , from april 1 , 2004 to september 30 , 2007 and continuing art for > 12 months adherence defined by mpr . in adjusted models , tenofovir - based regimens were not included due to relatively small number of patients who received these drugs ( n = 636 ) and deaths documented among this group ( n = 2 ) .
art = antiretroviral therapy ; d4 t = stavudine ; zdv = zidovudine ; 3tc = lamivudine ; nvp = nevirapine ; efv = efavirenz .
while trends in cd4 response , haemoglobin response and weight gain appeared similar for individuals in the optimal and suboptimal adherence categories , outcomes generally appeared worse among those with poor adherence ( figure 3 ) . when compared with individuals with 80% adherence , for example , those with poor adherence appeared to have an attenuated cd4 response at 18 months ( 185 vs 217 cells/l ; p < 0.001 ) , 24 months ( 213 vs 246 cells/l ; p < 0.001 ) , 30 months ( 226 vs 261 cells/l ; p < 0.001 ) and 36 months ( 245 vs 275 cells/l ; p < 0.01 ) .
those with < 80% mpr in their first 12 months also had attenuated increases in weight and haemoglobin at 18 months ( 5.0 vs 5.8 kg ; p < 0.001 and 1.7 vs 2.0 g / dl ; p < 0.001 ) , 24 months ( 5.5 vs 6.0 kg ; p < 0.05 and 1.7 vs 2.0 g / dl ; p < 0.001 ) , 30 months ( 5.8 vs 6.3 kg ; p < 0.17 and 1.8 vs 2.1 g / dl ; p < 0.01 ) and 36 months ( 5.6 vs 6.4 kg ; p < 0.06 and 2.0 vs 2.1 g / dl ; p = 0.35 ) . 
 figure
3immunologic and clinical responses by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 , and remaining on art for > 12 months .
these include ( a ) cd4 lymphocyte count , ( b ) haemoglobin and ( c ) weight immunologic and clinical responses by adherence category for art - nave adults initiating art in lusaka , zambia , between april 1 , 2004 and september 30 , 2007 , and remaining on art for > 12 months .
these include ( a ) cd4 lymphocyte count , ( b ) haemoglobin and ( c ) weight
we investigated art adherence in an extremely busy , public sector art program in sub - saharan africa . when optimal adherence was defined as mpr  95% , 60% met this criterion .
less than 10% met criteria for poor adherence ( mpr < 80% ) ; however , we observed poor clinical and immunologic response among individuals in this group .
although routine viral load data are not available in our setting , the 80% mpr threshold appears to hold some significance for crude measures of treatment response such as mortality and cd4 lymphocyte count improvement .
mpr and mpr - like measurements for adherence ( e.g. pharmacy refills , timeliness to clinical appointments ) have been closely associated with virologic and clinical outcomes among patients on art .
we observed increased mortality after 12 months among those with adherence < 80% : a finding similar to other studies in the published literature .
for example , hogg and colleagues found that intermittent use of art ( defined as drug refills of < 75% ) was associated with a nearly 3-fold risk in mortality in british columbia .
nachega et al . found that adherence to antiretroviral drug refills of < 80% was associated with a 3-fold increase for death in the south african private sector .
the risk for adverse outcomes observed in this cohort was of a slightly lesser magnitude when compared with other published series .
to better understand the impact of adherence on later outcomes , we included only individuals enrolled in the program for > 12 months .
thus , there is selection bias towards longer term survivors , regardless of drug adherence behaviour .
this is most evident in the baseline characteristics of the population , where those in the lower adherence stratifications had somewhat higher median cd4 lymphocyte counts .
the attenuated effect may be a reflection of the higher baseline mortality risk in zambia  regardless of immune status  compared with canada or south africa .
as in other studies , we observed an association between adherence and cd4 lymphocyte response .
individuals with adherence of < 80% had an attenuated response at 18 , 24 , 30 and 36 months when compared with those at or above this mpr threshold .
haemoglobin and weight ( usually described through bmi ) are other clinical measures shown to be independently predictive of mortality among patients initiating art .
the post-12-month mortality rate observed in this cohort ( 2.1 deaths/100 patient - years ) was slightly higher than what has been reported among hiv - uninfected individuals in africa ( 0.60.8 deaths/100 patient - years ) , and well below that of hiv - infected individuals without access to treatment ( 1113 deaths/100 patient - years ) .
our analysis cohort comprised individuals who were likely healthier than the general population initiating art , having survived beyond periods of highest mortality risk ( i.e. first 90 days on art ) to at least 12 months .
although systems are in place to follow up those with missed visits , nearly 10% were late for appointments or withdrew altogether in the post-12-month period , a scenario common to other sub - saharan programs .
if a significant proportion of follow - up losses were related to death  a distinct possibility given the local tradition of returning to the rural family home at times of severe illness 
then this would lead to underestimated mortality . for individual patient care , we recognize that the utility of our findings may be limited .
we focused on a survival outcome due to constraints of our programmatic database , but the ability to predict virologic suppression may be more relevant for clinical decision making .
bisson and colleagues , for example , demonstrated that pharmacy refill - based adherence measures may perform better than cd4 monitoring to predict virologic failure ; overall performance of adherence , however , still led to significant misclassification of patient outcomes ( i.e. missed virologic failure , unnecessary regimen change ) across several different thresholds .
we observed similar findings among patients with discordant clinical and immunologic treatment responses in lusaka , suggesting that mpr measurements alone may be insufficient to predict virologic suppression .
instead , it should either be considered as a triaging tool or as part of more extensive algorithms in predicting virologic failure .
in addition , while 95% adherence threshold is commonly referenced , recent studies have shown that even moderate levels ( 8090% ) of adherence can result in viral suppression when combination regimens are used .
establishment of adherence thresholds that reliably predict virologic treatment failure and viral drug resistance could greatly assist individual patient care in resource - constrained settings .
in contrast , our demonstrated association between mpr and mortality could provide an important framework for program monitoring in african settings . in lusaka ,
for example , we currently utilize a programmatic database to generate facility - level reports for clinical care quality and performance .
an aggregate mpr metric could be generated for a given facility and serve as a clinic - level performance indicator .
sites with a high proportion of patients with poor adherence ( e.g. < 80% ) could be identified and evaluated for potential interventions incorporating patient reminders , community education or adherence support .
this feedback loop between patient outcomes and service improvement is a critical link to maintaining a high standard of clinical care , particularly in settings where hiv services are expanding rapidly and task shifting is employed to relieve critical health personnel shortages .
aggregate data could also assist policy makers and program managers at the district , provincial and national level , as they tailor specific interventions to optimize treatment . to our knowledge , this is the largest african cohort in the published literature evaluated for adherence , owing to the unprecedented resources made available through the zambian government , the global fund for aids , tuberculosis and malaria ; and the us president 's emergency plan for aids relief .
we believe the pharmacy data to be complete because of the free antiretroviral drugs provided by the zambian ministry of health ( thus reducing the probability of drug collection at non - study sites ) , and standardized data capture across all sites .
one limitation of this analysis is our reliance on mpr ; in many ways , it is a crude measure of adherence .
although simple to calculate , it does not describe the actual ingestion of medication or the pattern of non - adherence ( e.g. frequency , duration ) .
patient outcomes in this urban population may also not be representative of those in rural areas , where a growing number of programs are now expanding in africa .
further work is needed to understand the role of adherence measurements such as mpr in such settings .
lastly , we were unable to fully account for the impact of food supplementation programs that were slowly rolled out in lusaka over the observation period .
recent work demonstrated a clear impact of food supplementation on individual - level adherence ; however , immunologic and clinical outcomes were unchanged at 6 and 12 months following art initiation . whether food supplementation might have an impact on survival is unknown .
in summary , we demonstrate that mpr correlates with patient outcomes in the settings of rapid service scale - up , task shifting and high disease burden .
our findings are thus applicable to the many urban public sector programs in africa seeking to expand services in the face of significant resource constraint .
although 80% mpr appears to be an important threshold for clinical outcomes and survival , its utility for individual patient care may be limited .
mpr thresholds that correlate with virologic failure and viral drug resistance should be delineated , given their direct relevance to clinical care .
centers for disease control and prevention ( cooperative agreement u62/ccu12354 ) through the president 's emergency plan for aids relief , and a grant for operations research for aids care and treatment in africa from the doris duke charitable foundation ( 2005047 ) . additional investigator salary or trainee support is provided by the national institutes of health ( k01-tw06670 ; k23-ai01411 ; p30-ai027767 ; d43-tw001035 ) ; doris duke clinical scientist development award ( 2007061 ) .
the findings and conclusions included herein are solely the responsibility of the authors and do not necessarily represent the official position of the centers for disease control and prevention .
 background high - level adherence to antiretroviral therapy ( art ) is associated with favourable patient outcomes . in resource - constrained settings , however , there are few validated measures . 
 we examined the correlation between clinical outcomes and the medication possession ratio ( mpr ) , a pharmacy - based measure of adherence.methods we analysed data from a large programmatic cohort across 18 primary care centres providing art in lusaka , zambia . 
 patients were stratified into three categories based on mpr - calculated adherence over the first 12 months : optimal ( 95% ) , suboptimal ( 8094% ) and poor ( < 80%).results overall , 27 115 treatment - nave adults initiated and continued art for 12 months : 17 060 ( 62.9% ) demonstrated optimal adherence , 7682 ( 28.3% ) had suboptimal adherence and 2373 ( 8.8% ) had poor adherence . when compared with those with optimal adherence , post-12-month mortality risk was similar among patients with sub - optimal adherence [ adjusted hazard ratio ( ahr ) = 1.0 ; 95% ci : 0.91.2 ] but higher in patients with poor adherence ( ahr = 1.7 ; 95% ci : 1.42.2 ) . those < 80% mpr also appeared to have an attenuated cd4 response at 18 months ( 185 cells/l vs 217 cells/l ; p < 0.001 ) , 24 months ( 213 cells/l vs 246 cells/l ; p < 0.001 ) , 30 months ( 226 cells/l vs 261 cells/l ; p < 0.001 ) and 36 months ( 245 cells/l vs 275 cells/l ; p < 0.01 ) when compared with those above this threshold.conclusions mpr was predictive of clinical outcomes and immunologic response in this large public sector antiretroviral treatment program . 
 this marker may have a role in guiding programmatic monitoring and clinical care in resource - constrained settings . 