the provision of antiretroviral therapy ( art ) in sub - saharan africa ( ssa ) has resulted in reduced mortality , morbidity , and an increase in life expectancy.1,2 despite these successes , approximately 59% of all people in africa remain without treatment despite being considered eligible.3 also , for those in care , improvements are required along every step of the care cascade to improve health outcomes for both individuals and the population.4 the first entry point to care is hiv testing , which is often accessed through provider - initiated testing at the health center . in many settings ,
provider - initiated testing has favored women and children , usually in the antenatal care ( anc ) period.5,6 there has been recent growing recognition that men are disadvantaged because no equivalent routine testing opportunity exists for them,7 and this is considered at least partly to account for the fact that men initiate art later than women,8 and have worse outcomes on antiretroviral therapy compared to women.913 in this study , we aimed to determine mortality between sexes after initiation of art in the greater kampala area of uganda .
we further sought to determine whether differences in disease progression across the sexes could be explained by differential access to care via anc services , and estimated how much of the increased risk of mortality in men can be explained by later art initiation .
all patient data for this study is from the mildmay uganda observational cohort ( mug).14 mildmay is a medical service organization providing art and other healthcare services to the hiv - positive community in uganda .
the organization opened in 1998 in order to provide palliative outpatient care for people living with hiv / aids , and to be a teaching and training center for hiv / aids healthcare personnel .
this study was restricted to patients who initiated art between january 2004 and april 2011 , were aged 14 years or older at baseline , and had completed the selection form .
selection forms contain baseline data including whether a woman was pregnant or eligible for art for prevention of mother to child transmission ( pmtct ) . to the best of our knowledge
, selection forms were missing completely at random ( ie events leading to missing selection forms are independent of variables of interest ) .
the primary outcome was all - cause mortality throughout the study period that ended in october 2011 to ensure that patients had the possibility of at least 6 months of follow - up time .
time was measured beginning at first art date and ending at either date of death , 6 months after last visit , or at end of study period , respectively .
follow - up time beyond the last visit is justified by the fact that death is externally observed .
the principal explanatory variables of interest were sex , baseline cd4-cell counts and world health organization disease stage .
baseline cd4 cell counts were obtained within 6 months before starting art . during the observation period
, the ugandan national guidelines stipulated that patients were considered eligible for art if they had a cd4 count 200 cells / mm ( this was changed to 350 cells / mm in 2012 ) .
we also measured demographic ( age , marital status , and education ) , behavioral ( sexual activity , disclosure to partner , and testing ) , and clinical variables ( hepatitis b and c , syphilis , malaria , and anemia ) .
women were deemed to be in antenatal care if they reported either being pregnant at baseline or being pmtct eligible . to determine the existence of any important differences between men and women with respect to demographic , behavioral , and clinical variables in the full cohort , we used fisher s exact and wilcoxon rank sum tests .
logistic regression and confidence intervals for difference in means were used to estimate the differences in disease progression , as defined by who disease stage and baseline cd4 cell counts , in men and women .
meier survival curves to demonstrate mortality over time in both the full and restricted cohorts .
we applied a weighted analysis whereby 30% of patients lost to follow - up were assumed to be dead , weighted by baseline cd4 and age , as suggested by egger et al.15 mediational modeling was conducted to estimate the proportion of increased risk of mortality in men attributable to later art initiation16 using recently developed methods for survival analysis.1719 mediator variables are distinguished from confounders in that they lie on the causal pathway .
the effect of the initial variable ( gender ) summed across all pathways is its total effect .
as shown in figure 1 , the total effect can be partitioned into the direct effect and the indirect effect . as with any model ,
the model assumptions must be met and , particularly for models considering causal pathways , it is important that confounding be fully controlled .
the ratio of indirect to total effects is the proportion of the effect attributable to the mediator . in this analysis we considered age as a confounder , gender as the initial variable , baseline cd4 as the mediator , and survival as the outcome .
we opted for the  product method16 of estimating the indirect effect which required the construction of a linear regression model for baseline cd4 and an accelerated failure time model with a weibull distribution using gender , baseline cd4 cell count , and age .
full details on the indirect effect estimation and the assumptions required for this model are available in the appendix .
confidence intervals for the indirect and total effects as well as their quotient ( the proportion of effect explained by cd4 ) were obtained by bootstrapping.1922 all analyses were done in sas version 9.3 ( sas institute inc , cary , nc , usa ) and r version 2.15 ( vienna , austria ) .
this study received ethical approval from the institutional review boards of the university of ottawa and mildmay uganda .
all patient data for this study is from the mildmay uganda observational cohort ( mug).14 mildmay is a medical service organization providing art and other healthcare services to the hiv - positive community in uganda .
the organization opened in 1998 in order to provide palliative outpatient care for people living with hiv / aids , and to be a teaching and training center for hiv / aids healthcare personnel .
this study was restricted to patients who initiated art between january 2004 and april 2011 , were aged 14 years or older at baseline , and had completed the selection form .
selection forms contain baseline data including whether a woman was pregnant or eligible for art for prevention of mother to child transmission ( pmtct ) . to the best of our knowledge
, selection forms were missing completely at random ( ie events leading to missing selection forms are independent of variables of interest ) .
the primary outcome was all - cause mortality throughout the study period that ended in october 2011 to ensure that patients had the possibility of at least 6 months of follow - up time .
time was measured beginning at first art date and ending at either date of death , 6 months after last visit , or at end of study period , respectively .
follow - up time beyond the last visit is justified by the fact that death is externally observed .
the principal explanatory variables of interest were sex , baseline cd4-cell counts and world health organization disease stage .
baseline cd4 cell counts were obtained within 6 months before starting art . during the observation period
, the ugandan national guidelines stipulated that patients were considered eligible for art if they had a cd4 count 200 cells / mm ( this was changed to 350 cells / mm in 2012 ) .
we also measured demographic ( age , marital status , and education ) , behavioral ( sexual activity , disclosure to partner , and testing ) , and clinical variables ( hepatitis b and c , syphilis , malaria , and anemia ) .
women were deemed to be in antenatal care if they reported either being pregnant at baseline or being pmtct eligible .
to determine the existence of any important differences between men and women with respect to demographic , behavioral , and clinical variables in the full cohort , we used fisher s exact and wilcoxon rank sum tests .
logistic regression and confidence intervals for difference in means were used to estimate the differences in disease progression , as defined by who disease stage and baseline cd4 cell counts , in men and women .
meier survival curves to demonstrate mortality over time in both the full and restricted cohorts .
we applied a weighted analysis whereby 30% of patients lost to follow - up were assumed to be dead , weighted by baseline cd4 and age , as suggested by egger et al.15 mediational modeling was conducted to estimate the proportion of increased risk of mortality in men attributable to later art initiation16 using recently developed methods for survival analysis.1719 mediator variables are distinguished from confounders in that they lie on the causal pathway .
the effect of the initial variable ( gender ) summed across all pathways is its total effect .
as shown in figure 1 , the total effect can be partitioned into the direct effect and the indirect effect . as with any model ,
the model assumptions must be met and , particularly for models considering causal pathways , it is important that confounding be fully controlled .
the ratio of indirect to total effects is the proportion of the effect attributable to the mediator . in this analysis we considered age as a confounder , gender as the initial variable , baseline cd4 as the mediator , and survival as the outcome .
we opted for the  product method16 of estimating the indirect effect which required the construction of a linear regression model for baseline cd4 and an accelerated failure time model with a weibull distribution using gender , baseline cd4 cell count , and age .
full details on the indirect effect estimation and the assumptions required for this model are available in the appendix .
confidence intervals for the indirect and total effects as well as their quotient ( the proportion of effect explained by cd4 ) were obtained by bootstrapping.1922 all analyses were done in sas version 9.3 ( sas institute inc , cary , nc , usa ) and r version 2.15 ( vienna , austria ) .
this study received ethical approval from the institutional review boards of the university of ottawa and mildmay uganda .
in total , 4775 patients aged 14 years or older initiated art between january 2004 and april 2011 .
the median age was 33 ( interquartile range [ iqr ] 2739 ) , and 1676 ( 35.1% ) were men . during this time period
there were 200 deaths over a median follow - up time of 3.25 years ( iqr 2.504.25 ) ; 135 patients were lost to follow - up ( 42 males and 93 females ) .
men tended to be older , were more likely to be married and sexually active , tended to be better educated , more likely to disclose their status to their partners , and more likely to be hepatitis b positive ( odds ratio [ or ] : 1.42 , 95% confidence interval [ ci ] : 1.10  1.85 ) .
there were 84/1676 ( 5.0% ) deaths among men and 116/3099 ( 3.7% ) among women .
when analyzing all patients , the p - value for the log - rank test was 0.02 indicating a higher rate of death among men ( figure 2 , panel a ) .
when we restricted this to the cohort involving only women who accessed care outside anc services , the p - value for the log - rank test was similar at 0.04 ( figure 2 , panel b ) . similarly , 42% of men compared to 32% of women presented for art at who stage 3 or 4 ( or : 1.46 ; 95% ci : 1.291.66 ) and this did not change much when anc cases were removed ( or : 1.54 ; 95% ci : 1.371.75 ) .
as shown in table 2 , the difference in cd4 cell count was only slightly larger , 23 versus 25 , when anc cases were included .
the weibull survival model shows that in univariate analysis , gender has a significant effect on survival ( hazard ratio [ hr ] : 1.38 ; 95% ci : 1.031.83 ) , but in the presence of the mediators and confounders its effect is no longer significant ( adjusted hazard ratio : 1.20 ; 95% ci : 0.951.64 ; table 3 ) .
the scale coefficient of 1.87 indicates that the hazard of death is declining with time , in keeping with the fact that the majority of the deaths occur within months of initiating art.10 
 table 4 presents the partitioning of the effect of gender into direct and indirect effects .
approximately 43% ( 95% ci : 22%113% ) of the additional deaths seen in men are attributable to their lower cd4 cell counts at baseline ( results for reduced cohort shown in table a2 ) . a sensitivity analysis restricted to the sample of those not accessing care through anc , is presented in table a3 in the appendix .
when we examined whether single men had differing baseline risk , according to baseline cd4 , compared with other groups , we found that single men had significantly lower cd4 ( median 99 , iqr 30190 ) than married men ( 120 , iqr 48199 ) [ p = 0.03 ] and compared to single women ( 144 , iqr 68209 ) [ p < 0.0001 ] .
although the international hiv / aids community has placed a particular emphasis on targeted art of female patients , there is emerging evidence that less men engage in care for hiv / aids in ssa , and have less favorable outcomes .
a proposed reason for this inconsistency is that antenatal care provides a platform through which women can access care more frequently and earlier in their disease progression.23 our study found that men had an increased risk of death and nearly half the additional deaths appear to be attributable to delayed engagement in care . in the multivariable model , we divided the effect of gender into the direct effect and the indirect effect ( effect due to cd4 at baseline )
. therefore , the fact that gender is not significant in the multivariable model , implies that the increased risk observed in men is not due to their gender , but mostly due to their lower baseline cd4 cell counts .
anc accounted for only a small fraction of this inconsistency . a sustained effort to reduce this discrepancy
our study had low rates of death and low rates of loss to follow - up .
the mildmay program puts emphasis on community care that may explain the high retention to care , an observation mirrored in other community - based care programs.24 although there is accumulating evidence that men across ssa are at increased risk of morbidity and mortality in comparison to women,25 our study was restricted to a single cohort in uganda .
our bivariate analyses reveal that our cohort has a relatively higher number of married men , suggesting that the engagement of women has led them to bring their husbands into care .
consequently the differences in disease progression reported in this cohort may underestimate the discrepancy in the community .
the role of antenatal care in the discrepancy between how men and women seek access to healthcare is often acknowledged , but seldom analyzed in detail .
our study clearly shows the existence of other , more important factors at the source of the divide .
it is well known that initiating care at a lower cd4 cell count increases the risk of mortality.26 therefore it is not surprising that our results show that the increased mortality in men can in part be explained by later initiation .
nonetheless , by quantifying the proportion of increased mortality attributable to later initiation we have highlighted the urgency of increasing engagement to care .
men are seldom targeted because they do not fall into our conventional definitions of vulnerability and marginality.27 on the contrary , in general , men are recognized for having poor health - seeking behavior , so that efforts to engage them are even more critical .
, the ministry of health has initiated men s health days.28 studies have shown that home - based testing programs are allowing men to test earlier , giving them a chance to engage in a timely fashion.29 encouraging men to accompany women in antenatal care , as recommended by who in uganda , has had some success in rwanda and may have a role in other settings,30 although this would only target couples with active relationships .
the implementation of programs to encourage further participation by men in care is a difficult task , but earlier recruitment into care remains the best method to align the health outcomes of men with those of women .
a growing number of studies are reporting that among hiv - positive individuals on art in ssa , men tend to be at higher risk of death as was the case in our cohort .
little has been done to determine the underlying causes that are crucial to making changes to the health systems that create them .
our study found that among the leading causes , and quite possibly the leading cause , is the lower cd4 cell counts at which men on average present themselves for art initiation . targeted campaigns need to continue to be evaluated , to reduce the gender disparity and improve testing , linkage to care , and ultimately health outcomes for men .
this study can contribute to the growing body of evidence designed to inform evidence - based policy , to reduce barriers to healthcare experienced by men .
finally , antenatal care programs are a key difference in how men and women access care and are often cited as a plausible cause for observed differences in health outcomes , yet this difference did not appear to have a large impact in our cohort .
our findings suggest that further investigation is needed as access to care through antenatal care may play a more muted role than believed in explaining the differences in art uptake between men and women .
data were acquired by sk , mn , dm , mo , mk , wm , sy and af . the analyses were conducted by sk , af , and ejm .
the canadian institutes of health research ( cihr ) provided funding for this analysis . no funding agency has seen this study .
 backgroundwe aimed to assess the relationship between gender and survival among adult patients newly enrolled on antiretroviral therapy ( art ) in uganda . 
 we also specifically examined the role of antenatal services in favoring women s access to hiv care.methodsfrom an observational cohort study , we assessed survival and used logistic regression and differences in means to compare men and women who did not access care through antenatal services . 
 differences were assessed on measures of disease progression ( who stage and cd4 count ) and demographic ( age , marital status , and education ) , behavioral ( sexual activity , disclosure to partner , and testing ) , and clinical variables ( hepatitis b and c , syphilis , malaria , and anemia ) . a mediational analysis that considered gender as the initial variable , time to death as the outcome , initial cd4 count as the mediator , and age as a covariate was performed using an accelerated failure time model with a weibull distribution.resultsbetween 2004 and 2011 , a total of 4775 patients initiated art , and after exclusions 4537 ( 93.2% ) were included in analysis . 
 men initiating art were more likely to have a who disease stage iii or iv ( odds ratio : 1.46 , 95% confidence interval [ ci ] : 1.291.66 ) , and lower cd4 cell counts compared to women ( median baseline cd4 124 cells / mm3 , interquartile range [ iqr ] : 43205 versus 147 cells / mm3 , iqr : 68212 , p - value < 0.0001 ) . 
 men were at an increased risk of death compared to women ( hazard ratio : 1.38 , 95% ci : 1.031.83 ) . 
 baseline cd4 cell counts accounted for 43% of the increased risk of death in men ( 95% ci : 22%113% ) . 
 access to care via antenatal services did not explain differences in outcomes.conclusionin this cohort there is a marked increase in risk of mortality for men and approximately half of it can be attributed to their later engagement in care . 
 more effort is required to engage men in care in a timely manner . 