This analysis, based on routinely collected data at clinics across South Africa, showed that there was high early mortality on ART with a large proportion (42.7%) of the deaths occurring in the first three months of treatment, consistent with other studies from sub-Saharan Africa [3
]. This is most likely attributable to very advanced disease at treatment start as evidenced by low CD4 count at baseline, typical of clinics in sub-Saharan Africa [8
]. High early on-ART mortality rates in resource-poor settings compared with industrialised countries are not completely explained by lower CD4 counts and more advanced clinical stage at baseline, but are probably compounded by co-morbidities, particularly tuberculosis, that are common in resource-poor settings[9
]. Thus there is a need to identify individuals at high risk of death who may benefit from investigation for concurrent disease within a more intensive case management programme. This analysis indicates that low CD4 count and low haemoglobin are important independent prognostic factors for mortality in this setting and either or both could be used to identify those at highest risk of death.
At three months after ART start, 13% of those with a baseline CD4 count below 50 had died compared with 3% of those with CD4 count of 50 and above, highlighting the strong association between baseline CD4 count and early mortality, consistent with other studies [3
]. Our results are also consistent with other studies showing that anaemia predicts mortality among individuals on ART in Africa and developed countries [12
] although evidence is limited and thus this analysis, from a large cohort receiving care at multiple clinics, adds valuable information to support this. Anaemia in these settings is associated with conditions such as tuberculosis [Hanifa Y, unpublished data, personal communication] which may not be clinically apparent, but could potentially be treated; as well as other co-morbidities such as malnutrition, gastrointestinal Kaposi's sarcoma etc [19
]. Thus those individuals starting ART with a low haemoglobin in these settings are in particular need of investigation for, and if necessary treatment of, tuberculosis. More generally haemoglobin levels could be used by clinics to identify more promptly participants that are at very high risk of mortality in ART programmes when they start treatment and be very useful in settings where CD4 counts are less widely available. There could then be a programme of intensified case management and monitoring for these individuals at high risk. This could also involve more investigation for co-morbidities especially tuberculosis but should not delay the start of ART as there is a very high mortality rate for those waiting to start ART [5
One in six participants in this cohort left the programme during follow-up, and for the majority of these there was none or only limited information on reasons for their departure, similar to other ART programmes in Africa [12
]. Although these individuals were similar to those alive at the end of follow-up in age, gender, CD4 count, viral load and BMI, the loss to follow-up may also lead to an under-estimate of mortality rates for this cohort as an unknown number of the 11.0% participants lost to follow-up may have died soon after leaving the programme. Studies in similar settings have shown that mortality is often underestimated when individuals are lost to follow-up and not actively traced [9
A strength of the data presented in this analysis is that individuals identified in this cohort had definitely started ART and collected their medication. This helps to reduce the bias that may occur if individuals who never started ART were contributing person-years to the study.
There were missing data for BMI (36.7%) but it was evaluated in the univariable and multivariable analyses and conclusions from the multivariable model were supported by multiple imputation methods. There was also no information on the cause of death for this cohort which would have been useful, as what had caused the early deaths and information regarding the deaths of those with very low haemoglobin would help to inform an intensified case management system. However there is increasing evidence from other studies about the importance of tuberculosis as an early cause of death [28
The results from this analysis give evidence that CD4 count and haemoglobin predict early mortality for individuals on ART in sub-Saharan Africa. Individuals starting ART with either low CD4 count or low haemoglobin should be targeted for intensified case management, including investigation for and treatment of coexistent infections, particularly tuberculosis in settings of high tuberculosis prevalence. In clinics without access to CD4 counts, haemoglobin may be useful to identify those at highest risk.