To optimize the benefits of ART, a number of overlapping short-term and long-term goals collectively require proficient and supportive delivery of treatment by a team of health-care workers and counsellors. The over-riding goal is to rapidly reduce mortality through diagnosis and treatment of co-morbidities, provision of co-trimoxazole prophylaxis and achievement of optimum virological and immunological responses to ART. Long-term goals include the retention of patients on ART with high rates of treatment adherence and sustained virological suppression.
In this paper, 3162 patients were started on ART in a South African treatment service studied over 7 years. Excellent early outcomes (mortality and virological and immunological responses) were sustained in sequential calendar periods of ART initiation. In contrast, however, cumulative rates of longer-term adverse outcomes of LTFU and virological failure deteriorated over time as the service enlarged and ratios of patient to health worker staff numbers are adversely affected. As ART services grow in seize, patient care and support systems may be overly focused on treatment initiation and the subsequent few months of care and that additional attention and resources are needed for ongoing treatment support in the longer term.
A key outcome of ART programmes is combined attrition due to death and LTFU. This was 37.4% after 6 years, which is similar to that observed in another programme in Cape Town.6
A previous meta-analysis of cohorts in sub-Saharan Africa reported average losses of approximately 40% after just two years.5
The probability of retaining approximately two-thirds of our cohort on ART after 6 years represents a considerable success. However, the risk of being lost to the programme increased with each successive calendar year of enrolment, suggesting a progressive deterioration in programme performance. To explore this further, we examined these different losses separately in addition to early and late virological responses to ART.
Between 8% and 26% of patients die during the first year of ART in treatment programmes in sub-Saharan Africa3
and yet, patients in this cohort had a one year mortality rate of 7.9%, despite many having advanced immunodeficiency. This represents among the lowest reported mortality rates in the region. Moreover, regardless of escalating patient case-load, one-year mortality rates did not differ between successive calendar periods of ART initiation. Thus, the over-riding goal of maintaining low mortality rates during scale-up of this service was achieved.
Virological suppression is another key early programmatic goal. Excellent suppression rates were observed, with ≥93% of patients having suppression <400 copies/mL at 16 weeks, and these rates did not vary significantly between successive years of recruitment. This is indicative of very high rates of initial adherence to effective treatment. We also examined the proportion of patients with a CD4 cell count <200 cells/uL at 48 weeks since this is the patient sub-set that remains at high ongoing risk of mortality and of morbidity.12, 14
This proportion decreased from approximately 90% at baseline to approximately 20-30% after 48 weeks of ART and did not significantly differ between sequential calendar periods of ART initiation. Thus, collective first year key outcomes of mortality and virological and immunological responses were sustained over 7 years during scale-up of this service. This suggests that standards of initial care and treatment support provided in the initial months of ART were sustained regardless of overall patient case-load in the service.
After the first year of ART, a key challenge is to retain patients within the cohort and maintain virological suppression. We found that the cumulative probability of being LTFU after 6 years ART was 29.1%, which is broadly similar to another programme in Cape Town.6
However, the proportion LTFU increased significantly between sequential calendar periods of ART initiation as observed elsewhere.6, 15, 16
Escalating patient case-load may be an important underlying factor as this may be associated with increasing clinic waiting times, shorter consultations, reduced opportunities for counselling and adherence support and over-stretching of human resources for patient tracing following missed appointments. Indeed, over the course of scale-up, the number of new patients enrolled per peer counsellor or per doctor increased several-fold ().
The increasing rates of LTFU were also paralleled by increasing risk of virological failure, further underscoring the suggestion that treatment support had diminished over time with increasing clinic size. The probability of virological failure in the whole cohort at 6 years was 23.1% and many patients who develop failure in this cohort have drug resistance mutations.17
Few other data are available from public sector programmes in sub-Saharan African due to a lack of availability of routine virological monitoring and directly comparable prospectively collected data are lacking.18
The failure rate we observed is higher than the rate of 14% reported in another programme in Cape Town6
, but definitions of failure and frequency of virological monitoring differed between programmes. The increasing rate of virological failure has important implications with regard to escalating rates of drug resistance and increased switching to protease-inhibitor-based second line therapy, which is considerably more expensive. Remaining therapeutic options thereafter are few.
The proportion of patients transferred between services in ART programmes in sub-Saharan Africa is highly variable, but a large meta-analysis reported a weighted average of just 1.1% after a median of 26 months ART.19
In contrast, approximately one fifth of our cohort was estimated to transfer care over 6 years of ART. The long-term outcomes of such patients are not known. The probability of being transferred out was much greater for patients initiating ART in more recent calendar periods. They may be several explanations for this. First, expansion in the availability of ART services in surrounding communities and elsewhere in South Africa has increasingly provided access for patients to be treated near their own homes. It is also likely that those enrolled in the clinic in the earlier years compared to later years had more attachment to the clinic, especially as in the earlier years clinics were small and little was known about likely outcomes. It is also possible that patients who resume work after a period of illness may wish to be transferred to other centres which are less busy, have shorter waiting times or are more conveniently located. The South African population is highly mobile and this provides a challenge to long-term care. Efficient referral and patient tracking systems are needed to facilitate uninterrupted care for such patients.
Strengths of this study include the fact that these data are from a primary care clinic within the South African public sector system. The cohort of over three thousand patients is very well characterized and has very complete prospectively recorded data on patient outcomes. This cohort has one of the longest durations of follow-up within the context of a public sector ART programmes in sub-Saharan Africa. The analysis of outcomes data by calendar period of enrolment provides critical insights into changing treatment outcomes over time.
Limitations include the analysis of multiple endpoints, which could increase the chance of false positive findings. To minimize this bias we analysed each outcome separately. Some deaths could have remained unascertained and recorded as LTFU. However, low CD4 cell counts were not a risk factor for LTFU () and the temporal distribution of deaths and LTFU differed (), suggesting that any such overlap was insubstantial. Although escalating size of the treatment cohort is suggested as a plausible factor underlying the rising risk of LTFU and virological failure over time, a causal association has not been demonstrated and other as yet unidentified factors may be important. The subsequent outcomes of patients transferred out to other services is unknown.
In summary, this analysis of a community-based ART services shows that mortality and immunological and virological responses during the first year were not compromised during scale-up, suggesting that patient preparation for ART and initial medical care were maintained at a high standard. However, the cumulative probability of patients being LTFU or developing virological failure deteriorated over time when comparing successive calendar periods of recruitment. This may reflect a diminishing capacity over time to adequately support patients during long-term therapy as clinic size escalates.