Factors associated with pre-ART loss-to-follow up in adults in rural KwaZulu-Natal, South Africa: a prospective cohort study

With an estimated 6.4 million people, South Africa has the world’s largest HIV-positive population [1]; among adults aged 15–49, HIV prevalence is estimated at 18.6 %. South Africa’s public sector antiretroviral (ART) programme began in 2004 and by the end of 2012 over two million were on treatment [1]. Even with expanded global ART guidelines [2], however, significant numbers remain ART-ineligible in countries such as South Africa not currently recommending treatment for all people living with HIV. Retention in care in this group is important for timely future ART initiation. Understanding loss-to-follow-up (LTFU) (non-attendance at scheduled clinic visits) from pre-ART care is also important for test-and-treat interventions [3].

Despite lower mortality rates, overall attrition (combined LTFU, death and transfer to another programme) for those ART ineligible is higher than for those ART-eligible [4]. Median attrition rates of 54 % (across studies with follow-ups from 7 months to 5 years) have been reported in sub-Saharan Africa (SSA) [5, 6]. Most studies have used a cut-off of CD4 <200 cells/mm³ for ART-eligibility [4] although South Africa guidelines for ART initiation in South Africa rose to CD4 counts of <500 cells/mm³ in January 2015, consistent with WHO guidelines at that time [7].

There have been few studies of LTFU correlates in SSA for individuals not yet ART-eligible, particularly those with a CD4 count of >500 cells/mm³. A clearer understanding of LTFU in this group may help develop targeted interventions to enhance programme retention. In South Africa, one study examined LTFU in adults (n = 4223, 84 % female) 13 months after an initial CD4 count of ≥200 cells/mm³ [8]. Higher LTFU levels were independently related to being employed, male, younger age, higher initial CD4 count, out-migration and greater household size. Thirty five per cent of individuals with an initial CD4 count of >500 cells/mm³ were retained in care. Elsewhere in South Africa [9], among 356 individuals newly enrolled in pre-ART care (CD4 count ≥250 cells/mm³), higher LTFU levels at one year were related to unemployment and higher initial CD4 count. As LTFU was more common in those with higher CD4 counts in both of these studies, there is a need to assess correlates of engagement in individuals before symptoms develop. In a third study, in Kenya [10], with 530 individuals with an initial CD4 count of ≥200 cells/mm³, higher LTFU levels at six months after registration in HIV care, were related to greater distance from a main road and being unmarried.

We were unable to find research on psychosocial correlates of LTFU in pre-ART care. Understanding these relationships may enable researchers to suggest why distal factors such as gender and employment are associated with LTFU. Psychosocial variables may be more amenable to intervention than structural or demographic factors. We recently found that, in those ART-eligible, higher LTFU rates were related to male sex, social support (increased openness and less reliance on family and friends), social capital (believing that community problems would be solved at higher levels, e.g., traditional and district leaders rather than individuals and neighbours), younger age and having children [11]. Predictors of LTFU in those not yet eligible for ART may be different.

We used data from a prospective cohort study of individuals recruited from HIV care clinics with a CD4 count of ≥500 cells/mm³ and not yet ART-eligible, in an area of high HIV prevalence and widespread ART availability in KwaZulu-Natal, South Africa [12, 13] to explore the associations between psychosocial, demographic and clinical variables and LTFU.

There were 247 participants (212 (85.8 %) female, 35 (14.2 %) male). The median follow-up time was 2.13 years (IQR 1.12–3.00), total study follow-up time 520.15 person-years. Median age was 34 years (IQR 27–43), and median CD4 count 631.5 cells/mm³ (IQR 559–768 cells/mm³) at recruitment. Ninety-five participants (38.5 %) had not received a previous CD4 test result prior to the baseline CD4 test (median number of previous CD4 tests 1, IQR 0–2).

Programme LTFU

The process of determining LTFU outcome is presented in Fig. 1. The midpoint between the last clinic visit attended and the next scheduled clinic visit (12 months later) was 183 days. Ninety-four individuals were LTFU (38.1 %). The overall LTFU rate was 18.07 per 100 person-years (95 % CI: 14.76–21.12). Eighty-six individuals remained ART-ineligible but not LTFU (34.8 %), 58 initiated ART (23.5 %: median time to initiation from recruitment in this group 1.89 years: IQR 1.39–2.65), seven died (2.8 %) and two transferred out (0.8 %). LTFU before a competing event was 13.5 % at one year and 34.4 % at three years.

We assessed the relationship between psychosocial, demographic and clinical variables and LTFU in HIV-positive individuals in pre-ART care. As seen in previous studies, the LTFU rate (38.1 %) was higher than in those eligible for or initiating ART [4, 11]. Direct comparisons between pre-ART cohorts and ART cohorts are problematic, however, as loss to follow-up from ART is conditional on having started ART.

The association between younger age and higher LTFU rates is consistent with other studies on pre-ART LTFU [8, 33] and with studies on those ART-eligible [11, 34]. How age impacts upon LTFU needs clarification. For example, beliefs about the consequences of engaging in care might differ with age [35] or there may be greater competing demands that impact upon clinic attendance in younger than in older individuals. Competing demands life activities have been reported as a barrier to patient retention in other studies [36]. The relationship between younger age and higher LTFU rates (across studies that analyse age and calculate LTFU differently) may have clinical implications. Integrating pre-ART care with services specific to younger peoples’ needs (e.g., reproductive health services [37]), could be considered. Strategies that have a potentially beneficial effect on retention in the pre-ART phase, regardless of age (e.g., mobile phone prompts [38], cotrimoxazole prophylaxis [39], transport vouchers [40], home counselling [41], and case management [42]), could also be implemented.

The association between greater openness to family and friends and LTFU was also seen in a parallel cohort of ART-eligible individuals [11]. Being open with family and friends may mean that emotional support is offered by one’s social network rather than sought from clinic staff. Being open with family and friends may provide the opportunity for others to provide reassurance to the individual that clinic attendance is not yet necessary. Future research could assess social support more comprehensively, or could use a qualitative approach to explore these possibilities in more depth.

The close to significant interaction between openness to family and friends and HIV partner disclosure is worth further examination. Lower LTFU rates among those not open with family and friends and not having disclosed their HIV status to a partner, suggests that clinic attendance may provide an important source of social support for this group. There have been reported sex differences in patterns of HIV disclosure, with women more likely to disclose to multiple categories of people [43]. The relationship between LTFU and the combined openness and partner disclosure variable in our sample, however, remained once sex was controlled for (in a predominantly female sample).

Taken together, both the main effect of openness with family and friends and the interaction between openness with family and friends and partner disclosure suggest that social support needs may be salient even when medical needs are less pressing. Further investigation of the relationship between social support and LTFU may highlight the need to strengthen psychosocial support services in pre-ART care. In sum, clinic attendance may be motivated by both social and health needs.

Greater LTFU was associated with having an HIV-negative partner rather than a partner who is HIV-positive or of unknown status. It may be that HIV positive partners are better able to support ongoing clinic attendance or that having an HIV negative partner is a barrier to retention. Future qualitative studies could investigate this finding further. LTFU was independently associated with number of children. There was no clear linear pattern between the number of children and LTFU, however. The category with the lowest LTFU rate in the final model was having no children. The precision of this estimate was low, due to the small number of childless individuals. A greater sample size would allow for more exploration of this and other effects. LFTU was also associated with a history of previous CD4 tests. Individuals who were recruited when they had received their first CD4 count had greater LTFU than those who were already in HIV care and had received previous CD4 counts. This result was unsurprising as the latter individuals had already shown their willingness and ability to return for at least one repeated CD4 test in pre-ART care.

A number of variables (male sex, the receipt of government grants, never having been married and outward migration) were not significantly associated with LTFU in our analyses, despite being previously identified as associated in other studies in the literature, perhaps due to insufficient statistical power. Some of these variables may have been related to other exposures that were in the final model (e.g., outward migration and the number of previous CD4 counts). Sex has been associated with time to ART-eligibility [44] in the same cohort, and travel costs have been identified as the largest expense for those in pre-ART care in the same programme [45]. Being unmarried and outward migration have both been shown to be related to LTFU in other pre-ART samples [8, 10].

The LTFU rate is this study appeared to be lower than those reported for individuals with a CD4 count of >500 mm/cells³ in an earlier study on the programme population [8]. Directly comparing between the studies is difficult, however. We only recruited from three of the 17 clinics that offered HIV care in the local programme, specifically those that were most accessible. In addition, our study only included individuals who had returned for the CD4 count that determined their eligibility for ART. In the earlier study, all individuals were included regardless of whether they had returned for their CD4 test result. Although the definition of LTFU was comparable in both studies, our longer follow-up period will have made it more likely that some individuals will have experienced symptoms as their CD4 count dropped [46]. This may have prompted clinic attendance. Finally, our study was based on data from a later time period, during which guidelines for ART eligibility changed significantly. Alternatively, our lower LTFU rate may in part have been due to prompting associated with on-going participation in the prospective cohort study [12] that involved interviews every six months either in clinic or by phone. A more ideal study design would have been to prospectively follow individuals in pre-ART care through the programme only, however using routine programme data would have meant that other data available to explore as factors associated with LTFU would have been limited. Study retention was, however, separate from ART programme retention, and did not rely on clinic attendance. For example, 39 % of the 6 month cohort study interviews were not conducted at the clinic [12]. Our sample was similar in demographic characteristics to pre-ART patients in the HIV treatment and care programme as a whole, including the sex ratio disparity [8], and mortality rates were consistent with other pre-ART studies [4]. Post-hoc analysis showed no differences in estimates when we conducted the analysis separately for those participants without a previous CD4 count (n = 95) and those with a previous CD4 count (n = 152).

This study assessed a wider range of variables (particularly psychosocial variables) than other studies and was strengthened by a prospective cohort design with data on clinic attendance collected over a four-year period. Considerable effort was made to minimise ascertainment bias (e.g., participant tracking in the context of the prospective cohort study [12] and cross-checking outcomes between databases). The Competing Risks regression analysis gave similar results to those produced by using Cox regression. It is acknowledged, however, that there are limitations with using Competing Risks regression, which assumes conditional independence of different events.

Some of the variables measured at recruitment may have changed over the study duration (e.g., openness with family and friends). Both initial and intervening unmeasured factors may have influenced whether patients were LTFU at the end of the study period (e.g., beliefs about the consequences of attending clinic, symptoms, nature of the patient-provider relationship, mood, migration or alcohol use). Future studies could use a larger sample and a theoretical framework of engagement in care to select potentially explanatory variables, (e.g., specific beliefs about care [35]), that might be amenable to intervention.

In summary, this study showed that being more open with family and friends, younger age, having fewer previous CD4 counts, number of children and most recent partner’s HIV negative status were independently related to higher rates of HIV treatment and care programme LTFU in individuals in pre-ART care. These relationships are important given the need to retain large numbers of HIV-positive individuals who are not ART-eligible (specifically those with a CD4 count of >500 cells/mm³) in long-term care. We also showed that even though the rates of LTFU may differ between those not yet eligible for ART and those who are eligible and/or on treatment, some of the predictors of LTFU may be similar [11].