Introduction
HIV/AIDS is a leading cause of infant mortality in sub-Saharan Africa [1,2]. Despite significant improvements in preventing vertical transmission, in the 21 Global Plan priority countries in sub-Saharan Africa, over 100 000 infants are infected with HIV annually and only 50% access life-saving antiretroviral therapy [2]. If untreated, up to 50% of HIV-infected infants die within 2 years of life, with mortality being high in the first few months of life [3,4]. Improving access to paediatric treatment is essential to achieving the UNAIDS global HIV 90–90–90 goals by 2030 [5].
The low retention of mothers and infants in HIV care is a major cause of the current gap in achieving the global targets for paediatric antiretroviral therapy. Factors such as inadequate case finding, delayed and inaccessible HIV testing services, nondisclosure of maternal HIV status, insufficient health education of patients, and poor integration of testing and clinical services are some of the main determinants for the loss to follow-up of mother–infant pairs along the HIV care pathway [6–21]. Testing for HIV at birth and at different clinic entry points, task shifting to community health workers, patient tracking systems, risk factor screening, and health education programmes have been suggested as interventions to address the loss to follow-up of HIV-infected infants [22–31]. Interventions to improve access to early infant HIV testing have included short message service (SMS) results delivery [32–34] and sample referral networks to reduce test turn-around times [35], use of dried blood spots for remote sample collection and referral [36], and test price reductions [37]. However, test turn-around times remain long, typically 20–60 days [30,35], and although these interventions have improved access to early infant HIV diagnosis [38], significant gaps still remain suggesting that they do not adequately address access to HIV testing, patient retention, and paediatric treatment [39].
The decentralization of rapid early infant diagnosis, enabled by the recent availability of point-of-care (POC) technologies, provides an opportunity to expand access to populations without effective laboratory services and to improve linkage to care [40,41]. Although the accuracy of these tests has been shown to be similar to reference laboratory platforms [42–44], including when used in Mozambique by nurses, their utility within clinical settings to improve patient outcomes is uncertain, and therefore, the extent of their adoption by health systems remains to be defined. We conducted a cluster-randomized trial to evaluate the effect of POC early infant diagnosis on rates of antiretroviral therapy initiation and retention of infants accessing routine postnatal services in primary healthcare clinics in Mozambique. This design was chosen to be logistically easier and more acceptable by the communities than an individual randomized controlled trial.
Methods
Study design
The current study was a prospective, cluster-randomized, controlled trial involving 16 urban, periurban, and rural public primary healthcare clinics in Maputo (n = 8) and Sofala (n = 8) provinces of Mozambique (Table 1). The health facilities were selected based on the following factors: routine early infant diagnosis and antiretroviral therapy services available, having one positive infant per month, and distance to the provincial capital city of less than 100 km to facilitate referral of laboratory samples. A total of 48 health facilities in both provinces were eligible for inclusion in the study as per the above criteria, with 16 health facilities selected for study inclusion by randomization. Positivity rate was defined by the proportion of infants with positive HIV diagnostic tests out of the total number of infants tested with valid results. This study was conducted within the routine clinical procedures of each study site.
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Table 1: Characteristics of 16 randomized healthcare clinics.
Participants
The study included all HIV-exposed infants who presented at regular consultation visits for early infant diagnosis in the Child at Risk Program, in which infants are routinely referred from maternity wards, immunization clinics, nutrition consultation, and well child programmes. Participants included in the study were eligible for routine early HIV infant testing in accordance with Mozambique's national guidelines, which stipulates that healthcare workers collect blood specimens from HIV-exposed infants aged 1–9 months for molecular HIV diagnosis. Infants who had a previous HIV-positive test result, were already on antiretroviral therapy, were older than 18 months, or had serious medical conditions that could be exacerbated by testing were excluded from the study. Individual patient informed consent was waived by the ethics committees in view of the cluster design of the trial.
Procedures
Randomization
Health facilities in each province were randomly allocated to the POC and laboratory study arms using a random number generator. The unit of randomization was the health facility and the unit of analysis was an HIV-exposed child.
Study arms
The intervention arm sites (POC) used the POC device, Alere q HIV-1/2 Detect system (Alere Inc, Waltham, Massachusetts, USA), for nucleic acid-based early infant diagnosis testing. Following a deployment workshop, trained and certified nurses at each site operated the POC devices. Nurses collected heel-prick or toe-prick capillary blood samples directly into testing cartridges and processed them according to the manufacturer's recommendations. Test run time was approximately 50 min. Caregivers were advised to wait for the results for same-day follow-up care, per national guidelines. When conducted, confirmatory testing in the POC arm was performed using the POC device. The standard-of-care (SOC) arm sites used existing reference laboratory testing for early infant diagnosis testing. Capillary blood samples were collected on dried blood spot cards and sent to central laboratories for testing using the Roche Cobas Amplirep/Cobas Taqman v2 (Roche Molecular Systems, Branchburg, New Jersey, USA). Results were returned to sites electronically using mobile (GPRS/SMS) technology [34]. When conducted, confirmatory testing in the SOC arm was performed using the reference laboratory test.
All 16 sites received brief clinical refresher training on best practices for the care cascade, early infant diagnosis algorithm, and paediatric antiretroviral therapy to ensure comparable quality of care. In both arms, nurses were encouraged to refer patients with HIV-positive results for antiretroviral therapy initiation on the same day of result availability, in line with Mozambique's national guidelines and WHO recommendations [45]. Subsequent clinical care was provided as per national guidelines. Minimal yet equal levels of supervision were provided across study arms.
Outcomes
The primary study outcomes were the proportion of HIV-positive infants initiating antiretroviral therapy within 60 days of sample collection; and the proportion of HIV-positive infants who initiated antiretroviral therapy that were retained in care at 90 days of follow-up. Patients were considered retained in care at 90 days if they had visited the health facility within the previous 30 days. Secondary outcomes for the study were the median age at and the median number of days between specimen collection and results received by patient; and the median age at and the median number of days between specimen collection and initiation of antiretroviral treatment (ART).
Sample size
The study sample size was calculated based on the assumption that 55% of HIV-infected children initiate treatment within 60 days of laboratory-based testing and 66% of these children are retained in care during their 1st year on treatment. These assumptions were developed from patient-level and national-level data reviews, respectively. The study sought to enrol and initiate antiretroviral therapy for 121 HIV-positive children in each arm to test a hypothesized increase of 20% antiretroviral therapy initiation and retention due to the introduction of POC testing to achieve a meaningful increase, assuming a type I error rate of 5%, statistical power of 80%, intracluster correlation of 0.025 with an average cluster size of 15, and 10% loss due to ineligibility (sample size was calculated at 109 in each arm before accounting for 10% loss due to ineligibility). Calculations for remaining outcomes required smaller sample sizes; therefore, the sample size calculation for the primary outcome drove study enrolment.
Data collection
Data including patient demographics, dates of sample collection, testing, results return, treatment initiation, and retention on treatment 3 months after initiation were collected from routine early infant diagnosis clinic registers and patient files. The Mozambique Ministry of Health national early infant diagnosis database was used to access additional data for data points that were illegible or missing from clinic records.
Statistical analysis
Data analysis was conducted once one study arm reached the required sample size. As only patient-level data were collected, no cluster-level analysis was considered with cluster adjustments made on standard errors and test statistics. Patient-level analysis was conducted using Generalized Estimating Equations to obtain estimates of RR of study outcomes and mean turnaround time for both arms, and adjusted for age and sex and for within-cluster correlation assuming an exchangeable working correlation matrix, as there was no significant reason to assume that the correlation of any pair of patients’ measurements would be different within a given health facility. Although higher than the hypothesized intracluster correction (0.025), the actual estimates were not statistically significant in each study arm. The 95% confidence intervals and P values were used for statistical inference. All analyses were performed using SAS/STAT software, version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).
Ethics committee approval
The current study was approved by Mozambique's National Health Bioethics Committee with the approval reference 80/CNBS/14 and Chesapeake International Review Board with the approval reference Pro00016467. This study was registered with the Clinical Trials group and is accessible via their website (http://www.clinicaltrials.gov, Study identifier: NCT02634450).
Results
The study was conducted between September 2015 and October 2016. A total of 3958 infants met the eligibility requirements for the study across the 16 sites and 3910 were included in the analysis (Fig. 1).
Fig. 1: Flow chart for patient cohorts in the intervention point-of-care and standard-of-care laboratory study arms.
Forty-eight infants were excluded either due to lack of data on age or being older than 18 months of age (17), or were already on antiretroviral therapy (1), or had a previous HIV-positive test result (30). A total of 2034 and 1876 infants were included, in the POC and SOC arms, respectively, and 48.6% of infants were female (Table 2).
Table 2: Demographic data of the point-of-care and laboratory study populations undergoing HIV early infant diagnosis testing and antiretroviral treatment at primary health clinics in Mozambique.
Median age at test sample collection was 34 days with 68.8% under 2 months of age. Most mothers (92.0%) received antiretroviral therapy (WHO Option B+), and 92.6% of infants received nevirapine prophylaxis. There were no significant differences in the sex, maternal and child treatment regimens, and proportion of HIV-infected infants between the two arms. Most patient records were complete; 5.9% of patient records lacked one or more demographic data points, whereas 16.4% lacked one or more pieces of information (dates or test results) in the testing and treatment cascade.
Infants in the POC arm were older at sample collection (median 40.0 days) than those in the SOC arm (33.0 days) (P < 0.001) (Table 3).
Table 3: Median ages at and days between steps along the testing and treatment cascade.
The median age of infants at the time test results were received by the patient, however, was significantly lower in the POC arm (41.0 days) compared with the SOC arm (172.0 days) (P < 0.001). The median time from sample collection to test results being received by the patient was 0.0 days in the POC arm and 125.0 days in the SOC arm (P < 0.001). Amongst infants who tested HIV-positive, the median time between sample collection and receipt of test results was less than 1 day in the POC arm and 152.5 days in the SOC arm (P < 0.001). No patients received test results on the same day of sample collection in the SOC arm; however, 98.2% (1989 of 2026) of all test results were received by caregivers on the same day of sample collection in the POC arm (Table 4).
Table 4: Proportions and risk ratios for achieving steps towards paediatric testing and treatment for infants tested undergoing point-of-care and laboratory standard-of-care early infant diagnosis at primary health clinics in Mozambique.
Further, 99.2% (2018 of 2034) and 99.6% (2026 of 2034) of test results were received by patients within 60 and 180 days of sample collection in the POC arm compared with 7.2% (135 of 1876) and 47.2% (885 of 1876) in the SOC arm, respectively (60 days RR(adj): 14.43 [7.1–29.5]; P < 0.001).
Linkage to antiretroviral therapy and time to antiretroviral therapy were significantly better with POC testing. The median time from sample collection to antiretroviral therapy initiation was 0.0 days in the POC arm and 127.0 days in the SOC arm (P < 0.001). More HIV-positive infants initiated antiretroviral therapy the same day and within 60 days and 180 days of sample collection in the POC arm [66.3% (116 of 175), 89.7% (157 of 175), and 90.3% (162 of 175)] compared with the SOC arm [0% (0 of 102), 12.75% (13 of 102), and 40.2% (41 of 102)] (60 days RR(adj): 7.34 [4.7–11.5]; P < 0.001) (Table 4 and Fig. 2).
Fig. 2: Kaplan–Meyer estimate of time from sample collection to antiretroviral treatment initiation for infants receiving point-of-care or laboratory-based early infant diagnosis at primary health clinics. Cox model with shared frailty (P < 0.001).
The median time from test results received by the patient and antiretroviral therapy initiation was the same between the two arms, 0.0 days, and similar proportions of infants initiated antiretroviral therapy the same day results were received [70.7% (116 of 164) and 65.3% (32 of 49), for POC and SOC arms, P = 0.553]. However, amongst infants who received test results, more infants initiated treatment within 30 days in the POC arm (92.7%, 152 of 164) than in the SOC arm (77.6%, 38 of 49) (RR(adj): 1.2 [1.1–1.4]; P < 0.004). Finally, retention between treatment initiation and 90 days postinitiation was higher in the POC arm compared with the SOC arm [61.59% (101 of 164) versus 42.86% (21 of 49); RR(adj): 1.40 [1.1–1.9]; P = 0.0274].
The effect of same day result receipt and antiretroviral initiation on retention of HIV-positive infants, irrespective of study arm, was investigated. No difference was detected in the proportion of infants retained on treatment by 90 days after initiation, irrespective of whether treatment started the same day as receiving the test result or later (60.81% for same day initiation versus 49.23% for delayed initiation, P = 0.4590).
Finally, confirmatory testing of infants with a positive test result happened more often in the POC arm (54.6%) compared with those in the SOC arm (13.9%). All infants in the POC arm with a recorded confirmatory test result were concordant. The invalid test rate in the POC arm was 7.0%, whereas the analytical error rate in the SOC arm was 9.6%.
Discussion
The routine use of POC early infant diagnosis in primary health clinics was associated with significant improvements across the cascade of care for HIV-exposed infants. With POC testing, median test turn-around time from sample collection to results received by patient decreased from 125 to 0 days and treatment initiation amongst HIV-infected infants increased by 95.1%. Antiretroviral therapy initiation by 60 days after sample collection increased seven-fold from 12.8 to 89.7%, and retention on treatment increased by 43.7% with POC testing, when compared with infants diagnosed with conventional laboratory-based testing. By 6 months after sample collection, antiretroviral therapy initiation in the laboratory-based tested arm rose to 40.2%; however, the earlier diagnosis and treatment associated with POC testing may provide an important opportunity to prevent the early peak of morbidity and mortality amongst untreated HIV-infected infants in the first few months of life [4]. POC early infant diagnosis may, therefore, provide a chance to accelerate achievement of ambitious paediatric HIV care aims recommended by the UNAIDS’ Fast Track 90–90–90 HIV targets, the WHO, and the goal of an AIDS-free generation [5,45,46].
The impact of POC testing on antiretroviral therapy initiation was primarily due to the increased ability of health facilities to quickly and successfully provide test results to infants and their caregivers. This enabled same day sample collection, diagnosis, and treatment initiation to infants who presented for care and tested HIV-positive. By avoiding long diagnostic delays, additional clinic visits, and the unpredictably long turn-around time of laboratory tests, POC early infant diagnosis reduced opportunities for loss to follow-up between sample collection and antiretroviral therapy initiation and enabled faster access to treatment. The WHO recommends that infants are tested within 8 weeks of birth and that test results are provided within 4 weeks of sample collection [47].
Amongst infants who received an HIV-positive test result, an additional 19.5% were initiated on antiretroviral therapy if they underwent POC testing compared with infants who received laboratory-based test results. This suggests that, in addition to increasing the proportion of infants who are successfully diagnosed and overall initiated on therapy, POC testing improved linkage to treatment after diagnosis. Previous studies on the effect of POC CD4+ testing in adults have failed to detect an improvement in postdiagnosis linkage to antiretroviral therapy. However, the clinical settings for these studies did not support same-day testing and antiretroviral therapy initiation which introduced delays in care and the opportunity for significant (40%) patient loss-to-follow-up postdiagnosis [40,41]. In the current study, the majority of POC and laboratory-based diagnosed infants who initiated antiretroviral therapy were initiated the same day of results receipt. Nevertheless, some SOC-diagnosed infants did not access treatment after receiving positive test results. This loss may have been due to poor integration of diagnostic procedures within clinical care, a previously observed weakness [7]. Loss to follow-up of infants between diagnosis and treatment can be as high as 40%, even in well established public antiretroviral therapy programmes such as in South Africa and Thailand [12,16]. Same-day POC early infant diagnosis testing and antiretroviral therapy initiation may help close this gap.
Infants tested at the POC also had higher retention after starting treatment; 61.6% of POC-diagnosed infants who started antiretroviral therapy were retained on treatment by 90 days postinitiation compared with 42.9% of laboratory-diagnosed infants, a 43.7% increase. The effect of POC testing on retention after treatment initiation may be related to the benefits of earlier diagnosis and quicker provision of care for infants vulnerable to HIV-related disease. It is worth noting that clinical training and supervision were similar between the arms, with the diagnostic technology as the only difference. Nevertheless, the high attrition rates on treatment observed in both arms (>40%) highlight the need for more efforts to improve long-term paediatric outcomes. Indeed, POC testing alone is unlikely to close all gaps in the HIV paediatric care cascade; additional interventions to improve case finding, earlier treatment, and retention are needed. Community-based testing and screening within alternate entry points such as maternity, nutrition, and outpatient wards, active patient tracking and follow-up with community health workers and mobile health initiatives, patient education on postnatal HIV care, and family-based treatment are examples of interventions that could compliment POC testing to improve access to paediatric diagnosis and treatment, and long-term infant outcomes [22–29]. Implementation studies are needed on the most cost-effective combination of services to deliver within different settings. It also remains to be seen whether POC testing can improve paediatric HIV case finding by delivering decentralized testing closer to communities.
In this study, HIV-positive infants, irrespective of arm, were significantly older than negative infants. In addition, though the HIV status of infants was unknown at the time of sample collection, HIV-positive infants in the POC arm were older at sample collection and diagnosis than in the SOC arm. The reasons for these differences were not assessed, but may have been related to the inclusion of infants waiting for laboratory testing since before the study start dates. However, age at sample collection did not significantly affect test turn-around time and treatment initiation rates. Furthermore, the median age at receipt of results in the POC arm was significantly lower (41 days) than the age at ART initiation (127 days) even though results were provided on the same day. This was because the median age calculation of receipt of results included all infants (HIV-positive and HIV-negative), whereas the median age calculation at ART initiation only included the subset of HIV-positive infants. Finally, although over 98% of infants in the POC arm received results on the same day, 37 infants did not. This was likely due to mothers leaving the healthcare facility before the end of test processing or not being mentally prepared to receive the results.
The current study had several limitations that may be sources of bias. First, although a randomized cluster design was used, the study was conducted within routine procedures at primary healthcare clinics instead of within a dedicated and more controlled study setting. This was done to assess the effect of POC early infant diagnosis within the routine clinical environment of intended use so that the results would be more generalizable. Second, although the clinics were representative of primary healthcare facilities in Mozambique and likely also of other resource-limited settings in sub-Saharan Africa [48], the turn-around time of laboratory-based testing from sample collection to results received by the patient was high at 125 days. This could have been due to a number of reasons, including inefficient sample transportation and laboratory processing, reagent stock-outs, and/or appointment practices for follow-up patient visits. Other settings with faster laboratory testing may result in better treatment access. The WHO recommends results be returned in under 1 month; however, historical national data demonstrate that the median turn-around time for laboratory testing in Mozambique consistently exceeded 1 month during the 3 years preceding this study. Furthermore, test turn-around times routinely exceed 30–60 days in other high HIV burden settings with high rates of paediatric preantiretroviral therapy loss to follow-up [8–11,13,15,16]. It is also unclear whether the benefits observed with same day testing and antiretroviral therapy initiation in this study will be achieved if test turn-around time exceeds 1 day, requiring patients to make additional clinic visits to receive test results before proceeding with care. This study did not assess whether POC technologies could improve retention of HIV-negative infants throughout the exposure period nor the impact of a rapid infant diagnosis on long-term morbidity and mortality; however, the benefit of earlier diagnosis and treatment in infants is well established. Due to the small number of clusters included in this study, there were a limited number of variables available to assess for potential imbalances and bias. Finally, the acceptability by nurses of POC testing was not robustly qualitatively assessed.
The primary end point sample size target in this study was 121 HIV-positive infants initiating antiretroviral therapy in each arm. Although participant enrolment into the two study arms was similar, the primary end point sample size was not reached for the SOC arm by the time the POC arm sample size was achieved due to the laboratory testing delays. The study was brought to an end once the POC arm had reached the sample size target. This was done because of the clear and statistically significant positive outcomes in the POC arm. Although this may have increased the type-I error rate and introduced some bias, given the magnitude of the difference in outcomes observed between POC and SOC arms, it is unlikely that the study conclusions were impacted by the relatively minor difference on the sample size of the SOC arm.
The reasons for loss-to-follow-up and the final status of lost infants were not determined in this study as the routine clinic records did not capture this information consistently, and as clinic staff conducted only moderate tracking of lost infants due to limited time and resources under routine care. The absence of unique patient identifier numbers to track patients across health facilities was also a limitation. It is possible that mothers may have accessed follow-up care at different facilities due to preference or other reasons. If this occurred on a significant scale, it may reduce the generalizability of the findings of this study. However, it is also likely that the long and variable laboratory test turn-around times (interquartile range 84–185 days) negatively impacted retention by reducing opportunities for quick clinical decision-making and the reliable scheduling of patient visits for follow-up care. Although not measured in this study, this may have contributed to perceptions of low-quality care and service inconsistency amongst patients and healthcare workers, undermining commitment to follow-up care, health education, patient tracking, and other steps along the paediatric care cascade at these clinics.
In conclusion, the use of POC early infant diagnosis in low-resource, routine primary healthcare settings demonstrated significant effect on access to paediatric HIV testing and treatment, including linkage to and retention on antiretroviral therapy, and may be an effective intervention to reduce the burden of paediatric HIV. POC testing also enabled improvements in the quality of care, such as same day diagnosis and treatment initiation, to be implemented. Given the current global gaps in access to early infant diagnosis and paediatric treatment, POC testing should be considered as a tool in scaling up access to treatment, especially in low-resource settings.
Acknowledgements
The authors are grateful to UNITAID, UNICEF, and the Government of Flanders who supported the work through funding point-of-care test consumables and point-of-care instruments, and for supporting staff and operational costs. The authors are also grateful for the invaluable work carried out by the staff at the study primary healthcare centres in Maputo and Sofala provinces.
The funders of the study had no role in study design, data collection, data analysis, data interpretation, and writing of the report.
Conflicts of interest
There are no conflicts of interest.
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