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Impact of SMS/GPRS Printers in Reducing Time to Early Infant Diagnosis Compared With Routine Result Reporting: A Systematic Review and Meta-Analysis

Background: Despite significant gains made toward improving access, early infant diagnosis (EID) testing programs suffer from long test turnaround times that result in substantial loss to follow-up and mortality associated with delays in antiretroviral therapy initiation. These delays in treatment initiation are particularly impactful because of significant HIV-related infant mortality observed by 2–3 months of age. Short message service (SMS) and general packet radio service (GPRS) printers allow test results to be transmitted immediately to health care facilities on completion of testing in the laboratory. Methods: We conducted a systematic review and meta-analysis to assess the benefit of using SMS/GPRS printers to increase the efficiency of EID test result delivery compared with traditional courier paper–based results delivery methods. Results: We identified 11 studies contributing data for over 16,000 patients from East and Southern Africa. The test turnaround time from specimen collection to result received at the health care facility with courier paper–based methods was 68.0 days (n = 6835), whereas the test turnaround time with SMS/GPRS printers was 51.1 days (n = 6711), resulting in a 2.5-week (25%) reduction in the turnaround time. Conclusions: Courier paper–based EID test result delivery methods are estimated to add 2.5 weeks to EID test turnaround times in low resource settings and increase the risk that infants receive test results during or after the early peak of infant mortality. SMS/GPRS result delivery to health care facility printers significantly reduced test turnaround time and may reduce this risk. SMS/GPRS printers should be considered for expedited delivery of EID and other centralized laboratory test results.


INTRODUCTION
Globally, approximately 50% of HIV-exposed infants receive an HIV test within the first 2 months of life. 1 Furthermore, of those found HIV-infected only 30% are on antiretroviral therapy. 1 Morbidity and mortality are high in untreated HIV-infected infants, and early initiation of antiretroviral therapy is strongly recommended by the World Health Organization (WHO) and national guidelines to reduce mortality. 2 The peak of mortality for HIV-infected infants is at 2-3 months of age, 3 and approximately 50% of HIVinfected infants die before 2 years of age. 4 The turnaround time of HIV testing for early infant diagnosis (EID), however, is often several weeks or months.
HIV diagnosis of infants younger than 18 months of age is conducted using molecular diagnostic technologies rather than serological methods because of the potential presence and persistence of maternal anti-HIV antibodies. 5 Virological testing for EID is, therefore, generally performed at central laboratories. However, test volumes are distributed across hundreds or thousands of health care facilities in most countries, and many patients do not have easy access to laboratories. With current technologies, very few infants have on-site, same-day access to this critical test. Test specimens and the subsequent test results are typically transported over long distances and this can introduce long testing and result reporting delays, especially for patients in rural and remote areas.
Traditional specimen referral networks link health care facilities lacking on-site testing throughout the national network with centralized laboratories. The specimen type used for EID, dried blood spots, are stable for relatively long periods at ambient temperatures and thus can be stored or transported up to weeks before laboratory processing. 6 Many specimen referral networks, however, are inefficient and unreliable because they are often informal, fragmented, and nonstandardized. The same specimen referral networks are also used to deliver test results to health care facilities. This often results in long turnaround times. Solutions and interventions to reduce long turnaround times, particularly for EID, are needed to ensure more efficient and reliable testing services to this vulnerable population.
Although courier paper-based result delivery methods contribute a significant proportion to the overall test turnaround times and delays, additional challenges exist. There are several phases in the testing cascade: specimen collection, specimen storage at facilities, specimen transportation to laboratories, specimen processing, testing, result delivery to facilities, and result delivery to clinician/patient. Each phase contributes to the overall delay in testing. To optimize conventional laboratory-based testing, each phase must be improved. Short message service (SMS) and general packet radio service (GPRS) printer systems are a relatively easy to implement technological tool that can support more efficient result delivery while the overall health system is enhanced.
SMS/GPRS printer systems to return test results from central laboratories to district hospitals or health care centers have been developed and implemented in several countries. SMS/GPRS printers are devices designed to reduce turnaround time for delivering laboratory test results to improve patient care and outcomes. On completion of testing, the laboratory can send the test result through an SMS or GPRS network system directly to a small printer at the health care facility for immediate retrieval. Understanding the impact of SMS/GPRS printers in returning results quicker will provide important information on this innovative technology, its possible role in initiating infants on antiretroviral therapy earlier, and ultimately guide investment to strengthen EID programs in countries.
Several studies have been published assessing the impact of SMS/GPRS printers to return EID test results. [7][8][9][10][11][12][13][14][15][16][17] We undertook this systematic review to comprehensively assess the impact of using SMS/GPRS printers in EID test result delivery compared with the traditional courier paper-based system, particularly focusing on test turnaround times. The results of this review were used to inform the revision of the WHO Consolidated ARV Guidelines released in early 2016.

Search Strategy and Study Selection
This review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), 18 and followed a study protocol. PubMed and EMBASE databases were searched from January 1, 2005, to March 1, 2015 to identify peer-reviewed original research. Search terms were developed using the PICO question format (population, intervention, comparator, and outcome) as follows: HIV-exposed infants (population), SMS/GPRS printers (intervention), conventional paper-based results (comparator), and outcomes (time to receipt of result and retention along the testing and treatment cascade). Conference abstracts within the search dates from the Conference on Retroviruses and Opportunistic Infections (CROI), International Conference on AIDS and STIs in Africa (ICASA), International AIDS Society (IAS), and AIDS Conference and bibliographies were also screened and reviewed for possible inclusion. Two independent reviewers screened all titles and abstracts for eligibility. Studies were included if they compared the impact of SMS/GPRS printers with traditional courier paper-based reporting and pertained to EID testing for infants younger than 18 months of age. The majority of EID testing was conducted at the traditional WHO-recommended 6 weeks of age. Data were extracted from each included study, including the sample size, test setting, study dates, outcomes, etc. Studies were assessed for quality, bias, and applicability following QUADAS-2 guidelines. 19 The overall quality of the evidence was assessed using the GRADE approach. 20 Heterogeneity was assessed by visual inspection of forest plots.

Study Characteristics and Assessment
From a total of 3127 articles screened, 11 studies met the inclusion criteria and were included in the review ( Fig. 1 and Table 1). 7-17 Over 16,000 patients were included in the analysis, and the median sample size per study was 1415 patients. Studies were performed in East and Southern Africa, spanning 8 countries. All studies were observational in design and conducted between 2008 and 2015.
Overall, the quality of the evidence contributing to this review was rated as low because of the lack of randomized controlled trials. Most studies reviewed and analyzed programmatic implementation data; therefore, limited bias or patient exclusion was expected. Some studies used a pre-post analysis, whereas others compared different groups of facilities with and without SMS/GPRS printers. Some temporal or facility bias could have been introduced, and there were some concerns about applicability: All studies were conducted in Africa in routine clinical settings, making the results potentially less applicable and generalizable to other regions.

Timeliness of Testing and Antiretroviral Therapy Initiation
Courier paper-based results were returned with a mean weighted turnaround time of 68.0 days between specimen collection and results received at the health care facility (n = 6835) ( Fig. 2A). By contrast, using SMS/GPRS printers to expedite result delivery from the laboratory to the health care facility reduced the overall mean weighted test turnaround time from specimen collection to result received to 51.1 days (n = 6711) (Fig. 2B). There was, however, some observed heterogeneity between the point estimates. The mean and median within-study differences observed for the turnaround time of results between SMS/GPRS printers and traditional courier paper-based results were 23 and 24 days, respectively, with a difference range of 9-33 days.
Two studies provided additional subanalyses. One study showed a significant reduction in the test turnaround from the laboratory to caregiver receipt when SMS/GPRS printers were used instead of paper-based methods (25.9 days versus 11.2 days) (Fig. 3A). 7 Furthermore, there were no clear differences between turnaround times in 2 different settings: urban and rural hospitals. A second study found a significant reduction in the time from laboratory testing to antiretroviral therapy initiation when SMS/GPRS printers were used (52.31 days versus 37.5 days) (Fig. 3B). 11

DISCUSSION
Traditional specimen transportation and courier paperbased result delivery networks are often associated with long test turnaround times. This review found that sending test results immediately from laboratories to SMS/GPRS printers at health care facilities can reduce the turnaround time between result generation at the laboratory and result receipt at the hospital or health center. We found that SMS/GPRS printers reduced the overall test turnaround time from specimen collection to results received in the health care facility by 17 days. SMS/GPRS printers are fairly easy to use and require minimal skills to operate, while significantly reducing the test turnaround time.
Mortality of untreated, HIV-positive infants peaks at 8-12 weeks of age. 4 Testing infants at 6 weeks of age would result in the courier paper-based result being returned to the health care facility by an average age of approximately 13 weeks after which time the caregiver must return to receive the result, a further delay (Fig. 4A). SMS/GPRS printers allow for the result to be returned to the health care facility by approximately 10 weeks of age (Fig. 4B). Although SMS/ GPRS printers will not prevent all the mortality observed for untreated HIV-infected infants, they have the potential to reduce the overall test turnaround times that are critical to supporting early ART initiation in HIV-infected infants, and this may reduce infant mortality. Furthermore, several countries are considering testing infants at birth. The role of SMS/GPRS printers at birth testing should be investigated to understand if they would support faster report transmission to avert the peak in mortality for HIV-infected infants.
Although this review focused on returning results specifically for conventional EID testing, the use of electronic communication could be effective for all tests for which specimen referral to centralized laboratories for testing is required: Chemistry, hematology, tuberculosis, opportunistic infection screening; HIV viral load; and hepatitis C diagnosis are regularly transported and tested at supporting laboratories. The use of SMS/GPRS printers implemented initially for returning EID test results could be expanded to include all diagnostic tests requiring laboratory referral to improve care and expedite clinical decision making.
There are several limitations to the evidence base included in this review. First, most studies were retrospective, nonrandomized designs, and none reported patient important clinical endpoints such as antiretroviral therapy initiation rates or mortality; both of these limitations have been identified as common limitations of studies of diagnostic tests. 21,22 Second, although substantial data were available, several studies (60%-70%) failed to report 95% confidence intervals or ranges; therefore, overall confidence intervals or levels of significance could not be calculated. Furthermore, there was heterogeneity between results and many studies were small, reducing the confidence in the overall result; however, heterogeneity is expected in implementation studies yet despite this, and the small sample size of many studies, an indicative trend and thus clear conclusions toward reduced turnaround time was observed across studies. The data were skewed by the largest data set, which also had the longest turnaround times for both groups. In addition, there were little or no data focusing on cost-effectiveness, acceptability, or linkage to care, including the timeliness of result retrieval by caregivers. Understanding the impact of SMS/GPRS printers on retention along the testing and treatment cascade and likelihood to initiate antiretroviral therapy would be beneficial.
SMS/GPRS printers are one of many recent innovations to support improved health care in resource-limited settings. 23 Additional, more sophisticated result transmission technologies are under development or currently exist using mobile applications and including bidirectional communication. Furthermore, several point-of-care testing technologies have entered the market or are in the development pipeline. Most of these technologies can transmit testing data to a central database to allow for remote yet rapid monitoring, more efficient problem resolution, and improved testing quality. 24,25 In addition, rapid diagnostic test readers can support the real-time testing procedure and interpretation of results as well as transmit testing data similar to the point-of-care technologies. 26,27 Linking laboratory information management systems with electronic patient management records, when and where they exist, can allow for easier and faster test result retrieval. Finally, direct communication with patients through secure text messaging services has been considered in several settings to further expedite test result delivery. 28,29 Although SMS/GPRS printers can reduce test turnaround times, ongoing challenges exist with any technology, including device malfunction, transmission interruption, remote troubleshooting difficulties, stock-out of printer paper, etc. Monitoring the functionality of these technologies is critical to a successful system. In addition to SMS/GPRS printers, significant improvements can be incorporated into the overall system. Challenges experienced in the laboratory, such  as reagent stock-outs, equipment breakdowns, and volumes exceeding capacity, can further delay testing and receipt of result. Nevertheless, an important reduction in test turnaround time could be significantly impactful given the high early mortality rates observed for untreated HIV-infected infants. This review informed the 2016 WHO recommendation that electronic communication (including SMS/GPRS printers) can be considered to transfer test results and reduce delays in acting on results of EID and other essential laboratory tests. 30