CASE STUDY

Rapid Syphilis Tests in Tanzania: A Long Road to Adoption

Submitted to: Bill and Melinda Gates Foundation Seattle, WA 98102 Prepared by: Lauren Kleutsch, MHS, Steven A. Harvey, PhD, and Waverly Rennie, MHS

Center for Human Services

Case Study

Rapid Syphilis Tests in Tanzania: A Long Road to Adoption

Prepared for the Bill & Melinda Gates Foundation Seattle, Washington

Lauren Kleutsch, MHS, Steven A. Harvey, PhD and Waverly Rennie, MHS

June 2009

Center for Human Services: The CHS mission is to help clients meet today’s challenges and take advantage of tomorrow’s opportunities by providing a comprehensive array of education, training, advocacy, and health-related programs and services.

Center for Human Services 7200 Wisconsin Avenue, Suite 600 Bethesda, MD 20814-4811 TEL 301-654-8338/FAX 301-941-8427 www.chs.urc.org

Suggested citation: L. Kleutsch, S.A. Harvey, and Waverly Rennie. 2009. Rapid syphilis tests in Tanzania: A long road to adoption. Case Study. Bethesda, MD: Center for Human Services.

For more information on this report, please contact Steven A. Harvey at [email protected].

TABLE OF CONTENTS ABBREVIATIONS .............................................................................................................................. ii INTRODUCTION ................................................................................................................................ 1 BACKGROUND ................................................................................................................................. 1 Syphilis: Natural History and Global Epidemiology .................................................................. 1 Disease Burden among Pregnant Women in Tanzania ............................................................... 1 Diagnostic Testing for Syphilis................................................................................................... 1 National Guidelines for Syphilis Diagnosis in Tanzania ............................................................ 2 Operational Challenges to Universal Syphilis Screening of Pregnant Women .......................... 3 The Sexually Transmitted Disease Diagnostics Initiative .......................................................... 4 POLICYMAKER CONCERNS WITH RSTS ........................................................................................... 6 COST AND FUNDING .................................................................................................................... 6 Quality and Performance ............................................................................................................ 7 Past Problems with Rapid Tests.................................................................................................. 7 CONCLUSIONS AND RECOMMENDATIONS ....................................................................................... 8 Conclusions................................................................................................................................. 8 Recommendations....................................................................................................................... 9 REFERENCES .................................................................................................................................. 11 APPENDIX: HEALTH PROVIDERS AND PROGRAM MANAGERS INTERVIEWED FOR DIAGNOSTICS COST ANALYSIS PROJECT .............................................................................................................. 13

TABLES AND FIGURE Table 1. Advantages and disadvantages of non-treponemal and rapid (treponemal) syphilis tests ................................................................................................................................. 3 Table 2. Sensitivity and specificity of the SD Bioline 3.0 rapid syphilis test ............................... 5 Table 3. Cost-effectiveness of rapid syphilis tests versus RPR (2005 US$)................................. 6 Figure 1. SDI activities related to RST adoption in Tanzania, 2003–2009 .................................... 5

i

ABBREVIATIONS ANC

Antenatal care

AIDS

Acquired immune deficiency syndrome

CHS

Center for Human Services

DALY

Disability-adjusted life year

DFID

United Kingdom Department for International Development

FTA-ABS

Fluorescent treponemal antibody-absorption

HIV

Human immunodeficiency virus

JICA

Japanese International Cooperation Agency

MHSW

Ministry of Health and Social Welfare

NACP

National AIDS Control Program

RCH

Reproductive and Child Health

RDT

Rapid diagnostic test

RPR

Rapid plasma reagin

RST

Rapid syphilis test

SDI

Sexually Transmitted Diseases Diagnostics Initiative

STI

Sexually transmitted infection

TDR

Special Program for Research and Training in Tropical Diseases

TPHA

Treponema pallidum hemagglutination assay

TPPA

Treponema pallidum particle agglutination assay

UNDP

United Nations Development Programme

UNFPA

United Nations Population Fund

VDRL

Venereal Disease Research Laboratory

WHO

World Health Organization

ii

INTRODUCTION Syphilis prevalence among pregnant women in Tanzania is estimated at 6.7%, and untreated maternal syphilis has a significant impact on birth outcomes.1,2 Despite a policy of universal syphilis screening for pregnant women and a very high rate of antenatal care (ANC) attendance, many ANC attendees are not tested for syphilis.3 Tanzania’s diagnostic testing approach may contribute to this failure. The Rapid Plasma Reagin (RPR) test, the most commonly used syphilis test in Tanzania, requires electricity, refrigeration, a rotator machine, and personnel with significant training to interpret test results. The Venereal Disease Research Laboratory (VDRL) test, a diagnostic based on the same principle as RPR, requires all this plus a microscope. Many rural health facilities lack one or more of these inputs. Rapid syphilis tests (RSTs) can function effectively in settings with minimal infrastructure and can be performed and interpreted by health workers with less training than that required for RPR or VDRL. The Sexually Transmitted Diseases Diagnostics Initiative (SDI) first recommended adoption of rapid syphilis testing in 2003, but RST use in Tanzania has not yet been implemented as a routine practice. This case study explores what has occurred since that 2003 recommendation and examines why debate about RST use continues today. To prepare the case study, the Center for Human Services (CHS) conducted interviews and focus group discussions with program managers, health service providers, and members of the logistics community in Tanzania. SDI provided additional information about its experience advocating for RST adoption. CHS also conducted a literature review of data on syphilis screening programs and rapid test introduction.

BACKGROUND Syphilis: Natural History and Global Epidemiology Syphilis is a sexually transmitted infection (STI) caused by the spirochete Treponema pallidum. Infection during pregnancy can lead to multiple complications. Approximately 30% of affected pregnancies end in stillbirth. Thirty percent of infected mothers give birth to a child with congenital syphilis, which can result in deformities, developmental delays, seizures, and a mortality rate of up to 50%. Some infants with congenital syphilis show symptoms at birth or in the first few months of life; others develop late congenital syphilis, manifesting after the child’s second year.4,5 Syphilis affects about a million pregnancies globally each year and contributes to about a third of the stillbirths in sub-Saharan Africa.2 Congenital syphilis can be prevented by screening early in pregnancy, treating seropositive pregnant women, and preventing re-infection.6 Infection is a particular public health concern in areas of southern Africa with high HIV/AIDS prevalence: The genital sores often caused by syphilis are associated with a two- to five-fold increase in the risk of transmitting or acquiring HIV. In Tanzania, overall HIV prevalence among adults aged 15–49 is estimated at 7%, slightly higher among women than men.7

Disease Burden among Pregnant Women in Tanzania The Tanzanian National AIDS Control Program (NACP) estimates that the overall syphilis prevalence among pregnant women in mainland Tanzania in 2003–2004 was 6.7%, ranging from 0.4% in Kilimanjaro region to 32% in Tabora.1 A 2002 study of pregnant women in Mwanza attributed 51% of stillbirths, 24% of preterm live births, and 17% of adverse pregnancy outcomes to maternal syphilis.8

Diagnostic Testing for Syphilis Like many sexually transmitted infections in limited-resource settings, syphilis is often diagnosed and treated syndromically. However, since syphilis symptoms are non-specific and since many infected individuals are asymptomatic, effective universal screening of a population subgroup (such as pregnant 1

women) requires a serological test. There are two basic types of serological tests for syphilis: treponemal and non-treponemal. Treponemal tests detect the presence of an antigen or antibody specific to T. pallidum. These tests can distinguish syphilis from other infections, but since the antigens or antibodies to which they react remain in the bloodstream for years after an infection is treated, these tests cannot distinguish between an active and a past infection. Non-treponemal tests detect the presence of reagin, an antibody that reacts to substances released by cells when they are damaged by T. pallidum. However, these tests are not specific to T. pallidum, so while more accurate than treponemal tests at distinguishing an active from a past infection, they can result in false positives among patients with certain types of non-syphilitic infections.9 In ideal circumstances, a patient thought to have syphilis is first screened using a non-treponemal test like RPR or VDRL to detect active infection. A treponemal test is then used to confirm that the infection is due to syphilis. Use of a treponemal test alone can result in overtreatment, but in settings where scarce resources preclude two-stage testing, overtreatment is less dangerous than leaving infected patients untreated in the absence of a confirmatory test.10 VDRL tests may be done on a blood serum sample or cerebrospinal fluid (to check for neurosyphilis). The test requires a 7 ml venous blood sample. To obtain serum, the patient’s blood is centrifuged for about 10 minutes or must sit for 20 minutes to allow the serum to separate from blood cells. The serum must then be heat-inactivated at 56°C for 30 minutes using a hot-water bath. The heated serum is mixed with reagent on a glass slide, and the mixture is read microscopically to detect clumping, which indicates a positive result. RPR tests work on the same principle as VDRL, but can be performed on unheated plasma or serum and do not require a microscope. A drop of serum or plasma is deposited on an 18 mm circle card test, followed by a drop of reagent, which is kept refrigerated and brought to room temperature before use. The test card is then rotated manually or in a mechanical rotator for eight minutes and inspected for clumping, indicating a positive result. Most test cards include negative and positive control wells for comparison. Over 20 different point-of-care rapid tests for syphilis have recently become commercially available. These RSTs have several advantages over diagnostics like RPR or VDRL. First, they are self-contained units requiring no additional equipment. Second, they do not require refrigeration. Third, while RPR results are open to subjective interpretation, RSTs are simpler to interpret and require less health worker training.11 Many RSTs rely on finger stick whole blood samples, eliminating the need for a venous blood draw and time-consuming serum separation. Finally, RSTs provide results in about 15 minutes, enabling immediate treatment.11,12 A major disadvantage of RSTs is that, like other treponemal tests, they do not distinguish between current and past infection. Table 1 compares the advantages and disadvantages of non-treponemal tests and RSTs.

National Guidelines for Syphilis Diagnosis in Tanzania Two programs address syphilis in Tanzania using different diagnostic approaches. The first is the Safe Motherhood Initiative housed within the Ministry of Health and Social Welfare’s Reproductive and Child Health (RCH) program. The Initiative mandates syphilis screening for all pregnant women.13 Most health facilities that provide syphilis screening use the RPR test, though some facilities continue to use the VDRL. Most facilities do not use a confirmatory test. The second program is the NACP. NACP guidelines do not stipulate the use of diagnostic tests to screen for syphilis among patients attending STI clinics. Instead, they recommend syndromic management.14

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Table 1. Advantages and disadvantages of non-treponemal and rapid (treponemal) syphilis tests† Non-treponemal tests (RPR and VDRL) Advantages

Disadvantages

Can distinguish between active and past, treated infection

Require electricity for refrigeration of reagent and for rotator and centrifuge machines

Can be used to monitor treatment success

Cannot be used with whole blood

Low cost

False negatives in early- and late-stage syphilis or with “prozone effect” in secondary syphilis Require microscope and/or health worker trained to interpret titres

Rapid treponemal tests Advantages Specific for Treponema pallidum Simple to perform Depend on capillary rather than venous blood draw

Disadvantages Cannot distinguish between active and past, treated infections Higher cost

Results are easier to interpret Can be used with whole blood, serum, or plasma (reduces time-consuming serum separation process) Shorter waiting time (eliminates problem of “missed treatment” for clients who do not return for results) Do not require refrigeration, electricity, or microscope † Adapted from SDI WHO, 2006 The Use of Rapid Syphilis Tests.15

Operational Challenges to Universal Syphilis Screening of Pregnant Women Despite Safe Motherhood Initiative guidelines and a very high rate of ANC attendance (94% of pregnant women complete at least one ANC visit), many ANC attendees are not tested for syphilis.16 A 2002 study of 342 ANC attendees found that only 39% were screened or booked for future screening.17 A 2006 service provision survey found that only 19% of Tanzanian health facilities routinely screened ANC clients for syphilis. Most sites that did provide screening were hospitals and private, for-profit institutions.3 Various factors may contribute to the low syphilis-screening rates. The 2002 study found that many participating ANC providers did not understand the implications of untreated maternal syphilis and considered screening a low priority.17 Confusion between programs with shared responsibility may also contribute to the low rates.18 Having multiple programs responsible for testing could cause conflict and competition around funding and procurement.17 The need for refrigeration of the reagent and agitation of the test card makes achievement of widespread screening more difficult. In locations with frequent electricity outages or where there is no rotator machine, ANC nurses must rotate test cards by hand for the requisite eight minutes, diverting attention away from patients and slowing care. Health care workers must be trained to interpret RPR titers, but one evaluation found that only 11 of 100 Tanzania staff participating in prenatal assessments had received this training. Screening services in many facilities were also hindered by the absence and turnover of the few RPR-trained staff.11 3

The Sexually Transmitted Disease Diagnostics Initiative In light of the operational challenges and limits posed by RPR testing in Tanzania, RSTs may offer significant opportunities to achieve universal screening for pregnant women. However, efforts by the Sexually Transmitted Disease Diagnostics Initiative (SDI) to increase access to this diagnostic alternative have not yet resulted in Tanzania’s adoption of RSTs. SDI, whose mission is to “promote the development, evaluation, and application of diagnostic tests for sexually transmitted infections appropriate for use in primary health care settings in developing countries,” has been active in advocating RSTs in Tanzania.19 Formed in 1990, SDI is part of the Special Program for Research and Training in Tropical Diseases (TDR) and is sponsored by the World Health Organization (WHO), UNICEF, the United Nations Development Program (UNDP), and the World Bank. SDI has proposed the “ASSURED” criteria as ideal characteristics for rapid tests in developing countries:8 A= Affordable S = Sensitive S = Specific U = User-friendly (simple to perform in a few steps with minimal training) R = Robust and rapid (results available in less than 30 minutes) E = Equipment-free D = Deliverable to those who need them In 2003, SDI published the results of a laboratory evaluation of the performance and operational characteristics of nine RSTs meeting the ASSURED criteria.20,21 The evaluation assessed clarity of kit instructions, technical complexity, and ease of interpreting results. It also gauged each test’s design, shelf life, storage temperature, time to results, additional supplies required, and specimen used. All nine tests showed acceptable sensitivity and specificity relative to the reference T. pallidum hemagglutination assay (TPHA) or T. pallidum particle agglutination assay (TPPA) test. Based on this evaluation, the four tests that use whole blood and do not require refrigeration (Determine® Syphilis TP, VisiTect Syphilis, Syphicheck-WB, and SD Bioline Syphilis 3.0.) were field-tested in Brazil, China, Haiti, and Tanzania in 2003–2004. This evaluation compared the RSTs against a reference treponemal standard test, using whole blood in clinics and whole blood and serum in laboratories.12 The RSTs and reference tests were in turn evaluated against a gold standard test. In Tanzania, the reference test was RPR and the gold standard the TPPA. Tanzania’s evaluation results indicated that when used with whole blood in a clinic setting, all four tests were highly specific (>95%), but their sensitivity ranged from 59.6 to 85.7%. SD Bioline Syphilis 3.0 had the highest sensitivity (85.7%) and a specificity of 98.1%. Table 2 presents detailed data on SD Bioline’s performance in all four countries.12 In 2005, SDI presented these field test results at a stakeholders’ meeting in Lilongwe attended by representatives from WHO, UNDP, UNICEF, the United Nations Population Fund (UNFPA), several major donors, and several officials from the Tanzanian Ministry of Health and Social Welfare (MHSW). Attendees seemed to agree that RSTs would offer a significant advantage over RPR in Tanzania.22 In 2006, SDI funded a pilot study examining the acceptability and feasibility of using rapid tests in Tanzanian clinics that had not previously conducted syphilis screening. The study, as yet unpublished, demonstrated that these tests were well accepted by staff and patients.22,23 In 2007, SDI received Gates Foundation funding for a multi-country study to demonstrate to policymakers that RSTs are cost-effective and that national level roll-out is feasible. The study is now underway at various levels of the health system in the Geita district of Tanzania’s Mwanza region, as well as in five other countries.22

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Table 2. Sensitivity and specificity of the SD Bioline 3.0 rapid syphilis test† Clinic: Using whole blood

Lab: Using whole blood

Lab: Using serum

Sensitivity

Specificity

Sensitivity

Specificity

Sensitivity

Specificity

% (95% CI)

% (95% CI)

% (95% CI)

% (95% CI)

% (95% CI)

% (95% CI)

Tanzania Brazil

85.7 (±8.4) 88.2 (±8.9)

98.1 (±1.2) 99.4 (±0.7)

90.9 (±6.9) ‡

96.1 (±1.6) ‡

90.9 (±6.9) 90.2 (±8.2)

95.5 (±1.8) 99.4 (±0.7)

China

87.6 (±6.8)

99.4 (±0.8)

87.6 (±6.8)

99.4 (±0.8)

95.5 (±4.3)

97.9 (±1.6)

Haiti

100*

98.3 (±1.2)

100*

98.5 (±1.1)

100*

98.5 (±1.1)

Country

† Adapted from Mabey et al., 2006.12 ‡ In Brazil, only serum was tested in the laboratory. * These results should be interpreted with caution since the sample sizes were small (n=30).

In 2008, SDI held two meetings with WHO, the RCH program, and the NACP to choose one RST for antenatal screening in Tanzania. Participants selected SD Bioline Syphilis 3.0.22 The decision was announced at an SDI-organized, July 2008 meeting, where national reproductive health program managers from nine African countries, including Tanzania, discussed RST scale-up as part of routine ANC services.22,23 According to SDI members, the Tanzania MHSW plans to adopt RSTs at the national level if the pilot, district-level roll-out in Geita District is successful. Figure 1 presents a timeline illustrating SDI activities since the initial laboratory evaluation published in 2003.

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Despite the technical advantages of RSTs over RPR and despite SDI’s advocacy efforts – which date back to before publication of the laboratory evaluation in 2003 – the shift to rapid tests has not yet occurred. Several factors have slowed the process, as discussed below.

POLICYMAKER CONCERNS WITH RSTS Key informants interviewed for this case study reported that many policymakers have shown reluctance to adopt rapid syphilis tests. Their concerns can be grouped into three categories: cost and funding, quality and performance, and past problems with rapid tests.

COST AND FUNDING Many policymakers have been concerned about the per-unit cost of RSTs, which can range from $0.47 to $1.00, depending on the manufacturer. By contrast, RPR costs between $0.15 and $0.23 per test.24,25 This difference may make RSTs unaffordable to some programs. A study by Vickerman et al. modeled cost-effectiveness of RPR versus the four evaluated RSTs (Table 3). The RSTs were all more expensive than RPR, but except for Determine® all also saved more disabilityadjusted life years (DALYs) by averting adverse birth outcomes. Bioline was found to be slightly more cost-effective than RPR, though the study authors say this finding should be interpreted with caution due to substantial uncertainty in simulations of the test’s sensitivity. The authors also report that the Mwanza antenatal clinic where the evaluation was conducted was better equipped than most Tanzanian clinics, so RPR’s sensitivity was relatively high in this setting, making it very cost-effective. They suggest that RPR would be less sensitive (and hence less cost-effective) in facilities lacking a rotator machine and consistent electricity: In such settings, RSTs would likely be more cost-effective than RPR.24 Table 3. Cost-effectiveness of rapid syphilis tests versus RPR (2005 US$) † ‡ Test Done on Serum*

Test Done on Whole Blood**

Cost of RST /cost of RPR

RST / RPR (cost per DALY saved)***

Cost per DALY saved

Cost of RST / cost of RPR

RST / RPR (cost per DALY saved)***

Type of test

Total cost

DALYs saved

Cost per DALY saved

RPR test

15,852

1321

12.00

NA

NA

12.00

NA

NA

Determine (Abbot)

22,372

1316

17.00

1.41

141.7% (119–247%)

16.80

1.39

140% (117–263%)

Visitect (Omega)

19,634

1373

14.30

1.24

119.2% (105–187%)

14.10

1.22

117.5% (104–173%)

Syphcheck (Qualpro)

19,599

1390

14.10

1.24

117.5% (105–183%)

13.90

1.22

115.8% (104–164%)

Bioline (SD)

16,874

1430

11.80

1.06

98.3% (91–125%)

12.10

1.05

100.8% (89–151%)

†

Adapted from Vickerman et al. 2006.22

‡ DALY, disability-adjusted life year; RPR, rapid plasma reagin. * Using data from the reference laboratory. ** Using data from antenatal clinics. *** Uncertainty bounds are in parentheses.

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A related concern was donor interest and commitment. Many respondents said that the switch from RPR to rapid tests was likely only with donor support but questioned whether donors would make STI screening a priority. In the words of one MHSW official: [Even if an RST were cheap], who will be funding it? Would partners fund it? They follow the fashion…. [Donors] aren’t willing to pay for STI screening in pregnant women or STI diagnosis and treatment in the STI clinics. The national health budget can’t pay for the diagnostics that are needed. Seventy percent of the health budget is supported by donors. That will continue for some time.

Other respondents spoke to sustainability, pointing out that even if donor support were available, the government would eventually have to fund the tests itself. As one donor representative said: A challenge to this introduction of new diagnostics is that once the international community determines that a diagnostic is important, it becomes a moral obligation to supply it. But if a donor pushes it through and then abandons it, the government is obligated to continue supplying the test. Then if [the government] decides they can no longer afford the newer technology, there may be nowhere to get the older, more affordable technology.

Clearly, considerations of cost, cost-effectiveness, and funding play a substantial role in policymakers’ decisions around diagnostic testing. Without donor support and a long-term plan for continued funding, policymakers may eschew new technologies.

Quality and Performance Although the sensitivity and specificity of RSTs compared favorably to RPR during evaluation, some policymakers expressed concern that RSTs were less accurate.12 Some may not have been aware that the tests had been evaluated and performed well. Others reported that the evaluation did not accurately reflect field conditions, making results unreliable: They said that test performance would be compromised by high temperatures and less than ideal storage conditions. They noted that the tests are said to be stable at “room temperature” (30°C, according to SD Bioline’s package insert) but that room temperature in rural Tanzania can reach 40°C. Respondents also worried about the need for quality control and indicated uncertainty about the required frequency of quality control measures. Finally, some health officials said they would hesitate to convert to RSTs because of potential supply chain complications. They expressed doubts that a single supplier could consistently provide enough tests for the whole country, despite manufacturers’ claims to the contrary. They also worried that changing to rapid tests would require adjustments to procurement and inventory management processes. Lastly, they raised concerns that an RST’s relatively short shelf life (18–24 months) would lead to stock-outs and/or waste.

Past Problems with Rapid Tests Experience with the introduction of other rapid tests may also have contributed to Tanzanian policymaker reluctance to embrace RSTs. For example, health care providers interviewed for this study reported that when some Tanzanian clinics introduced malaria rapid diagnostic tests (RDTs), clients questioned test accuracy and either sought microscopic diagnosis elsewhere or demanded treatment regardless of RDT outcome. Health personnel also mentioned problems with HIV rapid tests. In 2006, the Tanzanian MHSW introduced a new algorithm for HIV testing in which SD Bioline HIV-1/2 3.0® rapid tests would be used as an initial screening test and Determine HIV-1/2® rapid tests as a confirmatory test. Capillus HIV-1/HIV-2® rapid tests, used in the previous algorithm, were dropped because they require cold-chain storage. Controversy erupted when the Capillus tests re-emerged in the 2007 National HIV Testing and Counseling Campaign. Respondents offered differing explanations for the re-emergence. One indicated that the government procured Capillus tests in order to exhaust funds already earmarked for that purpose. Another suggested that the government decided to use up the Capillus stock on hand before procuring Determine tests. The Ministry reported having purchased additional Capillus tests because training on the new algorithm had not been completed in some parts of the country.26 Some media sources alleged 7

favoritism and corruption. An investigation by the Public Procurement Regulatory Authority found no evidence of wrongdoing, but some stakeholders still questioned the motive behind the re-emergence of Capillus.9,26 Disorganization and miscommunication during the transition, with the consequent corruption allegations, may have contributed to the current skepticism about a switch to RSTs. Moreover, several respondents reported that over-assertiveness from test manufacturers has made decision makers wary. Health officials may be assuming that those who promote new technologies, be they manufacturers or groups like SDI, are doing so principally out of self-interest.

CONCLUSIONS AND RECOMMENDATIONS Conclusions From a technological point of view, the use of rapid syphilis diagnostic tests would make it possible to screen a much larger percentage of pregnant women in Tanzania than currently receive screening with RPR or VDRL. Adopting RSTs would eliminate several major barriers to universal screening, including the need for electricity, laboratory equipment, and highly trained personnel. One might ask, then, why RSTs are still not widely used in Tanzania nearly a decade after they became available. What such a question would overlook, however, is that “available” is a relative term. To the manufacturer who developed a new diagnostic, it might have become “available” as soon as efficacy tests demonstrated sensitivity and specificity as high or nearly as high as the current standard. In the world of syphilis rapid tests, that might have been 2000 or 2001. To the WHO and affiliated entities like SDI, RSTs might only have become available for practical purposes after additional lab and field trials. In terms of this case study, that would have been in 2003 after the laboratory evaluation of the nine RSTs or in 2004 after the four-country field test. However, SDI only presented results from this four-country study at its Lilongwe stakeholders’ meeting in mid-2005, and neither study was published until late 2006.12,15,20 Developingcountry stakeholders seeking confirmation that a diagnostic test functions effectively in settings similar to their own could credibly argue that RSTs became “available” only upon publication of those results. But even the 2004 study, which demonstrated acceptable sensitivity and specificity in field conditions, did not address the acceptability of RSTs to health workers and patients or the feasibility of using them on a dayto-day basis. These questions were not addressed until the 2006 SDI study, whose results are as yet unpublished. A cautious program or finance manager might make the case that implementation of a new technology should only begin after demonstration of feasibility. From this perspective, the pilot roll-out of SD Bioline Syphilis 3.0, begun in Tanzania in 2008, was a timely – perhaps even rapid – move to adopt a technology that for practical purposes has only become “available” within the last 24–36 months. As the Tanzania experience demonstrates, accumulating the necessary evidence to move from development to implementation can be a lengthy process. One might argue that Tanzanian policymakers hesitant to adopt RSTs are being overly cautious or even unreasonably resistant. However, program managers, particularly in an environment of scarce resources, often want empirical evidence that a new technology will work effectively in their own context. The fact that a diagnostic is efficacious (i.e., works well under laboratory conditions) does not necessarily mean it will prove reliable in a real world environment of high heat and humidity, extended storage, use by personnel with varying training and skills, and so on. Results from other settings – even other developing-country settings – are often not sufficiently convincing to policy gatekeepers. Previous negative experience – or experience key constituents perceive to be negative, such as the misunderstandings that occurred in Tanzania over the use of HIV rapid tests – can fuel skepticism and resistance. The country’s dual approach to syphilis diagnosis – syndromic in STI clinics versus test-based for ANC – probably leads to confusion and may cause health workers to downplay the importance of syphilis in pregnancy and of asymptomatic infection. Lack of clarity about how to assure the quality of a new technology and a new process can generate concerns about the time and human resources needed for monitoring. 8

Cost is also a consideration. Tanzania has about 1.5 million births per year.27 At US $0.15–0.23 per test, screening 1.5 million women for syphilis using RPR would cost US $225,000–$345,000. At US $0.47– 1.00 per test, screening the same number of women using an RST would cost US $705,000–$1.5 million. Screening all pregnant women would cost more, since the 1.5 million figure excludes miscarriages and abortions. One optic through which to view these figures is Tanzania’s annual per capita government expenditure on health, estimated by the WHO to have been US $13 in 2006.28 With a population of roughly 40 million, that amounts to a total government health expenditure of US $520 million. Universal syphilis testing of pregnant women using the low estimate of per unit cost for RPR would thus represent 0.04% of total government spending on health, compared to 0.29% using the high estimate of per unit costs for RSTs – a significant difference. Another optic is donor contribution to overall health spending nationally, estimated by the WHO to be about 44%.28 This is much less than the 70% mentioned by the MHSW official quoted earlier, but still quite high. Donors fund much of the limited syphilis testing that takes place currently in Tanzania, but both health officials and donor representatives interviewed for this case study reported that syphilis – and STI diagnosis in general – is low on the donor list of priorities. One interviewee reported that JICA, which has provided support for limited syphilis testing over many years, is anxious to end this component of its assistance. A possible response to concerns about cost might be to emphasize the greater cost-effectiveness of RSTs compared to RPR. As noted earlier, the Vickerman study found that the cost per DALY saved through RST diagnosis is about equal to or perhaps a bit better than that of RPR.24 Bioline, the RST selected for pilot implementation in Tanzania, was actually slightly less sensitive than RPR when evaluated in Tanzania.12 But as one interviewee pointed out, RPR’s sensitivity is largely theoretical since most Tanzanian health facilities cannot perform it and the sensitivity of any diagnostic is zero when it’s not being used. Taking into account the feasibility of using Bioline, its real cost-effectiveness is probably much higher than that of RPR. But introducing RSTs for routine ANC screening would still require a significant investment above current expenditures. It is not clear that the government is able or the donors willing to commit to that investment.

Recommendations Tanzania’s experience with RSTs indicates that technological advantages alone are not sufficient to ensure rapid adoption of a new diagnostic test. A more effective approach might combine a program of accelerated efficacy, effectiveness, feasibility, and acceptability testing with consensus building at both the national and international level, including attention to policy development and financing. Development and testing of a new product is a time-consuming, multi-stage process. It is difficult to plan and secure funding for one stage before completing the previous one. Two strategies might help accelerate this process without compromising product quality. First, devoting more resources to fieldtesting might speed up efficacy, effectiveness, feasibility, and acceptability testing. For instance, rather than carrying out each stage of testing over 18–24 months, it might be possible to achieve the same sample sizes in 9–12 months by fielding larger research teams in a larger number of sites simultaneously. Such an approach would represent a significantly increased management burden. It would require increased vigilance by investigators and research coordinators to ensure a sufficiently high standard of data quality within a compressed fieldwork schedule. Similarly, additional resources for data analysis could reduce the time elapsed from completion of field work to presentation of results. Second, donors supporting diagnostics research could negotiate accelerated publication schedules with appropriate scientific journals. The Lancet and other journals have accelerated-publication provisions that facilitate rapid diffusion of important research results while maintaining a rigorous standard of peer review. Consensus building with key country-level decision makers would be critical throughout this process. Ideally, program managers and other leaders within the target market would be included in predevelopment discussions about desired product characteristics. They would also participate in field trial 9

design, including conversations about acceptable levels and types of evidence required to substantiate product efficacy, effectiveness, and so on at each stage. This might reduce the need for multiple field trials in locations with only slightly differing characteristics. Finally, such leaders would also be involved in discussions about and development of implementation policies. Key policy questions might include: At what level of the health system will the new product be used? By what types of health workers? In what circumstances? What biosecurity or other safety measures will be needed? What is an adequate algorithm for periodic quality assurance? Similar discussions should take place simultaneously within country. In-country stakeholders should also participate in discussions about how pilot testing and rollout will occur. In what locations should they begin? What steps are needed to address logistics? What additional supplies are needed to ensure the test will function? What training and supervision are required? Recent experiences with the roll-out of new medications and diagnostics illustrate the complexity of adopting new practices. Implementation of artemisinin combination therapy for malaria has been delayed in many countries when changes to first-line treatment were announced before appropriate inputs and policies were in place. Roll-out of antiretroviral therapy for HIV/AIDS requires a plethora of support structures to function effectively. To facilitate rapid uptake of new diagnostic tests, donors and multilateral organizations might work with national and regional stakeholders to develop model policies addressing key questions. In addition to donors, organizations such as the Foundation for Innovative New Diagnostics and TDR can contribute to consensus building around technical issues. WHO’s participation is essential: Many countries rely upon WHO approval as the signal that a new policy or technology is indicated. One area in need of additional thought is how to identify the most effective channels for diffusing information about new diagnostic and other health and medical technologies to practitioners and other stakeholders within country. While publication in leading Western journals has great value for disseminating scientific knowledge to certain constituencies, developing-country medical and health practitioners and managers often lack access to these sources. Experimentation with different strategies for reaching key withincountry constituencies will help facilitate participation and uptake. Last is the matter of cost. RSTs remain significantly more expensive per unit than RPR. While it is tempting to think that lowering their price would solve the problem, the reality is probably more complicated. Lack of electricity, laboratory equipment, and sufficiently trained personnel are all barriers to RPR use in Tanzania, but they are not the only barriers. Some proportion of the missed opportunity for screening of pregnant women is due to inadequate funding, even in health facilities with the necessary infrastructure to carry it out. Funding for syphilis prevention and treatment is simply a lower priority for both donors and the Tanzanian health system than is funding for higher profile diseases like AIDS, malaria, and tuberculosis. Selling RSTs at a higher price on the private market might help subsidize the cost in the public system, but the private market in countries like Tanzania is probably quite small. Donors, multilateral and bilateral organizations, and host country governments will have to work together to increase the profile of syphilis as a key public health problem. Until that happens, even the best new technology at the lowest possible price will seem out of reach to governments like Tanzania’s and less than completely compelling to its frontline health workers.

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United Republic of Tanzania, Ministry of Health, Reproductive and Child Health Section. April 2004. National Guidelines for Screening and Treatment of Syphilis during Pregnancy. Dar es Salaam, Tanzania: Author.

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United Republic of Tanzania, Ministry of Health and Social Welfare, Reproductive and Child Health and National AIDS Control Programs. 2002. Training curriculum on sexually transmitted infections. Dar es Salaam, Tanzania: Author.

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Peeling, R.W., Mabey, D., Fitzgerald, D.W., and Watson-Jones, D. 2004. Avoiding HIV and dying of syphilis. The Lancet, 364 (9445): 1561–63. 11

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APPENDIX: Health providers and program managers interviewed for this case study Dr. Aziz Abdallah, Pediatric HIV Care and Treatment Officer, Columbia University, ICAP. Dar es Salaam. 4/03/2007. Dr. Lakha Al Nur, Managing Director, Oyster Bay Pharmacy. Dar es Salaam. n.d. John Amenyah, Country Director, JSI Deliver. Dar es Salaam. 4/16/2007. Dr. Eugene Ashile, Physician, HERI Dispensary. Arusha. 4/04/2007. Mr. V. Barongo, Warehouse Officer, Medical Stores Department. Mwanza. n.d. Dr. Zachary Berege, Acting Chief Medical Officer, Ministry of Health and Social Welfare. Dar es Salaam. 3/3/2007. Dr. Mark Bura, Program Manager, East, Central, and Southern African (ECSA) Health Community. Arusha. 4/23/2007. Dr. H. Bwhana, Regional Medical Officer, Ministry of Health and Social Welfare. Mwanza. 4/23/2007. Dr. Chonde, TB Laboratory Director, Ministry of Health and Social Welfare. Dar es Salaam. n.d. Amy Cunningham, Country Director, Columbia University ICAP. Dar es Salaam. 4/11/2007. Dr. Saidi Egwaga, Director, National TB and Leprosy Program Ministry of Health and Social Welfare. Dar es Salaam. 4/13/2007. Khalid S. Hassan, Lab Coordinator, National AIDS Control Program. Dar es Salaam. 4/24/2007. Agatha Haule, Program Officer, PMTCT, Elizabeth Glaser Pediatric AIDS Foundation. Dar es Salaam. 4/25/2007. Geert Haverkamp, Program Director, PHARMACESS. Dar es Salaam. n.d. Mr. Ishijima Hisahiro, Health Cooperation Planning Advisor to the Chief Medical Officer, Japan International Cooperation Agency/Ministry of Health and Social Welfare. Dar es Salaam. 4/16/2007. Dr. Innocent, Chief of Tuberculosis Control, Magu District, Ministry of Health and Social Welfare. Magu. n.d. Dr. Yaha Ipuge, Country Director, Clinton HIV/AIDS Initiative. Dar es Salaam. n.d. Dr. Patrick Kachur, Malaria Advisor, CDC-Atlanta. Dar es Salaam. 2/18/2007. Mr. Charles Kagoma, HIV/AIDS Laboratory Services, WHO Country Office. Dar es Salaam. 4/24/2007. Dr. Pastory Kahbi, Acting District Medical Officer and Director, Magu District Hospital. Magu. n.d. Dr. Amos Kahwa, Researcher, National Institute for Medical Research. Dar es Salaam. n.d.

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Dr. Adeline Kimambo, Director, Christian Social Services Commission. Dar es Salaam. 4/19/2007. Dr. Paul Kimanzi, Country Director, AMREF. Dar es Salaam. n.d. Dr. Lameck Kipilyango, Senior Warehouse Officer and Acting Area Manager, Medical Stores Department. Mwanza. n.d. Emma Lekashinga, Care and Treatment Pharmacist, National AIDS Control Program. Dar es Salaam. 4/24/2007. Charles Llewellyn, Health Officer, USAID. Dar es Salaam. 2/13/2007. Mr. M. Lubisi, Receiving/Dispatch Supervisor, Medical Stores Department. Mwanza. n.d. Dr. Dominique Luboja, Regional Health Officer, Mwanza. Mwanza. 4/23/2007 Mr. Maximilia Mapunda, Health Economist, Ministry of Health and Social Welfare. Dar es Salaam. 4/11/2007. Dr. Mfungo Marero, Director Care and Treatment, National Malaria Control Program. Dar es Salaam. 4/03/2007. Dr. Charles Masambu, Assistant Director of Diagnostics Services. Dar es Salaam. 4/20/2007 and 03/04/2009. Dr. Julius Massaga, Director, Center for Excellence in Malaria Interventions. Dar es Salaam. 4/03/2007. Dr. Peter McElroy, PMI Advisor, Center for Disease Control. Dar es Salaam. n.d. Lena Mfalila, Coordinator, Safe Motherhood Initiative, Ministry of Health and Social Welfare. Dar es Salaam. n.d. Dr. Gabriel Mliga, Director of Human Resource Development, Ministry of Health and Social Welfare. Dar es Salaam. 4/25/2007. Mr. Kaisi Mnabukula, District Health Administrator, Ministry of Health and Social Welfare. Magu. n.d. Dr. Fabrizio Molteni, Malaria Technical Advisor to National Malaria Control Program, Research Triangle International. Dar es Salaam. n.d. Dr. Suzy Mosha, Physician, Vingunguti Clinic. Dar es Salaam. 3/14/2009. Dr. Mary Moshana, Sexually Transmitted Infections Program Officer, National AIDS Control Program, Dar es Salaam. n.d. Dr. Godwin Munuo, TB/HIV Specialist, Association of Private Health Facilitates of Tanzania (APHFTA). Dar es Salaam. 4/20/2007. Dr. Suleiman C. Muttani, Hospital Director, Temeke Municipal Hospital. Dar es Salaam. 4/16/2007. Dr. Alex Mwita, Program Director, National Malaria Control Program. Dar es Salaam. 4/17/2007. Jared O. Ndiege, Accountant/Administrator, Association of Private Health Facilitates of Tanzania (APHFTA). Dar es Salaam. 4/20/2007. 14

Lucy Nderimo, Acting Director, Tanzanian Medical Stores Department. Dar es Salaam. 4/20/2007. Peace Nyangoyo, Logistics Associate, JSI Deliver. Dar es Salaam. 4/16/2007. Ssanyu Nyinondi, Logistics Associate, JSI Deliver. Dar es Salaam. 4/16/2007. Dr. David Ocheng, Lab Director, AMREF. Dar es Salaam. n.d. Dr. Samuel Ogillo, Program Manager, Association of Private Health Facilitates of Tanzania (APHFTA). Dar es Salaam. 4/20/2007. Dr. Solomon Ole Lgilunore, District Medical Officer, Arusha Municipal Council, Ministry of Health and Social Welfare. Arusha. 4/24/2007. Bharat Rajani, Managing Director, Biocare Health Products Company. Dar es Salaam. 4/18/2007. Tim Rosche, Country Director, JSI Deliver. Dar es Salaam. n.d. Dr. Neema Rusibamayila, Integrated Management of Childhood Illnesses (IMCI) Director, Ministry of Health and Social Welfare. Dar es Salaam. 4/13/2007. Dr. Rene Salgado, USAID President's Malaria Initiative/JSI. Dar es Salaam. 2/13/2007. Dr. Patrick Swai, Senior Project Management Specialist, HIV, PEPFAR. Dar es Salaam. n.d. Byekwaso Tabura, Acting Director of Customer Services and Sales, JSI Deliver. Dar es Salaam. 4/16/2007. Dr. Joseph Temba, Director, Tanzania Commission for AIDS (TACAIDS). Dar es Salaam. n.d. Joseph Wanyoike, Country Analyst, Clinton HIV/AIDS Initiative. Dar es Salaam. 4/16/2007. Nurse in Charge and Staff Physician, Mkonoo Health Center, Arusha. 4/23/2007. Counter Attendant, for-profit pharmacy. Arusha. 4/23/2007.

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