Bridging the Treatment Gap for RHD in Sub-Saharan Africa:

A Uganda—Case Western Reserve University Partnership

Final Report May, 2018

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Dear Medtronic Philanthropy,

On behalf of the entire RHD Action Uganda team, I would like to thank Medtronic Philanthropy for the visionary action you have taken to fight rheumatic heart disease (RHD) worldwide. Your tireless efforts have built a global movement that have now culminated in the passage of a World Health Assembly resolution on RHD and a renewed sense of optimism that it may finally be Time to Tackle RHD for the world’s poorest populations. We are proud that Uganda has played a foundational role in this effort. Here we present a final report describing the key accomplishments of the Uganda RHD control program during the 5-year Medtronic Foundation grant period (2013-2018). As the “Bridging the Treatment Gap for RHD in Sub-Saharan Africa” project as it was originally titled has evolved into what is now RHD Action-Uganda, our vision for what we could originally accomplish has expanded in ways we could not imagine. We hope you will agree that we have exceed our original goals, and, importantly, have established a sustainable way forward for the national RHD control program that is integrated into a national cardiovascular care development plan.

Highlights of our accomplishments include: • Creation of a national network of Regional Centers of Excellence in RHD Care • Robust infrastructure for patient support and empowerment, including patient support groups and training for people living with RHD (PLWRHD) • One of the largest registries of PLWRHD in the world • Cutting edge epidemiologic research on the burden of latent and clinical RHD, acute rheumatic fever, and group A strep pharyngitis • High impact qualitative research with PLWRHD to identify priorities and barriers to care for penicillin prophylaxis, primary prevention of rheumatic fever, and maternal health. • Development of a new Treatment Cascade framework to measure care quality in Uganda and potentially other settings around the world • Echo screening of over 13,000 children for latent RHD • Advanced training in interventional cardiology for Uganda Heart Institute physicians who now independently perform percutaneous valvuloplasty for rheumatic mitral stenosis • A Uganda RHD Stakeholders Meeting in November 2017 which featured over 100 guests, international invitees from over 10 countries, and a day-long event for PLWRHD.

Thank you again for your generous support of our program. The people of Uganda—particularly Ugandans living with RHD—will be forever grateful for the revolution in cardiovascular care that you have helped to spark.

Sincerely,

Chris T. Longenecker, MD; Project Director, RHD Action Uganda Director, Research & Innovation Center University Hospitals Harrington Heart & Vascular Institute Assistant Professor of Medicine; Case Western Reserve University School of Medicine

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An Historical Perspective Since establishing the first programs in medical research and education in Uganda in the late 1980’s, Case Western Reserve University (CWRU) has contributed substantially to the Ugandan response to HIV/AIDS and tuberculosis. Together with CWRU and in-country partners such as Makerere University, the Joint Clinical Research Centre (JCRC), and others, the government of Uganda established a world-class infrastructure for HIV/AIDS that was seen as a model for others around the world. In the last decade, however, there has been increasing interest in developing cardiovascular care capacity in Uganda, along with other chronic non-communicable diseases such as cancer and diabetes. Makerere University was awarded the Medical Education Partnership Initiative Cardiovascular Linked Award (MEPI-CVD, R23 TW008861) in 2011 to help develop a cardiovascular workforce. CWRU and the Uganda Heart Institute (UHI) were natural partners in this effort. As part of the bilateral exchanges that resulted, it became clear that rheumatic heart disease (RHD) was a significant problem to be addressed and led to the proposal submitted to Medtronic Foundation in 2012. The overarching goal of the Medtronic Foundation proposal was to create a national RHD care infrastructure by leveraging existing HIV/AIDS resources. Key components of the proposal were to establish a regional center of excellence model, to make echocardiography available outside of Kampala, to remove barriers to benzathine penicillin G adherence, and to improve upon a nascent National RHD Registry. In the first pilot year of the grant, we were asked to make close partnerships with others in the RHD space and quickly engaged Drs. Andrea Beaton and Craig Sable from Children’s National Medical Center in Washington, DC. In the sections that follow, we will first describe our approach and secondly our deliverable outputs. Throughout, we will describe lessons learned for others that seek to jumpstart similar national RHD programs in the sub-Saharan African context. An abbreviated open-access version of this report was published this year in Global Heart[1] and is included in Appendix A.

A Human-Centered Approach Our approach borrows heavily from human-centered design concepts; however, we did not formally adhere to published approaches. In general, we embraced four concepts which we will highlight in more detail • Collaboration • Human-centeredness (patients and providers) • Stakeholder engagement Collaboration Out CWRU team of adult cardiologists, infectious disease specialists, and nurse researcher had admittedly very little previous experience with RHD care or connection to the RHD research and advocacy community. From the outset, we viewed this as a strength, but needed to work collaboratively to establish working relationships with others. Within the first year of the grant (2013), the team conducted several calls with the Children’s National Medical Center team and agreed to collaborate on projects such as echo screening for latent RHD and provision of follow-up care for children found to have RHD. In 2014, Dr. Longenecker traveled to an RHD conference hosted by Medtronic Foundation in Fiji which was followed by the World Cardiology Congress. Here he established connections with the various Australia and New Zealand researchers such as Dr. Jonathan Carapetis, Dr. Rosemary Weber, and others. In 2015, the RHD

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Action collaborative was launched, allowing more formal interaction with the World Heart Federation and the RhEACH (RHD Evidence-Advocacy-Communication-Hope) organization. In 2015 and on, Dr. Emmy Okello was able to establish connections with other African partners through the Pan African Society of Cardiology (PASCAR). A full listing of partners is displayed in Table 1. Table 1: Uganda and International Collaborators Engaged in the Development of a National RHD Control Program. Adapted from Longenecker et al.[1]

Uganda International

Children’s National Health System (Washington, Uganda Ministry of Health DC, USA) Federal University of Minas Gerais Uganda Heart Institute (Belo Horizonte, Brazil) World Heart Federation Joint Clinical Research Center (Geneva, Switzerland) RhEACH: Rheumatic Heart Disease Evidence- Makerere University Advocacy-Communication-Hope (Perth, Australia; Cape Town, South Africa) Pan-African Society of Cardiology Mbarara University of Sciences & Technology (Cape Town, South Africa) The Salam Centre for Cardiac Surgery Gulu University (Khartoum, Sudan) Imaging the World

(Charlotte, VT, USA) An important lesson learned is the critical nature of within country partnerships when trying to leverage existing HIV infrastructure to deliver non-communicable disease care. The leaders of the Uganda partners (Table 1) had to be willing to share resources and to share credit/recognition in order for the project to succeed. It helped that leaders of the JCRC and UHI knew each other from medical training; however, they had never worked together before in a formal manner. Additionally, it was important for US partners to share credit and responsibility equally with Uganda partners. Some specific policies were developed such as the need to have all partner logos displayed on materials related to the project and to have equal representation on the manuscript oversight committee. Additionally, whenever the first author of a paper was Ugandan, the senior author was from the US and vice versa. Promoting Ugandan leaders in ways such as having them represent the project at international meetings helped to ensure the sustainability of the program. With growing collaboration, we were able to bring multiple sources of funding to the program to ensure the financial solvency of our efforts over the medium term. In particular, there has been close coordination of funding with the Children’s National Medical Center programs. For example, the Medtronic Foundation grant initially supported staff salaries in Gulu and funding for the pediatric support group activities (run by the salaried staff) was provided through Rotary International. In this sense, the Medtronic Foundation grant has been a catalyst for additional funding (Table 2). Our long-term strategy

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has always been to engage the government to support the efforts of a National RHD control program; however, we realistically saw the value in establishing a broad base of funding to make sure these efforts had time to take root. We believe that a 5-year time frame is not realistic to establish a well-integrated RHD control program in a moderately sized low-income sub-Saharan African country with few healthcare resources; however, we have shown that the seeds can be firmly established in this time frame even on a limited budget.

Patient-Centeredness Early on, we recognized that patients (we prefer to use people living with RHD or PLWRHD) must be empowered to make changes to improve RHD care in Uganda. To engage PLWRHD, we employed the following methods: (1) patient support groups, and (2) PLWRHD leadership development, and (3) focus group discussions. Support groups for pediatric and adult PLWRHD were established with funding from this grant, Rotary International, and the Medtronic Bakken Award to Tom Okello (a Ugandan PLWRHD) in 2015. The structure of the support groups—now with chapters in Gulu, Kampala, and Mbarara—varies by location and is driven by the members. The activities range from activities for children to educational activities to advocacy to peer-support. Some members of the Kampala group based at the UHI, were selected for leadership development training. These include: • Tom Okello: A long-term survivor of RHD who underwent double valve replacement surgery in his teenage years, two decades later Tom was an outspoken advocate for RHD who had an infectiously optimistic and joyful personality that inspired others. In 2015, he received the Bakken Invitation Award for his work in co-founding the RHD support group at the UHI. Tom died tragically in early January, 2018. His efforts were commemorated in a special ceremony at the 2018 World Health Assembly.

• Christine Katusiime: Together with Tom Okello, Christine is a PLWRHD who took a leading role in organizing the Listen to My Heart event for PLWRHD at the 2017 RHD Stakeholders Meeting. Additionally, Christine traveled to the 2018 World Health Assembly to represent Uganda at the RHD side events. Read more about Christine in her Listen to My Heart profile (Appendix B)

• Flavia Kamalembo: Flavia is a mother and nurse who has been living with RHD since childhood. She was chosen to represent Ugandan PLWRHD at the first RHD Action patient event in Cape Town in 2016. Because of her inspiring story and public speaking skills, she was then asked to travel to the World Health Assembly in 2017 to speak on behalf of the new RHD resolution (Appendix B).

In addition to the patient support groups and various PLWRHD leadership development activities, our team felt it was critical to solicit feedback from PLRHD on specific topics in order to refine our program activities. Thus, we’ve conducted a number of qualitative research studies using rigorous and scientifically valid analysis of focus group discussions led by Ugandan social scientists with assistance from US trainees and Dr. Allison Webel, an experienced PhD nurse researcher at the CWRU School of Nursing. The results

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of these studies—described in more detail in our deliverables section—have been published in high impact peer-reviewed journals so that others around the world will benefit from these insights.

Stakeholder engagement Our team recognized that the sustainability of a national RHD program is dependent on real engagement with the Government of Uganda as well as local stakeholders in each of the regions where we established Centers of Excellence. We developed our program as a pilot which could eventually be adopted by the Government of Uganda and implemented through the Ministry of Health or the UHI. Throughout the 5 years of the grant, we have updated Ministry of Health officials on our progress and engaged them on how to move it toward sustainability (see Figure 1 for important milestones). This has culminated with the creation of the RHD advisory council in 2018 and a general agreement that the regional center of excellence model is the best way to improve RHD services beyond Kampala. Figure 1: Timeline of engagement with the Ugandan government and world policy makers

Figure 2: Initial meeting with the Permanent Figure 3: Drs. Charles Olaro and Joyce Moriku Secretary of the Ministry of Health. (From left attend the Uganda RHD Stakeholders Meeting, to right, Dr. John Omagino, Permanent November 2018. Secretary Dr. Asuman Kukwago Kawuzi, Dr. Marco Costa, and Dr. Chris Longenecker)

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Financial Sustainability

The core principles of collaboration, patient centeredness, and stakeholder engagement have helped us convince funders, including the Ugandan government, that the National RHD Control Program delivers value and is worth supporting financially to ensure its long-term viability. Non-governmental funding sources of RHD work in Uganda are summarized in Table 2. Table 2: Non-governmental funding sources for the Uganda RHD Control Program. RHD, rheumatic heart disease; NIH, National Institutes of Health; MEPI-CVD, Medical Education Partnership Initiative Cardiovascular Disease linked award; CNHS, Children’s National Health System. Adapted from Longenecker et al.[1]

Medtronic Global Health Foundation RHD Action ($6 million; 2014-2019) RHD Action Uganda ($1.3 million; PI Longenecker 2013-2018)

NIH and Fogarty International Center Medical Education Partnership Initiative (MEPI- CVD; PI Sewankambo; $2.5million)

NURTURE: Research Training and Mentoring Program for Career Development of Faculty at Makerere University College of Health Sciences (PI Sewankambo; $4million)

American Heart Association Strategically Focused Research Network Grant ($3.7 million, PI Sable (CNHS); 2017-2021)

THRiVE Consortium THRiVE-2 Fellowship (PI Okello; $75,000)

Gift of Life and Rotary International Through CNHS partners; congenital heart disease surgical program; Supplemental support of Gulu

and Lira Regional Centers

General Electric Healthcare Ultrasound donation

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Delivering Value What follows is a summary of the deliverable outputs of our grant. Where possible, we have included more detail—including copies of published works and examples of educational materials—as Appendices.

The Regional Centers of Excellence Model The foundation of our program was to leverage an existing network of JCRC Regional Centers of Excellence to create RHD Regional Centers of Excellence (Figure 4). This process began in year 1, with the formation of the JCRC-Lubowa site, and then expanded to Mbarara (year 2), Gulu (year 3), and Lira (year 4). The exact ways in which we would “leverage” the existing HIV infrastructure depended heavily on local conditions and what was available. For example, at Lubowa, there was plenty of physical space to use, which allowed the creation of a separate “cardiac lab”. In other locations, administrative support was highly skilled but nursing support was lacking. We came to realize that a core package generally consisted of a team of 1-2 specialized nurses, a physician champion, and some kind of ultrasound machine access (portable, hand-held, or other). Wireless mobile internet and airtime were important to budget for as well. Figure 4: The RHD Regional Centers of Excellence. Adapted from Longenecker et al.[1]

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Lubowa (2013): In the summer of 2013, we identified a space within the first floor of the JCRC-Lubowa site where RHD patients are now seen for penicillin injections and follow-up visits (Figure 5). We constructed the space to our own design and purchased a standard ultrasound machine (initially a Sonosite M-Turbo, which was upgraded to a Phillips CX50 in 2014) and ECG machine. There is a separate, private space for BPG injections.

Figure 5: The cardiac lab and RHD clinic at JCRC-Lubowa was completed in August, 2013. RHD patients have a separate waiting room and private clinic that is set apart from the HIV clinic. Echocardiography and ECG are performed in the exam room. The Lubowa clinic currently follows ~90 PLWRHD with latent RHD or mild, stable RHD symptoms. Occasionally, if a patient is seen with signs of decompensated heart failure, arrangements are made for admission to the UHI inpatient ward, and some have been transferred back to UHI for ongoing care as their clinical status has worsened. In addition to seeing PLWRHD for physician follow-up, echocardiograms, and BPG injections, the JCRC cardiac lab is also used to provide cardiac and non-cardiac ultrasound (e.g. to evaluate deep venous thrombosis and abdominal complaints) and ECGs for the clinical care of HIV-infected patients on the ward. • Two examples of how the cardiac capabilities at the JCRC have improved the care of HIV- infected patients at the JCRC. A patient with severe respiratory distress was initially treated for pneumonia. When her condition did not improve, she received treatment for supected culture- negative TB. An echocardiogram performed by Dr. Mirembe was able to identify classic features of mitral valve RHD and the patient was referred to the UHI for further management. Another young woman presented with abdominal pain and a quick ultasound scan revealed an ectopic pregnancy, and she was appropriately referred for surgery at Mulago Hospital.

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We are also using these facilities to conduct research on cardiovascular disease in patients with HIV infection. Funding for these projects comes from the National Institutes of Health (K23 to Chris Longenecker; K23 to Sahera Dirajlal-Fargo) and Gilead (WAVES clinical trial of antiretroviral therapy, sub- award to the JCRC). These funding sources have provided salary support and additional training opportunities for HIV specialists. For example, Dr. Grace Mirembe travelled to the University of Wisconsin for training in vascular ultrasound with Dr. Jim Stein and to Cleveland for echocardiography training in January, 2015. Grace’s story is illustrative of the opportunity that exists to leverage HIV/AIDS infrastructure in sub-Saharan Africa. She is a pediatrician trained in HIV/AIDS care, but over the years she saw the number of children living with HIV/AIDS decrease dramatically in Kampala due to effective maternal to child transmission policies. Prior to the opening of the JCRC Cardiac Lab, she learned how to perform limited vascular ultrasound for a research study in children but was eager to use her skills to treat more patients clinically. Our RHD collaboration and subsequent research funding allowed her to focus on cardiovascular medicine and imaging in children and adults, while quality HIV/AIDS care for children could still be efficiently provided by a smaller group of pediatricians.

Mbarara (2014): The Mbarara Regional Center is run as a collaboration between the JCRC and Mbarara University of Science & Technology with nursing staff from Mbarara Regional Referral Hospital (Figure 6). Having the JCRC Centre of Excellence take the administrative lead streamlined the initial management of the center, but the management is now being transitioned to Mbarara Regional Referral Hospital. Figure 6: Administrative structure for RHD clinic at Mbarara

Administrative Structure for Rheumatic Heart Disease (RHD) Clinic at Mbarara

Mbarara University JCRC - Mbarara RHD collaboration funded by

partners Medtronic Grant Collaborating Collaborating

Department of Department of RHD Clinic Pediatrics Medicine Administration Structure Partial

Administrative salary support

Dorah Nampijja Joselyn Theresa Data entry Adherence (pediatric Rwebembera Ngidire staff Counselors for RHD Clinic for Clinical Staffing Staffing Clinical cardiology) (adult cardiology) (clinic nurse)

RHD Clinic Logistics: Staff Provided by JCRC-Mbarara - Held in location of current Adult Cardiology and Staff Provided by Mbarara University Pediatric Chronic Disease Clinics on Tuesday and Friday afternoons = Reporting - Jointly staffed by Pediatric and Adult Cardiology - Adult echo machine with pediatric probe available for = Funding clinic use = Mutually Reporting

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A centerpiece of the Mbarara Regional Center has been a strong interface with local schools and commitment to training. In June 2015, we conducted echocardiographic screening at 3 local schools, where we also provided education to teachers and school children. Then, in March 2016, we followed with expanded RHD training for 26 teachers from 15 schools in the Mbarara region. Dr. Joselyn Rwebembera (UHI) led the training, with support from Dr. Musiime (JCRC) and other local Mbarara physicians. Materials that were developed for this program which could be used for similar future training include (1) program agenda, (2) curriculum including Powerpoint presentations, (3) pre- and post- knowledge tests, and (4) evaluation forms. From 2013 to 2017, over 200 nurses, physicians, and teachers have been trained through RHD Action Uganda (Table 3). Table 3: Human resources developed by RHD Action Uganda from 2013-2017 2013 2014 2015 2016 2017 Total Nurses/Technicians 40 64 11 5 2 122 Physicians 13 13 3 10 2 41 Community Members (including teachers) 0 5 5 30 20 60 Total 223

Gulu (2015) The RHD research activities in Gulu predate the establishment of the Regional Center and began with an initial echo screening study conducted by the Children’s National Medical Center team in October of 2013. There was a basic clinical follow-up program established for the 200 children identified with RHD through echo screening, and this clinic received additional referrals to care for children with RHD. A general cardiology clinic was established in November 2014 and was staffed by Dr. Twalib Aliku (UHI). This clinic currently provides cardiac care for patients with RHD, as well as a variety of other cardiac conditions, from almost every district in Northern Uganda. The establishment of this clinic has greatly decreased the need to travel to the nation’s capital of Kampala for care, which is cost prohibitive for most patients from this region. In July 2015, the Regional Center of Excellence was launched at the Gulu site and PLWRHD began enrolling into the National Registry. The clinic currently follows over 400 PLWRHD from screening studies and clinically manifest cases, with new patients being enrolled weekly. The clinic also provides over 200 patients with injectable benzathine Figure 7: The Gulu pediatric support group penicillin G each month and heart failure medications for those with severe disease. Additionally, 60 children from the Registry currently participate in a pediatric support group (Figure 7) that meets monthly and is focused on increasing social support for those who are diagnosed through games and crafts. Since the launch of the cardiac clinic, 12 patients have received life-saving heart valve surgery (6 in Uganda, 6 abroad) with funding from Gift of Life International and others. With increasing capacity to perform valve surgery at the Uganda Heart

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Institute, it is our hope that many more children will have this opportunity in the coming years. Innocent, Patricia, and Angioletta (left to right in Figure 8) were all referred for valve surgery through the Registry and successfully operated on by the Children’s National Medical Center visiting team in December 2017. All three participate in the monthly peer support group and are doing very well. Innocent is now in school for the first time since 2012. Figure 8: Gulu children with RHD have successfully undergone lifesaving surgery in Uganda and abroad (from left to right; Innocent, Patricia, and Angioletta).

The introduction of an RHD Center of Excellence in the north of Uganda has expanded access considerably to PLWRHD from this low-resource part of the country. Figure 9 demonstrates how access to cardiac services has expanded since the first echo screening study in 2013. Figure 9: Temporal trends in Northern Region access to cardiac services at Gulu Regional Referral Hospital, 2013-2017. Red represents Gulu district; blue represents new districts that referred patients in 2015; and green represents the additional districts that referred patients in 2017.

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My New Family By Jenipher Kamarembo, Gulu Clinic Nurse Wednesday April 11, 2018 at Gulu Referral Hospital Cardiac Unit

Patients are seated randomly outside the three small unit blocks awaiting their drugs to be refilled while others are back to receive their periodic monthly lifesaving dose of Benzathine penicillin injections for the secondary prevention of RHD.

Seated alone and deep in reflection is a young patient with a laid back demeanor. He only slightly opens his mouth to expose his bright white teeth to give smile only to expose the sadness in his heart. Phillip is a 16-year-old student of Opit Senior Secondary School in senior two. Phillip realized that he had a heart condition called Rheumatic Heart Disease in 2014. Like many of these patients, not until he was examined by a team of medics during a school screening program, did he know of his diagnosis.

Phillip says,” When I was diagnosed with a heart problem, I was heartbroken. At birth, I was also diagnosed with Sickle Cell. I then gave up on life and wanted to die. The doctors talked to my parents who then counseled me to begin coming for treatment and join the Pediatric Support Group-Gulu. The Support Group became my new family. I was counseled and this consoled me and made me emotionally stronger.” Remarked Phillip. “I was told I can heal, that is why I live normally like other people. At the Support Group, they make you strong hearted to face your problem. “

While at the Support Group, we are trained and taught about the heart and the problem with our hearts. This training empowers us and consoles us,” said Phillip. In the past, “I would feel so weak and at times get a lot of pain in my throat and chest. When I go farming, I do little work and easily get tired.” Phillip said.

Phillip also says that the Support Group enables them to play games together and learn how to relate with each other.

“They use very kind words which consoles you and makes you feel normal like others”, says Phiona, another patient who had joined us.

“I had given up on life and wanted to die. I never believed I would live to join Senior Secondary School but now I want to be a Doctor.” Remarked Phillip. When asked why he wants to be a doctor, Phillip said he wants to help other patients the way he has been helped using the knowledge he got as a patient.

When asked for his wish for the Support Group, Phillip said, “I wish we had our own home with more equipment and things to play and have more teaching to console us and inform us about our sickness.”

Phillip’s message to those who support the Support Group is,” Please don’t stop because we will die. I now don’t want to die.”

To my fellow patients he says, “We have this sickness, it exists but it can heal when treated. Let’s keep praying to God to heal us.”

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Lira (2016-2017) The Lira Regional Center of Excellence for RHD was the first center to be established outside of the JCRC network of HIV Centers of Excellence. The reason for this was that we wanted to take advantage of additional relationships with the hospital there where current Minister of Health, the Hon. Dr. Jane Aceng was previously Director. The UHI was performing monthly outreaches to the Lira hospital and had identified several physician and nurse champions that wanted to improve RHD care. The lesson learned is that a program should develop along avenues that have the most local support where local “champions” will help ensure success of the project. In 2016, we launched a handheld echocardiography project which aimed to improve the local diagnostic capacity for not only RHD, but also 6 broad causes of heart failure [valvular heart disease (including RHD), dilated cardiomyopathy, right heart disease, pericardial disease, hypertensive heart disease, and congenital heart disease]. Over the next year and a half, data have been collected on the diagnostic accuracy of non-experts to classify heart disease into one of these categories or to exclude heart disease as a cause of the patient’s symptoms. These data are currently being analyzed and will be published in late 2018 or 2019.

National RHD Registry The National RHD Registry began as a paper registry in 2011, and was housed at the UHI. With funding from this grant, the scope expanded to an online RedCap platform in 2013 that could be accessed online from any site around the country. Table 4 below shows enrollment into the registry by year, and Table 5 shows the current enrollment stratified by site and sex. As of mid-May 2018, there were over 2000 PLWRHD enrolled in the Registry. Table 4: Uganda National RHD Registry enrollment by year. These numbers exclude N=34 patients with missing enrollment date and/or clinic site. Site 2013 2014 2015 2016 2017 May 2018 UHI 540 851 997 1139 1295 1334 JCRC-Lubowa 53 93 102 91 89 89 Mbarara -- 14 46 73 96 96 Gulu -- -- 182 289 375 389 Lira ------43 72 Total 593 1,022 1,327 1,592 1,898 1,980

Table 5: Current Uganda National RHD Registry enrollment by site and sex. N=21 patients with missing sex and/or clinic site excluded. % female at each site shown in parentheses. Site Male Female Total UHI 393 942 (71%) 1335 JCRC-Lubowa 25 65 (72%) 90 Mbarara 34 67 (66%) 101 Gulu 161 234 (59%) 395 Lira 31 41 (57%) 72 Total 593 1,022 (68%) 1,993

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The Registry quickly became a powerful tool for epidemiologic analyses and has provided data for a number of papers describing the scope of the RHD burden in Uganda (see Appendix C for complete list of publications that have been partially supported by this grant). For example, the prevalence of clinical RHD cases was mapped by district as shown in Figure 10. We have formed a manuscript steering committee with representation from all stakeholders and drafted a Charter that formalizes the process for submitting proposals which will use Registry data. To date, four proposals have been approved. Figure 10: RHD Registry Enrollment by District of Residence (cases/100,000 district residents). Adapted from Okello et al.[2]

Mortality due to RHD in Uganda is nearly 18% over one year as we showed in an early publication using 12-month follow-up data from the paper-based registry. This is one of the few modern studies to show an independent mortality benefit of BPG adherence in both men and women (Figure 11); thus providing rationale for >80% of injections as a clinically relevant definition of optimal adherence in Uganda. Figure 11: PLWRHD have very high mortality over 1 year in Uganda; however, they are less likely to die if they are adherent to BPG. Although this seems intuitive, there is limited evidence to prove this for patients with advanced clinical disease. From Okello et al.[3]

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There have been 345 deaths among PLWRHD in the National RHD Registry since it was established in 2010. As a preliminary unpublished exploration into whether RHD Action activities have begun to have an impact on outcomes, we divided PLWRHD into 2 enrollment periods of ~1000 subjects each (2010- 2014 vs. 2015-2018). Median time of follow-up in the Registry is now 2.6 years. As shown in Figure 12, subjects enrolled in recent years have better survival over time compared to subjects enrolled in the early period. In Cox proportional hazards models adjusting for age at enrollment and gender, there was ~33% lower risk of mortality in 2015-2018 compared to 2010-2014 (HR 0.67, 95% CI 0.52-0.86). However, further adjustment for disease category (latent vs. clinical) attenuated the risk difference such that it was no longer statistically significant (HR 0.87, 95% CI 0.67-1.12; p=0.284). This is because we have enrolled more subjects with mild or latent subclinical disease in recent years. Nonetheless, there is a suggestion that our efforts are truly beginning to have an impact on this devastating disease in Uganda. Figure 12: Survival among PLWRHD enrolled in the National RHD Registry has improved over time since the introduction of the RHD Action program.

Besides providing valuable epidemiologic surveillance data, the Registry is also a tool for local clinicians to identify those PLWRHD who have fallen out of care or who have poor documented adherence to BPG prophylaxis. Some clinics have additional fields that they use (e.g. “next appointment date” for the Gulu clinic). While the current iteration of the Registry contains a lot of useful information for researchers, we have learned that the amount of data collected comes at a cost in terms of human resources and time required to complete the data forms. Subsequent iterations of the Registry may collect fewer data in order to make the process more efficient for frontline providers.

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We have desired to find a cheap, user-friendly alternative software platform which will be sustainable over the long-term; however, we have not successfully identified a product which fulfills the current needs and is financially viable. Thus, the plan is to continue the RedCap registry indefinitely, which will require IRB oversight and approval at Case Western and Makerere University. The costs associated with this are minimal, since there are no direct costs and just time/effort of maintaining IRB approval.

The RHD Treatment Cascade One of the pivotal innovations of RHD Action Uganda was to devise a framework for evaluating RHD treatment outcomes by adapting a “lesson learned” from HIV/AIDS. The HIV/AIDS treatment cascade model (Figure 13) has been a useful tool for measuring the success of HIV/AIDS treatment programs with widespread adoption all around the world. UNAIDS has set goals for all programs to aim for “90-90-90”— 90% of HIV+ subjects being aware of their diagnosis, 90% of those who have a diagnosis being engaged in longitudinal care, and 90% of those engaged in care having undetectable HIV virus in the blood. Figure 13: The HIV/AIDS treatment cascade in the United States. Of the approximately one million people living with HIV in the United States, only 30% have achieved viral suppression. Source data from CDC National HIV Surveillance System and Medical Monitoring Project, 2011. From Longenecker et al.[1]

Similar to HIV/AIDS, RHD is a chronic disease that must first be properly diagnosed, then patients must be linked to and engaged in regular longitudinal follow-up, where they are prescribed long-term medical therapy (i.e. BPG injections) that must be adhered to in order to provide clinical benefit. So in

17 consultation with the team, we created an RHD Treatment Cascade with the following categories as defined by our publication in Circulation: Cardiovascular Quality and Outcomes in November 2017[4]: • Retained in care—defined as all living patients with at least one in-person clinic visit in the past 56 weeks [52 weeks + 4 week grace period for those patients (particularly borderline RHD patients in more remote areas) who might only follow-up once yearly]. • Prescribed BPG—defined as all retained participants who had been given a prescription for monthly BPG at last recorded follow-up. Outcomes of “prescribed” and “adherent” exclude those with borderline disease, since our program guidelines do not recommend antibiotic prophylaxis for this group and WHF guidelines offer no recommendation. • Adherent to BPG—defined as all prescribed participants who had received ≥80% of prescribed BPG doses in the last 12 months. This is a widely accepted definition of optimal adherence and was associated with improved outcomes in a prior study from Uganda[3].

Figure 14 shows what the RHD Treatment Cascade looks like in Uganda in mid-2016. As has been shown in the HIV/AIDS literature, retention in care is typically one of the biggest barriers to achieving the ultimate goal of optimal adherence to therapy. It is not adherence per se, since in our study, over 90% of subjects who were retained in care were optimally adherent to penicillin.

Figure 14: The RHD Treatment Cascade in Uganda. The left axis and blue bars indicate the number of patients in each outcome category of the treatment cascade, while the right axis and orange points indicate the percentage of patients as a proportion of the parent (prior) category. From Longenecker et al.[4]

We hope that the RHD Treatment Cascade will be used by others as a tool for monitoring and evaluation of national RHD control programs around the world. One of the challenges is collecting data

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in a way that these reports can be routinely provided with little data cleaning or manipulation. For example, if the Uganda RHD Registry database had been designed a priori for this purpose, it would be easier to produce these reports. Our team has not been able to achieve this goal to date, but are actively working on a solution.

Qualitative Research on Barriers and Facilitators of High Quality RHD Care and Prevention Our team has conducted a number of rigorously designed qualitative and mixed-methods studies to probe deeper the myriad reasons why PLRHD may or may not ultimately receive the high quality care that they deserve in Uganda. Two of these have been published in peer reviewed journals[5, 6] and one is currently in preparation for submission. We describe these studies—which were led by Dr. Allison Webel at the CWRU School of Nursing—in more detail below. Barriers and Facilitators of Penicillin Prophylaxis: To build on prior qualitative research from our group on the knowledge of RHD within local communities, we explored further the barriers and facilitators of penicillin prophylaxis adherence among patients with RHD. Studies prior to 2013 had shown that adherence was poor in the Ugandan population—optimal adherence rates were barely over 50%. We sought to explore the reasons behind the poor adherence. Notably, this study pre-dated the development of our treatment cascade metrics, and the results of this study provided rationale for the cascade framework. The study design is described in Figure 15. Transcripts of these focus groups were analyzed, and the results were used to create a socio-ecologic model (Figure 16). In addition to informing the Treatment Cascade metrics, this model also helped to inform subsequent training programs about the reasons why patients may or may not be optimally adherent.

Figure 15: Qualitative study of barriers and facilitators of penicillin prophylaxis—Study Design.

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Figure 16: A qualitative study of 40 RHD patients revealed unique barriers and facilitators of penicillin adherence in our population.

Motivations of women living with RHD in Uganda: Clinicians who work with PLWRHD in resource limited settings around the world are intuitively aware of the complex issues and unique barriers of women with RHD who are pregnant or who wish to have children; however, few have scientifically examined the motivations of women with RHD or explored in-depth issues of stigma, childbearing, contraception use, and anticoagulation use. We conducted focus groups among 25 participants and surveyed 50 additional women with RHD who attended clinic at the UHI. What emerged from the focus group transcripts was evidence that for Ugandan women with RHD, the decision to become pregnant is a calculated risk that is influenced by important external and internal factors as shown in Figure 17. Other themes included misconceptions about medication side-effects, black-and-white recommendations from physicians, reproductive decision-making controlled by male partners or in-laws, the financial burden of RHD, and considerable stigma against RHD patients, often more severe than that directed against patients with HIV. As part of this mixed-methods study, we also surveyed women (58% were on warfarin) about their knowledge of the risks of warfarin during pregnancy. Only about half knew that warfarin could cause birth defects and only 12% used contraception while taking warfarin.

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These results suggest that there is considerable room to improve counseling and education services for women of childbearing age who may be interested in making a calculated risk to have children. Co-first author of this study, Dr. Juliet Nabaale has now become the go-to provider for maternal cardiovascular disease management at the UHI, and so women with RHD in the Kampala area are often seen by Juliet to help manage their disease during pregnancy.

Figure 17: A qualitative study of 25 women with RHD revealed that the decision to have children is a calculated risk influenced by a variety of internal and external factors.

A Needs Assessment for Primary Prevention of Rheumatic Fever: The most recent qualitative research project of our group was to engage Ugandans in the community including key stakeholders and policy influencers about the primary prevention of rheumatic fever in Uganda. Twenty-seven key informant interviews were conducted in Mbarara and Gulu during 2017 with key stakeholders such as health workers, teachers, and district health officials (Table 6). The structure and content of the interview guide were based on the Needs Assessment Tool (NAT) developed by RhEACH. An overarching theme of these interviews was that Uganda is in a time of transition, and participants consistently felt that access to resources such as clinic space, sanitation, electricity, health workers, and medications is getting worse as population growth outpaces government spending on these areas. Minor themes were that community strengths and foreign aid could be harnessed for RHD

21 prevention. Life barriers, comorbid health conditions, and alternative health beliefs were mentioned as barriers to effective RHD prevention. Table 6: Needs Assessment Participants (n=27). Women (n=11) Men (n=16) Health Care Workers Village Health Team Members & Community Health Workers 2 5 Nurses 5 1 Nurse Assistant 1 0 Health Center III Clinical Officer 1 1 Government and Non-Governmental Officials District Chief Administer 0 1 Social Services Secretary 0 1 District Director of Health Services 0 1 District Health Inspector 0 1 Local Council Leader 1 2 Teacher 0 1 Social Worker 1 0 Caregiver of PLWRHD 0 1 NGO Worker 0 1

Technology The Ugandan members of our team have consistently stressed two important themes that could vastly improve the way they deliver care to PLWRHD with advanced disease in Uganda—access to technology and advanced training. A lower level technology that is central to the diagnosis of rheumatic heart disease is echocardiography. This Medtronic Foundation grant made possible the procurement of 2 portable ultrasound machines for use at Lubowa and Mbarara. In addition, portable ultrasound machines were donated by GE for use in Lira and Gulu through the Children’s National Medical Center group. These devices have been used to screen over 13,000 people (mostly children) for latent or subclinical rheumatic heart disease since 2013 (Figure 18), and have been used in an innovative program in Lira to help non-

Figure 18: Over 13,000 people have been screened for subclinical RHD at: • Primary schools in Kampala, Mbarara, and Gulu • JCRC-Lubowa and Baylor HIV clinics • Families of PLWRHD in Gulu • Community-based screening of adults in Gulu

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expert frontline health workers make cardiac diagnoses in patients with signs and symptoms of heart failure (see Lira section above). Although from a public health perspective, advanced tertiary care for RHD may not be the most cost-effective, we and especially our Ugandan colleagues have felt strongly that there is a moral imperative to improve these services for PLWRHD, including access to surgery and percutaneous mitral valvuloplasty (Figure 19). A catheterization laboratory was built at the Uganda Heart Institute and completed construction in 2012. This new technical capability was empowering for emerging physician leaders who struggled previously with being unable to treat patients with advanced disease. Visiting teams from Case Western/University Hospitals, Children’s National Medical Center, and others have conducted procedures using the UHI cath lab and often bring donated consumables from the United States. University Hospitals physicians have made 4 such trips since 2013. More importantly than the technology itself, however, are the human resources and training required for Ugandans to successfully conduct life-saving procedures on their own. Figure 19: Dr. Marco Costa and Dr. Emmy Okello performing a balloon mitral valvuloplasty procedure in the UHI catheterization laboratory.

Human Resources/Training Training has been a clear priority of RHD Action Uganda since the beginning of our program. As shown in Table 3 above (Mbarara section, p. 11), we have trained well over 200 nurses, physicians, and community members in RHD. Our training programs have ranged from community based 1-2 day courses targeted towards teachers or healthcare providers (Figure 20) to week-long intensive apprenticeships at

Figure 20: Dr. Longenecker and JCRC staff conducting a training course for primary care nurses and physicians in September 2013.

23 the Uganda Heart Institute for Regional Center staff, to year-long training for Ugandan physicians in interventional cardiology, heart failure, and cardiac anesthesia at University Hospitals of Cleveland. The training opportunities in Cleveland are made possible by a unique medical licensing mechanism in Ohio known as the Clinical Research Faculty Certificate program, which allows Ugandan physicians to practice in a supervised academic setting as part of a research and teaching exchange. Two interventional cardiologists, 2 heart failure specialists, and 1 cardiac anesthesiologist have been trained through this initiative. The training at University Hospitals in coronary intervention was adequate for Drs. James Kayima and Emmy Okello to start a coronary intervention program in Kampala (including primary percutaneous coronary intervention for acute myocardial infarction); however, mastering percutaneous balloon valvuloplasty for rheumatic mitral stenosis required more intensive training in an RHD endemic setting. To accomplish this, we connected Emmy Okello and Joselyn Rwebembera (echo specialist @ UHI) to a group at Federal University of Minas Gerais in Brazil who were friends and colleagues of Dr. Marco Costa. In October 2016, Drs. Okello and Rwebembera traveled to Belo Horizonte, Brazil for 2 weeks of training which included 18 PBMV procedures with echo guidance, pre-procedure transesophageal echos to rule out left atrial appendage clot, and additional educational talks/symposia. In November 2016, the UHI team performed their first independent valvuloplasty procedure, and have since performed over 50 mitral valvuloplasties. The UHI now has a reputation as a center of excellence for this procedure, and Dr. Okello has been invited to give international lectures about his experience in developing the program. In addition, the UHI is now independently able to conduct a limited number of low-risk valve replacement surgeries with a South African trained Ugandan surgeon (Figure 21). Figure 21: Cardiac surgery—including valve replacements for RHD—are now conducted independently at the UHI and with the assistance of visiting surgical teams.

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Expanding access to valve replacement surgery requires building additional infrastructure to support long-term follow-up of these patients. In particular, access to anti-coagulation monitoring services is essential to prevent complications of mechanical heart valves. Thus, we have made point of care INR testing available at each of the regional centers through a program administered by the UHI. The funding for the initial purchase of equipment and monitoring strips came from the Medtronic Foundation Grant and will be supported by the UHI and/or other grants in future years. Uganda National RHD Program The rapid scale-up of cardiovascular care services that has occurred in Uganda as part of the CWRU and Children’s National Medical Center collaborations with the UHI, Makerere University, and others has gained the support and attention of the Ugandan government. In 2016, the UHI was given semi-autonomous status within the government through an Act of Parliament. With this came additional financial support of the UHI, much of it going to RHD care. The best estimates are that RHD now makes up ~50% (USD $200,000) of the overall UHI budget for recurrent heart failure and open heart surgery. As previously mentioned, we have had continual contact with Ugandan government and ministry of health officials throughout the development of this National RHD Pilot Program. Our engagement with the government culminated with a large Uganda RHD Stakeholders Meeting hosted by our RHD Action Uganda team at the Protea Hotel in November 2017. There were over 100 attendees from 10 countries, but the majority were from Uganda including 11 representatives of the Ugandan government (Figure 22). At a closed door meeting of government officials and RHD Action representatives, the MOH committed to the formation of an “RHD Advisory Committee”. Terms of Reference have been drafted (Appendix D), and Dr. Okello has assembled a preliminary list of committee members that is awaiting approval by the MOH. This transfer of supervisory authority is a major milestone, but we anticipate close involvement from all stakeholders including CWRU and Children’s National Medical Center as the transition is made under the leadership of the UHI. Figure 22: The Uganda RHD Stakeholders Meeting, November 2017.

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Conclusion: An Emerging Zeitgeist of Optimism. It’s Time to Tackle RHD! Much has been accomplished in five years under RHD Action Uganda; however, more than any one program accomplishment, the most significant outcome of this Medtronic Philanthropy grant in Uganda has been a sense of optimism and enthusiasm that touches Ugandans living with RHD and all those who work with PLWRHD. With the passage of the Global Resolution on Rheumatic Fever and Rheumatic Heart Disease at the World Health Assembly in Geneva on May 25, 2018 as this report was being assembled, there is a sense that it is finally “Time to Tackle RHD” with more resources globally, and in Uganda specifically. For its part, our Ugandan team is committed to using this spirit of optimism to further advance RHD care over the next 5 years and beyond. RHD Action has developed the Priorities Pyramid to help advocates, care providers, NGOs, and national programs identify targeted areas of need. Our program has touched on nearly all aspects of the pyramid, with the most intense focus on RHD Control Programmes and People living with RHD, with relatively little focus on the Group A Strep Vaccine (Figure 23). Yet, even for vaccine efforts, the Uganda site has contributed Group A strep samples and there is ongoing work in this area as part of the AHA Strategically Focused Research Network Grant. Once again, we are truly thankful of the visionary efforts of Medtronic Philanthropy in supporting RHD work globally and the Uganda program in particular. Webale Nyo! Figure 23: The RHD Action Priorities Pyramid. RHD Action Uganda has touched on all aspects of the pyramid over the past 5 years, with areas of most intense effort highlighted in darker red and areas of less focus in light pink.

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References: 1. Longenecker CT, Kalra A, Okello E, Lwabi P, Omagino JO, Kityo C, et al. A Human-Centered Approach to CV Care: Infrastructure Development in Uganda. Glob Heart 2018. 2. Okello E, Longenecker CT, Scheel A, Aliku T, Rwebembera J, Mirembe G, et al. Impact of regionalisation of a national rheumatic heart disease registry: the Ugandan experience. Heart Asia 2018; 10(1):e010981. 3. Okello E, Longenecker CT, Beaton A, Kamya MR, Lwabi P. Rheumatic heart disease in Uganda: predictors of morbidity and mortality one year after presentation. BMC cardiovascular disorders 2017; 17(1):20. 4. Longenecker CT, Morris SR, Aliku TO, Beaton A, Costa MA, Kamya MR, et al. Rheumatic Heart Disease Treatment Cascade in Uganda. Circ Cardiovasc Qual Outcomes 2017; 10(11). 5. Chang AY, Nabbaale J, Nalubwama H, Okello E, Ssinabulya I, Longenecker CT, et al. Motivations of women in Uganda living with rheumatic heart disease: A mixed methods study of experiences in stigma, childbearing, anticoagulation, and contraception. PLoS One 2018; 13(3):e0194030. 6. Huck DM, Nalubwama H, Longenecker CT, Frank SH, Okello E, Webel AR. A qualitative examination of secondary prophylaxis in rheumatic heart disease: factors influencing adherence to secondary prophylaxis in Uganda. Glob Heart 2015; 10(1):63-69 e61.

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Appendix A:

Longenecker et al. A Human-Centered Approach to Cardiovascular Care Infrastructure Development in Uganda. Global Heart, 2018. j INNOVATIONS & CONCEPTS gSOLUTIONS

A Human-Centered Approach to CV Care Infrastructure Development in Uganda Christopher T. Longenecker*,y, Ankur Kalra*,y, Emmy Okelloz, Peter Lwabiz, John O. Omaginoz, Cissy Kityox, Moses R. Kamyajj, Allison R. Webel{, Daniel I. Simon*,y, Robert A. Salata*,y, Marco A. Costa*,y Cleveland, OH, USA; and Kampala, Uganda

ABSTRACT In this case study, we describe an ongoing approach to develop sustainable acute and chronic cardiovascular care infrastructure in Uganda that involves patient and provider participation. Leveraging strong infrastructure Dr. Longenecker has received research grants for HIV/AIDS care delivery, University Hospitals Harrington Heart and Vascular Institute and Case Western from Gilead Sciences, Reserve University have partnered with U.S. and Ugandan collaborators to improve cardiovascular Bristol-Myers Squibb, and capabilities. The collaboration has solicited innovative solutions from patients and providers focusing on Medtronic Philanthropy; and honoraria from Gilead education and advanced training, penicillin supply, diagnostic strategy (e.g., hand-held ultrasound), Sciences. All other authors maternal health, and community awareness. Key outcomes of this approach have been the completion of report no relationships that formal training of the first interventional cardiologists and heart failure specialists in the country, could be construed as a conflict of interest. establishment of 4 integrated regional centers of excellence in rheumatic heart disease care with a national This work was supported in rheumatic heart disease registry, a penicillin distribution and adherence support program focused on part by a grant from the retention in care, access to imaging technology, and in-country capabilities to treat advanced rheumatic Medtronic Global Health Foundation and by the heart valve disease. National Institutes of Health (R23 TW008861, D43 TW010132, and K23 HL123341). From the *Division of Car- The growing global burden of noncommunicable dis- GAINING INSIGHT diovascular Medicine, Uni- versity Hospitals Cleveland ease (NCD) has been well-documented [1] and is straining A history of relationship building Medical Center, Cleveland, health systems in low-income countries that already have a OH, USA; yDepartment of CWRU established the first research and medical education high burden of infectious diseases, including human im- Medicine, Case Western program in Uganda in 1989, when then Chair of Medicine munodeficiency virus/acquired immunodeficiency syn- Reserve University School and Nobel Laureate Dr. Fred Robbins was invited by the of Medicine, Cleveland, drome (HIV/AIDS) [2]. In sub-Saharan Africa, public and government of Uganda to help respond to the HIV/AIDS OH, USA; zUganda Heart private investment in health care infrastructure is needed to epidemic. For over 25 years, CWRU and UH physicians Institute, Kampala, Uganda; translate recent successes in HIV/AIDS care to those with xJoint Clinical Research have contributed significantly to capacity-building efforts other chronic diseases such as cardiovascular disease and Centre, Kampala, Uganda; with key Ugandan partners such as Makerere University to advance human health more holistically. Yet, financial ||Department of Medicine, and a network of HIV/AIDS clinics known as the Joint Makerere University School investment alone is not the cure. We believe that a human- Clinical Research Centre (JCRC). With technical assistance of Medicine, Mulago Hill, centered, participatory approach grounded in a clear un- Kampala, Uganda; and the from UH/CWRU, the JCRC has established a world-class derstanding of the human needs of patients, providers, and {Frances Payne Bolton infrastructure throughout Uganda to promote community society will lead to scalable and cost-effective innovations School of Nursing, Case awareness of HIV/AIDS, perform clinical and epidemio- Western Reserve Univer- in low-income countries [3]. logical research, establish treatment protocols, and train sity, Cleveland, OH, USA. In this paper, we describe a case study of cardiovas- health care professionals in HIV/AIDS care [4-7]. Correspondence: C. T. cular care infrastructure development in the resource- Longenecker (cxl473@case. In 2011, the UH/CWRUeUganda collaboration limited East African nation of Uganda, led by university edu). expanded beyond HIV and infectious diseases to cardiovas- hospitals (UH) Harrington Heart and Vascular Institute and cular disease with initial support from the National Institutes GLOBAL HEART Case Western Reserve University (CWRU) School of © 2018 The Authors. Pub- of Health and Fogarty International Center through the Medicine in collaboration with key U.S. and Ugandan lished by Elsevier Ltd. on Medical Education Partnership Initiative Cardiovascular partners. Our overarching goal is to develop capabilities behalf of World Heart Linked Award (R24 TW008861). The Uganda Heart Institute Federation (Geneva). This is and improve heart care by focusing on sustainability and (UHI)—a semi-autonomous heart center at Mulago Hospital an open access article un- decentralization of services from its capital Kampala to that had been building pediatric congenital heart disease der the CC BY license other regions of the country. Our approach leverages long- (http://creativecommons. surgery capacity [8] in partnership with Children’sNational standing academic collaboration and pre-existing HIV/ org/licenses/by/4.0/). Medical Center (Washington, DC, USA)—was engaged early - - AIDS infrastructure and has proven to be an effective VOL. ,NO. , 2018 on as a key partner. In August 2012, UH cardiologists were ISSN 2211-8160 model for North-South collaboration in health sector invited through the Medical Education Partnership Initiative https://doi.org/10.1016/ development. j.gheart.2018.02.002

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TABLE 1. Partners for the Ugandan cardiovascular care development program RHD was an ideal starting point for heart care expansion in Uganda International Uganda because it affects both children and adults, it has a broad and deep socioeconomic impact, is diagnosed clin- Uganda Ministry of Health Children’s National Health System ically with the assistance of basic cardiovascular technol- (Washington, DC, USA) ogies such as echocardiography, requires chronic care Uganda Heart Institute Federal University of Minas Gerais coordination and medication adherence, and in advanced (Belo Horizonte, Brazil) stages, requires percutaneous or surgical intervention. The Joint Clinical Research Center World Heart Federation (Geneva, Switzerland) idea was simple—improving RHD care would likely Makerere University RhEACH: Rheumatic Heart Disease improve many aspects of heart disease care in Uganda. Evidence-Advocacy-Communication-Hope Our decision to focus on RHD was also timely, as the (Perth, Australia; Cape Town, South Africa) Medtronic Foundation and the World Heart Federation Mbarara University of Sciences Pan-African Society of Cardiology were considering new initiatives to eradicate RHD. In & Technology (Cape Town, South Africa) February 2013, UH/CWRU received a 5-year, $1.3 million Gulu University The Salam Centre for Cardiac Surgery grant from the Medtronic Foundation to “leverage long- (Khartoum, Sudan) term partnerships and existing HIV/AIDS infrastructure Imaging the World (Charlotte, VT, USA) to create a comprehensive RHD treatment program in Uganda” [12]. In 2014, the Medtronic Foundation launched RHD Action, a $6 million commitment to a Cardiovascular Linked Award program to perform some of global movement of RHD technical assistance and advo- the first procedures in a new catheterization laboratory at cacy partners, and Uganda was invited to be 1 of the 2 UHI, including the first percutaneous balloon mitral valvu- founding “country partners.” The collaboration was loplasty for rheumatic mitral stenosis [9],thefirst complex, rebranded as RHD ActioneUganda. Since then, additional multivessel percutaneous coronary intervention, and the first sources of funding and partnerships have been added peripheral artery angioplasty. (Tables 1 and 2) to widen its scope and sustainability. A key insight from this historic visit was that the model of individual trips by external experts to treat a limited number of patients—a strategy often used throughout sub- The stakeholders: Patients and providers Saharan Africa—would not effectively build capabilities Rheumatic fever is an abnormal immune response to and was not sustainable. Therefore, we sought a more invasive group A streptococcal infection (typically phar- comprehensive strategy to develop sustainable cardiovas- yngitis) that primarily affects children ages 5 to 15, leading cular care capabilities in the country. The first step was to to chronic valvular RHD over time and causing heart fail- identify a single disease model that was meaningful to ure and early mortality, most commonly in early adulthood people living in Uganda and find a solution that would be [10]. Penicillin is a proven treatment for rheumatic fever desirable by local stakeholders and feasible to implement. and chronic RHD that substantially reduces the occurrence The human cost of rheumatic heart disease (RHD) of future attacks and progression of valve disease [13].To affecting young adults who would otherwise contribute to be effective, however, penicillin must be administered as an society is well known [10]. Once a major cause of chronic injection every 4 weeks, and therefore, requires effective illness in the United States, RHD has become a neglected chronic care delivery systems [10]. disease in the West that nonetheless continues to ravage Similar to RHD, patients with other cardiovascular dis- poor nations around the globe [11]. For many reasons, eases such as cardiomyopathy or congenital heart disease

TABLE 2. Funding sources for the Ugandan cardiovascular care development program. Medtronic Global Health Foundation (Minneapolis, MN, USA) RHD Action ($6 million; 2014 to 2019) RHD Action Uganda ($1.3 million; PI Longenecker 2013 to 2018) NIH and Fogarty International Center (Bethesda, MD, USA) Medical Education Partnership Initiative (MEPI-CVD; PI Sewankambo; $2.5 million) NURTURE: Research Training and Mentoring Program for Career Development of Faculty at Makerere University College of Health Sciences (PI Sewankambo; $4 million) American Heart Association (Dallas, TX, USA) Strategically Focused Research Network Grant ($3.7 million, PI Sable (CNHS); 2017 to 2021) THRiVE Consortium (Kampala, Uganda, and Cambridge, UK) THRiVE-2 Fellowship (PI Okello; $75,000) Gift of Life and Rotary International (Evanston, IL, USA) Through CNHS partners; congenital heart disease surgical program; Supplemental support of Gulu and Lira Regional Centers General Electric Healthcare (Chicago, IL, USA) Ultrasonography donation

CNHS, Children’s National Health System; MEPI-CVD, Medical Education Partnership Initiative Cardiovascular Disease linked award; NIH, National Institutes of Health; PI, principal investigator; RHD, rheumatic heart disease; THRiVE, Training Health Researchers into Vocational Excellence in East Africa.

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require chronic longitudinal care. Yet, the Ugandan health care system has limited capacity to monitor patients with 100% chronic illnesses longitudinally [14,15]. The public health 86% response to HIV/AIDS began to change this paradigm. As a 80% result of the President’s Emergency Plan to Fund AIDS Relief and other programs, antiretroviral therapy is now widely available and chronic care is delivered efficiently in local 60% clinics; however, it is not clear that the President’s Emergency 40% Plan to Fund AIDS Relief has improved care for chronic 40% 37% NCDs, and in some cases may have siphoned off resources 30% [5,16]. To improve delivery of chronic cardiovascular care ser- 20% vices in Uganda, a human-centered participatory approach that involved both patients and providers was needed [17]. 0% Listening to Ugandan providers, it was clear that improving Diagnosed Engaged Prescribed Virally the quality of cardiovascular care in Uganda would require a in care ART suppressed massive effort to train and repurpose a health care workforce. The problem as our team saw it was that Ugandans living with FIGURE 1. The HIV/AIDS treatment cascade in the HIV were able to find effective and efficient care delivered by United States. Of the approximately 1 million people an extensive network of clinics across the country, but pa- living with HIV in the United States, only 30% have ach- tients with cardiovascular diseases were left waiting in crow- ieved viral suppression. Adapted from U.S. Department of ded clinics for hours to see clinicians who did not have the Health and Human Services [22]. Source data from the training or tools to appropriately manage the disease. Centers for Disease Control and Prevention National HIV Surveillance System and Medical Monitoring Project (USA); 2011. AIDS, acquired immunodeficiency syndrome; FOSTERING INNOVATION HIV, human immunodeficiency virus. A latticework on which to build The HIV/AIDS infrastructure that had been scaled up with local circumstances. The coverage of the JCRC network — massive global funding was a model for quality chronic care was not consistent across the country with some areas of delivery, but could it also be “leveraged” to provide quality high-density coverage and other areas with substantial gaps care for other NCD services [18-20]? This question has been in coverage. The JCRC infrastructure was designed pri- framed in 2 ways: (1) Can HIV/AIDS infrastructure be used marily to conduct research studies and was less suited to to provide care for HIV-uninfected individuals with NCD? providing clinical care. Furthermore, because of persistent (2) Can NCD services be integrated into HIV clinics to stigma, there was a chance that some HIV-uninfected pa- improve the control of NCD comorbidities among people tients with RHD would be uncomfortable seeking care at a living with HIV [19]? We felt that the second approach site known to previously provide HIV care. Finally, RHD would have the greatest impact on public health. care requires occasional consultation with specialists, but In our case, the JCRC had already established a the UHI physicians were few in number and concentrated network of Regional Centers of Excellence for HIV care that geographically in the capital city of Kampala. New insights fi served as nodes within a lattice network covering the entire from both patients and providers were needed to gure out country of Uganda. In initial brainstorming sessions and how to surmount these challenges. planning meetings, administrative infrastructure was the most readily identified strength to be repurposed, but New insights from patients additional ideas included: (1) using nurses who were In order to engage patients, our team conducted a series of trained in HIV care to deliver penicillin injections; (2) us- focus group discussions (FGD) with patients who suffered ing HIV counselors to improve retention in care and from RHD. These FGD were conducted by trained social adherence to penicillin; (3) using the HIV Treatment scientists with institutional review board approval and Cascade model [21,22] (Figure 1) to evaluate program according to standard qualitative research methods. Our effectiveness; (4) using physical space to establish cardiac methods and results have been reported separately [23-25]. clinics; and (5) using the communications department to In these studies, patients provided the following key in- develop patient education materials. sights on how to improve RHD care in Uganda. Potential challenges were quickly identified. The na- ture of the lattice network was not consistent throughout Penicillin adherence among patients with the country. For example, the Regional Centers of Excel- RHD. Our initial FGDs were designed to elicit barriers and lence had varying degrees of administrative and human facilitators of penicillin adherence using a socioecological resource capacity, so a core package of interventions for the model of health to frame the discussion [23]. Lack of re- RHD program had to be substantially altered according to sources and injection site pain were personal barriers to

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penicillin adherence. Similarly, interpersonal barriers from ongoing conversations about program development included lack of family/social support. Unskilled health rather than from formal FGD or qualitative research. Two care providers, penicillin stock-outs, and long wait times main themes emerged from that conversations about how were systemic barriers. Patients suggested that in- to improve cardiovascular care throughout the country. terventions aimed at improving social support (e.g., home visits) and reducing barriers to getting to clinic (e.g., Advanced training. Until recently, advanced cardiovas- reimbursement for bus fare) would greatly facilitate cular services offered at the UHI, such as complex adherence. While measures to reduce injection site pain congenital heart surgery, were dependent largely on were greatly appreciated, its fear was not typically the visiting surgical teams from Europe and the United States. primary reason why patients missed their penicillin in- Yet, the need was much larger than the capacity this jections. These insights contrasted with our team’s pre- strategy provided. On the adult side, this was even more conceived notions about why patients may not be apparent, as a catheterization laboratory existed, but no adherent. Finally, we also conducted a FGD among a small Ugandan physician was capable of performing procedures number of HIV-infected patients who also had RHD. We independently. For RHD patients in particular, a large found that learning how to be adherent to daily antire- number of patients with rheumatic mitral stenosis could be troviral therapy helped these patients understand the treated with percutaneous balloon mitral valvuloplasty if chronic nature of RHD and helped them to be more the expertise was available locally. Ultimately, if enough adherent to their penicillin injections. Perhaps these pa- experts were trained in Uganda, there would no longer be a tients with HIV and RHD would be effective peer coun- need for visiting teams. selors for those who had trouble with adherence. Similarly to the UHI, physicians who were trained in Primary prevention of RHD. Because acute RF and HIV/AIDS care at JCRC desired opportunities for advanced RHD result from repeated streptococcal throat infections in training. As more HIV providers had been trained across children, we wanted to know about the health care prac- the country, the JCRC providers found that they were no tices of children and their caretakers. In FGDs, we longer as busy as they used to be in the early days of the discovered that children rarely reported having a sore epidemic. Perhaps their skills as chronic care providers throat, and that when they did, their parents first took could be repurposed to treat patients with RHD. them to a traditional healer for care [24]. If antibiotics were administered, they typically could only afford 1 or 2 doses. Access to technology. Our Ugandan colleagues Children and adults also had very poor baseline awareness frequently commented that the main reason physicians of RHD, but they were eager to learn more. Caregivers were leaving the country to practice in the United States or suggested that radio and television advertisements in the Europe was not primarily economic (although this did play local language would be the most effective way to educate a role), but rather frustration with not being able to the public, as not all children attended school. accurately diagnose and effectively manage disease in a resource-limited setting. Although cardiologists in Kampala Maternal health issues for women with RHD. A had access to echocardiography, treadmill stress testing, special population of patients with RHD are women of and a cardiac catheterization laboratory, providers prac- reproductive age. Because pregnancy puts increased de- ticing in other parts of the country were often left without mands on the heart, these women are at increased risk of even a sphygmomanometer. Although ultrasonography decompensation and death [26]. We were curious to know and computed tomography scanners were occasionally whether women of reproductive age were being counseled available at regional centers, when they broke down it took on the risks of getting pregnant and whether they had months or even years for their repair if needed. Fortu- adequate access to family planning services. Women in our nately, over the last decade, technological innovation has FGD felt strongly that others would look down on them if led to high-quality ultrasonography being packaged into they were unable to have children due to a heart condition small handheld units. These units were less expensive and and therefore saw pregnancy as a calculated risk [25]. could be easily sent for repair if necessary. Thus, handheld Often, their reproductive decision making was controlled ultrasonography might be used to help health care workers by male partners or in-laws, and few were aware of the in remote regions of the country to accurately diagnose birth defects caused by some of the medicines they were conditions such as RHD and empower them to do the taking. These women felt that a clinic especially designed work they were trained to do in medical school. to take care of pregnant women with cardiovascular dis- In the next section, we describe how our collaboration eases would be beneficial. implemented these new ideas from patients and providers to deliver value—higher quality heart care at lower cost— New insights from providers for all Ugandans. The effort has begun with the RHD Ugandan partners have been instrumental in designing the program rolled out over a lattice of HIV/AIDS infrastruc- nature of our many programs, including the RHD treat- ture, but the vision is for a self-sustaining network ment network. The insights from Ugandan providers came providing care to patients with all sorts of heart diseases.

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DELIVERING VALUE The Regional Centers of Excellence model e The core activity of RHD Action Uganda was to create a Regional Centers of Excellence network of Regional Centers of Excellence that could provide core RHD services closer to where patients lived. The program began in the region surrounding the capital city of Kampala, with the creation of a regional center at JCRCeLubowa in the first year. Subsequently, the program expanded to Mbarara, Gulu, and Lira (Figure 2). Local conditions determined how HIV/AIDS infrastructure could be repurposed for RHD care. At Lubowa, for example, plentiful physical space allowed for the construction of a cardiac clinic. In Gulu, the JCRC facility was located 10 km outside of town, which was impractical for seeing large numbers of patients. Physician champions were not equally available at all locations. Similarly, administrative and support staff were more or less available at certain loca- tions based on other projects that demanded their time and attention. Over the years, we have determined that a core team of 1 to 2 specialized nurses with at least 1 physician champion, along with an ultrasonography machine (or multiple hand- held machines), and wireless mobile Internet access and airtime (for data management and communication) are required to operate a regional center. The collaboration is UHI (Kampala) N UHI 1,139 poised to take this model to other regional centers in future Lubowa Lubowa 91 years, based on priorities of the collaborating partners and the Mbarara Regional Ministry of Health. Centers of Mbarara 73 Gulu Excellence Gulu 289 Lira Lira 20 A national RHD registry FIGURE 2. Regional Centers of Excellence for RHD Care A key requirement of coordinated chronic care is the in Uganda. The chart displays the total number of pa- existence of a register to keep track of patients, schedule tients enrolled in the national registry per site as of appointments, and track adherence to therapy. The collab- January 2017. RHD, rheumatic heart disease; UHI, Uganda oration decided to create a web-based RHD registry that Heart Institute. could be easily accessible at each regional site. Thus, a na- tional record was created that could be queried at any time e for clinical or epidemiological purposes. The RHD Registry targeted by RHD Action Uganda. Our FGD with patients is approved by U.S. and Ugandan institutional review and data from the national registry taught us that in- boards and all patients sign written informed consent to terventions should be targeted toward retention in care [23]. have their clinical information collected for epidemiological Some regional centers experimented with transportation research. In addition, providers felt that it was important to reimbursement for certain patients, whereas home visits develop metrics around how the system was functioning from social workers were required in other cases. A peer- and whether specific interventions might work. Here again, support group comprising patients with RHD has recently we borrowed from HIV/AIDS models to create the RHD been formed that provides a program of peer-counseling for Treatment Cascade (Figure 3) [27]. We found that retention patients who are lost to follow-up or not retained in care. in care was the most significant barrier along the cascade, Because patients described frequent stock-outs of penicillin while rates of optimal adherence to benzathine penicillin G at local clinics, we began giving some patients a 3-month were high among those patients who were retained in care supply of penicillin to take home with them every time they [27]. Our analysis also showed that distance to a local health came to see the doctor at the regional center. center and access to a regional RHD center of excellence were associated with improved retention and adherence, suggesting that our efforts to decentralize care had signifi- Maternal health cant impact on these care quality metrics [27]. As mentioned previously, pregnant mothers with RHD and other forms of cardiovascular diseases are at high risk for decompensation and death [26]. In response to feedback Penicillin from both patients and providers, we have been developing Penicillin adherence for patients with known RHD (i.e., interventions to address the unique issues of this popula- secondary prevention) is the primary outcome measure tion. A physician leader at UHI is establishing a maternal

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that technology can provide. Handheld ultrasonography is 1400 100% such a technology that has the power to revolutionize heart 90% care, especially in more rural areas of Uganda. 1200 With colleagues from Children’s National Medical 80% Center in Washington, DC, we are conducting a trial of

1000 70% handheld ultrasonography to improve diagnosis of heart failure symptoms at the Lira Regional Centre. Selected 60% nonspecialist physicians, clinical officers, and nurses have 800 learned to use the Vscan (General Electric Healthcare, Little 50% Chalfont, United Kingdom) to diagnose RHD, dilated 600 # of paents 40% cardiomyopathy, hypertensive heart disease, pericardial effusion/tamponade, isolated right heart failure, and 400 30% congenital heart diseases. These major categories of heart failure symptoms have dramatically different treatments. 20% 200 Prior to the introduction of ultrasonography, patients 10% without a cardiac cause of their symptoms were often treated as having heart disease, whereas many with heart 0 0% Alive Retained Prescribed Adherent disease were often given a noncardiac diagnosis such as Cascade category 1,231 701 554 499 pneumonia. We hope that access to this simple diagnostic % of parent category 82% 57% 92% 91% tool in the hands of nonspecialists will dramatically improve patient outcomes. FIGURE 3. The RHD treatment cascade in Uganda. The left axis and orange bars indicate the number of patients Training in each outcome category of the treatment cascade, whereas the right axis and red points indicate the per- Training has been a core principle of RHD Action from the centage of patients as a proportion of the parent (prior) very beginning. The Ugandan providers demanded it, and category. Error bars reflect the 95% confidence interval. there was no other option to solve the profound human All patients in the registry were included to assess out- resource problem. We were fortunate to be able to provide comes of alive and retained, but patients with borderline targeted academic exchanges with Makerere faculty ’ fi RHD were excluded from assessing the outcomes of through Ohio s Clinical Research Faculty Certi cate pro- prescribed and adherent. Used with permission from gram [29]. In this way, 2 UHI cardiologists were able to Longenecker et al. [27]. RHD, rheumatic heart disease. receive advanced experience in interventional cardiology techniques in exchange for teaching medical residents and students at UH/CWRU. Two additional UHI cardiologists trained in advanced heart failure in Cleveland, and an cardiovascular care clinic that will provide coordinated anesthesiologist is currently training in cardiac anesthesia consultative services for these high-risk patients. Addi- and critical care. As evidenced by the large number of tionally, in a project led by Children’s National Medical Center and Imaging the World (a nongovernmental organization that aims to bring accessible, affordable, and high-quality ultrasonography to remote and underserved communities), mothers are being screened for RHD with echocardiography at the time of prenatal ultrasonography in several locations around the country. As is the case throughout sub-Saharan Africa, there is a substantial overlap between the HIV/AIDS care lattice and maternal- child health lattice at the governmental and nongovern- mental levels [28], providing opportunity to bring in additional partners with mutual interest in improving RHD care and heart care more broadly.

Technology The message from both patients and providers is that technology has the potential to revolutionize health care in Uganda, but a focus on value is critically important. One FIGURE 4. Dr. Marco A. Costa and Dr. Emmy Okello needs to look no further than the mobile phone to un- performing the first percutaneous mitral valvuloplasty derstand the profound improvements in standard of living for rheumatic mitral stenosis in August 2012.

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partners and diverse funding sources (Tables 1 and 2), the 4. Cohen RL, Li Y, Giese R, Mancuso JD. An evaluation of the President’s cardiovascular care development program in Uganda also Emergency Plan for AIDS Relief effect on health systems strengthening in sub-Saharan Africa. J Acquir Immune Defic Syndr 2013;62:471–9. builds on a lattice of relationships that have been forged 5. Lohman N, Hagopian A, Luboga SA, et al. District health officer per- because of mutual interests and backgrounds. Our rela- ceptions of PEPFAR’sinfluence on the health system in Uganda, tionship with colleagues in Brazil facilitated travel of 2005e2011. Int J Health Policy Manag 2016;6:83–95. Ugandan physicians to Belo Horizonte in Minas Gerais to 6. Paton NI, Kityo C, Hoppe A, et al., for the EARNEST Trial Team. Assessment of second-line antiretroviral regimens for HIV therapy in learn percutaneous balloon mitral valvuloplasty for rheu- – fi Africa. N Engl J Med 2014;371:234 47. matic mitral stenosis. The rst percutaneous balloon mitral 7. Abongomera G, Kiwuwa-Muyingo S, Revill P,et al., for the Lablite Project valvuloplasties were performed by the UH/CWRU visiting Team. Population level usage of health services, and HIV testing and team in August 2012 (Figure 4). Four years later, in care, prior to decentralization of antiretroviral therapy in Agago District December 2016, the UHI team performed their first in- in rural Northern Uganda. BMC Health Serv Res 2015;15:527. 8. Aliku TO, Lubega S, Namuyonga J, et al. Pediatric cardiovascular care dependent valvuloplasty and is now growing the volume of in Uganda: current status, challenges, and opportunities for the these procedures with the aim to become a center of future. Ann Pediatr Cardiol 2017;10:50–7. excellence for mitral valvuloplasty in East Africa. 9. Longenecker CT, Okello E, Lwabi P, Costa MA, Simon DI, Salata RA. Nursing education in Uganda has not historically included Management of rheumatic heart disease in Uganda: the emerging research or higher level administrative skills, but several nurses epidemic of non-AIDS comorbidity in resource-limited settings. J Acquir Immune Defic Syndr 2014;65:e79–80. requested to receive training and mentorship through working 10. Sika-Paotonu D, Beaton A, Raghu A, Steer A, Carapetis J. Acute rheu- with us on special projects. By closely involving nurses in matic fever and rheumatic heart disease. In: Ferretti JJ, Stevens DL, ongoing research projects, we hope to inspire young nurses to Fischetti VA, editors. Streptococcus pyogenes: Basic Biology to Clinical ask novel and interesting questions about how to advance Manifestations. Oklahoma City, OK: University of Oklahoma Health Sciences Center; 2016. p. 1–57. health in their unique settings. Two examples are a nurse who 11. Watkins DA, Johnson CO, Colquhoun SM, et al. Global, regional, and directs a project on handheld ultrasound in Lira, and another national burden of rheumatic heart disease, 1990e2015. N Engl J nurse who is being mentored to transition into a nurse coor- Med 2017;377:713–22. dinator for the Gulu Regional Center. 12. Longenecker CT, Lwabi P, Kityo C, et al. Leveraging existing HIV/AIDS infrastructure for rheumatic heart disease care in Uganda: a collab- orative disease surveillance and management program. Glob Heart CONCLUSIONS 2014;9:e55. 13. Manyemba J, Mayosi BM. Penicillin for secondary prevention of The Ugandan health care system is clearly under-resourced rheumatic fever. Cochrane Database Syst Rev 2002;(3):CD002227. to provide high-quality heart care to all of its 36 million 14. Schwartz JI, Dunkle A, Akiteng AR, et al. Towards reframing health citizens; however, the Ugandan Ministry of Health has service delivery in Uganda: the Uganda Initiative for Integrated committed substantial resources to support UHI’s vision to Management of Non-Communicable Diseases. Glob Health Action 2015;8:26537. decentralize its services and improve referral networks 15. Schwartz JI, Guwatudde D, Nugent R, Kiiza CM. Looking at non- across the country over the next decade. The results of our communicable diseases in Uganda through a local lens: an analysis initial success with the RHD Action pilot program illustrate using locally derived data. Global Health 2014;10:77. how the government might leverage existing latticework 16. Odekunle FF, Odekunle RO. The impact of the US president’s emer- (such as HIV/AIDS clinics or maternal-child health pro- gency plan for AIDS relief (PEPFAR) HIV and AIDS program on the Nigerian health system. Pan Afr Med J 2016;25:143. grams) to provide core NCD services and even more 17. Matheson GO, Pacione C, Shultz RK, Klugl M. Leveraging human- specialized forms of heart care. The UH/CWRUeUganda centered design in chronic disease prevention. Am J Prev Med partnership will remain critical to future scalability by 2015;48:472–9. continuing to provide research and training opportunities 18. Gupta N, Bukhman G. Leveraging the lessons learned from HIV/AIDS through an iterative and continuous cycle of program for coordinated chronic care delivery in resource-poor settings. Healthc (Amst) 2015;3:215–20. development. For some problems, we have been through 19. Rabkin M, Nishtar S. Scaling up chronic care systems: leveraging HIV the cycle 2 or 3 times; for others, the cycle is just begin- programs to support noncommunicable disease services. J Acquir ning. Regardless, the future of heart care in Uganda is Immune Defic Syndr 2011;57(Suppl 2):S87–90. bright as long as the focus remains human-centered on 20. Rabkin M, Kruk ME, El-Sadr WM. HIV, aging and continuity care: patients and their providers. strengthening health systems to support services for noncommunicable diseases in low-income countries. AIDS 2012;26(Suppl 1):S77–83. 21. Gardner EM, McLees MP, Steiner JF, del Rio C, Burman WJ. The REFERENCES spectrum of engagement in HIV care and its relevance to test-and- 1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. treat strategies for prevention of HIV infection. Clin Infect Dis Global, regional, and national incidence, prevalence, and years lived 2011;52:793–800. with disability for 328 diseases and injuries for 195 countries, 22. US Department of Health and Human Services. HIV Care Continuum. 1990e2016: a systematic analysis for the Global Burden of Disease 2017. Available at: https://www.hiv.gov/federal-response/policies- Study 2016. Lancet 2017;390:1211–59. issues/hiv-aids-care-continuum. Accessed August 17, 2017. 2. Duffy M, Ojikutu B, Andrian S, Sohng E, Minior T, Hirschhorn LR. Non- 23. Huck DM, Nalubwama H, Longenecker CT, Frank SH, Okello E, communicable diseases and HIV care and treatment: models of in- Webel AR. A qualitative examination of secondary prophylaxis in tegrated service delivery. Trop Med Int Health 2017;22:926–37. rheumatic heart disease: factors influencing adherence to secondary 3. Barasa FA, Vedanthan R, Pastakia SD, et al. Approaches to sustainable prophylaxis in Uganda. Glob Heart 2015;10:63–69.e1. capacity building for cardiovascular disease care in Kenya. Cardiol Clin 24. Moini B, Hanson JE, Webel A, Nalubwama H, Salata R, Longenecker C. 2017;35:145–52. Promoting primary prevention of rheumatic heart disease in Uganda:

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a qualitative study of group A streptococcal pharyngitis awareness in 27. Longenecker CT, Morris SR, Aliku TO, et al. Rheumatic heart disease urban and rural communities. Glob Heart 2014;9:e256. treatment cascade in Uganda. Circ Cardiovasc Qual Outcomes 2017; 25. Chang AY, Nabaale J, Nalubwama H, et al. Characteristics and Moti- 10:e004037. vations of Women of Reproductive Age in Uganda with Rheumatic 28. Fowkes FJ, Draper BL, Hellard M, Stoove M. Achieving development goals Heart Disease: A Mixed Methods Study. Ann Glob Health 2017;83: for HIV, tuberculosis and malaria in sub-Saharan Africa through integrated 171e172. antenatal care: barriers and challenges. BMC Med 2016;14:202. 26. Sliwa K, Johnson MR, Zilla P, Roos-Hesselink JW. Management of 29. LAWriter Ohio Laws and Rules. Ohio Revised Code 4731.293 Clinical valvular disease in pregnancy: a global perspective. Eur Heart J 2015; Research Faculty Certificate. Available at: http://codes.ohio.gov/ 36:1078–89. orc/4731.293. Accessed August 28, 2017.

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Profiles of two Ugandan women living with RHD LISTEN TO MY HEART A Passion for Patient Advocacy Christine’s Story Christine, 25 years old, has recently finished her Bachelor’s degree in Industrial and Organisational Psychology at Makerere University in Kampala, Uganda’s sprawling capital city. It’s been a long journey from 2002 when she was first diagnosed with RHD.

RHD is a preventable and treatable 13 years old, Rotary International’s Gift is healthy because of good lifestyle form of heart disease that affects of Life provided funds for Christine’s choices, taking her medications and 33 million people around the world, surgery in India. Her parents saved keeping follow-up appointments. She particularly children and young people and raised money for transport using has mechanical valves that produce living in resource-limited settings local television and radio appeals. a soft click-click sound, and takes characterised by overcrowding. antibiotics to prevent a relapse of the It typically begins in childhood as In September, 2005, Christine left her streptococcus infection that originally strep throat, and if left untreated rural village in Western Uganda for damaged her heart can progress to serious heart damage. the long voyage to Amrita Hospital in Kerala, India for a procedure to repair Christine knows that early diagnosis Christine is an active member and her damaged heart valves. A boy from and treatment prevent long-term vice chairperson of the Rheumatic another village also made that trip to complications of RHD. She is also very Heart Disease (RHD) Support Group at India for heart surgery. A little older aware of the knowledge gap about Uganda Heart Institute. This group offers than Christine, and much sicker, his the causes and proper treatment peer support for medication adherence mother was chosen to accompany of the sore throat and rheumatic and advocates for the empowerment both children to India. Anxious and fever in her communities. Christine of People Living with RHD (PLWRHD). worried, Christine’s family remained at has been touched by the kindness The group also provides community home. After three weeks, the children and generosity of others along her outreach for PLWRHD, to bring “lost were well enough to travel home. journey back to health. She has patients” back to care. Christine has never seen that boy again personally faced the challenges but he has never left her thoughts. that PLWRHD encounter and now Christine’s passion comes from her dedicates her time and energy to personal experience as a PLWRHD Now Christine is a young woman with help others manage their disease and her desire to help others whose aspirations for a family and career. She to live a full and healthy life. experiences may not have been as positive as her own. ‘I think we can fight RHD to live a healthy and happy life Christine had always been a small despite the challenges we sometimes meet.’ and weak child. When her parents took her to local clinics, the diagnosis was always “malaria.” Frustrated, her parents also took her to the local Christine has shared her story in the hope that it church for prayers and to traditional will raise the profile of healers for herbal treatments. Finally, rheumatic heart disease. an x-ray revealed a heart problem. There is much to do to increase awareness of Christine started medication that made RHD at the local, regional and global levels. To find her feel better, however her parents out more, please go to were told she needed heart surgery in www.rhdaction.org. India – an expense her parents could never afford. When Christine was

RHD Action @RHDAction #rhdaction www.rhdaction.org LISTEN TO MY HEART A Passion for Patient Advocacy Flavia’s Story Flavia is a mother, wife and a nurse who has RHD. She is also a tireless advocate for People Living with RHD, networking and speaking on behalf of both health workers and PLWRHD to the global health community.

Globally, RHD is the most common RHD Patient Support Group at the in her leg to open a damaged valve. She cause of acquired heart disease in Mulago Hospital. She was recognised says it has greatly increased her quality children and young adults, claiming by her colleagues as a passionate of life reporting that she can work over 300 000 lives annually and advocate, so she was chosen to harder, and even run with no challenges. affecting 33 million people. Many RHD represent PLWRHD at the first RHD She is playing with her sons and enrolled patients first present with advanced Action patient event in Cape Town in a master’s nursing programme. disease after a long symptom-free in 2016. Participating in this meeting period. Women suffering from RHD was a turning point in her life; she In July 2017, Flavia was invited to a third often present during pregnancy being met many people who were living global conference in Barcelona, Spain a stressful time for the heart. successfully with their disease. for the World Congress of Paediatric Cardiology and Cardiac Surgery. She Flavia is a mother, wife, and nurse who Flavia’s talent for advocacy was shared her story as a PLWRHD and has RHD. Growing up near Kampala she also noticed by the global RHD health worker in a developing country. remembers being very sick with fever community. In May 2017, she was Again, she formed new and important and sore throat as a child. But she was invited to speak at the 70th World relationships with other patient never diagnosed with acute rheumatic Health Assembly in Geneva to advocacy groups. fever. She also remembers, while in support the new RHD Resolution. university, when her heart was beating Flavia continues her work as a PLWRHD fast and she had little energy. She went Shortly before the Geneva trip, Flavia advocate in both her local and global to the hospital and was given blood underwent valvuloplasty at Uganda communities. She is now a social media pressure medication. She felt better after Heart Institute. A small balloon was expert, maintaining her new relationships two months so she stopped taking it. inserted into her heart through a vein on Twitter, Facebook and What’s App.

After graduating university, Flavia ‘I did not know how long my life would be so I was not got married and started her family. Just after her first baby was born, she thinking about the future until I met a lot of people who was diagnosed with RHD when the were successfully living with RHD at a patient event.’ fast heart beats and lack of energy returned. This time she was coughing blood and short of breath.

Her second pregnancy was successful but worrisome as Flavia now knew she had RHD. She had been told it was too risky to fall pregnant again. Flavia’s Flavia’s experiences as both a PLWRHD and health second baby boy is now a healthy worker have provided toddler but delivery was difficult insight and fuelled her and he was seriously underweight. passion to support other Flavia now works as a nurse, raises people living with heart her family, and is a member of the disease across the globe.

RHD Action @RHDAction #rhdaction www.rhdaction.org Appendix C:

Publications from RHD Action Uganda, 2013-2018

1. Huck DM, Nalubwama H, Longenecker CT, Frank S, Okello E, Webel A. A Qualitative Examination of Secondary Prophylaxis in Patients Affected with Rheumatic Heart Disease in Uganda. Global Heart. 2015 Mar;10(1):63- 69.

2. Huck DM, Okello E, Mirembe G, Ssinabulya I, Zidar DA, Silverman G, Getu L, Nowacki A, Calabrese L, Salata RA, Longenecker CT. Role of Natural Auto-antibodies in Inflammatory Disease: Ugandans with Rheumatic Heart Disease and HIV. EBioMed. 2016. Feb 6;5:161-6.

3. Gleason B, Mirembe G, Namuyonga J, Okello E, Lwabi P, Lubega I, Lubega S, Musiime V, Kityo C, Salata RA, Longenecker CT. Prevalence of latent rheumatic heart disease among HIV-infected children in Kampala, Uganda. J Acquir Immune Defic Syndr. 2016 Feb 1;71(2):196-9.

4. Engelman D, Okello E, Beaton A, Selnow G, Remenyi B, Watson C, Longenecker CT, Sable C, Steer AC. Evaluation of computer-based training for health workers in echocardiography for rheumatic heart disease. Global Heart. 2017; 12(1):17-23.e8.

5. Okello E, Longenecker CT, Beaton A, Kamya MR, Lwabi P. Rheumatic Heart Disease in Uganda: Predictors of Morbidity and Mortality One Year after Presentation. BMC Cardiovasc Disord. 2017 Jan 7;17(1):20

6. Moloi AH, Mall S, Engel ME, Stafford R, Zhu ZW, Zuhlke LJ, Watkins DA. The Health Systems Barriers and Facilitators for RHD Prevalence: An Epidemiological Meta-Analysis From Uganda and Tanzania. Glob Heart. 2017 Mar;12(1):5-15.e3.

7. Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, Forouzanfar MH, Longenecker CT, Mayosi BM, Mensah GA, Nascimento BR, Ribeiro ALP, Sable CA, Steer AC, Naghavi M, Mokdad AH, Murray CJL, Vos T, Carapetis JR, Roth GA. The Global, Regional, and National Burden of Rheumatic Heart Disease, 1990-2013. N Eng J Med. 2017 Aug 24;377(8):713-722.

8. Stehouwer N, Okello E, Gupta V, Bailey A, Josephson RA, Madan-Mohan SK, Osman M, Longenecker CT. Development and Validation of a Teaching Module for Echocardiographic Scoring of Rheumatic Mitral Stenosis. Glob Heart. 2017 Aug 31. pii: S2211-8160(17)30050-9. [Epub ahead of print]

9. Longenecker CT*, Morris SR*, Aliku TO, Beaton A, Costa MA, Kamya MR, Kityo C, Lwabi P, Mirembe G, Nampijja D, Rwebembera J, Sable C, Salata RA, Scheel A, Simon DI, Ssinabulya I, Okello E. Rheumatic Heart Disease Treatment Cascade in Uganda. Circ Cardiovasc Qual Outcomes. 2017 Nov;10(11). *Co-first authors 10. Beaton A, Aliku T, Dewyer A, Jacobs M, Jiang J, Longenecker CT, Lubega S, Mirabel M, Mirembe G, Namuyonga J, Okello E, Scheel A, Tenywa E, Sable C, Lwabi P. Latent Rheumatic Heart Disease: Identifying the Children at Highest Risk of Unfavorable Outcome. Circulation. 2017 Dec 5;136(23):2233-2244.

11. Scheel A, Beaton A, Okello E, Longenecker CT, Otim IO, Lwabi P, Sable C, Webel A, Aliku T. The Impact of Peer Support Group for Children with Rheumatic Heart Disease in Uganda. Patient Educ Couns. 2018 Jan;101(1):119-123.

12. Okello E, Longenecker CT, Scheel A, Aliku T, Rwebembera J, Mirembe G, Sable C, Lwabi P, Beaton A. The Impact of Regionalization of a National Rheumatic Heart Disease Registry: The Ugandan Experience. Heart Asia. 2018 Jan 13;10(1):e010981.

13. Chang AY, Nabbaale J, Nalubwama H, Okello E, Ssinabulya I, Longenecker CT, Webel AR. Motivations of Women of Reproductive Age in Uganda with Rheumatic Heart Disease: A Mixed Methods Study of Experiences in Stigma, Childbearing, Anticoagulation, and Contraception. PLoS One. 2018 Mar 28;13(3):e0194030.

14. Longenecker CT, Kalra A, Okello E, Lwabi P, Omagino JO, Kityo C, Kamya MR, Webel AR, Simon DI, Salata RA, Costa MA. A Human-Centered Approach to Cardiovascular Care Infrastructure Development in Uganda. Glob Heart. 2018 Apr 20. [Epub ahead of print] Appendix D :

Uganda National Advisory Committee Draft Terms of Reference

National RHD Advisory Committee, Uganda Terms of Reference Background In November 2017, to support the scale up of RHD Control programme activities, the Ministry of Health, Uganda, agreed to convene an RHD Advisory Committee with support from the Ugandan Heart Institue and RHD Action.

Responsibilities

The Advisory Committee (AC) will support the Ministry of Health in the following: - Identify goals and targets for the Ministry of Health. - Identify entry points across the health system for the inclusion of RHD interventions. - Support implementation of the WHA Resolution on Rheumatic Fever and Rheumatic Heart Disease. - Develop evidence based, locally adapted, clinical management guidelines. - Advise on the coordination of a national RHD control programme. - Engage relevant ministries across government in the delivery of the RHD control programme. - Fundraise, mobilise resources or advocate for financial support of the programme. - Represent the programme to people living with RHD.

Operational Policies

- The Advisory Committee (AC) will be chaired by the Director General, Clinical Services. - The Chairperson will preside over all meetings and will be responsible for facilitating the mission of the Advisory Committee and any Sub‐Groups that may be established - The Ugandan Heart Institute will prepare and follow up on the meetings, and will maintain contact with AC members on a permanent basis. - Advisory Committee meetings will be held bi-monthly - Financial costs incurred by members to attend meetings shall normally be covered by members’ parent organizations, or individually

Advisory Group Members will: - Participate in the work of the Group bi-monthly attending meetings in person. - Represent their organization and sector, i.e. are able to speak for (or engage other parts of their organization /sector’s preferences, experience, capabilities, etc.). - Contribute their personal time, expertise, networks, etc. - Leverage their organizations’ resources (i.e. local insights, technical expertise/assistance, networks, staff time, infrastructure, marketing skills, logistical support, etc.) for the AC’s work.

Membership A selected, limited and diverse number of participants in terms of sectors and geographical distribution will be targeted, enlisting those that can bring to the table expertise in their areas of work. - The AC shall have no more than 9 representatives

- The AC shall include representatives from the Ministries of Health, Education and Finance (4 people) - The AC shall include a representative of People Living with RHD (1) - The AC shall include at least two representatives of the Ugandan Heart Institute (2) - The AC shall include at least two representatives from civil society - Representatives on the advisory committee will be nominated by the Ugandan Heart Institute and approved by the Ministry of Health - AC members will serve for one year terms (recurring) but will be changed as necessary to be determined by the Ugandan Heart Institute (UHI)