HARVARD T.H. CHAN SCHOOL OF AIDS INITIATIVE spotlight spring 2016

Botswana Leads in HIV Treatment

Billions of dollars are spent every year on HIV/AIDS treatment programs. But how well are they working?

In the African country of Botswana, where 25% of adults (aged 16-49) are HIV positive, the answer is extremely well. In a recent paper in The Lancet HIV, researchers showed that Botswana is close to reaching the ambitious UNAIDS 90-90-90 goals. Photo by Dominic Chavez In 2014, UNAIDS proposed new testing and treatment targets directed towards ending the AIDS epidemic: by the year 2020, 90% The Blood in the Freezer of all HIV-infected people would know their HIV status; 90% of those diagnosed with HIV would One tiny vial of blood contains a re- at the BHP headquarters in Gaborone, be on antiretroviral therapy (ART); markable amount of genetic informa- Botswana. Most are blood samples and 90% of those on ART would tion about both the person from whom collected from tens of thousands of have a suppressed viral load (very it was drawn and infectious agents like patients who have participated in BHP low levels of HIV in their blood). A HIV circulating at the time of the needle clinical trials over the past 20 years. growing body of research shows prick. Because HIV mutates so quickly, Besides blood samples, the biorepository that providing ART to people living having access to lots of samples to study also includes specimens of hair, tissue, with HIV, besides being good for is a valuable resource. “It’s a diamond for breast milk, and other bodily secretions. their own health, lessens their science,” said Sikhulile Moyo, Labora- tory Manager at the Botswana Harvard The samples were collected for one chance of transmitting HIV to reason: to end the HIV/AIDS epidemic. others. AIDS Institute Partnership (BHP). He was referring to the blood samples Botswana has one of the highest rates Researchers Surprised banked in the BHP freezers. “Specimens of HIV in the world with about 25% would be a more accurate term,” he cor- of adults infected. When the BHP The data for the paper was taken rected, “biological samples freely given was established in 1996, hospitals from the Botswana Combination to be processed for diagnosis or disease were overcrowded with very sick Prevention Project (BCPP), an monitoring.” AIDS patients. There was no available on-going clinical trial designed treatment. Death, often agonizing, was to measure how well a package Over 1.5 million specimens are stored the expected outcome.

(continues on page 2) (continues on page 3) Botswana Leads in HIV Treatment (continued from page 1)

come close to Botswana’s coverage.

Why has a middle-income African nation with a high HIV prevalence been able to create a more successful HIV treatment program than richer Western countries?

“Remember that the set-up of the Botswana national health system is that 95% of all people are within five- kilometer access of a healthcare facility,” said Dr. Tendani Gaolathe, BCPP Project Director and first author on The Lancet HIV paper.

“In Botswana, there’s been dedicated governmental action at the highest level to take responsibility for the epidemic. Healthcare, including antiretroviral treatment, is free for all citizens in the country,” said Essex. “The government From left: Lyorlumun Uhaa, UNICEF; Michel Sidibé, UNAIDS; , Harvard AIDS Initiative; Pride Chigwedere, UNAIDS, at a meeting for African Leaders in Addis Ababa. Photo by Aida Muluneh has also sought international cooperation with us and others to of HIV prevention measures receiving ART who had a verifiable viral get the latest advice and the best reduces the rate of new . load test, 2517 (96%) had a suppressed understanding of what can be done.” Researchers at the Harvard AIDS HIV viral load. Initiative (HAI) and their colleagues Attainable & Meaningful For a national HIV treatment program at the Botswana Harvard AIDS to achieve viral suppression in 96% When the UNAIDS 90-90-90 targets Institute Partnership (BHP) are of patients on ARVs is considered were first announced, many in the responsible for the design exceptional. The high rate was a international community questioned and evaluation of the project. surprise, even to the researchers. whether they were achievable, Adults aged 16 especially by 2020 in resource- strapped countries with a high burden to 64 were re- This is significant work as it provides cruited from a of HIV. The findings from Botswana random sample further evidence that UNAIDS 90-90-90 indicate that the targets are attainable. of 20% of house- treatment targets are both realistic and “This is significant work as it provides holds in each achievable. further evidence that UNAIDS 90-90-90 of 30 Botswana treatment targets are both realistic and villages.Partici- Michel Sidibé, UNAIDS Executive Director achievable,” said UNAIDS Executive pants answered Director Michel Sidibé. questionnaires and were tested for HIV. “I thought it would be very good, by The data collected from the BCPP is which I would have said 90% or so. I “The targets are definitely more than among the most complete population- was surprised that it was as high as bureaucratic goal posts,” said Essex. level estimates of HIV available for 96%,” said Max Essex, Senior Principal “It’s clear that rates of new infections southern Africa, the epicenter of the Investigator of the BCPP and Chair of will go down dramatically as a result of AIDS epidemic. both HAI and BHP. reaching these goals.”

Of the 12,610 participants surveyed, Why Botswana? 3596 (29%) were infected with HIV. Of those individuals, 2995 (83%) already According to a recent analysis of HIV The BCPP is funded by the President’s knew their HIV status. Among those treatment programs, no country has Emergency Plan for AIDS Relief who knew their status, 2617 (87%) were yet met the overall UNAIDS goals. Very (PEPFAR), through the Centers for receiving ART. Of the 2609 individuals few countries, including the U.S., have Disease Control and Prevention.

2 The Blood in the Freezer (continued from page 1)

In 2002, Botswana’s Ministry of Health storing over a million samples becomes with a temperature monitoring system launched a national antiretroviral an issue. The BHP currently houses 70 connected to the internet, a mobile program to provide free AIDS drugs freezers at headquarters. The majority phone network, and a security company. to eligible citizens. The BHP played an of samples are kept in big freezers at important advisory role in planning, close to -80°C, but viable cells used for Freezers are expected to last ten years implementing, and monitoring the immunological studies are stored in or longer, but disasters happen. If a program. BHP clinical trials evaluated liquid nitrogen tanks at -140°C. freezer breaks down in the middle of the different drug regimens. Samples in night, Moyo is awakened by a text and the freezers come from those trials and Each big freezer costs about $25,000, a phone call. If he’s not available, the others that followed. Today, with proper weighs 805 pounds, and can hold 24 security company works its way down a treatment, people living with HIV can steel racks of 2000 separate vials for a list of key staff contacts, with Dr. Joseph expect to live a nearly normal life. total of 48,000 samples. Each sample Makhema, CEO of the BHP, last on the is bar-coded with a unique identifier. list. Whoever responds must quickly “What we have in the freezers is a his- Descriptive information such as date and move samples to a reserve freezer the tory of the AIDS epidemic in Bo- time of collection, study identifier, and BHP is required to have available at all tswana,” said Moyo. There are blood specimen type is stored in an electronic times. When the power fails, a back-up samples from across the spectrum of inventory system that links to non- generator keeps the freezers cold. the epidemic: from studies in the 1990s confidential demographics such as the before the national program, to studies age and sex of the participant. Samples Shared Access of treatment-naïve patients beginning are anonymized, meaning personal drug regimens in the 2000s, to current information such as name and address The stored samples are useful not only for studies of sero-converters—people re- has been removed. the BHP, but for the global HIV/AIDS cently infected with HIV. research community. When a study Because the samples are irreplaceable, participant signs a consent form allowing Freezers efforts are taken to ensure their safety the use of his or her sample for a specific Though each sample is small in size, and integrity. The freezers are equipped research study, the participant has the

BHP lab technicians store cell samples in liquid nitrogen tanks at -140°C. Photo by Dominic Chavez

3 option to sign a second consent form that Britain, the U.S. and Canada. others to help us chew the pie.” allows the unused portion of the sample “BHP acts as the custodian,” said “The samples are valuable because they to be used for future HIV research. Moyo. “This resource is open to other represent a unique population of HIV- as long as their research has infected people at different stages of In addition to BHP scientists and been approved.” Though scientists the epidemic,” said Max Essex, Chair students, researchers from other have a reputation for being highly of the Harvard AIDS Initiative and the countries can request samples for their competitive, AIDS researchers have a Botswana Harvard Partnership. “These HIV studies. If the study doesn’t overlap history of working together. Most large samples can be used to address a range with work already underway and an HIV/AIDS studies are collaborative of research questions, from how much ethics review board approves the study, efforts across institutions and countries. the virus might have evolved over the last samples will be packed and shipped, as “At BHP, we can try to chew the pie,” 20 years to how the epidemic itself has they have been to , Great said Moyo, “but we definitely need changed over that time.” spotlight Published by the Harvard T. H. Chan School of Public Health AIDS Initiative 651 Huntington Avenue Boston, MA 02115 Chair: Dr. Max Essex Executive Director: Dr. Richard Marlink Phone: 617-432-6106 Email: [email protected] Web: www.aids.harvard.edu PUBLICATIONS STAFF Editor: Martha Henry Print & Web Designer: Lucia Ricci Thanks to: Pride Chigwedere, Nealia Khan, Sally Madiba, Lendsey Melton, Sikhulile Moyo, Vlad Novitsky, Molly Pretorius Holme, Erik van Widenfelt, Melissa Zahralban-Steele

“Evolutionary trends and dynamics of Sikhulile Moyo HIV-1C in Botswana,” he used new molecular and serological methods to A native of , Sikhulile Moyo identify and characterize early founder moved to Botswana after completing his viruses. And, yes, the samples for his undergraduate degree at the University research came from the BHP freezers. of Zimbabwe, Harare in 1996. Moyo is happily married and has two He started working at the Botswana sons and a daughter. He and his wife Harvard Partnership as a Lab Assistant in sponsor several children, both relatives 2003 and was promoted to Laboratory and non-relatives, at a school each year. Coordinator, then Deputy Lab Manager, He loves singing, composes gospel songs, then to his current position as Lab and is recording his second album. Manager. “I wake up daily inching towards He holds Master’s degrees in Applied pursuing my goals with vigor and Microbiology and Public Health. In a relentless commitment,” said Moyo. few months, he’ll complete his PhD in “Working with scientists and mentors Medical Virology from Stellenbosch at BHP has made me realize that every University, South Africa. For his thesis, moment is a great moment for action.”

HAI is dedicated to research and education to end the AIDS epidemic in Africa and developing countries. Since 1988, HAI has been at the forefront of HIV/AIDS laboratory research, clinical H A I trials, education, and leadership. visit our website www.aids.harvard.edu

4 After the Capture THE CARE AND TREATMENT OF DATA

Erik van Widenfelt. Photo by Dominic Chavez

“Data! Data! Data!” he cried impatiently. data management system, but couldn’t people—talking to them about the im- “I can’t make bricks without clay!” find an affordable system that met their portance of knowing their HIV status or needs. Erik took on the task. He recruit- participating in the study,” said Erik. “If Sherlock Holmes ed six local computer-science graduates we find someone who’s good at counsel- to help with the software design. Using ing and dealing with people, we’ll make open-source code, the team developed sure that person—as long as they’ve got Science depends on data. A large clini- a flexible data management system for enough fingers to hit the keyboard—can cal trial like the Botswana Combination complex clinical trials. operate the system.” Prevention Project (BCPP) depends on lots of data. When the multi-year trial Research Assistants (RAs) used to gather The software itself drives the process. in 30 Botswana villages concludes, re- information on paper forms. That infor- As an RA enters data into a laptop, the searchers hope their data will provide a mation would be keyed into a computer system directs next steps. If a participant better understanding of how to prevent by a data entry person, usually weeks lat- answers a question one way, required in- HIV infections. er at an entirely different location. The formation fields and follow-up questions process was vulnerable to error. In a pilot appear. Answers must be entered before To assure that the data is as reliable as study, Erik developed a data manage- continuing to the next step. The system possible, every bit of BCPP information ment system that allowed RAs to enter guides RAs through the process, allowing is captured electronically. Though your information directly into a laptop, elimi- them to concentrate on the participant doctor’s office may still be transitioning nating both the paper forms and the er- and keeping the conversation as com- from pencil to keyboard, the BCPP field rors that accompany them. fortable as possible. team uses laptops exclusively. “Going to paper is not an option,” said Erik van The BCPP protocol is complex with Fast & Accurate lots of rules to follow. Most study inter- Widenfelt, Director of Data Operations After completing household visits for the and Information Technology at the Bo- views take place inside people’s homes, not in the controlled environment of a day, RAs head back to two trailers parked tswana Harvard AIDS Institute Partner- outside a local clinic. The trailers serve as ship (BHP), who designed a system to clinic. Babies may be crying, dogs bark- ing, music playing. Chaos or not, RAs the field team’s base of operation in a vil- capture, store, and access the enormous lage. When the RA is within a 15-meter amount of data being generated. are tasked with following a strict proto- col. Erik’s team designed an easy-to-use radius of the IT trailer, the laptop auto- matically connects to the secure Wi-Fi Electronic & Local tool that guides RAs through the inter- view process. network broadcasting from the trailer. In the planning stages, BCPP leaders Data synchronizes off the laptop and up- looked into purchasing an off-the-shelf “Our RAs have to be good at dealing with loads onto a server. (continues on page 6)

5 If we find someone who’s good at nators in Gaborone, Info for Geeks counseling and dealing with people, review the data to we’ll make sure that person—as see what’s going on in the field and make The BCPP DMS is a suite of long as they’ve got enough fingers any necessary adjust- Python modules that extend to hit the keyboard—can operate the ments. the Django framework system. When the driver de- for clinical trials research. livers the cool box All code is open-source, Erik van Widenfelt to BHP, samples are updated daily, and available again reconciled. on GitHub. Researchers HIV+ samples are At the mobile lab, the RA hands over designing complex clinical tested for viral load. Most samples are trials are welcome to use the small tubes of blood from study par- stored in BHP freezers. Some are sent and customize the code for ticipants. The Lab Assistant, viewing a to the Essex Lab in Boston for genetic their studies. screen with the data just downloaded analysis. from the RA’s laptop, reconciles the tubes with the data and prints a barcode The time difference between Gaborone label for each tube. and Boston is six hours. When she ar- rives at her Harvard office, Nealia Khan, The lab is equipped with a centrifuge to the BCPP Data Manager, accesses new separate whole blood into buffy coat and data on the BHP server in Gaborone. large geographic area. In the past, it took plasma. Erik’s system indicates which Data is encrypted at this and every other months or years for a study of this mag- tubes need processing and generates a step of the process. Nealia cleans the data nitude to have data ready for publica- packing list for loading tubes into a cool and creates reports for conference calls. tion. The BCPP does it in days. “As we box. Several times a week, a driver picks shift from paper-based to electronic col- up the cool box and delivers it to BHP “That means that when we have weekly lection, that interval just keeps shrink- headquarters in Gaborone. calls, we have up-to-date information,” ing,” said Erik. said Erik. “On a Wednesday, we have In the middle of the night, when RAs Tuesday night information. That’s how “It’s been extremely important to mod- are hopefully sound asleep, data on the good it is.” ernize data collection, efficiency, and server in the IT trailer is transmitted to quality,” said Max Essex, Senior Princi- a server at BHP headquarters. The next The BCPP data management system pal Investigator of the BCPP and Chair morning, Drs. Unoda Chakalisa and Eti- demonstrates that high-quality research of the Harvard AIDS Initiative and the enne Kadima, the BCPP Study Coordi- data can be collected quickly across a Botswana Harvard Partnership.

FLOW OF BLOOD AND DATA

6 Profile

Erik van Widenfelt

When he first arrived in Botswana, Erik wasn’t an IT guy. After graduating from the University of Michigan with a de- gree in cellular and molecular biology, he joined the Peace Corps in 1986 and taught science and English in Ghanzi, a dusty outpost on the edge of the Kalahari Desert. When his two-year assignment was up, he stayed on. “I wanted to continue teaching, to grow the reading program I had started, and Nealia Khan to give the school a bit of continuity,” said Erik, who comes from a family of teachers. He taught kids in their early What is Data Cleaning? teens. Many had trouble with basic read- socially acceptable answers. ing skills. The school library was full of Data cleaning is the process of de- books— John Grisham novels, old en- tecting and correcting bad records It’s not the RA’s job to question a cyclopedias, books in Afrikaans—books in a data file. Much of the early participant’s memory or integrity. with little relevance to his students’ lives. BCPP data came from a baseline household questionnaire. Research Well-designed questionnaires in- Erik worked with the headmaster to pur- Assistants (RAs) interviewed thou- clude redundancy to help verify chase books his students could read and sands of study participants and re- responses. The same question may enjoy. “I developed in them the habit to corded their answers on laptops. be asked several times in different read a book successfully, even if it was The use of customized software ways. For example, if a participant easy, and let them work their way up to minimized data entry errors. says she has never been tested for more challenging books.” HIV, yet has her own prescription As data was collected, Nealia Khan, for HIV drugs, then a “logic-check” He taught for another three years, then the BCPP Data Manager, cleaned it would flag her answers. moved to the capital, Gaborone, where using the following steps: he worked for the Botswana Book Cen- Derive variables from raw data. tre, developing software for their book Confirm that data exists and con- ordering and inventory systems. Though forms to expectations. A variable is derived using ques- Erik had learned some programming at tionaire answers and other avail- Does the file contain information in able information. the University of Michigan, his comput- the right format with the approxi- er skills are largely self-taught. mate number of records expect- Take ART status—whether a par- He got married and started a family. His ed? For example, does the batch ticipant with HIV is on antiretrovi- oldest son is named Oarabile, which in of data contain information from ral treatment (ART). If a participant Setswana means He has answered; his several hundred study participants says he’s not on ART, but records brother is Moratiwa, meaning He is loved. from a pair of villages in Botswana? at the local clinic show he once had a prescription for ART and a sup- Reconcile discrepancies in an- A few years later, Erik left the bookstore pressed viral load, it’s possible he swers from study participants. to start his own computer business. In stopped taking his medication. The 2000, the Botswana Harvard AIDS In- For various reasons, study par- team investigates further to deter- stitute Partnership (BHP) hired him as ticipants don’t always tell the mine if he’s a treatment defaulter. a consultant. AIDS was on the rise in truth. They may misunderstand southern Africa. People at many of the a question, misremember past After the data has been cleaned, companies Erik worked with were get- events, or feel obliged to offer investigators begin their analysis. ting sick and dying. In 2001, as the BHP began their first large clinical trials, Erik (continues on back page)

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HAI is dedicated to research and education to end the AIDS epidemic in Africa and developing countries. For over 25 years, HAI has been at the forefront of HIV/AIDS laboratory research, clinical trials, education, and leadership.

spotlispring g ht 2016

Answering important questions often necessitates the creation of new tools and systems. Because they work at the forefront of AIDS research, HAI scientists must invent and adapt and repurpose on a daily basis. This issue of Spotlight delves into the infrastructure behind the studies, as well as notable findings from the Botswana Combination Prevention Project.

(continued from page 7) was offered a full-time position. Since to be productive with limited resources.” then, he’s been responsible for coordinat- ing all research data. Because all BHP research projects de- pend on access to data, Erik’s job can be “He understands what’s needed for large exhausting, with long and stressful days. field studies when you don’t have ac- To balance work, he plays drums, often cess to internet or electricity,” said Max performing with bands around Gabo- Essex, who has high praise for the data rone. “Music requires thought and ef- management system Erik created for the fort, but is different enough from my BCPP. “He understands the importance work that it’s a wonderful distraction,” of collecting high-quality data and then he said. “No circuits or software in a assuring that it’s accessible and analyz- drum set!” able by a variety of people with varying degrees of expertise.” Yet there are similarities between com- puter science and percussion. As Erik ex- “I’m grateful to Max for giving me a lot of plained, “Data management, like drum- space and support to run with my ideas,” ming, is a supportive activity. People don’t said Erik. “Peace Corps was similar. We usually appreciate how important these were expected to be creative and trusted efforts are until something goes wrong.” Erik van Widenfelt