Shahin Lockman, MD, MSc: Collaborating on Cutting-Edge Research in Botswana
On Thanksgiving Day, Shahin Lockman, MD, MSc, of the Division of Infectious Diseases, received a WhatsApp message from her colleague in Botswana. The message, from Sikhulile Moyo, MSc, MPH, PhD, laboratory director at the Botswana-Harvard AIDS Institute Partnership (BHP) in Gaborone, the nation’s capital, contained screenshots of mutations found in an unnamed SARS-CoV-2 variant. Both Moyo and Lockman knew that its mutations were cause for concern and urgency.
One week earlier, Moyo’s team had sequenced what is now known as the Omicron variant and subsequently shared the full sequence publicly, followed shortly by South Africa. Collaboration and preparation were key to its discovery; the team that identified the new strain had already been conducting genomic SARS-CoV-2 surveillance in Botswana for months. The day after Lockman and Moyo exchanged messages, the World Health Organization (WHO) designated Omicron a “variant of concern.” Little is known about the variant, including its severity and transmissibility, and whether currently available vaccines will provide adequate protection against it. However, Lockman pinpointed one positive of Omicron: it has shed light on the cutting-edge work being done in laboratories like Moyo’s.
“The fact that we have a variant with the potential to escape immunity is not surprising, and I would be shocked if this is the last variant we see,” said Lockman. “What’s amazing is the near real-time sequencing available in Botswana. Without that capacity in the region, weeks could have passed before this variant would have been detected.” Lockman also points to the urgency of equitable global access to SARS-CoV-2 vaccines and therapeutics.
A Process Decades in the Making
Lockman has been a long-time associate with BHP, a collaboration between Botswana’s Ministry of Health and the Harvard T.H. Chan School of Public Health AIDS Initiative. Her position in the Brigham’s Division of Infectious Diseases has allowed her to spend ample time in Botswana, advocating for HIV-positive pregnant and breastfeeding women and training scientists from southern Africa to serve their region. “You cannot build high quality genomic sequencing capacity overnight.” said Lockman. “And it’s not simply about having the right machine in the lab. It’s about having expert scientists, trained staff, supply chains to order reagents and a quality assurance team.” Many other U.S. scientists, such as Scott Dryden-Peterson, MD, also of the Brigham’s Division of Infectious Diseases, and African scientists collaborate at BHP.
While BHP has made headlines for its role in identifying Omicron, the institute usually focuses on researching and remedying HIV in the region — the reason for its state-of-the-art sequencing technology.
“Identifying Omicron in this lab was a result of a 20-year process of collaborative growth, training, and capacity-building of and by African scientists,” she said.
Lockman first traveled to Botswana in 1996, where she researched tuberculosis (TB) with the Botswana Ministry of Health and the U.S. Centers for Disease Control and Prevention. She soon realized that HIV was raging through the region unidentified — 90 percent of inpatients with TB also had HIV.
“At the time, there was terrible stigma surrounding the disease, and almost no HIV testing. Absolutely no treatment, nothing,” said Lockman. “It was an all-hands-on deck situation. Any tiny contribution we could make was worth it, because it was clear that HIV would be devastating to the region.”
After her initial stint in Botswana ended in 1998, she returned as a fellow with the Brigham’s Division of Infectious Diseases.
“I came to the Brigham for its outstanding clinical infectious diseases training in order to return to Africa to work with colleagues there on HIV, and the education I received was unparalleled,” said Lockman. “The excellent quality of patient care, the teamwork and the communication are what keeps many of us working with the hospital.”
An Error of Omission: Excluding Pregnant Women from HIV Drug Trials
While researching HIV in Botswana, Lockman noticed that pregnant and breastfeeding women were usually left out of clinical trials for HIV medications — a purposeful error of omission.
“When you do not study new drugs in pregnant or breastfeeding women, the drugs that are used may end up being less safe, less well-tolerated, less effective and worse for the mother’s health, or women may avoid taking medications during pregnancy that they need,” said Lockman. “The mother’s health is often considered secondary, but her health matters in and of itself, and her health will also have effects on the outcomes for a baby.”
In the past, pregnant and breastfeeding women have been prescribed older, less well-researched drugs to combat cases of HIV, which may have grave consequences on fetal health. For example, nevirapine was once used globally to treat HIV-positive pregnant women, but further testing showed it led to a heightened risk for stillbirth. Lopinavir/ritonavir, a boosted protease inhibitor, was once considered a preferred HIV treatment in pregnancy. But when studied more closely, the drug was shown to cause higher rates of pre-term birth and low birth weight which are especially concerning outcomes in low-resource settings.
“It is paternalistic,” said Lockman describing the routine exclusion of pregnant and breastfeeding women from HIV clinical trials. “Women with HIV have protested at meetings and have said, ‘We are not just vessels for babies, and we are suffering using older regimens. It is not right to keep us from choosing whether to take part in studies or whether to take certain drugs.’”
Across-the-Board Improvements in Clinical Trials
Besides HIV treatments, most other drugs are not tested on pregnant or breastfeeding women during clinical trials. Even though scientists estimate that 64 to 90 percent of pregnant or breastfeeding women use prescribed or over-the-counter medications, a study found that about three quarters of drugs approved by the U.S. Food & Drug Administration (FDA) between 2000 and 2010 had no pregnancy safety data, and 98 percent had unknown teratogenic risk.
“Not every new or existing drug needs to be studied in pregnancy,” said Lockman. “That is not feasible, ethical or necessary. But when we are talking about drugs or vaccines that will be used by many young women, it is important and necessary to include pregnant women in trials.” Lockman noted that pregnant and breastfeeding women were not included in trials of vaccines for SARS-CoV-2, initially leaving women on their own to make decisions. (Studies after the vaccines were made more widely available have found that they are safe for people who are pregnant or breastfeeding.)
“Clinical outcomes of SARS-CoV-2 are significantly worse for pregnant women than those who are not pregnant, and SARS-CoV-2 infection in pregnancy also increases the risk of some pregnancy complications. But since pregnant and breastfeeding women were excluded from vaccine trials, pregnant women were left to bear the initial risk of taking new vaccines without monitoring and support that would be provided through a trial,” said Lockman. “Many pregnant women chose not to get vaccinated and are still hesitant even though the vaccines have been shown to be safe. This often leads to bad consequences for women and their babies, as they don’t have the extra protection provided by a vaccine if they’re infected with SARS-CoV-2.”
Looking to the Future: Mentoring Southern African Scientists
Lockman and other researchers at BHP have made great inroads to improving health care in Botswana, but she is most looking forward to what is still to come.
“The most exciting part of our work now is mentoring and training,” said Lockman, mentioning she has received grants to support nearly 20 “bright young researchers and scientists,” most from southern Africa, at various stages in their careers. “As we move forward, I see those of us from the U.S. taking a back seat, as scientists from southern Africa lead innovation in HIV treatment and other fields.”
Lockman also mentioned developing collaborative networks across the continent and world as a goal of the BHP. “We want to work with others beyond the borders of Botswana,” she said, mentioning collaboration on SARS-CoV-2 with the Africa Health Research Institute in Durban, South Africa as one example of regional collaboration.
“The Botswana Harvard Partnership is a center of excellence for clinical trials,” added Lockman. “There are people who have trained here that go on to leadership positions in public health or research in Botswana or elsewhere, disseminating knowledge and experience throughout the region and world.”
“Brilliant researchers are everywhere,” concluded Lockman. “Given the opportunity to develop, grow and lead, they make remarkable contributions.”
The WHO releases a call to action for HIV drug developers
On Dec. 1, World AIDS Day, Lockman collaborated with high-level colleagues and bioethicists from the WHO, the National Institutes of Health IMPAACT network, the FDA and European Medicines Agency, community members, industry representatives and others to publish a call to action entitled “Research for informed choices: Accelerating the study of new drugs for HIV in pregnant and breastfeeding women.” This calls for steps that can improve timely access to dosing and safety data for pregnant and breastfeeding women, including:
- Completing non-clinical studies earlier in drug development,
- Obtaining pregnancy pharmacokinetics data for new drugs,
- Giving women who become pregnant while taking part in clinical trials the opportunity to consent to stay in the trial, if certain conditions are met,
- Conducting dedicated, timely pregnancy safety studies for priority drugs and
- Developing comprehensive strategic surveillance programs for drug safety following clinical trials.
The call’s full text can be found here.