NIH Trial Gives People with Lupus Data to Inform Treatment Decisions 

In people with a form of lupus called systemic lupus erythematosus (SLE), the risk for a severe flare-up of disease was low for both individuals who tapered off long-term immunosuppressive therapy and those who remained on it, a clinical trial has found. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, sponsored and funded the trial. The findings were reported today in the journal The Lancet Rheumatology.

SLE is a chronic autoimmune disease in which the immune system attacks healthy tissues and organs.  An estimated 450,000 people in the United States have the disease. Medications that doctors prescribe for people with SLE help suppress or tamp down their overactive immune systems. One of the most prescribed immunosuppressants for SLE, mycophenolate mofetil or MMF, effectively treats moderate and severe forms of the disease but also increases the risk of infections, cancers, severe birth defects, miscarriage, and impaired responses to vaccines when the drug is used long-term. Tapering off MMF once SLE symptoms subside reduces these side effects but could risk exposing the individual to a disease flare with the potential to cause a range of symptoms, including fatigue, rash, arthritis, and internal organ damage. 

Until today's report, little evidence existed to help people with SLE and their physicians understand the likelihood of a flare after tapering off MMF. The new findings will help people with SLE make informed decisions about withdrawing treatment based on their personal circumstances and risk tolerance. 

The NIAID-funded Autoimmunity Centers of Excellence network conducted the trial under the leadership of Judith A. James, M.D., Ph.D., and Eliza F. Chakravarty, M.D. Dr. James is professor and chair of the Arthritis & Clinical Immunology Research Program at the Oklahoma Medical Research Foundation. Dr. Chakravarty was an associate professor in the same program during the study. The National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of NIH, supports the database for the biological samples processed during the trial.

The trial involved 102 people with SLE ages 18 to 70 whose symptoms had subsided after treatment with MMF. Participants had been taking the drug for an average of 6.6 years. Eighty-four percent of participants were female, reflecting the disproportionate prevalence of lupus in women. Seventy-six percent of participants had a history of lupus nephritis—kidney inflammation that can harm kidney function. Forty-one percent of participants were Black, 40% were White, 21% were Hispanic/Latino, 10% were Asian, and 2% were American Indian/Alaska Native.

The study team assigned participants at random to either taper off MMF over a 12-week period or to remain on their baseline MMF dose. Investigators followed the participants for 60 weeks to monitor if and when they experienced a flare severe or persistent enough to require either new immunosuppressive therapy or higher doses of it. 

By week 60, 9 of 51 participants in the MMF withdrawal group and 5 of 49 in the MMF maintenance group had severe or persistent flares requiring new or increased immunosuppressive therapy. The estimated risk of such flares by week 60—a metric that reflected both occurrence and timing—was up to 18% in the withdrawal group and 11% in the maintenance group. The investigators also looked at five different measures of lupus flares and found that treatment withdrawal consistently led to a 6% to 8% increase in the risk for flares. For participants with a history of kidney disease, the increase in risk was higher, at 14%. One benefit of MMF withdrawal, however, was a reduction in infections. Forty-six percent of the withdrawal group had at least one infection compared with 64% of the maintenance group. 

This study is the first clinical trial of therapy withdrawal in people with SLE who no longer experience symptoms on long-term MMF, according to the researchers. Their findings suggest that MMF may be safely withdrawn in many people with stable SLE, they write, but larger studies and longer follow-up are still needed.

Reference: EF Chakravarty, et al. Mycophenolate mofetil withdrawal in systemic lupus erythematosus patients. The Lancet Rheumatology DOI: 10.1016/S2665-9913(23)00320-X (2024).

Certain antibodies that pass through the placenta are associated with the improved survival of infants who acquire HIV through nursing, according to findings published in the journal, Open Forum Infectious Diseases. The Kenya-based study observed that preexisting antibodies that target a specific region of Env—a protein on HIV’s surface—were correlated with delayed HIV acquisition in infants exposed to the virus as well as a lower amount of virus circulating in the blood of infants who acquired HIV. Both of these conditions are known to help extend survival in infants with HIV.

Env has long been a target of potential HIV vaccines and monoclonal antibodies. It is present on HIV’s surface and widely understood to play a key role alerting immune cells to the presence of HIV in the body. In this study, antibodies that specifically targeted constant region 5 (C5) of Env were observed to have a positive correlation with infant survival, while there was not a consistent correlation observed between infant survival and antibody responses to other Env regions studied. 

“Some areas of Env are easier for the immune system to ‘see’ than others, and antibodies to only certain parts of Env may be protective. The study found that the C5 region of Env may be a potential protective target for biomedical HIV interventions for infants,” said Dwight E. Yin, M.D., Ph.D., medical officer in the Division of AIDS at the National Institute of Allergy and Infectious Diseases, which funded the study. 

The role of preexisting antibodies in infant outcomes can best be evaluated in cases where infants are HIV negative at birth but are later exposed to HIV through nursing, allowing antibodies to be measured around the time of HIV exposure. In this study, researchers used blood plasma samples that were taken from two cohorts of infants and birth parents. Both cohorts participated in research before effective antiretroviral therapy to prevent vertical HIV transmission was available in Kenya. Samples were analyzed for infants that were HIV-free at birth, had a nursing history of three or more months or nursed until the time of HIV acquisition, and for whom a plasma sample was available from the first week of life, when preexisting antibodies would be measurable. Key findings included the following:

• In the first cohort, 21 infants acquired HIV during the study while 51 did not. Of the 21 infants living with HIV (ILWH), 13 survived until age 2.
• In the second cohort, 15 of the 86 infants acquired HIV while 72 did not. Of the 15 ILWH, eight survived the 1 to 2-year follow-up period.
• C5-specific antibodies were detected in greater numbers within plasma samples of surviving infants; higher numbers of C5-specific antibodies were also associated with lower viral load set point and delayed HIV acquisition in both cohorts.

“These findings reinforce that not all babies exposed to HIV acquire the virus and of those who do, not all progress to death, even over an extended period of observation,” said Ruth Nduati, M.B.Ch.B., M. Med., M.P.H., a pediatrician in the Department of Paediatrics and Child Health at the University of Nairobi, a paper co-author and a lead investigator of a study cohort called the Nairobi Breastfeeding Trial. “We know that mothers provide passive immunity to their babies, and this is an important factor in protecting the infant from infections and, in the case of HIV, moderating the course of illness.” 

The study sheds light on the possible role of preexisting antibodies in determining infant outcomes while highlighting the need for further studies to determine whether such antibodies can inform preventive or therapeutic strategies for HIV.

Reference: Yaffe, ZA et al. Passively Acquired Constant Region 5-Specific Antibodies Associated with Improved Survival in Infants Who Acquire Human Immunodeficiency Virus. Open Forum Infectious Diseases. DOI: 10.1093/ofid/ofad316 (2023).

Following a peak in the summer of 2022, new infections in the mpox clade IIb outbreak have decreased, due in part to the rapid availability and uptake of vaccines and other preventive measures. However, mpox remains a health threat, and no treatment has been proven safe and effective for people experiencing mpox disease.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, launched the STOMP trial to determine whether the antiviral drug tecovirimat can safely and effectively treat mpox. Tecovirimat, also known as TPOXX, was initially developed and approved by the Food and Drug Administration to treat smallpox—a species of virus closely related to mpox—but the drug’s safety and efficacy as an mpox treatment has not been established. The STOMP trial is a phase 3 study that aims to enroll about 500 people—a process that may require considerable time while mpox burden is low in study countries. NIAID continues to prioritize this study even while case counts are low.

VIDEO: Cyrus Javan of NIAID’s Division of AIDS explains the importance of the STOMP trial (audio description version here):

The STOMP trial was designed to be as inclusive as possible to ensure study results provide information on how tecovirimat works in the diverse populations affected by mpox. The trial is enrolling adults and children of all races and sexes, people with HIV, and pregnant and lactating people across 60 sites in the United States and Mexico, with an option for remote enrollment from other U.S. locations. More sites are expected to open in East Asia and South America.

The mpox virus has been endemic—occurring regularly—in west, central and east Africa since the first case of human mpox disease was identified in 1970. Mpox can cause flu-like symptoms and painful blisters or sores on the skin. People who acquire mpox tend to clear the infection on their own, but the virus can cause serious disease in children, pregnant people, and other people with compromised immune systems, including individuals with advanced HIV disease. Rare but serious complications of mpox include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

Completing the STOMP trial is essential, not only to evaluate a therapeutic option for the current mpox outbreak, but also to guide preparation for future outbreaks and provide evidence that could inform medical practice in historically endemic countries. The STOMP trial is sponsored by NIAID and led by the NIAID-funded Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG).

Beyond STOMP, NIAID is co-sponsoring the PALM007 trial of tecovirimat as treatment for clade I mpox in the Democratic Republic of the Congo (DRC) with the DRC’s National Institute of Biomedical Research. PALM007 is actively enrolling. In addition, NIAID is sponsoring an immunogenicity study of the JYNNEOS preventive vaccine, which has completed enrollment and is expected to report initial results in 2024. More information about these studies, including enrollment in STOMP and PALM007, is available here:

STOMP tecovirimat treatment study 
PALM007 tecovirimat treatment study
JYNNEOS vaccine study

NIAID-Funded Study Traces Evolution of Malaria Drug Resistance in E. Africa – Emergence of Artemisinin Partial Resistance Mutations Found Across Uganda

Emerging resistance to common malaria treatments in Uganda could be connected to inconsistent use of measures to control mosquito populations, according to new findings published in the New England Journal of Medicine. The trend is worrisome, the NIAID-funded scientists state, because resistance mutations they tracked are taking root and spreading. Researchers at the University of California at San Francisco (UCSF), funded in part by NIAID’s International Centers of Excellence for Malaria Research program, led the international collaboration.

Malaria is one of the most common and serious infectious diseases. The World Health Organization (WHO) estimates that about half of the world’s population is at risk of getting malaria, which is caused primarily by Plasmodium falciparum parasites spread through the bites of female Anopheles mosquitos. In 2021, WHO estimated that about 247 million people contracted malaria in 85 countries; about 619,000 people died. About 95% of cases and deaths were in Africa.

For decades a combination of measures has resulted in effective malaria control in Africa: preventing malaria transmission with bed nets treated with insecticides; spraying insecticides indoors; treating malaria with artemisinin-based combination medicines; and preventing malaria with other drugs.

Artemisinins – originally extracted from the sweet wormwood plant, but also now available synthetically – rapidly eliminate malaria parasites from the bloodstream. They are used in combination with other longer-lasting drugs to effectively treat malaria. Beginning in 2008, however, studies in Southeast Asia identified poor results from artemisinins and eventually from artemisinin-based combination malaria treatments. Scientists soon found the primary reason – a protein (PfK13) in P. falciparum had developed mutations that made it partially resistant to artemisinins.

Since then, scientists in Africa have watched for the same mutations to emerge. The NEJM study identified five of these mutations, each of which may lead to partial resistance, that have emerged in different parts of Uganda. Their work used data from malaria cases and annual patient surveillance throughout Uganda between 2014 and 2022.

They found that two of the five key mutations appeared in far northern Uganda in 2016-17. The mutations then spread across much of northern Uganda and nearby regions, appearing in up to 54% of cases in one district. The other three key mutations emerged in western Uganda in about 2021-22, with prevalence up to 20% to 40% in different districts.

The study notes that in parts of Uganda where indoor spraying stopped between 2014 and 2018, cases of malaria quickly surged. Likewise, the emergence of any of the five key resistance mutations also surged, suggesting that the emergence was aided by malaria epidemics in populations where malaria had previously been well-controlled.

The researchers have different theories about how and why the mutations emerged. Their leading hypothesis, which they have targeted for more study, is that in populations with a low level of immunity to malaria, an epidemic increases the likelihood that resistance will emerge. “In northern Uganda,” the study states, “this scenario occurred after the withdrawal of effective malaria control, leading to high incidence of malaria in a population with relatively low antimalarial immunity.” They also suggest that fluctuating malaria transmission contributed to the emergence of drug resistance in southwestern Uganda. They emphasize the importance of maintaining malaria control interventions, with attention to malaria outbreaks, to decrease the likelihood of emergence or spread of drug resistance.

Others working on the project with UCSF include scientists from the Infectious Diseases Research Collaboration and Makerere University in Uganda; the University of Tubingen in Germany; Brown University in Rhode Island; and Dominican University of California.

Reference: 

M Conrad et al. Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda. New England Journal of Medicine DOI: 10.1056/NEJMoa2211803 (2023).