This blog is adapted and cross-posted from HIV.gov. 

On March 6 as the 2024 Conference on Retroviruses and Opportunistic Infections (CROI) was winding down, HIV.gov spoke with Carl Dieffenbach, Ph.D., director of NIAID's Division of AIDS, about highlights of long-acting HIV treatment research discussed at the conference. He spoke with Brian Minalga, M.S.W., deputy director of the NIH-supported Office of HIV/AIDS Network Coordination. Watch their conversation below:

Research Suggests Possible Expanded Options for Long-Acting HIV Treatment

Dr. Dieffenbach highlighted findings from several clinical trials and a plenary session presented at CROI about current and future options for long-acting antiretroviral treatment (ART) for HIV.

First, he discussed a NIAID-supported randomized clinical trial that found that long-acting ART with cabotegravir and rilpivirine was superior in suppressing HIV replication compared to daily oral ART in adults who had been unable to maintain viral suppression through an oral daily regimen. The LATITUDE study enrolled participants in 31 sites in the United States. Last month, the trial’s Data and Safety Monitoring Board conducted a planned review of interim data and recommended halting randomization and offering all eligible study participants long-acting ART based on its observed superior viral suppression of HIV. At CROI, study leaders reported that the interim analysis of data from 294 participants showed that the chance of experiencing unsuppressed HIV was 7% among people taking long-acting ART compared to 25% among those taking daily oral ART. The likelihood of discontinuing the assigned regimen due to adverse events or experiencing unsuppressed HIV was 10% among people taking long-acting ART compared to 26% among those taking daily ART. These findings were statistically significant. Dr. Dieffenbach observed that these results may support expanding the use of long-acting ART among a broader population. Read the study abstract. Read more in this NIAID news release.

Another ongoing clinical trial reported initial findings on the safety of the same long-acting injectable treatment regimen for adolescents with HIV with a suppressed viral load. The NIH-supported MOCHA study enrolled participants aged 12 to 17 who were virally suppressed in Botswana, South Africa, Thailand, Uganda, and the United States. In what he characterized as very encouraging results, Aditya Gaur, M.D. of St. Jude Children's Research Hospital, one of the trial’s co-chairs, reported that after the first six months all participants remained virally suppressed, and the level of the ART in their systems was comparable to what has been shown as efficacious in adult studies of the same drug. He also reported that, while about one-third of the participants reported an injection-site reaction, there were no surprising or unanticipated adverse events. These data support the use of cabotegravir and rilpivirine in virally suppressed adolescents, according to Dr. Gaur and colleagues. Dr. Dieffenbach noted that NIH will continue to support safety and dosing studies to determine the proper doses for adolescents and that these studies could eventually expand access to this long-acting HIV treatment to more people.
Read the abstract. Read NIAID’s news release about the study.

In addition, Dr. Dieffenbach mentioned an industry-sponsored Phase 2 trial that presented 24-week results of an oral once-weekly investigational combination of two drugs (islatravir and lenacapavir). Researchers reported that the investigational combination maintained a high level of viral suppression among study participants and was well tolerated. The study will continue to gather data and suggests that a weekly oral HIV treatment regimen could someday be possible. Read the abstract.

Finally, Dr. Dieffenbach discussed Wednesday’s plenary session by Charles Flexner, M.D. of The Johns Hopkins University School of Medicine, which was titled “The End of Oral? How Long-Acting Formulations Are Changing the Management of Infectious Diseases.” In his big picture, future-focused presentation exploring long-acting drug delivery, Dr. Flexner observed that there is a need for HIV products with less frequent dosing, greater convenience, and greater likelihood of viral suppression, as well as for the prevention and treatment of other diseases, including tuberculosis, malaria, and viral hepatitis. He discussed recent advances in formulation science that are going to help make available better replacements for daily oral drugs for HIV and many other infectious diseases. Dr. Dieffenbach underscored Dr. Flexner’s point that these novel products must be developed with access and equity in mind so that people who need them, especially in resource-limited settings, can use them.

Key Takeaways

Reflecting on key takeaways from the entire conference, both Dr. Dieffenbach and Brian pointed to the importance of partnership between the HIV community and scientists in all aspects of HIV research, a theme also discussed in HIV.gov’s conversation with Dr. LaRon Nelson from the conference. In terms of research highlights, Dr. Dieffenbach pointed to the results reported from the IMPAACT P1115 study in which several children who started HIV treatment within hours of birth later surpassed a year of HIV remission after a treatment pause. (See HIV.gov’s interview with Dr. Deborah Persaud about this study.) He also noted that the additional data accumulating on the effectiveness of Doxy-PEP is encouraging and will hopefully soon be reflected in clinical guidelines that help to reduce the incidence of syphilis, chlamydia, and gonorrhea in men who have sex with men and transgender women.

Catch Up on More HIV Research Updates

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s blog and social media channels.

About CROI

More than 3,600 HIV and infectious disease researchers from 73 countries gathered in Denver and virtually from March 3-6 this year for CROI, an annual scientific meeting on the latest research that can help accelerate global progress in the response to HIV and other infectious diseases, including STIs and viral hepatitis. Over 1,000 summaries of original research were presented. Visit the conference Web site for more information. Session webcasts and more information will be published there for public access.

This blog is adapted and cross-posted from HIV.gov. 

On the final day of the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), HIV.gov spoke with Deborah Persaud, M.D., professor of Pediatrics at the Johns Hopkins University School of Medicine and director of the Division of Pediatric Infectious Diseases at Johns Hopkins Children's Center, who reported findings from a study about whether very early initiation of antiretroviral therapy (ART) may limit the establishment of HIV reservoirs in newborns, potentially enabling ART-free remission. Dr. Persaud spoke with Catey Laube of NIAID’s Office of Communications and Government Relations. Watch their conversation below:

Four Children Achieve ART-free HIV Remission

The study Dr. Persaud presented at CROI began 10 years ago. HIV.gov spoke to Dr. Persaud at CROI 2013 when she presented the case of an infant born with HIV in Mississippi who initiated treatment at 30 hours of life, was taken off their ART at 18 months of age and remained in remission with no evidence of detectable HIV for 27 months. This was an uncommon finding because, typically, an interruption in treatment will lead to rapid resumption of HIV replication and detectable virus in the blood within weeks. Dr. Persaud and colleagues then began the NIH-supported study she reported on at CROI this year to carefully replicate that result in a research setting to determine whether the ART-free remission the “Mississippi baby” experienced was due to the very early start of HIV treatment within hours after birth and could be effective in other children.

Dr. Persaud reported on the experience of six children, all aged 5 years, who met multiple criteria to be eligible for a closely monitored ART interruption and whose parents consented. Four of the six children experienced HIV remission, defined as the absence of evidence of replicating virus for at least 48 weeks off ART. One of them had detectable HIV after 80 weeks. Two children did not experience remission, and their HIV became detectable within a few weeks after ART interruption. Children whose HIV became detectable resumed ART. The other three remain in remission. These promising findings will be followed by additional research to better understand the biological process that enabled the children to experience HIV remission off ART and to study early ART with newer drug regimens than were used in this initial study. Dr. Persaud cautioned that much more evidence is needed before this approach could be possible outside of the strictly monitored research setting. Read the study abstract. Read NIAID’s summary of the study findings.

Other Studies of Interest Presented on Wednesday

Some of the other NIH-supported research presented at CROI included a study that identified sex-based differences in latent HIV reservoirs, highlighting unique aspects of reservoirs in women. The findings point to the importance of including cisgender women in HIV cure studies. Read the study abstract. Another showed that a novel hepatitis B vaccine achieved up to 99% protection in people with HIV who had previously not responded to conventional hepatitis B vaccines. Read the study abstract.

Catch Up on More HIV Research Updates

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s social media channels and recapped here on the blog this week and next week.

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).

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).