Switching to an antiretroviral therapy (ART) regimen containing the drug dolutegravir was associated with a significant temporary increase in reservoirs of latent HIV, according to a new analysis from a study in Uganda. HIV reservoirs are cells where HIV lies dormant and cannot be reached by the immune system or ART. They are central to HIV’s persistence, preventing current treatments from clearing the virus from the body. The findings were published today in eBioMedicine.

When taken as prescribed, ART can stop HIV from replicating. The different classes of available antiretroviral drugs (ARVs) interrupt different stages of HIV replication. People are often prescribed drug regimens composed of multiple drug classes to increase the likelihood that ART will fully suppress HIV replication. In 2018, many countries began using dolutegravir-based ART regimens following studies that showed the drug had higher efficacy and fewer side effects than the drugs that had been in use previously. Uganda was among these countries and recommended dolutegravir together with the ARVs tenofovir and lamivudine for all people whose HIV was treatable with those drugs.

In 2015, NIH scientists and researchers from the Rakai Health Sciences Program in Uganda began a longitudinal study of reservoirs among people with HIV in the Rakai and Kyotera Districts in Uganda. Study participants were people whose HIV was suppressed by ART and had agreed to provide blood samples and receive a routine physical examination annually. People meeting study entry criteria continued to enroll each year. As part of this study, the team examined whether the introduction of dolutegravir-based regimens in 2018 had any effect on the makeup of HIV reservoirs in study participants. At the time of the published analysis, 63% of participants were female. The study observed that HIV reservoir size was generally decreasing as participants remained virally suppressed for longer periods. In the analysis of samples provided post-dolutegravir introduction, they observed a surprising 1.7-fold average increase in HIV reservoir size above pre-dolutegravir levels, which lasted for approximately a year, then returned to normal. This effect was consistent across the majority of study participants regardless of how long they had been living with HIV. 

According to the study authors, no other study has found significant differences in HIV reservoir characteristics due to ART regimen changes, but previous research has identified changes in immune characteristics and cardiovascular disease risk, as well as other effects in the period after dolutegravir initiation, suggesting the body goes through a period of adjustment when switching to use the new drug. The authors state that it is important to explore whether other populations experience the same temporary reservoir increase post-dolutegravir initiation, and that more research is needed to understand the mechanism causing the increase, especially if it is starting dolutegravir or stopping the previous ARV. They further suggest that these findings may inform HIV cure research, including approaches referred to as “Shock and Kill” that attempt to stimulate HIV reservoirs to resume activity, then promptly remove them. The authors did not observe any negative clinical ramifications, such as loss of viral control, associated with this finding.  

Most HIV reservoir research has been conducted among predominantly male study populations in Europe and North America, unlike the primarily female participants in this study. The authors highlight the importance of exploring sex-based differences in HIV reservoir characteristics and the inclusion of representative populations in HIV studies.

This research was conducted by NIAID, Western University, and the Rakai Health Sciences Program and with co-funding from other NIH institutes, the Gilead HIV Cure Grants Program, the Canadian Institutes of Health Research, and the Ontario Genomics-Canadian Statistical Sciences Institute.

Reference:

RC Ferreira, et al., Temporary increase in circulating replication-competent latent HIV-infected resting CD4+ T cells after switch to an integrase inhibitor based antiretroviral regimen. eBioMedicine DOI: 10.1016/j.ebiom.2024.105040 (2024)

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.

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

During the first full day of presentations at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI), HIV.gov spoke with Carl Dieffenbach, Ph.D., director of NIAID’s Division of AIDS, about research presented on Doxy-PEP for sexually transmitted infections (STIs) and HIV vaccines. He spoke with Louis Shackelford of the HIV Vaccine Trials Network. Watch their conversation.

Louis also spoke with LaRon Nelson, Ph.D., R.N., F.N.P., F.N.A.P., F.N.Y.A.M., F.A.A., about community-engaged research, HIV prevention at CROI, and a new study (HPTN 096) he is leading to reduce HIV rates among Black men who have sex with men (inclusive of cisgender and transgender men) in the southern United States. Dr. Nelson is a professor and the associate dean at the Yale School of Nursing. Watch their conversation.

Insights from Doxy-PEP Use in Real World Settings

At last year’s CROI, researchers presented results from an NIH-supported study on using a preventive dose of the antibiotic doxycycline as post-exposure prophylaxis within 72 hours after condomless sex to prevent bacterial STIs, an approach that has become known as Doxy-PEP. (View last year’s Doxy-PEP discussion with Dr. Dieffenbach.) Here at CROI 2024, Dr. Annie Luetkemeyer of the University of California, San Francisco, shared additional findings from the open-label extension of that original study, which found sustained reduction of bacterial STIs among men who have sex with men and transgender women living with HIV or on PrEP in Seattle and San Francisco. The San Francisco AIDS Foundation (SFAF) was one of the first organizations in the United States to roll out Doxy-PEP, beginning in late 2022 when it was offered to all active PrEP clients at their visits at the Magnet clinic. SFAF medical director Dr. Hyman Scott reported that there was high uptake among clients and that bacterial STIs decreased by nearly 60% in less than a year at SFAF’s clinic. The decline was highest for syphilis (78%) and chlamydia (67%). 

The San Francisco Department of Public Health (SFDPH) presented the first findings to measure the effect of Doxy-PEP at the population level. Their analysis, presented by epidemiologist Madeline Sankaran, showed a substantial and sustained decline in the number of chlamydia and early syphilis infections in San Francisco among men who have sex with men and transgender women over the 13 months after the Department released guidelines for the use of Doxy-PEP. As in the other studies presented, SFDPH did not see corresponding significant declines in gonorrhea. Doxy-PEP is not recommended for cis-gender women because there is not yet evidence to suggest it is effective for them.

HIV Vaccine Trials Continue

Dr. Dieffenbach also discussed ongoing research to find a vaccine to prevent HIV, the topic of several presentations at the conference so far. Since there are a number of Phase I HIV vaccine trials currently underway, he and Louis spoke about what those smaller trials do. Then they discussed what some of the HIV vaccine trials currently underway are exploring.

Other Studies of Interest Presented on Monday

Some of the other studies presented centered on broadly neutralizing antibodies (bNAbs), including bNAbs as part of HIV therapy and how different HIV variants can affect bNAb efficacy as a treatment method. A new analysis from the pivotal HVTN 083 study of long-acting PrEP with cabotegravir found no significant risk of hypertension in people using the method, which had been a concern in some previous clinical studies of the same class of antiretroviral drugs.

Community-Engaged Research

The importance and significant benefits of involving community in all aspects of HIV research was the first topic Dr. Nelson and Louis discussed. “If we don’t have community voices or engaged communities, we aren’t going to be asking the right questions or designing the studies in the best ways that will produce the outcome that we need, and we won’t end up with answers that are as relevant as they could be,” Dr. Nelson observed. He pointed to the dapivirine vaginal ring as an example of better outcomes because communities were involved in research. He said he hopes that community engagement in research continues to become more and more common, but it requires that researchers be willing to listen and, when needed, change their plans based on what they hear from community.

HIV Prevention Research at CROI

Dr. Nelson highlighted some of the HIV prevention topics at CROI that have caught his attention, such as increasing equitable use of long-acting injectable forms of HIV PrEP and treatment among different populations and in different countries. Other discussions of interest have included early studies on potentially very long-acting forms of HIV PrEP and exploration of possible dual prevention tools that would provide users with both HIV PrEP and contraception.

HPTN 096 Study

Finally, Dr. Nelson discussed an example of community-informed research that will soon be underway: the NIH-supported study through the HIV Prevention Trials Network (HPTN) known as HPTN 096. It aims to reduce HIV rates among Black men who have sex with men in the southern United States using a strategy developed based on what communities have told Dr. Nelson and colleagues is needed to do so. As a result, the study includes a package of four interventions which simultaneously address social, structural, institutional, and behavioral barriers to HIV prevention and care. HPTN 096 will soon launch in Atlanta, south Florida, Montgomery, Memphis, and Dallas.

More HIV Research Updates to Follow on HIV.gov

HIV.gov will be sharing additional video interviews from CROI 2024 with Dr. Dieffenbach, CDC’s Dr. Jono Mermin and Dr. Robyn Neblett Fanfair, and others. You can find all of them on HIV.gov’s social media channels and recapped here on the blog.

A messenger RNA (mRNA) vaccine designed to prevent human cytomegalovirus (CMV) elicited long-lasting CMV-specific responses from several types of immune cells, outperforming a previous vaccine concept in multiple measures in a NIAID-supported laboratory study. The findings were published in the Journal of Infectious Diseases.

CMV has been present in much of the global population for centuries. Most people with CMV experience no symptoms and are unaware that they are living with the virus, but CMV is dangerous for people with compromised immune systems and for babies. It is the most common infectious cause of birth defects in the United States. When babies acquire CMV through birth it is called congenital CMV, and it affects about 1 out of every 200 children. Of babies with CMV, about 1 in 5 will experience long-term health effects, including hearing or vision loss, developmental and motor delays, seizures, or microcephaly (a small head). Infants born before 30 weeks’ gestational age or with low weight for age that have CMV may be susceptible to additional complications.

There is no preventive vaccine for CMV, and treatment options are limited. An effective CMV vaccine could present needless suffering for millions of babies, and research has been progressing for decades. A recent vaccine candidate was designed to use a laboratory-developed protein from CMV’s surface called glycoprotein B (gB)—known to assist CMV in fusing with and entering human cells—to safely teach the immune system how to respond to CMV exposure without causing disease. The vaccine provided about 50% protection from CMV in Phase 2 trials, but that effect was insufficient for the concept to advance to large efficacy studies. 

A different, mRNA-based, vaccine is now in a Phase 3 efficacy study in cisgender women with no existing CMV infection. The vaccine was designed to instruct cells to produce the gB protein while also producing a combination of five other glycoproteins on CMV’s surface, which like gB are involved in human cell entry.

To better understand how the mRNA vaccine might perform in comparison to gB-based vaccine, researchers examined the immune cells present in blood samples provided by people when they participated in previous studies of each vaccine. The study team performed several assays—laboratory tests—and made the following key observations:

• The mRNA vaccine generated higher levels of antibodies to the five glycoproteins unique to the that vaccine in the form of immunoglobulin G (IgG) antibodies, which are associated with long-term immunity.
• The mRNA vaccine generated more potent signals that the immune system was prepared to deploy antibodies to surround and neutralize—destroy—CMV.
• The gB-based vaccine generated higher levels of IgG antibodies to gB.
• Immune responses to both vaccines were greater in study participants with no existing CMV, but the vaccines still amplified immune system activity in people already living with the virus. 

The authors concluded that the mRNA vaccine concept showed promise for better performance than its predecessor in ongoing clinical studies, of which results are expected soon. These results also highlight an opportunity to reformulate the mRNA vaccine to increase the amount of gB proteins it generates, which in tun could improve gB-specific immune responses.

This work was led by Weill Cornell Medicine in collaboration with the Duke Human Vaccine Institute at Duke University Medical Center, Vanderbilt University, Cincinnati Children’s Hospital Medical Center, and Moderna, Inc. in Cambridge, Mass. Moderna co-funded the research with NIAID.

Reference: X Hu, et al. Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine. Journal of Infectious Diseases DOI: 10.1093/infdis/jiad593 (2024). 

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).