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)

Women account for approximately 23 percent of people with HIV in the United States. In recent years, women aged 25 to 34 comprised the highest number of new diagnoses. Furthermore, Black women, transgender women, and women aged 13 through 24 are more likely to experience health disparities associated with lack of access to HIV testing, treatment, and prevention resources. This weekend marked National Women and Girls HIV/AIDS Awareness Day. NIAID supports research programs that focus on HIV and other health outcomes in women to inform and enable more targeted and effective HIV prevention, care, and treatment.

American Women: Assessing Risk Epidemiologically (AWARE) 

The AWARE project aims to explore the multiple risks and vulnerabilities that lead to higher rates of HIV and other sexually transmitted infection (STI) acquisition in women, including transgender women. In the United States, the rate of new HIV diagnoses in Black women is about 14 times higher than their non-Black counterparts, and AWARE is designed to engage diverse racial and ethnic minorities, including Black women. AWARE is a national digital cohort with a primary goal of identifying women with greater likelihood of acquiring HIV and investigating contributing factors. The research group also seeks to design tailored and effective approaches to reaching women who reside in rural and underserved communities of color with HIV prevention and awareness resources. 

CAMELLIA Cohort: A Longitudinal Study to Understand Sexual Health and Prevention Among Women in Alabama 

The CAMELLIA Cohort supports cisgender and transgender women in Alabama who had a recent STI acquisitions and are impacted by disparities surrounding the lack of access to and the utilization of PrEP. The research program also uses a population-based approach to better understand how the quality of HIV and STI testing, in addition to HIV PrEP access, can be improved. CAMELLIA is sponsored by the University of Alabama at Birmingham in collaboration with NIAID and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

HIV and Women at the 2024 Conference on Retroviruses and Opportunistic Infections (CROI)

At CROI 2024, NIAID-supported studies reported results on women-controlled HIV prevention and cardiovascular health in women with HIV:

• Pregnant people are three times more likely to acquire HIV than those who are not pregnant. The NIAID-sponsored DELIVER study, conducted by the Microbicide Trials Network, showed that the dapivirine vaginal ring and oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine- were each safe for HIV prevention throughout pregnancy. The large clinical study was conducted in Malawi, South Africa, Uganda and Zimbabwe. Learn more about the DELIVER results presented at CROI. 
• A new analysis from the NIH-supported REPRIEVE trial found that the elevated cardiovascular disease risk among people with HIV is even greater than predicted by a standard risk calculator in several groups, including Black people and cisgender women. The study team concluded that updated tools are needed to facilitate precision, high-quality care of the diverse population with HIV. REPRIEVE enrolled 7,769 people with HIV across 12 countries, of whom 31% were women. Learn more about the REPRIEVE analysis presented at CROI, and the primary analysis that found pitavastatin reduced the risk of major adverse cardiovascular events by 35% in people with HIV. 

The NIH Office of AIDS Research (OAR) and Office of Research on Women’s Health (ORWH) jointly lead NIH’s HIV and Women Signature Program. The cornerstone of this new program is an intersectional, equity-informed, data-driven approach to research on HIV and women. The Signature Program advances the NIH vision for women's health, a world in which all women, girls, and gender-diverse people receive evidence-based care, prevention, and treatment tailored to their unique needs, circumstances, and goals. A new position paper, published February 26 in The Lancet HIV, outlines the framework for NIH's approach to research on HIV and women and highlights selected topics of relevance for women, girls, and gender-diverse people with or affected by HIV. The program also supports women in science careers to meet their full professional potential. From March 21-22, the OAR and ORWH will host the NIH HIV & Women Scientific Workshop: Centering the Health of Women in HIV Research. The workshop will review the state of the science on HIV and women to inform the future research agenda. Learn more.

The 2024 U.S. government theme for National Women and Girls HIV/AIDS Awareness Day is “Prevention and Testing at Every Age. Care and Treatment at Every Stage.” NIAID remains committed to advancing HIV research and prevention efforts for cisgender and transgender women alike. 

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. 

On Tuesday 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 on common health complications of HIV and the safety of an HIV prevention tool during pregnancy. He spoke with Miss Molly Moon, M.S.W., Deputy Director of the NIH-supported Office of HIV/AIDS Network Coordination. Watch their conversation below: 

Liver and Cardiovascular Complications of HIV

Dr. Dieffenbach highlighted research findings presented at CROI about addressing both liver and cardiovascular complications among people with HIV. First, researchers reported that a weekly injection of semaglutide was safe and reduced the amount of fat in the liver by 31% in people with HIV and metabolic dysfunction-associated steatotic liver disease (MASLD) after 24 weeks. An estimated 30-40% of people with HIV experience MASLD, which was previously known as nonalcoholic fatty liver disease. MASLD is characterized by the accumulation of excess fat in the liver that is not caused by alcohol consumption or viral hepatitis. The pilot study involved 49 participants whose HIV viral load was suppressed by treatment who took low weekly doses of semaglutide, which is FDA-approved for treatment of type 2 diabetes and weight loss but had not previously been studied for its effect on MASLD in people with HIV. Read the CROI 2024 study abstract. Read NIAID’s summary of the study findings.

Second, researchers shared new analysis resulting from the NIH-supported REPRIEVE trial, which  enrolled thousands of participants in 12 countries. Their analysis reveals that a standard tool used by health care providers to estimate the risk of cardiovascular events in people and determine whether they should be prescribed preventive statin therapy was moderately effective in predicting cardiovascular death, heart attack, or stroke over five years among people with HIV. However, the tool under-predicted cardiovascular events in women, Black/African Americans, and participants from high-income regions. The researchers suggested that the performance of this tool in these subgroups should be considered when using it to guide prescribing statins for cardiovascular prevention among people with HIV. Read the CROI 2024 study abstract. Last summer, REPRIEVE reported its key finding that statins, a class of cholesterol-lowering medications, may offset the high risk of cardiovascular disease in people with HIV by more than a third, potentially preventing one in five major cardiovascular events or premature deaths in this population. Informed by those findings, new clinical guidelines, Recommendations for the Use of Statin Therapy as Primary Prevention of Atherosclerotic Cardiovascular Disease in People with HIV, were recently published. (View HIV.gov’s 2023 conversations about REPRIEVE trial findings.) 

Safety of Dapivirine Ring for HIV Prevention During Pregnancy

Dr. Dieffenbach also discussed new data presented at CROI on the safety of the dapivirine vaginal ring used for HIV prevention. The dapivirine ring is made of flexible silicone, continuously releases the antiretroviral drug dapivirine into the vagina, and is replaced monthly by the user. Its use is approved for HIV prevention in several African countries where adolescent girls and young women are among the groups most likely to benefit. The new data from an NIH-supported study found the ring to be safe throughout pregnancy, a period during which pregnant people are three times more likely to acquire HIV through sex. Dr. Dieffenbach observed that these findings expand HIV prevention choices for women at various stages of their lives. Read the CROI 2024 study abstract. Read NIAID’s summary of the study findings. 

Other Studies of Interest Presented on Tuesday

Some of the other studies presented included a trial showing that offering participants a choice and an opportunity to switch between long-acting injectable cabotegravir, daily oral PrEP, or post-exposure prophylaxis (PEP) increased the amount of time people were using a biomedical HIV prevention method and reduced HIV acquisition compared to offering only oral PrEP and PEP. Read the CROI 2024 study abstract. Another study of antiretroviral therapy during menopause found that switching to a drug regimen with an integrase strand transfer inhibitor (INSTI, a category of antiretroviral drugs) was associated with early accelerated increases in waist circumference and body mass index when compared to people who did not switch to an INSTI-based regimen during late peri-menopause and post-menopause. Read the CROI 2024 study abstract.

Stay Tuned for More HIV Research Updates

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. 

What do we know about oral pre-exposure prophylaxis in cisgender women?

Pivotal studies supported by NIAID demonstrated that oral pre-exposure prophylaxis (PrEP) reduces an individual’s likelihood of acquiring HIV through sex by up to 99% when taken as prescribed. Since the release of those findings, 69 countries have approved HIV PrEP products, and an estimated 5.6 million people have initiated PrEP worldwide. In addition to demonstrating oral PrEP’s high efficacy, research has revealed important differences in individual and population-group preferences in oral PrEP use, particularly that cisgender women participating in studies often did not take oral PrEP as prescribed—and the intervention’s effectiveness declined when doses were taken less frequently. The reasons cited for inconsistent use by the cisgender women who participated in those studies were numerous and suggest that while oral PrEP is safe and highly effective, consistently taking a daily pill for HIV prevention may not be acceptable or feasible for all lifestyles. 

In contrast to the experience of cisgender women, studies of oral PrEP in gay, bisexual and other men who have sex with men (hereafter referred to as men who have sex with men), as well as transgender women, showed high acceptability and efficacy, even when PrEP use was high but imperfect—between 4 and 6 doses per week. Clinical guidelines currently suggest men who have sex with men can experience oral PrEP’s benefits even if they miss doses occasionally; conversely, effectiveness of oral PrEP among cisgender women in studies led to guidelines suggesting that they must consistently take PrEP daily, based on the available estimates of PrEP’s effectiveness in that population. These recommendations were also based on observed differences in the way oral PrEP drugs accumulate in cervicovaginal versus rectal tissues—drug concentrations in the cervix and vagina tended to be lower than in the rectum with similar dosing. Data remain inconclusive on the minimum necessary tissue drug levels for effective oral PrEP in cisgender women and on the relationship between dosing and efficacy. 

What are we learning now?

A new Gilead-supported analysis of combined data from post-marketing demonstration projects suggests that oral PrEP may work as well in cisgender women as it does in men who have sex with men. This analysis showed that oral PrEP maintained high efficacy in cisgender women who took between 4 and 6 doses per week. The findings were published today in the Journal of the American Medical Association.

In their research, an international multidisciplinary team of scientists led by Jeanne Marrazzo, M.D., M.P.H., in her previous role at the University of Alabama at Birmingham, pooled data from 11 studies conducted after oral PrEP was approved by the Food and Drug Administration, 5 of which were funded by NIH, to characterize the relationship between oral PrEP use and its efficacy among cisgender women. The authors reviewed data from 6,296 cisgender women in Botswana, India, Kenya, South Africa, Uganda and the United States. Measures of pill taking were available for 2,955 of 6,296 total study participants. Using a mathematical modeling approach used in previous PrEP use studies, the authors grouped data by the estimated frequency of participants’ oral PrEP use: consistently daily (7 doses per week), consistently high (4-6 doses per week), high, but declining (from 4-6 to 2-3 doses per week), and consistently low (less than 2 doses per week) and noted how many people acquired HIV in each group. 

Among their findings, the authors found that none of the 498 cisgender women in the consistently daily (7 doses per week) group acquired HIV. Further, they found that of the 658 cisgender women in the consistently high (4-6 doses per week) group, only one acquired HIV, which translated to an incidence rate similar to that observed in men who have sex with men who took oral PrEP with the same frequency in prior studies. The team concluded that cisgender women with consistently daily (7 doses per week) or consistently high (4–6 doses per week) oral PrEP use experienced very low HIV incidence.

“Evidence gaps have led to cisgender women being counseled to follow oral PrEP dosing with complete rigidity, which can undermine their motivation to use this highly effective tool,” said Dr. Marrazzo, now NIAID Director. “By combining data from several moderately sized studies, we have revealed a trend in prevention-effective use that suggests brief dosing interruptions should not stop cisgender women from experiencing the potentially life-changing benefits of oral PrEP.”

What’s next?

More data are needed to fully understand the mechanisms by which oral PrEP prevents HIV in cisgender women, including the role that cervicovaginal and rectal tissue concentrations have in its efficacy. Inclusion of cisgender women in HIV prevention research across their lifespan and collection of these data helps regulators, clinicians and cisgender women make informed decisions regarding any potential dosing interruptions when using oral PrEP. More data are also needed on the safety and efficacy of newer oral PrEP formulations in cisgender women.

In addition to oral PrEP, NIAID supports the development of long-acting PrEP formulations. Large studies found injectable PrEP administered every two months was more effective than daily oral PrEP at preventing HIV acquisition in cisgender women, cisgender men who have sex with men and transgender women. That formulation is being rolled out, and a twice-yearly injectable formulation is being studied for safety, efficacy, and acceptability. In addition, a vaginal ring containing dapivirine is approved for HIV prevention in Europe and several countries in sub-Saharan Africa.

Reference: J Marrazzo, et al., “HIV Pre-Exposure Prophylaxis with Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women.” Journal of the American Medical Association DOI: 10.1001/jama.2024.0464 (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).