Around the world, millions of people are living with HIV, each with their own story, challenges, and hopes.
In the last few decades, antiretroviral therapy has transformed HIV from a fatal diagnosis into a manageable disease, and stigma has declined in many communities. Despite progress in treatment and awareness, critical barriers remain. Millions of people living with HIV still fall through the cracks because the systems are unequal, resources are limited, and stigma persists.
In a session titled, Better meeting the needs of people living with HIV, health experts reminded us that science, care, and human rights must move together if we are to achieve real change.
Dr. Xu Yu of Harvard Medical School is leading groundbreaking research that shows how the body’s own immune system can keep HIV under control, potentially transforming treatment, management, and even the search for a cure in ways that are accessible to all. While, Uganda’s Dr. Cissy Kityo Mutuluuza, the Executive Director of the Joint Clinical Research Center, is pioneering Africa’s first trial on long-acting antiretroviral therapy and working to ensure that advances in gene therapy and cure research are within reach for communities in the Global South.
As the world pushes toward ending the epidemic, one urgent question remains: How can we do better? How can we ensure our efforts reach every person and leave no one behind?
Understanding the HIV reservoir
Dr Yu’s laboratory studies the molecular and cellular mechanisms involved in viral immune control, focusing on the interaction between innate and adaptive immune responses. A recent study from her team used next-generation sequencing technology to characterize HIV-1 reservoir cells in people with spontaneous, drug-free control of HIV, also known as elite controllers, and in people with long-term suppressive antiretroviral therapy.
She shedded light on the critical challenge of HIV reservoir cells – the main obstacle to curing HIV.
“HIV reservoir cells represent the main barrier to curing HIV,” said Dr. Yu. “These cells contain HIV DNA that integrates into the host genome and are not affected by standard antiretroviral therapy (ART), which is why the virus can rebound if treatment is stopped.”
Despite being extremely rare, she said that these cells can persist for decades, making lifelong treatment necessary for people living with HIV. In recent years, Dr. Yu said that cutting-edge, high-resolution molecular assays have made it possible to study these elusive cells in much greater detail. “With these tools, we can analyze samples directly from study participants without artificial stimulation or manipulation,” she said.
These advanced techniques, she added, allow researchers to examine key characteristics of the infected cells, including the HIV sequence, where the virus integrates into the host’s chromosomes, how actively the virus is transcribed, and even the cell’s surface features, all at a single-cell, single-genome level. “One important observation is that the majority of HIV-infected cells carry defective proviruses,” Dr. Yu said.
“In fact, only about 5-10% of all infected cells harbor genome-intact proviruses capable of producing replication-competent virus. Distinguishing cells with intact versus defective proviruses is critical, as these two cell types appear to behave quite differently in vivo. Our understanding of the HIV reservoir has advanced significantly through studying HIV elite controllers, a rare group of individuals who can maintain undetectable viremia in the absence of any antiretroviral therapy and serve as a model for a cure of HIV infection.”
According to Dr. Yu, insights from elite controllers have helped gain a better understanding of two forms of a possible cure for HIV infection. “One is a virological cure, which we define as the absence of intact or replication-competent proviruses in a very large number of cells analyzed. The other is a functional cure, seen in people who still carry intact proviruses but are able to maintain undetectable viremia without any treatment.”
“To study the viral reservoir in elite controllers, we compared the frequency of intact proviruses in these individuals with a group of people living with HIV who had been on suppressive antiretroviral therapy (ART) for a median of nine years,” said Dr. Yu. “As expected, on a cohort level, elite controllers had significantly lower levels of intact proviruses than those on ART.”
However, intact reservoir sizes among elite controllers were highly diverse, she said. “Some individuals had relatively high levels of intact proviruses, while others had extremely low, or even undetectable levels,” she said.
Dr. Yu said two such exceptional cases, known as the San Francisco patient and the Esperanza patient.
“In both individuals, we detected multiple defective proviruses, which is consistent with their history of HIV infection. But despite analyzing over one billion blood cells from each, we did not find any intact or replication-competent proviruses.” These findings, she explained, suggest the possibility that these individuals may have achieved a biological cure of HIV through natural immunity.
Loreen Willenberg, also known as the San Francisco patient, was diagnosed with HIV in 1992. In contrast to most people living with HIV, she has never required antiretroviral therapy to control her infection.
Dr. Yu provided an update on Willenberg, saying that HIV RNA has remained undetectable without any antiretroviral therapy (ART) for the past six years.
“With her permission, I’m sharing some difficult personal news,” Dr. Yu said. “In July 2022, she was diagnosed with lung cancer and has since undergone extensive chemotherapy, which, as many of you know, is highly immunosuppressive.”
Remarkably, despite this profound immunosuppression, Willenberg has continued to maintain undetectable levels of HIV RNA without ART. “This observation is most consistent with a biological cure of HIV infection,” Dr. Yu said, “rather than immune-mediated control of the virus”.
She said the Esperanza patient diagnosed with HIV in 2013 is also doing well and remains off therapy with no detectable HIV RNA. The Esperanza Patient is the second individual known to have cleared the infection naturally.
“I’m happy to report that Esperanza patient now has two children, both of whom are HIV-free,” said Dr. Yu.
Elite controller offers new clues in search for HIV cure
Dr. Yu said that HIV tends to integrate into genes, which constitute only about 20% of the human genome, likely to exploit the host’s transcriptional machinery for its own gene expression. She said that only a small fraction of HIV proviruses integrate into non-genetic regions, areas that are generally less transcriptionally active. She described findings from a person living with HIV on suppressive antiretroviral therapy for approximately 11 years, where a phylogenetic tree revealed a diverse array of intact proviruses, many integrated into genetic locations with ready access to the host’s transcriptional machinery. In contrast, she presented data from an elite controller who, despite having relatively high levels of intact proviruses, maintained undetectable viremia without treatment for nearly 30 years.
“HIV prefers to integrate into genes, where it can easily access the host’s transcriptional machinery,” said Dr. Yu. “But in elite controllers, over 60% of intact proviruses are found in non-genic or heterochromatin regions, areas associated with deep latency.”
This pattern, she said, appears to protect against viral reactivation and is what her team refers to as a “blocked-locked” reservoir profile. ‘We see this same profile not just in blood, but also in lymphoid tissues of elite controllers,” she added.
Long-term ART users show a similar trend, though it takes decades. “Over time, immune pressure clears proviruses in accessible regions, while those in deep latency persist and even expand,” said Dr. Yu. “Eventually, their reservoir profiles resemble elite controllers.”
Notably, her team found that people who maintained viral control after stopping treatment had more intact proviruses in heterochromatin regions, while those who rebounded had proviruses in gene-rich regions. “This suggests the integration site may predict the likelihood of rebound,” she said.
Early ART also shows promise
“Just one year after early treatment, we saw a faster shift toward deep latency than we typically see after nine years of ART in chronic infection,” she said.
Dr. Yu also called attention to the gender gap in research: “Women make up 54% of people living with HIV, but just 19% of HIV cure study participants.” Yet women are more likely to be spontaneous controllers and, in her study, had more clonally expanded proviruses in heterochromatin.
“Women showed stronger innate immune traits,” she said, including more antiviral dendritic cells and NK cells without inhibitory receptors. “These findings suggest that innate immunity – and sex-based differences – may play a key role in shaping the HIV reservoir.”
Dr. Yu said that the proviral integration site profile could act as a biomarker to assess immune pressure on the HIV reservoir, potentially serving as a tool to evaluate the effectiveness of future HIV cure therapies. She urged the need for further research to understand the immune selection mechanisms shaping the reservoir, which could inform strategies for achieving an HIV cure.
Long-acting ART in low- and middle-income countries
Dr. Cissy Kityo Mutuluuza is at the forefront of HIV/AIDS research in Uganda and around the world with one primary goal in mind: to find a cure.
Dr. Kityo worked on more than 100 trials for the treatment of HIV and related conditions. Her studies on HIV prevention and vaccine preparation have informed policy and practice in low- and middle-income countries. She presented a well-substantiated argument for implementing long-acting ART, particularly CAB+RPV LAI, as an alternative to oral ART administered daily.
At the end of 2024, she said, 77% of people living with HIV worldwide were on ART, with the vast majority 91%, or 28.8 million people, residing in low- and middle-income countries, and 75% of those in sub-Saharan Africa.
She said that the highest numbers of people with unsuppressed viral loads are also concentrated in these regions. Low- and middle-income countries experienced an eight-year delay in accessing ART compared to high-income countries, with significant scale-up efforts commencing only in 2004.
“This is where the burden of HIV lies. This is where we have the most numbers when it comes to antiretroviral therapy,” she said.
“Following successful registration trials, the first long-acting ART regimen – cabotegravir combined with rilpivirine – was approved in 2021 for use in high-income countries. That same year marked a milestone for sub-Saharan Africa with the launch of the first Phase III clinical trial, called CARES,” she said. “This [CARES trial] was funded by Johnson & Johnson and coordinated by the Joint Clinical Research Center in Uganda.”
But with promising scientific advancements underway, the critical question now arises. How long will it take for long-acting ART to get to low- and middle-income countries where the majority of patients are?
She aligned her remarks with the UNAIDS 95-95-95 targets.
“In alignment with these goals, there is a proposed fourth target – the ‘fourth 90‘ – which calls on all of us to prioritize the long-term well-being of people living with HIV,” said Dr. Kityo.
The original 95-95-95 targets required 95% of people living with HIV to know their status, 95% to be on antiretroviral therapy (ART), and 95% to be suppressed by ART. The “fourth 90” addresses the important issue of preventing new infections, which is vital to eradicating the AIDS epidemic. She explained that HIV treatment has now evolved beyond just viral suppression to meet broader patient needs.
“Duotherapy – long-acting regimens, whether oral or injectable – is the era of HIV treatment now.”
Dr. Kityo said that although duotherapy and long-acting regimens represent a significant leap forward, many patients still struggle with daily pill fatigue, limited treatment choices, and a desire for more convenient dosing. A two-month injectable regimen could address many of these concerns, but its availability remains out of reach for most people in resource-limited settings.
“Long-acting antiretroviral therapy has the potential to enhance ART delivery and support achieving widespread viral suppression targets, particularly in low- and middle-income countries where these numbers are,” said Dr. Kityo. “This is an important step in reaching the global target of ending AIDS as a public health threat by 2030.”
“The efficacy of cabotegravir or the cabotegravir and rilpivirine combination has been robustly validated through Phase III clinical trials, establishing its potential as a long-acting antiretroviral therapy option.”
She said that evidence from clinical trials has led to the inclusion of cabotegravir and rilpivirine as a recommended switch option for biologically suppressed people living with HIV in treatment guidelines issued by key global bodies, including IAS, the U.S. Department of Health and Human Services, and the European AIDS Clinical Society.
Dr. Kityo spoke of a survey from the registration trials involving 532 participants, revealing that 98% preferred the long-acting injectable regimen over their previous oral therapy by Week 48. Most participants favored a preference for the cabotegravir and reprivirin long-acting regimen administered every eight weeks compared to the oral or four-weekly options. She said that the reported reasons for this preference closely align with the previously identified and met needs of people living with HIV, including treatment convenience, reduced pill burden, and improved psychological well-being.
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She said small-scale studies show that long-acting cabotegravir and rilpivirine can be effective even among viremic patients – those with detectable viral loads – positioning the regimen as a viable alternative to daily oral ART. These findings are critical, Dr Kityo said, because most existing trials were done in high-income countries, while the majority of people living with HIV, especially Black African women, are in African treatment programs.
“We have different HIV subtypes. We also have widespread prior exposure to non-nucleoside reverse transcriptase inhibitors NNRTIs (a class of antiretroviral drugs used to treat HIV ) and significant levels of pretreatment drug resistance,” said Dr. Kityo. “Treatment strategies differ, with viral load monitoring and safety assessments often occurring less frequently than in high-income countries.”
Routine viral load monitoring is less frequent in low-resource settings, she said, making it essential to generate local evidence. According to Dr. Kityo, these results demonstrate that long-acting ART is not only clinically effective but also widely preferred, regardless of geographic location, supporting its potential for broader rollout in African treatment programs.
“The WHO updates indicated that long-acting injectable cabotegravir plus rilpivirine can be used as an alternative switching option in adults and adolescents who are stable on oral ART and without active hepatitis B infection. This may not be as exciting for high-income countries, but for us it is—because none of our ministries or governments would adopt this strategy unless WHO recommends it,” she said.
“So we are very excited about this step. We have provided evidence, and now we have guidelines.”
However, Dr. Kityo warned that despite WHO’s support, implementation delays are expected. Johnson & Johnson’s exit from rilpivirine production has created a major gap. While recent licensing news allows three manufacturers to produce generic cabotegravir and rilpivirine, widespread access isn’t expected before 2027, and supply chain limitations could cause further setbacks.
There are cold chain challenges, she said, but existing immunization infrastructure in many countries could support rollout.
Dr. Kityo said barriers to LA-ART are not new – oral therapy faced them too – but added that now is the time to prepare. She also looked ahead to potential regimens like CAB plus lenacapavir, calling it a promising combination if supported by strong clinical evidence.
She expressed concern that adolescents and children are lagging in long-acting ART research, with phase two trials for adolescents starting four years after adult studies and a sub-Saharan African study beginning in 2023, nine years later, with no phase three or implementation trials for these groups.
Dr. Kityo shared innovative developments, including cabotegravir dosing every four months and lenacapavir every year, as well as potential delivery methods like implants lasting 6-12 months and patches, signaling an exciting future for long-acting therapies.
“For us in low- and middle-income countries, we have to catch up quickly so that we are not left behind,” said Dr. Kityo.
