Colourised transmission electron micrograph of an HIV-1 virus particle (yellow/gold) budding from the plasma membrane of an infected H9 T cell (purple/green).
A team of scientists at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and the University of Regensburg has unveiled insights into how HIV-1 skilfully hijacks cellular machinery for its own survival. By dissecting the molecular interplay between the virus and its host, the researchers identified novel strategies that HIV-1 employs to ensure its replication while suppressing the host’s cellular defences. The study was published in the journal Nature Structural and Molecular Biology.
HIV-1, like other viruses, lacks the machinery to produce its own proteins and must rely on the host cell to translate its genetic instructions. After entering host cells, it seizes control of the translation process, which converts messenger ribonucleic acid (mRNA) into proteins. “In this study, we combined ribosome profiling, RNA sequencing and RNA structural probing to map the viral and host translational landscape and pausing during replication of the virus in unprecedented detail,” says corresponding author Neva Caliskan.
Cheat Codes of Viral Translation
One of the key findings was the discovery of previously unrecognized elements in HIV-1 RNA called upstream open reading frames (uORFs) and internal open reading frames (iORFs). These “hidden gene fragments” may play a crucial role in fine-tuning the production of viral proteins as well as the interaction with the host immune system. “For instance, uORFs and iORFs can act as regulators, ensuring precise timing and levels of protein synthesis”, explains Anuja Kibe, a postdoctoral researcher at the HIRI and first author of the study.
Another important discovery was an intricate RNA structure near the critical “frameshift site” in the viral genome. This frameshift site is essential for the virus to produce the correct proportions of two key proteins, Gag and Gag-Pol, which are necessary for assembling infectious particles and replication of HIV-1. The researchers demonstrated that this extended RNA fold not only promotes ribosome collisions upstream of the site (a mechanism that appears to regulate translation) but also maintains the frameshifting efficiency. “Our team also showed that targeting this RNA structure with antisense molecules could significantly reduce frameshift efficiency by nearly 40 percent, offering a promising new avenue for antiviral drug development”, reports Caliskan.
A Game of Priorities
Redmond Smyth, a former Helmholtz Young Investigator Group Leader at the HIRI and currently a group leader at the Centre National de Recherche Scientifique (CNRS) in Strasbourg, France, mentions, “Interestingly, our analysis revealed that, while HIV-1 mRNAs are translated efficiently throughout infection, the virus suppresses the protein production of the host, particularly at the translation initiation stage.” This allows HIV-1 to prioritise its own needs while effectively stalling the host defence mechanisms. Thus, the virus can manipulate the host cell machinery in ways that remain robust even under stress conditions.
More Than Traffic Jams
The researchers also observed that ribosomes collide at specific regions of the viral RNA, particularly upstream of the frameshift site. “These collisions are not accidental but are instead tightly regulated pauses that may influence how ribosomes interact with downstream RNA structures,” says Florian Erhard, study co-author and Chair of Computational Immunology at the University of Regensburg.
Overall, the study provides not only a detailed map of the translational landscape of HIV-1 infected cells but also a wealth of potential targets for therapeutic intervention. The identification of RNA structures and genetic elements critical for viral replication highlights new opportunities for the development of drugs aimed at disrupting these processes. “By understanding how the virus cleverly manipulates our cells, these discoveries will bring us closer to innovative treatments that could one day turn tables and outsmart the virus itself,” Caliskan adds.
Colourised scanning electron micrograph of HIV (yellow) infecting a human T9 cell (blue). Credit: NIH
Highly effective treatments for HIV have existed since the mid-1990s. But while these treatments keep people healthy, we do not yet have a safe and scalable way to completely rid the body of the virus. In this Spotlight special briefing, Elri Voigt takes stock of where we are in the decades-long search for an HIV cure.
As the science stands, the vast majority of the roughly eight million people in South Africa living with HIV will have to take treatment for the rest of their lives. This is because the antiretrovirals used to treat HIV prevents the virus from replicating but cannot eliminate it from the body. As soon as treatment is stopped, the virus rebounds, resulting in illness and eventually an early death.
A handful of people have been cured of HIV, but these “cures” involve very risky bone marrow transplants given as part of cancer treatment. The harsh reality is that 40 years into the HIV epidemic, and despite major scientific advances, we don’t yet have a viable cure for the roughly 40 million people on the planet who are living with the virus.
The good news, as one will see at any major AIDS conference these days, is that researchers around the world are working very hard to find a cure. In this #InTheSpotlight special briefing, we take a closer look at what progress has been made on this fascinating scientific journey and ask what the possible routes are toward an HIV cure.
What do we actually mean by a cure?
Dr Sharon Lewin, a leading figure in the world of HIV cure research and the inaugural director of the Peter Doherty Institute for Infection and Immunity in Melbourne, explains that a true “cure” for HIV would mean that there is not a single HIV infected cell left in a person’s body.
By contrast, “remission” would mean that the virus is still in the body, but it is being kept under control by the immune system. This could theoretically happen if the amount of HIV infected cells in a person’s body has been reduced to very low levels and the immune system’s ability to control those remaining cells has been enhanced. Basically, Lewin says, it is when the immune system does what antiretroviral therapy (ART) does without needing to take medication. Another term for this is ART-free viral load control.
There are some people living with HIV called “elite controllers” whose immune systems can naturally, without ART, control HIV. There are also extraordinary elite controllers, says Lewin, who through their immune response have been able to get rid of every single piece of the virus that they had in their bodies. Studying what is special about these rare people has been a key area of research in recent years.
Along with concepts like cure, remission, and control, it also helps to understand where vaccines fit in. As Jessica Salzwedel, the senior programme manager for research engagement at New York-based NGO AVAC, explains, a potential HIV vaccine might be therapeutic and not necessarily preventative. A therapeutic vaccine would be given to someone who is already living with HIV, in the hope that the vaccine would prime their immune system to better fight HIV or potentially clear it.
Why don’t we have a viable cure yet?
Finding cures for viral infections is not unheard of. In fact, one of the most consequential medical breakthroughs of the last decade or so was the development of a highly effective cure for hepatitis C. Unfortunately, it seems HIV is a much tougher nut to crack.
HIV works largely by invading a type of immune cell called a CD4 cell. Once inside, HIV writes its own genetic information into the cell’s DNA and then uses the cell’s machinery to produce more HIV. Eventually, the infected CD4 cell bursts and dies. Different types of antiretrovirals work by gumming up different stages of this process by which HIV invades and exploits CD4 cells. Most antiretroviral treatment regimens used today contain two drugs that target two different stages of this process. These medicines can drive HIV replication in the body down to near zero – which is why people who are stable on ART can live essentially normal, healthy lives.
Unfortunately, that is not the full story. As Lewin explains, the virus has a range of “tricks” that allows it to stay in someone’s body for much longer. One of those tricks is that HIV uses one of the immune system’s greatest assets against it. A person’s immune system contains cells that function as an immunological memory – essentially memory cells – which are designed to survive for a very long time. These memory cells, which include special CD4+ (CD4 positive) T-cells, contain information about which antigens it has encountered during a person’s lifetime. This helps the immune system recognise and kill those antigens faster the next time they enter the body.
HIV writes its own genetic code into some of these memory cells, which helps it stay in the body for as long as that person is alive. Lewin explains that once someone is on treatment, these immune system cells infected with HIV go silent and the virus stops replicating. These silent cells that contain infectious virus are rare, about one in every million, and can’t be found easily by the immune system, allowing the virus to hide in an inactive state but still able to release virus should the cell one day be activated.
These memory cells are found mainly in the lymph nodes, although they can also hide away in the gut, the spleen, and even the brain. Collectively, these HIV-infected cells in hiding are known as the latent reservoir. Should someone stop taking antiretroviral treatment, some of the cells in this latent reservoir could reactivate and start replicating again.
Lewin says researchers are getting better at finding these latent HIV-infected cells, but there still isn’t a way to easily tag these cells and destroy them.
Three lines of investigation
According to Lewin, researchers are exploring three broad strategies in search of an HIV cure.
Firstly, with a strategy called “shock and kill”, researchers try to reactivate (shock) the virus in the cells where it is hiding and then destroy (kill) it once it is flushed out. Such an approach will likely require at least two medicines – one to shock and one to kill. Unfortunately, attempts to find treatments that reliably shock HIV-infected cells out of their slumber has not borne much fruit so far.
Secondly, with “block and lock”, researchers hope to permanently silence the HIV that is hiding away in a person’s body. The aim here is to keep HIV latent for good, so that we never need to worry about killing it. This approach might involve using ART together with a latency promoting agent, of which several are currently being researched. “Block and lock” approaches have been picking up momentum in recent years.
Thirdly, with gene editing, researchers aim to “edit” cells to make them resistant to HIV or remove HIV from them. For example, CD4 cells can be modified to not have the specific receptor called CCR5 that HIV requires to gain entry into the cell. Essentially, if you remove the CCR5 receptor from a cell, HIV has no way in and the cell becomes immune to HIV. In this area, there have been some tantalising developments, but nothing yet that amounts to a workable cure. For example, in one study, people had their blood drawn, the CCR5 receptors removed from the CD4 cells in the blood, and then had the blood reinfused. It worked somewhat, but not nearly well enough to call it a cure.
These three categories are not the only way to think about potential cures.
Broadly, we can think about there being two big “buckets” of approaches for an HIV cure, says Salzwedel. The first “bucket” of approaches targets the virus, and those approaches are trying to remove HIV from the cell or “silencing” it so even if it is still present there is no replication. The other “bucket” of approaches looks at the host – or the person living with HIV – and improving their immune system so it can adequately kill HIV or make the cells that have HIV in them easier to spot so these cells can’t hide from the immune system. She says a combination of approaches from both “buckets” will probably need to be used for a cure.
A resource of HIV cure trials maintained by Treatment Action Group, a New York-based advocacy organisation, lists hundreds of clinical trials currently underway that are trying these different approaches or combinations of approaches.
What about the people who have been cured?
As mentioned earlier, one area of research has involved trying to understand “elite controllers”. Another critically important group of people in the search for a cure are the seven or so people who were living with HIV, but who have been cured. Some of these people, like Timothy Ray Brown and Adam Castillejo, have become minor celebrities in the HIV world.
Lewin explains that people like Brown and Castallejo, both of whom have essentially no HIV left in their bodies, had to go through interventions that can’t be replicated in everyone. Both had a type of blood cancer and were living with HIV. They had to undergo chemotherapy which wiped out their bone marrow, including the cells that had HIV in them. They were then given a whole new bone marrow system through a donation from someone who was naturally resistant to HIV since their CD4 cells do not have CCR5 receptors. This allowed the latently infected cells to be “flushed out” of their bodies. One of the other people cured of HIV received a bone marrow transplant from umbilical cord blood.
Such transplants are not things you can do for everyone who is living with HIV, its expensive and the severe risks of the procedure can only be taken in people living with both HIV and certain cancers. Even so, these cases, says Salzwedel, has shown us that it is possible to cure HIV and made us aware of some of the challenges.
Lewin says that cases like those of Brown and Castallejo helped advance gene editing approaches because they showed that not having CCR5 receptors makes CD4 cells essentially immune to HIV. This led to studies using special gene scissors – a technique called CRISPR – to find the gene for the CCR5 receptor in cells and remove it. CRISPR has also been used experimentally to remove HIV from cells.
So far only a small number of studies have been conducted using CRISPR-based gene editing approaches in an attempt to cure HIV – and these were mostly in the lab or in mice and monkeys. The first human gene editing study for CCR5 was done ex vivo – meaning cells were taken out of the body, edited, and then reinfused into the body. The first clinical trial of CRISPR for HIV in vivo – meaning it is done inside the body – is currently underway and early results were presented in July at the AIDS 2024 conference. While initial results in monkeys were promising, the early findings in humans were disappointing. EBT-101, the specific type of CRISPR treatment, did not prevent HIV from returning once treatment was stopped – although one study participant’s HIV only started replicating again after 16 weeks. A longer follow-up study is currently open in the United States for enrolment.
Gene editing could also potentially be used to strengthen the immune system. This could work, Lewin explains, by inserting a new gene that produces an antibody against HIV into cells and then putting those cells back into the body. “So instead of giving an infusion of an antibody, your own body makes the antibody. And that’s been done successfully in people with HIV on ART in two separate clinical trials and more recently in infant monkeys where ART was stopped,” she says. “The investigators injected CRISPR that delivered two different antibodies to infant monkeys who are infected with a monkey adapted form of HIV virus and on ART. The infant monkey’s muscle cells then start making the antibodies, and when they stopped ART, the antibodies kicked in and kept the virus under control, so that’s the most successful type of gene therapy,” Lewin says.
Boosting the immune response
Another promising avenue is broadly neutralising antibodies (bNAbs) – the broadly refers to the ability of these antibodies to neutralise a range of different HIV viral strains. Broadly neutralising antibodies can work as an antiviral while present in the body, but they can also trigger the immune system to control the virus and, according to Lewin, figuring out how bNAbs do this is a very important part of current cure research. Broadly neutralising antibodies that are HIV specific, work by binding with the virus and eliminating it while also enhancing a person’s immune system so it can control the virus that remains in the body by hiding in the immune system’s memory cells. Broadly neutralising antibodies potentially have this beneficial effect on immune control by activating CD4 and CD8 responses – part of the immune system’s defence – to kill HIV cells. There have been several clinical trials where a subset of participants who have been given bNAbs have been able to control the HIV virus for six months after stopping ART and when the bNAbs are no longer detected in blood. The scientific challenge is that this beneficial effect was only seen in a subset of participants and the duration of control is not fully understood as most clinical trials only assess participants up to 24 weeks off of ART.
Lewin says a small study has also looked at using anti-PD1, an antibody that reverses immune system exhaustion and essentially “revs” up the immune system to keep fighting HIV. Early study findings were presented at the Conference on Retroviruses and Opportunistic Infections (CROI) this year. Participants stopped ART and were given four doses of the antibody, called Budigalimab, or placebo over 29 weeks. Six out of the nine people who received the antibody had delayed viral rebound and/or ART free control, and two people had viral control off ART for over 29 weeks. The antibody will now be evaluated in a larger study.
Additional approaches, according to Dr Daniel Douek, an expert in immunology and the Chief of the Human Immunology Section at the National Institute of Allergy and Infectious Diseases in the United States, include HIV vaccines, which so far have not generated a strong enough immune response to be considered successful. Douek was speaking on an IAS webinar on HIV cure research. Another promising approach is to start someone on ART as quickly as possible after infection in the hope of preventing the establishment of the latent reservoir.
Suppressing the immune system with a drug has also been tried, says Douek, and research so far in this area warrants further investigation. While it seems counterintuitive, the researchers wanted to see if suppressing immune system cells might stop or reduce HIV replication because the virus likes to replicate in activated immune cells. People living with HIV, even when on treatment have a lot of activated immune cells. The drug Ruxolitnib, which is used to treat graft-versus-host disease in transplant patients, was given to 60 people living with HIV alongside their HIV treatment. After five weeks, there was a decrease in markers of immune activation and cell survival. And between five and 12 weeks of using this combination, those with large viral reservoirs displayed signs that their reservoirs were reducing in size. However, Douek cautioned that much more work needs to be done before we can draw firm conclusions about the value of this approach .
What comes next?
Though we don’t yet have a viable cure for HIV, Lewin says a lot of progress has been made, especially over the decade and a half since Brown was cured. We now know a lot more than we did about the virus and how it hides away in cells. Today, she says, we have cure interventions that work well in monkeys and some interventions being investigated in human clinical trials have induced ART-free viral control in some participants. But she is also clear that it will probably be “a very long time” before you can go to your doctor and get an HIV cure.
In this #InTheSpotlight special briefing, we have focused on the science, but as we have learnt from the new hepatitis C cures and from HIV prevention injections, the journey from the lab to your local clinic can be a very long one and involves far more than just the science.
According to Lewin, a successful HIV cure will have to tick several boxes. She says one needs an intervention that is durable, so that it leads to ART-free viral load control over a prolonged period of time. At this point, an intervention that allows for control over two, three or five years, is seen as worthwhile. Although the ideal would be to give something once and have ART-free viral load control over a lifetime. The intervention also needs to be scalable, so it can be given to a lot of people. It also needs to be cheap.
And if there is one insight we’ve gained over our many years covering HIV, it is that affordability and sufficient supply are not things we can take for granted. Given that many of the potential cures involve treatments that are substantially more complicated to produce and administer than antiretrovirals, the challenges here might be more acute than what we’ve seen before.
That we will eventually get a cure is also by no means inevitable. This is why it is critically important that governments and philanthropies continue to invest in cure research and support programmes such as the International AIDS Society’s Toward an HIV Cure initiative. Among others, this initiative is helping to build the capacity needed to conduct cure research in low-and-middle income countries.
Right now, even under a best-case scenario, a world without a cure will mean that many millions of people will still be living with HIV until late in the 21st century. A successful cure could change this trajectory. Ultimately, Salzwedel is right when she says: “We can’t really end an epidemic without a cure”.
The Institute for Health Metrics and Evaluation (IHME) has published a new study in The Lancet HIV journal that revealed significant progress in the global fight against HIV/AIDS, alongside a stark warning that current trends indicate the world is not on track to meet the ambitious UNAIDS 2030 targets.
The research, which analysed the global, regional, and national burden of HIV/AIDS among 204 countries and territories from 1990 to 2021 and forecasted trends to 2050, highlighted a mixed landscape of achievements and challenges in the battle against this global epidemic.
Between 2010 and 2021, new HIV infections decreased from 2.1 million to 1.7 million, and HIV-related deaths decreased from 1.2 million to 718 000. Despite this progress, researchers found regional variation in the HIV response and forecast the world is not on track to meet UNAIDS 2030 targets to cut new HIV infections and AIDS-related deaths by 90%.
Sub-Saharan Africa leads the world in cutting new HIV infections and deaths from the disease
The global decline in HIV incidence is largely driven by sub-Saharan Africa, where the likelihood of getting HIV over a lifetime has fallen by 60% since its peak in 1995. This region also achieved the largest decrease in population without a suppressed level of HIV (PUV), from 19.7 million people in 2003 to 11.3 million people in 2021.
In contrast, the lifetime probability of HIV acquisition increased from 0.4% to 2.8% between 1995 and 2021, while PUV rose from 310 000 people to 680 000 people between 2003 and 2021 in Central Europe, Eastern Europe, and Central Asia.
“The world has made remarkable global progress to significantly reduce the number of new HIV infections and lives lost to the disease, yet there are remaining challenges to overcome,” said Dr. Hmwe Kyu, IHME Associate Professor and study author. “More than a million people acquire a new HIV infection each year and, of the 40 million people living with HIV, a quarter are not receiving treatment,” she added.
Despite progress, UNAIDS’s HIV infection reduction and AIDS-related deaths 2030 targets won’t be met
Although substantial progress has been made against HIV incidence and AIDS-related mortality, the world is not on target to meet the UN’s 2030 targets to reduce new HIV infections and AIDS-related deaths by 90%.
The number of people living with HIV is expected to peak at 44.4 million by 2039, followed by a gradual decrease to 43.4 million people by 2050.
“The global community must make sustained and substantive efforts to sharpen the focus on prevention, optimize access to antiretroviral therapy, and make HIV testing widely available to achieve prompt diagnosis and linkage to care,” said Dr. Kyu.
New cases of HIV, and deaths associated with the disease, are expected to continue to decrease globally. However, long-term increases have been forecast in North Africa and the Middle East, where only 67% of people living with HIV are aware of their status, 50% access ART, and 45% are virally suppressed.
“Although new HIV infections and HIV-related mortality have fallen globally, they are increasing in several nations and regions. Our analysis is designed to inform countries’ sustained response to HIV that includes expanded access to lifesaving antiretroviral therapy (ART), effective prevention options, and innovative care models,” said Austin Carter, IHME Research Scientist.
The study authors set a series of recommendations to sustain and invigorate the global HIV response, including the strengthening of the US President’s Emergency Plan for AIDS Relief (PEPFAR) and other similar public health programs dedicated to HIV control, as well as the expansion of prevention services, with a multitude of existing and emerging technologies. Additionally, interventions and care delivery models that work must be studied and implemented effectively and equitably, with special emphasis on measuring progress and addressing remaining gaps in our collective goal of ending the HIV epidemic.
The findings and recommendations from the new study by the GBD 2021 HIV collaborators serve as a call to action for governments, health care providers, and the global community to renew their commitment to ending the HIV epidemic. Only through sustained, comprehensive, and equitable efforts will the world be able to achieve the UNAIDS 2030 targets and ultimately eradicate HIV/AIDS as a public health threat.
Photo by Miguel Á. Padriñán: https://www.pexels.com/photo/syringe-and-pills-on-blue-background-3936368/
For oral medications that prevent new HIV infection to be effective, the patient must take certain actions, including attending doctor’s visits every three months and – most importantly – consistency.
These daily oral antiretrovirals, more commonly referred to as PrEP (pre-exposure prophylaxis), such as Truvada®, are extremely effective at HIV prevention, but only if they are taken daily as directed. Truvada’s efficacy is greatly compromised when taken inconsistently.
However, results from a recent Gilead-funded clinical trial (Purpose-2) led by physicians at Emory University and Grady Health System indicate that a twice-yearly injection of Lenacapavir offers a 96% reduced risk of infection overall, making the injection significantly more effective than the daily oral PrEP. The findings were recently published in the New England Journal of Medicine.
“Seeing these high levels of efficacy – at almost 100% – in an injectable that people only have to take every six months is incredible,” says Colleen Kelley, MD, lead author of the study and professor in the School of Medicine at Emory University. “This is a considerable and profound advancement in medicine, especially for people whose circumstances don’t allow them to take a daily oral medication, and for those among populations disproportionately impacted by HIV.”
In the randomised, double-blind, Phase III clinical trial comparing the efficacy of the two medications, 99% of the participants in the Lenacapavir group did not acquire an HIV infection. During the trial, only two participants in the Lenacapavir group, comprised of 2,179 people, acquired HIV. This compares to nine new HIV infections in the Truvada®group, which had 1,086 people. The trial showed that adherence to the injectable was higher than of the daily oral pill.
Kelley adds that while PrEP is incredibly effective at preventing infection, part of what made the injection more effective in the clinical trial was the challenges associated with adherence to a daily oral pill.
“What we see over time is that about half of people who start taking daily oral PrEP stop within a year due to various factors,” says Kelley, referencing healthcare disparities in general. “Having an effective injectable that is only needed twice annually is very significant for people who have trouble accessing healthcare or staying adherent to daily, oral pills.”
The inclusion of racially, ethnically, and gender-diverse participants in the clinical trial was notable because it was representative of populations disproportionately impacted by HIV in real time. For example, the trial groups were comprised of cisgender men and gender-diverse people at 88 sites in Peru, Brazil, Argentina, Mexico, South Africa, Thailand, and the US.
According to the study, the same populations that are disproportionately impacted by HIV are the same populations that have limited access to PrEP – or may have difficulty consistently taking the oral antiretroviral medication – ultimately highlighting the need for more options. The study also indicates that more than half of the new HIV infections nationwide in 2022 were among cisgender gay men, and 70% of those were among Black or Hispanic individuals.
Valeria Cantos, MD, associate professor in the School of Medicine at Emory University, physician at Grady Memorial Hospital, and the principal investigator for the clinical trial at the Grady research site, emphasized the importance of having trials that include populations truly representative of the patients that Grady serves.
“At Grady, our focus is on increased representation of underserved and vulnerable populations, acknowledging and addressing the distrust towards research held by some community members due to prior abuses or neglect of these populations by research institutions in the past,” Cantos says. “Grady is an established, trusted research site because of its commitment to equity.”
At the Grady clinical trial site, medical materials were available in Spanish, and bilingual staff members recruited and enrolled trial participants who only spoke Spanish. Cantos also indicated that the site enrolled participants who are representative of the populations that would benefit the most from Lenacapavir. In addition to Grady, the Hope Clinic and Emory Midtown Hospital were among the 88 sites supporting the clinical trial.
“We are not reaching everyone we need to reach with our current HIV prevention interventions, such as those who are disproportionately impacted by HIV and health care disparities,” says Kelley. “For people that are unable to take the daily oral pills, the injectable agents can really give incredible efficacy and be a game changer in helping them stay HIV negative.”
Since the Phase III clinical trial has been completed and submitted by the FDA for consideration, Kelley is hopeful that Lenacapavir may be approved by 2025 for commercial use.
A University of Minnesota Medical School research team has found that giving iron supplements to children living with human immunodeficiency virus (HIV) in sub-Saharan Africa could be an important first step in optimising brain development.
The study, published in Lancet HIV, demonstrates that iron, while often withheld from children with HIV due to fear of increasing infection risk, is in fact beneficial. This finding paves the way for future research examining iron’s role in neurodevelopmental outcomes in children with HIV.
“With the success and widespread availability of antiretroviral therapy (ART), children with HIV in sub-Saharan Africa are living longer, and optimising their brain development is a new public health imperative,” said Sarah Cusick, PhD, associate professor at the U of M Medical School and a member of the Masonic Institute for the Developing Brain.
Between May 2018 and November 2019, researchers enrolled 200 children with HIV and anaemia who had received ART for at least six months. The study participants were randomly chosen to receive either iron supplements or a placebo for three months. Children who received iron had higher haemoglobin concentrations and better markers of iron nutrition than those who received the placebo. There also was no evidence of increased risk of infection.
According to Dr Cusick, further research is needed to assess brain development and infection risk over a longer period of time.
Rates of HIV and Hepatitis C are “extremely high” among people who inject illicit drugs, according to new research by TB HIV Care. The organisation tested over 1200 injecting drug users in Tshwane, eThekwini, Mashishing and Mbombela (formerly Nelspruit).
In Tshwane 72% tested positive for HIV and nearly 90% had antibodies for hepatitis C virus (HCV), which could indicate past or present infection.
HCV is a blood-borne virus which damages the liver. When left undiagnosed it can be fatal, though it’s usually curable if treated.
Less than half of those who tested positive for HIV in Tshwane were aware of their HIV status. As such they would not have been on treatment and could have been spreading the virus without knowing.
Survey Site
HIV Prevalence among people who inject drugs
Antibodies for Hepatitis C among people who inject drugs
Share of HIV positive people who knew their status
eThekwini
49%
75%
76%
Mashishing
45%
41%
77%
Mbombela
30%
91%
64%
Tshwane
72%
89%
48%
Results of the TB HIV Care survey of four cities.
People who inject drugs (such as heroin) are at a higher risk of contracting HIV and HCV when needles are shared – something which happens because drug users don’t have easy access to new ones.
This has long been a problem in South Africa and appears to be getting worse. Research conducted in eThekwini in 2013 found that 17% of injecting drug users were HIV-positive. According to the new research, a decade later the figure has nearly tripled to 49%.
Professor Harry Hausler, CEO of TB HIV Care and a former technical advisor to the National Department of Health on TB/HIV, believes the main reason for this “massive” uptick in blood-borne diseases among drug users is “the limited access to needle and syringe programs” in the country.
Government ignored its own solution
Research shows overwhelmingly that providing clean needles to drug users reduces the spread of HIV, not only by removing the need to share injecting equipment but often because needle programs offer other services such as health education and condoms.
A large review published in 2017 identified 133 academic studies on needle and syringe programs (commonly known as NSP). The results were “supportive of the effectiveness of NSP in reducing HIV transmission among [people who inject drugs], as well as in reducing HCV infection, although the latter to a lesser extent”.
Yet despite these formal policy commitments, there is virtually no public funding for such interventions.
A person discards used needles in a specialised bin provided by TB HIV Care at a mobile clinic in Wynberg, Cape Town.
One exception is the Pretoria-based Community Oriented Substance Use Program, sponsored by the Tshwane Municipality. It has been left to non-profit groups, such as TB HIV Care, to provide these services. According to Hausler, the organisation currently provides clean needles to nearly 10 000 injecting drug users in Cape Town, Nelson Mandela Bay, eThekwini, Tshwane and Mbombela.
Users access needles from drop-in centres as well as mobile clinics – usually vans that get driven on set days to areas where injecting users congregate. Users discard their old needles in specialised bins provided by TB HIV Care. They will then receive a pack, which includes clean needles, alcohol swabs and sterile water.
Nurses are present at the mobile clinics so users can also get tested for HIV and HCV. They also offer ordinary medical services, such as cleaning and bandaging wounds.
Mobile clinics are also manned by psychosocial and human rights workers, and peer educators (people who were beneficiaries but now work for TB HIV Care) from whom users can get counselling or report abuses.
“We’re not just a needle provision organisation”, says Loraine Moses, who oversees quality standards for the program. “We’re a health services organisation”. Users have to register with peers and get health counselling and education before getting their needles, she says.
Beneficiaries have access to various amenities at TB HIV Care’s drop-in centres, including showers, lounging areas and washing machines.
Anthony (surname withheld), previously a heroin user for 15 years, who now volunteers for TB HIV Care, spoke to GroundUp at a drop-in centre in Cape Town.
“In the beginning, I started experimenting with friends in school [but] after my mother passed away, I found that there are those properties in [heroin] that calm you and numb pain, so that’s when I started to delve [into the drug] more.”
After ending up on the street and becoming “a slave to that drug”, he increasingly wanted to get sober. Fetching needles from a TB HIV Care site, he began speaking with one of the peers. The person told him about TB HIV Care’s opioid agonist program, which helps users to quit or reduce their heroin intake.
Opioid agonists are drugs which block heroin withdrawal. Methadone is the most widely known. Numerous clinical trials show that initiatives which offer methadone to heroin users over an extended period are more effective than rehab programs that force users to quit cold turkey.
Hausler says that TB HIV Care currently provides methadone to over 1100 people. Along with the medicine, they receive counselling and are assisted with finding shelter, and in some cases to reintegrate with their families.
Anthony says he’s been taking methadone since June last year. The program also helped him link up with a shelter and get an ID document so that he could find work.
“Being a client at TB HIV Care has helped me a lot to reintegrate back into society,” he says. “Being on the street, you lose a lot of yourself”.
A notice board at the TB HIV Care drop-in centre in central Cape Town.
Law enforcement continues to confiscate needles
Local governments have assisted TB HIV Care with some of its services. The City of Cape Town provides the HIV tests for use at mobile clinics, according to Hausler.
And yet, not only has the government failed to directly fund the sterile needle programs but in some cases it appears to work against them.
Research carried out by TB HIV Care shows that users frequently have their injecting equipment confiscated by law enforcement officers.
In Tshwane and eThekwini more than half of all people surveyed said that the authorities had seized or destroyed their needles at least once in the previous six months.
Outcome
Mashishing
Mbombela
eThekwini
Tshwane
No
57%
76%
31%
36%
Yes, In the last 6 months
18%
20%
64%
54%
Yes, but not in the last 6 months
25%
4%
5%
10%
Results of survey question: Have you ever had your needles and syringes confiscated or destroyed by a police officer/law enforcement? Source: TB HIV Care
“What’s very frustrating is that there are two arms of government,” says Hausler. “There’s health and then there’s police. And police are confiscating needles and syringes that we’ve been providing to clients – [even though what we’re doing] is a clearly endorsed health intervention.”
Hausler notes that in some cases the organisation has “really good alliances with local police”, but in other cases it is a constant battle.
“There needs to be better mainstreaming of education of officials across all government departments on the … HIV and TB response [plans],” says Hausler. “If people were really sensitised, we would not run up against as many obstacles.”
Asked for comment, Gauteng SAPS spokesperson Lieutenant Colonel Mavela Masondo told GroundUp that “possession of needles is not a criminal offence. Therefore, we cannot arrest a person [for] possession of needles, and neither can we confiscate needles”.
Note: The full report by TB HIV Care, which received assistance from the United States CDC, is not yet publicly available. A 16 page summary of some of the findings can be found here.
Professor Harry Hausler, CEO of TB HIV Care, at his office in Cape Town.
In June, we heard what could be this year’s biggest HIV breakthrough: a twice-yearly injection can prevent HIV infection. Findings from a second large study of the jab has now confirmed that it works. Elri Voigt goes over the new findings and unpacks the licenses that are expected to facilitate the availability of generic versions of the jab in over a hundred countries, including South Africa.
The second of two pivotal studies of a six-monthly HIV prevention injection containing the antiretroviral drug lenacapavir has confirmed that the jab works remarkably well.
The first study, called PURPOSE 1, found that the jab is safe and highly effective at preventing HIV infection in women. The second, called PURPOSE 2, found the same for cisgender men, transgender men, transgender women and non-binary people who have sex with men assigned male at birth.
Interim findings from PURPOSE 2 were presented last week at the HIV Research for Prevention (HIVR4P) conference in Lima, Peru.
The researchers compared the safety and efficacy of lenacapavir injections every six months to a daily HIV prevention pill – a combination of emtricitabine and tenofovir disoproxil fumarate, called F/TDF. The results have not yet been published in a peer reviewed journal, but is expected to be soon, according to Principal Investigator for PURPOSE 2 Dr Colleen Kelley, a professor of medicine at Emory University’s School of Medicine.
In the PURPOSE 1 study, none of the 2 134 people receiving the lenacapavir injection got HIV during the study. In PURPOSE 2, there were two HIV infections among the 2 179 people receiving the injection. These numbers are dramatically better than those for HIV prevention pills and for people in the communities where the study was done who were not receiving prevention injections or pills.
These findings mean the evidence is now in place for the manufacturer, Gilead Sciences, to file with regulatory authorities to register lenacapavir injections for HIV prevention. Such registration is required before the jab can be marketed for prevention. Lenacapavir injections are already registered in some countries as a last resort treatment for HIV, but not yet in South Africa.
“Now that we have a comprehensive dataset across multiple study populations, Gilead will work urgently with regulatory, government, public health and community partners to ensure that, if approved, we can deliver twice-yearly lenacapavir for PrEP worldwide, for all those who want or need PrEP,” Daniel O’Day, the chairperson and Chief Executive Officer of Gilead said in a press release. (PrEP, or pre-exposure prophylaxis, refers to taking antiretrovirals to prevent HIV infection.)
Top line findings
The interim results presented at HIVR4P by Kelley, showed that when compared to the background HIV incidence calculated in the study, lenacapavir reduced HIV infections by 96%. And when compared to the F/TDF prevention pill, the injection reduced HIV infections by 89%.
Among the 3 265 participants enrolled in the study, 11 people acquired HIV- two of the 2 179 people who were assigned to the lenacapavir arm and nine of the 1 086 participants assigned to the prevention pill arm. This translated to HIV incidence of 0.93 per 100 person years in the prevention pill arm compared to only 0.1 per 100 person years in the lenacapavir arm.
This was compared to the background incidence, which was determined when screening eligible participants for HIV. Out of 4 634 people screened for the study, 378 or 8.2% were diagnosed with HIV. Based on further laboratory testing, it was estimated that of those 378 people, 45 or 11.9% recently acquired HIV (classified as being within the last 120 days or so). This latter group provided the background HIV incidence, which was estimated to be 2.37 per 100 person years.
This is a novel study design, Kelley told Spotlight, because this calculation was used to estimate the HIV incidence that would have occurred in a placebo group without actually enrolling a placebo group.
“It’s no longer ethical to have a placebo group in HIV PrEP trials because we know that we have effective PrEP agents,” she said. “Yet, it’s almost essential to have a placebo group when you design a clinical trial so that you can really say how effective your medication, your new agent is [compared] to having nothing.”
When asked at a press conference about the two breakthrough infections in the lenacapavir arm, Kelley said the analysis for this is ongoing and will hopefully be available at a future conference and in a journal soon. She said that the two breakthrough infections in the lenacapavir arm were detected by routine testing during the study.
Principal Investigator for PURPOSE 2 Professor Colleen Kelley at the 5th HIV Research for Prevention Conference in Lima, Peru. (Photo: Nicole Bergman/IAS)
Kelley added that around 90% of participants in the two study arms were able to receive their injection on time. “So, we at least know that the injections were delivered in a timely fashion for almost all participants,” she said.
Whether or not the two infections occurred in people who had received the jabs on time and according to the study protocol will be closely watched as more study details is shared in the coming months.
To be enrolled in the study, participants had to meet several criteria. They had to be older than 16, never received HIV prevention injections before, weigh more than 35kg, have good kidney function, not have been tested for HIV in the last 12 weeks, and had to have been sexually active in the last 12 months.
All study participants were given a pill a day and an injection, those in the lenacapavir arm received two 1.5 ml lenacapavir injections every six months and a daily placebo pill, while those in the prevention pill arm received the daily F/TDF pill and a placebo injection every six months.
The study was conducted across seven countries, with 6 sites located in South Africa and others in Argentina, Brazil, Mexico, Peru, Thailand, and the United States, according to study data on Gilead’s website.
Safety data
Overall, Kelley said lenacapavir was safe and well-tolerated despite some side effects, mainly related to the injections. A total of 43 people dropped out of the study due to side effects.
The most common adverse event in the study was injection site reactions. There were more injection site reactions in the lenacapavir arm compared to the prevention pill arm. 29 people dropped out of the study because of these, 26 in the lenacapavir arm and 3 in the prevention pill arm (people in this study arm received placebo jabs).
The most common injection site reaction were subcutaneous nodules – these are harmless, usually invisible, small lumps under the skin. Nodules occur because lenacapavir is injected under the skin where it forms a drug depot. Injection site reactions and nodule size decreased with subsequent injections. This side effect and trend of decreasing reactions was also noted in the PURPOSE 1 study. Other injection site reactions were pain and erythema which is a type of skin rash.
According to Kelley, there were no serious adverse events related to injection site reactions.
When injection site reactions are excluded, according to Kelley, the other adverse events were similar across both arms, with 74% of participants in each arm experiencing an adverse event. The majority were mild or moderate.
Seven participants in each study arm dropped out due to side effects that weren’t related to injection site reactions. Those who discontinued from the lenacapavir arm will be given prevention pills for a year. This is done to protect these participants, Kelley explained, from potentially acquiring HIV when lenacapavir levels wane, as well as to reduce the risk of potential drug resistance developing.
There were a few serious adverse events, although Kelley told Spotlight she does not currently have any additional information on what these were. She explained that a serious adverse event is generally classified as something like hospitalisation, a life-threatening condition, an important medical event or adverse pregnancy outcome.
“Usually when we look at something like this, we look at the rates compared in the two arms of the study and it was 3% in the LEN [lenacapavir] arm and 4% in the F/TDF arm, so they were equal, essentially the same in both study arms,” Kelly said.
There were six deaths during the study, but none were related to the study drugs.
Next steps for lenacapavir
Now that the interim results have been announced, both studies have been unblinded and entered an open-label phase where participants have the choice of switching to or continuing with the injection.
Professor Linda-Gail Bekker, the Chief Executive Officer at the Desmond Tutu Health Foundation, recently said on a webinar hosted by the South African Health Technologies Advocacy Coalition, that study participants are now able to use the PrEP option they’d prefer – either oral PrEP or the injection. This means all participants will be able to access lenacapavir through the studies if they wanted to use it.
But it will likely be a while before anyone outside of these studies can access lenacapavir as HIV prevention.
“This is an incredible intervention. Now we have to make sure everyone can get it and that’s going to be the most important next step, ensuring that everyone who needs this drug has access,” Kelley told Spotlight.
Gilead’s generic licensing agreement and pricing
What we do know so far about the next steps for lenacapavir is that the process to allow for generic manufacturing has started. This month, Gilead released its voluntary licensing agreements with six generic companies for manufacturing cheaper versions of lenacapavir.
Dr Andrew Gray, a senior lecturer in Pharmacology at the University of KwaZulu-Natal, told Spotlight that no South African firms have been included in the voluntary licenses – four of the generic licensees are in India, one is in Pakistan, and one is in Egypt.
“In essence, they [the generic companies] are allowed to sell their generic versions in a number of identified countries, specified by Gilead,” Gray said. The agreement lists 120 countries, including South Africa.
Gilead itself will also be prioritising the registration of lenacapavir in 18 countries, which it said represent about 70% of the HIV burden in the countries named in the license. The list includes South Africa, Uganda, and Botswana. Gilead says it will start filing for registration with regulatory authorities by the end of the year.
It will be important to see how quickly Gilead seeks regulatory approval for lenacapavir with the South African Health Products Regulatory Authority (SAHPRA), Gray said. Registration with SAHPRA will be required before the injection can be rolled out in South Africa.
In putting together this timeline, we’ve spoken to several well-placed experts, but we stress that this is very much a back-of-the-envelope exercise and far from set in stone. (Infograph: Spotlight)
Some countries won’t be able to procure generics
Gilead received criticism for several omissions from the list of countries that the generic manufacturers can sell to. The US-based HIV advocacy group AIDS Vaccine Advocacy Coalition, among others, pointed out the exclusion of several countries which have high HIV incidence. Some of those countries participated in PURPOSE 2- namely Brazil, Argentina, Mexico and Peru.
A spokesperson from Gilead told Spotlight the manufacturer’s access policy included tailored approaches to ensure rapid and broad access of lenacapavir and it objectively considered the countries where a voluntary licence would provide the most benefit.
“Gilead’s voluntary licence primarily covers countries based on economic need and HIV burden, which are primarily low- and lower-middle income countries. The voluntary licence also covers certain middle-income countries with limited access to healthcare,” the spokesperson said.
Acknowledging that some middle-income countries do have a high HIV burden, Gilead is “exploring several innovative strategies to support access to LEN for PrEP (if approved), including tiered pricing, and are working with payors to establish fast, efficient pathways to help reach people who need or want PrEP”, said the spokesperson.
“Ensuring access in middle-income and upper-middle income countries, including those in Latin America, is a priority for Gilead. Planning for these countries, incorporating input from advocates and global health organizations, is ongoing and updates will be shared as discussions progress,” the spokesperson added. “Additionally, Gilead is committed to ensuring that individuals who participated in the PURPOSE studies have been offered and will be able to stay on open label lenacapavir until it is available in their country.”
The company’s decision to license generic manufacturers directly is at odds with earlier calls from several activist groups and UNAIDS to license via the UN-backed Medicines Patent Pool.
Pricing
It will also be important to see if Gilead will disclose a single exit price for the South African market, according to Gray.
In its press release announcing the voluntary licensing agreement, Gilead stated it will “support low-cost access to the drug in high-incidence, resource-limited countries through a two-part strategy: establishing a robust voluntary licensing program and planning to provide Gilead-supplied product at no profit to Gilead until generic manufacturers are able to fully support demand”.
It is too early in the process to reveal a price for lenacapavir yet, the spokesperson from Gilead told Spotlight.
“While Gilead prepares for global regulatory filings, it is too early to disclose the price of lenacapavir for HIV prevention. Our pledge is to price our medicines to reflect the value they deliver to people, patients, healthcare systems and society. For Gilead-branded lenacapavir, we do plan to price it at no profit to Gilead in 18 select high-incidence, resource-limited countries until generic manufacturers are able to fully support demand,” the spokesperson said.
Spotlight previously reported on research that estimated that if produced at sufficient volumes, the price of lenacapavir could be drastically reduced to levels likely considered affordable by the South African government. For instance, if enough volume was produced to supply 10 million people with PrEP, the price for the injection could be as low as $40 (under R800) per person per year. At the moment, Gilead supplies lenacapavir for HIV treatment in wealthy countries for about $40 000 per person per year.
Gilead’s lenacapavir product will be the first to register in South Africa and will almost certainly be the only lenacapavir product available here for several years – that is because it is expected to take generic manufacturers a few years before they can start producing generic lenacapavir. Based on calculations made for other PrEP products, it seems unlikely that the Department of Health would be willing to procure lenacapavir at a price significantly above R1 000 per person per year. The HIV prevention pill currently costs government around R800 per person per year.
A therapy showing promise to help control tuberculosis (TB) does not interfere with combined antiretroviral therapy (cART), according to research by Texas Biomedical Research Institute (Texas Biomed) which was recently published in JCI Insight.
“This is an important hurdle that this host-directed therapy had to clear in order to help patients battling both HIV and TB,” said study leader Professor Smriti Mehra, PhD of Texas Biomed.
TB is responsible for more than 1.3 million deaths worldwide every year. Dr. Mehra and her team have been investigating a therapy currently used in cancer as a potential treatment for patients with drug-resistant TB and/or comorbid HIV. While many cases of TB can be controlled with months of antibiotics, the infection can return in people who are immunocompromised as a result of HIV. Now that cART is so effective at controlling HIV, a resurging TB infection can often be deadly to those individuals.
Dr Mehra is studying a host-directed therapy that blocks or inhibits an immune system protein naturally found in the body. The protein, called IDO (short for Indoleamine-2,3-dioxygenase), normally suppresses the immune system, preventing it from causing excessive inflammation and organ damage. Inhibiting IDO for short intervals of time has led to more successful cancer treatments. Dr. Mehra’s team has previously shown the same approach improves control of TB in conjunction with antibiotics.
This current study in nonhuman primates with both TB and simian immunodeficiency virus, the nonhuman primate version of HIV, showed the IDO inhibitor does not interfere with cART.
Researchers compare the impacts of cART by itself versus cART plus the IDO inhibitor in lung tissue of nonhuman primates with both TB and SIV. Left: Following just cART, significantly more IDO is detected in pink. Right: With the IDO inhibitor and cART, immune cells recruited to fight bacteria are observed inside the granuloma, a hallmark structure of TB. Specifically, CD4+ T cells are in green and CD68 proteins expressed by macrophages are in red.
“There was no increase in viral load in animals given cART and the IDO inhibitor, compared with animals only given cART, proving the inhibitor is safe to give to patients with HIV,” Dr. Mehra said.
Now that the researchers have shown the inhibitor works well in conjunction with TB antibiotics and with cART separately, they plan to study how it performs when given in conjunction with both antibiotics and cART together. This treatment regimen is standard for patients with both HIV and active TB. Dr. Mehra said that longer-term studies are also needed to confirm there are no unintended side effects.
The IDO inhibitor is already FDA-approved for use in patients with cancer, which shortens the path to potential approval for patients with TB/HIV when compared with developing a brand-new drug.
The African Centre for Disease Control and World Health Organization have raised the alarm following a drastic uptick in mpox cases. This surge is being driven by a new strain of the virus. Elri Voigt reports about what we know so far and potential implications for South Africa.
Mpox, a viral illness first identified in Africa in 1970, made headlines in 2022 when it spread across the globe for the first time. Since then, the outbreak has evolved, with multiple strains of the virus circulating in different countries. A new strain, known as clade Ib, first discovered in the Democratic of the Republic of Congo (DRC), is responsible for much of the most recent surge in mpox cases.
These recent developments are complex, and the situation is likely to change. This was the common theme of a special session on the mpox outbreak during the World Health Organization (WHO) Regional Committee for Africa meeting at the end of August. This session took place two weeks after the WHO declared the outbreak to be a Public Health Emergency of International Concern.
“We don’t have one outbreak. We have multiple outbreaks in one,” Dr Jean Kaseya, the Director General of the African Centre for Disease Control (CDC) remarked.
These outbreaks are caused by different clades of the mpox virus. Clades are a classification system based on the genetic similarities between different strains of a virus, explained Professor Tulio de Oliveira, Director of the Centre for Epidemic Response and Innovation (CERI) at Stellenbosch University (SU). “So, what it means is that when we see a genetic change [in a virus] that’s really visible and that may have impacted it, normally we call it a different clade or genotype or variant,” he said.
This is similar to classifying different strains of SARS-CoV-2 as variants, Dr Duduzile Ndwandwe, a molecular biologist working for Cochrane South Africa, an intramural research unit within the South African Medical Research Council, told Spotlight.
She explained that the different mpox clades and sub-clades have mutated so they have genetic differences but still fall under the umbrella of mpox.
“In a nutshell…it’s just talking about the differences in the genome sequence of the virus, how many mutations [it has] or how big the mutations are in that virus’s strain of mpox,” she said.
‘Jump in evolution’
Dr Aida Sivro, senior scientist at the Centre for the AIDS programme of Research in South Africa (CAPRISA), in 2022 told Spotlight that there are two clades of the mpox virus, which were then referred to as the Central African Clade (clade I) and the West African Clade (clade II).
Since then, clade I went through a big jump in evolution and a sub-clade emerged in the DRC, now called clade Ib, De Oliveira told Spotlight. The previous outbreak in 2022 was mostly driven by another sub-clade called clade IIb.
To further complicate matters, there’s a third strain of the virus also circulating – clade Ia.
At the moment, the DRC accounts for about 90% of mpox cases in the African Region, according to Dr Fiona Braka, the Emergency Response Manager for WHO’s AFRO region. She explained that right now the situation is not fully understood because a lack of diagnostics and testing capabilities is limiting understanding of the true burden of disease.
What we do know, she said, is that there are two distinct outbreaks in the DRC. Based on the information currently available, clade Ia is circulating in regions in the country where mpox is considered endemic and affecting mostly children. While clade Ib is spreading mostly among adults in the eastern provinces of South Kivu and North Kivu.
The clade Ib strain has since spread from the DRC to neighbouring countries Burundi, Rwanda, Uganda and Kenya, according to Braka. Sweden and Thailand have also identified one case each.
As of 1 September, the WHO reported that there have been 3 751 confirmed cases of mpox and 32 deaths across 14 countries in African in 2024 alone. But there are many more suspected cases of mpox that have not been tested.
Implications for South Africa
De Oliveira said at this point, South Africa shouldn’t be overly concerned about mpox, but it should be alert. The best way to do this is to make sure the public know what the symptoms are so they can present for diagnosis and treatment if they suspect they have the virus.
In a similar vein, Ndwandwe said the public shouldn’t panic, but we as a country need to remain vigilant. She added that because clade Ib is spreading on the African continent, there is a risk of it spreading to South Africa through cross-border travel, making it a public health concern.
This year, 24 cases of mpox have been reported in South Africa. Three people have died, while 19 have recovered. Two people are still considered to have active disease, with the most recent case identified in early August.
But this doesn’t necessarily mean there aren’t more cases of mpox in the country. “What we do suspect is that we may have milder cases that are actually not reported,” Nevashan Govender, the operation manager of the Emergency Operations Center at the National Institute for Communicable Diseases (NICD) told Spotlight.
He said so far, all the cases in the country have been caused by clade IIb and no cases of clade Ib have been identified.
A polymerase-chain-reaction (PCR) test is the gold standard test used to determine whether someone has mpox. But genome sequencing would need to be done to identify what clade they have.
Lots of unknowns around new strain
At the moment, there are a lot of unknowns around clade Ib.
What is of concern, according to Braka is the severity of disease seen especially in people who are immunocompromised and in pregnant women and children. Ndwandwe added to this and said there is a concern that clade Ib has higher fatality rates than clade IIb.
De Oliveira cautioned against jumping to conclusions about the severity of this new clade without sufficient data. He said we don’t know for sure yet if clade Ib is causing more severe disease than IIb. What we do know from mpox in general, he said, is that when someone is immunocompromised in some way, they tend to develop more severe symptoms.
Govender echoed De Oliveira’s caution that we don’t yet know enough about clade Ib to say definitively if it is for example more transmissible than other clades
“It’s not to say that it isn’t [more transmissible], but there is just not a lot of evidence stating that it is absolutely true…There’s a lot of knowledge and information gaps,” he said.
The NICD in a recent update also stressed that there are a lot of unknowns about this new strain. It added: “South Africa continues to prioritise enhanced surveillance and raising awareness for mpox.”
The state of vaccines and treatment for mpox
Spotlight reported previously that the smallpox vaccine, which hasn’t been routinely administered in South Africa since the 1980s when smallpox was eradicated, is thought to offer some degree of protection against mpox. However, it’s difficult to predict just how much protection the smallpox vaccine would provide, Sirvo told Spotlight for that previous article.
There are currently three vaccines against mpox that have been approved in some countries, a spokesperson from the vaccine alliance Gavi told Spotlight. These are LC16m8, JYNNEOS and ACAM2000.
LC16m8 is a third-generation small pox vaccine manufactured by KM Biologics. According to WHO, from 2022 it had mainly been used in Japan.
The JYNNEOS vaccine is a third-generation smallpox vaccine, manufactured by Bavarian Nordic, Ndwandwe said, and it was used during the outbreak in 2022. She added that this vaccine is considered the preferred option due to its safety profile and targeted protection against mpox.
ACAM2000 is a second-generation vaccine for smallpox and manufactured by Emergent BioSolutions. But it was only approved by the FDA for use in those at high risk for mpox at the end of August this year. It was not widely used during the 2022 outbreak but was available in some places under a compassionate use protocol (a means of providing medicines or vaccines that have not yet been registered).
In 2022, the Centre for Disease Control (CDC) recommended that JYNNEOS be used as the primary vaccine against mpox because it was associated with fewer side effects than ACAM2000.
While these vaccines exist, it doesn’t mean everyone can access them easily. Countries on the African continent have so far relied on vaccine donations facilitated by the WHO, with an initial 10 000 doses expected to arrive in Africa sometime this month.
Vaccine manufacturers KM Biologics and Bavarian Nordic have submitted proposals to the WHO for emergency use listing (EUL), according to WHO Director-General Dr Tedros Adhanom Ghebreyesus. He added this will allow UNICEF and the vaccine alliance GAVI to buy the vaccines to supply to countries that haven’t issued their own national regulatory approval yet.
The treatment options for mpox are also limited. According to this WHO factsheet on mpox, some antivirals have received emergency use authorisation in some countries and are being evaluated in clinical trials. However, so far there is no proven effective antiviral treatment for mpox.
Tecovirimat, which was approved to treat smallpox, is one of these antivirals being evaluated. According to the CDC, studies in animals have shown the antiviral might help treat mpox but it is still considered an investigational drug for mpox. The drug has been used in some cases of severe mpox.
When asked about this, Ndwandwe agreed more research needs to be conducted to fully understand the evidence around using Tecovirimat. “But what we know now is that the fact that it was authorised for compassionate use, there is some benefit to using that treatment, given that there isn’t any other [treatment,” she said.
Mpox vaccine and treatment availability in South Africa
According to De Oliveira, a small batch of vaccines against mpox and an antiviral drug were made available to South Africa through donations during the outbreak earlier this year.
But the country would need more vaccines if cases increase to protect those at risk for severe disease.
At the moment, South Africa does not have access to any mpox vaccines and has asked for a donation of 40 000 vaccine doses, Foster Mohale, spokesperson for the health department told Spotlight. The country has requested the JYNNEOS vaccine, based on the recommendation by the National Advisory Group on Immunisation.
He added that South Africa’s request to its international partners and the WHO is ongoing support with access to tecovirimat should the need increase. He also requested the WHO’s assistance in procuring the 40 000 vaccine doses to vaccinate high-risk groups if mpox cases increase.
When asked if the department will be entirely reliant on donations of mpox vaccines or would seek to procure its own if cases increase, Mohale said it depends. “South Africa has been in communication with the vaccine manufacturer, Bavarian Nordic, and will consider procurement if needed,” he added.
Because there is a shortage of mpox vaccines and treatment and uncertainty about the sustainability of donated supplies, Ndwandwe said: “Our best defence at this point in time is to prevent [the spread of mpox cases] as much as possible and detect the cases as they start, early on.”
Symptoms of mpox
Govender said the NICD is urging people not to panic but to stay informed on the signs and symptoms of mpox using some of the accurate information available from either the National Department of Health or the NICD.
“The first line of defence for any public health emergency and outbreak comes from when people take initiative to protect themselves,” he said.
Mpox, which is spread by close contact, either household or sexual contact, with someone who has the virus, could initially manifest in flu-like symptoms or the characteristic mpox rash. These include a fever, sore throat, muscle aches, headaches and swollen lymph nodes, according to the WHO factsheet on mpox. The rash starts flat and then becomes a blister filled with fluid, which eventually dries and falls off. The rash can occur on someone’s palms or soles of their feet, face, mouth and throat and sometimes the genital areas.
Children, pregnant women and those who are immunocompromised are most at risk for developing severe disease or dying, the factsheet stated. This includes people living with HIV whose viral load is not well controlled.
Mpox is a virus and as with all viral infections it’s the immune system that fights it off, Ndwandwe explained. However, if someone is immunocompromised, so has a weakened immune system, there is a greater chance that the mpox virus will overtake their immune system and cause severe disease.
This is one of the reasons why we would be concerned about the disease in South Africa, Professor Helen Rees, the Co-Chair of the Incident Management Team (IMT) on mpox, previously told eNCA.
“We have many people living with HIV in the country, many of whom are on antiretroviral therapy, their immune system is good. But we have many others, who don’t know what their status is and might be vulnerable to severe mpox,” she said.
Finalised data published in the New England Journal of Medicine, has confirmed the stunning results of a trial in which a twice-yearly dose of lenacapavir completely prevented HIV infection in a group of adolescent girls and women in South Africa and Uganda.
A major challenge with HIV prophylaxis with cisgender women is adherence and persistence with daily oral regimens. The twice-yearly subcutaneous injection of lenacapavir helps to circumvent these problems by offering extended protection.
Based on the initial results announced by Gilead Sciences on the 20th of June, the PURPOSE 1 phase 3 clinical trial met its key efficacy endpoints of superiority of twice-yearly lenacapavir to once-daily oral (emtricitabine 200mg and tenofovir disoproxil fumarate 300mg; F/TDF) and background HIV incidence. Given the strength of these results, the blinded phase of the trial was halted and open-label lenacapavir was offered to all participants.
The double-blind, randomised, controlled trial recruited 5338 participants who were initially HIV-negative. They were randomised 2:2:1 ratio to receive subcutaneous lenacapavir every 26 weeks, daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral F/TDF (active control); all participants also received the alternate subcutaneous or oral placebo. They compared the efficacy of lenacapavir and F/TAF with F/TDF against the estimated background incidence of HIV infection.
Among the 2134 participants in the lenacapavir group, there were 0 infections (0 per 100 person-years). Meanwhile in the F/TAF group, there were 39 infections among 2136 participants (2.02 per 100 person-years) and 16 infections among the F/TDF group’s 1068 participants (1.69 per 100 person-years).
HIV incidence with lenacapavir was significantly lower than background HIV incidence and than HIV incidence with F/TDF. HIV incidence with F/TAF did not differ significantly from background HIV incidence, and no evidence of a meaningful difference in HIV incidence was observed between F/TAF and F/TDF.
The researchers did note that adherence to F/TAF and F/TDF was low. While no safety concerns were found, injection-site reactions were more common in the lenacapavir group (68.8%) than in the placebo injection group (F/TAF and F/TDF combined) (34.9%); 4 participants in the lenacapavir group (0.2%) discontinued the trial regimen owing to injection-site reactions.
