A new study published in the New England Journal of Medicine found that statins, a class of cholesterol-lowering medications, may offset the high risk of cardiovascular disease in people living with HIV by more than a third, potentially preventing one in five major cardiovascular events or premature deaths in this population. People living with HIV can have a 50–100% increased risk for cardiovascular disease.
“This research suggests that statins may provide an accessible, cost-effective measure to improve the cardiovascular health and quality of life for people living with HIV,” said Gary H. Gibbons, MD, director of the National Heart, Lung, and Blood Institute (NHLBI), a study funder. “Additional research can further expand on this effect, while providing a roadmap to rapidly translate research findings into clinical practice.”
For the double-blinded phase 3 trial, known as Randomised Trial to Prevent Vascular Events in HIV (REPRIEVE) study, researchers randomised participants into either a treatment group, where they received pitavastatin calcium daily or a control group receiving placebo. The researchers followed participants for about five years, but ended the trial early when they discovered the treatment benefits outweighed potential risks.
To understand the benefits, the researchers compared how often participants in each group experienced major cardiovascular events, including heart attacks, strokes, or surgery to open a blocked artery. They found participants who took daily pitavastatin had 35% fewer major cardiovascular events than those who took a placebo. The researchers also measured the number of deaths in combination with major cardiovascular events during the study period and found participants in the treatment group were 21% less likely than those in the placebo group to experience these events. Additionally, those taking pitavastatin had a 30% reduction in their low-density lipoprotein (LDL) cholesterol levels.
“Lowering LDL cholesterol levels reduces risks for cardiovascular events, like having a heart attack and stroke, but these findings suggest there may be additional effects of statin therapy that explain these reduced risks among people living with HIV,” said Steven K. Grinspoon, MD, the study chair. “Ongoing research about how statin therapy may affect inflammation and increased immune activation among people with HIV may help us better understand the additional benefits we’re seeing with this treatment approach.”
To support optimal health outcomes among the study participants, normal liver and kidney function were an enrolment criteria. They were also required to take antiretroviral therapy, which itself is critical to reducing the risk of HIV complications and related comorbidities, including cardiovascular disease.
Beginning in 2015, REPRIEVE enrolled 7769 adults, ages 40–75, from 145 sites in 12 countries. Adults in the study were an average age of 50 and had low-to-moderate risks for cardiovascular disease, which meant they normally would not have been prescribed statins. Women accounted for 31% of participants. Approximately 41% of study participants identified as Black, 35% as white, 15% as Asian, and 9% as another race.
In what is likely one of the largest treatment rollouts in South African history, well over four million people living with HIV have started taking the antiretroviral dolutegravir since its introduction around four years ago. Now, according to a recent study published in the Lancet medical journal, use of dolutegravir in South Africa is associated with more people staying on treatment and higher rates of viral suppression.
The use of a three-in-one combination of the antiretroviral drugs tenofovir, lamivudine and dolutegravir (TLD for short) for the treatment of HIV was first recommended by the World Health Organization (WHO) in 2018. A year later it was recommended in the South African treatment guidelines as first line treatment for HIV and a three-year tender was awarded. Since then, dolutegravir has largely replaced another antiretroviral called efavirenz.
Today, TLD is the recommended treatment option for most people living with HIV in the country. The 2023 National antiretroviral (ARV) guidelines also include recommendations for the use of child-friendly formulations of dolutegravir and dolutegravir containing regimens in kids. Spotlight reported on these here.
Around 4.7m people in SA taking dolutegravir
According to Foster Mohale, spokesperson for the National Department of Health, in 2019 the HIV clinical guidelines were revised to include a fixed combination dose of TLD “for all eligible people for use as the first line regimen.”
Based on this, the department set a goal that 90% of those eligible for it should receive TLD as a first line regimen. In terms of meeting this goal, Mohale says that by March 2023, just over four million (4 127 427) people were on TLD. Additionally, about 650 000 (653 884) people were on other dolutegravir based regimens. Altogether, there are thus now over 4.7 million people in the country on treatment combinations that include dolutegravir.
“Based on the March 2023 data, 90% of clients on first line regimen were on TLD. However, performance varies by province,” he says.
Of the total number of people on ART in the public health sector, 75.8% are on TLD, according to Mohale.
Trends in the roll out
While on paper the country’s transition from efavirenz to dolutegravir-based regimens seems to have been smooth, the reality on the ground has been more complex. A study published in the Lancet earlier this year looked at real-world rollout data from 2019 to 2022. The study was conducted in 59 clinics across the country and collected data from two cohorts-one cohort were first time initiators of ART and the other were transitioning from regimens that did not include dolutegravir to ones that did.
In the initiator cohort, just over 45 000 people were initiated on ART between December 2019 and February 2022. Of those, 68.9% were initiated on dolutegravir-based regimens, 31.1% on efavirenz-based regimens, and 0.1% on nevirapine-based regimens.
Those initiated on dolutegravir-based regimens were more likely to still be on treatment a year later and were also more likely to be virally suppressed than those who were initiated on the other regimens.
In December 2019, in the transition cohort, just over 180 000 people were on a non-dolutegravir first line regimen. By February 2022, 67% of them had transitioned to a dolutegravir-based regimen. These people were also more likely to be retained in care at 12 months and be virologically suppressed than those who had not switched to a dolutegravir-based regimen.
“That’s good for a number of reasons. It means that the treatment’s working, people are less likely to get unwell and also, they can’t transmit the virus onto other people,” explains Dr Jienchi Dorward, one of the study authors and an academic clinical lecturer at the University of Oxford and honorary associate scientist at the Centre for the AIDS Programme of Research in South Africa (CAPRISA).
‘Bumpy transition’
Dr Yukteshwar Sookrajh, a Senior Medical Practitioner at the eThekwini Municipality Health Unit who was also involved in the study, tells Spotlight that the rollout quickly gathered momentum.
“But initially there were some issues to navigate around drug interactions; concurrent TB infection and the use of dolutegravir in women of childbearing potential,” he says. “Once those concerns were addressed, the comfort of switching to dolutegravir was increased and we find that the majority of our patients have now safely transitioned across to dolutegravir-based regimens.”
In many ways South Africa was slow in rolling out dolutegravir compared to other African countries, according to Professor Francois Venter, the head of Ezintsha at Wits University. Reasons for this, he says, include an initial concern around the safety of dolutegravir use among pregnant women, and disruption in training due to the COVID-19 pandemic.
He says that the South African Clinicians society was alerted during the COVID-19 pandemic that many patients in the public health sector had still not been transitioned to dolutegravir. An education campaign was then launched to encourage clinicians to start or switch patients to dolutegravir.
However, as it stands now the rollout of the drug in the public sector has been a huge success, despite what Venter calls a “bumpy transition”.
Initial safety concerns
One important reason to conduct the study reported in the Lancet, according to Dorward, was a safety concern regarding the use of dolutegravir by pregnant women. An earlier study conducted in Botswana called Tsepamo found a higher prevalence of neural-tube defects (a type of birth defect) associated with dolutegravir exposure at conception than with other types of antiretroviral exposure. As more data has been gathered since, it has however become clear that dolutegravir does not in fact increase the risk of neural-tube defects.
But the Tsepamo scare did impact who was initiated and transitioned onto dolutegravir in first two years of the rollout.
“The initial concerns around neural-tube defects and the use of dolutegravir in women of childbearing potential clearly hampered rollout of dolutegravir in women – and this has been clearly demonstrated in this study,” says Sookrajh.
The Lancet study found that pregnant women and non-pregnant women were less likely to be initiated on dolutegravir than men early in the rollout, with the biggest difference between women and men aged 15 to 24 years old. This difference decreased with age and by age 55 there was no difference between men and women receiving dolutegravir.
But this changed over time and by September 2021 women were as likely to get initiated on dolutegravir as men. Spotlight previously reported that the rollout was done in two stages. In the first stage men, adolescent boys, women on reliable contraception, and older women were prioritised.
Of those who started treatment during the study period, 46.9% of the pregnant women in the cohort were initiated on dolutegravir-based regimens, while 63.9% of the non-pregnant women and 82.3% of the men in the cohort were initiated on dolutegravir-based regimens.
“In both those groups [cohorts] we found that women were less likely than men to get dolutegravir, but interestingly, this was particularly in younger women,” Dorward explains. “As time went on, the difference between men and women became much less…around June to September 2021 was a time period where we found that women and men pretty much began to equally get dolutegravir.”
Dorward says the data showed an uptick in women in the study being given dolutegravir once the South African guidelines changed to reflect that there was no longer a concern around neural-tube defects. It is thus likely that the safety concern was responsible for the lower initial uptake among young women.
He adds that the messaging around this potential risk was based on the evidence available at the time and was clearly outlined in the guideline document and training for dolutegravir use, but these did not appear to adequately allay these concerns among healthcare workers.
“The risks versus benefits needed to be messaged in a more effective way such that healthcare workers were more comfortable and confident in offering dolutegravir to women,” he says. Based on this experience Sookrajh adds that in future there needs to be more engagement with “practitioners on the ground to determine what type of messaging and supportive materials are required to facilitate better understanding of guidelines at the coal face.”
Another concern for some healthcare workers has been that dolutegravir-based regimens have been associated with greater weight gain than efavirenz-based regimens. But, as argued in a recent editorial in the Southern African Journal of HIV medicine, association is not the same as causation and it may well be that efavirenz inhibits weight gain rather than dolutegravir promoting it. People living with HIV who start taking antiretroviral medicines often gain weight as their health recovers.
New guidelines should further boost uptake
Sookrajh says that the National Department of Health’s antiretroviral (ARV) 2023 guidelines will further improve the uptake of dolutegravir in the public healthcare system.
“With the April 2023 National Department of Health ARV Guidelines, we actually find that further barriers to switching to dolutegravir have been removed and dolutegravir is clearly placed as the preferred drug of choice in almost all scenarios for both first- and second-line antiretrovirals,” he says.
“I think the new [ARV] guidelines hopefully will be a big improvement for people who are on treatment, and part of that is possible because we’re using the drug that is better. You’re less likely to get resistance with dolutegravir so we’re less worried if people don’t take treatment properly that they might get drug resistance, although we still need more research to be sure about that,” Dorward says. “And it’s still very important for people to take treatment consistently to suppress the virus and maintain their own health and prevent onward transmission.”
According to Venter, there needs to be proper resistance surveillance to detect potential dolutegravir resistance.
“We can’t take for granted we’ll never have resistance [to dolutegravir]…eventually there will be the occasional patient that does have resistance, but we need proper surveillance there,” he says. “And then we need to keep an eye on things. There are still patients getting HIV…there’s still a lot of new infections…we need to make that stop…we’ve got amazing PrEP and way too few people getting it. So, we do need to start addressing that.” (PrEP, or pre-exposure prophylaxis, refers to antiretrovirals taken to prevent HIV infection.)
Venter adds that while successful in the public health sector, the uptake of dolutegravir has been extremely slow in the private health sector for reasons unknown to him.
Several sessions at the 11th SA AIDS conference, recently held in Durban, highlighted the worrying fact that key HIV numbers such as treatment coverage are much lower in children than in adults. There is hope, however, that new treatments and new treatment guidelines might help close the gap.
In a plenary session, Dr Sandile Buthelezi, Director General of the National Department of Health, told delegates that on UNAIDS’ 95-95-95 targets, children in South Africa are at 81-65-68. This means that 81% of children living with HIV have been diagnosed, 65% of those diagnosed are on antiretroviral treatment, and 68% of those on treatment are virally suppressed. For the South African population as a whole, the numbers are at 94-76-92.
Throughout the conference, various speakers highlighted the fact that only 65% of children who have been diagnosed are on treatment as a particular concern. To close the gap and reach UNAIDS’ target of 95%, just over an additional 88 000 children would need to be initiated on treatment.
Professor Lee Fairlie, Director of Maternal and Child Health at Wits RHI, said in a presentation that only 52% of children younger than 14 living with HIV are on treatment. Fairlie also pointed out that children lagged behind substantially when it comes to viral suppression, and this is particularly challenging in the youngest age groups.
Not all bad news
But it was not all bad news at this year’s conference. One piece of good news is that new and better child-friendly antiretroviral formulations are being rolled out in South Africa. These new treatments should make it easier for children to start and stay on treatment – children often find it difficult to take medicines formulated for adults, due to factors like incorrect dosing, large pills, and bad taste.
The National Department of Health recently updated the country’s antiretroviral treatment guidelines to allow for the use of several of these new formulations and better HIV treatment regimens for children. Most notable is the introduction of a new regimen consisting of the medicines abacavir, lamivudine and dolutegravir (ALD for short).
Speaking at the conference, Dr Leon Levin, a paediatrician who has been treating infants, children, and adolescents living with HIV for almost three decades, pointed out that the availability of new paediatric formulations had a major impact on the new treatment guidelines. (Spotlight previously reported on the registration of some of these new formulations here.) Levin is also the Senior Technical Advisor in Paediatrics at the NGO Right to Care.
One such child-friendly formulation is a 120/60mg scored, dispersible tablet of abacavir and lamivudine that can be taken in patients who weigh between 3 and 25kg. It is given once daily and two generics are registered with the South African Regulatory Authority (SAHPRA). “It’s going to literally replace all the other paediatric Abacavir+3TC formulations. You can swallow it, chew it, crush it, or dissolve it in water. So [it’s] very versatile,” he said.
Also important is a paediatric formulation of the antiretroviral dolutegravir – a medicine that forms the backbone of HIV treatment in adults. According to Levin, the child-friendly version of dolutegravir is not available to everyone yet, and many clinicians still need to undergo training on how to use it. It is a 10mg dispersible, scored tablet given once daily that can be used at 3kg and higher and from four weeks of age onward. There are two generic versions of this product registered with SAHPRA.
The introduction of paediatric dolutegravir is likely to overshadow the introduction of a four-in-one formulation of abacavir, lamivudine, lopinavir/ritonavir. The four-in-one combination has to be taken twice daily, is strawberry flavoured and comes in a powder form. “Unfortunately, this product to nobody’s fault was launched at the same time as paediatric dolutegravir. Which means paediatric dolutegravir is going to take centre stage and this product unfortunately is not going to be used much,” Levin said.
Updated guidelines
Levin explained that the changes to South Africa’s treatment guidelines focused on doing two main things when it comes to children living with HIV, the first is to implement an optimised regimen – the ALD regimen and the second is to create an “enabling environment to support engagement in care and adherence”. He said that with the new guidelines, we can expect “much improved [viral] suppression, optimised regimens, improved synchronisation of clinic visits, happier patients and their families and clinicians as well”.
A big change to the guidelines is that now children who weigh 3kg and are four weeks of age should be started on the ALD regimen, instead of the abacavir, lamivudine, and lopinavir/ritonavir regimen that was previously recommended. “This is a major change. It’s a fantastic, well-tolerated regimen. It’s potent and you’re going to get around a lot of the issues you had with these younger children,” Levin said.
Once the children on this regimen get to 30kg, they will be switched to a regimen containing tenofovir, dolutegravir, and lamivudine (TLD for short). TLD is also the regimen adults living with HIV in South Africa are offered when starting treatment for the first time.
For children who are already on treatment, the new guidelines recommend that all children who are four weeks of age and older and weigh 3kg or more should be transitioned to a dolutegravir-containing regimen. For children with suppressed viral loads, the switch to ALD or TLD is straightforward, while for children without viral suppression, it can get more complicated.
Another important change is that children over five years of age are now eligible for Repeat Prescription Collection Strategies (RPCs) if they are virally suppressed and had an age-appropriate disclosure, which means that their HIV status has been explained to them in a way that is appropriate for their age, as outlined in the guidelines. For children under five, they can be given a three months supply at a time, providing they are at least six months old. Levin pointed out that whenever RCPs or a three months supply is considered for children, it is essential to look at where and how the parents may be receiving their own antiretroviral treatment so that it can be co-ordinated, and parents don’t have to go to two different places to collect the medications.
New options in the pipeline
While the paediatric formulations included in the new guidelines are a step forward, there are experimental treatments in the pipeline that may make treatment yet more convenient for children.
“There’s a rich pipeline of new combinations and drug delivery developments. Hopefully, this will further improve access, clinical and virological outcomes,” Fairlie said in a conference presentation. “Obviously, the paediatric market is extremely small and then one has to maintain enthusiasm for manufacturers to actually continue to look at the paediatric population. And so, merging of treatments and prophylaxis regimens is really what would work going forwards.”
In her presentation, she specifically referred to long-acting formulations of cabotegravir (CAB-LA) and rilpivirine (RPV). CAB-LA has already been approved by SAHPRA for HIV prevention in adults and, as Spotlight reported last week, pilot projects evaluating how to best provide the CAB-LA injection in South Africa are set to start soon. The combination of CAB-LA and rilpivirine injections has been approved for the treatment of HIV in adults by the United States Food and Drug Administration, but not yet by SAHPRA. The injections are administered every two months.
Fairlie says that currently there are several studies either ongoing or set to start soon for the use of these agents in the paediatric and adolescent age groups. In addition, there are also trials planned to test another long-acting medication called lenacapavir in adolescents and broadly neutralising antibodies (bNAbs) in children.
She also highlighted several improved delivery methods that are in the pipeline for paediatrics. These include a mechanism that doesn’t require water, like oro-dispersible tablets, also known as fast melts, which disintegrate in the mouth as well as oral films that stick to the mouth, disintegrate there, and dissolve. There are also various tablet options that are small enough for children to swallow easily. Like multi-particulates, which are small and solid, multiple-unit dosages that can take the form of granules, pellets, or beads. Mini-tablets are also a prospect – these are compressed tablets no larger than 4ml. Finally, there are novel mechanisms like long-acting oral drug delivery systems and micro-array patches. Fairlie explained that long-acting oral drugs are where a drug is stored in the centre of a capsule that has a number of “arms”, which are able to keep the capsule in the stomach and slowly dissolve and release the drug into the stomach. This allows for slow-release dosing. The “arms” tend to break down after about seven days.
June is Men’s Health Month and while the focus is mostly on men’s attitudes about their health, it is also worth reflecting on the health sector’s attitudes toward men.
We hear many stereotypes about men and health, but how many of those are actually true?
A few years ago representatives of The Mpilo Project spoke to more than 2 000 men in KwaZulu-Natal and Mpumalanga to understand why many find it hard to engage with HIV testing and treatment. We uncovered several myths and misperceptions in the process.
One common myth is that men are stubborn and apathetic about HIV – that they aren’t listening and don’t care. While many men may indeed wear a mask of indifference, HIV leaves many of them feeling paralysed by fear and anxiety. This is why we need a health service delivery approach rooted in encouragement and reassurance, not scolding and pressure.
Another common misconception is that men are mainly just workers who need practical solutions like convenient clinic hours and quick service. The reality is that men are complex human beings who face social and emotional barriers as well as practical ones. We need solutions that address both practical and psychosocial barriers.
There is also a view that sources of support are available and that men just fail to access them, perhaps because “they don’t really want support”. In fact, many men are hungry for support but see no sources that feel safe or relatable. They experience counselling as scripted, one-directional, overly technical, and often judgmental. The key is to give men the right sources of support and to speak empathetically to their individual issues and concerns.
Finally, there is a view that healthcare providers are helping men by taking proactive approaches like provider-initiated testing and tracking-tracing. But these often leave men feeling hunted and ambushed by the health system. We need proactive approaches that leave men feeling like they still have control over their own lives and decisions and help them develop their own internal motivation to start and stay on treatment.
These and other misconceptions can lead healthcare providers to conclude that men are simply difficult if not impossible to reach. But once we understand their barriers, that picture changes dramatically.
The 11th SA AIDS Conference concluded last week and in one of the plenary sessions we had the opportunity to respond to the question: “Strategies for reaching men—are we seeing a return on investment?”
The short answer is yes!
Since 2017, the percentage of men with HIV in South Africa who know their status has increased from 78% to 94%, nearly on par with women. We can attribute that in part to approaches like HIV self-testing that have made it quick, easy, and private for men to learn their status.
We’ve also seen good progress on viral suppression, which has increased from 82% to 93%, again comparable to the rate among women – proof that men on treatment are fully capable of being adherent.
Yet only 70% of men who know they have HIV are currently on treatment – hardly any increase at all from 68% in 2017.
Given the progress we’ve seen in men testing for HIV and achieving viral suppression, the persistent gap in men on treatment suggests that something is wrong – not with men but with the HIV treatment services and support we are offering them.
The good news
The good news is that we know much more than we did a few years ago about what works. Here are three examples.
The MINA campaign aims to reach men with “the new HIV story” by featuring stories from real men living a healthy, happy life with HIV on social media, television, radio, billboards, etc. The campaign also helps men feel more welcome in the clinic, using signage and materials to send the signal to men that “this is your space too”. MINA-supported districts and facilities have seen strong growth in testing and linkage, as well as modest improvement in retention in care.
The Coach Mpilo model employs men who are thriving with HIV as coaches of men at risk of non-initiation or disengagement. Coaches provide a safe, relatable source of support and serve as living proof that HIV is not the end of the road. Piloted in 2020 and currently implemented in 18 districts, the model is achieving 97% linkage to care and 94% retention.
The B-OK bead bottles are a simple visual tool for helping people to understand the benefits of HIV treatment and viral suppression and, more importantly, to build the motivation to start and stay on treatment. Red beads are HIV; black beads are healthy cells. A mixed bottle represents most people upon diagnosis. A red bottle represents the virus multiplying uncontrolled in the absence of treatment. A black bottle with one red bead represents viral suppression achieved through treatment adherence. In an evaluation of the tool, understanding of how HIV treatment works increased from 12.5% to 92.5%.
Men are not indifferent about their health and they are not inherently poor health-seekers. If many of them are avoiding healthcare services, let’s consider that it may be because they are not getting what they need from these services.
We have seen that men do engage when we in the public health sector meet them where they are rather than where we want them to be; when we speak to their needs and priorities rather than ours; when we give them the right sources of support rather than one-size-fits-all, and when we help them build understanding and motivation rather than simply instructing.
When we invest, we see returns. Let’s keep investing in scaling what works.
*Malone is the Project Director of The Mpilo Project, PSI.
The Southern African HIV Clinicians Society has just released their updated 2023 guidelines for Antiretroviral Therapy in Adults. These updates reflect the changing treatment paradigms of the current era, specifically the consolidation towards dolutegravir- and darunavir-based treatment regimens, rather than efavirenz- or lopinavir-ritonavir based ones.
They are optimised for accessibility and are available in a PDF format for download, or are viewable as an online version directly on the website. The online version is in an easily navigable form, with the menu guiding readers to the different modules.
The new guidelines also incorporate numerous other changes to ensure that they stay up-to-date and helpful to the healthcare workers who use them. Some of the key changes include:
• Recommendation to shift most patients to a dolutegravir-based regimen if possible.
• For patients requiring a protease inhibitor (PI), recommendation for darunavir as the PI of choice, and for lopinavir/ritonavir to only be considered where a PI is required to be co-administered with rifampicin-based tuberculosis treatment.
• New recommendations on the move away from routine use of zidovudine (AZT) in second-line therapy in favour of recycling tenofovir or, inpatients with renal dysfunction, abacavir.
• Advice on how to assess the increase in serum creatinine seen with dolutegravir/tenofovir fixed dose therapy.
• Guidance on the role of tenofovir alafenamide; TAF.
• Inclusion of enhanced baseline screening for tuberculosis and sexually transmitted infections.
• Expansion of the module on HIV and mental health.
While many antiretroviral therapy (ART) guidelines are available internationally, the current guidelines have been written to address issues relevant to Southern Africa. Only treatment and diagnostic options available in Southern Africa are included. These guidelines also consider affordability because of the region’s low- and middle-income countries. The guideline authors also recognise and addressed the need to bridge the gap in treatment recommendations between public and private sector programmes, as many patients transition between the two sectors for treatment.
New research from Oregon Health & Science University is helping explain why at least five people have become HIV-free after receiving a stem cell transplant. The study’s insights may bring scientists closer to developing what they hope will become a widespread cure for HIV, hopefully without the need for costly techniques like stem cell therapy.
Published today in the journal Immunity, the OHSU-led study describes how two nonhuman primates were cured of the monkey form of HIV after receiving a stem cell transplant. It also reveals that two circumstances must co-exist for a cure to occur and documents the order in which HIV is cleared from the body – details that can inform efforts to make this cure applicable to more people.
“Five patients have already demonstrated that HIV can be cured,” said the study’s lead researcher, Jonah Sacha, PhD, OHSU professor.
“This study is helping us home in on the mechanisms involved in making that cure happen,” Sacha continued. “We hope our discoveries will help to make this cure work for anyone, and ideally through a single injection instead of a stem cell transplant.”
The first known case of HIV being cured through a stem cell transplant was reported in 2009. A man who was living with HIV was also diagnosed with acute myeloid leukemia, a type of cancer, and underwent a stem cell transplant in Berlin, Germany. Stem cell transplants, which are also called bone marrow transplants, are used to treat some forms of cancer. Known as the Berlin patient, he received donated stem cells from someone with a mutated CCR5 gene, which normally codes for a receptor on the surface of white blood cells that HIV uses to infect new cells. A CCR5 mutation makes it difficult for the virus to infect cells, and can make people resistant to HIV. Since the Berlin patient, four more people have been similarly cured.
This study was conducted with a species of nonhuman primate known as Mauritian cynomolgus macaques, which the research team previously demonstrated can successfully receive stem cell transplants. While all of the study’s eight subjects had HIV, four of them underwent a transplant with stem cells from HIV-negative donors, and the other half served as the study’s controls and went without transplants.
Of the four that received transplants, two were cured of HIV after successfully being treated for graft-versus-host disease, which is commonly associated with stem cell transplants.
Other researchers have tried to cure nonhuman primates of HIV using similar methods, but this study marks the first time that HIV-cured research animals have survived long term. Both remain alive and HIV-free today, about four years after transplantation. Sacha attributes their survival to exceptional care from Oregon National Primate Research Center veterinarians and the support of two study coauthors, OHSU clinicians who care for people who undergo stem cell transplants: Richard T. Maziarz, M.D., and Gabrielle Meyers, M.D.
“These results highlight the power of linking human clinical studies with pre-clinical macaque experiments to answer questions that would be almost impossible to do otherwise, as well as demonstrate a path forward to curing human disease,” said Maziarz, a professor of medicine in the OHSU School of Medicine and medical director of the adult blood and marrow stem cell transplant and cellular therapy programs in the OHSU Knight Cancer Institute.
The how behind the cure
Although Sacha said it was gratifying to confirm stem cell transplantation cured the nonhuman primates, he and his fellow scientists also wanted to understand how it worked. While evaluating samples from the subjects, the scientists determined there were two different, but equally important, ways they beat HIV.
First, the transplanted donor stem cells helped kill the recipients’ HIV-infected cells by recognizing them as foreign invaders and attacking them, similar to the process of graft-versus-leukaemia that can cure people of cancer.
Second, in the two subjects that were not cured, the virus managed to jump into the transplanted donor cells. A subsequent experiment verified that HIV was able to infect the donor cells while they were attacking HIV. This led the researchers to determine that stopping HIV from using the CCR5 receptor to infect donor cells is also needed for a cure to occur.
The researchers also discovered that HIV was cleared from the subjects’ bodies in a series of steps. First, the scientists saw that HIV was no longer detectable in blood circulating in their arms and legs. Next, they couldn’t find HIV in lymph nodes, or lumps of immune tissue that contain white blood cells and fight infection. Lymph nodes in the limbs were the first to be HIV-free, followed by lymph nodes in the abdomen.
The step-wise fashion by which the scientists observed HIV being cleared could help physicians as they evaluate the effectiveness of potential HIV cures. For example, clinicians could focus on analysing blood collected from both peripheral veins and lymph nodes. This knowledge may also help explain why some patients who have received transplants initially have appeared to be cured, but HIV was later detected. Sacha hypothesises that those patients may have had a small reservoir of HIV in their abdominal lymph nodes that enabled the virus to persist and spread again throughout the body.
Sacha and colleagues continue to study the two nonhuman primates cured of HIV. Next, they plan to dig deeper into their immune responses, including identifying all of the specific immune cells involved and which specific cells or molecules were targeted by the immune system.
In the RADIANT-TB randomised controlled trial carried out in Khayelitsha, researchers found that tuberculosis (TB) patients with HIV taking a double dose of dolutegravir had similar viral suppression to those taking a single dose plus placebo. The findings, published in The Lancet HIV, suggest that a only once-daily dolutegravir is feasible in patients with HIV-associated tuberculosis.
WHO’s preferred first-line antiretroviral therapy (ART) regimen for adults and adolescents with HIV is dolutegravir, combined with tenofovir and lamivudine or emtricitabine. A disadvantage of dolutegravir is substantial drug–drug interaction with rifampicin, which is important as tuberculosis is the most common cause of hospitalisation and mortality among people living with HIV.
The drug–drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, but is a challenge in resource-constrained settings. The researchers sought to investigate whether virological outcomes with standard-dose dolutegravir-based ART are acceptable in people with HIV on rifampicin-based antituberculosis therapy.
RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial in Khayelitsha, Cape Town, South Africa. Participants were aged over 18 years, with plasma HIV-1 RNA >1000 copies/mL, CD4 count > 100 cells/μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than three months. Participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50mg dolutegravir 12h later or the same drugs but with placebo in place of the supplemental dolutegravir. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first two months followed by isoniazid and rifampicin for four months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies/mL) at week 24 analysed in the modified intention-to-treat population.
No treatment-related dolutegravir resistance emerged in the trial, and though not significant, an increase in insomnia was noted in the supplemental dolutegravir arm. In terms of future research, it is questionable whether a phase 3 trial would be needed given the significant time required for a policy change. Limitations included the study not being powered to compare efficacy.
The authors concluded, “Our findings suggest that twice-daily dolutegravir dosing might be unnecessary in people with HIV-associated tuberculosis. More evidence, from cohort studies or possibly a phase 3 trial, might be necessary to change policy on the need for a supplemental dolutegravir dose with rifampicin-based antituberculosis therapy.”
According to new research findings published in iScience, people living with HIV with a history of pulmonary tuberculosis had broader and more potent HIV antibody responses and differences in HIV sequences predicted to be antibody-resistant as compared to those without tuberculosis. The study suggests that concomitant tuberculosis disease has a significant impact on HIV immune responses and the viruses circulating in people living with HIV.
Tuberculosis infects more than 2 billion people in the world, and although tuberculosis is the most common co-infection in people living with HIV, previous studies have not examined how tuberculosis impacts HIV immune responses and virus characteristics.
This study suggest that tuberculosis may impact the efficacy of antibody based prevention and therapeutic strategies. Vaccines to elicit antibodies and antibodies are also being investigated as a means to treat and cure HIV. Higher prevalence of antibody resistant strains along with tuberculosis disease implies that these antibody-based interventions are more likely to in fail in these individuals.
“Tuberculosis is extremely common, especially in regions of the world with high levels of ongoing HIV transmission, and impacts both the immune responses and the characteristics of the circulating virus in people living with HIV so it is imperative we understand the relationship between the two,” said Manish Sagar, MD, an internist at Boston Medical Center and Professor of Medicine at Boston University Chobanian & Avedisian School of Medicine. “These studies have implications for HIV vaccines and antibody based HIV therapeutics.”
Researchers worked closely with investigators in Uganda and at the AIDS Clinical Trial Group (ACTG) to collect samples from people newly diagnosed with HIV that either did or did not have tuberculosis. From these individuals, they examined samples collected prior to and about 6 months after the start of HIV medications. Researchers compared antibodies, plasma inflammatory markers, and HIV sequences in the baseline and in treatment samples.
Tuberculosis disease is associated with higher prevalence of the some antibody-resistant HIV. High ongoing HIV transmission in areas of the world with frequent tuberculosis disease suggest that a potential vaccine that elicits broad and potent antibodies may not work because these geographic regions are more likely to have antibody resistant strains.
This has implications for HIV vaccine strategies as they aim to generate antibodies that can block the virus after exposure. Generating broad and potent HIV antibodies remains a monumentally difficult goal. Understanding the biological pathways behind the broadly potent antibody responses generated by tuberculosis could provide insight into how tuberculosis enhances HIV antibody responses. This in turn could be leveraged to develop novel strategies for eliciting broad and potent HIV antibodies.
Gene editing therapy aimed at two targets – HIV-1 and CCR5, the co-receptor that helps the virus get into cells – can effectively eliminate HIV infection, report scientists in PNAS. This is the first to combine a dual gene-editing strategy with antiretroviral drugs to cure animals of HIV-1.
“The idea to bring together the excision of HIV-1 DNA with inactivation of CCR5 using gene-editing technology builds on observations from reported cures in human HIV patients,” said Kamel Khalili, PhD, professor at the Lewis Katz School of Medicine. “In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukaemia, and the donor cells that were used carried inactivating CCR5 mutations.”
Dr Khalili and Howard E. Gendelman, MD, professor at UNMC, were senior investigators on the new study from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center (UNMC). The two researchers have been long-time collaborators and have strategically combined their research strengths to find a cure for HIV.
“We are true partners, and what we achieved here is really spectacular,” Dr Gendelman said. “Dr Khalili’s team generated the essential gene-editing constructs, and we then applied those constructs in our LASER-ART mouse model at Nebraska, figuring out when to administer gene-editing therapy and carrying out analyses to maximise HIV-1 excision, CCR5 inactivation, and suppression of viral growth.”
In previous work, Drs Khalili and Gendelman and their respective teams showed that HIV can be edited out from the genomes of live, humanised HIV-infected mice, leading to a cure in some animals. For that research, CRISPR gene-editing technology for targeting HIV-1 was combined with a therapeutic strategy known as long-acting slow-effective release (LASER) antiretroviral therapy (ART). LASER ART holds HIV replication at low levels for long periods of time, decreasing the frequency of ART administration.
Despite being able to eliminate HIV in LASER-ART mice, the researchers found that HIV could eventually re-emerge from tissue reservoirs and cause rebound infection. This effect is similar to rebound infection in human patients who have been taking ART but suddenly stop or experience a disruption in treatment. HIV integrates its DNA into the genome of host cells, it can lie dormant in tissue reservoirs for long periods of time, out of reach of antiretroviral drugs. As a consequence, when ART is stopped, HIV replication renews, giving rise to AIDS.
To prevent rebound infection, Dr Khalili and colleagues began work on next-generation CRISPR technology for HIV excision, developing a new, dual system aimed at permanently eliminating HIV from the animal model. “From success stories of human HIV patients who have undergone bone marrow transplantation for leukaemia and been cured of HIV, our hypothesis was that the loss of the virus’s receptor, CCR5, is important to permanently eliminating HIV infection,” he explained. They developed a simple and more practical procedure for the inactivation of CCR5 that includes an IV inoculation of the CRISPR gene editing molecule.
Experiments in humanized LASER-ART mice carried out by Dr Gendelman’s team showed that the constructs developed at Temple, when administered together, resulted in viral suppression, restoration of human T-cells, and elimination of replicating HIV-1 in 58% of infected animals. The findings support the idea that CCR5 has a key role in facilitating HIV infection.
The Temple team also anticipates soon testing the dual gene-editing strategy in non-human primates.
The new dual CRISPR gene-editing strategy holds exceptional promise for treating HIV in humans. “It is a simple and relatively inexpensive approach,” Dr Khalili noted. “The type of bone marrow transplant that has brought about cures in humans is reserved for patients who also have leukaemia. It requires multiple rounds of radiation and is not applicable in resource-limited regions, where HIV infection tends to be most common.”
Colourised scanning electron micrograph of HIV (yellow) infecting a human T9 cell (blue). Credit: NIH
A large randomised controlled trial into using statins in people with HIV and low-to-moderate cardiovascular risk was stopped early due to clear benefits, according to an update posted online in JAMA Network. Participants, who were taking 4mg pitavastatin calcium daily, saw a 35% reduction in risk with no significant difference in adverse events compared to placebo, according to the National Institutes of Health.
This recommendation came after a planned interim analysis of data from the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) study, which enrolled 7769 participants, across 12 countries across Asia, Europe, North America, South America and Africa. Participants were aged 40–75 years, had 100 cells/mm3 of blood at enrollment, and had low-to-moderate traditional cardiovascular disease risk that would not typically be considered for statin treatment.
It was not clear if statins would have the same effect in people living with HIV and who have premature cardiovascular disease despite having low-to-moderate traditional risk. The interim analysis was compelling enough that the study’s independent Data Safety and Monitoring Board recommended at its latest regular meeting that it be halted early given adequate evidence of efficacy.
The study participants are being notified of the findings and will continue to be monitored for several months. Study results from the review are expected to be published in the coming weeks.
