The investigational HIV ‘Mosaico’ vaccine regimen was safe but did not provide protection against HIV acquisition, an independent data and safety monitoring board (DSMB) has determined. Based on the DSMB’s recommendation, the study will be discontinued. This follows the failure of the similar ‘Imbokodo’ vaccine in sub-Saharan Africa.
The HPX3002/HVTN 706, or ‘Mosaico’ Phase 3 clinical trial began in 2019 and involved 3900 volunteers in Europe, North America and South America. The participants were men who have sex with men (MSM) or transgender people.
The Janssen-developed vaccine was based on ‘mosaic’ immunogens, which are vaccine components featuring elements of multiple HIV subtypes, in order to induce immune responses against a wide variety of global HIV strains. The investigational vaccine regimen consisted of four injections over a year of Ad26.Mos4.HIV, with the mosaic immunogens delivered by a common-cold virus (adenovirus serotype 26, or Ad26). The final two vaccinations were accompanied by a bivalent (two-component) HIV envelope protein formulation, combining clade C gp140 and mosaic gp140 envelope proteins, adjuvanted by aluminium phosphate to boost immune responses. All study vaccinations were completed in October 2022.
In early studies, this vaccine combination induced strong antibody and T-cell responses and protected monkeys exposed to SIV, the simian cousin of HIV. The vaccines however failed to stimulate production of broadly neutralising antibodies (bNAbs) that disable multiple HIV variants, according to aidsmap. In that study, the vaccine conferred a 25.2% effectiveness in protection, but not the 50% necessary for an effective vaccine.
In its scheduled data review, the DSMB determined there were no safety issues with the experimental vaccine regimen. However, the number of HIV infections were equivalent between the vaccine and placebo arms of the study. During the clinical trial, all participants were offered comprehensive HIV prevention tools, including pre-exposure prophylaxis, or PrEP. Study staff ensured that participants who acquired HIV during the trial were promptly referred for medical care and treatment. Participants are being notified of the findings, and further analyses of the study data are planned.
The Mosaico findings track with developments in the Phase 2b ‘Imbokodo’ (HPX2008/HVTN 705) clinical trial, which was testing a similar HIV vaccine regimen in young women in sub-Saharan Africa. A DSMB determined in 2021 that the experimental vaccine regimen in that study was also safe but ineffective in protecting against HIV acquisition.
According to World Population Review, South Africa has one of the highest HIV prevalence in the world; ranking 4th with 19.1% in 2020, coupled with the highest burden of people living with HIV (PLHIV) globally, at an estimated 8.45 million.
In an effort to address these issues, and particularly change the stigma associated with the disease, the United States President’s Emergency Plan for AIDS Relief (PEPFAR), the United States Agency for International Development (USAID) and the National Department of Health (NDoH) partnered with Project Last Mile and FCB Joburg to launch MINA. For Men. For Health, an initiative aimed at encouraging men to get tested for HIV and provide communal support to begin – and stay on – treatment for those who tested HIV positive.
The campaign seeks to unpack the societal stigmas that result in men not wanting to get tested and then to adhere to taking Antiretroviral Treatment (ART). Beyond this, the campaign provided a safe space for men to express and share their experiences and fears and to address the various misconceptions about living with HIV. Leaning on insights garnered through community coaches and interactions with men living with HIV, a platform was created which gave men the tools and resources they need to take control of their lives and their HIV status. This was MINA. For Men. For Health.
The campaign’s concept emanated from the idea that men could dispel fears of prioritising their health, giving them exposure to a community of men just like them, which remains a great source of support. In the execution stage, this was coupled with brand ambassadors and social media assets that carried the campaign on social platforms, including collateral for presence and awareness in clinics across the country in severely affected communities. The in-clinic journey was an integral part of the campaign as it was vital to intercept and engage clients in real-time who may have been at the clinic for other reasons, to consider getting tested for HIV or begin/continue with their treatment.
MINA. For Men. For Health has demonstrated success in areas where individuals were exposed to brand messaging. Some key statistics include:
1. For every R17 of PEPFAR funding, R51 of earned media was generated.
2. On average, 48 000 more men tested for HIV per quarter in MINA. For Men. For Health activity facilities than non-activity facilities post-launch.
3. Nationally, first quarter post-launch saw a 7% increase in men’s linkage to care.
There has been a notable increase in the number of men who tested for HIV over the campaign period, with more than 107 290 men having tested since campaign’s inception in November 2020, with a subsequent increase in men commencing ART.
“The efforts and campaigns providing a positive narrative around HIV are now showing success across the board in combating the perceptions around the disease. In addition, the campaign is generating a positive framework to aid men living with HIV to express themselves, get the necessary care, and remain on treatment.” says Rodney Knotts, Senior Marketing Advisor at USAID.
“Currently, we are looking at ways to increase the presence of MINA. For Men. For Health, as mass media and social marketing have long been used as tools to increase education, decrease stigma, and promote behaviour change in the fight against HIV/AIDS in South Africa,” says Jonathan Wolberg, Creative Director at FCB Joburg.
Although South Africa has made significant strides over the last decade in combating HIV-AIDS, complacency will turn back the clock on gains made through consistent community engagement, screening and treatment.
MINA. For Men. For Health continues to play an essential role in addressing this public health challenge that still very much has a place in South African society.
“MINA. For Men. For Health is all about changing and mainstreaming conversations around HIV. With our above-the-line, digital and in clinic campaign, we not only hope to support and empower men living with HIV, but also their partners, families and communities. Our goal is to impact social change and perceptions for all South Africans around this completely treatable chronic condition,” says Amanda Manchia, PLM Strategic Marketing Project Lead.
As we approach World AIDS Day on 1 December, healthcare providers will be offering HIV screening and testing as part of a comprehensive health service.
One aspect in which more equality is arguably needed is between the quality of HIV testing services and aiming to test as many people as possible.
Progress against targets?
It is estimated that 13.9% of South Africa’s population is living with HIV and that the absolute number of people living with HIV in the country has increased from 3.8 million in 2002 to 7.8 million in 2021. This number has continued to rise since the death rate has declined much more rapidly than the rate of new HIV infections.
The most widely used measure of a country’s HIV response in recent years has been the UNAIDS 90-90-90 targets. These aim at 90% of people living with HIV knowing their status, 90% of those diagnosed started on ARVs, and 90% of those on ARVs being virally suppressed by 2020. The goal post has now shifted to 95-95-95.
Earlier this year, Health Minister Dr Joe Phaahla said that in South Africa we are on 94-78-89.
This indicates that we are close to reaching the first 95. It also suggests that our HIV testing efforts have generally been a success, including the introduction of HIV Rapid Testing and HIV Self Screening as HIV testing models. But, as we collectively meet these targets, it is important to focus on the quality of HIV rapid testing to ensure that we align with HIV testing standards.
Focus on quality
The quality of HIV Rapid testing to some extent depends on laboratories, but often it is driven by HIV counsellors and service delivery NGOs. As a public health professional managing the National HIV Testing Quality Assurance and Laboratory Systems Strengthening programme, seconded to the Department of Health through SEAD Consulting, it is my job to support NGOs, the Department of Health, and the Department of Correctional Services in implementing quality assurance of HIV Testing and in improving the laboratory systems between health facilities and the National Health Laboratory Service.
As someone who has worked in all aspects of primary healthcare, I am painfully aware of the shortcuts sometimes taken, but also of the impossible expectation of ‘quick services’ linked to HIV testing.
As a healthcare provider, I received peer mentorship upon entry into primary healthcare settings – but I later learnt that this mentorship provided incorrect guidance on HIV testing.
This gave me sleepless nights and fuelled my desire to support other healthcare workers in conducting quality HIV testing to avoid possible misdiagnosis and delays to critical treatment. It is imperative that everyone understands their role when it comes to HIV testing and that we move away from siloed approaches in prevention and curative spaces but integrate both quality and ambitious targets. One cannot be seen in isolation from the other.
So, how are HIV tests supposed to be done?
Firstly, there are multiple things to look out for when having an HIV test done. HIV testing should be conducted by a trained healthcare worker, using nationally approved test kits which are kept in temperature-controlled spaces. Test kits should not be exposed to extreme heat of more than 30 degrees Celsius as it fries the device, which could lead to incorrect results.
Secondly, each test has an expiry date, its own pipette (plastic or glass device to collect the blood), its own buffer (liquid that assists the blood to move across the test strip) and its own incubation time (time it takes for a reaction or outcome of the test).
When being tested, the fingertip needs to be cleaned with an alcohol-based swab, and then the first drop of blood should be wiped away to avoid contamination of the sample. The second drop of blood is then collected with the specific pipette to the required amount for that test. Once collected, the blood is inserted into the well of the test and the required number of drops of buffer is added. Lastly, the timer is set to the manufacturer’s time for each test kit.
The time is of utmost importance, as reading it too early could lead to false HIV-negative results, whereas reading it too long after the time could lead to false HIV-positive results. It is for this reason that each HIV tester needs to have a digital timer that is able to count down and sound an alarm when the time has been reached.
Additional aspects linked to the quality of HIV testing are Personal Protective Equipment (Aprons, gloves, and sanitiser) – these need to be worn by the HIV tester as part of infection control. Also important are ice packs – if you are being tested in a gazebo in the community, the HIV tester needs to ensure that the HIV test kits are kept cool to avoid malfunction or damage.
These are the basics we must get right.
The quality of HIV testing is as important as getting the test done. Too often short cuts, time constraints, and lack of staff impact the quality of testing. To be in a position where we can really celebrate the numbers – the progress – it is essential that we must get these basics right.
*Sparks is a Public Health Professional at SEAD consulting, a co-convenor at the School of Public Health, University of the Western Cape, a Senior Aspen New Voices Fellow, and a Global Atlantic Fellow for Health Equity.
Research from South Africa and the UK has found that people living with HIV have a significantly delayed internal body clock, consistent with the symptoms of jet lag. The findings, which appear in the Journal of Pineal Research, may explain some of the health problems experienced by people with HIV, and guide research towards improving their quality of life.
Researchers from the University of the Witwatersrand and University of Cape Town along with Northumbria and Surrey universities in the UK and studied people aged 45 years and above living in Mpumalanga province, where nearly one in four people is living with HIV. As such, the infection is endemic and does not associate with any difference in lifestyle.
They found that physiological daily rhythms, as measured by the hormone melatonin, were delayed by more than an hour on average in HIV positive participants. Their sleep cycle was also shorter, with researchers noting that their sleep started later and finished earlier.
This suggests the possibility that HIV infection may cause a circadian rhythm disorder similar to the disruption experienced in shift work or jet lag.
The authors believe that this body clock disruption may contribute significantly to the increased burden of health problems that people living with HIV are experiencing despite successful treatment, such as an increased risk of cardiovascular, metabolic, and psychiatric disorders.
Researchers believe there is a strong need for further funding to identify whether similar disruption to the body clock is experienced by younger people living with HIV in other countries.
“The participants living with HIV essentially experience the one-hour disruption associated with switching to daylight savings time, but every single morning,” says corresponding author Malcolm von Schantz, Professor of Chronobiology at Northumbria University.
“This happens in spite of the fact that essentially everybody is exposed to the same light-dark cycle. Our findings have important potential implications for the health and wellbeing of people living with HIV, especially given the well-established relationships between disrupted circadian rhythms and sleep deprivation.”
Senior author Dr Karine Scheuermaier of Wits University added: “This is very similar to the risk profile observed in shift workers. Understanding and mitigating this disruption may be an important step towards helping people living with HIV live healthier lives.”
“Our findings identify an urgent research topic,” says Xavier Gómez-Olivé, also from the University of the Witwatersrand, whose research grant funded the study. “The next step must be to establish if the same body clock disruption exists in people living with HIV who are younger and who live in other countries.”
Co-author Dale Rae, of the University of Cape Town, added “This is a great example of the importance of studying sleep in people living in Africa, and demonstrates how findings from this research can also be relevant to people anywhere in the world.”
As people with HIV age, their risk of myocardial infarction increases far more if they also have untreated hepatitis C virus, according to new research published today in the Journal of the American Heart Association.
According to the findings, even with antiretroviral therapy (ART), the risk of myocardial infarction (MI) among people with HIV is at least 50% higher than people without HIV. This new study evaluated if people with HIV who also have hepatitis C have a higher risk of MI.
“HIV and hepatitis C coinfection occurs because they share a transmission route – both viruses may be transmitted through blood-to-blood contact,” said Associate Professor Keri N. Althoff, PhD, MPH, senior author of the study. “Due in part to the inflammation from the chronic immune activation of two viral infections, we hypothesised that people with HIV and hepatitis C would have a higher risk of heart attack as they aged compared to those with HIV alone.”
Researchers analysed health information for 23 361 people with HIV in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) between 2000–2017 started on antiretroviral treatment for HIV, median age 45 at enrolment. One in 5 study participants (4677) were also positive for hepatitis C. During a median follow-up of about 4 years, the researchers compared the occurrence of a heart attack between the HIV-only and the HIV-hepatitis C co-infected groups as a whole, and by each decade of age.
The analysis found:
With each decade of increasing age, MI incidence increased 30% in people with HIV alone and 85% in those who were also positive for hepatitis C.
The risk of heart attack increased in participants who also had traditional heart disease risk factors such as high blood pressure (more than 3 times), smoking (90%) and Type 2 diabetes (46%).
The risk of heart attack was also higher (40%) in participants with certain HIV-related factors such as low levels of CD4 immune cells (200 cells/mm3, signalling greater immune dysfunction) and 45% in those who took protease inhibitors (one type of ART linked to metabolic conditions).
“People who are living with HIV or hepatitis C should ask their doctor about treatment options for the viruses and other ways to reduce their cardiovascular disease risk,” said Assistant Professor Raynell Lang, MD, MSc, lead study author.
“Several mechanisms may be involved in the increased heart attack risk among co-infected patients. One contributing factor may be the inflammation associated with having two chronic viral infections,” A/Prof Lang said. “There also may be differences in risk factors for cardiovascular disease and non-medical factors that influence health among people with HIV and hepatitis C that plays a role in the increased risk.”
“Our findings suggest that HIV and hepatitis C co-infections need more research, which may inform future treatment guidelines and standards of care,” Althoff said.
The study is limited by not having information on additional factors associated with heart attack risk such as diet, exercise or family history of chronic health conditions. Results from this study of people with HIV receiving care in North America may not be generalizable to people with HIV elsewhere. In addition, the study period included time prior to the availability of more advanced hepatitis C treatments.
“Because effective and well-tolerated hepatitis C therapy was not available during several years of our study period, we were unable to evaluate the association of treated hepatitis C infection on cardiovascular risk among people with HIV. This will be an important question to answer in future studies,” Lang said.
Researchers from Tel Aviv University have demonstrated success of a novel technology that may be developed into a one-time vaccine to treat people with HIV and AIDS. Using CRISPR technology, the researchers engineered B cells that in turn stimulate the immune system to produce HIV-neutralising antibodies.
Published in Nature, the study was led by Dr Adi Barzel and PhD student Alessio Nehmad and conducted in collaboration with additional researchers from Israel and the US.
“Based on this study,” said Dr Barzel, “we can expect that over the coming years we will be able to produce a medication for AIDS, additional infectious diseases and certain types of cancer caused by a virus, such as cervical cancer, head and neck cancer and more.”
He explains that the treatment can become a kind of permanent medication, lingering in the body to fight the virus. “We developed an innovative treatment that may defeat the virus with a one-time injection, with the potential of bringing about tremendous improvement in the patients’ condition. When the engineered B cells encounter the virus, the virus stimulates and encourages them to divide, so we are utilising the very cause of the disease to combat it. Furthermore, if the virus changes, the B cells will also change accordingly in order to combat it, so we have created the first medication ever that can evolve in the body and defeat viruses in the ‘arms race’.”
When they mature, the antibody-generating B cells move into the blood and lymphatic system and from there to the different body parts.
Dr Barzel explained: “Until now, only a few scientists, and we among them, had been able to engineer B cells outside of the body. In this study, we were the first to do this within body and then make those cells generate the desired antibodies. The genetic engineering is conducted with viral carriers derived from viruses that were also engineered. We did this to avoid causing any damage, and solely bring the gene coded for the antibody into the B cells in the body.”
“Additionally, in this case we have been able to accurately introduce the antibodies into a desired site in the B cell genome. All lab models that had been administered the treatment responded, and had high quantities of the desired antibody in their blood. We produced the antibody from the blood and made sure it was actually effective in neutralising the HIV virus in the lab dish.”
Scientists have now uncovered how the innate immune system detects even very small amounts of HIV-1.The findings, published in Molecular Cell, reveal a two-step molecular strategy that jolts the innate immune response into action when exposed to HIV-1. This has important implications for developing new HIV treatments and vaccines, as well as helping understand the innate immune response in other contexts such as Alzheimer’s.
“This research delineates how the immune system can recognise a very cryptic virus, and then activate the downstream cascade that leads to immunological activation,” says Sumit Chanda, PhD, professor in the Department of Immunology and Microbiology. “From a therapeutic potential perspective, these findings open up new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions for preventing HIV infection.”
The innate immune system is activated before the adaptive immune system, which is the body’s secondary line of defense that involves more specialised functions, such as generating antibodies. One of the innate immune system’s primary responsibilities is recognizing between “self” (our own proteins and genetic material) and foreign elements (such as viruses or other pathogens). Cyclic GMP-AMP synthase (cGAS) is a key signaling protein in the innate immune system that senses DNA floating in a cell. If cGAS does detect a foreign presence, it activates a molecular pathway to fight off the invader.
However, because HIV-1 is an RNA virus, it produces very little DNA – so little, in fact, that scientists have not understood how cGAS and the innate immune system are able to detect it and distinguish it from our own DNA.
Scripps Research scientists discovered that the innate immune system requires a two-step security check for it to activate against HIV-1. The first step involves a protein called polyglutamine binding protein 1 (PQBP1), which recognises the HIV-1 outer shell as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert signal to summon cGAS. Once the viral shell begins to disassemble, cGAS activates additional immune-related pathways against the virus.
The researchers were initially surprised to find that two steps are required for innate immune activation against HIV-1, as most other DNA-encoding viruses only activate cGAS in one step. This is a similar concept to technologies that use two-factor authentication, such as requiring users to enter a password and then respond to a confirmation email.
This two-part mechanism also opens the door to vaccination approaches that can exploit the immune cascade that is initiated before the virus can start to replicate in the host cell, after PQBP1 has decorated the molecule.
“While the adaptive immune system has been a main focus for HIV research and vaccine development, our discoveries clearly show the critical role the innate immune response plays in detecting the virus,” said Sunnie Yoh, PhD, first author of the study and senior staff scientist in Chanda’s lab. “In modulating the narrow window in this two-step process – after PQBP1 has decorated the viral capsid, and before the virus is able to insert itself into the host genome and replicate – there is the potential to develop novel adjuvanted vaccine strategies against HIV-1.”
By shedding light on the workings of the innate immune system, these findings also illuminate how our bodies respond to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau – the protein that becomes dysregulated in Alzheimer’s disease – and activate the same inflammatory cGAS pathway. The researchers will continue to investigate how the innate immune system is involved in disease onset and progression, as well as how it distinguishes between self and foreign cells.
Within just two to three years of infection, HIV causes an “early and substantial” impact on ageing in infected people, accelerating epigenetic changes and telomere shortening associated with normal ageing, according to a study in iScience.
The findings suggest that new HIV infection may act to reduce an individual’s life span by five years compared to an uninfected person.
“Our work demonstrates that even in the early months and years of living with HIV, the virus has already set into motion an accelerated ageing process at the DNA level,” said lead author Elizabeth Crabb Breen, a professor emerita at UCLA. “This emphasises the critical importance of early HIV diagnosis and an awareness of ageing-related problems, as well as the value of preventing HIV infection in the first place.”
In previous studies, HIV and antiretroviral treatment has been observed to accelerate age-related conditions such as cardiovascular and renal disease, grail and cognitive impairment.
Researchers analysed stored blood samples from 102 men collected six months or less before they became infected with HIV and again two to three years after infection. They compared these with matching samples from 102 non-infected age-matched men taken over the same time period. All the men were participants in the Multicenter AIDS Cohort Study, an ongoing US study initiated in 1984.
The study examined how HIV affects epigenetic DNA methylation. Epigenetic changes are those made in response to the influence of outside factors such as disease that affect how genes behave without changing the genes themselves.
Five epigenetic measures of ageing were analysed – four of them are epigenetic ‘ clocks’, each of which uses a slightly different approach to estimate biological age acceleration in years, relative to chronologic age. The fifth measure assessed telomere length, which shorten with age and cell divisions.
Compared to non-infected controls, HIV-infected individuals showed significant age acceleration in each of the four epigenetic clock measurements – ranging from 1.9 to 4.8 years – as well as telomere shortening over the period beginning just before infection and ending two to three years after, in the absence of highly active antiretroviral treatment.
“Our access to rare, well-characterised samples allowed us to design this study in a way that leaves little doubt about the role of HIV in eliciting biological signatures of early ageing,” said senior author Professor Beth Jamieson. “Our long-term goal is to determine whether we can use any of these signatures to predict whether an individual is at increased risk for specific ageing-related disease outcomes, thus exposing new targets for intervention therapeutics.”
Study limitations included having only men as participants, with few non-white participants. The sample size was also too small to take into consideration later effects of highly active antiretroviral treatment or to predict clinical outcomes. Additionally, there presently is no consensus on what is normal ageing or how to define it, the researchers wrote.
Kaposi sarcoma on the skin of an AIDS patient. Credit: National Cancer Institute
A study published in Cell Reportshas identified a protein in the cancer cell’s nucleus as a critical agent keeping Kaposi sarcoma-associated herpesvirus (KSHV) dormant and hidden from the immune system. The virus, in the same family as Epstein-Barr virus, is linked to AIDS-related Castleman’s disease and cancers such as Kaposi sarcoma.
Up to 50% of the population in some parts of Africa are affected with KSHV, though not everyone with KSHV will develop Kaposi sarcoma. Those who do typically have a weakened immune system due to HIV infection, organ transplant, being older or other factors.
The introduction of antiretroviral therapy significantly reduced AIDS-related Kaposi sarcoma prevalence in Western countries; however, in sub-Saharan Africa, the disease continues to have a poor prognosis.
On entry into a human cell the virus causes a hidden infection in the nucleus: the virus simply latches onto parts of the cell’s chromosomes without replicating.
Researchers studied KSHV’s latent-lytic switch, a process in which the virus exits its dormancy state to replicate in the host cell. This replication phase, called the lytic cycle, ends with the disintegration of the cell and the release of the viruses, infecting neighbouring cells.
“The virus likes to stay silent as long as possible to avoid being detected by the body’s immune system,” said Professor Yoshihiro Izumiya, the study’s senior author.
The team sought to understand the mechanisms behind this latent-lytic switch and the role the host cell environment played in this process.
“Where the virus latches onto the host cell, how it manages to stay dormant, and what triggers its activation were very exciting and important puzzles to solve,” Prof Izumiya said.
The study identified where the virus genome could be found on the host genome.
Izumiya and his team profiled and analysed chromosomal interactions on three cancer cell lines naturally infected with KSHV, locating the virus’s preferred chromosome docking sites. The binding patterns, similar among the three cancer cell lines, showed a nuclear ecosystem that can attract and help keep the virus in its silent form.
The team also found that CHD4 (chromodomain helicase DNA binding protein 4) binds to the virus’s genomic elements. CHD4, a protein in the host cell’s chromosomes, suppresses the work of the gene responsible for viral replication. The study showed that CHD4 is a key regulator of the KSHV latency-lytic switch.
“The location where the virus genome attaches to the host chromosome is not random,” said Ashish Kumar, a postdoctoral researcher in Izumiya Lab and the paper’s first author. “Without having enriched CHD4 protein, the virus starts to replicate, kicking in a cell destructive mode. For the virus to select CHD4 among many other host proteins, CHD4 must play a unique and important role in host cells.”
Virology can help identify cellular proteins essential for cell homeostasis. Over millions of years, the virus’s genome developed to encode or assemble a small number of very efficient proteins, which strategically connect to host cell proteins to keep viral chromatin dormant and impact the host cell’s tumour suppression function.
“We used virology as an entry point to shed light on the function of CHD4 in gene regulation in general. During virus-host co-evolution, KSHV cleverly learned to hijack host proteins that can help keep the gene responsible for viral replication dormant.”
The researchers found a viral protein which could serve as the basis for a replication inhibitor. Since CHD4 is critical for cancer cell growth in a variety of cancers, they hope this virus-host interaction could inform cancer treatment research.
Despite the greater safety and efficacy of a new short course treatment for HIV-related cryptococcal meningitis (CM), access to the treatment in South Africa will be a challenge, according to a pair of articles by Spotlight.
Following positive results of a trial, the World Health Organization last week announced new recommendations for the treatment of CM, with a single high dose of L-AmB followed by two weeks of flucytosine and fluconazole.
Using L-AmB (AmBisome) and flucytosine for the treatment of CM will be a welcome change for South Africa, which has the world’s highest burden of the condition. This shorter course with fewer side effects than the current treatment involving amphotericin-B could save lives as well as clinical resources in the public sector, but at present the treatment is hamstrung by pricing and availability uncertainty, with a course of L-AmB currently only available at a steep cost.
“Amphotericin B [deoxycholate] is a drug that doctors and nurses used to call ampho-terrible,” Amir Shroufi, Médecins Sans Frontières (MSF) Southern Africa board member told Spotlight.
He explained that “it’s a really nasty drug, doctors and nurses don’t like it because it can cause severe anaemia. It’s toxic to the kidneys, so it can cause kidney damage and even kidney failure… and the infusion line used for the drug can often become infected and it can cause inflammation of the veins where it’s going into the body.”
L-AmB is a “much better drug”, he said, with great benefits of administering it for one day as opposed to a week or two. The seriousness of CM meant hospitalisation will still be required, pointed out Dr Jacqui Miot, division director of the Wits Health Economics and Epidemiology Research office, but means that patients won’t be tethered to a drip and may be able to go home sooner.
Under the treatment regimen, a patient receives a single high dose of L-AmB on the first day of treatment, followed by a 14-day course of flucytosine and fluconazole pills.
For a 60kg patient at the recommended dosage, twelve 50mg vials of L-AmB are needed, which at Gilead’s promised access price would be R2 880. Key Oncologics’ currently charges R34 560 for 12 vials.
Even given the availability of L-AmB, Shrouifi warns that “whatever you’re doing, you have to have flucytosine. That’s your baseline, even if you’re giving liposomal amphotericin B, you have to have the flucytosine”.
Flucytosine is an old, off-patent medicine developed in the 1950s. Despite its age and its demonstrated efficacy in the landmark ACTA trial four years ago, flucytosine was only recently authorised for use in South Africa and is only slowly being rolled out.
Amir Shroufi warned that access to the life-saving medicine remains a major issue. “Doctors are not being given the tools they need to treat [CM],” he said. “The first tool they have to have is flucytosine and they still don’t have flucytosine. So, that’s the thing that needs to happen urgently, you know, tomorrow! Everyone with cryptococcal meningitis must get access to flucytosine.”
Like L-AmB, Mylan’s 250mg and 500mg flucytosine tablets were only registered recently, in December 2021. The Department of Health’s target price for a pack of 100 tablets is R1 500. Fortunately, it appears that the Clinton Health Access Initiative (CHAI) will be able to secure packs of 100 at R1 470 each for use in South Africa’s flucytosine access programme.
The next steps for rollout of flucytosine will be inclusion on the national essential medicines list and in CM treatment guidelines before tenders can be put out.
