The South African HIV Clinicians Society (SAHCS) have recently announced a clinical update on the dolutegravir (DGT)-based regimens for first- and second-line antiretroviral therapy. This comes in the wake of positive findings from a number of clinical trials.
“Based on data from several recent trials, we now recommend that all patients > 10 years old and 35 kg on tenofovir/emtricitabine (or lamivudine)/efavirenz (TEE/TLE) or NVP-based regimens be switched to tenofovir/lamivudine/dolutegravir (TLD) regardless of the viral load (VL) result. In addition, all patients > 10 years old and > 35 kg on a regimen of two nucleoside reverse transcriptase inhibitors (NRTI) with a boosted protease inhibitor (PI) (eg, lopinavir/ritonavir (LPV/r) or atazanavir/ritonavir (ATV/r)) and a suppressed VL can be switched to TLD, regardless of prior resistance patterns or treatment history.”
In South Africa, pre-treatment resistance to nonnucleoside reverse transcriptase inhibitors (NNRTI)-based antiretroviral therapy regimens has been rising. Meanwhile, DTG has a higher barrier to resistance and reduced side effects. This prompted the Department of Health to recommend that patients on NNRTI-based ART regimens be switched to DTG-based regimens. This transition is slower than desired partly because a documented suppressed VL is required prior to switching from TEE/TLE to TLD. Since this recommendation was first made, evidence from several trials (NADIA, VISEND and ARTIST) has demonstrated that tenofovir with lamivudine can be safely and effectively recycled from a first- to a second-line regimen. Therefore, the SAHCS has stated that “in patients with virological failure on a TEE or TLE regimen a single drug can be switched (efavirenz to dolutegravir ie, TLD as secondline), resulting in virological suppression comparable to or better than alternative second-line options.”
The guidelines also outline the results of the NADIA, VISEND and ARTIST trials conducted in southern African countries, as well as the single-arm DAWNING trial.
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.
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.
A new short course of treatment for HIV-associated cryptococcal meningitis is as effective as the longer, standard one, and is better tolerated, according to a real-world study in the New England Journal of Medicine.
The international study involved a randomised trial in southern and eastern Africa. This new ‘one-dose’ approach offers a practical, easier-to-administer and better tolerated treatment for HIV-associated cryptococcal meningitis in Africa, the researchers said.
Cryptococcal meningitis causes a serious disease in immunosuppressed people living with HIV, with around 180 000 cryptococcal meningitis-related deaths each year, mostly in sub-Saharan Africa. Current treatments are either a 7 or 14-day course of amphotericin-B, combined with either oral antifungal tablets or oral fluconazole.
This new trial investigated whether a single high dose of liposomal amphotericin-B (L-AmB, Ambisome) paired with two oral antifungals, fluconazole and flucytosine, was as effective at reducing deaths as the currently recommended WHO first-line treatment based on seven days of Amphotericin-B therapy.
Dr Melanie Alufandika-Moyo, study author and the lead research doctor at the Malawi-Liverpool Wellcome Unit, said: “Cryptococcal meningitis is the most common type of adult meningitis in much of Africa. Without effective treatment, infection progresses quickly, often resulting in deaths. Current treatment requires prolonged hospitalisation, intensive nursing care and costly laboratory monitoring which can be expensive for the healthcare system and the patient. Amphotericin-B can also cause kidney damage and blood problems.
“We urgently need new ways of treating the disease, so it’s fantastic that we were able to show a new streamlined treatment, requiring just one intravenous infusion, is as effective and less dangerous for patients.”
More than 800 adult patients with a first episode of HIV-associated cryptococcal meningitis, from five countries in southern and eastern Africa, took part in the trial.
Half received, and half received standard care. After 10 weeks, 25% (101/407) of people in the AmBisome arm died compared to 29% (117/407) in the control arm – this is among the lowest mortality rate reported from a major cryptococcal meningitis trial in Africa, despite more than a quarter of participants presenting with very severe disease.
Drug-related toxicity was significantly lower in the new ‘one-dose’ AmBisome arm. Anaemia occurred in 13% of AmBisome participants compared to 39% in the control arm, with more participants in the control arm needing blood transfusions. Far less drug related kidney toxicity was observed in the one dose AmBisome arm than in the control arm.
AmBisome, a liposomal formulation of amphotericin-B, was suspected to be an effective cryptococcal meningitis treatment as it is less toxic and can be given in large doses that remain in the brain for some time. A single, high-dose of AmBisome had previously been shown to be effective at clearing Cryptococcus from around the brain, which prompted the real-world trial.
Professor Tom Harrison from St George’s, University of London, who co-led the trial with Professor Joe Jarvis from the London School of Hygiene & Tropical Medicine and Botswana Harvard AIDS Institute Partnership, said: “These exciting results represent the culmination of a long programme of collaborative work to optimise antifungal drug combinations and reduce deaths from this terrible infection, and provide the strong evidence needed for policymakers to decide how cryptococcal meningitis should be treated going forward.
“Fortunately, with the support of advocates and funders, Ambisome and flucytosine are now becoming more available, which is essential to enable wide-scale implementation of this novel treatment regimen.”
Professor Joe Jarvis, the lead author of the study, said: “The results of this trial have the potential to transform how cryptococcal meningitis is treated and the management of advanced HIV-related disease in sub-Saharan Africa. It has far fewer significant side effects, which is obviously hugely important, and has the potential to prevent a large number of deaths in low-resource settings by being both easier to administer and cost-effective.”
Study imitations included the current lack of access to Ambisome and flucytosine, the key components of this novel treatment regimen, in many low-resource settings. To address this, an additional five years funding has been received.
A trial has successfully used a novel treatment of anti-HIV antibodies to achieve viral suppression in several HIV patients. The results published in Nature, would enable a treatment not reliant on vigilant daily dosing and which could potentially reduce the body’s reservoir of HIV, something antiretroviral drugs cannot do. The antibody treatment could be used in combination with long-acting antiretrovirals, or alone after such medications have sufficiently brought down viral levels.
“The idea is that you would still be on HIV treatment, but instead of having to take a pill every day, with the long-acting versions of the antibodies, patients would be able to take infusions every six months,” said Professor Marina Caskey, who co-led the study.
In this trial, 18 participants received seven infusions of a pair of broadly neutralising antibodies over five months, while discontinuing their antiretroviral medications. Thirteen of these participants maintained viral suppression for at least five months, and in a few cases over a year, suggesting the antibodies are able to control viruses that are sensitive to the antibodies and prevent viral levels from rising to dangerous levels.
Besides suppressing the virus, antibody therapy may also have an effect on cells infected with HIV that cannot be eliminated by antiretroviral drugs. “Ultimately, with any treatment, we’d like to see a decline in the reservoir of infected T-cells, which fuel rebound when therapy is discontinued,” says Christian Gaebler, an assistant professor of clinical investigation in Nussenzweig’s lab and the study’s first author. After therapy, the team detected a decrease in the infected T-cells, specifically those that harbor intact viruses capable of replication. “It’s a promising finding that we hope to follow up on in future, larger studies,” Gaebler says.
The new study built on a previous, shorter trial in which participants had received three antibody infusions over six weeks. The researchers found that administering additional infusions was generally safe and well-tolerated, and the longer treatment period did not result in the emergence of new resistant variants.
Even with antiretroviral therapy, HIV still lingers in the body, preventing complete cure. Now, new research published in PLOS Pathogens, revealed a possible answer to why HIV persists in the body: a lack of a certain protein in HIV patients’ killer T cells. The discovery also explained why people with HIV have less risk of developing multiple sclerosis (MS).
Because this protein, CD73 is responsible for migration and cell movement into the tissue, the lack of the protein compromises the ability of killer T cells to find and eliminate HIV-infected cells, explained immunologist Shokrollah Elahi, lead researcher of the study.
“This mechanism explains one potential reason for why HIV stays in human tissues forever,” he said, adding that the research also shows the complexity of HIV infection.
“This provides us the opportunity to come up with potential new treatments that would help killer T cells migrate better to gain access to the infected cells in different tissues.”
After spending three years identifying the role of CD73, Elahi turned his focus to understanding potential causes for the drastic reduction. He found it is partly due to the chronic inflammation that is common among people living with HIV.
“Following extensive studies, we discovered that chronic inflammation results in increased levels of a type of RNA found in cells and in blood, called microRNAs,” he explained. “These are very small types of RNA that can bind to messenger RNAs to block them from making CD73 protein. We found this was causing the CD73 gene to be suppressed.”
This discovery also helps explain why people with HIV have a lower risk of developing MS, Elahi noted.
“Our findings suggest that reduced or eliminated CD73 can be beneficial in HIV-infected individuals to protect them against MS. Therefore, targeting CD73 could be a novel potential therapeutic marker for MS patients.”
Elahi said the research could next look into seeing how to turn on the CD73 gene in patients with HIV and off in those with MS.
Médecins Sans Frontières (MSF) has warned that pharmaceutical company ViiV’s recent decisionnot to pursue voluntary licensing for the long-acting HIV prophylactic cabotegravir (CAB-LA) means that lower cost generic production in low- and middle-income countries (LMICs) is effectively locked out for countries like South Africa.
CAB-LA was approved for the prevention of HIV infection by the USFDA in December 2021, and ViiV currently charges $3700 (R55 000) per vial in the US ($22 200/R333 000 annually per person). The Clinton Health Access Initiative (CHAI) has shown that generic manufacturers could produce this drug for around $2.60 (R39) per vial (less than $20/R3000 per person per year). Although ViiV has publicly said they would provide CAB-LA for their at-cost price in many LMICs, they have yet to announce what that price is.
According to MSF, generic manufacturer prices are often much lower than the patented drug – and they can even produce complicated formulations like CAB-LA. The generic equivalent [PDF] of ViiV’s paediatric formulation of the HIV drug dolutegravir costs 22 times less.
Amanda Banda, Infectious Diseases Policy and Advocacy Advisor of the MSF Access Campaign, said: “What good is HIV prevention if the people who need it can’t afford it? This is the most effective form of HIV prevention for vulnerable and marginalised communities and yet ViiV is delaying the ability of generic manufacturers to supply the drug, meaning that many people across low- and middle-income countries who would benefit from the medicine to prevent HIV infection won’t be able to access it. CAB-LA will need to be available at a price that is comparable to currently available oral PrEP if country treatment programs and donors are expected to scale up its use to the levels needed – and it’s hard to imagine that ViiV will make CAB-LA available at less than $40 (R600) per year. ViiV needs to immediately sign a licensing deal with the Medicines Patent Pool so that more affordable generics can be produced, and more lives can be saved.”
Dr Tom Ellman, Head of MSF’s South African Medical Unit said: “We want to urgently make this drug available for people at high risk of HIV infection in our programs in sub-Saharan Africa – we don’t want a donation with many strings attached from the corporation; it is not the role of ViiV to control the use of a drug that is approved by the USFDA. We want ViiV to sell us this drug at an affordable price.”
Luc Montagnier, the French virologist credited as being a co-discoverer of the human immunodeficiency virus (HIV), has died aged 89. He jointly received the 2008 Nobel Prize was jointly awarded to Montagnier for his work in isolating the virus.
He was lauded for his crucial research, but in later life he was criticised for unscientific claims about autism and COVID.
Local news site FranceSoir reported that he died on Tuesday in Neuilly-sur-Seine “surrounded by his children”.
The virologist first began working on the virus in the early 1980s while at the Pasteur Institute in France. Montagnier and his team examined tissue samples from patients who had the mysterious new syndrome.
In 1983, Luc Montagnier’s team at the Pasteur Institute in Paris discovered HIV‑1. They cultured T cells from a lymph node biopsy from a 33-year-old homosexual French patient with symptoms that can precede AIDS (subsequently called pre-AIDS), such as lymphadenopathy. Finding that they had isolated a retrovirus, they were able to infect T cells from a healthy donor, but were unable to infect other cell types, including B cells and fibroblasts.
The group concluded that this patient at risk for AIDS was infected with a T cell–tropic retrovirus; however they could only tentatively associate it with AIDS. In 2008, Luc Montagnier and Françoise Barré-Sinoussi from his team were awarded the Nobel Prize for the isolation and characterisation of HIV-1.
However, US scientist Robert Gallo published similar findings in the same edition of Science in which the Pasteur team had announced theirs. He later concluded that the virus caused Aids. This led to years of heated debate over who actually discovered HIV.
Gallo revealed in 1991 that the virus he found came from the Pasteur Institute the year before, and the two men publicly agreed in 2002 that Montagnier’s team discovered HIV, but that Gallo first showed its role in causing Aids.
However, when Montagnier and Barré-Sinoussi were awarded the Nobel Prize in 2008 for their work – alongside Harald zur Hausen for his work on cervical cancer – the committee made no mention of Gallo, which provoked controversy.
Later on, Montagnier attracted great criticism for a series of unscientific claims, including over the causes of autism and later over the origins of COVID.
French media first reported that he had died at the American hospital in Neuilly-sur-Seine on 8 February, and his death was officially declared by authorities some time later.
A new, more virulent and more damaging HIV variant has been discovered in the Netherlands.
Viral mutations are a source of concern because they can affect transmissibility and other factors. There have been fears of this happening in HIV-1, and now a new, highly virulent HIV strain in the Netherlands has been identified in a study. The results are published today in Science.
Prior to antiretroviral treatment, individuals infected with the new “VB variant” (for virulent subtype B) showed significant differences compared with individuals infected with other HIV variants:
A viral load between 3.5 and 5.5 times higher.
A doubled rate of CD4 cell decline (the hallmark of immune system damage by HIV), placing them at risk of developing AIDS much more rapidly.
Increased risk of transmitting the virus to others.
Fortunately, individuals with the VB variant had similar immune system recovery and survival to individuals with other HIV variants. However, because the VB variant causes a faster drop in immune system strength, early diagnosis and treatment is critical.
Researching the mechanism that causes the VB variant to be more transmissible and damaging to the immune system could lead to new targets for next-generation antiretroviral drugs. The VB variant is characterised by many mutations spread throughout the genome, meaning that a single genetic cause cannot currently be identified
Lead author Dr Chris Wymant said: ‘Before this study, the genetics of the HIV virus were known to be relevant for virulence, implying that the evolution of a new variant could change its impact on health. Discovery of the VB variant demonstrated this, providing a rare example of the risk posed by viral virulence evolution.’
Senior author Professor Christophe Fraser added: ‘Our findings emphasise the importance of World Health Organization guidance that individuals at risk of acquiring HIV have access to regular testing to allow early diagnosis, followed by immediate treatment. This limits the amount of time HIV can damage an individual’s immune system and jeopardise their health. It also ensures that HIV is suppressed as quickly as possible, which prevents transmission to other individuals.’
The VB variant was first identified in 17 HIV positive individuals from the BEEHIVE project, an ongoing study which collects samples from across Europe and Uganda. Since 15 of these people came from the Netherlands, the researchers then analysed data from a cohort of over 6700 HIV positive individuals in the Netherlands. This identified an additional 92 individuals with the variant, from all regions of the Netherlands, bringing the total to 109.
The researchers estimate that the VB variant first arose during the late 1980s and 1990s in the Netherlands, spreading more quickly than other HIV variants during the 2000s. However its spread has been declining since around 2010. The research team believe that the VB variant arose in spite of widespread treatment in the Netherlands, not because of it, since effective treatment can suppress transmission.
Since individuals with the VB variant are demographically similar, the spread is likely due to the properties of the virus itself.
In an article awaiting peer review, doctors in South Africa report on the case of a 22-year-old female with uncontrolled advanced HIV infection and a SARS-CoV-2 infection that lasted 9 months, during which time the virus accumulated more than 20 additional mutations. Antiretroviral therapy suppressed HIV and cleared the coronavirus within 6–9 weeks.
One hypothesis for novel variants is that they arise in severely immunocompromised individuals. Being unable to clear the virus because of a weakened immune response results in a persistent infection, letting mutations accumulate – some of which may allow immune evasion. In one case, SARS-CoV-2 in a female leukaemia patient developed seven mutations over three months of infection.
The authors describe a case of persistent SARS-CoV-2 infection, lasting for at least 9 months, in a severely immunocompromised woman with HIV that had challenges with adherence to antiretroviral therapy.
In mid-September 2021, a female in her 20s was admitted to a tertiary hospital in Cape Town with a one-week history of sore throat, malaise, poor appetite and dysphagia. The patient was infected with HIV at birth. In January 2021, her antiretroviral therapy (ART) regimen had been changed to tenofovir, emtricitabine and efavirenz, but she had difficulty adhering. In August 2021 she moved from rural KwaZulu-Natal to Cape Town. She stated that she had not received a COVID vaccination.
“On physical examination, the patient was wasted but had no palpable lymph nodes,” the authors report. “She was awake and lucid, with no focal neurological deficits. She was not in respiratory distress with an oxygen saturation of 98% on room air. The cardiovascular and abdominal examinations, renal function, white cell count and liver enzymes were without abnormalities. Her CD4 count was 9 cells/μL and her plasma HIV viral load 4.60 log10 viral RNA copies/mL, indicating advanced HIV infection, poorly controlled by ART.
“During a prolonged hospital stay the patient experienced multiple complications requiring treatment. Following adherence counselling, antiretroviral therapy was reinitiated with a new regimen of tenofovir/efavirenz/dolutegravir a week after admission.”
The patient tested positive for COVID on 25 September 2021, with genomic sequencing indicating the Beta variant. However, in October, the patient later revealed that she had tested positive for COVID in January 2021. On 25 November 2021, the patient’s HIV viral load was <50 copies/ml and a PCR test was negative for COVID. While there was no CD4 count performed, suppressed HIV replication and clearance of the SARS-CoV-2 infection suggest her immune system had recovered to some degree.
Phylogenetic analysis showed that the samples indicated an ongoing infection instead of re-infections. During the 9 months of infection, the virus acquired at least 10 mutations in the spike glycoprotein and 11 other mutations over and above the lineage-defining mutations for Beta.
The authors consider it unlikely that the novel variant described spread into the general population, and stress that it does not prove that any of the other novel variants originated from an immunocompromised host in this fashion.
Increased vigilance is warranted to benefit affected individuals and prevent the emergence of novel SARS-CoV-2 variants. They ascribed the detection of the case to good connections between sequencing laboratories, routine diagnostic laboratories and frontline clinicians.
The authors concluded that their experience “reinforces previous reports that effective ART is the key to controlling such events. Once HIV replication is brought under control and immune reconstitution commences, rapid clearance of SARS-CoV-2 is achieved, probably even before full immune reconstitution occurs. This underscores the broader point that gaps in the HIV care cascade need to be closed which will benefit other conditions and public health problems, too, including COVID.”
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