Category: HIV

Categories : Cardiovascular Disease HIVTags :

People with HIV and Hepatitis C Have Increased Heart Attack Risk

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Source: Wikimedia Commons CC0

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.

Source: American Heart Association

Categories : HIV Obstetrics & GynaecologyTags :

Dolutegravir-based ART is Better for Pregnant Individuals with HIV-1

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pregnant woman holding her belly
Source: Anna Hecker on Unsplash

Dolutegravir-based antiretroviral therapies (ART) for HIV-1 are more effective for pregnant individuals than some other ART regimens commonly used in the US and Europe, according to a study available online in NEJM.

The study, led by Harvard T.H. Chan School of Public Health researchers, showed that pregnant individuals who took dolutegravir-based regimens had a high probability of being virally suppressed at delivery. No differences were seen in adverse birth outcome risks (preterm birth, low birth weight, small for gestational age, or neonatal death) between dolutegravir-based regimens and the other contemporary regimens.

“Globally, a dolutegravir-based regimen is currently recommended for treating HIV, and this is the first study to directly compare regimens including dolutegravir to other antiretroviral regimens, such as raltegravir-based regimens, that are also listed as ‘Preferred’ in US perinatal guidelines,” said senior research scientistKunjal Patel, lead author of the study.

Dolutegravir, is a newer antiretroviral part of a once-a-day regimen that has been shown to be more effective, easier to tolerate, and less likely to create new drug resistance in people with HIV-1. However, limited data have been available about its effectiveness and safety in pregnancy compared with regimens that commonly have been used during pregnancy in the US and Europe.

In the current observational study, the researchers compared dolutegravir use in pregnancy with atazanavir/ritonavir, darunavir/ritonavir, and raltegravir antiviral regimens that are currently classified as “Preferred” for use in pregnancy in the US About half of the participants started ART before conception. At delivery, 96.7% of pregnancies of participants who received dolutegravir were virally suppressed, whereas those of participants who took atazanavir/ritonavir or raltegravir had viral suppression of 84.0% and 89.2%, respectively.

“We think the observed differences are due to dolutegravir’s ability to rapidly decrease viral loads and its ease of use as part of a once-daily regimen that’s available as a fixed-dose combination,” said Patel. “Our results highlight the continual need for systematic studies that compare new antiretroviral regimens with those already in clinical practice to help inform the evolution of guidelines and clinical practice over time.”

Source: Harvard T.H. Chan School of Public Health

Categories : HIVTags :

A Step Closer to a Once-off Treatment for HIV

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HIV invading a human cell
HIV invading a human cell: Credit NIH

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.”

Source: Tel Aviv University

Categories : HIVTags :

Antibody Cocktail Could Treat HIV while Minimising Escape Risk

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HIV Infecting a T9 Cell. Credit: NIH

Specifically designed cocktails of broadly neutralising antibodies (bNAbs) could help treat HIV while minimising the risk of the virus escaping treatment, researchers reported in eLife.

The study shows that computational approaches to selecting combinations of bNAbs based on viral genetics could help prevent viral escape, making HIV treatment more effective. It may also offer a strategy for designing effective combinations of bNAbs for treating other rapidly evolving pathogens.

bNAbs offer a promising new tool to treat or potentially cure infections with rapidly evolving viruses such as HIV. Clinical trials using a single bNAb to treat HIV have shown that some viral strains may survive the treatment and lead to a rebound of viruses in the blood. Combinations of bNAbs may therefore be a more effective approach, but finding the best combinations is a challenge. 

“For our study, we proposed using a computational approach to predict the effectiveness of bNAb combinations based on the HIV genetics,” said researcher Colin LaMont.

LaMont and colleagues analysed the genetics of HIV viruses collected over 10 years from 11 untreated patients with HIV, and used this data to predict which viral strains might be able to escape treatment with different bNAbs and whether dodging bNAbs had a survival cost. Next, using computational methods, they applied the knowledge gained to predict viral rebounds in three real-life trials of bNAbs.

Finally, the team used their computational approach to find a combination of bNAbs that is least likely to allow any virus to escape. They also found that some bNAbs, such as 10-1074, are better against diverse populations of viruses because mutations that allow viruses to escape also make the virus less likely to survive. Others, including PGT121, are more effective against less diverse viral populations because mutations that enable escape are rare. Overall, the results suggested that the optimal combination includes three bNAbs: PG9, PGT151 and VRC01. 

“We’ve shown the combination of PG9, PGT151 and VRC01 reduces the chance of viral rebound to less than 1%,” LaMont said. “It does this by targeting three different regions of the virus’ protective outer wrapping, or envelope.” 

“Combining bNAbs, administered via intravenous infusion every few months, with current antiretroviral therapies (ART) that require daily doses could further improve long-term HIV treatment success,” suggested senior author Armita Nourmohammad, Assistant Professor at the University of Washington.

ART hinders HIV multiplication and ability to create new variants, limiting the genetic diversity of the viral population and reducing the odds of bNAb escape variants emerging. The authors say that more studies are needed to confirm the potential benefits of combining ART and bNAbs. 

“Our study shows that leveraging genetic data can help us design more effective HIV therapies,” Asst Prof Nourmohammad concluded. “Our approach may also be useful for designing therapies against other rapidly evolving agents that cause disease, such as the Hepatitis C virus, drug-resistant bacteria, or cancer tumour cells.”  

Source: eLife Sciences

Categories : HIVTags :

Innate Immune System Detects HIV-1 with a Two-step Strategy

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HIV invading a human cell
HIV invading a human cell: Credit NIH

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.

Source: Scripps Research Institute

Categories : Ageing HIVTags :

HIV Infection Found to Accelerate Ageing Process

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HIV Infecting a T9 Cell. Credit: NIH

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.

Source: UCLA

Categories : HIVTags :

SA HIV Clinicians Update Dolutegravir Guidelines

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HIV themed candle
Image by Sergey Mikheev on Unsplash

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.

The clinical guidelines are available for download as a PDF.

“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.

Source: South African HIV Clinicians

Categories : Cancer HIVTags :

How Kaposi Sarcoma-associated Herpesvirus Evades the Immune System

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Kaposi sarcoma on the skin of an AIDS patient. Credit: National Cancer Institute

A study published in Cell Reports has 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.

Source: University of California – Davis Health

Categories : Diseases, Syndromes and Conditions HIVTags :

New Drugs for Cryptococcal Meningitis Sorely Needed in SA

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Brain scan image
Image source: Mart Production on Pexels

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.

Source 1: Spotlight

Source 2: Spotlight

Categories : HIVTags :

‘One-dose’ Course Effective for HIV-associated Cryptococcal Meningitis

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HIV invading a human cell
HIV invading a human cell: Credit NIH

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.

Source: London School of Hygiene and Tropical Medicine