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HIV game-change with SAHPRA approval and vaccine trial breakthrough

In what is being hailed as a breakthrough for HIV treatment in South Africa, the South African Health Products Regulatory Authority (SAHPRA) has approved drugmaker ViiV Healthcare’s new HIV prevention jab CAB-LA for “people at substantial risk of HIV infection”.

The good news comes as US scientists report that they are a step closer to what they believe is a groundbreaking vaccine that could change the face of HIV treatment, notes Medical Brief.

CAB-LA, taken every two months, virtually eliminates the chances of contracting HIV through sex and, according to SAHPRA CEO Boitumelo Semete-Makokotlela, is authorised for use in people who weigh 35kg or more, and is not indicated for pregnant women, as “safety has not yet been sufficiently demonstrated in pregnant women”, she says.

The injection has also been approved in the US, Australia and Zimbabwe.

The injection could be rolled out on a large scale within nine months, depending on the price at which the drugmaker will sell it, and will be sold in South Africa under the brand name Apretude, but whether the Health Department buys it will depend on the price at which ViiV Healthcare is prepared to sell it to the government.  

The National Essential Medicines List Committee, a group of experts appointed by the Health Minister to advise him about medicines, will now conduct a budget assessment, which will take two to three months.

And in the case of the US research findings, the scientists say apart from possibly being a breakthrough for HIV treatment, the vaccine technology could also impact the development of treatments for flu, hepatitis C and coronaviruses.

In the Cape, Mia Malan and Mohale Moloi, writing for Bhekisisa, spoke to young women who have been in a CAB-LA trial and using the injection for the past six months.

Amanda Roberts (23), a teaching assistant, is waiting for her two-monthly CAB-LA shot to be injected into her buttocks – a lifesaving measure because it virtually eliminates the possibility of her contracting HIV through sex.

The Emavundleni Prevention Research Centre, run by the Desmond Tutu HIV Centre at the University of Cape Town, is a world-class clinical trial site. Part of the open-label phase of a study called HPTN 084 is unfolding here. In an open-label study both the researchers and trial participants know which drug volunteers get.

In this study, Roberts and more than 3 200 other women from sub-Saharan Africa get CAB-LA. Researchers are looking at how easy or difficult it is to roll out the medication because scientists have already established that it works extremely well to prevent HIV infection.

After SAHPRA approval a price can be negotiated with the manufacturer. This information can help the government to know what resources they will need or what obstacles they can expect along the way, when (and if) it eventually rolls out the injection to hundreds of thousands of people.

The less often you take the pill, the less effective it is

CAB-LA stands for long-acting (LA) cabotegravir, an antiretroviral drug used by some HIV-infected people, with other ARVs, to keep the virus from making copies of itself. Taken before exposure to HIV, it’s called pre-exposure prophylaxis (PrEP).

“It works a little bit like a contraceptive injection, which prevents you from getting pregnant,” says Linda-Gail Bekker, the head of the Desmond Tutu HIV Centre and one of the lead investigators of the South African part of the HPTN 084 trial. “The injected drug (cabotegravir) goes into the muscle and sits there for two months, from where it slowly dissolves into the bloodstream. And then it works its magic by preventing HIV from entering your cells.”

Before Roberts took CAB-LA, she used a daily HIV prevention pill that consists of two ARVs, tenofovir and emtricitabine, for five years, but it was difficult to remember to swallow it each day.

“I had to take the pill at the same time every day for it to work (best), but this wasn’t possible over weekends when I went to parties. I didn’t want to carry my medication with me, because people would think I’m sick when they saw me take it, and spread rumours that I’m HIV positive.

“That’s when the problem started with me skipping some of the days.”

The less often Roberts took the pill, which could reduce her chances of getting infected with HIV by more than 90%, the less effective it was.

“That’s why I’m relieved that I now only have to come to the clinic once every eight weeks,” she says. “I feel safer.”

The jab works better than a daily pill

Roberts isn’t the only person for whom CAB-LA works better than a daily pill. Studies have found that the jab works 66% better in men who have sex with men and transgender women and is 88% more effective at preventing HIV infection in young women than oral PrEP. Researchers think it’s probably because the injection is so much easier to take, because you only need it once every two months.

A recent modelling study published in The Lancet HIV revealed that, compared with the daily pill, CAB-LA can reduce HIV infections and Aids deaths by more than three times. In actual numbers, this translates to CAB-LA preventing between 35 600 and 52 000 new infections a year compared to the pill’s 9 000 to 16 800.

These cuts are substantial. South Africa currently has 200 000 new HIV infections per year, 30 000 of them among young women. So CAB-LA can potentially lower new infections by 15-28% over the next 20 years.

By 2025, South Africa wants to more than halve yearly new infections to 74 000 or fewer, but that will be through many methods, not just CAB-LA.

This could include, for instance, increasing the number of HIV-positive people on treatment (when people with HIV use ARVs correctly, the amount of virus in their bodies becomes so little that it becomes scientifically impossible for them to transmit HIV to their sexual partners); getting people to take oral PrEP; making available a vaginal ring, which women can insert to help prevent infection and that the Health Department will soon start to procure; promoting condom use and advocating for delayed sexual debut among teens.

By the end of September, 726 745 people in SA had started the pill at 3 162 public health facilities and partner sites.

But the problem, worldwide, is that the uptake of the pill has been much lower than expected, so much so that the United Nations’ goal to get 3m people globally on the pill by 2020 was missed by two-thirds.

Moreover, many people who take the pill don’t use it consistently, so don’t get the full benefit.

How much does CAB-LA cost?

CAB-LA has been available in the US for the past year.  But there’s a catch.

The jab, made by the drug company ViiV Healthcare, is sold in the US at R54 000 a pop. According to The Lancet modelling study, that is 200 times more than what would be sensible for South Africa to pay.

Why?

The researchers calculated that for CAB-LA to be cost-effective for South Africa, the Health Department shouldn’t fork out more than double than what they pay for the daily HIV prevention pill. A month of pill supplies per patient costs the government R60 (this is only the cost of the pill and doesn’t include administrative fees such as health workers’ time, transport costs, etc.), so the public health sector shouldn’t pay more than R240 (twice the price of the pill) per two-monthly shot (the study says between $9.03 and $14.47 based on USD-ZAR exchange rates at the time of the research’s publication).

But ViiV Healthcare’s head of research and development, Kimberly Smith, told Bhekisisa it’s impossible to produce the jab at the same cost as a pill.

“CAB-LA is a sterile, injectable product with a very complex manufacturing process. The instances where it’s been compared to the manufacturing cost of a simple, white pill are just not realistic.”

Cheaper, generic versions of CAB-LA will make the jab considerably more affordable. ViiV Healthcare already has an agreement with the Medicines Patent Pool, an international organisation that helps to get such non-brand products made, to grant licences to three generic drugmakers. But, once the licences have been awarded, it will take between three and five years for the manufacturers to prepare for production and have ready-made jabs to sell.

So what happens in the meantime?

To get around this, ViiV Healthcare has offered to market their branded product at a much reduced, “not-for-profit” price to 90 poorer countries until generic products are available. South Africa is included in this list of countries.

But the drugmaker hasn’t yet announced what this price will be, and the fee will depend on how many orders donors and governments can commit to, as production at scale will reduce costs.

The Lancet HIV study, as well as scientists and activists interviewed by Bhekisisa, report that the price that ViiV Healthcare is considering ranges between R4 080 and R4 590 per patient per year – far above what South Africa can afford.

At R60 per patient per month, the annual cost per patient per year of the daily pill comes to R720 (without administrative costs). If the suggested price ranges that ViiV Healthcare is considering are correct, they’re considerably higher than what researchers say would be cost effective for South Africa.

But Smith says: “There are a lot of prices floating around, and for the most part, they’re inaccurate, because they don’t fully take into account some of the complexities, such as volume, that will influence the cost.”

Will the Health Department buy CAB-LA?

The only African country whose medicines regulator has approved CAB-LA as a form of HIV prevention so far is Zimbabwe, but the country hasn’t started to roll it out.

The Health Department’s director of affordable medicine, Khadija Jamaloodien, says the updating process and budget assessment may take between two and three months. NThe National Essential Medicines List Committee (NEMLC) will then decide if it’s worth it for SA to roll CAB-LA out in the public sector and, if so, recommend a price.

Jamaloodien explains: “SAHPRA looks at safety, efficacy and quality data of a product to establish if it’s safe to use and if it works the way a manufacturer says it does. NEMLC, on the other hand, compares the product to the current standard of care (in this case the daily HIV prevention pill) to determine if buying the product (in this case CAB-LA) makes economic sense.

“Just because CAB-LA works better than the daily HIV prevention pill, doesn’t mean that we necessarily need to pay double the price.”

“With a monopoly, negotiations become more challenging, because they hold us to ransom,” Jamaloodien said. “But that doesn’t mean we can bluntly accept the price ViiV Healthcare puts on the table.”

Jamaloodien says if NEMLC recommends buying the jab, the Health Department will go out on tender, which will take about six months. That could mean SA could potentially see the mass roll-out of the jab within nine months after SAHPRA registration.

Will people use the jab?

That, however, doesn’t mean people would necessarily line up for it.

“We need to learn from the mistakes we made with the roll-out of oral PrEP,” Bekker says. “In part, we’ve had a low uptake because we stigmatised the pill by initially rationing the commodity and making it available only to high risk groups like sex workers and men who have sex with men.

“This led to people in the larger society, who are also at risk of HIV infection, thinking that the pill wasn’t for them. We’re going to have to work hard at creating demand.”

Mitchell Warren, who heads up the US-based advocacy organisation Avac concurs: “CAB-LA on its own will not end the HIV epidemic. But I can tell you that without it, in the absence of a vaccine, we will never end the pandemic.”

In the meantime, US scientists are one step closer to developing a breakthrough technology that could lead to a vaccine for HIV, according to the journal Science, which published phase 1 results of a small clinical trial for a vaccine technology that aims to cause the body to create a rare kind of cell.

“At the most general level, the results show that one can design vaccines that induce antibodies with pre-specified genetic features, and this may herald a new era of precision vaccines,” William Schief, PhD, a researcher at The Scripps Research Institute and study co-author, told the American Association for the Advancement of Science (AAAS).

Medscape reports that the study was the first to test the approach in humans and was effective in 97% – or 35 of 36 – participants. The vaccine technology is called “germline targeting”. Trial results show that “one can design a vaccine that elicits made-to-order antibodies in humans”, Schief said.

In addition to possibly being a breakthrough for the treatment of HIV, the vaccine technology could also impact the development of treatments for flu, hepatitis C and coronaviruses, study authors wrote.

Previous HIV vaccine attempts were not able to cause the production of specialised cells known as “broadly neutralising antibodies”.

“Call them super antibodies, if you want,” said University of Minnesota HIV researcher Dr Timothy Schacker, who was not involved in the research. “The hope is that if you can induce this kind of immunity in people, you can protect them from some of these viruses we've had a very hard time designing vaccines for that are effective. So this is an important step forward.”iop

Study authors said this is just the first step in the multi-phase vaccine design, which so far is a theory. Further study is needed to see if the next steps also work in humans and, then, if all the steps can be linked together, and can be effective against HIV.

Study 1 details

Relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis in South Africa based on the HPTN 083 and HPTN 084 trials: a modelled economic evaluation and threshold analysis

Lise Jamieson, Leigh F Johnson, Brooke E Nichols, Sinead Delany-Moretlwe, Mina C Hosseinipour, Colin Russell, Gesine Meyer-Rath

Published in The Lancet HIV

Summary
Background Long-acting injectable cabotegravir, a drug taken every 2 months, has been shown to be more effective at preventing HIV infection than daily oral tenofovir disoproxil fumarate and emtricitabine, but its cost-effectiveness in a high-prevalence setting is not known. We aimed to estimate the incremental cost-effectiveness of long-acting injectable cabotegravir compared with tenofovir disoproxil fumarate and emtricitabine in South Africa, using methods standard to government planning, and to determine the threshold price at which long-acting injectable cabotegravir is as cost-effective as tenofovir disoproxil fumarate and emtricitabine.

Methods
In this modelled economic evaluation and threshold analysis, we updated a deterministic model of the South African HIV epidemic with data from the HPTN 083 and HPTN 084 trials to evaluate the effect of tenofovir disoproxil fumarate and emtricitabine and long-acting injectable cabotegravir provision to heterosexual adolescents and young women and men aged 15–24 years, female sex workers, and men who have sex with men. We estimated the average intervention cost, in 2021 US$, using ingredients-based costing, and modelled the cost-effectiveness of two coverage scenarios (medium or high, assuming higher uptake of long-acting injectable cabotegravir than tenofovir disoproxil fumarate and emtricitabine throughout) and, for long-acting injectable cabotegravir, two duration subscenarios (minimum: same pre-exposure prophylaxis duration as for tenofovir disoproxil fumarate and emtricitabine; maximum: longer duration than tenofovir disoproxil fumarate and emtricitabine) over 2022–41.

Findings
Across long-acting injectable cabotegravir scenarios, 15–28% more new HIV infections were averted compared with the baseline scenario (current tenofovir disoproxil fumarate and emtricitabine roll-out). In scenarios with increased coverage with oral tenofovir disoproxil fumarate and emtricitabine, 4–8% more new HIV infections were averted compared with the baseline scenario. If long-acting injectable cabotegravir drug costs were equal to those of tenofovir disoproxil fumarate and emtricitabine for the same 2-month period, the incremental cost of longacting injectable cabotegravir to the HIV programme was higher than that of tenofovir disoproxil fumarate and emtricitabine (5–10% vs 2–4%) due to higher assumed uptake of long-acting injectable cabotegravir. The cost per infection averted was $6053–6610 (tenofovir disoproxil fumarate and emtricitabine) and $4471–6785 (long-acting injectable cabotegravir). The cost per long-acting cabotegravir injection needed to be less than twice that of a 2-month supply of tenofovir disoproxil fumarate and emtricitabine to remain as cost-effective, with threshold prices ranging between $9·03 per injection (high coverage; maximum duration) and $14·47 per injection (medium coverage; minimum duration).

Interpretation
Long-acting injectable cabotegravir could potentially substantially change HIV prevention. However, for its implementation to be financially feasible across low-income and middle-income countries with high HIV incidence, long-acting injectable cabotegravir must be reasonably priced.

Study 2 details

Vaccination induces HIV broadly neutralising antibody precursors in humans

David Leggat, Kristen Cohen,  Jordan Willis, William Fulp, William Schief et al.

Published in Science on 2 December 2022

Abstract

Introduction
Vaccines that induce antibodies with predefined genetic features and binding specificities have promise to combat viruses with high antigenic diversity such as HIV, influenza, hepatitis C virus, and betacoronaviruses. Although these pathogens have eluded the development of vaccines that induce broad immunity covering their antigenic diversity, broadly neutralising antibodies (bnAbs) have been discovered. Such bnAbs bind to relatively conserved epitopes on membrane glycoproteins of each pathogen, with features of each antibody allowing binding to a particular epitope. If vaccines could be developed to consistently induce similar bnAbs, preferably in conjunction with broad T cell immunity, protection against these pathogens might be achieved.

Rationale
bnAbs acquire affinity-enhancing mutations when a bnAb-precursor B cell mutates and matures from the original naïve B cell (or “germline”) state. Germline-targeting vaccine design aims to induce bnAbs by stimulating rare bnAb-precursor B cells that have antibody genes and other properties needed to develop into bnAbs for a specific epitope. This “priming” step must generate a pool of bnAb-precursor–derived germinal centre and/or memory B cells that are susceptible to reactivation by a boost immunogen closer in structure to the native viral glycoprotein. Sequential boosting with immunogens of increasing similarity to the native glycoprotein then aims to guide somatic hypermutation and affinity maturation to produce bnAbs that target the desired epitope.

Results
We conducted a first-in-human test of the germline-targeting strategy by evaluating the safety and immune responses of a germline-targeting priming vaccine candidate, eOD-GT8 60mer nanoparticle adjuvanted with AS01B, in the IAVI G001 phase 1 clinical trial. Each participant received two administrations of placebo, low-dose vaccine, or high-dose vaccine 8 weeks apart. The eOD-GT8 immunogen was designed to activate B cell precursors for HIV VRC01-class bnAbs defined by their usage of heavy chain variable gene alleles VH1-2*02 or *04 and any light chain complementarity determining region 3 with a length of five amino acids. We collected immune cells from the blood and lymph nodes of participants and carried out epitope-specific B cell sorting, B cell receptor (BCR) sequencing, and bioinformatic and statistical analyses. We also produced monoclonal antibodies and measured their binding affinities for the vaccine antigen. The vaccine had a favourable safety profile and induced VRC01-class responses in 97% (35 of 36) of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G memory B cells in blood. bnAb-precursors shared multiple properties with bnAbs and made substantial gains in somatic hypermutation and affinity with the boost.

Conclusion
The results establish clinical proof of concept for the germline-targeting vaccine design priming strategy, support development of boosting regimens to generate VRC01-class bnAb responses against HIV, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.

 

The Lancet article – Relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis in SA (Open access)

 

Bhekisisa article – If the price is right: The anti-HIV jab could be in clinics by August 2023 (Creative Commons Licence)

 

Bhekisisa article – Anti-HIV jab has been approved in SA, here's why it will cost more than the pill (Creative Commons Licence)

 

Science article – Vaccination induces HIV broadly neutralising antibody precursors in humans (Open access)

 

Medscape article – HIV Vaccine Trial Makes Pivotal Leap Toward Making ‘Super Antibodies’ (Open access)

 

See more from MedicalBrief archives:

 

MSF plea for HIV PrEP drug to be affordable

 

Zimbabwe the first to green-light injectable HIV prevention drug

 

Cost and uncertainty over uptake bedevil Africa’s uptake of injectable PrEp

 

 

 

 

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