What will it take to bring HIV-prevention injections to SA’s clinics?

After 40 years United Nations Programme on HIV/AIDS (UNAIDS) and the World Bank are reporting a “groundbreaking” breakthrough towards the development of an HIV vaccine. (Photo: thenewhumanitarian.org/Wikipedia)

By Catherine Tomlinson

1 Sep 2021

An antiretroviral injection administered every two months has been shown to be highly effective in preventing people from getting HIV in two large trials. Catherine Tomlinson asks what needs to happen before these injections become available to people in South Africa.

An antiretroviral injection administered every two months has been shown to be highly effective in preventing people from getting HIV in two large trials. In addition, a number of acceptability analyses and civil society engagement have found that people like the product and are eager for it to become available.

Sibongile Tshabalala, national chairperson of the Treatment Action Campaign (TAC), tells Spotlight that groups they consult with all would prefer an injection over a pill (oral PrEP]. “They ask us how long are we going to wait to have access to it?”

The new two-monthly injectable product referred to by Tshabalala is a long-acting, injectable version of the antiretroviral medicine cabotegravir – commonly known as CAB LA. CAB LA is not yet available in South Africa for procurement but has been trialled here as part of two large-scale phase 3 multi-country trials: HPTN 083 and HPTN 084.

Both trials – one in cisgender gay men, men who have sex with men and transwomen, and another in cisgender women – were stopped early after evidence showed that CAB LA is more effective than daily HIV prevention pills in preventing HIV infection. The pill or oral PrEP (pre-exposure prophylaxis) used in the study was the current World Health Organization-recommended gold standard of a combination of the antiretrovirals tenofovir and emtricitabine. The HPTN 083 trial showed that CAB LA is 66% more effective in preventing HIV than oral daily PrEP among men who have sex with men and transgender women. The HPTN 084 trial demonstrated that CAB LA is 89% more effective at preventing HIV in women than oral daily PrEP.

Research is under way to assess the safety and tolerability of CAB LA among adolescents and women who are pregnant and breastfeeding.

Why is CAB LA more effective than oral PrEP in preventing HIV infections?

Oral daily PrEP is a highly effective method of preventing HIV and is the backbone of many countries’ HIV-prevention strategies. When taken correctly, oral daily PrEP reduces one’s risk of contracting HIV to almost zero. So, given its high effectiveness, how can CAB LA be so much more effective?

Researchers believe the superior efficacy seen for CAB LA is because the drug does not rely on people remembering or being able to take pills daily – as required for oral daily PrEP.

“Both of these agents are very effective in preventing HIV, [but] the trials showed that the injectable agents were more effective in preventing HIV than the oral agents and that’s most likely because of the adherence advantage that they offer”, explains Professor Sinéad Delany-Moretlwe, HPTN 084 Protocol Chair.

An HIV/AIDS patient holds antiretroviral medication. While taking any medication daily as prescribed can be difficult, taking oral daily PrEP has unique challenges. (Photo: Unknown)

“The effectiveness of oral PrEP is entirely dependent on you taking the pill every day. Once you stop taking it you will lose protection a couple of days later,” says Professor Gesine Meyer-Rath from the Wits Health Economics and Epidemiology Research Office (HE2RO). “But with CAB LA you have this beautiful kind of protection that still continues for two to three months.” (While the HPTN 083 and 084 trials assessed the efficacy of CAB LA injections every two months, participants had a 12-week window to receive their injections, and data on the efficacy of CAB LA taken every 12 weeks are forthcoming.)

While taking any medication daily as prescribed can be difficult, taking oral daily PrEP has unique challenges given its association with sexual activity and HIV status, as well as the lack of negotiating power of many vulnerable individuals and communities at risk for HIV.

“For many people at risk for HIV, their lives and the circumstances around their lives make it harder to take a pill a day and so the injections give them a convenient and discreet method of HIV prevention”, says Delany-Moretlwe. She adds that women experiencing intimate partner violence have higher risks of getting HIV and may not be in a position to negotiate the use of and adhere to daily oral tablets.

Dr Yogan Pillay, country director for the Clinton Health Access Initiative (CHAI) in South Africa, notes that for CAB LA “people don’t have to remember to take it daily, they don’t have to have any container in the home… so they can take it discreetly. That has been one of the challenges with oral PrEP. It can’t be taken discreetly and because oral PrEP is an antiretroviral, people taking it are often thought to be HIV positive and pretending to be negative.”

“In the communities, people don’t understand that ARVs are also used for HIV prevention like we do in civil society,” says Tshabalala. “If you are a woman living with a man or have multiple partners it can be difficult to take daily PrEP because of stigma. Some don’t take the pills correctly because they are not open with partners about why they are taking PrEP. Taking pills in front of other people is difficult if you are not open.”

How acceptable are injections?

While some people may be averse to receiving injections, analyses conducted to date have shown that long-acting injections are a highly acceptable and preferred method of HIV prevention for most people.

Lise Jamieson, a senior researcher from HE2RO, says “there have been a number of acceptability studies and pretty much for all of them there has been a higher preference for CAB LA, or any injectable, than for oral daily PrEP – including a study done in men in South Africa, where 48% said they preferred a long-acting injectable product compared with 33% who said they would use oral PrEP.” In South Africa, “25% of sexually active women use injectable contraception”.

“Clearly there are people who are happy coming into a clinic every two to three months to get an injection – it’s easy. This is an accepted technology,” says Jamieson.

“The ease of having a long-active injectable for contraceptives is shown in the numbers”, says Pillay. “We have far more people on injectable contraceptives than orals.”

Dr Lauren Jankelowitz, CEO of the Southern African HIV Clinicians Society, tells Spotlight: “The South African population likes injections. There have been a number of studies [on] why and it’s the kind of convenience and not having to think about it all the time – but also there is a sense of quality care when you get an injection. When you leave with pills, it doesn’t have quite the same feel.

“It just makes PrEP even easier than it is now. So, we think it’s got enormous potential. It’s another game-changer,” says Jankelowitz. “If it can be timed together with contraceptive injections, if you can go in and get your injections in one shot and then go in a couple of months later – that would be ideal.”

Can the roll-out of CAB LA build on efforts to scale up oral PrEP?

According to the Department of Health, by June 2021, 298,815 people have been started on oral PrEP in the public sector. While this figure is low when considered against the size of South Africa’s at-risk population and the ongoing stubbornly high rates of HIV incidence in the country, it does represent a substantial increase in public-sector PrEP initiation over the past two years. By the end of 2019 only about 50,000 people had been initiated on PrEP.

Oral PrEP was first made available in select public-sector sites in South Africa in 2016 for sex workers. In 2017, eligibility for oral PrEP was expanded to include men who have sex with men and young women at risk of getting HIV. Today, any person who self-identifies as at risk for HIV and whose lab tests demonstrate good kidney health is eligible to receive oral daily PrEP – however, access to public-sector facilities providing PrEP remains a challenge.

The Department of Health told Spotlight in February 2020 that it aimed to make PrEP available in all public health clinics and community health centres by September 2020. The department’s ambitious roll-out plans collided with the start of the Covid-19 pandemic and its targets were not met. However, the number of public-sector facilities providing oral PrEP has improved significantly over the past two years.

That number rose from 160 in August 2020 to 1,227 in January 2021. By the end of June 2021, 1,851 public health facilities had begun providing PrEP. This accounts for 53.4% of the targeted public health facilities in the country, according to figures provided by the department.

Access varies across the country. In the best-performing province, KwaZulu-Natal, oral PrEP is available in 589 public primary healthcare facilities – or 94.2% of targeted primary healthcare facilities. In the worst-performing province, the Western Cape, oral PrEP is available in only 14 public primary healthcare facilities, representing a mere 6%.

While there is substantial room to strengthen HIV-prevention efforts in the country by expanding access to oral PrEP, policymakers and researchers believe that introducing new HIV-prevention tools such as long-acting injectables and the dapivirine vaginal ring will benefit from lessons learnt and systems developed as part of the oral PrEP roll-out. The ring has shown only moderate effectiveness in phase 3 trials, but has received a WHO recommendation and will offer women an alternative to oral PrEP once available.

“If we are looking at how we have approached the implementation of PrEP – which was a very systematic approach – if we follow the same approach for any of the new products, we should have a fairly seamless introduction,” says Hasina Subedar, technical adviser to the Department of Health on HIV prevention. Subedar adds that the department already has several tools in place, which were developed for the oral PrEP programme, that can be used and adapted for the introduction of new biomedical prevention technologies. “We have a monitoring and evaluation system in place, we have planning tools in place, we have job aids, and an online training programme.” In addition, the department had developed a framework outlining all the steps required for implementing a new biomedical HIV-prevention product – from registration, financial planning and budget mobilisation, to development of implementation plans, communication and mobilisation.

How long will it be before people can get CAB LA at their local clinics?

Researchers and policymakers estimate that, given all the processes that must still be completed, it will be a couple of years before CAB LA is available in public health facilities. “There are still a lot of moving parts to this. My hope is that we could start serious discussions in the first quarter of next year, with the hope of having it maybe in the last quarter of 2022, first quarter of 2023. I think most people are looking at 2023,” says Pillay.

While some people may be averse to receiving injections, analyses conducted to date have shown that long-acting injections are a highly acceptable and preferred method of HIV prevention for most people. (Photo: thenewhumanitarian.org/Wikipedia)

“I imagine this is sort of a couple of years’ worth of work to get it into the public sector, but I do think what we have learnt from Covid-19 is you can go much faster if you want to,” says Delany-Moretlwe. She adds that trial participants continue to receive CAB LA through open-label amendments to the trial “while we wait for registration”, and that access should also become available through certain sites set up to conduct operational trials before registration to inform the national roll-out.

Jankelowitz notes that community demand for CAB LA can speed up its introduction “because as soon as the community drives the process, it changes everything”.

“Dolutegravir [a critical medicine for HIV treatment] came in quickly because the community called for it.”

What needs to happen for CAB LA to be rolled out in the public sector?

While CAB LA has been shown to be highly effective in trials, a number of processes still need to take place before it can be provided at public-sector facilities. These include national registration, demand forecasting, budgeting, product tendering, and policy and guideline development. Work must also be done to ensure that the health system and health workers are properly capacitated to provide new prevention technologies since the provision of CAB LA, as well as the dapivirine ring, are expected to increase nurses’ workloads. They must also be trained to counsel individuals on the risks and benefits of different products.

“What we ultimately aspire to is this notion of shared decision-making where a client can say what are their preferences and then the healthcare provider can say here are the products and these are their differences and trade-offs,” says Delany-Moretlwe. “I don’t think we do a very good job in the health system of being able to help people make these kinds of decisions.”

Critical first steps: Registration and pricing

Before the Department of Health can start providing the injection to people, CAB LA must be reviewed and registered by the South African Health Products Regulatory Authority (Sahpra).

“Before we can actually as a department start looking at the development of the policy and the guidelines, there are two prerequisites that need to happen. The one is that it needs WHO PQ (prequalification) approval – this is quite an important step because it does legitimise the use of the product and usually this happens after there has been FDA (US Food and Drug Administration) approval or EMA (European Medicines Agency) approval, and then also we need Sahpra approval,” says Subedar. “We want to be sure that any product we are considering as a department has gone through the necessary evaluation process to be safe and to show that it is fit for purpose.”

ViiV Healthcare, the company with monopoly rights to manufacture CAB LA and market the product in South Africa, has not yet made a submission to register CAB LA in the country. ViiV initiated a rolling submission for review and registration of CAB LA for HIV prevention with the FDA in May 2021. Because the FDA has given CAB LA breakthrough drug status (which provides for expedited review), the product may be registered in the US by early 2022.

In response to queries on when ViiV would seek WHO PQ approval and Sahpra registration, Melinda Stubbee, ViiV’s global communications director, tells Spotlight: “We plan to start submission of regulatory files with global regulatory authorities by the end of this year.”

While CAB LA will be eligible for fast-track review by Sahpra once a regulatory application is submitted by ViiV, this can still be a lengthy process that delays the introduction of critical new health technologies long after they are available in other parts of the world. The median approval time for fast-track applications by the regulator in 2017 was 609 calendar days. However, new reliance models subsequently implemented by Sahpra should allow for faster review and approval of products already registered by the FDA and approved by the WHO.

Jankelowitz notes that “there are examples of Sahpra being able to move quite quickly – it helps to have the department on board”. The regulator “moved quite quickly with Covid vaccines”.

How much will CAB LA cost?

It is currently unknown what CAB LA will cost. “We do not comment on pricing in any market until our product is approved,” says ViiV’s Stubbee.

It is anticipated that the South African government and other buyers will negotiate with ViiV around a price, which will be affected by volumes ordered. Pillay tells Spotlight that South Africa may join other buyers, such as the Global Fund and Pepfar, to negotiate lower prices by combining their markets to achieve larger volume guarantees. “This is all a volumes game. If there are no volumes and the prices are sky-high, then no one is going to get it,” says Pillay.

Health economists Lise Jamieson and Gesine Meyer-Rath have also begun work to project the impact of CAB LA in target populations in South Africa, and determine the price at which the product is cost-effective compared with oral PrEP.

Jamieson says that “from preliminary results, we can see that CAB LA has the ability to avert twice as many HIV infections at the population level compared with oral PrEP”. In determining a cost-effective price, HE2RO would consider the current cost of oral PrEP (R60 per month in the public sector), as well as the cost savings to the HIV treatment programme of preventing new HIV infections.

Meyer-Rath adds that market size will also affect price. “We have a little bit of wiggle room on the CAB LA compared with the oral PrEP. Because it is more effective we could accept a slightly higher price than, let’s say, the oral PrEP price, but also since this is potentially a drug that has a very big market, it is in the interest of the manufacturer to think about the total budget that South Africa can afford for PrEP overall – especially if demand goes through the roof. If you get access to a much bigger market, then you should be in a position to also come down on the price.”

Jamieson and Meyer-Rath say that once their research is complete, its results will be widely shared and able to be used by the Department of Health to assist in its negotiations with ViiV. They note, however, that while their work will set an upper threshold price at which CAB LA will be cost-effective for use in the public sector, there may still be room for the department to negotiate lower prices if the cost of production plus reasonable profit is lower than the threshold price.

ViiV currently holds two patents on CAB LA lasting until 2031. However, if the company is unwilling to supply the product at an affordable price, South Africa can use provisions in its patent and competition laws to allow generic producers into the market, as was done for HIV treatment in the country.

“There has to be generic competition for CAB LA – either that or the prices have to be low enough,” says Meyer-Rath. “We can’t try to solve the HIV epidemic with an expensive product. It won’t happen. I do think CAB LA is our first good shot at actually getting a prevention intervention out there that people like, accept, demand, and will continue to use – not all of which is true for oral PrEP, unfortunately.”

Where will the budget come from?

The Department of Health is facing large budget cuts, which have resulted in funding cuts to the country’s HIV programme. Cuts announced in 2021 included a R6.4-billion from the HIV/AIDS programme over the next three years.

“There is a big budget challenge currently,” says Pillay. “So as a substitution for the oral, it needs to be at the same price point or thereabouts, otherwise it is going to need additional funding and you have to find it from somewhere. Now the question is where do you get additional funding from? You have to take it out of the current HIV conditional grant, which means you have to stop doing something. What do you stop doing?”

Subedar notes that donor support could be sought to kickstart implementation of both CAB LA and the dapivirine ring, as was done for the introduction of oral PrEP.

While budget availability is a major challenge for introducing any new products in the current financial climate, Delany-Moretlwe believes that as more prevention technologies come to the market, it will build the case for investment in our prevention infrastructure. “Covid-19 and vaccines have sort of shifted in people’s minds the importance of prevention. People now recognise that you don’t end pandemics through treating them, you end them through large-scale, high-coverage prevention.” DM/MC

Note: A representative of the TAC is quoted in this article. Spotlight is published by SECTION27 and the TAC, but is editorially independent, an independence that the editors guard jealously. Spotlight is a member of the South African Press Council.

* This article was produced by Spotlight – health journalism in the public interest.

Categories:

Tags:

DM is much better if you are signed in...

South Africa