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SPOTLIGHT IN-DEPTH

New guidelines and medicines poised to boost TB prevention in SA

New and repurposed medicines bedaquiline, pretomanid, linezolid, and moxifloxacin are combined in the shorter six-month regimen. (Photo: EPA/Nic Bothma/Wikipedia)

The rollout of new TB prevention medicines in South Africa has progressed slower than expected and new TB prevention guidelines have been delayed. But, reports Catherine Tomlinson, new guidelines should soon be approved and things appear to be falling into place for a faster rollout of the new medicines.

For many, learning that you have tuberculosis (TB) can be an anxiety-inducing experience. Not only due to concerns about one’s own health but also due to concerns about transmitting TB to other members of your family and household. These fears may be allayed when one learns that there are pills that people at risk of TB can take to prevent falling sick.

Such prophylactic treatment, commonly referred to as TB preventative therapy or TPT, has been available in South Africa since the early 2000s. Yet, while TPT is widely available in the public sector, South Africa largely continues to use an outdated TPT regimen known as isoniazid preventative therapy or IPT, despite evidence that newer, shorter TPT regimens have higher completion rates and fewer serious side effects. IPT has to be taken for anything from six to 36 months, while newer regimens are taken for three or less.

At the same time, South Africa continues to largely restrict eligibility for TPT to people living with HIV and household contacts of people with TB that are under the age of five. As a result, HIV-negative family members of people with TB who are older than five are unable to access TPT through the public sector.

In their current form, South Africa’s TPT guidelines are out of step with the World Health Organization’s (WHO’s) guidance on TPT that recommends the use of new, shorter course TPT regimens, as well as providing TPT to all household contacts of people with TB.

Yet, according to Lynette Mabote, TPT advocacy consultant for Treatment Action Group (A New York-based advocacy group), South Africa is poised to bring its TPT policy in alignment with WHO recommendations, if new TPT guidelines developed through the TB Think Tank (an advisory body) are adopted and implemented by government.

Professor Salome Charalambous, group chief scientific officer at the Aurum Institute says that “the new guidelines have been developed, they’ve been in development for about two years [and] the plans at the moment are for them to go through the National Health Council”. She adds that the guidelines are set to be tabled at the National Health Council later this month.

Professor Gavin Churchyard, CEO of the Aurum Institute, notes, however, that for the new guidelines to be implemented, it is essential that all medicines used in short course TPT regimens are included on the essential medicines list.

What is short course TPT?

While a couple of new, short-course TPT regimens are recommended by the WHO, the regimen that South Africa is poised to start rolling out if the new guidelines are adopted is 3HP.

The 3HP regimen involves taking the medicines isoniazid and rifapentine once a week for three months. According to Charalambous, 3HP can be given to all people at risk of TB over the age of two that are not pregnant, HIV-negative, or HIV-positive, and stable on antiretroviral treatment. (Studies to assess the safety of providing 3HP to groups not currently eligible for this treatment are underway).

Churchyard explains that programmatic evidence shows that treatment completion rates for 3HP are higher than those for IPT. “The programmatic evidence suggests that it’s fine to give [3HP] self-administered under programmatic conditions and it’s associated with high treatment completion rates, whereas IPT is associated with a much lower treatment completion rate. With respect to safety, there are numerous studies showing that the safety profile of 3HP is better [than IPT],” he adds.

Charalambous explains that while 3HP can cause side effects, the side effects associated with 3HP are less serious than those associated with IPT. According to Charalambous, in some cases, people receiving 3HP can experience “a hypersensitivity reaction, just like a flu-like illness… which is thought to be less of a problem than hepatitis”. When taken over long durations, as when used in IPT, isoniazid can cause liver damage and even hepatitis in some patients.

Wieda Human, of TB Proof (a local TB advocacy group), explains that “shorter TPT regimens that include rifapentine have shown a decreased risk of liver toxicity and other adverse events compared to IPT”.

So, given the benefits of 3HP, why has it taken so long to roll out?

The need for new short-course TPT regimens, specifically 3HP, to combat TB, has been recognised and called for by civil society and even government for many years.

The National Department of Health highlighted the need to “revise South Africa’s [TPT] guidelines to include 3HP” in the 2017 – 2022 National Strategic Plan on HIV, TB and STIs published in 2018. In 2019, a coalition of civil society groups welcomed draft guidelines for TPT in South Africa and called on the department to ensure the timely release of finalised guidelines introducing short-course TPT regimens.

TB Proof’s Human says that unmet promises for updated TPT guidelines date even further back. “The revised TPT guidelines, which expand coverage to all close contacts regardless of age, have been promised since 2017.”

Several challenges have contributed to the delayed release of the updated TPT guidelines in South Africa. Mabote says of the guidelines that “these ones have had a lot of bad luck because they’ve been going around the scientific circles and there’s been a lot of disagreement”. She notes that disagreements have centred on whether introducing 3HP, which is more expensive than IPT and expanding eligibility to all household contacts is necessary given the increased costs it will place on the already overburdened public health system. She adds that these arguments have now mostly been settled as buy-in regarding the cost-effectiveness of these interventions has been secured.

According to Churchyard, they have done a number of modelled cost-effectiveness studies. “In South Africa, 3HP is cost-effective, and that’s largely because of our high costs of routine care within the country. In South Africa, there are clear cost-effectiveness benefits.”

Charalambous adds that the need to update the draft TPT guidelines as new evidence has also contributed to delays in finalising the guidelines.

The years-long delay in updating the TPT guidelines to introduce 3HP defied early expectations that South Africa would be the first country to introduce new, short-course TPT regimens.

“The guideline development process for South Africa started in early 2019. We thought that South Africa being the country that always excels at these things… would move fast, but we are still waiting for those guidelines to be released,” says Mabote.

Churchyard adds, “We thought South Africa was going to be… the first out the gates implementing, showing the world how it is done, [but it] is one of the last to actually come in. The first country to adopt 3HP was our neighbour Mozambique”, says Churchyard, adding that several other countries in the region have already rolled out 3HP.

Preparing for national rollout

If South Africa adopts new TPT guidelines later this month that provide for the national rollout of 3HP, it will be able to draw on groundwork already undertaken to enable the rollout. With the support of the Aurum Institute, the National Department of Health in April 2019 began piloting 3HP in four districts — OR Tambo, eThekwini, Ehlanzeni, and the City of Johannesburg.

According to Foster Mohale, spokesperson for the health department, 3HP is now available in 226 of the 395 targeted health clinics in the four districts. Charalambous notes that as of the end of March 2022, 16,000 people were initiated on 3HP in the four districts.

“A lot of provinces have already received training through the Impaact4TB project… by Aurum and other partners,” says Mabote. She adds that the health department is rolling out more training of healthcare workers and civil society has started doing work to generate community demand for 3HP. “I think we need to do a lot more, but at least the work is underway,” says Mabote.

Price and tenders

In addition to updating the TPT guidelines, all medicines needed for 3HP must be included on South Africa’s essential medicines list to enable its national rollout. 3HP involves a combination of isoniazid and rifapentine. Isoniazid, which is used both for TB prevention and treatment, is already included on South Africa’s essential medicine list (EML). Rifapentine, however, is not. Its inclusion on the EML was previously rejected by the National Essential Medicines List Committee due to its high price.

Up until March this year, only pharmaceutical company Sanofi’s rifapentine product was registered with the South African Health Products Regulatory Authority (Sahpra) and available for use in the country. The health department currently pays R399 ($25) to Sanofi for a three-month course of rifapentine. The cost of 3HP is, however, expected to decline with the introduction of new competitor products in the market.

In March 2022, Sahpra registered pharmaceutical company Macleods fixed-dose combinations of isoniazid and rifapentine. In addition to bringing down the weekly pill burden from ten to four pills (including vitamin B6, which should be taken together with 3HP to reduce the risks of side effects), having an additional product on the market is also expected to reduce prices.

Another company, Lupin, is also planning to manufacture and market rifapentine, but did not respond by time of publication to a request for comment from Spotlight on its plans to register its rifapentine products in South Africa.

Mohale told Spotlight that while the department has previously procured Sanofi’s rifapentine for use in pilot sites, the health department expects to begin procuring Macleod’s fixed-dose combination 3HP tablets if they are available at an affordable price. Mohale says that “pricing for public sector procurement is pending finalisation,” and notes that once a price is available, the National Essential Medicines List Committee (NEMLC) will review whether rifapentine can be included on the national essential medicines list. He notes that the NEMLC review will consider the price parity between 3HP and twelve months of IPT “for the current indication of TPT for people living with HIV initiating antiretroviral treatment”. He adds that “the ​indication for TPT for all household contacts is currently under NEMLC review”.

If the NEMLC approves rifapentine’s inclusion on the EML, then it will be procured in the next TB medicines tender that is expected to be published in September 2022. The amount of rifapentine to be tendered will depend on eligibility requirements set in the guidelines and by the NEMLC. In the case that 3HP is approved for all household contacts of people living with TB, significantly greater stock of rifapentine will have to be procured than if this group is excluded from eligibility. However, procuring larger quantities of 3HP may help the health department secure lower prices.

What will companies likely charge for rifapentine?

While South Africa procures medicines at a national or provincial level, when tendering TB medicines, it is able to benchmark and negotiate against prices charged by medicine manufacturers to the Global Drug Facility (GDF) through which multiple low- and middle-income countries pool their buying power to procure TB medicines.

Together with the GDF, Unitaid and other partners negotiated a lower price for rifapentine from Sanofi of $15 (R239) per patient. Mabote, however, notes that Sanofi has indicated that they will not continue to supply rifapentine at $15 per course and are planning to raise the price of a treatment course to between $20 (R318) and $27 (R430).

Macleods has agreed to sell their fixed-dose combination of rifapentine and isoniazid for $15 per patient course to the GDF, but Mohale from the health department notes that the $15 global access price “does not include VAT, customs clearance, and last-mile costs”.

Mabote explains that when freight, customs clearance, warehousing and distribution costs are added, the costs of Macleods’ 3HP regimen go up to around $17.25 (R275).

By comparison, a 12-month course of IPT at current South African tender prices costs around R192 ($12).

Medicines access advocates are continuing to push for lower prices for 3HP. Treatment Action Group has argued that, if more suppliers enter the market and demanded volumes increase, companies can sell 3HP for as little as $10 per course while still realising reasonable returns based on what it costs to manufacture the medicine. DM/MC

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

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