PEP: the potential, limitations, and how it can help end leprosy
A guide to break down misconceptions and help you engage funders and donors
PEP (post-exposure prophylaxis) has become the leprosy world’s biggest buzzword in recent years. PEP is a way of preventing leprosy from developing in people who have already been exposed to the disease. This is done through antibiotic distribution and, if implemented correctly, PEP has the potential to move us towards a world without leprosy.
But, as with anything so potentially transformative, PEP is often over-simplified and misunderstood. In this article, we speak to Duane Hinders, one of NLR’s leads on PEP and the manager of the PEP++ project, a partnership with The Leprosy Mission and other key stakeholders.
We ask Duane what PEP is and what it is not, what PEP might be and how we get it to reach its potential. We ask who needs to be on board to make PEP a success and the best way to sell PEP to those people.
DH: PEP can mean a lot of different things given the different possible regimens for leprosy and other infectious diseases. A large number of diseases use mass drug administration for prevention or early treatment, but in the leprosy world, it traditionally means SDR-PEP. This stands for Single Dose Rifampicin post-exposure prophylaxis, which in practice means we give a single dose of the antibiotic rifampicin to anyone who we believe has been exposed to leprosy, especially close contacts of persons recently diagnosed with the disease.
In most countries, implementing SDR-PEP means that a person diagnosed with leprosy will give health workers the names of their closest contacts, especially those with whom they share living quarters. Those people will either be invited to a primary care health facility or receive a home visit and subsequently be screened and offered a single dose of rifampicin.
SDR-PEP is what has been approved within the WHO’s leprosy guidelines and has become official government policy in a number of key countries, such as India, Indonesia, Nepal, Tanzania, and others.
DH: Yes, it does work, but it is not flawless. Over the years, many researchers tested different PEP regimens with generally positive results. The Leprosy Mission and NLR supported their partners at Erasmus Medical Center, Rotterdam, to run a study called COLEP in Bangladesh early in the millennium. It was this study that definitively demonstrated to the world that PEP could work against leprosy. It showed that SDR-PEP prevents around 60 percent of contacts from developing the disease after they have been exposed to leprosy bacteria.
SDR-PEP works particularly well in people who are more distant from the index case, but the efficacy drops as genetic or physical proximity increases. If you are a blood relative of someone who has recently been diagnosed with leprosy, SDR-PEP will only be about 24 percent effective.
© Mahinthan Someswarapillai
The other limitation with PEP is that it is not like a vaccine; you will not have immunity from leprosy if you have taken a single dose of rifampicin. That single dose of rifampicin will do what any antibiotic does; it only kills the bacteria in your system at the time.
The COLEP study found that people who receive SDR-PEP will have significantly lower risk of developing leprosy for two years after they take their dose of rifampicin due to the long incubation period. For this reason, we promote a re-treatment roughly every two years for contacts in highly endemic areas if re-infection may have possibly taken place.
One way to provide more lasting protection would be if we combined PEP with immunoprophylaxis, such as LepVax, one leprosy vaccine that is currently under study. Combining PEP with a vaccine would mean that PEP would kill off any existing bacteria in the body and the vaccine, if proven to be effective, would promote a lasting immune response against future infections.
DH: We have modelling that shows us that, if we could administer 40 million doses of SDR-PEP globally, we could reduce leprosy disease by 90 percent in a little over 20 years. So yes, SDR-PEP does have some serious potential to be a game changing tool. The challenge we are facing is that we don’t know exactly who those 40 million people should be. We are using mapping techniques and results from other studies to better understand who falls into the population at risk for developing leprosy.
However, it will likely not be enough to give PEP only to close contacts of index cases. There are too many people who are diagnosed with leprosy without knowing from whom they may have caught it; they do not know anyone who has or had the disease. This happens in highly endemic communities, where there is enough leprosy present in the community for the disease to be transmitted even outside of close-contact situations, like households and work places.
This is where we utilise the potential of focal mass drug administration. With this approach, we would use spatial methods/mapping to define a highly endemic area and distribute SDR-PEP on a mass scale. But as I said, the challenge is still working out which districts would benefit from focal mass drug administration. For this we hope to run ‘blanket campaign’ trials in the coming years to define how effective mapping efforts are to help locate areas with high numbers of new cases and prevent others in the future.
If we could administer 40 million doses of SDR-PEP globally, we could reduce leprosy disease by 90 percent in a little over 20 years.
This type of blanket approach seeks to give SDR-PEP to 100-150 people per index case, but we need additional funding. There is also a very important Global Leprosy Mapping Initiative, funded and implemented by several ILEP partners, which will be crucial in helping us to identify leprosy hotspots that would benefit from SDR-PEP, as well as improving the overall quality of leprosy data.
DH: There are people who are sceptical about SDR-PEP. A lot of the scepticism comes from places with high rates of tuberculosis. As well as being the most potent drug within Multi-Drug Therapy (the combination of antibiotics that cures leprosy), rifampicin is a front-line medication against TB.
In communities where TB is a significant threat, scientists and clinicians are reluctant to distribute large amounts of rifampicin because they are worried about antimicrobial resistance (AMR). If TB infection becomes resistant to rifampicin, we would have a significant problem in terms of first-line treatment and potential extremely resistant cases.
We had an expert committee of TB and leprosy specialists consider this question in 2016 and they concluded that administering a single dose of rifampicin to patients is a negligible risk to increase AMR, even in endemic districts for tuberculosis.
Of course, there are those who are still sceptical and that is understandable. It is why we have to consider more effective approaches to PEP, particularly those that make use of more than one form of antibiotic, which would significantly reduce the risk of AMR and increase the effectiveness of PEP.
DH: There are a handful of studies around the world that are looking at whether other forms of PEP might be effective against leprosy. Our project, PEP++, is looking at using an additional antibiotic called clarithromycin alongside rifampicin.
This approach would see contacts of index cases receive clarithromycin and rifampicin three times at intervals of approximately four weeks. As well as removing the concerns about AMR, we hope that this approach will make PEP more effective, particularly for those individuals who have had the most exposure to leprosy (those household contacts and blood relatives who receive only 25 percent protection from SDR-PEP).
© Ricardo Franco
We are very hopeful about the potential for PEP++ to be even more effective in preventing leprosy, but we also recognise the challenge posed by administering two antibiotics to the same person three times in a short period of time. In our trial to date, about 50 percent of intervention area contacts have taken all three doses, but there is always a lag time before other doses can be offered. We hope to have 75-80 percent full adherence to the new regimen by the end of the trial. However, that level of adherence may be hard to achieve when trial-specific research assistants are not present.
The saving grace is that health systems would not have to administer PEP++ to all contacts of index cases. We expect it to be a powerful tool, but not every person would need such a powerful tool to prevent leprosy. But, even with only the closest contacts receiving PEP++, we acknowledge there will be logistical challenges.
There is a team at the University of Antwerp who are looking at an enhanced PEP regimen using rifampicin alongside bedaquiline in a single dose. This would mean close contacts receive one dose of each medication, which may prove easier to manage in some districts.
DH: The first doses of PEP++ were administered early in 2020, but that was right at the beginning of the pandemic. The trial only really began in earnest in the second half of 2022. We want to enrol 202,000 people from India, Nepal, Bangladesh, Indonesia, and Brazil onto the study. We are hoping that might be achieved by the end of 2023 or very early in 2024, which would mean the final participants in the study would have their follow-up completed in March 2026. We hope to publish our findings later that year.
DH: The starting point for that answer has to be the governments and health systems who would have a responsibility for implementing PEP. The good news is that many governments are responding positively to PEP and are interested to get on board.
The bigger challenge we are facing is with the drug companies that produce the medications, especially rifampicin. Whatever form PEP takes in the future, it is likely that rifampicin will be a key component and it is often difficult to access.
The challenges in accessing rifampicin are partly because of government regulations and partly because the manufacturers have reduced the supply since the pandemic. Even in countries like India, where there are several rifampicin manufacturers, there are still problems, mostly due to bureaucratic issues that do not allow for national distribution. The method for individual states to purchase it is convoluted and often leads to significant delays in SDR-PEP roll-out.
In countries like Ethiopia and Mozambique, where rifampicin is not produced, we have faced constant difficulties with rifampicin availability, shipping, importation, costs, delays, and government approvals.
So, to make PEP a success, we need drug companies and government systems to be working much better together. As Novartis currently provides rifampicin for MDT worldwide, we might have hoped that they could support in providing extra supplies for PEP, but that does not yet seem to be the case.
Lastly, we need to get the sceptics on board. Hopefully we can do that by demonstrating the efficacy of multi-antibiotic regimens of PEP, but ideally we can convince them long before these studies publish their findings. SDR-PEP is a very effective tool and we should not waste time waiting for new regimens before we start implementing the one we already have.
DH: There are probably two methods for this: the personal impact approach and the evidence-based, institutional one. If we start by showing stakeholders the impact PEP has had on a person’s life, we are in a good position. To show that a child has avoided a life of preventable disability and stigma because of a single dose of medication, that’s powerful. In too many countries, being diagnosed with leprosy is a traumatic experience and we have the power to prevent that.
If PEP works well, we may never know who would have been diagnosed with leprosy without our intervention, but that should not stop us from taking the stories of people who have experienced the sadness of a leprosy diagnosis and telling policymakers, health officials, supporters, donors, and anyone who will listen that this sadness was entirely preventable.
If we want to move on from personal storytelling, PEP has a good story to tell on a policy and social level.
© Ruth Towell
We can start by talking about the impact that leprosy has on national economies. There are millions of people living with preventable disabilities, many of whom are not able to contribute as they would have liked in the workforce and instead are reliant on disability pensions. The cost of one dose of rifampicin is less than one euro and the cost of administering PEP through healthcare systems is also very low. These are remarkably low costs when compared to the blow of losing working-age adults from the workforce and a lifetime of providing disability pensions.
The LPEP Study demonstrated how PEP can be implemented effectively through existing government programmes, so governments do not need to reinvent the wheel or bring in further human resources to the health system to make PEP implementation happen. If you can integrate PEP into the public health system through community health workers, you are looking at an incredibly low cost intervention that will have a massive impact on lives, communities, and national economies.
Lastly, we can incentivise governments by eventually certifying an end to leprosy in their territories. As more countries eliminate leprosy using the WHO leprosy elimination indicators, we can celebrate with governments, provide official certification, and set them up as an example of how leprosy can be eliminated from this world, country by country.
On Thursday 1 June, The Leprosy Mission and NLR are hosting a panel discussion webinar with PEP experts from a range of disciplines. We will be unpacking the potential of PEP, the challenges we face, and how we can overcome these challenges.
Sign up here >
