In a recent BMJ Blog Dr Rupert Whitaker cast a critical eye on Pre-Exposure Prophylaxis (PrEP) for the prevention of HIV infection, questioning its role as a public health intervention. The piece is challenging and although it rightly emphasises the need for a carefully planned implementation, it contains a number of factual inaccuracies and conceptual misunderstandings that need to be addressed.
PrEP and/or condoms
The blog starts with the statement that “[PrEP] works in just the same way as condoms do in real life”. This is not the case and it is something important to understand. Condoms provide a physical barrier which prevents the transmission of HIV; PrEP offers a chemical barrier which prevents the acquisition of HIV. The distinction between transmission and acquisition is not trivial.
With condoms, an uninfected person is physically protected against exposure to the virus; with PrEP a person can be exposed to the virus but the presence of enough antiviral drugs at the point of entry will protect them against viral infection. A more judicious comparison would have been between PrEP and treatment.
As a consequence, it is all or nothing with condoms whilst PrEP is more forgiving.
Truvada is currently the only drug approved for PrEP and only in the USA where it is prescribed as a daily regimen for the prevention of HIV infection in HIV negative people. Adherence to the regimen is crucial to PrEP effectiveness but missing a pill occasionally will not affect the protection PrEP offers as dramatically as would not using condoms on a random sexual encounter.
During the HIV Research for Prevention (HIVR4P) Conference in Cape Town in October 2014, Jared Baeten, a clinical investigator in several PrEP studies, noted that: “You don’t always have to be perfect to be good enough.”
Clinical studies have demonstrated that Truvada still offers a high level of protection even when users are not perfect adherers. In the iPrEX study, which showed a 44% reduction in the risk of infection, it was calculated that PrEP users were taking their pills on average four times a week rather than daily. It is doubtful that condoms would achieve similar level of efficacy if used similarly.
It is worth stressing time and again that PrEP is not primarily targeted at people who are comfortable with using condoms on a regular basis.
Condoms remain the preferred prevention method for the majority of gay men attending sexual health clinic. Regular condom users should be encouraged and supported to carry on using condoms which offer a high level of protection when used correctly and consistently.
PrEP is aimed at those who struggle using condoms consistently or at all. Baseline data from the PROUD study shows that only 40% of study participants were using condoms as their main HIV prevention strategy (notably 38% uses sero-sorting with negative). PROUD study participants are educated, visit GUM clinics regularly and are not ignorant of the risks associated with their sexual practices. Their main reason for not using condoms was that they did not like them. Nevertheless they were keen to do something to protect themselves against HIV and saw PrEP as an option.
Dr Whitaker assumes that PrEP will not work as well as condom (“is [PrEP] more sexually health effective than condoms in real life (probably not)”). But as scientific writer Gus Cairns wrote: “These [PrEP] studies demolish several assertions made by critics of PrEP. Firstly that condoms work better than PrEP. They don’t.” A study conducted by the CDC concluded that consistent condom use in anal sex prevents 70% of HIV infections. This is less than the 92% protection calculated in iPrEX for those with high level of Truvada in their blood (consistent with them taking their pills regularly) and less than the figure expected to come out of the IPERGAY study (better than iPrEX and estimated to be in the order of 80%).
The real issue with PrEP is that, unlike condoms, it does not protect against other sexually transmitted infections (STIs). The rate of STIs has been increasing in the UK for several years and their prevention should be integrated into a broader framework for sexual health as well as in the management of PrEP.
In the end, it is not PrEP versus condom, it is HIV prevention that people are happy and willing to use and that works versus HIV prevention that they don’t want to use and therefore can’t work.
Delivering effective PrEP
At the CROI conference in Boston in 2011, an HIV activist dubbed PrEP a “boutique intervention”. Nowadays, with South Africa having issued PrEP guidance it is clear that it won’t be restricted to developed countries. Regrettably, the UK is lagging behind, pondering issues of cost-effectiveness and stakeholders management since 2012.
PrEP does have a cost. A monthly course of Truvada is about £400 in the UK but with the advent of generics the price will come down. It is worth remembering that PrEP is not for life and that in the context of a fragile economic recovery and diminishing investments in the national health system, the cost of inaction and of new HIV infections adds one billion a year in HIV treatment cost to the NHS.
It should be clarified that PrEP effectiveness is not “predicated upon the continuation of the same level of condom use in at risk population” as stated by Dr Whitaker. PrEP efficacy is predicated on PrEP users taking their pills as prescribed.
Current epidemiological models are looking at the effectiveness of PrEP at population level and so are taking into consideration various coverage, adherence, and effectiveness of entire population. But PrEP is not for everybody and this is apparent from the slow uptake of Truvada in the USA since it has been approved in 2012. A recent analysis of PrEP prescription counted 3,253 total unique PrEP users since January 2012, a majority of them to women. So far, there has been no rush for a magic pill.
It would be misguided to consider PrEP as an intervention to be rolled out immediately on a large scale, with the expectation that it will make a difference at population level. PrEP efficacy at population level is debatable as much as that of Treatment for Prevention is. That PrEP may only work at individual level should in no circumstances prevent or delay its implementation. PrEP will not appeal to everybody and it may remain an intervention rolled out on a limited scale.
The assumption that PrEP will not be delivered in conjunction with competent behavioural health services or as part of comprehensive services of prevention is surprising and at odds with the paradigm change that has seen the HIV prevention field moving from single intervention to combination prevention more than four years ago.
And so are the doubts raised about the ability of the medical staff to be able to deliver behavioural interventions or to follow guidelines. This may be true for some overburdened staff but my experience is that GUM clinic consultants and nurses are doing their best to provide support to their patients in several areas. If they can do this in the context of treatment they should be trusted to deliver the same level of care in the context of prevention.
For PrEP users such support may be a requirement. But it would be a misrepresentation to describe, or dare I say caricature, PrEP users as being de facto in need of intensive psychological or social support. For some this support may just not be needed. PrEP offers an opportunity to engage with at risk population, not a threat. This is exactly what the PROUD study team did and we should build on their experience so that Sexual Health Clinics can deliver the best possible comprehensive PrEP package to their clients.
It is hard to disagree with Dr Whitaker that rolling out PrEP is not just about giving away free pills, but that it will require a comprehensive care package. US research clinicians have engaged with service providers as early as 2010. Why this is not happening in the UK is the real question. No PrEP advocate lives in denial and none is “Pretending that PrEP solves the behavioural and social issues around risky sex and intravenous drug use.” None believes PrEP is a magic bullet and none believes “that there will be a pill for bad housing soon.” Tabloid reporting and shallow statement of support should not be mistaken for well researched and comprehensive advocacy work.
PrEP side effects
Truvada, like any medicine has side effects. These are well characterised with a decade of data providing a comprehensive safety profile for a drug commonly used in the treatment of HIV infection worldwide. Noticeably, there was no major or recurring safety concerns in any of the clinical studies of PrEP. Of course the effects of a life on Truvada are not known, but again, PrEP is not for life.
Commenting on this issue in The Washington Post, Dawn Smith, head of biomedical interventions activity in the epidemiology branch of CDC’s Division of HIV/AIDS Prevention noted that “The drug is generally well tolerated. Nausea, dizziness and headaches usually subside in the first month; there’s also a mild risk of kidney damage and bone mineral density changes” adding, “There hasn’t been any significant [kidney] disease seen in any of the thousands of participants in the trials. In a Thai study that followed people who used Truvada prophylactically for up to five years, none of the participants developed kidney trouble.”
These side effects can be explained to prospective PrEP users who should be supported in making an informed decision before starting PrEP. It is not for the medical establishment or HIV activists to decide what those who are considering using PrEP should be doing. This is a particularly salient argument considering Dr Whitaker’s interest in shifting medicine from physician centred to patient centred.
In the real world, the main side effect of PrEP is “Peace of Mind” (unattributed quote). Outside clinical studies the easiest way to deal with side effects is simply to stop using Truvada. A number of PrEP users will end up not using PrEP but their initial engagement with HIV prevention services will provide an opportunity to engage with them and address both their HIV prevention and health needs.
This is exactly what an intelligently implemented PrEP could achieve and which Dr Whitaker doubt it would achieve when asking if “this intervention help people stay healthy and how?” Listening to PROUD participants talking about being in the study, the answer for me is a resounding yes!
There is of course the issue of drug resistance which is often raised as an argument against PrEP. Drug resistance was rare in iPrEX and other PrEP studies and was traced back to the time participants seroconverted. This is a risk that can be managed with early detection of resistance therefore allowing for therapeutic choices that minimize additional mutations that could compromise therapeutic options.
The apparition of resistant HIV strains in people not using PrEP consistently cannot be excluded, but this is also true of people using Truvada for treatment. Drug resistance is an inescapable evolutionary process. It will happen; the question is how soon and how to minimise the risk? This can be explained and understood by prospective PrEP users, as it is by those receiving treatment. Adherence counselling will play a key role in the successful delivery of PrEP and in reducing risk of resistance. But note that no amount of adherence counselling will make people who think they are not at risk of infection take their pills, as was the case in some of the PrEP trials that failed to demonstrate efficacy.
Lastly, a note on the ethics of PrEP in the form of a question: is it ethical to withhold HIV prevention that we know work from people who are willing to take control of their sex life?
PrEP debates are useful but not if they revolve around misconceptions, misunderstandings and only foster doubts about the validity or soundness of research, and beyond on HIV treatment. Too many are already stopping treatment on spurious grounds. Too much stigma from outside and from within the communities is preventing people accessing HIV prevention and care and beyond health care.
If we want to take the PrEP agenda to the next level we first need to stop spreading misconceptions about it. We need to stop pitting one HIV prevention tool against another. We need to listen to people who want to uses these new HIV prevention technologies. We need to learn and build on what is making IPERGAY and PROUD a success, as well as on the knowledge acquired during the conduct of the six previous PrEP studies, the successful as well as the unsuccessful ones.
PrEP is not the latest in a long line of hyped fads; it is a driving force for change, change in HIV prevention services but also health care services. It can lead to social change and cultural changes. At heart, we need to trust users and providers and provide them with the support they need to make PrEP a success.
To quote again Jared Baeten “the barriers are real… and sometimes they are us.” We can only make PrEP a success by working together on the challenges it raises, by being bold and in sync with our times. Not by being scared of it.
~rjtSelected references (links in the text)
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Cairns G. “D-day for the Pill for HIV.” The Huffington Posted 05 November 2014.
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Flash C et al. “Two years of Truvada for pre-exposure prophylaxis utilization in the US.” International Congress of Drug Therapy in HIV Infection, abstract P198, Glasgow, 2014.
Boerner H. “The world’s most effective HIV prevention drug hasn’t lived up to its potential.” The Washington Post 03 November 2014.
Henley J. “Rupert Whitaker: ‘We have to see patients as people, not collections of diseases’.” The Guardian, 1 February 2011.
Highleyman L. “HIV Drug Therapy: Truvada PrEP Use Rising, Especially Among Men.” HIV and Hepatitis, 06 November 2014.
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Gafos M, et al. “Sexual Behaviour Profile of Gay and Other Men Who Have Sex with Men Enrolled in the PROUD Pre-exposure Prophylaxis Open-label Pilot Study in England.” HIVR4P, Cape Town South Africa 28-31 October 2014
Smith D et al. “Condom efficacy by consistency of use among MSM: US”. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 32, 2013.
Underhill K, et al. “Implementation Science of Pre-exposure Prophylaxis: Preparing for Public Use” Current HIV/AIDS Reports, 2010, 7(4): 210-219.