A “grab to protect profits” that shows no commitment towards ending Ireland’s HIV epidemic.
Gilead’s recent commencement of a legal bid to stop generic pre-exposure prophylaxis (PrEP) antiretrovirals entering the Irish market prompts strong comment from sexual health advocate Mr Adam Shanley.
“I feel like it’s a grab to protect their profits, and this isn’t something that is surprising — it is literally history repeating itself, when we saw the similar situation [with pharma companies] in the era of AZT and the first wave of antiretroviral treatment,” Mr Shanley told the <strong><em>Medical Independent</em></strong> (<strong><em>MI</em></strong>).
Gilead says it reserves the right to protect its “intellectual property” in regard to its antiretroviral product Truvada (emtricitabine and tenofovir disoproxil fumarate).
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<strong>Mr Adam Shanley</strong>
In 2016, Truvada was licensed in Europe for PrEP (in combination with safer sex practices). Gilead has submitted a reimbursement application to the HSE for Truvada’s PrEP indication. Currently, Truvada may be obtained on prescription, but it costs upwards of €400 for a one-month supply. Consequently, there are an unknown number of people in Ireland, primarily men who have sex with men (MSM), accessing generic PrEP online at cheaper prices and self-medicating.
Rising HIV notifications in Ireland (the highest on record last year), the strong evidence base supporting PrEP as a HIV prevention tool, and its inaccessibility through official channels provide plenty of context to Mr Shanley’s remarks, as do lessons from the past.
In the chronology of HIV, the emergence of evidence supporting PrEP as a HIV prevention tool may well prove to be one of the most significant milestones.
The PROUD study in the UK, for example, reported in 2015 that daily oral PrEP (Truvada) reduced the risk of HIV infection by 86 per cent for high-risk gay people and other MSM. It gauged effectiveness of Truvada as PrEP in a “real-world situation” where participants knew they were taking an active drug.
Participants were randomised to receive PrEP immediately, or after 12 months. The participating sexual health research clinics integrated PrEP into their routine HIV risk reduction programmes. The study found no difference in the two cohorts in the number of men diagnosed with other STIs.
Ireland requires every weapon in the arsenal of HIV prevention, as new diagnoses have increased by 35 per cent since 2011. Some 512 people in Ireland were newly diagnosed as living with HIV in 2016, compared with 485 in 2015, according to the Health Protection Surveillance Centre (HPSC). The increase has particularly concerned MSM.
But Gilead’s recent legal bid in Ireland represents another potential road-block to PrEP’s accessibility.
It has a supplementary protection certificate (SPC) or patent extension on Truvada, but its validity has been challenged by generic pharmaceutical companies in a UK court, which has referred the matter to the Court of Justice of the European Union.
According to Gilead’s spokesperson, the European patent for Truvada expires in July 2017, “but in those countries where we have a valid SPC, granted back in 2005, it extends our intellectual property rights for Truvada until 2020. Gilead reserves the right to protect and enforce its Truvada SPCs and any other intellectual property that is infringed. Any actions we take may vary from country-to-country in line with different local commercial and legal frameworks. We cannot provide further comment on ongoing cases either in Ireland or elsewhere.”
Gilead’s applications for injunctions are listed to be heard on 3 October at the High Court (Commercial). The cases are described as ‘Gilead Sciences Inc & Anor versus Accord Healthcare Ltd & Anor’ and ‘Gilead Sciences Inc versus Mylan SAS & Ors’.
Meanwhile, Gilead’s spokesperson told <strong><em>MI</em></strong> it initiated the reimbursement process for Truvada as PrEP “by submitting a ‘rapid review’ assessment” to the National Centre for Pharmacoeconomics (NCPE) at the beginning of June 2017. It is awaiting the NCPE’s recommendations.
“While confidential, we can confirm that this medicine is provided at a discounted price in line with the industry agreements. To note, there is no system in place in Ireland which would allow companies to offer different price schemes for different indications of the same medicine. However, Gilead has always been and remains ready to work with all stakeholders to support access to its medicines for those who need them.”
The HSE said expenditure on Truvada (for HIV treatment) was not centrally located, as individual hospitals order all antiretrovirals.
<h3 class=”subheadMIstyles”>Demonstration project</h3>
In late 2015, based on “further evidence of the effectiveness and acceptability” of PrEP, the World Health Organisation (WHO) issued an extended recommendation that PrEP should be offered to all people at substantial risk of HIV infection as part of a combination approach. The WHO, which had circulated a recommendation in 2014 in support of offering PrEP to MSM, noted that no evidence for risk compensation in sexual practices, such as decreased condom use or more sexual partners, had emerged in PrEP studies or programmes.
PrEP was recognised in Ireland’s <em>National Sexual Health Strategy 2015-2020</em> through a recommendation to develop and implement guidelines for “the appropriate use of antiretroviral therapy in HIV prevention”.
“PrEP works”, says Dr Fiona Lyons, Clinical Lead of the HSE Sexual Health and Crisis Pregnancy Programme (SHCPP). However, the Consultant in Genitourinary and HIV medicine at St James’s Hospital, Dublin, stresses it must be part of a combination approach, alongside elements such as condom use, regular testing, treatment as prevention, access to post-exposure prophylaxis (PEP) and support to make better choices to minimise risk.
A priority action in the <em>2017 HSE National Service Plan</em> was commencement of work on a “National PrEP Demonstration Project”. An SHCPP document on funding sent to the HSE Health and Wellbeing Division in January 2017, obtained by <strong><em>MI</em></strong> under Freedom of Information legislation, stated that the programme was “proposing to commence a National HSE PrEP Demonstration Project in 2017/2018 at a cost of €200,000/300,000… The SHCPP had anticipated funding this from existing resources by reviewing current service arrangements and identifying cost savings.”
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<strong>Dr Fiona Lyons</strong>
However, as of 20 December 2016, “the future of this project may be in question, as it has not been possible to secure a drug donation for the project”, stated the document. “The current cost of [the] drug for the project is prohibitive and it is anticipated that generic preparations will be available in Q3 2017.”
Speaking to <strong><em>MI</em></strong> on 3 July last, Dr Lyons said the demonstration project is not being pursued at this juncture. However, she said work-streams relating to PrEP are ongoing, with the assistance of a multi-sectoral PrEP Working Group that convened in May 2016.
“The view of the PrEP Working Group now is that the window of opportunity for doing a PrEP demonstration project has closed,” said Dr Lyons. “If we got to a situation where Truvada was going to be reimbursed or there was going to be a mechanism for reimbursing Truvada for PrEP established in the short-to-medium term, and it was going to take 18-to-24 months to do a full demonstration project… is that fair to the system, when you are limiting access for something that is reimbursed?
“So collectively within the PrEP Working Group, the decision was made that while we aren’t going to do a formal demonstration project, we do need to understand what the system needs to know about, to be ready for PrEP at such a time that it becomes reimbursable.”
An early action was the development of guidance for clinicians in response to the reality that people were accessing PrEP online. Concerns had arisen about the potential harm associated with people taking medication without “appropriate monitoring and evaluation”.
Dr Lyons referred to community-based movements in other countries, including the UK, to support people in sourcing from suppliers that provide the legitimate drug. However, she said the UK and Ireland have differing legislative frameworks.
In Ireland, it is against the law to supply prescription medicines by mail order (including through the Internet). However, in the UK, prescription medications may be sourced over the Internet for personal use for up to a three-month supply.
The Irish guidance is about informing clinicians on issues of law, ethics and duty of care. It is out to consultation. “We put together a document to support clinicians in those situations where they become aware of people who are sourcing medicines over the Internet and it is about protecting [the health of] those individuals — that is the objective of that exercise and that was one of the first things that came out of the PrEP Working Group.”
It is not known how many people in Ireland are accessing PrEP online, according to Mr Shanley, who is Director of the Gay Switchboard, Manager of the Know Now rapid HIV testing pilot and an outreach worker at the HSE’s Gay Men’s Health Service (GMHS).
However, interest has “ramped-up considerably” over recent months due to dramatic declines in new HIV diagnoses reported at sexual health centres in London (see above), in addition to media attention on rising HIV rates.
Mr Shanley said there is a responsibility on clinicians in Ireland to be able to explain what is available, and not necessarily how it is available, “but there are people in the community who are expressly saying ‘you go onto this website, this is how you go about it and it will arrive at your address’… ”
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<h3><strong>PrEP — the experience in London </strong></h3>
Dean Street in Soho, London, which is part of the Chelsea and Westminster Hospital NHS Foundation Trust, is one of Europe’s largest HIV and sexual health clinics. The majority of its patients are MSM and it caters to the biggest HIV cohort in Europe.
Dr Emma Devitt, Consultant in Infectious Diseases at Dean Street, says it began to receive increasing enquiries on PrEP in 2015, in tandem with the emergence of strong supporting data, such as from the PROUD study.
“PrEP was not available on the NHS in England and it still isn’t,” Dr Devitt tells <strong><em>MI</em></strong>. “So in September 2015, we set up the first PrEP clinic that we are aware of in the UK, where people were able to come in and have a discussion with a health professional about PrEP and about HIV prevention in general and get advice.”
This service was “inundated”, according to Dr Devitt, as, around the same time, the gay community was mobilising to make people more aware of the availability of generic PrEP through websites such as iwantprepnow.co.uk and prepster.info.
“There were a lot of people looking at accessing generic PrEP online, because to buy Truvada or branded PrEP in England costs about £400 a month and obviously that is not accessible to everybody who would want to go on PrEP,” outlines Dr Devitt.
In early 2016, due to demand, Dean Street commenced a generic PrEP monitoring service. “We have several hundred people who we are monitoring on PrEP now and it is very, very easy to integrate that into a routine sexual health service.”
Dean Street comprises of two clinics: 56 Dean Street, which is the original sexual health and HIV service, and the nearby Dean Street Express. The latter clinic provides a walk-in service, whereby asymptomatic patients can access a full sexual health screen and have their results texted to them in six-to-12 hours.
“We were seeing huge numbers of people coming through that service looking for more HIV prevention. So the PrEP monitoring is all integrated into our very busy sexual health service — people come in, they have a sexual health screening and HIV test, they have a risk assessment with a health professional, a nurse or a doctor or health advisor, and based on that, then we advise on HIV prevention.”
However, like colleagues in Ireland, Dr Devitt stresses that HIV prevention is about much more than PrEP alone.
“HIV prevention is regular testing, which is facilitated by the express clinic; it is also prompt testing and diagnosis of things like chlamydia and gonorrhoea, because we know that other infections can increase the rates of transmission of HIV… so getting those results back within the day has meant people were getting treated a week, a week-and-a-half quicker than they would have been in a traditional clinic, where the test results can take up to two weeks to come back.”
Other important aspects of HIV prevention are ‘treatment as prevention’ as well as PEP, which is available on the NHS, outlines Dr Devitt. This is in addition to standard sexual health advice, such as promotion of condom use.
“So it is all of that, along with advising people about PrEP and whether they are at risk and how to access it and what monitoring they may need — that is the whole ethos of the clinic.”
What indicators are used to identify patients who should consider using PrEP?
Dr Devitt says there are a number of guidance documents from the US and Europe, including from the British HIV Association and the British Association for Sexual Health and HIV.
Broadly speaking, it is indications such as unprotected anal intercourse, recent need for treatment of a bacterial STI, and use of PEP.
As to PrEP medication adherence, the clinic has not noted problems. Dr Devitt says that there are two ways of taking PrEP — once-daily Truvada/generic, which is utilised by the majority of Dean Street’s patients who take PrEP; and event-based PrEP, as investigated in the IPERGAY study.
“That is one of the things involved in the counselling in the clinic — to decide with the individual what their risk profile is like and which way they want to take it,” explains Dr Devitt. She said PrEP is intended for a period of risk and “not something you would expect people to take life-long”.
Truvada is used routinely in HIV care and is very well-tolerated, according to Dr Devitt. In respect of commencing the medication as PrEP, it is very important to first ascertain the patient’s HIV and hepatitis B statuses.
The clinic also monitors renal function for potential side-effects associated with tenofovir but renal toxicity is uncommon, outlines Dr Devitt.
Asked how the clinic supported the increased activity associated with PrEP monitoring and advice, Dr Devitt says: “Well, we just had to incorporate it into our day-to-day consultation. We are very lucky; we have a very well-run, well-staffed, efficient service. So a lot of this prevention discussion we were having anyway, it was part of our care plan for all of these patients and then we developed a new pro forma and new protocol as part of the consultation… ”
When the PrEP service commenced, a grant facilitated therapeutic drug monitoring.
“We did therapeutic drug monitoring on several hundred patients coming with their own sourced generic PrEP, and essentially they were all within therapeutic drug levels; we had no cause for concern to the degree now that if individuals are buying their PrEP from the verified links through the IwantPrEPNow website, we don’t do therapeutic drug monitoring anymore.”
Dean Street has seen a dramatic reduction in the rate of new HIV diagnoses. This has been due to a number of factors, including PrEP.
“At the end of 2016, six months ago, we had a very dramatic finding of a 42 per cent reduction in our new HIV diagnoses at Dean Street… essentially, we were diagnosing, in 2015, up to 70 new HIV cases a month, which is a few a day because we are only closed on Sundays, and that has dramatically fallen to less than 20 or so a month. So between 2015 and 2016, we had a 42 per cent reduction in our new HIV diagnoses and we think that this is attributable to all of those components of the prevention package — so the opening of Dean Street Express, access to frequent testing and early STI treatment, but also we were starting HIV-positive people earlier on treatment — so treatment as prevention.
“And then, at the end of 2015 into 2016, PrEP came on, so that certainly was a major contributing factor to the whole package of HIV prevention, which has seen this dramatic drop. This data then was mirrored by four of the other big HIV clinics in London with similar or slightly less drops in their new HIV diagnoses, so this is a really dramatic finding that hasn’t been seen in the 30-odd years of the epidemic in gay men, and this is really exciting.”
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<h3 class=”subheadMIstyles”>Online purchases</h3>
Some men in Ireland have reported obtaining generic PrEP online at a cost of $150 for three months’ supply, using guidance provided by the IwantPrEPNow website in the UK, according to the excellent recent paper <em>Pre-exposure Prophylaxis (PrEP) Scoping and Policy Options Review</em> (2017), written by international development specialist Dr Ann Nolan and commissioned by HIV Ireland and the Gay Health Network.
“Men importing PrEP in the FGD [focus group discussions] reported that they knew of people who had provided an address in Northern Ireland where online purchase of up to three months’ supply of medication online is permitted. The men had not experienced themselves or knew of anyone who had had the PrEP supply seized by customs and one participant reported that at least one clinician has advised that in the event that an import of generic PrEP is seized, he/she would be prepared to provide a retrospective prescription to satisfy customs officials.”
A HPRA spokesperson told <strong><em>MI</em></strong> it “has recently detained a small quantity of product, illegally supplied into this jurisdiction by mail order. This is an ongoing investigation. No comment can be made at this stage regarding the circumstances involved in this detention”. <strong><em>MI</em></strong> understands, however, that seizures of PrEP medications have happened on a number of occasions.
“The HPRA works closely with Revenue’s Customs Service and An Garda Síochána to monitor and investigate instances of illegal supply of medicines through retail sales in Ireland and via the Internet and actively enforces against suspected breaches of the law. The HPRA is aware that PrEP medicines are being supplied online, in contravention of Irish legislation.
“Under Irish law, the supply of prescription-only medicines online into this State is illegal. As Northern Ireland is a separate jurisdiction, it will be a matter for the relevant authorities there to determine if the supply into that jurisdiction is a breach of legislation.”
<h3 class=”subheadMIstyles”>‘Immediate steps’</h3>
The report by Dr Nolan concluded that evidence for PrEP efficacy coupled with the risk profile of key populations in Ireland, increasing incidence of HIV, PrEP’s “policy coherence” with Ireland’s international policy position and a high level of support for PrEP implementation among key stakeholders and potential end-users, “points to the need for immediate steps to be taken to make PrEP available to key populations at substantial risk of HIV acquisition as part of a comprehensive package of HIV prevention measures”.
The report added that “the failure to provide HIV testing and clinical monitoring to MSM who are self-purchasing and administering PrEP is a risk to the individual and broader public health. While multi-drug resistance levels are generally low, the risks are increased if people with an undiagnosed HIV infection are acquiring PrEP online.”
One dedicated sexual health clinic “said in interview that they are providing HIV testing and clinical monitoring to men who are taking PrEP but this is unofficial and neither funded nor supported by the HSE”.
However, the report also noted concerns among healthcare providers around “the capacity of an already over-stretched sexual health service to absorb a cohort of HIV-negative clients” in respect of initiating PrEP services.
Asked if PrEP monitoring would be a huge additional workload on sexual health clinics, Dr Lyons said there were alternate ways of looking at this: people who may be considered candidates for PrEP should be attending sexual health clinics anyway. At the same time, PrEP could be the leverage to get people accessing care who are currently not engaged, and the impact of this is not fully known.
The SHCPP and HPSC have used available Irish data to develop a PrEP cascade to estimate the numbers of MSM likely to avail of PrEP in the first year of its availability in Ireland.
The estimates, which are based on MSM aged 18-to-64 years, found that 9,947 MSM may be eligible for PrEP, with the estimated number of MSM likely to present for PrEP in Ireland at a range of 1,492-to-4,476.
The estimated number of MSM in Ireland who may avail of PrEP within the first year of its availability was adjusted to 865-to-2,596 after applying an assumed uptake of 58 per cent and this would represent approximately 1-to-3 per cent of MSM aged 18-to-64.
“Applying the approach used in Scotland to estimate PrEP for those other than MSM, we considered the upper range of our PrEP estimate of 2,683 to be inclusive of other populations at substantial risk of sexually-acquired HIV,” added the SHCPP/HPSC paper.
Work is ongoing with HIQA around costings, while standards are being developed that will apply to Irish services providing PrEP in the future, said Dr Lyons.
Speaking to <strong><em>MI</em></strong> before reports of Gilead’s court action in Ireland, Dr Lyons said the state of play regarding generics was also under examination.
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<h3 class=”subheadMIstyles”>CURRENT STATUS: The situation in the UK</h3>
PrEP will soon be available on the NHS in Scotland and as part of a pilot in Wales. In England, a trial involving 10,000 people at risk of HIV starts this summer.
Dr Michael Brady, Medical Director at the Terrence Higgins Trust, UK, described PrEP as a “game-changer” for HIV prevention.
“Together with condoms, increased HIV testing and treatment as prevention, we now have all the tools to stop HIV transmission here in the UK. Already, we have started to see what can be achieved when all these tools are used, with Public Health England reporting a reversal of the HIV epidemic in gay and bisexual men in England, including a 25 per cent drop in new HIV diagnoses in gay men in London.”
As well as protecting people from an incurable and highly-stigmatised condition, the NHS will save £360,000 in lifetime treatment costs for every person who would have become HIV positive without PrEP, he said.
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<h3 class=”subheadMIstyles”>‘Morality’</h3>
The ‘elephant in the room’ is the potential for wider discussion on PrEP to become mired in emotive and judgemental debate.
The fact that many conditions, including cardiovascular disease, diabetes, obesity and a number of cancers are strongly lifestyle related could be lost in a cacophony of argument and, in some cases, prejudice.
Dr Lyons said “it is helpful to look at the science and the science says that as part of a combination HIV prevention approach, PrEP works”.
Mr Shanley said arguments against public funding of a HIV prevention drug can be “difficult to hear as a gay man”.
“But a lot of the time, I think it can be really short-sighted. We are not very far off conversations that were had when we were talking about the introduction of the contraceptive pill; there was pearl-clutching around ‘it’s going to make people ditch condoms’… We have had this conversation before and the reality is, will some people ditch condoms? Yes, some people will ditch condoms. The reality is that there are uncountable numbers of people who aren’t wearing condoms in the first place and that is why we are in this position.”
Minister for Health Simon Harris has said little-to-nothing on sexual health, HIV and PrEP since taking up the portfolio in May 2016. This is disappointing, said Mr Shanley.
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<strong>Minister for Health Simon Harris</strong>
“I think as Minister for Health, he has a really important remit to address this — even to start speaking about it, as his predecessor and our Taoiseach Leo Varadkar did in launching the sexual health strategy, in making the initial funds available for the pilot project Know Now, and ultimately at Pride recently the Taoiseach did mention in his speech that it was time to act up on sexual health for the community, which was great to hear… I would encourage him to stand by that and see it as a priority.”
Mr Shanley also urged “rational” thinking on PrEP. He said there are numerous other ongoing pieces of work to promote sexual health, including among MSM, such as making condoms and lubricant much more freely accessible at gay bars and clubs through GMHS outreach services. The HSE has also committed funding to the Know Now HIV testing pilot that commenced through lottery funds.
“Nobody advocating for the introduction of PrEP will ever advocate for or say, ‘it’s an option for you now to drop condoms’,” said Mr Shanley. “We have rising rates of gonorrhoea and syphilis and the recent reports from the WHO [on antimicrobial resistance] are very concerning. That all has to play in the mix.
“But what we are talking about, ultimately, is that we know there’s a drug out there that is proven to stop, nearly overwhelmingly and totally, new HIV infections… We can look at that as a burden to the exchequer, or we can look at having access to PrEP for those at high risk of HIV infection and then potentially quelling that longer-term cost.”
