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HIV/AIDS

PrEP should be a key component of a comprehensive HIV prevention package fully funded on the NHS

Abstract
Pre-exposure prophylaxis (PrEP) is the medication taken by HIV-negative individuals to reduce their risk of contracting HIV infection. The large evidence base for the use of PrEP has been reviewed and recommended by the World Health Organization (WHO), a specialised agency of the United Nations that is concerned with international public health, the Joint United Nations Programme on HIV and AIDS (UNAIDS) and the National Institute for Health and Care Excellence (NICE), England’s health technology assessment body. NHS England, the body that sets the priorities and direction of the NHS and commissions healthcare services in England, does not currently fund PrEP despite the increasing numbers of HIV infections in the UK. This article aims to review why PrEP should be fully funded through the NHS and the issues that need to be considered, primarily its efficacy and cost as well as risk of side effects, changes in condom use, rates of sexually transmitted infections and drug resistance. It will outline the arguments supporting the use of PrEP as part of a comprehensive HIV prevention package on the NHS.
Keywords: AIDS, emtricitabine, HIV, NHS, pre-exposure prophylaxis, PrEP, prevention, tenofovir, Truvada®.
Original submitted: 17 October 2016; Revised submitted: 2 November 2016; Accepted for publication: 9 November 2016

Scanning electron micrograph (SEM) of a lymphocyte with HIV cluster

Source: Fox-NCI / Phanie / Science Photo Library

Pre-exposure prophylaxis (PrEP) is medication (usually used as part of HIV treatment) that can be taken by HIV-negative individuals to reduce the risk of acquiring HIV. PrEP is currently not available through the NHS and the responsibility of any future funding has been disputed by NHS England. In the image, a Scanning electron micrograph (SEM) of a lymphocyte with HIV cluster.

Key points

  • Pre-exposure prophylaxis (PrEP) is medication (usually used as part of HIV treatment) that can be taken by HIV-negative individuals to reduce the risk of acquiring HIV.
  • PrEP has been recommended by the World Health Organization (WHO), the Joint United Nations Programme on HIV and AIDS (UNAIDS), the National Institute for Health and Care Excellence (NICE), European AIDS Clinical Society (EACS), British HIV Association (BHIVA) and British Association for Sexual Health and HIV (BASHH) following numerous studies showing its effectiveness.
  • PrEP is currently not available through the NHS and the responsibility of any future funding has been disputed by NHS England.
  • The HIV epidemic is worsening in the UK and PrEP could be a cost-effective public health intervention to tackle this; it could even potentially save money for the NHS.
  • Concerns have been raised that availability of PrEP on the NHS could reduce condom use and influence rates of sexually transmitted infections and drug resistance.

Introduction

Pre-exposure prophylaxis (PrEP) is a HIV prevention strategy that involves the use of anti-retrovirals taken by individuals who are HIV negative to reduce the risk of acquiring HIV. The majority of the clinical research has focused on oral tenofovir based PrEP regimens, with most trials using a combination pill (Truvada®, Gilead Sciences Inc., California, United States) that contains tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). These drugs are usually used as part of a combination regimen to treat HIV. They are nucleoside reverse transcriptase inhibitors and work by inhibiting the HIV-1 viral enzyme reverse transcriptase disrupting the formation of viral DNA, thereby halting HIV replication[1]. When Truvada® is taken as PrEP it cannot prevent the transmission of HIV to the person who is taking it, but inhibits viral replication within their body, limiting the number of infected cells, allowing natural immune responses to eradicate these infected cells[2].

Post-exposure prophylaxis (PEP) is another HIV prevention strategy and uses the same mechanism but is instead taken after exposure to HIV to reduce the chance of HIV infection. It is not used as a regular preventative method, instead it is taken in an emergency up to 72 hours after exposure. PrEP is a combination regimen of three antiretrovirals, the first-line choice is Truvada® (TDF and FTC) and raltegravir, and is taken for four weeks. Other HIV prevention strategies include the use of condoms, male circumcision, testing for HIV and sexually transmitted infections (STIs) and an approach known as ‘treatment as prevention’ (TasP).

TasP refers to HIV prevention methods that use antiretroviral treatment (ART) in HIV positive patients with the aim of reducing their viral load, decreasing the risk of HIV transmission. Needle exchange and universal antenatal screening have been successful strategies in dramatically reducing HIV transmission rates in intravenous drug users and from mothers to children.

This article aims to review the evidence around issues with PrEP use, primarily its efficacy and cost as well as risk of side effects, changes in condom use, rates of STIs and drug resistance. It will attempt to outline the arguments that support the use of PrEP as a key HIV prevention strategy, alongside regular testing and treatment for STIs, TasP, free condoms and ongoing behavioural counselling, to provide a better and more comprehensive HIV prevention package available through the NHS.

Source selection

Publications from global health organisations (World Health Organization [WHO] and the Joint United Nations Programme on HIV and AIDS [UNAIDS]) were chosen as they included extensive reviews of PrEP studies, as well as a meta-analysis. Europe-wide guidelines, as well as those from other countries were examined, in order to assess recommendations elsewhere and compare them to the review undertaken by the National Institute for Health and Care Excellence (NICE) and NHS England. The NHS England PrEP policy provided in depth detail about how PrEP could be made available in England. Individual studies and systematic reviews have been included to provide a summary of evidence supporting the use of PrEP clinically. The judicial review report and details of the High Court PrEP case have been provided to explain the progress made so far in England. Public health reports have been used to quote rates of STIs as well as other conditions. Popular opinion has been drawn from mainstream media sites to reflect how the population may perceive the future roll-out of PrEP.

Evidence for PrEP

Global PrEP research has been continuous for over ten years, and has focused on different agents and populations. A large proportion of trials have studied PrEP in men who have sex with men (MSM), as the burden of HIV infection is 19-fold higher in this group compared with the general population globally. PrEP use in transgender women has been studied in the main PrEP trials[3],[4], owing to the 49-fold higher risk of HIV infection in this population[5]. Many people do not realise that the prevalence of HIV in the UK is almost as high for black African heterosexual women as it is for MSM; 1 in 22 are living with HIV compared with 1 in 20, respectively[6]. This is important when considering the evidence for PrEP obtained in the UK.

Table 1 demonstrates the PrEP studies that have been included in the ‘new medicine evidence summary’ by NICE, England’s health technology assessment body, released in October 2016[7]. These four trials, iPrEx[3], Intervention Préventive de l’Exposition aux Risques avec et pour les Gays (IPERGAY) study[8], PROUD[4] and Partners PrEP[9”, were reviewed by NICE as they provide “the best available evidence for the use of Truvada® for PrEP in a UK setting”[7]. These trials include high numbers of patients and the ‘at risk’ groups mentioned above. The only UK study, PROUD, included MSM and transgender women; however, more data in heterosexual black Africans may be needed in a UK setting.

Table 1: the pre-exposure prophylaxis (PrEP) studies that have been included in the ‘new medicine evidence summary’ by the National Institute for Health and Care Excellence (NICE). MSM = Men who have sex with men, RCT = randomised controlled trial, Viread = tenofovir disoproxil fumarate only
Trial LocationPopulationPrEP regimenTrial typeNumber of study subjectsResults announcedReduction in HIV-1 incidence (%)
iPrExBrazil, Peru, Ecuador, South Africa, United StatesMSM, transgender women Daily Truvada®Double blind RCT2,499201044
IPERGAYCanada, France, GermanyMSM“On demand” Truvada®RCT including double blind and open label phases414201586
PROUDUKMSM, transgender women Daily Truvada®Open label RCT545201586
Partners PrEPKenya, UgandaSerodiscordant heterosexual couplesDaily Viread or Truvada®Double blind RCT4,7582012Viread = 67; Truvada® = 75 

In these four trials[3],[4],[8],[9], Truvada® reduced the relative risk of acquiring HIV infection by 44–86% compared with placebo or no prophylaxis[7]. ‘On demand’ dosing was used in the IPERGAY study[8] and requires doses to be taken before and after sex; it is also called ‘event based’ or ‘intermittent’ dosing. The majority of trials have used once daily dosing of Truvada®[3],[4],[9],[10],[11],[12] and this is the dosing regimen approved by the European Medicines Agency, an EU agency focusing on the protection of public and animal health through the scientific evaluation and supervision of medicines, in July 2016[13].

NICE also considered the World Health Organization (WHO), an agency of the United Nations that is concerned with international public health, systematic review and meta-analysis of oral tenofovir based PrEP studies which examined multiple randomised controlled PrEP trials[7]. Their meta-analysis concluded that patients assigned oral PrEP containing tenofovir had a 51% reduction in the risk of HIV infection (RR: 0.49; 95% CI: 0.33–0.73, P =0.001)[5]. Adjusted efficacy using tenofovir plasma levels were reported in many of the trials: the reduction in incidence increased to 74%, 85%, 90% and 92%[14] for the Bangkok[15], TDF2[10], Partners PrEP[9] and iPrEx[3] trials, respectively. When the WHO restricted their meta-analysis results to studies of high adherence (tenofovir detection in >70% of subjects) a 70% reduction (RR: 0.30; 95% CI: 0.21–0.45; P <0.0001) in the risk of HIV infection was demonstrated[5].

Studies in women have provided mixed results, the Pre-exposure Prophylaxis Trial for HIV Prevention among African Women (FEM-PrEP)[11] and the Vaginal and Oral Interventions to Control the Epidemic trial (VOICE)[12] were unable to demonstrate efficacy of PrEP in heterosexual women and had to be discontinued early. This was because of extremely poor adherence — only 12% of participants regularly took the drug for the length of the trial[11],[12],[16]. Trials examining serodiscordant couples (one partner is HIV positive and the other is HIV negative) demonstrated that when women adhere to PrEP it is effective[9]. In this context, having a known HIV positive partner promoted good adherence. Follow-up studies have shown that reasons for non-adherence included lack of support or discouragement from others, unknown effectiveness of the drug, perceptions of HIV risk and concerns about side effects[16]. It is important to note that compared with other similar trials, adherence was also low in the iPrEx study, which included only MSM and transgender women, and evidence of benefit was still found[3]. This potentially indicates that Truvada® can be more forgiving of imperfect use for rectal rather than vaginal exposure to HIV, likely owing to differential concentrations of the drug in rectal compared with vaginal tissues.

The concentrations of tenofovir and emtricitabine vary according to the mucosal tissue — tenofovir levels have been shown to reach a tenth of the levels in cervical tissue cells compared with the levels in rectal tissue cells[17]. In addition, tenofovir will take longer to reach maximum levels in the cervix; 10–12 days compared with five days in the rectum[17]. Consequently, ‘on demand’ dosing is not advisable for women[18]. Additionally, two studies included in the WHO meta-analysis (IAVI Kenya[19] and IAVI Uganda trials[20]) compared daily versus intermittent dosing and although the patient numbers were small, they demonstrated that adherence is much higher with daily dosing[5].

Access to PrEP

PrEP has been available in the United States since 2012 when the US Food and Drug Administration (FDA), a federal agency of the United States Department of Health and Human Services, approved Truvada® as a daily preventative medicine against HIV[21]. Other countries have since followed and PrEP is also available in Canada[22], Australia[23], France[24], South Africa[25], Kenya[26] and Norway[27]. The Centers for Disease Control and Prevention (CDC), a public health institute of the United States focusing on the protection of public health and safety through the control and prevention of disease, injury, and disability, issued guidance in 2014 for clinicians to support their patients taking PrEP[28]. In 2015 the WHO, UNAIDS and European AIDS Clinical Society published guidance recommending PrEP as an additional HIV preventative method[5],[29],[30].

As PrEP is currently not funded by the NHS, in the UK an unusual situation has arisen whereby individuals who self-identify as being at high risk of HIV are using a website to source and pay for their generic Truvada® medication from overseas. Community advocates have developed a trusted website and UK genito-urinary medicine (GUM) clinics are able to signpost individuals to the site and in turn the website will also direct PrEP users to the clinics that offer safety monitoring while they are taking PrEP[31]. Some clinics have been offering PrEP users therapeutic drug monitoring (TDM) to check for the presence of tenofovir and emtricitabine in their blood. As part of this process, the generic brand the PrEP user takes and batch number are recorded[18]. The TDM results and batch numbers are then shared on the website and using social media sites; to date, none have proved counterfeit[32]. The joint collaboration between community advocates and healthcare professionals to improve access to information and support for individuals wishing to take PrEP has evolved and appears to be working well. However, this is clearly not an ideal situation and the British HIV Association (BHIVA) and British Association for Sexual Health and HIV (BASHH) issued a position statement in 2015[33] followed by an update in 2016[34]. The aim of the position statements were to inform and guide healthcare professionals on how to have an informed discussion about PrEP with patients. In these position statements, BHIVA and BASHH strongly recommend that PrEP should be made available within a comprehensive HIV prevention package to the most ‘at risk’ populations[33],[34]. Doctors and community advocates have also collaborated to publish a guide for buying PrEP safely online that can be found online and handed out in UK GUM clinics[18].

Another unusual feature of the PrEP story is the legal battle between NHS England and local authorities over whose responsibility it is to fund PrEP. As a consequence of the NHS Act 2006[35] much of the responsibility for public health was transferred from the NHS to local authorities. As the use of Truvada® as part of PrEP is as a preventative medicine, NHS England has argued that it was the responsibility of local authorities to fund it. Local authorities countered that this would be near impossible with the funds available and therefore would have resulted in a postcode lottery for those wanting access[2]. Furthermore, NHS England already funds Truvada® and raltegravir when used as PEP[2].

The National AIDS Trust (NAT), a UK charity, went to the High Court seeking a judicial review over the unethical interpretation of the NHS Act 2006 by NHS England. NAT were successful with this case and the High Court judge ruled that NHS England were wrong to decide they could not fund PrEP because exclusion of preventative treatments would run counter to the duties of NHS England[2],[36]. NHS England appealed this judgement, however, the Court of Appeal ruled in favour of NAT in November 2016[37]. The Health Select Committee, a committee of the British House of Commons, have also recently published a critical report on public health confirming that the NHS Act 2006 division of services is seriously problematic[38].

What is perplexing is why NHS England committed to the roll-out of PrEP by leading an 18-month policy-making review in 2015/2016 but then withdrew PrEP from the specialised commissioning process in March 2016. The judicial review began soon after this withdrawal and resulted in the outcome above. Following this, despite NHS England’s appeal, public consultation opened on the policy specification on PrEP that was written by NHS England’s HIV Clinical Reference Group[39]. At the time of writing this article, the Clinical Priorities Advisory Group (CPAG) had recently met to decide what NHS England will commission for 2016/2017 and whether this will include PrEP. We eagerly await the CPAG’s verdict on PrEP availability.

Should NHS England fund PrEP?

According to Public Health England (PHE), an executive agency of the Department of Health that protects and improves the nation’s health and well-being, “the number of people living with HIV in the UK continues to increase and the number living with undiagnosed HIV remains high.” In 2014, 103,700 people were living with HIV in the UK and around 18,100 of those were unaware of their infection and the risk of onward transmission[6]. Despite having more HIV positive people on treatment (TasP), increased HIV testing, continued emphasis on condom use and PEP, the UK has not managed to halt the expanding epidemic. There are still around 6,000 new HIV diagnoses each year and this results in a substantial burden of care on the NHS[6]. New diagnoses in the MSM population continue to rise, with 3,360 men newly diagnosed in 2014, the largest number ever recorded[6]. This accounts for more than half of all new HIV diagnoses (n=6,151)[6].

In 2014, UNAIDS set a global target of ‘90:90:90’ to reach by the year 2020: 90% of those who live with HIV should know their status, 90% of those who are HIV positive should be on antiretroviral therapy (ART) and 90% on ART should have an undetectable viral load[40]. This initiative aims to reduce transmission of HIV and improve the health of HIV positive people, which in the longer term aims for no new HIV infections and no person living with HIV developing AIDS[41]. The UK has already achieved the latter two of these three 90% goals, however, in 2014, only 83% of people living with HIV knew their status[6].

In other words, in the UK, we are succeeding at getting people on treatment and achieving viral suppression but more must be done to find and identify those individuals who are HIV positive. This has personal, public health and economic consequences. Overall, two out of five HIV diagnoses in 2014 were considered ‘late’ (CD4 less than 350) in the UK[6]. Despite improved HIV testing the number of MSM diagnosed late remains high — 974 out of 3,360 diagnosed in 2014[6]. The situation is even worse for heterosexuals where 55% are diagnosed ‘late’[6],[41]. Levels of transmission will continue to rise if HIV positive people remain unaware of their infection. Scaling up HIV testing will not solve this problem alone because it is impossible to rely on the testing of HIV positive individuals before onward transmission occurs.

Condoms and STIs

Repeatedly during discussions with others about PrEP, I hear the response “why can’t people just wear condoms?”. There are multiple reasons why we cannot rely on condoms to eliminate the HIV epidemic. Intentional unprotected sex happens for various reasons, for example, condoms weren’t available at the time, sex occurred when drunk or high or condoms caused reduced sexual pleasure. For some people it is not always possible to get their partners to wear condoms, this could be for cultural and religious reasons or because of domestic violence. Condoms also break and/or slip off. As well as individual behaviours, poverty, homelessness, homophobia and racism contribute to low condom use[42]. The reality is that condoms do not work for everyone and they are not used all of the time. Condoms alone are also not the answer to the ever increasing epidemic.

Intentional unprotected sex seems to be the controversial issue here. Following the announcement of the judicial review[35], highly stigmatising headlines were published in mainstream media[43],[44]. Critics claim PrEP is a ‘promiscuity pill’[43], attracting moral panic among the public, similar to the contraceptive pill response in the 1960’s[45]. It can be surprising how quick people are to judge others for their personal and life decisions. Some people will always struggle with condoms and blaming them may only exacerbate the problem. Behaviour change counselling is already part of practice in GUM clinics, however, changing behaviour is challenging. We are aware of the difficulty in stopping smoking, eating healthy and exercising more and, consequently, smoking and obesity related morbidities are high in the UK[46],[47]. The NHS was created to improve physical and mental health for all, regardless of how these infirmities occur. This first principle that guides the NHS states that the NHS has a wider social duty to “promote equality through the services it provides and to pay particular attention to groups where improvements in health are not keeping pace with the rest of the population”[48]. The HIV epidemic is worsening for at risk groups and this must be addressed[6].

Possible changes in condom use after introduction of PrEP is another contentious issue. As described earlier, critics believe that PrEP users will stop using condoms when they start taking Truvada® as PrEP[49],[50]. For those regularly and intentionally not using condoms, and those who are unable to negotiate condom use, unprotected sex will continue and for this reason PrEP is key to protecting these individuals, as well as preventing further transmission of HIV. Individuals who practice safe sex the majority of the time are unlikely to need PrEP and if they request it, a risk assessment will be undertaken, reassurance and advice on how to access PEP if needed will also be provided[51]. For those individuals that lie between these two groups, PrEP may be indicated based on a risk assessment[52].

This issue goes hand in hand with the question mark over whether STIs will increase with PrEP use. The IPERGAY study results demonstrated that the proportion of participants with a new STI during follow-up were similar in both groups, with 41% in the PrEP group and 33% in the placebo group (P =0.10)[8]. Hepatitis C rates were also the same in both groups[52]. Sexual behaviour also did not differ between the two groups, which was to be expected because this was a placebo-controlled trial. The PROUD and iPrEX studies attempted to mimic real life conditions as open-label studies[3],[4]. The iPrEX trial demonstrated that sexual behaviour did not change and STIs did not increase among those individuals who were taking PrEP[3]. PROUD demonstrated a similar lack of STI increase (including hepatitis C) in PrEP users, however, the authors did observe a significant difference in sexual behaviour, but only among those reporting ten or more partners with whom they had receptive anal sex without a condom[4]. This is one of the very high risk groups that should be targeted for the use of PrEP.

The Kaiser Permanente Medical Center (San Francisco, United States) published data in 2015 about its PrEP initiators that demonstrated that STI prevalence did increase among these patients and for a small proportion who were asked about behavioural change, they reported a 41% decrease in condom use[53]. The same medical centre also had no new HIV infections among those who had started PrEP in a two-year period[53]. In September 2016, the San Francisco Department of Public Health released its 2015 HIV epidemiology annual report[54]. This showed that their numbers of new HIV infections are continuing to fall and a sharper reduction was seen following the introduction of PrEP in 2012[54].

We could compare this issue to other interventions and associated concerns over promotion of high-risk behaviours. Over-the-counter emergency hormonal contraception did not result in increased promiscuity[55], nor did needle exchange programmes result in higher rates of intravenous drug use[56]. It is worth stating that PrEP uptake is also an opportunity to increase patient STI screening, which is especially useful as the vast majority of STIs are asymptomatic. The updated 2016 WHO guidelines for HIV prevention state that people who are at substantial risk of acquiring HIV are often medically underserved and providing PrEP will give people the opportunity to access to a range of other health services[57]. Those accessing PrEP will be seen every three months where they will undergo HIV, hepatitis B/C and STI tests, as well as risk and adherence assessments, and behaviour change counselling[51]. Syphilis rates[58] and Neisseria gonorrhoeae antimicrobial resistance[58] is on the rise in the UK, and increased STI screening and treatment may help to reduce the frequency of drug-resistant gonococcal strains.

Unfortunately, we cannot predict how condom use and STI rates will change if PrEP is introduced. A small increase in treatable bacterial STIs is a small price to pay for being able to not only halt rising HIV diagnoses but also reduce the epidemic in the UK. Professor McCormack was the lead investigator for PROUD and explained at the Conference on Retroviruses and Opportunistic Infections (CROI), (22–25 February 2016, Boston, United States) that “the pre-existing trajectory of rising STIs (among MSM) is carrying on, but PrEP means HIV doesn’t have to rise too”[59].

Costs

When NHS England states that funding of PrEP will result in other specialised groups missing out[36], it makes the argument for PrEP even more divisive. For those people who are not convinced that PrEP is needed based on an expanding epidemic, worsening health inequalities and fair NHS treatment, they may show support when presented with the economic argument.

In 2014 NHS England launched the ‘Five Year Forward View’ – a new vision for healthcare in England that requires “radical upgrades in prevention and public health”[60]. PrEP could be one of these ‘radical’ approaches, although describing it as ‘radical’ is questionable as it makes economic sense. Lifetime treatment of HIV costs on average around £360,000[61] and the annual cost of antiretrovirals to the NHS in 2019 is predicted to be £559 million[62], which is based on a projected rise in HIV infections of 8%[62]. This figure also highlights the extent to which pharmaceutical companies profit out of this incurable disease.

According to the impact assessment report for the NHS England clinical commissioning policy on PrEP, the financial impact is as follows: the cost per patient in the first year of implementation is £4,000–£4,800[51]. This assumes PrEP effectiveness to be 64%, which is a modest estimate as many trials have shown results that exceed this figure[4],[8],[9]. The impact figures are based on the current BNF price of Truvada® at £355.73 for one month’s supply[63]. However, the actual cost to the NHS may be lower as confidential prices are currently in place for use of Truvada® in people with diagnosed HIV[50]. A commercially confidential price for Truvada® use as PrEP may also have been offered by Gilead during the public consultation process[50].

Tenofovir disoproxil fumarate (TDF) is due to come off patent in Europe in December 2017 and emtricitabine (FTC) does not have a patent in Europe[34]. The estimated maximum level of drug cost reduction is 90% based on other examples of generic discounting, however, generics for PrEP are not expected to be available until 2018–2022[51]. The initial wait will be for generic TDF, which will be taken as a two-tablet regimen with FTC, and a further wait for a generic combination pill of TDF and FTC. Meanwhile, 17 people every day will be diagnosed with HIV in the UK[64].

It is important to remember that most PrEP users are unlikely to be continuously taking the drug for years, rather using it for periods where they would be at increased risk. The impact report also states that a PHE model (that uses trial data) predicts that the use of PEP is likely to reduce by 90%, which is a considerable cost saving because it is a one-month course of medication and just under 6,000 people accessed it in 2014[51].

The directors of public health for Hertfordshire and Blackburn councils also highlight this point and stated that “increasing numbers of commentators claim that the long-term fiscal benefits of PrEP will return substantial dividends for health systems”[65]. England’s chief medical officer, Dame Sally Davies also recently said: “whatever one thinks about PrEP morally, I can tell you that it is a cost-effective public health intervention, so I do believe our system should fund it”[66]. The HIV Pharmacy Association (HIVPA) have also commented that PrEP is a “highly cost-effective intervention” and urged “NHS England to realise that it would be the sole beneficiary of the cost avoidance (of antiretroviral treatment)”[36].

Side effects and resistance

For those who take PrEP and do not acquire HIV, there is no possibility of having drug-resistant HIV. However, if someone who is not fully adherent to their PrEP, becomes infected with HIV and carries on taking their PrEP in the same manner, resistance may develop[67]. There have been reports of only a handful of cases of this happening in trials[67],[68]. The majority of these patients were already infected with HIV when they started PrEP which stresses the point of accurate HIV testing upon initiation, an essential part of the PrEP service if rolled out fully in the UK[51]. ‘Fourth generation’ HIV blood tests will be used to show the patient’s HIV status approximately four weeks before the test. If exposure to HIV may have occurred during this period, then the patient would delay starting PrEP until this four-week ‘window of risk’ passed and that this was confirmed with a negative HIV blood test[18].

With regard to resistance, the study individuals who were infected with HIV while not fully adherent to PrEP developed resistance to emtricitabine only[69]. Therefore, tenofovir could still be used as an active agent along with multiple other anti-retrovirals[69]. It is important to note that PrEP would be supplied at three monthly visits, always with a HIV test and adherence counselling, reducing the chance of resistance emerging.

The WHO systematic review and meta-analysis for PrEP concluded that the risk of drug resistance was low overall and mainly occurred in those who were acutely infected with HIV when PrEP treatment was commenced[5],[7]. At a population level, the risk of resistance is unknown and active surveillance would be required, which is already in place in the UK through the HIV resistance database[7].

Transmitted resistance is also a possibility. At the 2016 CROI conference, a case report was presented about an MSM individual who was taking PrEP and seroconverted (became HIV antibody positive) with a multi-class resistant HIV virus that included resistance to tenofovir and emtricitabine[70]. This is the first documented case of breakthrough HIV infection with long-term adherence to PrEP. Following this, the patient was successfully treated and achieved viral suppression. In terms of numbers, only one case has occurred, despite around 80,000 people accessing PrEP in the United States since 2012[71]. A study using the UK’s HIV Drug Resistance Database, evaluated the extent of potential resistance to PrEP within the UK HIV-1-infectious MSM population. The population level of prevalence of PrEP resistance in these individuals in 2008 was 1.6% for TDF, 0.9% for TDF/FTC and 4.1% for FTC[72]. Although these United States and UK figures demonstrate how rare PrEP resistance is, this is another reason to stress the importance of condoms in clinic.

As for any preventative medicine given to healthy individuals, side effects need to be considered. The summary of product characteristics (SPC) for Truvada® lists headache, nausea and diarrhoea as very common side effects (affecting one in ten people)[1]. The main concerns are over longer term effects on renal function and bone density, however, many patients are unlikely to take PrEP long-term. Tenofovir and emtricitabine are primarily renally excreted, hence the SPC states that Truvada® for PrEP is not recommended in people with creatinine clearance <60ml/min[7]. Increased creatinine and osteomalacia are listed as uncommon and rare side effects, respectively, in the SPC[1]. In the iPrEx study, raised creatinine levels were observed in 2% of the Truvada® group and 1% of the placebo group[3], and in the IPERGAY study, this was 18% compared with 10%[8]; for both of these trials no patient discontinued treatment because of raised creatinine. In the PROUD study, three of 275 people in the immediate Truvada® group interrupted treatment because of high creatinine levels, however, PrEP was restarted in all these people[7]. To prevent any renal adverse drug reactions, the draft NHS England PrEP policy recommends to incorporate serum creatinine and urinalysis monitoring into clinic visits including at baseline[51].

Conclusion

As quoted by many leading HIV clinicians, researchers and charities, PrEP is a ‘game changing’ drug strategy[73],[74]. This is because PrEP could have a hugely beneficial effect on the UK’s HIV epidemic if made available through the NHS. As the number of those living with HIV still continues to rise[6], it is clear that we need another tool for HIV prevention. PrEP is also a cost-effective public health intervention, which in the long term has the potential to save money for the NHS[66]. The evidence supporting its use is impressive, particularly when considering the meta-analysis completed by the WHO, which demonstrated a 70% reduction in HIV infection with PrEP use[5]. As stated in the NICE evidence review for PrEP “there is little doubt that Truvada® is effective in reducing HIV acquisition”, however, drug resistance, condom use and safety need to be considered. The draft NHS England PrEP policy demonstrates how these risks will be addressed and monitored. Based on this evidence and the arguments outlined in this article, it is my opinion that PrEP should now become a key HIV prevention strategy, alongside regular testing and treatment for STIs, TasP, free condoms and ongoing behavioural counselling, to provide a better and more comprehensive HIV prevention package.

Author disclosure and conflicts of interest

The author has received a grant from Gilead Sciences Inc. for attendance of a conference and has attended educational evenings sponsored by this company.

Citation: Clinical Pharmacist DOI: 10.1211/CP.2016.20201939

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