Background: Pre-exposure prophylaxis (PrEP) is the use of HIV anti-retroviral therapy to prevent HIV transmission in people at high risk of HIV acquisition. PrEP is highly efficacious when taken either daily, or in an on-demand schedule. In Australia co-formulated tenofovir-emtricitabine is registered for daily use for PrEP, however, this co-formulation is not listed yet on the national subsidized medicines list. We describe a study protocol that aims to demonstrate if the provision of PrEP to up to 3800 individuals at risk of HIV in Victoria, Australia reduces HIV incidence locally by 25% generally and 30% among GBM.
Methods: PrEPX is a population level intervention study in Victoria, Australia in which generic PrEP will be delivered to 3800 individuals for up to 36 months. Study eligibility is consistent with the recently updated 2017 Australian PrEP guidelines. Participants will attend study clinics, shared care clinics, or outreach clinics for quarterly HIV/STI screening, biannual renal function tests and other clinical care as required. Study visits and STI diagnoses will be recorded electronically through the ACCESS surveillance system. At each study visit participants will be invited to complete behioral surveys that collect demographics and sexual risk data. Diagnosis and behioral data will be compared between PrEPX participants and other individuals testing within the ACCESS surveillance system. A subset of participants will complete in depth surveys and interviews to collect attitudes, beliefs and acceptability data. Participating clinics will provide clinic level data on implementation and management of PrEPX participants. The population level impact on HIV incidence will be assessed using Victorian HIV notification data.
Discussion: This study will collect evidence on the real world impact of delivery of PrEP to 3800 individuals at risk of acquiring HIV in Victoria. This study will provide important information for the broader implementation of PrEP planning upon listing of the tenofovir-emtricitabine on the national subsidized list of medicines. The study is registered on the Australian New Zealand Clinical Trials Registry (ACTRN12616001215415)
Keywords: PrEP, HIV, MSM, prevention, protocol
IntroductionIn Australia, HIV is largely concentrated among gay, bisexual and other men who he sex with men (GBM). Almost three quarters of annual notifications are among men reporting male to male sex as their exposure to HIV, with other exposures such as injecting drug use, heterosexual sex and being born in a high prevalence country being less commonly reported (1). In 2015 there were 1025 new HIV diagnoses in Australia and there were an estimated 25,313 people living with HIV (PLWH) (estimated prevalence of 0.1%) (1, 2). Despite significant investment in, and uptake of, HIV prevention activities, the annual number of HIV notifications has remained stable over the last four years (1).
HIV pre-exposure prophylaxis (PrEP) is the newest tool in the HIV prevention toolkit. PrEP is the use of tenofovir and emtricitabine on a daily or on demand schedule to prevent HIV transmission (3, 4). There is substantial evidence of the safety, efficacy and effectiveness of PrEP at reducing HIV transmission in GBM, trans-women, heterosexual men and women and people who inject drugs (3, 5–11). The efficacy of PrEP is directly correlated with medication adherence (12, 13) with recent open label trials reporting high adherence and greater reduction in risk of HIV acquisition compared to earlier, blinded studies (13, 14). While PrEP is highly effective at reducing HIV transmission it confers no protective effect against sexually transmissible infections (STIs) with the exception of HSV2 infections (15, 16). Concerns he been raised that PrEP use would increase condomless peno-anal or peno-vaginal sex, number of sex partners and in turn incidence of STIs, however there is mixed evidence of such changes occurring (11, 14, 17). In 2015 the World Health Organisation recommended PrEP as an HIV prevention option for all key populations (18). As at November 2017, PrEP is approved for use by the regulatory authorities of at least 20 countries, including Australia. Although approximately 30 countries currently run or plan to implement PrEP demonstration projects (19), there are as yet no publications which confirm the population level impact of PrEP.
Australian PrEP guidelines are based on individuals' risk of HIV acquisition. PrEP is recommended for people reporting high or moderate risk for acquiring HIV through male to male sex, heterosexual sex, and/or injecting drug use. Recent changes to the guidelines also permit clinicians' discretionary prescription of PrEP (20).
PrEP is currently registered for use in Australia, and will be listed on the national list of medicines [the Pharmaceutical Benefits Scheme (PBS)] on 01 April 2018. In 2016, three pharmaceutical companies had their co-formulated tenofovir and emtricitabine products approved by Australia's Therapeutic Goods Administration (TGA) for use in HIV prevention (21–23). In Australia, medicines listed on the PBS cost $39 AUD or $7 AUD for person eligible for concession (24) per dispensed medication, but because PrEP is not currently subsidized through the PBS obtaining PrEP via a private prescription incurs costs up to $900 AUD per month (25, 26). Generic PrEP can be imported from overseas through the TGA personal importation scheme, wherein registered medical practitioners provide individuals with clinical monitoring and 3-monthly prescriptions for PrEP (27). The cost of personally importing PrEP ranges between $70–230 USD (approximately $90–300 AUD) for a 3 month supply (28, 29); delays in customs and shipping he been reported (30). Finally, PrEP can be accessed through jurisdiction-level PrEP implementation projects, which either provide participants free study medication, or require that participants pay costs commensurate with current PBS prices. Six of the eight Australian jurisdictions offer PrEP via population intervention studies, with the size and number of studies increasing significantly since the first PrEP demonstration project, VicPrEP, began enrolment in Victoria in June 2014 (Table 1) (17, 31–36). VicPrEP demonstrated that PrEP could be successfully prescribed and managed in general practice in Victoria, providing preliminary evidence for the current, larger demonstration study, PrEPX (17).
Table 1.PrEPX study timeline, 2013–2019.
Phase Date Activity Pre-PrEPX 2013–2014 Community advocacy for PrEP access and forums held by VAC to discuss PrEP, PrEP stigma and future clinical trials. Jun 2014–Dec 2016 VicPrEP study−30 month demonstration project enrolled 114 participants across four sites in Melbourne. Jun–Aug 2015 PrEP'D for Change and PrEPaccessNOW formed. General practitioners developed guidelines for prescribing off-label PrEP. Dec 2015 Victorian PrEP Accord was signed. Signatories include VAC, LPV, PrEP'DforChange, PrEPaccessNOW, time4PrEp, VicPrEP. PrEPX planning Sep-Dec 2015 Approached clinics and community pharmacies to participate in the PrEPX study. Approached peak organizations including VAC, LPV, VACCHO, Centre for Culture, Ethnicity and Health. 29 Jan 2016 Funding announced by the Victorian DHHS, Alfred Health and VAC for 2,600 places in PrEPX study. 30 Jan 2016 Study registration opened using REDCap on the Alfred hospital website. Data collected: name, contact details, preferred clinic to attend for PrEPX, whether participant was on PrEP. 22 Jul 2016 2049 people registered interest on online formClinics provided with partially de-identified list from registration form to enable workforce planning when study openedRegistered individuals emailed about study opening dates and booking information for their preferred clinic. PrEPX study period 26 Jul 2016 PrEPX enrolment began (we one of study enrolment) 2600 places opened, 150 of these reserved for priority populations including people who inject drugs and/or people in serodiscordant heterosexual partnerships with high or medium risk for HIV acquisition as per PrEP prescribing guidelines (Table 2). 14 Oct 2016 PrEPX study neared enrolment capacityStudy enrolment stopped at 2200 participants to allow for people who had booked an appointment and not yet attended to join the study, with other places reserved for priority populations.First waitlist was opened, pending further funding. 17 Jan 2017 Additional 600 places in PrEPX announced, funded by VAC. 19 Jan 2017 Additional places released (we two of study enrolment)All 575 people registered on the waitlist were provided a study place. Clinics were provided a list of participants as per original PrEP enrolment. 20 Jan 2017 Waitlist was reopened. 28 Mar 2017 Additional 600 places announced, funded by Victorian DHHS. 29 Mar 2017 Additional places released (we three study enrolment)All 617 people registered on the waitlist were provided a study place Clinics were provided list of participants as per original PrEP enrolment. 30 Mar 2017 Waitlist was reopenedWaitlist remains open November 27th 2017. 30 June 2019 PrEP-X study estimated end date. Open in a new tabVicPrEP, Victorian PrEP demonstration study; PrEPX, Victorian PrEP population level study; PrEPX-SA, expansion of PrEPX study to South Australia; VAC, Victorian AIDS Council, LPV, Living Positive Victoria; VACCHO, Victorian Aboriginal Community Controlled Health Organisation Inc.; DHHS, Department of Health and Human Services.
Rationale for this studyPrEP randomized controlled trials and PrEP demonstration projects he shown that the use of tenofovir and emtricitabine is safe, highly efficacious and effective in the prevention of HIV infection (3, 6, 9, 11). Based on this current knowledge of PrEP we are introducing this HIV intervention tool at a population level in Victoria to people at high risk of HIV infection to help reduce new HIV infections in the State.
The VicPrEP study showed that during a period of 12 months of PrEP use, adherence to drug schedule was high. (17). In some studies, including VicPrEP, STIs he increased and condom use has declined (11, 17). However interpretation of these findings is not straightforward and requires further follow-up combined with the planning and implementation of innovative STI prevention strategies. Furthermore, individuals who receive PrEP attend their healthcare practitioners on a quarterly basis, which may afford individuals the opportunity to enhance other aspects of their health including blood pressure management, assistance with managing depression, drug and alcohol use and vaccinations.
Study aimsIn Victoria, three quarters of new HIV diagnoses are among GBM and the knowledge of, interest and willingness to use PrEP is high amongst GBM at higher risk of HIV acquisition (37). We hypothesize that the provision of PrEP to individuals at high risk of HIV would be both justified and feasible and could achieve a population level reduction in HIV incidence. The primary aim of this study is to determine if the provision of PrEP for 36 months to 2,600 people at high risk of HIV infection in Victoria will result in a 30% decline in new HIV infections in GBM and a 25% state wide decline in new HIV infections.
The study's secondary aims are to explore:
Baseline demographics, behior, HIV risk factors, prevalence of STIs and blood borne viruses among GBM presenting for PrEP.
Attitudes to PrEP, reasons for taking PrEP and attitudes around sexual behior since the ailability of PrEP.
PrEP adherence.
Changes in sexual behior and STI rates among PrEP users.
Use of non-occupation post exposure prophylaxis (NPEP) in Victoria.
The capacity of study clinics to prescribe PrEP.
Any ancillary health outcomes associated with PrEPX participation.
Methods Study designPrEPX is a prospective, population-level intervention study, designed to emulate “real world” conditions to reflect the likely clinical scenario were tenofovir and emtricitabine to become subsided by the PBS for use as HIV PrEP in Australia. People interested in participating in PrEPX may register their interest in the registration or waitlists or directly approach participating clinics to enquire about the study. Participating clinicians may recommend PrEP, and participation in PrEPX, to their clients. Participants will be provided with daily co-formulated generic tenofovir with emtricitabine purchased from Mylan Pharmaceuticals, Australian Sponsor- Alphapharm (38).
The investigators approached community organizations in Victoria representing people who are gay and bisexual, trans and gender diverse, Aboriginal and/or Torres Strait Islanders, and culturally and linguistically diverse to gain their input on the PrEPX study design and suitability for their constituents, prior to obtaining study funding. Organizations were offered financial support to develop pathways to facilitate their target populations' participation in PrEPX. All the community organizations approached agreed to engage with and support PrEPX (Table 1).
Study settingThe study is set in Victoria, the second most populous Australian state with a population of 6.2 million people and about 45,000 GBM (2, 39). In 2015, there were 286 new HIV diagnoses in Victoria of which 148 were defined as newly acquired [evidence of diagnosis within 12 months of infection (40)], with diagnosis rates of 4.8 and 2.0 per 100,000 population, respectively (1). In metropolitan Melbourne (the capital of Victoria), where approximately 80% of people newly diagnosed with HIV in Victoria reside (41), PLWH and GBM are cared for by three types of clinics: a small number of general practice clinics that he high caseloads of PLWH and GBM, state-funded sexual health services, and infectious disease (ID) clinics at teaching hospitals. The Alfred Hospital provides a state wide HIV service. These three types of clinics are staffed by general practitioners, sexual health clinicians and infectious disease clinicians who are licensed to prescribe antiretroviral medications on the PBS. Since 2013, the PBS has provided ARVs to PLWH at any CD4 cell count (previously restricted to a CD4 cell count below 500 cells/ml). PrEPX study sites include GBM specialist GP clinics, state-funded sexual health service, the Alfred hospital HIV service, shared care and outreach study sites (Table 1).
Engagement of clinics, pharmacies and community organizationsPrior to seeking funding for PrEPX, the investigators approached seven clinical services to determine their interest and capacity to undertake the PrEPX study. The study offered either a $100 AUD payment per participant enrolled, or a part-time nurse to support enrolment of study participants. All clinical sites approached by investigators (n = 7) agreed to participate in the study and then received site initiation and training by an investigator and/ or a clinical trial nurse.
In Australia clinical trial medications are conventionally free of charge and are dispensed by hospital-based pharmacies. However, to mimic real world conditions, PrEPX participants can he their PrEP medication dispensed by community pharmacies located close to the study clinics. Participants are required to pay a co-payment to simulate the co-payment costs that Australian residents pay for medications listed on the PBS (26). The investigators approached five community pharmacies to determine if they would dispense PrEPX study medication. All community pharmacies approached by investigators agreed to participate in the study and received appropriate facilities and training to conform with good clinical research practice.
Shared care and outreach study sitesThe PrEPX shared care model is based on existing models of clinical shared care in Victoria. These models ensure individuals are able to access services across outer metropolitan Melbourne, regional and rural Victoria. The shared care model aims to improve geographic access, equity and convenience and the model was used to provide PrEP sites outside of metropolitan Melbourne.
Within this shared care model the participant is enrolled as a study participant at the Alfred Hospital while receiving care with their general practitioner at a remote site (remote GP). The PrEPX investigator (based at the Alfred hospital) is responsible for confirming study eligibility, for enrolling the participant, providing clinical monitoring, PrEPX study drug prescription and oversight of the shared care remote GP. Test results are maintained at both the remote GP and Alfred Hospital PrEPX sites; results are discussed between practitioners (PrEPX investigator and shared care site GP) as required. Study drug can be dispensed by a participating PrEPX community pharmacy site or the hospital pharmacy can dispense and send the study drug to the participant via registered mail. For participants receiving study drug at the baseline visit via mail, the investigator provides a follow-up phone call to the participant, reaffirming dispensing information and receipt of study drug.
Within the outreach clinic model a clinician from the Alfred Hospital attends a rural or regional clinic in Victoria. Study participants are enrolled at the remote clinic into the PrEPX study as an Alfred Hospital patient and assigned an Alfred Hospital unique reference number.
Details of the participant's enrolment are entered into the participant's local medical records at the outreach clinic. The Alfred Hospital PrEPX clinician will he access to the study participants medical records at the outreach clinic. Pathology tests are collected at a local Pathology Service provider and the results are sent to the Alfred Hospital and to the outreach clinic. Follow-up care is provided by the local healthcare provider. Study drug is dispensed and sent to the participant via registered mail from the Alfred Hospital Clinical Trials pharmacy.
Study fundingPrEPX received funding from the Victorian Department of Health and Human Services (DHHS) on 29 January 2016 for 2,600 study places. An additional 600 places were funded by the Victorian AIDS Council (announced on 19 January 2017) and a further 600 places were funded by the Victorian DHHS (announced on 28 March 2017). Hence a total of 3,800 participants will be enrolled into the PrEPX study. Waitlists were established in anticipation of these two funding injections (Table 1).
Study participants Inclusion criteriaEligible participants must be HIV-negative at their baseline PrEPX appointment, aged 18 years and over, he an estimated glomerular filtration (eGFR) rate of >60 mL/min/ 1.73 m2 and meet the behioral eligibility criteria of the 2015 ASHM PrEP Guidelines (42). Eligible participants are individuals reporting male to male sex, injecting drug use and/or serodiscordant heterosexual sex with high or medium risk for HIV acquisition (Table 2) (42). Individuals not meeting these behioral eligibility criteria can be enrolled at the clinician's discretion, if the clinician is of the opinion that the patient would benefit from being on PrEP (Table 2).
Table 2.Eligibility criteria for PrEPX Study.
Gay, bisexual and transgender people Heterosexual and transgender people People who inject drugs Predicted risk of the study participant in the next 3 months Likely to he multiple events of condomless anal intercourse (CLAI), with or without sharing intrenous drug use equipment Likely to he multiple events of condomless anal or vaginal intercourse, with or without sharing intrenous drug use equipment Likely to he multiple events of sharing needles or injecting equipment with an HIV positive individual or a homosexually active man and has inadequate access to safe injecting equipment AND Reported risk in the past 3 months (unless other timeframe stated) Is a regular sexual partner of an HIV-positive male partner with whom condoms were not consistently used (HIV positive partner is not on treatment and/or has detectable HIV viral load) Is a regular sexual partner of an HIV-positive man or woman with whom condoms were not consistently used in the last 3 months (HIV positive partner is not on treatment and/or has detectable viral load) At least one episode of receptive CLAI with any casual HIV-positive male partner or a male partner of unknown HIV status A diagnosis of rectal gonorrhoeae, chlamydia and/or syphilis during the last 3 months or at screening Has used methamphetamine Has had more than one episode of anal intercourse in the last 3 months when proper condom use was not achieved (e.g., condoms slipped off or broke) Is uncircumcised and reports more than one episode of insertive CLAI in the last 3 months where the serostatus of their partner was not known, or the partner was HIV positive and not on antiretroviral treatment Has been sharing needles or injecting equipment with an HIV positive individual or with a homosexually active man Clinicians' discretion All people who do not report any of the above risk factors should still be considered at risk of HIV infection and evaluated on a case-by-case basis. Open in a new tabAdapted from National prescribing guidelines (20).
Exclusion criteriaParticipants are excluded if they are HIV-positive as confirmed by HIV antibody/antigen and western blot testing; he signs and/or symptoms of acute HIV infection; are not eligible for Australia's universal healthcare system Medicare (43); are unwilling to provide consent to follow-up; he an eGFR of