HIV Early Treatment Workshop Planning for removal of the CD4 <500 requirement for prescribing ART

1. HIV Early Treatment WorkshopPlanning for removal of theCD4 <500 requirement for prescribing ART A partnership between

2. Support for this webinar • Australasian Society for HIV Medicine • ACT, NSW, QLD, SA, TAS, VIC, WA governments • ViiV Healthcareand Gilead Sciences • Additional support is being sought to support this national educational program and a series of local reports back and case discussions

3. Support for the PBAC Submission • ASHM, AFAO, NAPWA, Kirby - Submission • Commonwealth Government – Fee waiver • ViiV Healthcare, Janssen – Financial support • NSW, NT, QLD, TAS, VIC – Financial support

4. Objectives • To develop a shared understanding of recent PBAC changes • To identify key issues which would: • recommend early treatment initiation • recommend delaying treatment initiation and • To explore these issues through the discussion of a number of clinical cases

5. PBAC Decision Levinia Crooks

6. Declarations of Interest • Levinia Crooks has no conflicts to declare and has not been assisted to attend any conferences or meetings • She sits on the Judging Panel for the Gilead Sciences Fellowship Research Grants Program, honoraria in respect of this activity are donated to the ASHM Gift Fund

7. PBAC Decision • Initial treatment of HIV infection in combination with other antiretroviral agents, in a patient who is antiretroviral treatment naïve following diagnosed HIV infection. • Continuing treatment of HIV infection in combination with other antiretroviral agents where the patient has previously received PBS-subsidised therapy for HIV infection. • The PBAC noted that the requested restriction would allow the initiation of ART at a CD4+ count >500 cells/mm3 for patients with HIV, irrespective of the presence of symptomatic disease.

8. Request • To remove the CD4+ cell count restriction for initiation of first line anti-retroviral therapy (ART) in asymptomatic, ART naïve HIV positive patients.

9. Economic Analysis • The PBAC considered that although the economic model had limitations, it was as accurate a depiction of the cost effectiveness as could be generated with the clinical data available.

10. Usage and Financial Implications • The PBAC considered that not all patients diagnosed with HIV infection would automatically start ART. Factors including age, adherence, preparedness and awareness of the lifelong commitment to therapy will all impact on the patient and physician decision to initiate treatment. • The PBAC agreed that the decision to initiate treatment is individualised and that people living with HIV in Australia are managed by a relatively small number of clinicians who are specifically trained to become Section 100 Highly Specialised Drug prescribers of ART. This promotes a relatively standardised approach to initiating and monitoring ART.

11. Rationale for Decision • The PBAC noted that the potential benefits of removing the CD4+ count restriction include: • Reduced transmission of HIV infection • Individualisation of patient therapy • Empowering patients to be able to choose when to commence therapy • The PBAC considered there to be an advantage to patients associated with being able to have greater choice, together with their prescribers, of when to initiate therapy with ART. The PBAC considered this greater choice to represent good Quality Use of Medicines.

12. Implementation • The PBAC released the Public Summary Document on 7 March 2014, which is available at http://www.pbs.gov.au/info/industry/listing/elements/pbac-meetings/psd • The change will come into effect with the release of the 1 April 2014 PBS Schedule of Pharmaceutical Benefits “Yellow Book”

13. New ART S100 prescribing criteria • Initial treatment of HIV infection in combination with other antiretroviral agents, in a patient who is antiretroviral treatment naïve following diagnosed HIV infection. • Continuing treatment of HIV infection in combination with other antiretroviral agents where the patient has previously received PBS-subsidised therapy for HIV infection.

14. Clinical Data and the PBAC Decision Edwina Wright

15. Declarations of Interest • Edwina Wright: Alfred Hospital, Monash University, the Burnet Institute and ASHM • President of ASHM • Chair or ASHM Clinical Oversight Committee • Victorian Department of Health Advisory Board for BBV • Chair of PBAC Submission Committee • Recipient of unrestricted funding for research from Gilead, Abbott, Janssen, BoeringherIngelheim • Payment for lectures from ViiV • Consultancy from ViiV, Gilead, MSD and Abbott

16. Clinical Trials • There were no head-to-head trials available directly comparing the initiation of treatment in ART naïve HIV positive patients with a CD4+ count of >500 cells/mm3 to deferred therapy. • The submission was based on: • Three randomised controlled trials - two measuring individual patient endpoints and one measuring transmission as a community endpoint; • Four observational studies; • Two ecological studies; and • Thirteen biological studies that evaluate the use of ART irrespective of CD4+ count.

17. Clinical claim not fully supported • Randomised trials, Hogan 2012 and SPARTAC 2013 used short term (12, 36 or 48 weeks) interrupted ART regimens prior to the commencement of long term ART (LART). Not directly relevant as treatment interruption is not recommended. • The results for risk of death or progression to AIDS from the observational studies were inconsistent. • The results reported in the ecological studies (Das 2010 and Geng 2012) are based on an assumption of cause and effect, and the analyses are unable to fully account for significant confounders (patient characteristics, differences in treatment regimens and health care practices).

18. Clinical Trials & Patient Benefit • The PBAC considered that based on the available information, it was not possible to quantify the clinical benefit to an individual patient from removing the CD4+ threshold for initiation of ART. They noted, however, that current expert opinion in Australia suggests that there is likely to be a net clinical benefit to patients from removal of the threshold compared to current clinical practice.

19. Clinical Claim • The PBAC noted that the applicant had clarified the clinical claim in the Pre-Sub-Committee Response. The submission’s claim was that there was sufficient evidence on pathophysiological, clinical, immunological, virological and ecological grounds to be able to offer ART to HIV+ individuals with a CD4+ count greater than 500 cells/mm3. The PBAC considered this claim to be reasonable and consistent with current Australian expert opinion.

20. Prevention Claim • The submission claimed that the early initiation of ART and increased viral suppression results in a reduction in the risk of transmission between partners. The PBAC noted that this claim was supported by evidence from Cohen 2011. The PBAC agreed with the Economic Sub-Committee (ESC) that the claim of reduced transmission was reasonable but that the size of any benefit remained unknown.

21. differences between the population in Cohen 2011 and the relevant Australian population including: 98% of couples enrolled in the trial were heterosexual; some HIV-related events in the trial were tuberculosis-related; and the criteria for initiating treatment in the trial was a CD4+ count of ≤250, not >500. • the likely presence of significant confounding in the ecological studies (Das 2010, Geng 2012), as described above.

22. PARTNER study CROI 2014 153LB HIV Transmission Risk Through Condomless Sex If HIV+ Partner On Suppressive ART: PARTNER Study Alison Rodger et al. • Background: The absolute risk of sexual HIV transmission on stable ART (HIV RNA viral load (VL) <200 c/mL) from condomless sex is unknown. Current limited data are largely focusing on vaginal sex • Methodology: The international, observational multi-centrestudy prospectively follows serodifferent couples (heterosexual (HT) and MSM) who had condomless penetrative anal or vaginal sex in the month prior to study entry, and where the HIV+ve partner is on ART. • Every 6 months, each partner completes a sexual behaviour questionnaire and the negative partner tests for HIV. • Eligibility of follow-up time in this transmission rate analysis required:continuedcondomless sex; not using PEP or PrEP; and latest VL <200 c/mL. For new diagnoses, phylogenetic analysis compared HIV-1 pol and envsequences by couple, after samples were anonymised. • This planned analysis reports the rate of occurrence of linked transmissions.

23. PARTNER Study • Results: By 1st November 2013, 1110 couples were enrolled. Of 1151 couple-years of follow-up (CYFU), 894 were eligible (586 in HT and 308 in MSM). • At baseline, the median duration on ART was 4.9 years (IQR: 1.9-11.4) and couples reported having condomless sex for a median 2 years (IQR: 0.5-6.3). • Condomless sex with a different partner outside the partnership during follow-up was reported by 27% MSM and 2% HT HIV-negative partners. • During follow-up, couples had condomless sex a median of 45 times/ year (IQR: 16-90). • Although some negative partners became HIV positive during FU, no phylogeneticallylinked transmissions occurred,

25. PARTNER Study • Conclusions: The overall risk of HIV transmission (in the context of previous sex without transmission) through condomless anal or vaginal sex from HIV positive people on ART with plasma VL < 200 copies/mL is extremely low, but uncertainty over the risk remains, particularly over receptive anal sex. • Additional follow-up in MSM is essential to provide more precise estimates for transmission risk given the current assumptions of safety in some communities.

26. Comparative Harms • Adverse events in RTs were similar across the patient groups for Cohen 2011 and SPARTAC 2013. There was limited reporting of adverse events in Hogan 2012. Differences in grade 3 or 4 laboratory abnormalities were reported in Cohen 2011: early therapy group (n=242, 27.3%); delayed therapy group (n=161, 18.4%), p<0.001. • The most frequent abnormalities included neutropenia, abnormal phosphate level and total bilirubin elevations (bilirubin elevations observed primarily in patients administered atazanavir).

27. Risks Comparable • The PBAC noted that the risks of treating asymptomatic patients with high CD4+ counts are largely similar to those of treating patients with advanced HIV (if time on treatment is not considered), with the exception of nevirapine, which was associated with an increased risk of toxicity in patients with higher CD4+ counts.

28. Julian Elliott Clinical Case Disucssions

29. Declarations of Interest • Julian Elliott: Head, Clinical Research, Department of Infectious Diseases, Alfred Hospital and Monash University • Member ASHM Board, Chari ASHM Sub-Committee on HIV Clinical Guidance • Institution receives funding for conduct of research studies from Merck, Gilead Sciences, ViiV Healthcare, BMS, Janssen, Tibotec, GSK