Vulnerable populations: Too little, too late or new opportunities?

Vulnerable popula,ons: Too li1le, too late or new

opportunity?

Prof. Chris,ne Katlama Mark Wainberg, PhD Réjean Thomas, MD Prof. Gilles Pialoux

• Cobicistat – A new pharmaco-‐enhancer or booster alterna2ve to ritonavir

• ATZ/r vs. ATZ/cobicistat1 – Proven virological non-‐inferiority – Incidence of most common adverse events (AEs) similar

between arms – Discon2nua2on rates due to AEs low and similar between arms – Grade 3/4 hyperbilirubinemia, increase in serum crea2nine, and

decrease in es2mated glomerular filtra2on rate (eGFR) significantly greater with cobicistat vs. ritonavir, but this difference did not lead to higher discon2nua2on rates due to bilirubin-‐related or renal AEs

New molecules

• CD4 > 350 and > 5009,10

– “20% of pa2ents treated at the L’Actuel medical clinic have CD4 > 500” (R. Thomas)

• The new therapeu,c approaches are simpler

• S,ll, it’s not rare that pa,ents refuse treatment

– Up to 57% of pa2ents refuse a treatment suggested by their doctor11

– 11% of pa2ents do not even begin treatment even if they have agreed to it11

Therapeu,c management threshold Opportuni,es and challenges

• Truvada for pre-‐exposure prophylaxis (iPrEx)12 – Poten2al risk of transmission of resistances13

– Mathema2cal models predict the appearance of resistance: • <4% poten2al resistance associated with this approach (PrEP)14 • 50-‐63% associated with an2retroviral therapy (ART)14 • 33-‐48% by transmission of resistant viruses14

• 3.5% risk of resistance around 2030 associated with PrEP in serodiscordant couples15

– Resistance to iPrEX16 • No cases in the iPrEx arm, but 1 case of K65R and 1 case of M184V in the placebo arm, reported to date

Resistance: risks and reality of the new approaches

• High rates of K65R in pa,ents naive to HIV subtype C aaer exposure to tenofovir (TDF)17

– d4T+3TC or TDF+3TC plus one NNRTI • 6% of virologic failures (n=35) • 69.7% among them have a K65R muta2on

• Poten2al reasons: – Faster selec2on of these muta2ons in vivo, longer dura2on in treatment

failure, or transmission of resistant virus

– Poten2al role of d4T as a vector of this phenomenon via transmission of resistant viruses18

– 35.7% of K65R in pa2ents with subtype C (vs. 2.2% for type B, and 3.7% for non-‐B/C)19

Resistance: HIV subtype C

• Risks associated with the introduc,on of new molecules: tenofovir (TDF), abacavir (ABC) and LPV/r on resistance20

– Since the increase in the use of TDF and ABC (2009), we've witnessed a significant increase in K65R and L74V

– Compared to the TDF/3TC/EFV combina2on (VF=31%), the risk of K65R is higher in the presence of NVP (VF=88%) and lower with LPV/r (VF=7%)

– 10% (n=42) of pa2ents had resistance to LPV/r – 4% (n=17) showed cross-‐resistance to DRV/r

Resistance: A South African experiment

• Who are these pa,ents? – CD4 <35021 or an HIV-‐defining illness regardless of the CD4

• They represent up to 59% of pa,ents in some cohorts22 – Oken do not perceive themselves to be at risk

Late Presenters: What should we do?

• The costs associated with their treatment are higher even though they die faster22 – These pa2ents represent 43.1% of new pa2ents – The cost associated with their treatment is between $27,275 and $ 61,615

higher than that of pa2ents who are treated early – Even aker 7 or 8 years of care, the difference in the cost of treatment between

these pa2ents and those who come early remains substan2al

• It's harder to achieve an undetectable viral load in these pa,ents23 – Aker an average treatment period of 3 years, there is a 13.9% rate of

treatment failures – To get a response, it takes on average 4.8 ± 2.1 (3-‐10) drugs

• The iden,fica,on and management of these pa,ents should be a priority24

• They represent one of the three most important problems associated with HIV in the United States24

Late Presenters: Economic Challenges

• Such pa,ents are at greater risk for AEs related to treatment25 – Increased risk of peripheral neuropathy if CD4 is lower than 50 – Greater risk of nausea and vomi2ng with LPV/r than with ATZ – Greater risk of having to stop treatment with LPV/r than with ATZ

• 35% vs. 10% – Increased incidence of lipodystrophy – Increased risk of haematological toxicity with AZT – Lower treatment adherence – Higher resistance rates

• 10.4% in Europe, in naïve pa2ents • 9% in Germany

– 7.6% to NRTIs – 2.5% to PIs and 2.6% to NNRTIs

Late Presenters: Tolerability Challenges

• Therapeu,c responses vary26 – ARTEMIS study

• More favorable virological response with DRV/r than with LPV/r27

– CASTLE study • More favorable virological response with ATZ/r than with LPV/r28

• Op,ons that offer higher resistance thresholds – A drug with a high gene2c barrier is an important inclusion in the ART

regimen of these pa2ents28 – Boosted PIs are the preferred regimen vs. NNRTIs in this popula2on28

• Consider pretreatment genotyping to determine the appropriate strategies if a rapid test result is possible30

Late Presenters: Therapeu,c Challenges

Pa2ent management: • Experiment with a hepa,,s C31 treatment with interferon

– Results of the meta-‐analysis: • Response rate of 54.3% among IDUs • Pa2ents with acute hepa22s: the response rates are 68.5% for IDUs and 81.5% among non-‐IDUs

• New op,ons without interferon – ALS 2200: Viral load reduc2on of 4.54 log10 in pa2ents with genotype 131

– GS-‐7977 (Gilead) and daclatasvir (BMS) 100% SVR at 4 weeks33

– BI201335 and BI207127, SOUND-‐C2 study34

• Results with boosted PIs – Boosted atazanavir-‐based HAART was the most resilient regimen and it was more effec2ve

than efavirenz-‐based HAART among IDUs35

• Review the treatment model for hepa,,s based on the HIV model

– Comprehensive care

Injec,on drug users

• Lower overdose rates35 – 35% reduc2on, 500m around the site vs. 9% elsewhere in the city

• Reduced risk of HIV and hepa,,s36 – Preven2on of 35 HIV cases/year – Preven2on of 3 deaths/year

• Centralized venue for user/pa,ent care • Effec,ve in terms of cost-‐benefit

The supervised injec,on sites approach Vancouver's INSITE Model

• Countries of the former USSR37,38 – Ukraine: nearly 1.6% of the popula2on aged 15-‐49 is HIV posi2ve

(n=440,000)

– Substance abuse is an important vector of transmission in those countries

– Heterosexual transmission of HIV remains a cri2cal issue especially among normally low-‐risk popula2ons38

– Substance abuse is criminalized in those countries37 • Confisca2on of syringes by police • Police arrests for possession of syringes • IDUs are tortured by police

• Africa and specific popula,ons – IDUs: yes even there, Nigerian Situa2on39 – MSM and HIV in Africa: underes2ma2on of a hidden reality40,41

Concentra,on of the epidemic

• Sexual Health Centre – Comprehensive approach:

• HIV, hepa22s, sexual health, HPV, addic2on • Post-‐exposure prophylaxis

• Point of service on the street: L’Actuel sur rue – Simple and quick screening

– Importance of clinical follow-‐up

A new model of care: from the clinic to the street

• Approval of an oral test in the USA42

– Sensi2vity: 92% • For 1 person in 12, the test does not detect the HIV posi2ve status

• Controversy – Screening at home

– Lack of support and monitoring in the case of a posi2ve test

• Encourages tes,ng • It is important to inform the public that treatments are

now simpler and more effec,ve

The new home screening tests: controversies or benefits?

• Challenges – Elimina2ng the context of criminaliza2on of HIV and substance abuse

– The s2gma associated with HIV

– Growing educa2onal needs because of the new treatments

– Reaching new clienteles • IDUs • Late presenters

– Treatment as preven2on, both for oneself and for others

• Dangers – Nega2ve impacts on preven2on programs by sending a too posi2ve

message, HIV/AIDS is not cured or serled, and hasn't disappeared

– Preven2on remains necessary

Conclusion

References New molecules 1. Gallant J et al. Cobicistat versus ritonavir as pharmacoenhancers in combina2on with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, ac2ve-‐controlled trial, week 48 results [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUAB0103.

Integrase inhibitors 2. Sax, P. et al. Analysis of efficacy by baseline HIV RNA: week 48 results from a phase 3 study of elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) compared to efavirenz/emtricitabine/tenofovir DF in treatment-‐naïve HIV-‐1-‐posi2ve subjects [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUPE028

3. DeJesus E. , et al. Analysis of efficacy by baseline viral load: phase 3 study comparing elvitegravir/cobicistat/emtricitabine/tenofovir DF (quad) versus ritonavir-‐boosted atazanavir plus emtricitabine/tenofovir DF in treatment-‐naïve HIV-‐1-‐posi2ve subjects: week 48 results. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUPE043

Integrase inhibitors (resistance) 4. Margot, N.A. et al. Low rates of integrase resistance for elvitegravir and raltegravir through week 96 in the phase 3 clinical study GS-‐US-‐183-‐0145[Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUPE050 5. Raffi, F. et al. Once-‐daily dolutegravir (DTG; S/GSK1349572) is non-‐inferior to raltegravir (RAL) in an2retroviral‑naive adults: 48 week results from SPRING-‐2 (ING113086) [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: THLBB04

6. Karmon, S. et al. Acquisi2on of transmired HIV-‐1 integrase drug resistance muta2ons in a New York City cohort [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUPE264

7. Blanco, J.L. et al. HIV-‐1 Integrase Inhibitor Resistance and Its Clinical Implica2ons. J Infect Dis. 2011 May 1;203(9):1204-‐14. Review.

8. Mesplède, T. et al. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS 2012, 7:000–000. DOI:10.1097/COH.0b013e328356db89

References (con,nued) Therapeu,c management threshold – Opportuni,es and challenges 9. An2retroviral Treatment of Adult HIV Infec2on2010 Recommenda2ons of the Interna2onal AIDS Society–USA Panel. JAMA. 2010;304(3):321-‐333. 10. Guidelines for the Use of An2retroviral Agents in HIV-‐1-‐Infected Adults and Adolescents. hrp://aidsinfo.nih.gov/guidelines (Accessed July 2012) 11. Maisels et al AIDS Pa2ent Care STDS 2001:15(4):185-‐91

Resistance: risks and reality of the new approaches 12. Grant, R.M. et al. Preexposure chemoprophylaxis for HIV preven2on in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-‐99. Epub 2010 Nov 23. 13. Supervie, V. et al. HIV, transmired drug resistance, and the paradox of preexposure prophylaxis. Proc Natl Acad Sci U S A. 2010 Jul 6;107(27):12381-‐6. Epub 2010 Jun 28. 14. van de Vijver, D. Pre-‐exposure prophylaxis (PrEP) will have a limited impact on the prevalence of HIV-‐1 drug resistance in sub-‐Saharan Africa: comparison of mathema2cal models [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: FRLBX04 15. Cambiano, V. et al. Pre-‐exposure prophylaxis: impact on resistance of targe2ng sero-‐discordant couples [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: LBPE26 16. Liegler, T. et al . 97LB. Drug Resistance and Minor Drug Resistant Variants in iPrEx [Abstract]. hrp://www.iprexnews.com/pdfswha2snew/abstracts.pdf/abstract97.pdf (Accessed July 2012)

Resistance: HIV subtype C 17. Sunpath, H. et al. High rate of K65R for ART naïve pa2ents with subtype C HIV infec2on failing a TDF-‐containing first-‐line regimen in South Africa [Journal Ar2cle]. AIDS. 2012 Jun 27. [Epub ahead of print] 18. Recordon-‐Pinson, P. et al. K65R in Subtype C HIV-‐1 Isolates from Pa2ents Failing on a First-‐Line Regimen Including d4T or AZT: Comparison of Sanger and UDP Sequencing Data. PLoS One. 2012; 7(5): e36549. Published online 2012 May 16. doi: 10.1371/journal.pone.0036549 19. Kosai, M.J. et al. Prevalence of low-‐level HIV-‐1 variants with reverse transcriptase muta2on K65R and the effect of an2retroviral drug exposure on variant levels. An2vir 2011;16(6):925-‐9

References (con,nued) Resistance: A South African experiment 20. Van Zyl, G. Changing parerns of NRTI and PI resistance muta2ons between 2006 and 2011 in >1,200 ART-‐experienced South African pa2ents: associa2on with the introduc2on of tenofovir (TDF) and abacavir (ABC) and with the cumula2ve effects of LPV/r therapy [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUAB0303

Late Presenters: What should we do? 20. An2nori, A. et al. Late presenta2on of HIV infec2on: a consensus defini2on. HIV Med. 2011 Jan;12(1):61-‐4. DOI: 10.1111/j.1468-‐1293.2010.00857.x. 21. D'Arminio Monforte, A. et al. HIV-‐Infected Late Presenter Pa2ents. AIDS Res Treat. 2012;2012:902679. Epub 2011 Nov 29.

Late Presenters: Economic Challenges 22. Fleishman, J.A. et al. The economic burden of late entry into medical care for pa2ents with HIV infec2on. Med Care. 2010 Dec;48(12):1071-‐9. 23. Jevtović, D. et al. The Prognosis of Late Presenters in the Era of Highly Ac2ve An2retroviral Therapy in Serbia. Open Virol J. 2009; 3: 84–88. 24. Mascolini, M. Three Biggest HIV Problems in the United States: Late Tes2ng, Late Care, Early dropout. hrp://www.centerforaids.org/pdfs/RITAsummer2011.pdf (Accessed July 2012)

Late Presenters: Tolerability Challenges 25. Rockstroh, J. et al. Management of late-‐presen2ng pa2ents with HIV infec2on. An2v Ther 2010;15(Suppl1):25-‐30

Late Presenters: Therapeu,c Challenges 26. Rockstroh, J. et al. Management of late-‐presen2ng pa2ents with HIV infec2on. An2v Ther 2010;15(Suppl1):25-‐30 27. Or2z, R. et al. Efficacy and safety of once-‐daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-‐naive HIV-‐1-‐infected pa2ents at week 48. AIDS. 2008 Jul 31;22(12):1389-‐97. 28. Molina, J.M. et al. Once-‐daily atazanavir/ritonavir versus twice-‐daily lopinavir/ritonavir, each in combina2on with tenofovir and emtricitabine, for management of an2retroviral-‐naive HIV-‐1-‐infected pa2ents: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-‐55. 29. von Wyl, V. et al. Emergence of HIV-‐1 drug resistance in previously untreated pa2ents ini2a2ng combina2on an2retroviral treatment: a comparison of different regimen types. Arch Intern Med. 2007 Sep 10;167(16):1782-‐90. 30. An2nori, A. et al. Report of a European Working Group on late presenta2on with HIV infec2on: recommenda2ons and regional varia2on. An2vir Ther. 2010;15 Suppl 1:31-‐5.

References (con,nued) Injec,on drug users 31. Hellard, M. et al. Hepa22s C treatment for injec2on drug users: a review of the available evidence. Clin Infect Dis 2009;49(4):561-‐73 32. hrp://hepa22scnewdrugs.blogspot.ca/2012/07/als-‐2200-‐vertex-‐announces-‐posi2ve.html (Accessed July 2012) 33. Sulkowski, M. et al. POTENT VIRAL SUPPRESSION WITH ALL-‐ORAL COMBINATION OF DACLATASVIR (NS5A INHIBITOR) AND GS-‐7977 (NS5B INHIBITOR), +/-‐RIBAVIRIN, IN TREATMENT-‐NAÏVE PATIENTS WITH CHRONIC HCV GT1, 2, or 3 [Abstract]. EASL 2012; April 18-‐22, 2012; Barcelona, Spain: 1422 34. Soriano, V. et al. THE EFFICACY AND SAFETY OF THE INTERFERON-‐FREE COMBINATION OF BI201335 AND BI207127 IN GENOTYPE 1 HCV PATIENTS WITH CIRRHOSIS -‐ INTERIM ANALYSIS FROM SOUND-‐C2 [Abstract]. EASL 2012; April 18-‐22, 2012; Barcelona, Spain: 1420 35. Lima, VD. et al. AIDS 2012; July 22-‐27, 2012; Washington, DC: – 26:00

The supervised injec,on sites approach: Vancouver's INSITE Model 35. Chris2an, G. et al. Overdose deaths and Vancouver's supervised injec2on facility. Lancet 2012; doi:10.1016/S0140-‐6736(12)60054-‐3 36. Andresen MA, Boyd N. A cost-‐benefit and cost-‐effec2veness analysis of Vancouver's supervised injec2on facility. Int J Drug Policy. 2010 Jan;21(1):70-‐6. Epub 2009 May 6.

Concentra,on of the epidemic 37. Booth, R. et al. Drug injectors, the "legal" system, and HIV in Odessa, Ukraine [Abstract]. IAS 2011; July 17-‐22, 2012; Rome, Italy: MOPE398 38. Saliuk, T. et al. The future shape of the HIV epidemic in Ukraine: HIV es2mates and model projec2ons [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: MOPE142 39. Eluwa et al. A profile on HIV and intravenous drug users in Nigeria: should we be alarmed? [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: MOPE232 40. Dunkle, K. et al. Consensual male-‐male sex, male-‐male sexual assault and prevalent HIV infec2on in South Africa: results from a popula2on-‐based household survey [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: MOPE300 41. Paul, J.P. et al HIV status unknown African American, Asian/PI and La2no men who have sex with men (MSM): self-‐perceived HIV status and sexual behavior [Abstract]. AIDS 2012; July 22-‐27, 2012; Washington, DC: TUPE488

References (con,nued) The new home screening tests: controversies or benefits? 42. hrp://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm310436.htm (Accessed July 2012)

Health & Medicine

Vulnerable populations: Too little, too late or new opportunities?