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

1. Vulnerable populations:Too little, too late or new opportunity? Prof. Christine Katlama Mark Wainberg, PhD Réjean Thomas, MD Prof. Gilles Pialoux

2. New molecules • Cobicistat • A new pharmaco-enhancer or booster alternative to ritonavir • ATZ/r vs. ATZ/cobicistat1 • Proven virological non-inferiority • Incidence of most common adverse events (AEs) similar between arms • Discontinuation rates due to AEs low and similar between arms • Grade 3/4 hyperbilirubinemia, increase in serum creatinine, and decrease in estimated glomerular filtration rate (eGFR) significantly greater with cobicistat vs. ritonavir, but this difference did not lead to higher discontinuation rates due to bilirubin-related or renal AEs

3. Therapeutic management threshold Opportunities and challenges • CD4 > 350 and > 5009,10 • “20% of patients treated at the L’Actuel medical clinic have CD4 > 500” (R. Thomas) • The new therapeutic approaches are simpler • Still, it’s not rare that patients refuse treatment • Up to 57% of patients refuse a treatment suggested by their doctor11 • 11% of patients do not even begin treatment even if they have agreed to it11

4. Resistance: risks and reality of the new approaches • Truvada for pre-exposure prophylaxis (iPrEx)12 • Potential risk of transmission of resistances13 • Mathematical models predict the appearance of resistance: • <4% potential resistance associated with this approach (PrEP)14 • 50-63% associated with antiretroviral 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

5. Resistance: HIV subtype C • High rates of K65R in patients naive to HIV subtype C after 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 mutation • Potential reasons: • Faster selection of these mutations in vivo, longer duration in treatment failure, or transmission of resistant virus • Potential role of d4T as a vector of this phenomenon via transmission of resistant viruses18 • 35.7% of K65R in patients with subtype C (vs. 2.2% for type B, and 3.7% for non-B/C)19

6. Resistance: A South African experiment • Risks associated with the introduction 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 combination (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 patients had resistance to LPV/r • 4% (n=17) showed cross-resistance to DRV/r

7. Late Presenters: What should we do? • Who are these patients? • CD4 <35021 or an HIV-defining illness regardless of the CD4 • They represent up to 59% of patients in some cohorts22 • Often do not perceive themselves to be at risk

8. Late Presenters: Economic Challenges • The costs associated with their treatment are higher even though they die faster22 • These patients represent 43.1% of new patients • The cost associated with their treatment is between $27,275 and $ 61,615 higher than that of patients who are treated early • Even after 7 or 8 years of care, the difference in the cost of treatment between these patients and those who come early remains substantial • It's harder to achieve an undetectable viral load in these patients23 • After 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 identification and management of these patients should be a priority24 • They represent one of the three most important problems associated with HIV in the United States24

9. Late Presenters:Tolerability Challenges • Such patients 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 vomiting 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 patients • 9% in Germany • 7.6% to NRTIs • 2.5% to PIs and 2.6% to NNRTIs

10. Late Presenters:Therapeutic Challenges • Therapeutic 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 • Options that offer higher resistance thresholds • A drug with a high genetic barrier is an important inclusion in the ART regimen of these patients28 • Boosted PIs are the preferred regimen vs. NNRTIs in this population28 • Consider pretreatment genotyping to determine the appropriate strategies if a rapid test result is possible30

11. Injection drug users Patient management: • Experiment with a hepatitis C31 treatment with interferon • Results of the meta-analysis: • Response rate of 54.3% among IDUs • Patients with acute hepatitis: the response rates are 68.5% for IDUs and 81.5% among non-IDUs • New options without interferon • ALS 2200: Viral load reduction of 4.54 log10 in patients 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 effective than efavirenz-based HAART among IDUs35 • Review the treatment model for hepatitis based on the HIV model • Comprehensive care

12. The supervised injection sites approach Vancouver's INSITE Model • Lower overdose rates35 • 35% reduction, 500m around the site vs. 9% elsewhere in the city • Reduced risk of HIV and hepatitis36 • Prevention of 35 HIV cases/year • Prevention of 3 deaths/year • Centralized venue for user/patient care • Effective in terms of cost-benefit

13. Concentration of the epidemic • Countries of the former USSR37,38 • Ukraine: nearly 1.6% of the population aged 15-49 is HIV positive (n=440,000) • Substance abuse is an important vector of transmission in those countries • Heterosexual transmission of HIV remains a critical issue especially among normally low-risk populations38 • Substance abuse is criminalized in those countries37 • Confiscation of syringes by police • Police arrests for possession of syringes • IDUs are tortured by police • Africa and specific populations • IDUs: yes even there, Nigerian Situation39 • MSM and HIV in Africa: underestimation of a hidden reality40,41

14. A new model of care:from the clinic to the street • Sexual Health Centre • Comprehensive approach: • HIV, hepatitis, sexual health, HPV, addiction • Post-exposure prophylaxis • Point of service on the street: L’Actuel sur rue • Simple and quick screening • Importance of clinical follow-up

15. The new home screening tests: controversies or benefits? • Approval of an oral test in the USA42 • Sensitivity: 92% • For 1 person in 12, the test does not detect the HIV positive status • Controversy • Screening at home • Lack of support and monitoring in the case of a positive test • Encourages testing • It is important to inform the public that treatments are now simpler and more effective

16. Conclusion • Challenges • Eliminating the context of criminalization of HIV and substance abuse • The stigma associated with HIV • Growing educational needs because of the new treatments • Reaching new clienteles • IDUs • Late presenters • Treatment as prevention, both for oneself and for others • Dangers • Negative impacts on prevention programs by sending a too positive message, HIV/AIDS is not cured or settled, and hasn't disappeared • Prevention remains necessary

17. References New molecules Gallant J et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: TUAB0103. Integrase inhibitors 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-positive subjects [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: TUPE028 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-positive subjects: week 48 results. AIDS 2012; July 22-27, 2012; Washington, DC: TUPE043 Integrase inhibitors (resistance) 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 Raffi, F. et al. Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral‑naive adults: 48 week results from SPRING-2 (ING113086) [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: THLBB04 Karmon, S. et al. Acquisition of transmitted HIV-1 integrase drug resistance mutations in a New York City cohort [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: TUPE264 Blanco, J.L. et al. HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications. J Infect Dis. 2011 May 1;203(9):1204-14. Review. Mesplède, T. et al. Resistance to HIV integrase inhibitors. Curr Opin HIV AIDS 2012, 7:000–000. DOI:10.1097/COH.0b013e328356db89

18. References (continued) Therapeutic management threshold – Opportunities and challenges • Antiretroviral Treatment of Adult HIV Infection2010 Recommendations of the International AIDS Society–USA Panel. JAMA. 2010;304(3):321-333. • Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. http://aidsinfo.nih.gov/guidelines (Accessed July 2012) • Maisels et al AIDS Patient Care STDS 2001:15(4):185-91 Resistance: risks and reality of the new approaches • Grant, R.M. et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010 Dec 30;363(27):2587-99. Epub 2010 Nov 23. • Supervie, V. et al. HIV, transmitted 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. • 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 mathematical models [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: FRLBX04 • Cambiano, V. et al. Pre-exposure prophylaxis: impact on resistance of targeting sero-discordant couples [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: LBPE26 • Liegler, T. et al . 97LB. Drug Resistance and Minor Drug Resistant Variants in iPrEx [Abstract]. http://www.iprexnews.com/pdfswhatisnew/abstracts.pdf/abstract97.pdf (Accessed July 2012) Resistance: HIV subtype C • Sunpath, H. et al. High rate of K65R for ART naïve patients with subtype C HIV infection failing a TDF-containing first-line regimen in South Africa [Journal Article]. AIDS. 2012 Jun 27. [Epub ahead of print] • Recordon-Pinson, P. et al. K65R in Subtype C HIV-1 Isolates from Patients 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 • Kosai, M.J. et al. Prevalence of low-level HIV-1 variants with reverse transcriptase mutation K65R and the effect of antiretroviral drug exposure on variant levels. Antivir 2011;16(6):925-9

19. References (continued) Resistance: A South African experiment • Van Zyl, G. Changing patterns of NRTI and PI resistance mutations between 2006 and 2011 in >1,200 ART-experienced South African patients: association with the introduction of tenofovir (TDF) and abacavir (ABC) and with the cumulative effects of LPV/r therapy[Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: TUAB0303 Late Presenters: What should we do? • Antinori, A. et al. Late presentation of HIV infection: a consensus definition. HIV Med. 2011 Jan;12(1):61-4. DOI: 10.1111/j.1468-1293.2010.00857.x. • D'Arminio Monforte, A. et al. HIV-Infected Late Presenter Patients. AIDS Res Treat. 2012;2012:902679. Epub 2011 Nov 29. Late Presenters: Economic Challenges • Fleishman, J.A. et al. The economic burden of late entry into medical care for patients with HIV infection. Med Care. 2010 Dec;48(12):1071-9. • Jevtović, D. et al. The Prognosis of Late Presenters in the Era of Highly Active Antiretroviral Therapy in Serbia. Open Virol J. 2009; 3: 84–88. • Mascolini, M. Three Biggest HIV Problems in the United States: Late Testing, Late Care, Early dropout. http://www.centerforaids.org/pdfs/RITAsummer2011.pdf (Accessed July 2012) Late Presenters: Tolerability Challenges • Rockstroh, J. et al. Management of late-presenting patients with HIV infection. Antiv Ther 2010;15(Suppl1):25-30 Late Presenters: Therapeutic Challenges • Rockstroh, J. et al. Management of late-presenting patients with HIV infection. Antiv Ther 2010;15(Suppl1):25-30 • Ortiz, R. et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008 Jul 31;22(12):1389-97. • Molina, J.M. et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55. • von Wyl, V. et al. Emergence of HIV-1 drug resistance in previously untreated patients initiating combination antiretroviral treatment: a comparison of different regimen types. Arch Intern Med. 2007 Sep 10;167(16):1782-90. • Antinori,  A. et al. Report of a European Working Group on late presentation with HIV infection: recommendations and regional variation. Antivir Ther. 2010;15 Suppl 1:31-5.

20. References (continued) Injection drug users • Hellard, M. et al. Hepatitis C treatment for injection drug users: a review of the available evidence. Clin Infect Dis 2009;49(4):561-73 • http://hepatitiscnewdrugs.blogspot.ca/2012/07/als-2200-vertex-announces-positive.html (Accessed July 2012) • 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 • 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 • Lima, VD. et al. AIDS 2012; July 22-27, 2012; Washington, DC: – 26:00 The supervised injection sites approach: Vancouver's INSITE Model • Christian, G. et al. Overdose deaths and Vancouver's supervised injection facility. Lancet 2012; doi:10.1016/S0140-6736(12)60054-3 • Andresen MA, Boyd N. A cost-benefit and cost-effectiveness analysis of Vancouver's supervised injection facility. Int J Drug Policy. 2010 Jan;21(1):70-6. Epub 2009 May 6. Concentration of the epidemic • Booth, R. et al. Drug injectors, the "legal" system, and HIV in Odessa, Ukraine [Abstract]. IAS 2011; July 17-22, 2012; Rome, Italy: MOPE398 • Saliuk, T. et al. The future shape of the HIV epidemic in Ukraine: HIV estimates and model projections [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: MOPE142 • 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 • Dunkle, K. et al. Consensual male-male sex, male-male sexual assault and prevalent HIV infection in South Africa: results from a population-based household survey [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: MOPE300 • Paul, J.P. et al HIV status unknown African American, Asian/PI and Latino men who have sex with men (MSM): self-perceived HIV status and sexual behavior [Abstract]. AIDS 2012; July 22-27, 2012; Washington, DC: TUPE488

21. References (continued) The new home screening tests: controversies or benefits? • http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/ucm310436.htm (Accessed July 2012)