Feedback from 15th IAS Conference 13-18 August 2006 Simon Collins HIV i-Base

1. Feedback from 15th IAS Conference 13-18 August 2006 Simon Collins HIV i-Base

2. Feedback from 15th IAS Conference Treatment access New drugs New strategies: boosted-PI monotherapy Other issues

3. Feedback from 15th IAS Conference Treatment access • many smaller studies including long-term data • working in all countries, access for women and children, TB coinfection, late diagnosis, adherence, side effects • funding - now 1.6 million on treatment, but dependent on funding increasing every year, if this is to expand

4. North Africa and the Middle East Europe and Central Asia East, South and South-East Asia Latin America and the Caribbean Sub-Saharan Africa Number of people on antiretroviral therapy in low- and middle-income countries, 2002‒2005 1400 1200 1000 People receiving therapy (thousands) 800 600 400 200 0 End 2002 Mid- 2003 End 2003 Mid- 2004 End 2004 Mid- 2005 End 2005 Piot WESS0102 2006 Report on the global AIDS epidemic (UNAIDS, 2006)

5. Scale up of treatment in the Elizabeth Glaser Pediatric AIDS Foundation “Project HEART” Initiating Care and ARV Treatment for over 68,000 people in 28 months at 95 sites in four African countries Côte d’Ivoire: 57 sites South Africa: 3 sites Marlink THAB0201

6. Mozambique Uganda Nigeria Malawi Zimbabwe Zambia Central African Republic Botswana Kenya Côte d'Ivoire Namibia Rwanda United Republic of Tanzania Burundi South Africa 10% 20% 30% 40% 50% 60% 70% Percentage of adults on ART who are women Percentage of HIV-infected persons who are women Women's access to HIV treatment, June 2006 - Piot

7. “Refuting the Afro-pessimists” • Adherence to ART is better in African programmes than in North America • A meta-analysis of 27 studies in sub-Saharan African countries and 31 North American studies showed that adequate adherence was observed in 77% of patients in Africa and 55% of patients in North America. • It is important to ensure that these reassuring initial rates of adherence will be sustained over time. • Data from Senegal suggest that the involvement of communities may be the key to maintaining adherence in the long term.

8. Stephen Lewis: closing ceremony “... we are on the cusp of a huge financial crisis... and have been lulled into a damaging false security (we jumped from $300 million a year… in the late 1990's, to $8.3 billion in 2005. It sounds impressive. But we need $15 billion in 2006, and $18 billion in 2007, and $22 billion in 2008. This will take us to $30 billion in 2010 … the moment of universal access to treatment, prevention and care.” “We're billions and billions short of those targets. If these circumstances continue, universal access is doomed. The financial promises made at the G8 Summit in Gleneagles one year ago, are already unraveling. We will never accumulate the extra $25 billion for Africa by 2010 as was committed.” “PEPFAR has not yet announced its extension beyond 2008; when it does (as it surely will), the annual contribution, given the other demands on the US Treasury, will probably remain at $3 billion a year. That large amount was a very significant percentage of the total expenditure on AIDS back in 2003/2004. But as a percentage of what is needed for global AIDS programmes in 2008 - $22 billion - $3 billion seems pretty paltry from the world's superpower.”

9. Feedback from 15th IAS Conference New drugs • MK-0518 • maraviroc • etravirine • TNX-355 • atripla, T-1144, T-999, PL-100 etc

10. MK-0518 Merck’s integrase inhibitor: great promise • MK-0518 is a strand transfer inhibitor of HIV integrase (integrase is 3-step process and K-0518 block the final step, where the viral DNA is spliced into the CD4-cell DNA) • In treatment naïve patients with HIV RNA ≥ 5000 copies/ml and CD4 ≥ 100/mm3, MK-0518 studied at four dose levels for 24 weeks: • had potent antiretroviral activity • 85-95% with HIV RNA < 50 copies/mL • achieved viral suppression faster than EFV • was generally well tolerated Markowitz THLB0214

11. Protocol 004: Study Design Part I Integrase Monotherapy for 10 days Part II Combination Therapy 4 doses 0518 vs EFV, All plus TDF/FTC Part I: 40 Rx-naïve ptsrandomised to 100, 200, 400, or 600mg 0518 twice daily, or placebo. 8 patients in each arm Part II: 150 Rx-naïve pts randomised to 100, 200, 400, or 600mg 0518 twice daily, or efavirenz, all +TDF/FTCfor 48 weeks 30 new patients in each arm • HIV RNA  of 1.7 – 2.2 log10 copies/mL • Morales-Ramirez et al, EACS 2005 IAC 2006 Abs# THLB0214 *TDF = tenofovir

12. Protocol 004: Baseline Characteristics * With TFV/3TC ** = geometric mean

13. Markowitz THLB0214

14. Markowitz THLB0214

15. Common (≥5%) drug related side effects Additional AEs seen at ≥ 5% in efavirenz group: Nightmare (11%) Vomiting (8%) Malaise (8%) Fatigue (5%) Disturbance in attention (5%) Lethargy (5%) Anxiety (5%) * With TFV/3TC

16. Maraviroc • Double-blind placebo controlled study in 190 mixed/dual tropic patients • Randomised to optimised background regimen (OBT) including at least one sensitive drug, plus either maraviroc once-daily (n=63), vs maraviroc twice daily (n-61) or placebo (n-60). [1] • Over 90% patients were PI-experienced • 50-60% currently using T-20 • Baseline CD4 count <100 cells/mm3 • Baseline viral load > 5logs respectively • >95% patients had dual/mixed tropism.

17. Maraviroc Table 1: Virologic and immunologic responses at week 24 As no progression of HIV, questions importance of tropism test???

18. Etravirine (TMC-125) Phase II study in 199 treatment experienced patients with documented NNRTI resistance and 3 or more primary PI mutations. Randomised to TMC125 (400 mg or 800 mg bid) with an investigator selected background, or standard-of-care control regimen. Median baseline CD4 - 100 cells/mm3; viral load 4.7 log copies/mL Table 1: Results of etravirine (TMC-125) at 48-weeks 400mg 800mg control Mean VL change (log) -0.88 * -1.01 * -0.14 Mean CD4 change +58 +61 +13 VL failure 9% 9% 78% Med. duration of Rx (wks) 48 wks 48 wks 18 wks * P <0.05 compared to control

19. TNX-355 Table 1: Baseline characteristics and ITT responses to TNX-355 15mg/kg +OBR 10mg/kg+OBR placebo+OBR N 28 27 27 Age 47 44 46 % male/female 78/22 93/7 89/11 Baseline CD4 (%<200) 299 (26%) 223 (51%) 245 (43%) Baseline VL (%>5log) 4.8 (26%) 5.0 (57%) 4.8 (33%) Mean change in CD4+ +51 (p=0.016) +48 (p=0.031) +1 Mean VL change wk-48 -0.71 (p<0.010) -0.96 (p<0.001) -0.14 N (%) >/= 1.0 log 9 (32) 10 (37) 3 (11) N (%) >/= 0.5 log 11 (39) (p=0.029) 12 (44) (p=0.014) 3 (11) % <400 (%<50) c/mL 7 (4) 4 (0) 0 (0) Median TLVR (days) 253 (p=0.003) 230 (p=0.003) 0 Ref: Norris D, Morales J, Godofsky E et al. TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 Weeks. Late breaker abstract THLB0218.

20. 1996: d4T/3TC/IDV 10 pills, TID 1998: ZDV/3TC/EFZ 5 pills, BID 2002: ZDV/3TC/EFV 3 pills, BID 2004: TVD or EPZ /EFV 2 pills, QD 2006: ATRIPLA 1 pill, QD Treatment Simplification* - 1996 - 2006 * Selected regimens Montaner WEPL0101

21. Early data on long-release entry inhibitors - ‘2nd generation T-20’ Subcutaneous Dose Cynomolgus monkey Normalized to 3 mg/Kg TRI-1144 ENF TRI-999

22. Potent, specific and non-cytotoxic HIV-1 protease inhibitor Favorable cross-resistance profile: MDR HIV PPL-100, prodrug of PL-100, is an oral HIV drug in clinical trials Safety in animal models No observed adverse effect levels in rats and dogs equivalent to ≥ 10g per day in man Favorable cardiovascular safety pharmacology and genotoxicity results Inexpensive and easy to manufacture: 5 synthesis steps PPL-100 has a favorable formulation: capsules, water soluble and bioavailable, co-formulation with other anti-virals PPL-100 is IP protected through 2023 PL-100 and Its Prodrug, PPL-100

23. Feedback from 15th IAS Conference 3. New strategies: • Kaletra monotherapy • Fosamprenavir/r vs Lopinavir/r • tenofovir/FTC vs AZT/3TC

24. Kaletra monotherapy • Three randomised trials using different study designs came to similar conclusions: • “For the majority of patients who have never failed on a Protease Inhibitor containing regimen, including naïve patients, Kaletra (LPV/r) monotherapy may be an effective, virologically suppressive and well tolerated regimen characterised by a high genetic barrier and by very low incidences of viral resistance.”

25. No. at risk LPV/r Arm EFV Arm 92 67 48 43 36 31 Time from LPV/r monotherapy to 1st of 2 VL > 50 c/mLLPV/r maintenance versus corresponding EFV subjects Cameron THLB0201

26. No. at risk LPV/r Arm EFV Arm 92 83 63 43 36 31 Time from LPV/r monotherapy to 1st of 2 VL > 500 c/mL LPV/r maintenance versus corresponding EFV subjects Cameron THLB0201

27. Kaletra monotherapy • 3 posters including 2 from UK • Examples of individual cases: tolerability, adherence etc • • In developed countries: treatment naïve, reduction NOT treatment experienced, or individualised: • Higher viral load rebound, viral failure, resistance • • In access countries: as second-line therapy

28. Fosamprenavir/r vs lopinavir/r • Median baseline CD4 ~ 200 cells/mm3 (with 15-18% < 50 cells/mm3) and viral load 5.1 log copies/mL (with 50% over 100,000 copies/mL). Median age was 37 years; 78% were male; 58% were white/Caucasian; and 11% were CDC Class C. • Fosamprenavir/r vs lopinavir/r in treatment-naive patients: 48-week results • FPV/r LPV/r • N 434 444 • % VL <400 c/mL, (%) * 73% 71% • % VL <50 c/mL (%) 66% 65% • Median CD4 change c/mm3 (IQR) +176 (106-281) +191 (124-287) • Virological failure; n (%) 16 (4%) 24 (5%) • Drug-related Grade 2-4 AEs; n (%) 55 (13%) 46 (10%) • Discontinuations due to AEs; n (%) 53 (12%) 43 (10%) • (95% CI -3.26, 5.47) • very high adherence rates (calculated by percentage of returned pills) of >/= 98% for the protease inhibitors and 99.4% for abacavir/3TC.

29. TDF/FTC/EFV vs AZT/3TC/EFV • Baseline median age 37, 14% female, 59% white, median viral load 5.0 copies/mL, median CD4 237 cells/mm3 • ITT, n=509, (n=22) with baseline NNRTI mutations • Week 96 results • TDF+FTC arm (n=244) CBV arm (n=243) • HIV RNA<400 c/mL 76% 64% (p=0.004) • HIV RNA<50 c/mL 69% 63% (p=0.15) • CD4 cell incease 270 237 (p=0.036) • A/e discont. 5% 11% (p<0.001) • (most common: anemia, nausea, fatigue, vomiting, rash) • Renal safety profile was also similar (serum creatinine, Cockcroft-Gault GFR (p=0.05). • Weight increase 2.7kg 0.5kg (p<0.001) • DEXA, median limb fat 7.7 kg, n=144 5.5 kg, n=136 (p<0.001) • No patient developed the K65R mutation. • Significantly more patients on AZT/3TC developed M184V/I (9 vs 2, p=0.037).

30. Feedback from 15th IAS Conference Other issues • Prevention: circumcision, PrEP, ARV treatment, HSV treatment • European resistance data • UK studies: late diagnosis, use of STARHS, complementary medicine and ARV interactions, UAI behavioural 5 cities study • Global: TB, HCV coinfection, children

31. Feedback from 15th IAS Conference • Circumcision studies 3-4 oral presentations, 5+ posters • PrEP • European resistance - SPREAD - 1083 newly diagnosed individuals from 17 countries (20% recent infections <1 year): 44% gay/bi, 42% heterosexual. 9% IVDU; 34% outside Western Europe. From 13 sub-types, ~9% had IAS-defined resistance - slightly higher in recent infections vs undefined infections. RTI -5-5% (30% >1 mutation); PI - 3%, NNRTI 2.6%; <1% dual-class resistance. TUAB 0101.

32. Feedback from 15th IAS Conference • Use of complementary alternative medicine - 10% - Cross sectional multiple choice questionnaire of ~250 patients: 154 (60%) using herbal remedies, 88 (34%) using physical treatment and 67 (25%) using both. 25 pts (10%) were asked to stop CAM because of potential interaction with ARVs, and slightly higher proportion (n=30) asked to be cautious. Only 50% had discussed CAM with their HIV doctor. - MOPE 0219 • UK late diagnosis and mortality - MOPE 0067, MOPE0296; • STARHS use - Brighton - 80/665 diagnoses identified as recent infections increasing from 20% in 1996 to 50% in 2004 - MOPE 0504 • UK UAI and behaviour of gay men in 5 UK cities ~ 4380 questionnaires and 3660 swabs. HIV prevalence - 12-14% in London and Brighton, 9% in Manchester, 3% in Glasgow and 5% in Edinburgh. 41% (range 33/48%, Manchester/Glasgow) HIV+ men were undiagnosed, and 50% (n=70) reported most recent result as HIV-negative (therefore believing they were HIV-negative). MOPE 0517 A second behaviour study reported higher rates of serosorting in heterosexual African HIV+ individuals - WEPDC05

33. The overlapping challenges of two epidemics: HIV and TB • TB is a leading cause of death in Africa and, in some settings, the leading cause of death among people with HIV • First 3-6 months after starting HAART may even have increase in TB followed by decline • Early diagnosis is required to further decrease this risk

34. High prevalence and mortality from extensively-drug resistant (XDR) TB in TB/HIV co-infected patients in rural South Africa Survival from time of Sputum Collection Gandhi THLB0210

35. <20% 20-40% 40-60% 11% 60-80% 0% >80% 25.5% 20% 9% 17% 6% 15% 87% 6% 16% 95% 12% 34% 79% 2% 83% 6% 82% 68% 81% 80% 16% 22% 5% 71% 29% 29% 82% 20% 1% 16% 69% 86% 32% 7% 49% 11% 66% <1% 15% 49% 59% 68% 5% 61% 14% 57% 3% 5% 8% 16% 2% 16% Hepatitis C/HIV co-infection in IDUs is a major issue in Europe IDU as % of all HIV/AIDS cases with known transmission routeNOTE: % of AIDS cases in countries not reporting HIV Sources: EuroHIV; national reports; Kruk WEAX0101

36. Children need to be on the global agenda • Children make up – • 14% of new global infections, • 18% of HIV related deaths • 5.6% of persons living with HIV KLINE WESY0104 UNICEF estimates that 660,000 children urgently require antiretroviral treatment, most of them in sub-Saharan Africa “Care of the infected and uninfected child must include treatment of their mothers and families” Ruth Nduati

37. 18 mo 12 mo Before 2 mo Successful clinical outcomes in children Puthanakit, WESY0102

38. “Open your purses, we need more nurses”, • The issue of nursing staff needs was a common theme through many presentations in Track B. • In sub Saharan Africa alone, more than 600,000 nurses are needed to deliver HIV care and other services • Nurses staff need to be supported and appropriately utilised “If I’d wanted to be an undertaker, I wouldn’t have trained as a nurse” South African nurse, quoted by Alta Van Dyke

39. Thanks • Slides: • Rapporteur summary of Track B: James McIntyre • New drugs from Late Breaker abstracts online • http://www.ias.se • (Follow link to conference, then conference programme, then related session link)