Prevention of HIV Infection Mark A Wainberg McGill University AIDS Centre Jewish General Hospital Montreal, Quebec, Canada

Palella F, et al. NEJM, Use of protease inhibitors Deaths Deaths per 100 Person-Years Therapy with a Protease Inhibitor (% of patient-days)

Patient Substitutions de codon associées à une pharmacorésistance Mutations - INTIMutations - INNTIMutations - IP 1 41L; 67N; 69N; 70R; 74V; 184V; 215F; 219Q 100I; 103N 10I; 36I; 54V; 63P; 71V; 73S; 82V; 90M 2 41L; 184V; 215Y103N, 179E 48V; 63P; 71V; 73S; 77I; 82A; 90M 3 Aucune103N 10I; 54V; 63P; 71V; 82T; 84V; 90M 4 184V; 215Y103N77I 5 184V108I20R, 77I 6 41L; 67N; 210W; 215YAucune63P; 71V; 73S; 90M 7 41L; 215Y101EAucune 8 41L; 215Y101EAucune Brenner, B. et coll., AIDS, 18(12), le 20 août 2004, p. 1653–1660. INTI : Inhibiteurs nucléosidiques de la transcriptase inverse INNTI : Inhibiteurs non nucléosidiques de la transcriptase inverse IP : Inhibiteurs de la protéase Exemples de transmission de virus multirésistants dans les cas d’une primo-infection par le VIH-1

C0160 N=9 103N C50 N=59 190A C99 N=33 103N C68 N=21 103R/108I /PI C42 N=6 103N/PI C105 N=7 103N Transmitted resistance to first generation NNRTIs, e.g. efavirenz, among treatment-naïve populations n=135

Transmitted NNRTI resistance rising in the post-HAART era

Global distribution of HIV-1 subtypes 1.3 million 4.8 million 2 million B 10% A 12% URF 4.2% AG 6.7% AE 3.1% G 5% D 3.6%

Rapid Selection of K65R Resistance in Subtype C Isolates

History of 23 Botswana Patients Treated with ddI/d4T plus 3TC or NVP No. Patients23 No. Patients failing15 No. Patients with K65R 7 No. Patients with L74V 0

Background -The Malawi ART program scale-up: >150,000 patients started on d4T/3TC/NVP -A substantial minority with have virologic failure and eventually clinical failure. -In failing patients resistance will be present -Few data from Africa on resistance patterns

Resistance Patterns% NNRTI mutations +/-184V containing virus + additional mutations TAM Containing Virus56% Tenofovir mutations (K65R or K70E)23% Tenofovir & TAM7% Q151M Complex19% Pan-Nucleoside Mutation Combinations Q151M Complex & Tenofovir mutations16% 69 insertion1% Pan-Nucleoside (Q151 & TDF associated mutations or 69 insertion) 17%

Fortunately, the WHO has now disrecommended the use of stavudine (d4T) and Triamune (d4T/3TC/NVP) in HIV therapy

But, it is possible that millions of people already harbour K65R and will now have limited treatment options. A recent study by Marconi et al (CROI, 2012) from South Africa suggests that this may be the case.

Should we have drug resistance concerns regarding the use of TDF/FTC in PreP, particularly in settings in which subtype C viruses are most prevalent?

HIV-1 Transmission Model Cohen et al, NEJM, 2011 Inoculum Mucosa Recipient Less fit, attenuated or stochastic event (R 0 <<1) Less fit virus (R 0 ~1) ~10 9 infection events >10 6 virions/ml plasma Time (days) Defective virus X (Most fit virus R 0 >>1)

Probability of HIV Transmission? ~1/1000 episodes for couples?? (Most recently Hughes et. al. JID) IS 1/1000 AN UNDERSESTIMATE?? -”exposed uninfected” partners -benefits of counseling - missing amplification factors

Amplified Transmission of HIV-1 Susceptibility Genital ulcers Inflammatory STDs Lack of Circumcision Cervical ectopy HLA Haplotype Cytokine profile Infectiousness Blood Viral Load Genital Tract Viral Load -Inflammatory STDs Viral clade ACUTE INFECTION

Transmission Virus Concentration in Extracellular Fluid or Plasma (Copies/ml) Time Post Exposure (days) Reservoir Virus dissemination Transit eclipse ? T0T0 Acute Phase Reactants Days -5 to-7 Immune Complexes Day 9 Onset cytokines apoptosis, Day 7 Free Antibody, Day 13 CD8 T Cell Responses CTL Escape Autologous Neutralizing Antibody Autologous Neutralizing Antibody Escape Acute HIV-1 Infection Cohen et al, NEJM, 2011

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms STDs Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

STDs Amplify HIV Transmission: Back to the Future (Cohen, JID, April) -Treatment of STDs has failed to reduce HIV acquisition -BUT risk has NOT gone away!!! -STDS CONTRIBUTE, LIKE IT OR NOT

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

Strategies for an HIV Vaccine HIV Infection and RNA set point No protection Infection prevented Protection through sterilizing immunity Protection against disease Reduced HV peak and “set point” initial infection “controlled” chronic infection with low set point HIV Transmission Antibodies Cell-Mediated Immunity

2F5, 4E10, CAP206-CH12 Membrane proximal 2G12 Carbohydrate CD4 binding site 1b12, VRC01, VRC02, VRC03, VRC-PG04, HJ16, CH13-CH18, CH30-CH32 V2,V3 Quaternary (conformational) PG9, PG16, CH01-CH04 gp41 three N-linked glycan epitope CH11 447, CH19

ART to Prevent Sexual Transmission of HIV -Post-exposure Prophylaxis (PEP)??? -Pre-exposure Prophylaxis (PrEP)???? -Treatment of the infected person???

CAPRISA 004: Topical Tenofovir for Women

The PrEP “Conundrum” Oral TVF-FTC (Truvada Combination) SUCCESS -iPREX: 42% prevention in MSM -TDF2: 63% protection with high risk -PIP: 73% protection in EU FAILURE -FEMPREP: Trial in women stopped -VOICE: Tenofovir in women stopped -VOICE: Tenofovir gel stopped (????) -VOICE: TVF-FTC oral ONGOING

Does PrEP WORK and HOW WELL?  Adherence  Tissue levels … Truvada PrEP APPROVED -MSM -Couples (??) -High RISK (???) INFRASTRUCTURE/LIMITS?

Four Prevention Opportunities YEARS Treatment Of HIV Reduced Infectivity INFECTED YEARS UNEXPOSED Behavioral, Structural Circumcision Condoms Cohen et al, JCI, 2008 Cohen IAS 2008 HOURS Vaccines ART PrEP Microbicides EXPOSED (precoital/coital) 72h Vaccines ART PEP EXPOSED (postcoital)

Treatment as Prevention “The Four Questions” 1)Do ART drugs prevent HIV transmission? 2)What do we tell infected people? 3)Can we reduce population HIV incidence? 4)Barriers to “Treatment as Prevention”?

Stable, healthy, serodiscordant couples, sexually active CD4 count: 350 to 550 cells/mm 3 Primary Transmission Endpoint Virally linked transmission events Primary Clinical Endpoint WHO stage 4 clinical events, pulmonary tuberculosis, severe bacterial infection and/or death HPTN 052 Study Design Immediate ART CD Delayed ART CD4 <250 Randomization

HPTN 052 Enrollment (Total Enrollment: 1763 couples) U.S. Brazil South Africa Botswana Kenya Thailand India Americas 278 Africa 954 Asia 531 Zimbabwe Malawi

Total HIV-1 Transmission Events: 39 HPTN 052: HIV-1 Transmission Linked Transmissions: 28 Unlinked or TBD Transmissions: 11 p < Immediate Arm: 1 Delayed Arm: 27 18/28 (64%) transmissions from infected participants with CD4 >350 cells/mm 3, and VL >50,000 copies/ml at transmission 23/28 (82%) transmissions in sub-Saharan Africa 18/28 (64%) transmissions from female to male partners

96% Results of the HPTN052 trial announced on 12 May 2011 show that if an HIV-positive person adheres to an effective antiretroviral therapy regimen, the risk of transmitting the virus to their uninfected sexual partner can be reduced by 96% UNAIDS 2011 AIDS at 30 SMARTER, FASTER, BETTER CAMPAIGN “Treatment for prevention is a game changer”. Michel Sidibe Executive Director of UNAIDS

HPTN 052: ADHERENCE MATTERS Immediate Arm Delayed Arm (not on ART) Delayed Arm (on ART) Months Proportion of participants with VL<400 at each visit

HPTN 052 Clinical Results  105 morbidity and mortality events (p<.01)  65 in delayed arm  40 in immediate arm  20 cases of extrapulmonary TB (p= )  17 in delayed arm  3 in immediate arm  23 deaths (NS)  13 in delayed arm  10 in immediate arm

HPTN 052: What’s Happened Next  All HIV infected subjects offered ART  Continued follow-up in HPTN index cases /1763 (96% retention) discordant couples (85% retention) -1561/1682 index cases are NOW on ART DURABILITY OF PREVENTION? DELAYED ART & CLINICAL OUTCOMES?

PEPFAR, WHO AND HPTN  ART for heterosexual discordant couples  Treat HIV before CD4 count falls below 350  Does ART prevent HIV transmission in… - MSM couples? -IDU transmission?

UNAIDS Strategy: Getting to Zero Vision and goals:Strategic directions: Zero new infections Revolutionize prevention Zero AIDS-related deaths Catalyze the next phase of treatment care and support Zero discrimination Advance human rights and gender equality for the HIV response

Thank you