Optimism or pessimism in microbicides research?

Anatoli Kamali MRC/UVRI Uganda Research Unit on AIDS

Introduction

• Microbicides: products designed for topical application (vaginal or rectal) to reduce HIV/STIs • • Women at higher risk of HIV infection – transmission dynamics – inability to negotiate safer sex e.g. condoms – condoms infrequently used among couples – desire to conceive Microbicides viewed as a Female controlled

method

HIV Prevalence with 95% CIs, by Gender (20-24 yr olds) 1990 1992 1994 1996 1998 2000 Survey Year 2002 Prevalence(Male) 95% CIs (Male) 2004 2006 Prevalence(Female) 95% CIs (Female) 2008

“Female-controlled” concept

• Advantages: – self insertion before sex – could be left in place after sex – effective for multiple intercourses – men “unaware” and no consent required – potentially prevent other STIs – increase sexual pleasure

APPLICATION INSTRUCTIONS X X

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Role of men in microbicides

• Microbicide gel also increase sexual pleasure in men – in communities where “dry sex” is not popular • A role in stable relationships e.g discordant couples

Acceptability studies

Safety and acceptability studies

Summary of findings

• Carraguard: safe and acceptable among Thai women up to x4/week with or without sex warranting phase III efficacy trial • PRO 2000 (0.5% and 2%): safe and well tolerated, justifying large-scale effectiveness trials

Safety and acceptability of penile applications

• BufferGel and PRO 2000 Gel daily (7 days) application to the penis – safe and well tolerated among healthy low risk men and HIV-positive men (Stephens et al. JAIDS: 2003;33:476-83) • Acceptable safety profiles

• Encouraging safety and acceptability data both in women and men justifying large scale efficacy trials in various populations • Optimistic that efficacy trials would show protection

Three generations of Microbicides

• • •

1 st

generation: Nonoxynol-9 and Savvy – Surfactants disrupt microbial cell membranes – Vaginal defence enhancers (BufferGel)- maintain or boost the acidity of the vagina

2 nd

generation: (PRO2000, Carraguard, CS) – entry inhibitors block cellular receptors and prevent HIV from attaching to and infecting target cells

3 rd

generation: ARV-based (tenofovir gel, dapivirine, and UC-781) – prevent HIV from replicating once inside a cell

First generation products

• No effect on HIV transmission • Nonoxynol-9: Evidence of toxicity that enhanced HIV transmission particularly among frequent users of gel ( Lancet 2002; 360: 971–77)

Second generation products

• Cellulose sulphate: A high rate of HIV acquisition - 25cs/16p 1.61 [0.86-3.01] (N Engl J Med 2008; 359: 463-72) • Carraguard: No effect on HIV transmission 134c/151p 0.89 [0.7-1.13] 372: 1977–87 Lancet 2008;

Summary

• • • No effect on HIV/STI transmission Evidence of toxicity and increased risk of transmission with some products “Worrying findings” to scientists, advocacy groups, policy makers and funding

HPTN 035 Phase II/IIB trial

• 4 arm trial in 4 African countries and USA •

PRO 2000 gel

, buffer gel, placebo gel and no gel arm

HPTN 035 results

• • Presented at CROI 2009; AIDS 2011; 25:957-66 HIV incidence rates: – PRO2000: 2.7 [1.9-3.7]; – Buffer gel: 4.1 [3.1-5.4] – Placebo: 3.9 [2.9-5.1]; No gel: 4.0 [3.0-5.3] • • PRO2000 gel:

HR 0.70

[0.46-1.08], p=0.10

Buffer gel HR: 1.10 [0.75-1.62], p=0.63

HPTN 035 PRO 2000 trial results

• • • “The results on PRO2000 are a

ray of hope for women“

“

A glimmer of hope

for a possible proof of concept” “MDP 301 should help refine estimate of how effective PRO2000 actually is, x 3 number of women, will yield an even more precise estimate of effectiveness”

MDP 301 trial

•

HIV-negative women

A phase 3 trial (2005 2008), enrolled 9385 at 13 clinics, at 6 research centres in four African countries under the MDP

MDP 301 trial

• Efficacy and safety of 0.5% and 2% PRO 2000 gels •

Feb 2008, IDMSC stopped the 2% gel arm (futility)

• Recommended 0.5% gel arm to continue

0.5% PRO 2000 gel

• Incidence 4.5 [3.8-5.4]; placebo 4.3 [3.6 5.2],

HR 1.05

(0.82-1.34)

Why lack of efficacy of PRO 2000 gel?

• • • Well demonstrated anti-HIV activity in preclinical studies Post coital diminished anti-viral activity (PD) and lower concentrations (PK) of PRO 2000 gel (Keller PLoS ONE 2010;5:e8781) – Semen, cervico-vaginal secretions and sex activity Lower concentration of products in vagina and mucosa than predicted

Next generation microbicides

• ARV-based microbicides offer optimism • • • 1% Tenofovir gel Dapivirine gel and ring Maraviroc

1% Tenofovir gel acceptability

• • Kenneth et al, AIDS 2006; 20:543-51 – 2-week course of 1% tenofovir vaginal gel 2x daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV positive women Rosen et al. J Women’s Health 2008; 17: 383-92 – Tenofovir gel among women in a Phase I Trial was well acceptable to almost all users

CAPRISA-004

• • 1% tenofovir gel – coitally dependent regimen (BAT24)

HIV: overall 39% reduction (6-61%, p=0.017)

• HSV-2: 51% reduction (95% CI 22%-70%, p=0.003) •

“Proof of concept”, an exciting milestone and historic results!

CAPRISA 004 effectiveness by adherence

• • • • High adherers (>80% gel use): 54% lower, p=0.025

Intermediate (50-80% gel use): 38% lower, p= 0.34

Low (< 50% gel use): 28% lower, p=0.30

Need to achieve high Tenofovir vaginal concentrations

Post CAPRISA 004

• WHO/UNAIDS meeting – priority next steps – Additional safety studies e.g among young women – FACTS trial to confirm findings (same regimen) – Simplified dosing and less frequent HIV testing (MDP 302)

FACTS 001, South Africa

• Phase III testing 1% tenofovir gel, same regimen as CAPRISA 004 • Launched October 2011 and results expected 2014

MTN-003 (VOICE)

• • Safety and effectiveness among women Daily 1% Tenofovir gel, oral Tenofovir and Truvada once a day 

Oral tenofovir and gel safe but not effective against HIV transmission



Oral Truvada arms continues, late 2012



“Disappointing findings and a large blow to the HIV prevention field!”

Conflicting CAPRISA and VOICE results

• • • Same product 1% Tenofovir Different dosing regimen daily vs BAT24 Possible explanations, but no answers yet – Adherence levels – Drug levels in genital tract – Risk behaviours of trial participants – Will be available at end of VOICE trial

Other microbicide formulations

• Gel formulations been mainly evaluated as “coitally-dependent” • “Coitally –dissociated” formulations – offer sustained delivery (IVR, injectable, implants) – IVR most advanced of all

Why a ring?

• • • • Long-acting: monthly or longer – improve adherence, hence better effectiveness Easy to use, comfortable – Flexible ring, can be self-inserted – Rarely felt by women or their male partners – Little or no impact on sexual activity Suitable for developing world – low manufacturing cost – Good safety and acceptability data Potential for drug combinations

Rectal microbicides

• • • Anal sex is a risk factor for HIV infection in both men and women Rectal mucosa different from the vagina and more vulnerable to HIV – single cell layer thick; contains many more CD4 receptors; more alkaline pH which is less protective than the acidic vaginal pH Rectal tract has greater surface area

the Future ….

• • • • • Requires both vaginal and rectal products Research is required to find the right drug at the right and in the right place Require a lot of support from funding agencies ARV-based combination products Challenges: drug toxicity, resistance

Combination Microbicides

• • Advantages: – Potential increased efficacy – Potential synergy and need for less drug Possible disadvantages – Difficulties in co-formulation – Increased cost – Potential for toxicity and resistance

Combination Microbicides

• Various combinations in development – Dapivirine/Tenofovir ring – Dapivirine/Maraviroc gel, film and ring form

Conclusions

• Data supports that high gel and condom use – Gel: 96.2% Carraguard, 95.9% placebo – Condom: 64·1% in both groups at last sex – MDP 301, mean reported gel use was 89% and condom 55-57% • ? Consistent gel use in real world

Conclusions

• • • • More potent ARV-based products and new formulations Long term effects of IVR – could disturb the vaginal environment and increase HIV acquisition risk?

Need to keep major donors interested and political will Optimistic that a microbicide dream will be a reality and turn the HIV epidemic in women and men

Optimistic

• A dream to a reality of a safe, effective and affordable microbicide • “ All our dreams can come true, if we have the courage to pursue them ” • Together we can turn the HIV epidemic in women and men

Acknowledgements

• Funders: MRC (UK), DFID, other agencies • Allan Stone, Annalene Nel, Elizabeth Bukusi, Janneke van de Wijgert and Sheena McCormack