ARV-based Microbicides and Resistance

Jeanne Marrazzo, M.D., M.P.H.University of Washington

John Mellors, M.D.University of Pittsburgh

Who we are? Jeanne Marrazzo, MD, MPH

Associate Professor of Infectious Diseases, University of Washington

Medical Director, STD/HIV Prevention Training Center Research focus on vaginal health, vaginitis, STI

diagnosis and prevention MTN-003 (VOICE) Study Co-chair

John Mellors, MD Chief of Infectious Diseases,University of Pittsburgh Oversees HIV-AIDS clinical research and primary care Research focus on ARV drug resistance MTN Virology Core Director

About the MTN

Funded by the U.S. National Institute of Allergy and Infectious Diseases until 2013

Co-funded by the National Institute of Mental Health and the National Institute of Child Health and Development

Based at the University of Pittsburgh and Magee-Womens Research Institute

18 clinical research sites in 7 countries

The MTN Mission

To reduce the sexual transmission of HIV through the evaluation of products applied topically to mucosal surfaces or administered orally

Presentation Overview

Key concepts: ARV and resistance PrEP Resistance: A one-act play ARV-based microbicides Oral PrEP Is resistance a risk? How can we reduce

any potential risk? Questions and open discussion

Key Concepts: HIV Life Cycle

1. Binding – HIV binds to T-cell via CD4 receptor.2. Fusion – HIV fuses with cell, dumps contents.3. Reverse Transcription – HIV genetic code (RNA)

changed into DNA by reverse transcriptase enzyme.

4. Integration – HIV DNA is inserted into infected cell's DNA by integrase enzyme.

5. Transcription – HIV DNA is transcribed (made into) HIV RNA

6. Translation - HIV RNA is translated into proteins7. Assembly and Release – Components of new

virus particles assemble and leave the cell.

HIV Life Cycle

From IAVI: Vaccine Blueprint 2006

1. Binding2. Fusion3. Reverse

Transcription4. Integration5. Transcription6. Translation7. Assembly

and Release

Key Concepts: ARVs

ARVs are drugs to treat HIV - designed to interfere with virus’s ability to replicate

They are best used in combination, i.e., anti-retroviral therapy (ART)

Different ARVs target different steps in the HIV life cycle

Generally, ARVs are safe and effective

Key Questions

What is resistance?

How does it happen?

Are you concerned about it?

Why are you concerned?

Key Concepts: Resistance

Definition: ability of a microorganism to survive and multiply in the presence of drugs that would normally kill or weaken it.

For HIV, drug resistance means the virus is no longer sensitive to one or more ARV

HIV is “resistant” to a medicine if it keeps reproducing even while a person is taking that medicine

Key Concepts: Resistance

How does it happen? The enzyme HIV needs to replicate is error

prone, resulting in mistakes (mutations) Some mutations make the virus not

sensitive to a drug The drug-resistant virus can now replicate

and take over other drug-sensitive virus

Resistant Virus: Like Hearty Weeds

What if you spray a garden with weed killer that works only on some weeds?

The other weeds will thrive, grow bigger and take over.

The bigger weeds will get bigger and bigger if the weed killer continues to be used -- the weed “killer” is like fertilizer for resistant weeds.

How do we suppress resistance?

Take away the “fertilizer” drug

Introduce a new drug that suppresses that HIV variant along with the others

Resistance is not all doom

Resistance is common in HIV-infected people being treated with ART Where ART is widely used, 5-20% of new HIV

infections can involve drug-resistant virus

Can be managed when detected early –suppressed by other ARV combinations

However, treatment options may be limited for some types of resistance.

Resistance: A Play in One Act

The cast (in order of appearance):

HIV “wild-type” virus: Audience volunteers

ARV #1: Lisa

HIV “mutant” (drug-resistant) virus: Sharon

ARV #2: Sean

Resistance: A Play in One Act

Scene 1 – InfectionScene 2 – Treatment with ARV #1

Virus suppressionScene 3 – ResistanceScene 4 – Treatment with ARV #2

Virus suppression

Curtain Call (Audience Applause)

What just happened and why?

The mutant virus was not sensitive to ARV#1, allowing it to replicate and start taking over the other virus sensitive to ARV#1.

When ARV#1 was taken away, the mutant virus no longer had an advantage and the wild-type virus could replicate, increase in number and become stronger than the mutant virus.

ARV#2 worked to suppress all virus, including the ARV#1 drug-resistant virus.

Will resistance be a problem?

We don’t know No scientific or clinical information is

available about the nature or incidence of resistance among those using ARV-based microbicides or oral ARVs for prevention

What do we know?

Resistant virus overtaken by sensitive virus within weeks of stopping ARVs Monkey studies: virus initially transmitted

is usually not drug-resistant, but resistance is more likely with time if the PrEP ARV is continued

What do we know? Mothers who took single dose nevirapine for

pMTCT and developed nevirapine resistance: no decrease in response to ARV treatment if initiated after 6 months (Mashi Study)

Adding single-dose Truvada to the standard method of preventing mother-to-child HIV transmission is a “new, effective and feasible approach to reducing maternal nevirapine resistance.”

The Lancet 2007; 370:1698-1705

What do we know? Resistant virus overtaken by sensitive virus

within weeks of stopping ARVs Monkey studies: virus initially transmitted

is usually not drug-resistant, but resistance is more likely with time if the PrEP ARV is continued

Resistance with PrEP?

Impact on future care for people infected while on PrEP is unknown

FHI trial in 936 HIV-negative women in Ghana (primarily), Cameroon and Nigeria with daily tenofovir: Tenofovir safe – no serious side effects 8 seroconversions occurred: 2 in the

active arm and 6 in placebo arm HIV infections too few to draw

conclusions on efficacy

Moving Forward

Resistance will be a risk associated with being in a study like VOICE

We have some information from different animal and human studies suggesting how resistance may develop in a participant

At the same time, much more research is needed because we know very little

The risks are not considered high enough to think that PrEP studies should not be done

Microbicides

What about ARV-based microbicides?

Evolution of the Microbicide Field

Focus on potent antiretrovirals rather than nonspecific inhibitors of HIV

Development of microbicides for use independent of the timing of sex: daily use sustained release delivery

Key Concepts: HIV Infection

Where different microbicides act

Shattock & Moore Nature Rev Microbiol 1:25-34, 2003

Many Microbicide CandidatesPre-Clinical Safety Efficacy

Entry Inhibitors Cyanovirin

BMS806

Plant lectins

New Polyanions

VivaGel

CAP

Polystyrene sulfate

Pro2000

Carraguard

Buffergel

ARV - NRTI Tenofovir Tenofovir

ARV - NNRTI DABO

MIV-150

UC-781

TMC-120

Membrane active SLS

Unclassified Bacteria Praneem

Combination PC-815

Truvada

NRTI/NNRTI

NRTI/P

NNRTI/P

Tenofovir Gel

Active ingredient is tenofovir, an ARV Oral tenofovir has good safety profile Gel has specific action against HIV Low levels of drug in the blood Low frequency of side effects Farthest along in clinical testing of ARV-

based microbicides

Tenofovir Gel: 8 Clinical Trials

HPTN 050 – Phase I safety HPTN 059 – Phase II expanded

safety/acceptability Male tolerance Tissue PK CAPRISA 004 – Phase IIb MTN-002 – Phase I PK (pregnant women) MTN-001- Phase II (oral tenofovir and gel) VOICE – Phase IIb

Tenofovir Gel - HPTN 059

Phase II study assessing local and systemic safety and acceptability of tenofovir gel used daily or before sex over 6 months

Study completed in 200 sexually active HIV- women at 3 sites in U.S. and India.

Results (at M2008): Daily use over 6 months not harmful Some women preferred daily use

Tenofovir Gel - MTN-001

Phase II adherence and PK study Comparing 3 daily regimens (oral, vaginal, and

dual use) in 144 sexually active, HIV- women at 6 sites in Uganda, South Africa and U.S.

Each regimen used for 6 weeks with 1 week off Differences in drug absorption (systemic and

local) to be evaluated at U.S. sites (48 women) Anticipate enrolling April/May/June 2008

Tenofovir Gel - MTN-002

First microbicide study in pregnancy Phase I study:

How does pregnancy affect drug absorption?

Is the drug transferred to the fetus? Tenofovir gel to be applied as one-time dose

in 16 HIV- women prior to scheduled caesarean delivery

IRB approval pending minor modifications

Tenofovir Gel - MTN-003 VOICE

Vaginal and Oral Interventions to Control the Epidemic (VOICE) Phase IIb safety & effectiveness trial,

5 study groups, 2 HIV prevention approaches: Once-a-day ARV tablet (PrEP) Once-a-day application of vaginal gel

4,200 women in Africa Start date October 2008

VOICE Study

TOTAL SAMPLE

(4200)

Oral Pill (2520)

Vaginal Gel(1680)

Truvada(840)

Tenofovir(840)

Oral Placebo(840)

Tenofovir Gel

(840)

Placebo Gel(840)

Two sequential randomizations. Women will use product daily for average of 21 months.

Why VOICE?

Tenofovir Tenofovir Gel Truvada

Which is safer?Which is effective?

Which will women use?

ARVs used in PrEP (and VOICE)

Tenofovir

NRTI approved for treatment of HIV-1 Dose - 300 mg tablet taken once a day Used in combination with other oral agents Safety profile comparable to placebo

Also called Viread® or TDF

ARVs used in PrEP (and VOICE)

Truvada

NRTI approved for treatment of HIV-1

Combination drug - tenofovir and emtricitibine (FTC)

One tablet contains 200mg of FTC and 300 mg tenofovir, taken once a day

Also called Truvada®, FTC/TDF or tenofovir+FTC

Tenofovir Gel - CAPRISA 004

USAID funded Phase IIb study of tenofovir gel Will enroll 980 women: family planning, STI

clinics, sex workers (3:2:1) Screening started 18 May 2007 Regimen: Gel used within 12 hours before and 12

hours after sex; max. 2 applications within 24 hours

Drug absorption studies are ongoing Effectiveness studies

Prevention of HIV when gel used with sex Prevention HIV when gel used daily

Tenofovir gel summary Studies completed in:

HIV+ women – safety, 2 weeks use HIV- women – safety and acceptability,

6 months use

Drug absorption, other safety studies ongoing

Effectiveness studies ongoing or planned: Prevention of HIV when used with sex Prevention HIV when used daily

UC-781 Gel: 5 Phase I studies Active ingredient is UC-781 NNRTI type-ARV Gel has specific action against HIV Phase 1 studies underway

Information on safety and acceptability Pharmacokinetic studies underway

Information on amount of drug absorbed

UC-781 Gel: 5 Phase I studies Safety and persistence in HIV- women

(NIAID/CONRAD) Safety and acceptability in HIV- women and male

partners (CDC/CONRAD) Safety and acceptability for rectal use in HIV-

men and women (NIAID/CONRAD) Male tolerance (CONRAD) Safety and acceptability of 2 different doses in

HIV- women and acceptability in male partners (CDC/CONRAD)

Dapivirine (TMC120)

Active ingredient is dapirivine NNRTI-type ARV Gel has specific action against HIV

Dapivirine (TMC120)

International Partnership for Microbicides developing as gel and vaginal ring

Phase 1 and Phase 1/2 drug absorption, safety and acceptability studies of both – completed or planned

Phase III study planned

ARV-based Microbicides

14 of 17 planned clinical trials are ARV-based microbicides

(Alliance for Microbicide Development) Other HIV-specific compounds are in

the pipeline

ARV-based Microbicides and PrEP

We’re in this together What happens in PrEP trials can be

instructive Resistance being studied in current

trials

Current PrEP StudiesCandidate name

Sponsor Formulation / Design

Population Sites

Tenofovir CDC Once daily dose Tenofovir

Phase III

2,000 injecting drug users

Thailand

TruvadaSwitched from tenofovir

CDC Once daily dose TruvadaPhase III

1,200 men & women

Botswana

Tenofovir CDC Clinical safety and behavior in once daily dosing of TenofovirPhase II

400 men who have sex with men

United States

Truvada NIH Once daily dose TruvadaPhase III

3,000 men who have sex with men

Peru / Ecuador/Other sites

Planned PrEP TrialsCandidate name

Sponsor Population Sites Start

Tenofovir Truvada

Gates 3,900 HIV discordant couples

Kenya and Uganda

Early 2008

Tenofovir Truvada

and

Tenofovir Gel

NIH

(VOICE)

4,200 heterosexual women

Southern Africa Mid 2008

Truvada Gates/

USAID

3,900 high risk women

Southern Africa 2008

Moving Forward Responsibly

We must minimize as much as possible ARV exposure by a woman who has become infected.

The VOICE Study: Taking Precautions To avoid enrolling anyone who is already

HIV-infected, all prospective participants will be screened for HIV

Participants will have HIV tests every month. HIV infections will be diagnosed quickly Study drug or microbicide will be stopped

immediately

Participants will only receive 30 doses of study drug at a time Participants can’t keep taking study drug for more

than 30 days without coming in for an HIV test.

Participants who become HIV-infected: Resistance testing

Indicates if person’s HIV is resistant to any drugs

Help healthcare providers decide which HIV drugs will work best or to avoid

Referred to local care and support services Medical care, including ART Psychosocial services Other programs, e.g., offered by CBOs

Invited into MTN-015 Frequent lab tests can help local provider better

manage HIV care of participant

The VOICE Study: Taking Precautions

Purpose of MTN-015 Assess potential long-term effects of exposure

to study product among women who become infected with HIV while taking part in MTN trials Characterize the natural history of HIV

infection and response to ART Assess differences in clinical progression

and response to ART among women assigned to an active study product compared to women assigned to a control product (or to no product)

Take-home Messages ARV-based microbicides are promising for HIV

prevention – HIV-specific Allow daily use, which may be more effective and

some women may prefer As pills, ARVs safe for treatment Resistance fairly common in treatment of HIV and

can be managed; lessons learned useful We don’t know risks for prevention – need to be

honest about what we know, don’t know We are being cautious – trials include several risk-

reduction measures

Thank You!

Key Concepts: HIV is Error Prone

HIV makes many millions of copies of itself in the body

The virus makes many mistakes when copying its genetic information

This means many, many types or variants of HIV existing in a person

Some of these variants are resistant to drugs (drug-resistant)

Your Questions Will those who get infected have HIV

resistant to the ARV in oral PrEP or ARV-based microbicide ? We don’t know anything for sure, but we will

monitor monthly for infection and stop gel or oral PrEP as soon as infection is detected.

Will this affect their subsequent care and choice of ARV treatment? We don’t know if this will be the same for

prevention as it is in the treatment setting

How will we talk about resistance? We will state clearly in the consent:

If you become infected and continue taking study drug you may develop resistant virus.

We think participants who take study drug during an infection that hasn’t yet been diagnosed will not likely be on study drug long enough to hurt future treatment options, but we cannot guarantee this.

The message will be repeated and explained throughout the study.