Microbicides Trials in India

[Guest guest]

Forwarded by Godwin, Phnom Penh

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Microbicides: Communities Ready and Trials Moving Forward

Third International Conference on AIDS in India

2 - 5 December 2001, Chennai, India

Special Report - Bobby Ramakant

At the recent AIDS India 2001 conference, an exclusive satellite

session on Microbicides was held in the main conference auditorium.

It was attended by many delegates and got an impressive response from

researchers, microbiologists, policy makers, and many from the NGO

sector in India.

Dr. Alan Stone, from the UK Medical Research Council and Dr Gita

Ramjee, from the South African Medical Research Council in Durban, co-chaired

the session, with Dr. N. M. , Head of Indian Experimental Medicine

and AIDS Resource Centre from Dr. MGR Medical University, Chennai, as the

moderator. Below are three reports based on panel presentations.

- - -

" Namakkal, is primed for microbicide research and acceptability study "

Dr. remarked that as " Microbicides is a new area for India, " it

is important to give it a focus at the congress. He explained that this

was the prime reason to select two experts (Dr. Stone and Dr. Ramjee) -

one each from a developed and a developing country - to have a better

understanding of the complexities of the issue and the relevance of

Microbicides in Indian context.

Dr. 's presentation was titled " Do Women need Microbicides? " He

began by discussing, starkly, the vulnerability and risk Indian women

face in contracting sexually transmitted infections (STIs) including HIV.

Twenty million births occur in India every year, with 1-4 % of all

pregnant women found to be HIV seropositive. He quoted a study in

which pregnant positive women who received AZT had one HIV-positive baby in

12 births, and without AZT had three HIV-positive infants in 12 births.

Only 59% of tested women return for their HIV test results; drug

affordability and accessibility continue to be obstacles to care; and 43% of

women give birth at home in India with trained or untrained midwives.

Discussing results from a recent study conducted by Dr. MGR Medical

University at an antenatal clinic in Namakkal, a small district 400 km

from Chennai, Dr. said that of 92.5% of study participants

responded " no " to a survey question that asked: " Will your husband

discuss the use of condom with you? " However 91% women responded " yes " when

asked if they would use a protective cream if given, to prevent STIs/HIV and

and pregnancies.

Dr. said that this is an important indicator to community preparedness

in India to products like microbicides.

The Namakkal experience has several learning lessons including: the

need for primary prevention of infection and behavioural modification of

men and women; challenges in seeking informed consent (such as female

autonomy, role of the husband); and also the role of the community,

local authority, health ministry and big pharmaceuticals. Pricing

microbicides may be another area of high concern in India, but that bridge

will be crossed when we get to it.

" Namakkal, is primed for microbicide research and acceptability

study " , he concluded

- - -

" First Microbicides may hit the market by 2006-2007 "

Dr. Alan Stone, from the UK Medical Research Council, spoke on

" Microbicides and their role in HIV Prevention " at the special

satellite session on Microbicides.

" WHO has stated that there are no safe and effective microbicides yet

on the market, " he began, and then re-framed the issue adding, " but we

already have developed several highly promising product leads (half a

dozen formulations), all of which have tested non-toxic too " .

Speaking to the vulnerability of women, Dr. Stone said that of the 5.3

million new HIV infections in 2000, half of them were in women.

Pointing to India, he added that STD clinics in Mumbai and Delhi noticed sharp

rise in their cases in past decade (by 64 %).

" But why do we need microbicides when effective options like male

condoms are there? " he asked rhetorically. Condoms, he said, are a

male-controlled option and provide good protection against a broad range of

STIs/HIV. However the use of the male condom is inconsistent as: men complain

that they reduce sexual pleasure; they reduce spontaneity; they question

the level of trust between partners; they challenge the accepted power

relationships when a woman asks a man to put a condom; and in couples

attempting to conceive a child - they prevent child-bearing.

Microbicides, on the contrary, are: female controlled prevention

options; requiring less or no negotiation with partners; are not a physical

barrier to sexual pleasure; do not interrupt the natural course of events

during sex (as microbicides are applied before-hand); broaden the range of

safer sex choices; and are not necessarily contraceptive.

He commended the formation of International Working Group on

Microbicides, which encompassed key players from WHO to local agencies like

AIDS Resource Centre at Dr.MGR Medical University in Chennai.

Commenting on the need to have microbicides that do not damage the

natural defence system of vagina, Dr Stone said that the internal vaginal wall

is an excellent natural barrier to STIs and HIV.

Dr. Stone marked the 'obligatory requirements' of having a safe and

effective microbicides. A microbicide, he said, should be highly

active against free and cell associated HIV. It should be active against a

range of HIV strains and sub-types. Microbicides, he added, must have a low

cyto-toxicity in vitro, must be non-mutagenic and stable in standard

tests, and effective in semen as well. Their compatibility with latex

is also mandatory. And above all, microbicide product leads must be

non-toxic in vitro too.

Enumerating preferable characteristics, Dr. Stone remarked that

microbicide product leads should: not have any activity against

lacto-bacilli; not be systemically absorbed; not have an offensive

colour, odour or taste; have an effectiveness that spans a broad spectrum of

STIs including HIV; and must be affordable and available in different

formulations.

Referring to Nonoxynol 9 (N-9) as a possible microbicidal agent, Dr

Stone quoted the UNAIDS 2000 report that stated that " N-9 actually increased

HIV acquisition in a study, " by irritating the inner vaginal walls, the

lesions made the study participants more vulnerable to HIV transmission.

These trials, he said, were disappointing because they were largely held

in sex workers' community (where frequency of sexual intercourse is

higher) and lesions once formed inside vagina, may take up to 2-3 days

to heal.

However N-9 no longer remains the lead product and, since then,

microbicide research has come up with several promising leads (more

than a dozen) with different mechanisms of action like antiretrovirals,

surfactants, sulphonated polymers, natural extracts, etc.

No side effects are reported in these current product leads however

clinical trials are still on-going. Microbicide research is following

two parallel tracks - one is with currently available product leads, and

the second is in basic research laboratories where new understanding of

HIV transmission and acquisition is opening up new vistas of second and

third generation product leads for microbicide research and development.

Dr. Alan Stone concluded optimistically. " The First Microbicide may

hit the market by 2006-2007 - which will be a low cost, broad spectrum,

self-administered, female controlled option to prevent transmission of

STIs including HIV. And this will be no magic bullet, rather it will

widen the range of existing options to prevent HIV transmission " .

- - -

" Three Microbicide - product leads to enter Phase III trials soon "

Dr. Gita Ramjee, from the Medical Research Council in Durban, South

Africa, spoke on " Vaginal Microbicides - Clinical Trials, Ethics, and

Acceptability " at the satellite session.

She explained in detail the various Phases - I, IIa and IIb, IIIa and

IIIb, and IV - in clinical trials. In Phase I are initial safety

trials of the product in question, Phase IIa is a pilot clinical trial to

evaluate efficacy and safety, Phase IIb is a pivotal trial that must adhere to

a rigorous demonstration of efficacy, Phase IIIa is conducted in the

target population, and Phase IIIb deals with quality of life and marketing

issues. Phase IV focuses on issues that arise once the product is

marketed and is based on observation or experience of the target population.

Currently, there are 14 microbicide product leads in the pre-clinical

phase. Six product leads have completed Phase I trials - cellulose

sulphate, PMPA, PSS, CSIG, Acidiform, and DS. And three products have

completed Phase II trials - Carraguard, Lactobacillus crispatus, and

PRO 2000- with Phase III trials planned to begin soon. Only two products

have undergone phase III before - both N-9 based products (conceptrol and

advantage 24) - that have been discontinued as N-9 has been shown to

increase the risk of HIV acquisition. The next three to enter Phase III

trials, however, have more hopes pinned on them.

The ethics of microbicide research and development, as in other

trials, are often tricky and controversial. Dr. Ramjee commented that in the\

'Vaginal Microbicide - COL 1492' multi-site study, several potent

ethical concerns came to the forefront including - the exclusion of some

HIV-positive women from the study, lack of care and support available

to HIV seroconverters, and the process of obtaining informed consent.

The COL 1492 study was conducted with 477 sex workers, where 20% of

them were illiterate. Maintaining confidentiality was critical, and HIV

positive women were separately counselled and trained to provide

convincing reasons when asked by their community members why they had

not participated in the study.

In Durban, women who seroconverted during the trials were provided

routine standard of care and treatment - but no ARVs. And in Abidjan, ARVs

were provided with the routine standard of care.

Commenting on " informed consent " , Dr Ramjee said that in Durban, 70%

of women had a very poor understanding of study objectives and 98% of

women had a poor understanding of potential effects and risks involved. To

address this finding, condom counselling was increased and study objectives

reiterated at every follow-up. In Cotonou, 45 % of women in the trials had a

very poor understanding of gel + condom use, and 75% women had no understanding

of the 'placebo' arm.

Dr. Ramjee categorically stated that " informed consent " is an ongoing

process, and there is a pressing need for repeated verification,

monitoring (by outside agency), and reiteration at every available

opportunity.

Sensitivity to cultural and moral values and building of mutually

respectful relationships between the research community and women

undergoing trials emerged as significant concerns during the COL 1492

study.

However, there were many positive outcomes of this study including

individual development of trial participants contrary to those who did

not participate in the trials, and a noticeable increase of self-esteem in

these women. Dr. Ramjee remarked that visible 'altruism' was also an

important indicator in most participants as they were not disappointed

by the research outcome of this study and were willing to participate in

future trials for an effective female controlled prevention option.

She expressed strongly, the need to prepare for adverse trial outcomes

before the trial begins.

Continuing, Dr. Ramjee said acceptability studies must go alongside

research and development. Acceptability studies have shown that a

potential microbicide must address issues related to following product

features: lubrication, types of formulation, insertion and aesthetic

appeal. It should also address social issues such as the impact on

condom usage, and the role of men.

Wrapping up her elaborate presentation, Dr.Gita Ramjee said that there

is no doubt about the compelling need for female controlled HIV

prevention intervention. She repeated that complex ethical issues can only be

resolved if developing countries come up with their own guidelines,

and researchers, community, and service providers work together - and not

in isolation.

Bobby Ramakant

HDN Key Correspondent, India

E-mail bobbyramakant@...

E-mail: correspondents@...

A cross posting from SEA-AIDS sea-aids@...

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