UK-CAB 3 – Meeting Report

Summary report from the meeting

Contents

Members and attendees

Introduction
HIV, pregnancy and maternal health

Sperm washing and HIV transmission risk reduction techniques

Tipranavir

Nevirapine

Feedback

Appendices

Presentations are all available to download as pdf files.

Members and attendees

Willys Akoko Africa Advocacy Project
Polly Clayden HIV i-Base
Simon Collins HIV i-Base
Richard Day Yorkshire Mesmec
Jenni Fredriksson Information Officer AVERT
Paul Hindley Rainbow Project
Paul Bateman Hat Trick Group/Haemophilia Society
Jim Jewers The Globe Center
Alan ? The Globe Center
Rupert Jones Barnardos Castle Project & THT Yorkshire
Edith Kaggwa Positively Women
Monica Kizairwe Blackliners
Andrew Lumsden HIV i-Base
Esther Moshinghi Positively Women
Joseph O? Vanguard
Jo Robinson THT. London
Solas, Edinburgh
Apologies:
Haydn Forde THT Living Well. London
Badru Male Blackliners
William Babumba African Policy Network
Minutes and reports: Andrew Lumsden and Simon Collins

1. Introduction

Simon Collins and Polly Clayden of HIV i-base welcomed those attending the third meeting of UK-CAB and Treatment Advocates Network and everyone introduced themselves.

At the first UK-CAB meeting in May 2002 professor Tim Peto of John Radcliffe Hospital, Oxford, and Douglas Newberry of the Medical Research Council described how to evaluate the worth of clinical trials and how best to explain their value to the patient. Gilead gave a presentation on tenofovir.

At the second in August 2002 professor Clive Loveday of the International Clinical Virology Centre spoke on resistance testing and was followed by Dr Mike Youle on salvage therapy. Bristol Myers Squib gave a presentation on atazanavir.

For the third meeting’s opening session in the morning, Karen Beckerman flew in from New York to speak of maternal health and the HIV pandemic. She is assistant professor of obstetrics and gynaecology at New York University and director of obstetrics at Bellevue Hospital, New York.

2. HIV, pregnancy and maternal health

In a fascinating and moving talk Dr Beckerman described how as a houseman at St Louis in Missouri in 1983 ‘we thought the virus would never reach us’ and that ‘women couldn’t get infected unless they were IV-drug users.’ She showed a map of what were then the known ‘hotspots’ or population concentrations in the USA of HIV infection, and they were all coastal. By 1993 St Louis had become ‘a huge hotspot – and this has not improved at all.’

Paediatric AIDS cases in the USA climbed till 1992 and the first availability of drugs capable of inhibiting vertical transmission (transmission of the virus from mother to infant). ‘Treat mom, and things should fall into place, was our attitude in the initially unknown world of HIV therapies’, said Dr Beckerman: ‘I want to suggest to you that it is the exciting development of effective HIV therapies which has achieved this. We now have to resist a ‘blame culture’ – and women are not to blame, given that in the developed world treatments exist – if their babies are born with HIV.

In the USA there are between 10-25 case s of HIV-infected mothers per 100,000 of population: in parts of sub-Saharan Africa, this is 25 per 100. ‘For every one infected mother I care for, in Africa I’d be caring for 1,000.’ Accurate data for Africa are scarce, but it would appear that 55% of infected individuals are women. We find that male-to-female transmission is ten times more efficient than female-to-male.

Dr Beckerman showed a chilling slide called ‘the Population Chimney’ from the UNAIDS report ‘Children on the Brink’. It predicts that on current trends HIV mortality in parts of Africa will produce ‘population pyramids’ never seen before, in which by 2010 men will be outnumbering women in each five-year cohort between 15 and 49 and teenagers will outnumber adults.

Even where no vertical transmission has occurred, the deaths of mothers are producing an unprecedented orphan crisis. In Zambia already there are 500,000 orphans, mostly uninfected, but facing extraordinary risks, including that of HIV-infection early in life. On present trends this situation is going to worsen in coming years.

The present official thinking, Dr Beckerman explained, is

  • Strengthen families (‘but how?’)
  • Protect children’s inheritance rights (‘but how?’)
  • Provide day centres
  • Waive school fees
  • Promote children’s rights

All of which, she commented, ‘sounds to me like the rhetoric of the developed world in the 1990s.’

Her solution: ‘Save the mothers!’

Dr Beckerman set out her ‘Principles of Care for the HIV-Infected

Mother’, saying ‘they are true in San Francisco and New York and anywhere in the world’ :

  • Safe shelter
  • Adequate nutrition
  • Transport
  • Self-determination

‘Self-determination’, she said, means that ‘a mother receives counselling and education but is NOT told what to do. It starts with reproductive choice. We direct women who have previously been told to/told not to/ have an abortion to the place appropriate to their decision. And remind them, the only person NOT crazy is themselves.’

Ques. What do you think about single-dose nevirapine as a treatment for mothers?

Resp. The virus is stopped, but then overcomes the drug quickly. HIV makes many mistakes as it replicates, and the mutation rates are high and resistance to one-drug matters a great deal. One dose of mono-nevirapine administered to mother and infant: reduced transmission at birth from 25% to 13%. But 13% transmission rate would be wholly unacceptable in the developed world where it is no more like 1%. In the Uganda trials 10 out of 46 mothers had detectable resistance even after six months so the true level of earlier resistance, that is still present but at levels that are too low too now detect, is likely to be even higher.

Ques. What do you advise?

Resp.Advocacy of this strategy of single-dose nevirapine to millions of African women seems scary to me: given that nevirapine is likely to be included in the first combination therapies available in Africa, these are women for whom the new combination therapies won’t work. For only slightly higher costs you could provide short term triple therapy for a few days and continue nucleosides for a few days longer to prevent nevirapine resistance.

Ques. Is the risk of resistance explained to mothers beforehand?

Resp.I do not think this is explained in Africa. I explain it in the US of course. In my practice I use combination therapy for mothers using 3,4 or 5 drugs, and expect near-zero vertical transmission.

Ques. The World Health Organisation is advocating single-dose nevirap ine?

Resp. Yes, and I think this is a real problem.

Dr Beckerman then explained her ‘Principles of Care for the HIV-Infected Mother’.

  • Protect moms from mono and dual therapies likely to induce resistance. So, contrary to US and UK health recommendations, I no longer advocate giving nevirapine at the time of labour.
  • AZT as a mono therapy is not recommended as it also induces resistance
  • Women refusing triple combination therapy should be offered zidovudine prophylaxis, but never combivir alone
  • Aggressive use of combination antiretroviral therapy to achieve durable suppression of maternal HIV replication and to protect the mother from induction of antiretroviral resistance
  • When the likelihood of non-adherence is high, do not offer nevirapine
  • Antiretrovirals that should be avoided if possible as part of triple therapy: efavirenz, stavudine, didanosine.

Ques. Please tell us about risk of malformations with HIV drugs.

Resp. The only reports of this have been from tests with monkeys, none with humans – and most HIV drugs have not undergone similar research. I have treated several women who were using had been using efavirenz containing regimens before they realised they were pregnant and I have not seen any problems. If a woman has had efavirenz, b y 18-20 weeks you can pretty safely rule out neural tube defects.

Ques. What about mitochondrial toxicity?

Resp. The French studies that detected this were taken very seriously and in the US we have been trying to replicate these results, but have not. In extensive and thorough case reviews of over 20,000 deliveries with the use of antiretroviral use during pregnancy, no such toxicity has been found.

Ques. Should these interventions be made at all?

Resp. I give a lot of toxic drugs to a lot of pregnant women, not only HIV-infected mothers. In an ideal world, the progress of every c hild exposed to antiretrovirals would be followed up to the age of 20 or so. But I don’t decide: mom decides.

Ques. In epilepsy, mothers continue to take their drugs during pregnancy for their own health.

Resp. I emphasise it’s really the mom’s choice: if she’s totally against it, she’s not going to take it – even if I prescribe combination therapy she will not take it when she gets home – but many of the mothers I have provided care to were initially very against therapy, but they nearly all decide to use HAART when given time and space to decide this themselves.

Ques. What about stopping treatment during the first trimester?

Resp. If a women is already on treatment when she finds outs she is pregnant, we do offer a treatment interruption in the first trimester, but most moms, however, choose not to interrupt. If a woman is not already on treatment then unless it is important for the mother HIV-care, we often delay starting treatment until after the first trimester, to minimise the difficulties of side effects associated with starting treatment, during the period when morning sickness is most difficult.

Other points made by Dr Beckerman were:

  • The mech anisms for vertical transmission remain unknown.
  • No data exist that demonstrate a benefit of an elective Caesarean to mother and baby when the mother is receiving potent combination therapy – ‘though I know my view is flying in the face of received opinion in the UK’
  • Overall, adherence is very good in our mothers.
  • The only reason we’re not talking of an orphan crisis in the USA now is because of ‘Treat mom!’
  • Ruptured membranes as a possible vertical transmission route is not found when moms have been on combination therapy.

Lively discussion continued through this first session of the morning:

Ques. Who should primarily provide care for pregnant mothers with HIV?

Resp. Obstetricians who manage diabetics and epileptics have generally not taken on the study of HIV – ideally, it should be people in maternal medicine who take responsibility.

Ques. How about the battle to use treatments in South Africa?

Resp. Treatment access has become a complicated human-rights issue. People are advocating mono-n evirapine whereas I do not. I’d advocate a safe short-term dual or triple strategy.

Ques. Should we mobilise more around women’s health? I find your approach so refreshing.

Resp. WORLD (Women Organised to Resist Life-threatening Disease) has given me much support. But women are too isolated politically. It’s an uphill battle. US government guidelines are still not good enough and are arguably even dangerous.

The transcription of this training, together with Dr Beckerman slides are available to download from the I-Base website.

http://www.i-base.info/ukcab/oct/beckerman.html

3. Sperm washing and HIV transmission risk reduction techniques

The second of the morning sessions was given by Leila Frodsham, clinical research fellow at the Chelsea and Westminster Hospital in London’s assisted conception unit, where she is mainly involved with positive women.

Women are referred to the unit seeking to have gametes removed for IV fertilisation. Normally 8-10 eggs are removed. A couple are vetted for their suitability under the government’s ‘Welfare of the Child’ guidelines which govern the rulings of the hospital ethical committee. ‘We must have a detailed HIV history. We want everything to be optimal.’

Sperm-washing of the male parent’s gametes where only the prospective father is HIV positive is a risk-reduction technique that as yet has resulted in no proven transmission from HIV+ male to HIV-negative partner. Since the programme began in April 1999, 59 such couples have been successfully treated with all partners (and therefore the eleven babies) are still HIV-negative. The unit is also planning to treat couples when partners are HIV-positive. Peri-menopausal couples are not denied treatment. It took a year to start treating positive women once permission was given.

Leila Frodsham emphasised that ‘it is extremely stressful having any kind of fertility treatment and choice of treatment centre is very limited as the Chelsea and Westminster unit is about the only place in the UK to provide this service. Fertiliy treatment is also very difficult to get funded in this country if you’re not in the right postal district.’

Ques. Is there slightly more chance for positive couples to get funding?

Resp. Yes, if they are persistent and determined patients with belligerent doctors.’

Ques. Could people s tore sperm before going on antiretrovirals?

Resp. We have done that. We offer frozen back-up. We can’t freeze eggs of positive women though we’re exploring it. We can store positive men’s sperm once it has been ‘washed’.

Ques. Are your criteria very strict?

Resp. So far I’ve only had one couple referred to us whom we refused to treat. He wouldn’t have an HIV test and we had a suspicion he was positive. Some couples do decide of their own accord not to go ahead.

Ques. Do you have many donors?

Resp. We’ve only had one donor, an egg donor. Most couples haven’t wanted an egg donor.

Ques. Would you give a second treatment if the first doesn’t take?

Resp. We would normally recommend three cycles.

Ques. Are the services available to gay men, with female friends?

Resp. We’d be happy to help. Our ethics committee makes the final decisions.

Ques. Would you treat someone using cannabis?

Resp. That’s quite detrimental to the sperm count. Cigarettes less so. You can practically spot cannabis-users from the sperm count. Alcohol has little effect. If you stop using cannabis f or a few months, the effect goes.

Ques. Do narcotic painkillers affect sperm?

Resp. No. But the ethical committee has problems over the welfare of the child if there is use of recreational drugs. Their GP must sign the ‘fit parents’ form.

Ques. What about the costs?

Resp. These do put a lot of people off. It might be say £2000 for a course of treatment – and there is still no guarantee that this will lead to a successful pregnancy.

Ques. How would you respond to men with haemophilia asking that they not have female offspring?

Resp. Gender selection for medical reasons is fine. No reference to the ethical committee is required.

Ques. Would you take a patient who’d already had children by means of fertility treatment?

Resp. Yes. We’ve accepted one with five such children already.

That concluded the two morning sessions.

4. Tipranavir

The afternoon’s presentation on tipranavir and nevirapine-associated side-effects, was initiated by Dr Kevin Curry, senior medical adviser working on tipranavir for the pharma company Boehringer Ingelheim (BI).

He explained how tipranavir, at present undergoing trials, with 26 or so sites in the UK. It is the first non-peptidic protease inhibitor (NPPI), a new generation salvage therapy product acting against wild-type HIV-I and HIV-2 to be taken in conjunction with ritonavir. There is to be a progress meeting with the Federal Drug Administration (FDA) in December.

‘In Phases II-III we are working on the optimal dose level.’ It looks as if a lower dose regime than the high-dose regime of twelve capsules taken twice a day with ritonavir yields a better viral load performance, possibly because of low adherence at the high-dose level.

The main side-effects are gastro intestinal: ‘We are not underestimating this. When we come back next year, it will be with a view to as few adverse events as possible.’

Ques. What happens to people at trial sites who are failing, and yet not randomised to receive tipranavir?

Resp. We’re in discussions with the FDA. We’re seeking to let people failing have it, but people might stop adhering to another treatment, and the viral load goes up, so they demand to be put on the tipranavir arm.

5. Nevirapine

The Boehringer Ingelheim presentation was continued by Dr Hubert Bland who discussed the ‘conventional wisdom’ that nevirapine is particularly prone to cause liver-toxicity or, particularly in women, rash – possibly because of over-dosing persons of lower body-mass.

He described how the drug was only belatedly found to have a use in the HIV community. It alters lipids favourably and trials are going on to examine the mechanics behind this. Results from the 2NN trial will be reported early in 2003 at CROI, and this large randomised study directly compares nevirapine to efavirenz. It also includes an arm that uses both efavirenz and nevirapine together in a dual-NNRTI combination and an arm using nevirapine as a once-daily drug.

Dr Bland said that nevirapine is most appropriately used in a triple regime. A tablet half the present size is being developed. ‘The bulk of the problems with rash or liver-toxicity arise in the first six weeks. There’s no evidence of mood-disorders associated with efavirenz.’

Ques. Is nevirapine easy to get resistant to?

Resp.If you took it by itself, you’d develop resistance. When taken in combination, we’ve no evidence of a greater risk than with any other regime. But if you stop nevirapine you should continue to talk the nucleoside drugs in your combination for several days afterwards. This is because nevirapine has a longer half-life and if all drug are stopped at the same time this increases the chance of developing resistance to nevirapine.

South African born Dr Bland described also the Viramune donation programme undertaken by BI in Africa. Though there was a lag in take-up, 86,000 mother-to-child pairs have been treated: ‘We would like to see a combination therapy donation programme.’ An agreement has been reached with a South African company to manufacture nevirapine at less than 10% of the developed world price – an BI will not receive any payment for this. This will supply the drug to15 sub-Saharan countries. ‘Nevirapine was declared ‘poison’ by the South African Ministry of Health two years ago. We’ve had to fight our way back from that.’

Ques. But how will you get it to the remoter areas and the very poor?

Repl. No drug company can supply free, large-scale. At that point, we must be looking at governments buying at low-cost from companies, and themselves supplying free.

6. Feedback

It was requested that at future UK-CAB presentations the technical information be less demanding than it has occasionally been during the three meetings so far – the example of trials was cited, with a suggestion that it is not necessary to know what each arm in a trial is doing. But equally it was objected that the community needs to know the underlying justification for pharmaceutical company claims.

7. Appendices

Slides from presentations for the August meeting: are all available to download as pdf files from the website

Transcriptions from the two training sessions from the August 2002 are now on-line.

PDF files of the slides for these sessions are on the same webpage.

Direct links for each talk are :

Genetic, resistance and HIV – Prof Clive Loveday

Approaches to Salvage Therapy

Dr Karen Beckerman

Karen Beckerman is assistant professor of obstetrics and gynaecology at New York University and director of obstetrics at Bellevue Hospital, New York. She is one of the most experienced obstetricians for treating HIV-positive women through pregnancy using combination therapy. Over 4 years ago at the World AIDS Conference in Geneva she reported that reducing viral load to undetectable levels using HAART had reduced transmission rates to approaching 0% at her clinic in over 70 pregnancies. This was the lowest transmission rate that had then been reported, and most studies during pregnancy until that time had also primarily focussed more on reducing the risk of transmission than primarily on the mothers health. To some extent this still continues today in some cases. She also reported that routine elected C-section delivery for HIV-positive mothers added no additional benefit to either the mother or babys’ health – although she argues that as will all other aspects of her care, this choice should be made by the mother in association with her heathcare team.

Both these issues are particularly relevant for us as advocates in the UK, where C-section is still routinely recommended even when this is not the mothers first preference. Use of AZT monotherapy or dual therapy with AZT/3TC is sometimes also still recommended despite the high risk of the mother developing resistance to these drugs.

Although single-dose nevirapine given to both the mother and baby prior to delivery and after birth reduces the risk of transmission (from 26 to 13%) Dr Beckerman argues that this in an inappropriate and very short sighted approach. It is bad for the mothers health, with a high risk of developing resistance to nevirapine – the drug that is also most likely to me made available for use in HAART in Africa (either by price reductions or in a generic formulation).

Edit
Published: October 25, 2002
Last edited: January 19, 2011