Protecting mothers from mono and dual therapies, and considering the value of Caesarean sections

1 December 2002. Related: Meeting report.

THE 3rd UNITED KINGDOM COMMUNITY ADVISORY BOARD (UK-CAB)
London, 25 October 2002
Andrew Lumsden, HIV i-Base

The third meeting of the United Kingdom Community Advisory Board (UK-CAB) organised by HIV i-Base, publishers of this journal, took place on 25 October. The group is open to people involved in HIV organisations providing treatment information and advocacy to HIV-positive people. It is a largely peer-led support group that focuses on training and provides a forum for the community to meet with industry.

At the first UK-CAB meeting in May 2002 professor Tim Peto of the 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 (Viread).

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 of the Royal Free Hospital, London, on salvage therapy. Bristol Myers Squib gave a presentation on atazanavir.

For the third meeting’s opening session in the morning, Dr Karen Beckerman, assistant professor of obstetrics and gynaecology at New York University and director of obstetrics at Bellevue Hospital, New York, spoke on maternal health and the HIV pandemic and Leila Frodsham from the Fertility Unit at the Chelsea and Westminster Hospital talked about subfertility, HIV and the assisted reproduction unit established for HIV-positive people at that hospital. Boehringer Ingelheim gave a presentation on tipranavir.

Dr Karen Beckerman

Karen Beckerman is one of the most experienced obstetricians treating HIV-positive women through pregnancy using combination therapy. More than four 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% in over 70 pregnancies at her clinic.

This was the lowest transmission rate that had then been reported. Most studies during pregnancy until that time had focused primarily on reducing the risk of transmission rather than on the mother’s health. This still continues today in some cases and settings.

Dr Beckerman also reported that routine elected Caesarean section (C-section) delivery for HIV-positive mothers added no additional benefit to either the mother’s or baby’s health – although she argues that as with all other aspects of her care, this choice should be made by the mother in association with her healthcare team.

Both these issues are particularly relevant for advocates in the UK, where C-section is still routinely recommended even when this is not the mother’s first preference. Use of AZT monotherapy or dual therapy with AZT/3TC is also sometimes 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 mother’s health, with a high risk of developing resistance to nevirapine – the drug that is also most likely to be made available for use in HAART in Africa (either by price reductions or in a generic formulation).

HIV, pregnancy and maternal health

In a fascinating and moving talk Dr Beckerman described how as a houseman at St Louis, 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 cases 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. Dr Beckerman said she finds that male-to-female transmission is 10 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.”

Turning to C – section, still so much preferred over vaginal delivery for the HIV-infected mother in the UK at present that, in the words of one community activist, there is in effect “little choice”, Dr Beckerman finds no additional health benefit in C – section to either mother or child and considers it unnecessary unless it is the mother’s preferred choice.

She is unusual too in her advocacy of full combination therapy for mothers: “I’m a big proponent of protecting mothers from mono and dual therapies as they are very likely to induce drug resistance. In pregnancy you’re on a time-line that’s very serious.”

Dr Beckerman answered many questions during the meeting.

Q: What determines the choice of delivery?

Response: It’s mom’s choice! I share the data; I inform them that they are only less likely to transmit the virus with a C-section if they are not using treatment, but that there’s no benefit in doing it after the onset of labour or if they are on triple drug therapy, nor probably if they are on a two-drug therapy.

The mother’s viral load at delivery is the MOST important determinant of vertical transmission.

I make it very clear to clients that I don’t know everything. My experience is that the majority of women know strongly what they want. I don’t withhold C-section, but I don’t recommend it.

Q: What do you think about single-dose nevirapine as a treatment for mothers?

R: 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 a 13% transmission rate would be wholly unacceptable in the developed world where it is 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 now too low to detect, is likely to be even higher.

Q: What do you advise?

R: 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.

Q: Is the risk of resistance explained to mothers beforehand?

R: I do not think this is explained in Africa. I explain it in the US of course. In my practice I employ combination therapy for mothers, using three, four or five drugs, and expect near-zero vertical transmission.

Q: The World Health Organisation is advocating single-dose nevirapine?

R: 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.

Q: Please tell us about risks of malformations with HIV drugs.

R: 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 or 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, by 18-20 weeks you can pretty safely rule out neural tube defects.

Q: What about mitochondrial toxicity?

R: 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 done so. In extensive and thorough case reviews of over 20,000 deliveries with antiretroviral use during pregnancy, no such toxicity has been found.

Q: Should these interventions be made at all?

R: 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 child exposed to antiretrovirals would be followed up to the age of 20 or so. But I don’t decide: mom decides.

Q: In epilepsy, should mothers continue to take their drugs during pregnancy for their own health?

R: 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.

Q: What about stopping treatment during the first trimester?

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

Other points made by Dr Beckerman were:

the mechanisms for vertical transmission remain unknown.
• no data exist that demonstrate a benefit of elective C – section 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:

Q: Who should primarily provide care for pregnant mothers with HIV?

R: 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.

Q: How about the battle to use treatments in South Africa?

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

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

R: 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’s slides, are available to download from the i-Base website at http://www.i-base.info/.

Sperm washing and HIV transmission risk reduction techniques

The second morning session was a presentation by Leila Frodsham, clinical research fellow at the assisted conception unit at London’s Chelsea and Westminster Hospital 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 11 babies) 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. Fertility treatment is also very difficult to get funded in this country if you’re not in the right postal district.’

Q: Is there slightly more chance for positive couples to get funding?

R: Yes, if they are persistent and determined patients with belligerent doctors.

Q: Could people store sperm before going on antiretrovirals?

R: 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’.

Q: Are your criteria very strict?

R: 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.

Q: Do you have many donors?

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

Q: Would you give a second treatment if the first doesn’t take?

R: We would normally recommend three cycles.

Q: Are the services available to gay men, with female friends?

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

Q: Would you treat someone using cannabis?

R: 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 for a few months, the effect goes.

Q: Do narcotic painkillers affect sperm?

R: 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.

Q: What about the costs?

R: These do put a lot of people off. It might be say £2,000 for a course of treatment – and there is still no guarantee that this will lead to a successful pregnancy.

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

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

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

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

That concluded the two morning sessions.

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 pharmaceutical company Boehringer Ingelheim (BI).

He explained how tipranavir, at present undergoing trials, with 26 or so sites in the UK, 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.

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 Conference on Retroviruses and Opportunistic Infections, 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.”

Anyone interested in attending future UK-CAB meetings should contact the i-Base office on 020 7407 8488.