HIV, Pregnancy and Maternal Health

Dr Karen Beckerman October 2002

This is a transcription of the training session on HIV, pregnancy and maternal health that was given to the UK-CAB by Dr Karen Beckerman. The full set of slides to accompany this talk will be available on the i-Base website with the other material from the October 2002 meeting.

Dr Karen Beckerman is assistant professor of obstetrics and gynaecology at New York University and director of obstetrics at Bellevue Hospital, New York. She is also 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 the Bay Area Clinic in San Francisco 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.

She also reported that routine elected C-section delivery for HIV-positive mothers added no additional benefit to either the mother or babies 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 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 reduced the risk of transmission (from 26 to 13% in the much publicised HIVNET 012 study, Dr Beckerman argues that adopting this treatment in an inappropriate and very short sighted approach. It is bad for the mothers health, with a high risk of developing resistance to NNRTIs ¥ drugs that are also most likely to be included in the first HAART regimens to be available in Africa (either by price reductions or in a generic formulation).

Transcription edited by Simon Collins.

Introduction

Today I’d like to talk about maternal health and the HIV pandemic.

I would be most comfortable if people would please interrupt me firstly if I am going on too slowly or, second, stating the obvious or not stating the obvious, and third, most of all, if you disagree with me or have questions about what I say.

There are a lot of controversial issues that I am going to cover and I don’t want to give the impression that a lot of this is not so.

My personal philosophy is that it is most important to take care of clients and at the same time to base our practice on the data we have and whatever studies and experience we collectively possess.

Having said that I am the highly experienced director of obstetrics at Bellevue Hospital – this is the end of my third month there! Even though I grew up in New York I’ve lived for 25 years in San Francisco – thinking it was a major urban centre – until I returned to New York which is quite different, a lot louder, a lot busier; so if I seem a little shell shocked this morning that would be why.

We’ll be covering HIV disease in the US, but focussing a lot on reproductive health and HIV principles of care which we can understand in universal terms but also separately in terms of the developed and developing worlds.  In terms of the developing world principles of care are now being generated and we have incomplete understanding of what principles of care of HIV infected women will be in the developed world. I will be skipping over preconception and early pregnancy counselling and talking a bit about vertical transmission and how to prevent it and also focussing on the global epidemic. Many of my slides in terms of the global picture and are meant to stimulate discussion and not to give my final word on something that I am not a first hand member of.

I would like to start with a bit of my own personal history. In 1983 I was a houseman in obstetrics and gynaecology in St Louis, Missouri.  We knew a bit about AIDS, not much, there was no test for the syndrome and there was no such word as HIV. We also believed quite firmly in St Louis that we were on an island – that the syndrome appeared in major urban centres associated with very specific risks – and St Louis was not one of those places and we therefore had very little to concern ourselves about or even think about.

HIV wasn’t even a part of the medical school curriculum at that time and there was no guidance or instructions for obstetrical house officers in how to manage patients. It was hotly debated at that time – or even not so hotly debated, it was just felt – that women could not get infected unless they were IV drug users. People said the vaginal mucosa barrier would too impermeable – if it was a virus – for that virus to cross. Well how wrong we were when ten years later St Louis was a hot spot in the American epidemic and we found ourselves with both the patterns of substance use nationally and the heterosexual spread of the virus right in the centre of a major focus of the epidemic in the mid West. This has not improved and St Louis is now an even brighter spot on the map of AIDS incidence in the US.

What has happened over this time?

We have identified HIV disease in women and in the US from the beginning it was linked with reproduction. The first HIV infected women were frequently diagnosed by the diagnosis of AIDS in their babies. We see in the era that I have been talking about so far a steady climb in the number of cases of paediatric AIDS up until around 1992.

This was when AZT (zidovudine) began to be used in pregnancy to specifically prevent vertical transmission. Probably the front part of this curve is responsible for levelling off the number of paediatric cases of AIDS in the US and then later causing this to fall. What I want to suggest to you however is that it is not AZT alone or, as some people would have it, elected Caesarean section that has caused the curve to continue to fall but rather the exciting events in 1995-96 with the appearance of HAART and the first actually effective HIV therapies.

One of the major themes in my work is to focus first on the health of the mother. In San Francisco when these medications came out we were proceeding blindly – we knew nothing of their safety, of their safety in women, or their safety in pregnant women. But our philosophy extended from the rest of our work in maternal field medicine and this was first to treat mom and then expect other things to fall into place behind it.

The situation in terms of vertical transmission was improving so rapidly in the late 1990s that the Paediatric AIDS Foundation issued a full-page advertisement in the New York Times (in December 1998) trying to get pregnant women diagnosed and to get them on AZT prophylaxis in

order to prevent transmission to their babies.

I found this advert particularly disturbing. I felt it pointed a very blaming finger at women with HIV, a very accusatory finger – you know – paediatric AIDS is because women who can’t avoid infection themselves… and I also felt that it was wrongly focussed. The focus that I would like to suggest to you now in 2002 is really that the crisis that we are facing in the developed and developing world is that what we would say in a picture like this is that the only thing worse for this baby than losing its mother to AIDS is finding out that it didn’t have to.

The orphan crisis internationally has taken off and there is no end in sight to what is going on. These are three children in Kenya, they are AIDS orphans, who have a nice hot mug of porridge, I guess, and who at least had breakfast this morning. Infected children will also suffer. The first three were uninfected orphans and will suffer.

The next slide is a baby in South Africa with PCP who has the luxury of dying with nasal canular oxygen to support him through his last days.

I find the map in the next slide from the San Francisco Chronicle to be helpful to review the scope of the pandemic in different settings as it maps out AIDS per 100 populations and this is in the States in the late 90s. For example California is a State with a higher incidence than most – about 25 or 26 per 100,000 – New York State is even higher at 70 per 100,000 and of course the District of Columbia is highest of all with 220 per 100,000. Generally throughout the States we are thinking of somewhere in the neighbourhood of between 10-25 cases per 100,000 population.

In Africa right now we don’t measure AIDS rates in terms of 100,000s – we measure them in terms of 100s. In so many parts of sub Saharan Africa it is not 25 per 100,000 but 25 per 100. We are looking at a problem that is a thousand times worse in Africa than it is in the West. That means the impact for me is that for every HIV infected mother that I take care of now, I would be caring for a thousand if I was in Africa. This is quite overwhelming from anyone’s perspective.

General incidences to December 2001 include 5 million new infections in 2001 and 800,000 children infected in Africa. The projections now are even higher than they were a year ago …  looking at orphans in sub Saharan Africa by 2010 does not alter the course of HIV disease in the West however

We have a paucity of data examining the effects of pregnancy on HIV progression in women in the developing world and we have almost no data on HIV disease in pregnant women in terms of the natural history of the disease in the developing world. Of course the epidemic in Africa is heterosexual and after infection there is a more rapid progression to AIDS. This is the level of the data – the numbers are so frightening that the only thing you can be is descriptive. Less than half of the people remain symptom free after three years. Median survival in the two studies that are quotable in terms of data is about nine years and survival with AIDS is considered short. This is just a more recent map of Africa and incidence of HIV disease there.

HIV and women in Africa

In Africa, 55% of those infected are women, and so women share a very large part of the burden of the epidemic. Interestingly male to female transmission appears to be ten times more efficient

than female to male. This makes me and many others who thought that vaginal mucosa is so thick that nothing would get across it and women wouldn’t be infected sexually by HIV disease, look like fools. It is now obvious that the absolute opposite is true. Women also appear to be infected early in their reproductive lives usually by older men. Rates of pregnancy are very high among African women with asymptomatic HIV.

I am not an epidemiologist but there is a lot of literature that refers to population pyramids or population ‘chimneys’ such as these from a very informative publication called Children on the Brink published by the US Agency for International Development. These pyramids refer to the distribution of populations across age ranges – which you can see up here on the Y axis – and then the distribution of men and women as you can see on both sides – then they have added this to the dark blue – the projections of what projections will be like in 2002 or what they will be like now – without the HIV epidemic and with the light blue how they look right now with the HIV epidemic in Africa. This is 2002 and we see the impact of the epidemic narrowing these bars in ages, for example 25-29, 35-39.

The fact that you can see this darkening at all in any of these age ranges at all is quite impressive but these changes are not staggering just by glancing at them. We see here in 2010 we have a narrowing of these populations at all levels but particularly in relatively young adults at the prime of their lives when these people would be engaging in farming, teaching, the most productive part of peoples lives, and of course they would be engaged in raising children – but now they are not. The other thing to notice is the shift in the ages from 15 through to 39 where women will be disproportionately affected and a massive shift of the proportion of women of reproductive age in comparison to men.

This population chimney actually refers to what the result of that will be in 2020 when it is thought that in many parts of Africa teenagers will out number adults.

One of the things that people aged 15-49 would be doing is raising children, which if they are dead they obviously can’t do. Those who have died of HIV infection in Africa have already left behind many orphans. A summary from UN AIDS said that in Zambia alone there are half a million orphans and that other countries are also highly affected.

These orphans will suffer greatly whether infected or not – these children in Lusaka are at a day time feeding centre and were interviewed by the New York Times in the summer of 1998. Large scale orphaning in history has been sporadic and short term. It has been due to immediate famine, natural disasters and of course to war. HIV orphaning is long term and chronic. It will worsen in coming decades. Most HIV orphans will be uninfected and all will face extraordinary risks of poor nutrition, inadequate housing and harshness and abuse, and in particular they will face the risk of acquisition of HIV disease themselves.

I find it interesting that in just about any literature you pick up about the orphan crisis – including ‘Children on the Brink’ – that the proposed solution to the crisis are ‘strengthening the coping capacities of families’ most of which make little sense if your parents are dead.

Protection of property and inheritance rights:

I don’t know if a farm for a three year old is going to be very helpful.

District AIDS committees, community day care centres, waiving school fees:

this would be a tremendous boon to many children in Africa, including HIV orphans, but if you don’t have enough food because your parents are dead you can’t go to school anyway.

Supporting youth expression, encouraging political will, reduction of stigma, promoting the rights of women and children, encouraging partnership and leadership:

a lot of this rhetoric to me sounds like the rhetoric surrounding the epidemic in the developed world in 1994.

What I would propose is that the most important way to deal with the orphan crisis is to save the lives of mothers and we know now that the only way to save the life of an infected person is with antiretroviral treatment. This is what I will focus on for the rest of the talk.

I will start with some principles of care for HIV infected mothers.

First there are universal requirements that any person has and in particular a pregnant person and in particular an HIV-positive pregnant person. For a woman coming into our office, or to any clinic, on the first visit include:

• does she have safe shelter
• where is her next meal
• does she have transportation to and from the clinic
• does she have transportation back home at night?

It may seem obvious or superfluous but even in the affluent city of San Francisco where we just saw women by referral, addressing safe shelter and adequate nutrition were critically important in about one third of our patients ¥ where a new patient would not have a place to go that night and did not know where the next meal was coming from. This doesn’t mean that all the women we care for face those problems but certainly as a baseline, if you don’t ask they won’t tell you. So these are the first considerations and they are true in San Francisco, New York and anywhere in the world.

The second consideration I would like to spend time on is self-determination. We don’t go into great detail on the first visit to our clinic but we certainly make women understand that the treatments and interventions they will have, will be those that they decide on, not those that they have to have, or that they must do to qualify for a programme. They understand that they will get a lot of counselling and a lot of education – but they won’t be told what to do.

Use of C-section

In the first years that I was taking care of HIV infected women, I was amazed that about half the clients referred to us came to us because they were told that they had to have an abortion. The other half that came to us came to us because they were told they couldn’t have an abortion! We did a rather busy service then directing women to where they could get the care of their choice. It was amazing that people would use the same arguments to withhold an abortion from a HIV infected woman that would also be used to insist on one.

So the whole world can sometimes seem crazy and the woman has to understand that the only person who is not crazy is themselves – and that their pregnancy is their choice, at least today and in most countries in the western world.

We talk to women about the importance of prophylaxis for opportunistic infections from the first day. We mention treatments, but on the first day one can only cover a limited amount and there is a lot of to talk about.

Use of C-section

We also mention to them some of the issues around delivery and also inform them that they don’t have to have C-section. We find many women coming into our offices very concerned that they have been told that they have to have a C-section because they are HIV infected.

Ques: I think that is still the consensus in the UK that you have to have C-section. We didn’t mention at the beginning that you were one of the first doctors to use combination therapy throughout pregnancy and that is very unusual in the UK. The whole question of choice is very unusual in the UK and from what I know about it even if you are told you have choice it is not presented as an open choice and so it doesn’t really existé

Ques: When talking about choice what do you base it on because if I presented with a very low CD4 count and a very high viral count would you really let me go and encourage me to have a normal delivery? I think there are issues like the CD4 count … I know it is coming into practice now in the UK … but what is the determinant for allowing a woman a normal delivery?

KB: It is the moms choice. I share with my clients the data. This clearly shows that for mothers who are on no therapy, or taking only AZT prophylaxis, then elective Caesarean section before the onset of labour will decrease their transmission rate probably by a factor between 2 and 6. In other words they would be that much less likely to transmit. I think most studies are in agreement with that. I also tell them there is no benefit from Caesarean section after the onset of labour or if ruptured membranes have occurred already.

I tell them there is no benefit from Caesarean section if they are on HIV therapy with at least three drugs – and even though I have quite a few slides that show women should not be exposed to two drug therapy there is no data suggesting that on two drug therapy that there is a reduction of transmission from Caesarean section.

These data now come from very large studies. ACTG316 was a massive study that showed there was no benefit to women who were on triple therapy to elective Caesarean section. In ACTG367 there was no benefit in Caesarean section to women who had two or three drugs.

Over all the most predictive risk of transmission is viral load and I interpret that to mean that maternal disease is the most important aspect of vertical transmission. Having said that it is interesting that even women who are on therapy but failing therapy with viral loads that are moderately high with high levels of resistance, both clinically and in the laboratory, it is not clear that they are going to transmit to their foetuses in the same way as women with wild type virus transmit.

So Caesarean section will not benefit those women. Having said that, I make it very clear to clients that I don’t know everything, and I am not the person to tell them either way. My experience is that the majority of women have very definite ideas about what they want or don’t want and some women absolutely want a C-section.

I used to withhold it. I don’t withhold it anymore, but I also don’t recommend it. I just present them with the data. The aspect that I find difficult about this is the women with the most advanced disease who you are most concerned about them transmitting but are also at the greatest risk from abdominal incision and Caesarean section and that makes the conundrum even harder in that setting.

Principles of care for pregnant women: avoiding resistance

Even before they require triple therapy I have become a big proponent of protecting mothers from mono and dual therapies likely to induce antiretroviral resistance and having seen the first emergence of resistance in my clients in the 1990s and having to face the challenges of viral load rebound during pregnancy. Dealing with breakthrough at any point is difficult and in pregnancy you are on a timeline that is very unforgiving. As care givers we are under a great deal of pressure to achieve a durable viral suppression over a shorter period of time than most HIV physicians.

I want to review the whole idea of drug effectiveness and risk of resistance. Nevirapine is an extremely popular therapy to give to pregnant women to prevent vertical transmission, and it is an extremely potent drug. But if nevirapine is only used on its own, although the risk of transmission is still reduced, the virus can rapidly mutate so that the drug then becomes completely ineffective for any further treatment for the mother for her own healthcare. AZT alone is a much less effective drug than nevirapine to reduce transmission, but it also has a lower risk of inducing resistance. As drug effectiveness gets even higher with three drug combinations we find the risk of resistance goes back down again.

Resistance is such a big deal in HIV infection because of the low fidelity of replication of the HIV 1 virus. This means the virus does not duplicate itself very well – it makes a lot of mistakes as it replicates within a human cell. When any DNA replicates it makes a lot of mistakes, but for example in mammalian cells the reason that we are not all mutants is because we have a so-called ‘proof reading’ ability. Enzymes can detect irregularities or mistakes in the new DNA that is being made and correct them. HIV does not have this ability.

Both HIV-1 reverse transcriptase and cellular RNA polymerase lack this ability to edit out mistakes so mutation rates in HIV are extremely numerous and very rapid. Most of us have read about the large number of virus, the billions per day that are produced, so if you have high levels of mutations, no ability to correct mutations, and then no ability to correct mutations and then high numbers of mutations – this is why HIV can mutate so rapidly. The types of mistakes we look at are insertions and deletions and RNA strand breaks forcing the so-called phenomenon of template switching – which is as if you were looking at words and you suddenly had the spaces between words moved over and in the wrong places between letters. Other sort of virologic things going on, all of these are mistakes that HIV mutation is already about.

Resistance to anti retroviral drugs matters a great deal. Unfortunately, clinical trials in the developing world specifically in Africa of nevirapine single dose prophylaxis given in labour. The results from these trials hit the international media a couple of years ago with great promise and great optimism about stopping vertical transmission in the developing world. Remember that this was a single dose of nevirapine to the infected mother, plus a single dose of nevirapine to the infant. Theoretically, we all knew about nevirapine resistance from the early 90s. The main reason the drug didn’t come into more common use until the late 90s was this resistance problem. When it was first given to infected individuals their viral load would go down for a month and then it would come right up again to pre-treatment levels. It was only later we found that it was a highly effective agent when it was used in combination with other reverse transcriptase inhibitors. But it was thought it may be the perfect agent to give to pregnant women to prevent vertical transmission – just to get viral replication shut down on the day of delivery and maybe also give one dose to the infant afterwards ¥ and that one dose surely could not matter, and would not induce resistance. Also, to some extent, the philosophy was, and continues to be, that resistance doesn’t matter in the developing world because these women are never going to have access to therapy anyway.

So the trial worked, transmission fell from 25% in controls to 13% of infants being infected (from mothers and infant each receiving a single dose. The pharmacokinetics of nevirapine in pregnant women and infants was also thought to be fabulous. The medication hangs around at therapeutic levels probably for about 48 hours after the first dose to the mother and about up to a week after the single dose given to the infant.

However, the workers in Uganda, in collaboration with John Hopkins University, were worried about resistance and they studied it very hard. Much to everyone’s surprise they reported that even though women only received one dose and even though they were tested six weeks after that dose, that about 20% had the technical resistance. This is six weeks to six months after no drug.

Many of you know that have worked with clients with resistance that once the pressure of an antiretroviral is removed there is a tendency to return to a wild type virus so that if a particular drug is not being taken at the time that we study resistance, a negative resistance test does not mean that the resistance is not there, it just means that you cannot detect it. Depending on the test you may need at least 10-50% of any species of resistant virus in order to detect resistance.

Q: Does this mean that you would not recommend this strategy?

KB: No, and I think the advocates for this strategy suggest giving single dose nevirapine to all HIV-positive African women in labour. That is the scale that is being spoken of. Most people also think that the first triple drug combinations that are going to be available to large numbers of people in Africa are going to be nevirapine-based combinations. So the first wave of antiretroviral combinations may be completely ineffective for many women.

Equally important is that transmission rates are still 13% among women who received the nevirapine prophylaxis and that rate would not be acceptable in the west right now. We look at transmission rates of 1% or less in our clients.

Q: It was higher as well with high viral load data the transmission rate went up to about 26% in women with highest viral load – which was comparable to doing nothing.

Even more of a concern was that of the thirty-six infants who were HIV-positive in the trial, eight had detectable non-nuke resistance at six weeks of age. This was also six weeks after the single dose and so probably many more than 20% who carry the resistance mutation if they haven’t seen the drug for six weeks.

Q: You talk about the thirty-six infected infants have they come from the forty-six mothers or is that unrelated statistics?

KB: It’s unrelated. The thirty-six infants come from the 13% where transmission occurred.

Q: What did the study do around breastfeeding? Was that part of the transmission rate?

KB: I was sent the manuscript to review and then I was told it would not be published because clearly this 13% was higher at eighteen months ¥ presumably because the benefit reduced as HIV-positive mothers breastfed.

Q: When they started mother to child prophylaxis in Botswana the pregnant mothers took home prescriptions for three months for combination therapy but one of the problems they found when planning to treat mothers after birth, was that mothers were passing their tablets onto relatives. Also husbands did not like them bringing their tablets home either, so they were taking them every second or third day and then having to go back and start all over again. They are looking at directly observed therapy now to watch mothers take their tablets and also medication after birth.

KB: You have an important point – fine if you just want to provide a safe harbour for the foetus to be born – but at least add Combivir (AZT and 3TC) to the nevirapine and maybe continue the Combivir for 48 or 72 hours after delivery so that mom doesn’t emerge resistant.

We know that nevirapine at a high enough viral load will reduce resistance, we can calculate it. We also know how nevirapine can be used so as not to induce resistance. This would be one of the methods I would use to address this very real problem.

Otherwise a considerable number of infants will still be infected under this regimen and most if not all of these infants will be non-nuke resistant and thereby be unable to benefit from any combination therapies that come their way.

I mentioned that PACTG316 study that I’m ashamed to say now that I participated in. In the States it was originally developed along the lines of HIVNET 012 but by the time it got out of committee four or five years later the HIV treatment was going through a revolution and so it was decided that nevirapine would be given to women in labour in addition to their standard therapy which through part of the study was AZT prophylaxis alone. In the mid part of the study a lot of Combivir was being used alone and then toward the end of the study triple drug therapy was being used. To enrol in the study you have to have never had an NNRTI before. When women were admitted in labour they were tested for resistance before they received this single dose of nevirapine and indeed no nevirapine resistance was detected at baseline in anybody enrolled in the study.

At six weeks post-partum, nevirapine resistance was detected in 7 of 43 samples tested and these 43 all came from people with detectable viral loads. These were people whose resistance was measured in the setting of virologic breakthrough from the standard therapy. You see a number here – 16% – close to what was seen in Uganda in the HIVNET 012.

Even more alarming, was that in six of these seven women, the viral load at the time of testing for resistance post partum was less than 4000 copies. These women may have had breakthrough but they were not failing therapy big time. There was one woman whose viral load was just over 300 who developed resistance from nevirapine prophylaxis.

Another principle of care of HIV-1 infected pregnant mothers, is protecting them from the mono and dual therapies that are likely to induce resistance. Even one dose of nevirapine prophylaxis is highly likely to result in NNRTI resistance unless it is given in a safe combination. I would just add – and I think this is probably relevant to the UK ¥ that in the US, nevirapine prophylaxis given in addition to standard antiretroviral therapy resulted in no benefit to mother or baby but did cause significant induction of NNTRI resistance in both women and infants.

Despite US public health service recommendations, and I suspect similar recommendations in the UK, I do not recommend adding nevirapine to a woman’s therapy when she is going through labour. There is nothing in the literature to support its use. I will readily admit that the idea is extremely attractive, I have done it in the past when we had no data and were proceeding blind – but now we have the data and the data show there is no benefit for anyone concerned (éexcept the manufacturers of the pheno- and genotypic resistance assays.)

Resistance in the developed world

We know that Combivir induces resistance at the same frequencies in pregnant women as it does in men – specifically the M184V resistance mutation to 3TC. One tiny study showed that of five mothers given Combivir alone in pregnancy, four developed M184. There are wider studies available now that confirm this, probably not at such a high level, but it is certainly there and this again can be transmitted to infants.

Data from ACTG185 study are relevant to us, in that as part of standard therapy, 14% of women received Combivir alone and 30% of these mothers had NRTI resistance by delivery. These women who had resistance by delivery were three times more likely to transmit HIV to their infant. The fact that they had resistance may have shown that they had more advanced disease and therefore were more likely to transmit to their infants. I would just also emphasise that none of these women carried PI resistance and we really don’t know yet what the natural history of PI resistance is going to be in pregnancy and vertical transmission.

In San Francisco we offer triple drug combinations to all of our clients even if their HIV disease is not very advanced. Some women also use 4 and 5-drug combinations when it is appropriate for their care.

Some women, about 5% of our patients, do not want a triple combination, not even a simple Combivir/nevirapine combination. These women should not be offered Combivir alone ¥ because of resistance. They are offered AZT prophylaxis with elected Caesarean section but never Combivir alone, as it will just knock out a whole category of drugs for future therapy. We want to treat mother and we want to protect her from induction of resistance.

Increased clearance of P450 metabolised drugs during pregnancy

The increased availability of twice daily combinations has been a huge progress but remember that cytochrome P450 activity is increased in pregnancy. It probably comes from placenta and indinavir given by itself every eight hours, as was commonly done a number of years ago, results in inadequate levels in pregnant women. This was shown in ACTG353 and also in a smaller study in San Francisco. This is a particular problem at the end of pregnancy and can be reversed by the simple addition of ritonavir which not only allows mom to take twice daily dosing it also involves moving indinavir levels throughout pregnancy. One ritonavir/indinavir combination we looked at was 200/800 and probably many combinations used today work just as well, 100/800 is probably just as good.

Problems with adherence

These are big problems with adherence in pregnancy. The tendency I have found in a lot of practitioners is that if they think a mother is going to have trouble taking her meds they revert to a non-nuke type regimen using nevirapine. However, I would suggest nevirapine is a bad drug to start with in a client where you anticipate adherence difficulties, because you just blow it early on in your therapy. I prefer to start mothers who I think will have adherence difficulty on a well tolerated PI based regimen such as combivir/nelfinavir for example and then if they are not adherent they are less likely to become resistant – and if they are adherent they can switch over to a non-nuke regimen with great ease either before or after the delivery of the baby. But don’t work on adherence with a nevirapine regimen even though it is extremely popular in pregnancy.

We offer triple drug therapy to any women regardless of the stage of her disease and if she doesn’t need therapy for her own health, then after the pregnancy HAART can be safely stopped. If she is on nevirapine you might want to continue her reverse transcriptase inhibitors for a few days longer because of the longer half-life of nevirapine. Treatment interruptions in these  mothers can be done quite safely.

Efavirenz in pregnancy

A want to say a couple of things about efavirenz (Sustiva). There has been concern about this drug because primate studies showed a high incidence of neuron 2 defects, such as missing eyes and other frightening structural abnormalities, in these primate foetuses. Those data interestingly enough were never published so I’ve never seen them first hand.

I am on the antiretroviral pregnancy registry and we now have 88 reports of mothers using efavirenz in pregnancy and there are four malformations that have been reported out of these 88 but none of them point to a specific abnormality that could be associated with efavirenz. They are distributed across the field of birth defects that occur in 3% of all new-borns. Four out of 88 is therefore not a high incidence of birth defects and more importantly there is no clustering, or no report in these perspective cases of one specific defect.

There are reports in the literature of two babies. It is unclear whether it is one report of two babies or two reports of the same baby in an efavirenz-exposed foetus but I would just stress to you all that you can’t look at this type of thing retrospectively. You can’t find a malformed baby and then say that is because the mother was on efavirenz. These things have to be tracked from the beginning of pregnancy forward. The registry does accept retrospective reports but you can’t look at a rate of birth defects from a retrospective report because you don’t know how many other women are out there taking efavirenz for their first trimester and had perfectly normal babies.

Q: Would you tell us some more about malformations?

KB: The only malformations that have ever been reported from an antiretroviral are theses in monkeys and essentially they have never been seen in humans. Also, most anti-HIV  drugs never were tested in this way ¥ so there is no data at all for all the other drugs that are used in pregnancy. If a mother comes in who has been taking efavirenz who didn’t know she was pregnant, and she’d had it during the first trimester, the first cases of these women were told they must have an abortion and it was widely recognised and a prevalent phenomenon. What we do if a woman has had efavirenz during the first trimester is we try to rule out birth defects as quickly as possible. Ultrasound as early as ten weeks can rule out [… ?] and at sixteen weeks you can rule out other major neural defects. At eighteen to twenty weeks you can very reliably rule out just about all defects. There is also maternal serum alpha … screening. It is a blood test on mom which is a screening tool to look for neural defects, spina-bifida and that sort of thing.

Q: I have heard about mitochondria toxicity dysfunction in babies exposed to antiretrovirals?

KB: That has been reported, mostly from France. In the US the entire community involved with maternal child and HIV has been struggling to find the same thing but so far we haven’t found it. Certainly it occurs to infected individuals on therapy including pregnant women.

Q: Are the mitochondria affected in infants after birth?

KB: This is the question of the hour. All of the cases are out of France. We have been tracking this in the registry and have been unable to detect a single one in the US. In addition the ACTG have reviewed all of its antiretroviral-exposed cases which comes to many thousands of children who have been exposed to AZT and 3TC and they are unable to pick this up in the ACTG. It is quite confusing. Do you have more data?

Q: No. I thought there was a change and then went back to normal within weeks. Babies born to mothers on treatment did have reduced mitochondria function but not so that it made any difference to their health.

KB: In the States I haven’t seen US data that has even shown the early change.

Q: Kees Brinkman who has been researching mitochondrial toxicity comes back to the lack of ‘control patients’ in these studies – because we don’t know what is normal for kids born to HIV+ or HIV-negative mothers – so we don’t really know what to expect those measurements to be in a new born. There is anecdotal evidence that kids are born that have certain sorts of indications that could possibly be that but tend to revert as they grow older, but there is nothing to actually label that this is what the child should be like in a setting with no HIV, no antiretrovirals and this is what this child is like. It ended up being a very emotional thing saying you couldn’t possibly take all those blood tests.

Q: This is really positive ¥ how many babies were in the US study where you looked retrospectively you found no toxicity?

KB: About 20,000.

Q: I am trying to understand what you are saying here. You are saying to be very cautious to draw any conclusions because in the general population birth defects also occur. But does it not happen with nevirapine? If we have to be cautious that in the rest of the population there are also a small percentage of babies with birth defects and if you give them nevirapine rather than efavirenz do you see the same birth defects. You don’t do you?

KB: So far they just reflect the data in this registry, just reflect the general population. It is not that there are no birth defects but there are birth defects in every population at about 3%.

Q: What are your thoughts about the long-term effects of children that have been born while their mothers have been taking antiretrovirals. Obviously you can’t tell me the answer because you can’t look into the future. But I think it is an ethical issue. Some parents might not want to go through all that because of the effects it might have on children in the long term because HIV doesn’t necessarily be transmitted to everybody, it doesn’t really affect everybody either. The developing child … what are your thoughts?

KB: You are asking someone who gives a lot of toxic drugs to a lot of pregnant women, not just who are HIV infected. I give known teratogenic drugs to mothers with seizure disorders to prevent seizures because I think that it is safer for a baby to be exposed to those medications than to suffer oxygen deprivation during a maternal seizure. Chronic hypertensive mothers, also require toxic drugs, so I am prejudiced and come from a prejudiced background.

In my early work when there were no combinations available to the women I was taking care of it always seemed to me that the greatest threat to any baby was HIV infection and that far outweighed any potential of the drug. Having said that in an ideal world I think that any antiretrovirally exposed baby should be followed up to age 23 and studied – but that is not going to happen. This pregnancy registry is just for birth defects, it is not for long term follow up. ACTG219 follows the graduates of the 076 trial but those babies are now10 or 11 at oldest.

Q: So we are not going to see data for the years to come?

Q: They are following kids in the UK…

Q: To what age?

Q: Indefinitely. Kids exposed to antiretrovirals, AZT prior to 076, they’d be 16? With combination therapy they’d be younger than that. It is one of those sort of risks that Karen has to decide what is worse.

KB: I don’t decide … Mum has to decide.

Q: So concerns for toxicity can be overly pessimistic. You’ve got all this exposure, children followed for ten years and still nothing there … children should be followed in case something happens but the odds are getting increasingly better.

Q: If you remember what happened with thalidomide, it was obvious. If you have something like epilepsy that is known to be teratogenic, if you have severe epilepsy your physician or you would have to decide not to take those drugs during pregnancy because you need them for your own health and I don’t think it would be a huge debate like it is with HIV.

KB: It is a problem. Some mothers stop their meds because they are terrified and then they start seizing. I’m not minimising it, we confront it a lot, particularly when you are dealing with pregnancy complicated by medical illness. You bring up another point that I really want to emphasise. It is the mother’s choice and if it isn’t her choice you are going to fail. You can’t shove the pills down her throat and if she is totally against it she’s not going to take it no matter what you write on a prescription or say to her. In my experience women who have AIDS never wanted to stop therapy. I haven’t had a single client who has had PCP who ever wanted to stop therapy.

Use of drugs during the first trimester

Q: What about stopping in the first trimester. Do you see people who are on combination and then want to stop? That might be when there is more risk of toxicity.

KB: We offer treatment interruption in first trimester for two reasons. One is for potential teratogenicity during first trimester. The second, and I think most important reason though is the nausea and vomiting of morning sickness. If you can just skip that whole period and that whole issue that could impact on adherence. Most of our moms don’t actually want to interrupt during first trimester and if they are on stable therapy already, they have tolerated their therapy pretty well. Having said that we don’t start agents in the first trimester, or switch in the first trimester. We wait until later on when they are feeling better and the chances of good adherence are much better – because we don’t want to compound nausea and vomiting in pregnancy by the initial side effects most people encounter.

With efavirenz you can consider a switch to nevirapine – and a lot of women have done very successfully and the big difference is that they take the non-nuke once a day instead of twice a day. Other patients haven’t wanted to switch their efavirenz or to stop it ¥ even though it is still contraindicated. One patient in particular had to continue it, and she knew everything. The baby was quite progressed to thirty weeks, so she just continued her efavirenz and she was fine and the baby was fine.

With amprenavir, there are unpublished reports of abnormal calcification of bones, but no human data. You might want to switch to another highly potent agent or combination such as a ritonavir ¥boosted PI combination.

d4T/ddI is a high potency combination and can be particularly effective in the setting of so-called pan resistance and virologic breakthrough. I have used it in several patients with very good success. A study out of Johannesburg showed it was highly effective at preventing transmission and none of the 30 babies in the study had any signs of lactic acidosis neither did the moms. However, very frightening reports appeared in the US about lactic acidosis during pregnancy so if mom has to go on that combination she has to be very closely monitored during pregnancy, but if she needs that combination she is also being closely monitored virologically. The South  African data was dual combination alone. Interestingly the same kind of resistance you receive with Combivir alone or nevirapine alone doesn’t seem to appear in AZT/ddI or d4T/ddI combinations and I don’t really understand that.

Risk factors for vertical transmission

Risk factors for transmission do include maternal CD4 counts but viral load is by far is the most highly predictive factor. Antiretroviral prophylaxis will modify transmission rates by the order of going down to around 10% maybe as low as 5%. Antiretroviral combination therapy will get transmission rates well below 5% maybe less than 1%. A prior infected child for a woman not on therapy is a risk factor for another infected child.

Of course signs of advanced AIDS such as weight loss, tuberculosis and opportunistic infections are high risk for vertical transmission. There would be lots of maternal blood in an umbilicus from a placenta – and this is just to remind you of the massive and intimate contact there is between the maternal and foetal circulation during pregnancy. Also, it may not just be the passage through the vagina and exposure to maternal genital secretions that is responsible for the transmission of HIV. The foetus is exposed, particularly at the end of pregnancy, to massive amounts of virus, even in the placenta alone during labour. Mechanisms for transmission remain unknown. Could exposure to maternal blood be a possible reason that babies get infected so much? Could this happen in placenta? We still don’t know.

I would like to discuss these data which appeared in 1996, the data generated in the early 90s, in women who received no antiretroviral prophylactics and no antiretrovirals at all. This is from the WITS study where they observed ruptured membranes in a large number of women, and as the length of ruptured membranes increased so did the possibility of transmission. Interestingly it never gets above 50% even when the membranes have been ruptured for as long as two days. It was from data like these, from here and elsewhere, that made people wonder if they could prevent ruptured membranes completely ¥ and whether Caesarean sections could cut down the transmission rate.

One of the questions in the early years that I asked myself was why does the probability of transmission never get greater than 50%. Could it be that there is something else besides ruptured membranes ¥ that the virus gets to the foetal compartment, and perhaps it is something like chorioamnionitis (a bacterial infection of foetal membranes and foetal tissues which happens as a result of ruptured membranes) and that sort of immune activation in the foetus might prime the foetus for a transmission … and there is evidence that chorioamnionitis is highly correlated with infection transmission probability.

We first saw in 1998 retrospective evidence of prevention of transmission by elected Caesarean section before labour and before ruptured membranes and another analysis appeared the next year in the New England Journal of prospective cohort studies where 8500 maternal/foetal pairs were examined and no mother out of these 8500 pairs received more than AZT alone and most mothers received no therapy at all. In this analysis there was no viral load data available whatsoever. It was a highly effective intervention – all these studies showed a reduction to about 10% to 2% on the order of five to six fold of transmission and this again we will see in the European collaboration.

But as I said before there is no data to demonstrate a benefit from Caesarean section to mothers who are receiving potent combination therapy. I will just add, because I know I am flying in the face of practice in the UK. I mentioned that mothers have their choice and we offer elected Caesarean section to our HIV infected mothers – I don’t have to live with an infected baby so it is not my decision. Clinically what worries me about elected Caesarean section is that it distracts both the care giving team, the mom, and her family from the critical issue of control of maternal plasma viremia during pregnancy, particularly at the end. It shifts the focus to the operative intervention away from the mother’s health. I suggest to you is the most important variable in terms not only of transmission of the virus but also the welfare of her child once it is born.

I would like to share with you some of our data from San Francisco general hospital. We asked ourselves about potent antiretroviral combinations and whether they were really making a difference to women. In the early years a lot of people said don’t give PIs to pregnant women: they won’t be able to take them, they don’t know how to take them, it is a terrible time for them to take them etc. It was very like farmer Fred from Zimbabwe who was told that as he did not own a watch he couldn’t successfully take combination therapy. This healthy guy appears before the audience at the recent Barcelona conference and says I am here today to tell you that I still don’t own a watch and I do take combination therapy.

Overall adherence was very good in our mothers. This is demonstrated by a retrospective historical review of the treatment experience of our moms (see slide). We didn’t see much change in viral load results in our mothers who took either no therapy or just AZT in those early years. As you see there was no significant change in their viral loads. A few years later Combivir was very popular in our practice and it did reduce viral burden somewhat by delivery. By far the most effective reduction of viral load we saw in our moms who were on three or more drugs.

Each one of these little panels represents mom’s viral load at baseline which was either at registration for prenatal care or the initiation of therapy, whichever came first. I just converted these data into a bar graph showing that mothers who received no drugs, with very small numbers, had no change. AZT alone did not influence the viral load; two drugs brought it down significantly; three drugs together was a highly significant change from here and we approach a mean drop of two logs below baseline during pregnancy which in any study or test of anti viral efficacy – as you can see is quite successful.

So does reducing a mother’s viral load make a difference? It did in our cohort. We have a lot more CD4 data on women receiving either zero or one medications and there is no difference here, two medications a slight trend upwards, and with three medications, an amazing change in CD4 counts as we can see in this bar graph – almost up to a mean gain of 200 for women receiving potent forms of combination therapy. It is a clear and enormous benefit to maternal health.

Karen Beckerman, October 2002.