CONFERENCE REPORT

2nd IAS Conference on HIV Pathogenesis and Treatment

13-16 July 2003, Paris

This biannual conference alternates with the years of the International AIDS conference. Location is also planned to alternate between a developed country and one where access to treatment is still not widely available - the first meeting was held in Buenos Aires in 2001 – in order to maintain a balance between new science and the importance of access issues.

The second meeting – this year in Paris – attracted 6,000 delegates from 120 countries. One thousand eight hundred abstracts were received, 180 of which were selected for oral presentations and more than 900 for poster presentations. None of them however were available online as we went to press - although webcasts and other resources for all conference plenaries and selected other sessions are provided by the Kaiser Family Foundation online; they do not include the facility to see the slides being referred to in the lectures:

http://www.kaisernetwork.org

Webcasts include:

Main Plemaries

  • Challenges and lessons learned in implementing antiretroviral therapy in the developing world
  • Host/virus mechanisms in the molecular pathogenesis of HIV
  • New antiretroviral drugs and therapeutic strategies
  • HIV vaccine research: the state of the science
  • HIV entry: insights into viral tropism, pathogenesis, and antiviral therapy
  • Mechanisms and management of metabolic complications associated with highly active antiretroviral therapy

Forum Lectures:

  • HIV drug resistance
  • The scaling-up of antiretroviral therapy in developing countries
  • Mother-to-child HIV transmission

Keynote Lectures:

  • 20 Years of HIV Science
  • From Science to Action: Challenges in Managing AIDS

All references are from the programme and abstracts of The 2nd IAS conference on HIV pathogenesis and treatment, Paris, France 13-16 July 2003 unless otherwise stated.

IAS: MOTHER TO CHILD TRANSMISSION

Nevirapine and MTCT: the single-dose backlash

Polly Clayden HIV i-Base

Strategies to reduce mother to child transmission (MTCT) both during labour and through breastfeeding were in the foreground more than ever at this conference.

More than 20 oral presentations and more than 50 posters evaluated various aspects of transmission from mother to child, but as usual data on maternal health before, during or after pregnancy, delivery and breastfeeding was scant.

Notably though, some of the most high profile presentations, not only acknowledged that ideally a woman would receive appropriate treatment for her own health but discussed alternative strategies to single dose NVP given to the mother at onset of labour followed by a dose to her infant.

Presumably an acknowledgement that ease of development of resistance (see report from Mexico Resistance meeting above) and an optimism that through MTCT Plus programmes and various other scaling up initiatives some women will eventually receive treatment, drove – what America likes to call – this “paradigm shift”. Anyway as Glenda Gray commented “We seem to be witnessing something of a nevirapine backlash…”

Single dose versus combination therapy “controversy”

As part of a series of sessions entitled “controversies” - two MTCT grandmasters - John Sullivan and Francois Dabis set out to convince us of the benefits of two possible reduction strategies. [1]

Dr Sullivan prefixed his talk with “Of course all these women should be treated with the very best combination therapy,” and then argued in favour of a universal application in high prevalence areas of 6mg NVP (post exposure prophylaxis) PEP to the infant (which showed promising results at Barcelona compared to including the maternal dose [2]). He suggested this would avoid both resistance in the mothers and the need for voluntary counselling and testing (VCT).

To avoid MTCT during breastfeeding he proposed using his own (in early trials) infant subcutaneous “controlled delivery system” of NVP prophylaxis or possibly a vaccine.

Dr Dabis then presented the case for more complex therapy, citing his group’s DITRAME Plus Trial using three drugs presented at this conference (see below). And the SIMBA study – using two drugs from 36 weeks gestation and infant prophylaxis of 3TC or NVP during breastfeeding (also described later in this article).

Dr Dabis was less concerned about the issue of resistance and more driven by the added potency of combination therapy compared to monotherapy.

Beyond nevirapine

In a state of the art lecture Dr Glenda Gray gave a fascinating overview of where we are with MTCT reduction in resource poor settings. [2]

She reminded us that 1,900-2,200 infants per day are estimated to be infected with HIV and although there have been several large randomised trials addressing this mode of transmission – HIVNET 012, SAINT, PETRA etc – only 3% of pregnant HIV positive women in Africa access an MTCT programme at all.

Although clearly we need better coverage of programmes, better programmes and as she pointed out, “We need not to be happy with transmission rates of around 8-12%”, Dr Gray was emphatic that we also need to be worried about NVP resistance. As part of her overview she discussed strategies using both alternative agents and avoiding using nevirapine only for the mother.

She highlighted the BMS: A1455-094 trial– first presented at the Durban conference – that achieved promising results, albeit in a very small study, showing short course d4T/ddI produce transmission rates of less than 5%. [3]

She presented a good case for tenofovir as an attractive possible new candidate for MTCT. This nucleotide reverse transcriptase inhibitor crosses the placenta, does not have to be phosphorylated to be active and has an intracellular half-life of 12-15 hours in activated lymphocytes. It has been shown to remain active against a variety of drug resistant HIV-1 strains in vitro and is less likely than NVP to prejudice future maternal therapeutic options. She explained that, although the PACTG have been working on a protocol for “anything between two and four years and still nothing’s happening” and “We need to rapidly translate dispatching new drugs into some kind of intervention.”

Strategies to avoid using NVP only are currently underway – the BI 1413 trial utilises what the Boehringer Ingelheim investigators call “functional monotherapy”. This three-arm study compares NVP single dose to NVP single dose plus ZDV/3TC (Combivir) for four and seven days in the intrapartum and post partum period to the mother. “Hopefully we will have the results in about a year’s time”, she explained.

She concluded her talk with a quote from Nelson Mandela from his opening address at this conference: “We have failed to translate our scientific progress into action where it is most needed…this is a global injustice…it is a travesty of human rights.”

Short course zidovudine and lamivudine and peripartum nevirapine

In this same session, Francois Dabis presented findings from the ANRS 1201 DITRAME Plus - an open-label non-randomised trial in Abidjan starting in September 2002. [5] In this trial women received ZDV/3TC (Combivir) from 32 weeks of gestation and single dose NVP at the beginning of labour. The maternal treatment (ZDV/3TC) was also continued three days postpartum.

The infant received post-exposure prophylaxis (PEP) for one week of ZDV syrup and a single dose of NVP syrup on day three.

Dr Dabis presented interim results showing a transmission rate of 5%, 5/99 children with 4-6 week follow up. He reported that all HIV-positive infants were infected in utero (RNA positive on day seven) and they were born to mothers with CD4 <500mm3. He concluded that this strategy prevents most peripartum transmission from mother to child. This trial is not powered to look at resistance in the mothers.

Breastfeeding

The other issue addressed in this session was transmission through breastfeeding. Dr Ruth Nduati delivered the state of the art lecture and emphasised that intrapartum antiretroviral prophylaxis alone does not work…Breastfeeding diminishes the efficacy of these protocols… Breastfeeding continues to be a reality” [6]

Mortality in breastfed and formula fed children

In an MTCT session the previous day Dr Becquet described a comparison between mortality rates in breast and formula fed children among children born to HIV-positive mothers in the DITRAME Plus ANRS 1202 cohort [7].

Mothers were given the choice between formula feeding (formula provided free) and exclusive breastfeeding for three months then early weaning. Mothers and infants were followed for two years. Of the 398 children enrolled, 201 (51.2%) received formula from birth, 175 (44.5%) were breastfed and 17 (4.3%) were mix-fed. Of the infants 28 children died, among them 11 who were HIV infected at six weeks of age. Among the HIV uninfected children four and two children died in the formula fed (n=187) and breastfed (n=166) groups respectively.

Dr Becquet reported that there was no evidence of a higher mortality in the formula fed HIV uninfected compared to the breastfed.

Mortality among HIV-infected mothers and children’s feeding modality

Dr Marie Louise Newell presented data on behalf of the Breastfeeding and HIV Transmission Study Group. She explained that we know very little about the effect of breastfeeding on the health of HIV positive women themselves and that the two studies to date conducted in Africa have presented conflicting results. One study in Nairobi and Kenya suggested that mortality in breastfeeding women was substantially higher than in non-breastfeeding women and another conducted in Durban suggested there was no difference.

This study evaluated mortality among a multi site cohort of 4,237 African mothers with available data to be eligible for analysis over a period of 18 months following delivery.

Dr Newell reported that the mothers’ median CD4 count around the time of delivery was 464 mm3. In the 18 months following delivery, 362 women died and the median time to death was 9.8 months. 3,717(87.7%) women ever breastfed and the median duration of breastfeeding was 8.8 months.

In univariate analysis feeding mode was not associated with mothers’ mortality (p>0.11). She reported that independent risk factors were: maternal CD4 count (lower CD4 <200 increased risk of 12 and 18 month mortality [p<0.001]); and child’s feeding mode (mothers who ever breastfed had lower risk at 12 moths than mothers of never breastfed children [p=0.033] but not at 18 months [p=0.068]).

She concluded that women who have advanced disease around the time of delivery had a greatly increased risk of dying in the months following, but mortality rates in the first 18 months postpartum were lower in women who ever than those who never breastfed. She suggested that this is because those women are healthy and are able to continue breastfeeding for longer periods. She explained, “This association is likely to be very complex and very difficult to evaluate in observational data but we are trying our best to investigate further”.

Formula is safe in a resource poor urban setting

Dr Coetzee, reporting on a study conducted in Khayelitsha, South Africa, described the formula versus breastfeeding issue and in turn appropriate guidelines as “a fierce debate”. [9]

Khayelitsha is a township outside Cape Town with approximately 500,000 inhabitants of which 10% are estimated to be HIV-positive and approximately 7,000 HIV positive women deliver each year. Since 1999 there has been an MTCT programme in Khayelitsha implemented by the Western Cape Provincial Health Department. As part of this programme, formula milk is offered free of charge to mothers for nine months (most households in Khayelitsha [71%] have available potable water) and support groups are provided.

Of a sample of 113 women attending the MTCT programme interviewed to evaluate the extent of the uptake of this intervention, 95% of women chose not to breastfeed at all, 3% of women had breastfed for between one and four days or mixed fed for one week. The mothers were also asked whether their children had experienced episodes of diarrhoea and 70% reported that they had not.

Despite the high prevalence Dr Coetzee reported stigma to be still very high and to be seen formula feeding can represent disclosure by bottle, so women have discussed in their support groups how they will lie to their friends and family – TB, hypertension, the milk did not come…”When people ask me why I am formula feeding, what they are really asking me is am I HIV positive?”

Nevertheless, the majority of women chose not to breastfeed and they make the decision themselves. Dr Coetzee concluded: “Formula feeding is safe and feasible in an urban environment where sufficient potable water is available.”

SIMBA study shows only 1% breastfeeding transmission rate

The jury is still out though as to whether formula feeding is always possible or even desirable in resource poor settings. Dr Vyankandondera from the SIMBA study – a randomised phase III open-label, multi-centre trial to evaluate the efficacy of prophylaxis with either 3TC or NVP to breastfed children to prevent postnatal HIV transmission – reported promising results in an oral late breaker.

A group of 413 antiretroviral naïve pregnant women were enrolled from centres in Rwanda and Uganda. The mothers received AZT/ddI dual therapy from 36 weeks gestation until one week postpartum and were provided with counselling on exclusive breastfeeding. The median viral load of the mothers at delivery was 2.66 logs copies/ml and median CD4 was 427mm3.

DNA HIV-1 PCR was performed on the infants at birth, six weeks, three months and six months. Three hundred and ninety-seven infants were randomised to receive either 3TC (n=199) or NVP (n=198) syrup. In the 3TC and NVP arms, respectively 90.5% and 86.5% were breastfed exclusively; 7% and 9.6% breast and bottle and 2.5% and 3.5% exclusively bottle-fed. The infants were fed for a median of 107 days in the 3TC arm and 106 days in the NVP arm.

Of the infants that were at risk after four weeks of age, late postnatal transmission occurred in 2/179 (1.1%) in the 3TC arm and 1/179 (0.6%) in the NVP arm. Dr Vayankandondera concluded that infant antiretroviral prophylactic intervention during breastfeeding, and counselling of breastfeeding mothers can reduce postnatal transmission from 15% to an incidence of 1% in the first six months of life. “These are the first data to show that mothers can safely breastfeed children, even in the presence of HIV infection,” he explained, and he added: “This strategy could greatly reduce the stigma associated with formula feeding”.

References

  1. Sullivan J, Dabis F, Luo C. The use of single-dose versus combination therapy to prevent mother-to-child transmission? Abstracts 196, 197.

  2. Gray G, Violari A, Chersich M et al. Preliminary analysis of a randomised controlled study to assess the role of post-exposure prophylaxis in reducing mother to child transmission of HIV-1 XIV International AIDS Conference, Barcelona, Spain July 7-12, 2002. Abstract  LbOR13.

  3. Gray G. Beyond nevirapine. Abstract 217.

  4. Gray G et al. Preliminary efficacy, safety, tolerability and pharmacokinetics of short course regimens of nucleoside analogues for the prevention of mother-to-child transmission of HIV. XIII International AIDS Conference; Durban, July 9-14. Abstract TuOrB355.

  5. Dabis F, Ekouevi DK, Rouet F et al. Effectiveness of a short course of zidovudine and lamivudine and peripartum nevirapine to prevent HIV-1 mother-to-child transmission. The ANRS 1201 DITRAME Plus trial, Abidjan, Cote d’Ivoire. Abstract 219.

  6. Nduati R. Efficacy of short course antiretroviral regimens in breastfeeding populations: narrowing the gap. Abstract 216.

  7. Becquet R, Becquet L, Ekouevi DK et al. Mortality in breastfed and formula fed children born to HIV infected women in a PMTCT project in Abidjan, Cote d’Ivoire: DITRAME Plus ANRS 1202 Abstract 63.

  8. Newell ML, Read J, Leroy V et al Mortality among HIV-infected mothers and children’s feeding modality; the breastfeeding and HIV international study (BHITS). Abstract 221.

  9. Coetzee D, Hilderbrand K, Goemaere E. Formula is safe in a resource poor urban setting with potable water. Abstract 220.

  10. Vyankandonera J, Luchters S, Hassink E et al. Reducing risk of HIV-1 transmission from mother to infant through breastfeeding using antiretroviral prophalylaxis in infants (SIMBA study). Abstract LB7.

comment

Use of 3TC or NVP for breastfeeding prophylaxis has the potential to save hundreds of thousands of newborn babies from contracting HIV via breast milk – after a period of triple combination therapy for their mothers has reduced the initial risk of infection. This was perhaps the most significant and important study presented at the IAS meeting.

Meanwhile a rather confusing decision was confirmed on July 28th by the Medicines Control Council (MCC) of South Africa to deregister nevirapine for use in mother-to-child transmission programmes. This decision is based on a rejection of the HIVNET 012 study, and the patent holders Boehringer Ingelheim has 90 days to provide the MCC with more data before the licence is withdrawn.

Understandably, this has caused an outcry from both the community and healthcare workers in South Africa. In a statement, the Treatment Action Campaign (TAC) explains: “Nurses and doctors in public hospitals have expressed dismay at this decision because it undermines the sustainability of the public sector MTCT programme.” They continue: “Nevirapine is not the only drug that can be used to reduce mother to child HIV transmission. AZT and other antiretrovirals can be used as individual drugs or in combination for this purpose. The TAC has for a long time called for hospitals and clinics, where capacity exists to begin using more effective regimens than short course nevirapine, but the reality is many facilities will not be in a position to upgrade their programmes to better regimens for months or even years to come. It is these facilities that will be endangered if the MCC carries out its threat”

The TAC describes the decision as disturbing and confusing, it believes it is politically motivated and threatens to vastly undermine MTCT programmes in South Africa.

At the South African AIDS Conference in Durban, an emergency plenary was arranged to discuss this issue before the closing ceremony. Precious Matsoso from the MCC presented “a regulators perspective” and explained why they found HIVNET 012 to be unacceptable as a pivotal study (for which it was not designed) and the concerns that had led to this decision. In her talk she announced that “combination antiretrovirals are available, they should be used to treat the mother”, which most would strongly agree with but it is hard to imagine how this might happen in a country that has no national treatment plan.

Catherine Wilfert the scientific director of the Elizabeth Glazer Paediatric AIDS Foundation and James McIntyre, Director of the Perinatal HIV Unit at the Chris Hani Baragwanath Hospital, Johannesburg presented trial and programme data to defend the use of nevirapine for this indication. Professor McIntyre was clear that: “We cannot compare programme data with randomised clinical trials but we urge the MCC to find ways to consider these data.”

Although there is consensus that nevirapine is by no means the best way to reduce mother to child transmission or to benefit maternal health. “We are the first to recognise that we could do even better,” Dr Wilfert explained. It is widely accepted that single dose nevirapine has been a central part of developing MTCT programmes that use more complex interventions and provide women with antenatal care. Professor McIntyre was most emphatic: “This would not have been possible without the use of a single dose regimen, this has been the building block of programmes.”

In the same plenary, making an impassioned plea for antiretrovirals for her people including nevirapine, activist Prudence Mabale the director of Positive Women Network said: “It is not just the drug - these programmes have changed women’s lives.”

Links

Complete statement TAC website:

http://www.tac.org.za

Reports from the South African AIDS Conference will be included in next issue of HTB.

HIV Treatment Bulletin Vol 4 No7 August / September 2003