Three trials bring African mother to child transmission down to four per cent; WHO vows to reconsider guidelines

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Three trials of various regimens of nevirapine plus NRTIs to prevent mother-to-baby transmission of HIV have brought the infection rate among newborn babies down to between below five per cent, the 12th Retrovirus Conference in Boston heard on Thursday.

The three presenters each finished their presentation with the declaration that “this is the lowest vertical transmission rate so far seen in Africa” – but the accolade actually went to the last presentation, the Mashi trial in Botswana, which achieved a transmission rate of 4.0 per cent.

During questions after the presentations, Professor Charles Gilks of the World Health Organization said that in the light of the new data the WHO would convene a special meeting to discuss whether to modify guidelines for the prevention of mother-to-baby transmission of HIV. This was widely interpreted as a promise to reconsider its endorsement of nevirapine monotherapy.

Glossary

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

protocol

A detailed research plan that describes the aims and objectives of a clinical trial and how it will be conducted.

resistance testing

Laboratory testing to determine if an individual’s HIV strain is resistant to anti-HIV drugs. 

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

monotherapy

Taking a drug on its own, rather than in combination with other drugs.

The studies were as follows:

DREAM

A study in the Italy/Mozambique research collaboration DREAM provided the most comprehensive antiretroviral regime, giving mothers nevirapine plus either AZT/3TC or d4T/3TC from the 25th week of pregnancy or 60 days pre-delivery to six months post-delivery. Babies were not given ARVs. A total of 778 women were offered and completed taking the protocol. There was an overall rate of transmission at birth of 4.1% but a marked disparity between AZT and d4T regimens, which achieved transmission rates of 3.7% and 11.1% respectively. No explanation was offered for this discrepancy.

One point four per cent of babies were infected through breast feeding in the first month and 0.6% after that leading to an overall transmission rate of 6.1%.

Three per cent of women experienced grade four liver toxicity but there were no nevirapine-related deaths. Twenty women were selected for resistance testing and three (15%) turned out to have nevirapine resistance mutations (Palombi).

DITRAME+

The French DITRAME+ study in the Côte d’Ivoire gave 329 women AZT and 3TC from 32 weeks of pregnancy to three days after giving birth. During labour they were given a single dose of nevirapine and an extra dose of AZT/3TC. Babies received AZT for seven days after birth and a single dose of nevirapine two days after birth.

The transmission rate six weeks after birth was 4.7%. Viral load in the women who transmitted HIV was at that point 145,000 and their CD4 count 293; in the non-transmitting woman viral load was 28,000 and CD4 count 416.

This study made intensive investigations into drug resistance, genotyping the HIV of every transmitting woman and a third of the non-transmitters. One non-transmitting woman had nevirapine and 3TC resistance mutations and three transmitting women had the 3TC M184V mutation alone. One infected baby had nevirapine resistance and three had M184V even though babies were not given 3TC (Chaix).

MASHI

The Botswana ‘Mashi’ study was a complex randomised placebo controlled study giving AZT and nevirapine in various combinations to mothers and babies, combined with breastfeeding interventions. The breast feeding transmission results are summarised in a separate article.

Furthermore a third of the way through recruitment the protocol was changed. Originally the trial gave all mothers AZT from 34 weeks to delivery, and to the babies from birth to one month. It then randomised participants to single-dose nevirapine to the mother in labour and to the baby less than three days after birth, or a nevirapine placebo to both. The nevirapine placebo was judged unethical due to protocol revisions, and the revised protocol gave nevirapine to all babies as soon as possible (an average of 24 minutes) after birth, though half of the mothers still got nevirapine placebo.

During the first study period there were 485 births. The transmission rates at birth were 3.7 per cent to babies given nevirapine and 4.5 per cent to babies given placebo. A month after birth these rates had risen to 5.3 and 6.2 per cent respectively.

During the second study period there were 694 births. The transmission rates at birth were 2.3 per cent for mother/baby pairs who both received nevirapine and 3.8 per cent where the mother received a placebo, rising to 3.7 and 4.3 per cent respectively a month after birth.

During the second study period HAART became available and 71 of the 694 women involved took it. The overall transmission rate at birth over the entire study was 4.0 per cent.

A resistance substudy found that 44 per cent of women given nevirapine developed resistance mutations. This compares with 1.14 per cent of women in the DITRAME+ study. Researchers were at a loss to explain how providing women with a ‘tail’ of three days’ AZT/3TC after giving birth had cut the resistance rate forty-fold, knowing that nevirapine has a longer half-life than this in many women (Shapiro).

References

Chaix ML et al. Addition of 3 days of ZDV + 3TC postpartum to a short course of ZDV + 3TC and single-dose NVP provides low rates of NVP resistance mutations and high efficacy in preventing peripartum HIV-1 transmission: ANRS DITRAME Plus, Abidjan, Cote D'Ivoire. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 72LB, 2005.

Palombi L et al. HAART in pregnancy: safety, effectiveness and protection from viral resistance: results from the DREAM cohort. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 67, 2005.

Shapiro R et al. Maternal single-dose nevirapine may not be needed to reduce mother to child transmission in the setting of maternal and infant zidovudine and infant single-dose nevirapine: results of a randomized clinical trial in Botswana. Twelfth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 74LB, 2005.