Breastfeeding and HIV transmission; Clinical trials for enfuvirtide (Fuzeon, T-20)

Breastfeeding is a risky proposition for babies born to HIV-positive women. About 15% of them become infected from virus-laden breast milk, and the odds are even worse if their mothers never received anti-HIV treatment before giving birth. Yet, in parts of the world where water quality is questionable, infant formula costly, and bottle feeding stigmatized, the vast majority of moms have little, if any, other choice. In Rwanda and Uganda, for example, far more than 90% of mothers breastfeed. However, a study conducted in those two countries shows that the consequences of breastfeeding can be significantly less lethal if both mother and child receive a short course of antiretroviral drugs, said researchers at the International AIDS Society meeting held in Paris last July. Spearheaded by the International Antiviral Therapy Evaluation Center in Amsterdam, the ‘Stopping Infection from Mother-to-child via Breastfeeding in Africa', or SIMBA, study monitored 358 at-risk breastfed babies. Their HIV-positive mothers received zidovudine plus didanosine beginning at the 36th week of pregnancy until a week after birth as well as intensive counselling on safe breastfeeding practices. The neonates dined exclusively on breast milk and received twice daily doses of either lamivudine or nevirapine until 1 month after they were weaned, usually at about 5 months of age. When tested at 6 months of age, only three of the infants were infected with HIV. For ethical reasons, the SIMBA study had no control group. Instead all the participating mothers and infants received antiretroviral drugs. But based on HIV transmission rates due to breastfeeding by moms who were treated during pregnancy, some 50 babies would probably have been infected if they had not received antivirals as well. `‘These are the first data to show that mothers can safely breastfeed children even in the presence of HIV infection,’’ says Joseph Vyankandondera, a doctor at the Centre Hospitalier de Kigali, Rwanda, one of the three study sites. And the protocol, he adds, ‘‘is simple and safe’'. The caveat, however, is the availability of the drugs. Vyankandondera estimates that a 6-month supply of antivirals for the infants costs about US$150, a sum beyond the means of most HIV-infected mothers in Africa and other poor regions. ‘‘There is no money available in Rwanda for these drugs,’’ he says, ‘‘but we are hoping that with these results we will receive donations.’' Clinical trials for enfuvirtide (Fuzeon, T-20) The 48-week results of the clinical trials for enfuvirtide, a costly and complex drug that blocks HIV from entering healthy immune cells, indicate that the ‘fusion inhibition’ strategy works. However, the findings do not erase concerns about the higher rates of bacterial pneumonia seen in patients receiving the drug, so a cohort study to address the issue has been initiated in the USA. Commercially known as Fuzeon, but previously called T-20, the molecule represents the first new class of anti-HIV treatments since 1996. While other drugs battle HIV only after the virus has invaded a cell, enfuvirtide keeps the pathogen out of cells in the first place. The compound binds to gp41, a glycoprotein on the viral envelope, preventing it from anchoring HIV onto a CD4 T cell. The ongoing TORO phase III clinical trials, which involve about 1000 patients, confirm that the keep-it-out approach is effective, even against drug-resistant HIV strains. After 48 weeks of treatment, 30.4% of the patients who received enfuvirtide along with three to five other antiretroviral medicines saw the amount of HIV in their blood fall from more than 5000 copies/ml to fewer than 400 copies/ml. Only 12% of the patients treated without the drug experienced a similar drop. In addition, patients receiving the fusion inhibitor had a bigger boost in the number of CD4 cells in their blood—91 × 106 cells/l compared to 45 × 106 cells/l for the patients receiving conventional antiretroviral drugs. But while the US Food and Drug Administration approved enfuvirtide in March, and the European Commission and authorities in Switzerland followed suit in May, one aspect of the clinical trial results has raised concerns. Patients receiving the drug came down with bacterial pneumonia more frequently—an average of 6.6 infections per 100 patient years versus 0.6 for the other patients. However, it is not clear that enfuvirtide is to blame, says Miklos Salgo, Clinical Science Leader for Fuzeon at F. Hoffmann-La Roche Ltd, which along with Trimeris Inc., developed the drug. ‘‘If we look at the [incidence rates of pneumonia] in the literature for HIV-infected patients, the rates for Fuzeon are more or less the same,’’ he says. ‘‘But for reasons that are not clear, the rates appear to be lower in the control arm of the TORO studies.’’ As a result, a cohort study in the US will track pneumonia infections in approximately 2000 HIV patients, one-fifth of whom will receive the fusion inhibitor. The life-extending benefits of enfuvirtide come at a price. An annual supply of the twice-daily, 90 mg injections costs about $20 000 per patient in the USA. According Roche, the pricing reflects costs associated with a technically challenging synthesis—making 1 kg of the 36-amino acid peptide requires 45 kg of raw materials and more than 100 production steps. The complex manufacturing will limit supply to 18 000 patients worldwide by the end of 2003. Production will be scaled up to meet the needs of a maximum of 39 000 people by the end of 2005. Authorization of the drug is pending in several countries, according to Roche. Enfuvirtide recently received approval in Canada and Australia.

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