Efforts to reduce perinatal transmission fuel  the debate over "haves" and "have nots"

BY LYNNE MELCOMBE

A new, short course of AZT has potential to rein in the galloping rate of mother-to-child transmission of HIV in the developing world.

Last year, about 550,000 infants, primarily in resource-poor nations, acquired HIV from their mothers during pregnancy, birth, or through breast feeding. That number will rise as HIV infection increases among women of childbearing age. In some countries, HIV is now the single greatest contributor to child mortality.

One of the biggest success stories at the 1994 AIDS conference in Yokohama concerned a 66% reduction in vertical HIV transmission in American and European clinical trials. Equally exciting at the 1996 conference in Vancouver was the news that the implementation of this research in the US had led to a 43% reduction in perinatal transmission overall.

At CHF1,000 to 1,500 per treatment, however, these reports offered little hope in the South where HIV infection is worst, challenging researchers to determine if a more affordable treatment could be developed. Nathan Shaffer of the HIV/AIDS Collaboration in Bangkok recently completed research demonstrating that it can. "We found a 50.1% reduction in transmission using oral, short-course AZT, or ‘the Bangkok regimen,’ if you will," says Shaffer. Transmission in a placebo group was 18% while among women receiving treatment it was 9%.

The short-course treatment includes three oral doses of AZT daily beginning at 36 weeks gestation and every three hours during labour, with no post-partum treatment of newborns and elimination of breast feeding. Shaffer estimates that 80% of the treatment effect can be explained by a significant reduction in viral load from 36 weeks to delivery, when the risk for transmission appears to be highest.

The short-course therapy also appears to increase adherence and decrease the risk that new, drug-resistant strains will develop. Adherence rises because the treatment has few side effects and is shorter and less complicated to stick with; extensive counselling and support also seem to be critical. Oral rather than intravenous medication during labour makes the therapy more accessible where hospital deliveries are not always possible. The resulting high rates of compliance combined with the shorter regimen may provide less opportunity for resistant strains to develop. Shaffer adds, "Once women know that the short-course regimen works well, we would expect this to be [another] strong motivator for high compliance."

Magnifying the impact of Shaffer’s findings, pharmaceutical giant Glaxo Wellcome announced in March that it would negotiate differential (reduced) pricing with developing nations to cut the cost of treating pregnant women there to just CHF75 to CHF200 per treatment. "We’re trying to establish that a differential pricing approach – particularly for a finite intervention like maternal/child transmission – is well-contained and cost effective," says Peter Young, a top executive at Glaxo.

Although Glaxo’s move is precedent-setting and their discounted price will make short-course therapy affordable in some countries, in sub-Saharan Africa, where HIV prevalence may be as high as 40%, the drug’s cost may still be beyond reach. This fuels the argument from some AIDS activists that, after the millions of dollars Glaxo has made on AZT, they should provide it free.

"You’re going to extremes when you talk about donation," says Young, noting that most rapid, private sector advances in HIV treatment have been funded by profits. "If you’re talking about extending this intervention as far as possible, the only generalisable model is predicated on differential pricing."

Young acknowledges that the discounted rates may remain beyond the resources of some nations, and require multiple sources of funding. But even if the drugs were free, he notes, the health infrastructure required to provide widespread counselling, testing, and treatment is not in place, and neither is the capital to build it. "Our feeling is that differential pricing at the level we’re talking about is a significant contribution from our side. Hopefully, that will be sufficient to encourage participation by other parties."

One area for other-party participation may be the provision of safe alternatives to breast feeding. The success of short-course therapy depends to an unknown extent on avoiding breast feeding. But in much of Africa, mothers must choose between exposing their infants to HIV through their breast milk or to an array of water-borne pathogens through infant formula. "Particularly in Africa, there is still a great concern about the role of breast feeding and whether the short course will reduce transmission or just shift it from the peripartum to the postpartum period," says Shaffer. "We need to know more about this, as quickly as possible."

Even infants who resist infection altogether are at risk. More than one study shows that, particularly in Africa, when a mother dies, her children’s risk of mortality increases independent of infection – and, unless affordable treatment becomes available to HIV positive mothers postpartum, they will die. How will short-course therapy and price reductions help these babies if companies like Glaxo don’t also price treatment within reach for their mothers?

"How indeed?" asks Young. "This is a very real problem. We’re not in a position to say to the affected governments, ‘You ought to treat the mothers.’" But if the governments feel the mothers should be treated, Glaxo should provide pricing consistent with the current reductions. That would involve indefinite treatment with triple-combination therapy and protease inhibitors, which would be "pretty ambitious," says Young. "But if the parties participating feel that the mothers deserve to be treated in their own right, we don’t want to be left as the solitary impediment because we’re charging western prices."

Research like Shaffer’s has given rise to controversy over the ethics of placebos, which has, in turn, generated research into the efficacy of placebo vs. equivalency trials. Dr James G Kahn, an associate professor with the University of California San Francisco (UCSF) Institute for Health Policy Studies and the AIDS Research Institute, compared the accuracy of data collected through placebo-controlled and equivalency trials of short-course ZDV therapy in Africa.

"I didn’t do an ethical analysis," says Kahn, "but part of the ethical debate is that we could just do equivalence trials. For a variety of reasons, I concluded that they wouldn’t work." Those reasons include problems with extrapolating results from studies of American women to an African population where immune status and breast-feeding practices, among other things, differ significantly. There are also problems with historical data in an area where transmission rates range from 25-40%. Kahn notes that when researchers performing a Thai trial of a two-week course of AZT compared results with historical data, "it looked like it worked. But luckily they had a placebo arm and were able to see that [the two-week course] was no better than the placebo."

As well, placebo-controlled trials can be completed more quickly than equivalency trials, leading to earlier program implementation and more lives saved, Kahn says. He estimates that 40,000 African lives could be saved for each year sooner that short-course, perinatal AZT programs are established.

While western ethicists argue against different standards of research and care in rich and poor nations, Dr Joseph Saba, a clinical research specialist, says using placebos is a matter of pragmatics. "There are already multiple standards," he says. "We’re aiming for a single one." That requires rapid accumulation of accurate, clear-cut data within the real context of the country. For example, only 20% of Ugandan women seek prenatal care prior to 34 weeks gestation. Therefore, equivalence trials extrapolated from ACTG 076, which starts as early as 14 weeks, only apply to 20% of the Ugandan population. "What about the other 80%?" asks Saba.

"Now we’ve dropped the placebo because the regimen is workable," he says. "We have a gold standard. That doesn’t mean we have two standards. If a woman comes to us before week 36, we’ll give her treatment. But now we’re also able to provide treatment to women who come at week 36."

Placebo also provides hard data for donors, says Saba. "You can’t go to donors and ask for CHF30 million when you only have vague data. What would they say? Already when we have clear data, we have to fight to get the money. You can’t make policy with wishy-washy data."

A similarly pragmatic approach guided Saba and Kahn’s research with Elliot Marseille, a doctor of public health at UCSF, on the cost effectiveness of short-course therapy in Tanzania and Thailand. It’s research that’s bound to make many people uncomfortable. Basically, it gives those who allocate resources a tool with which to perform economic triage, a monetary scale that weighs the cost of intervention against the fiscal value of years of life saved. (For an explanation of their analytical method, see "Hard Decisions in the Real World.")

"We haven’t chosen this epidemic and we’re not happy with it," says Saba. "But maybe AIDS will break ground for some creative solutions to distribution of, at least, health-care resources," he says. Thirty million people worldwide need treatment, while millions more can benefit from prevention. But over the last five years, while the epidemic has raged in the South, spending on global communication has increased six-fold and health budgets have increased by zero.

Explaining the motivation for much of the controversial thinking taking place in the developing world today, Saba says, "I truly think it’s time to look outside the box."

BY  LYNNE   MELCOMBE

Marseille, Kahn, and Saba’s research into the cost effectiveness of short-course AZT therapy is an example of the harsh pragmatics driving decision making in the South and sparking ethical debate in the North. Their analysis involves calculating the cost of intervention, which includes counselling and testing (C&T) plus treatment, and subtracting the life-time medical costs averted for infants in whom HIV infection is avoided.

For example, says Marseille, for every 100 Tanzanian women who go to a clinic for C&T, 15 are HIV positive. Nine of those will complete the C&T, of which six or seven will agree to AZT therapy and infection will be averted in three or four infants.

Consequently, the cost of providing C&T to 100 women in Tanzania, at CHF6 each, will be added to the CHF60 cost of providing AZT to each of six or seven women. These numbers are then compared with years of life saved and their monetary value.

"This kind of economic appraisal of health benefits makes a lot of people uncomfortable," says Marseille. "You can take issue both with the philosophical underpinnings and the way they’re used." But it provides a common metric for comparing otherwise different types of programmes such as immunisation and perinatal intervention, and comparing the costs of similar programs in different areas.

It may seem crazy, says Marseille, but it gives those who provide and allocate resources a basis for determining how much money spent on which programmes in which areas will save the most lives and limit the damage of one of history’s worst epidemics.

these stories can also be found in The Bridge, the onsite print newspaper          

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