Preventing Mother-Infant Transmission Worldwide: What Is Needed?

Interview with Joseph Saba, M.D.

Every year over 500,000 infants are infected with HIV from their mother, before or during birth or shortly after, and almost 500,000 children die. More than half of these infections and deaths could be prevented by treating pregnant women before birth. A recent clinical trial in Thailand showed that a less-intensive AZT regimen, suitable for developing countries, was effective. Two weeks later, Glaxo-Wellcome offered to reduce the price of the drug for treating pregnant women by up to 75% -- an important step forward, as it brings the drug cost of the full regimen to as low as $50.

But aside from cost of the drug, there are major logistical problems to making this treatment available. We asked Joseph Saba, M.D., Clinical Research Specialist with UNAIDS (the Joint United Nations Programme on HIV/AIDS), to explain what is needed now.

AIDS Treatment News: Give our readers a short history on antiretroviral drug treatment to prevent mother-to-infant HIV transmission.

Dr. Saba: Everything started in 1994 when the first results of the study ACTG 076 -- a clinical trial in pregnant women in the U.S. and Europe -- showed that AZT started between week 14 and 34 of pregnancy and continued until delivery, and given after birth for six weeks to the baby, could very significantly reduce the risk of mother-child transmission. Following these results, the World Health Organization held a meeting in Geneva to see how they could be applicable to the developing countries.

It became clear that these results were not applicable in many countries, because the AZT regimen was long, and started before most women come to prenatal clinic in many developing countries; also, this regimen required intravenous treatment. It was logistically and financially impossible to implement in many developing countries.

So new trials were designed to test regimens that could be more widely used. One of these trials, sponsored by the U.S. Centers for Disease Control and conducted in Thailand, was completed in December 1997; the analysis was then done and results were announced in February of this year. This trial showed that transmission could be greatly reduced with a regimen which starts at week 36 of pregnancy, is given to women twice daily instead of five times daily the way the ACTG 076 regimen was, did not require intravenous treatment during delivery, and did not require treatment of the baby. So it is shorter and much easier to apply, and could work in developing countries. Other trials are now testing different regimens -- without the placebo arms, which were stopped after the Thailand results became available. While these trials are ongoing we have been working on how to make any intervention that is applicable in developing countries really within the reach of these countries.

Several issues had to be addressed. How could the prenatal care system be adapted? What are the requirements in terms of voluntary counseling and testing? Will the women accept the intervention? And is it cost-effective, compared with other public-health programs?

We found that the treatment was acceptable; the women really wanted to use antiretrovirals to save their children from getting infected. Accepting the testing is a different issue, because it can result in discrimination, and then the women are afraid from their husband, or their family, or at their work. But once the testing has been done, they usually agree to take the medication.

When the Thai study results were announced, we adopted our cost-effectiveness model and found that this treatment was clearly cost effective -- saving as many lives and sometimes more than the same investment in blood screening for HIV. It compares well to other public-health interventions.

Also while the trials were ongoing, we were in discussions with Glaxo-Wellcome. They were involved in these studies, and we continued discussion on how we could make the regime affordable to developing countries. You probably know about the Glaxo Wellcome announcement [on price reductions for AZT].

So as soon as we got the results, we were able to figure out how practical this intervention could be, and how applicable it is in developing countries.

ATN: What is needed now?

Dr. Saba: Last month in Geneva, a meeting hosted by UNAIDS in collaboration with WHO and UNICEF looked at the practical aspects, and the next steps now. This group decided to set up a mechanism to accelerate technical development and discuss the logistics with the countries interested in doing programs, to make this happen as quickly as possible.

ATN: To give people a sense of the overall size of the effort required, about how many women each year become pregnant who are HIV positive?

Dr. Saba: According to UNAIDS estimates, more than half a million babies each year are born with HIV infection, or acquire it early after birth, from mother-to-child transmission. So working from the HIV transmission rate, we estimate that between two and three million pregnant women are HIV-infected.

ATN: How many women will have to be tested to find them?

Dr. Saba: That depends on the HIV prevalence. In countries like Zimbabwe, where 35% of pregnant women are infected, you would have to test three times more. In countries where fifteen percent of the women are infected, seven times more women must be tested. In countries like Thailand, where the prevalence is 2.4%, you could compute similarly.

We modeled the cost effectiveness, and if the prevalence rate is very low, then maybe one should not use a program of mass testing and counseling, but either target settings where prevalence is higher, or focus testing on those women known to be exposed to HIV in one way or another. When the prevalence rate is over 5%, it may be more cost-effective to offer testing to everybody. We will need to test many more women than are HIV-positive -- maybe 20 or 30 million -- to provide this treatment worldwide.

There are major problems in reaching many of these women. In some countries, fewer than 60% of pregnant women attend prenatal clinics. Many come at least once for prenatal care, but they do not necessarily deliver; in some areas of Tanzania or Uganda, for example, as few as 30% of women who have come for prenatal care deliver at the hospital. The reason is usually just the lack of transport, the lack of a telephone, to get there. But many come to a clinic during pregnancy, so at this time we could consider giving them the antiretroviral treatment.

Making such a program available to all pregnant women who really need it will take a long time. First you need to reach the women who attend prenatal clinic -- then the women who do not attend, which is difficult.

We need to look at this like the vaccine programs. This treatment is like a vaccine for the child, for preventing HIV infection in the child. When the expanded programs on immunization were established, it took years to be able to reach the whole population in a country.

ATN: Therefore this will be a long-term effort, working with the countries, and different in each country?

Dr. Saba: Yes, exactly. It is a long-term effort which needs to start now. We also must strengthen prenatal care; you need to have trained doctors and nurses, and have adequate care given to pregnant women, if we are to give them antiretrovirals.

And one must not forget about transmission through breast feeding, and the need to provide these women alternatives; this also requires logistics.

ATN: How can we approach the problem of violence and discrimination against women who test positive?

Dr. Saba: That is a very serious problem. There are basic principles. One must respect the choice of women to be tested and counseled. Also, this must be done in a very confidential way, with appropriate counseling. Confidentiality is essential because it will increase the credibility of the center in the testing process, and also it will help protect the women against any possible discrimination.

ATN: Are there programs in operation today where AZT is being delivered at a reduced price?

Dr. Saba: Not yet, but many countries are already designing programs, and some have contacted Glaxo Wellcome. We hope that within the next few months we will have programs ready to go in these countries. Thailand, for example, is very interested in implementing the process as quickly as possible; so is Zimbabwe.

ATN: What can our readers do, what can AIDS organizations within the United States do to help in this process?

Dr. Saba: It will be a lot of work for everybody -- in designing programs, in helping the countries, helping the communities in these countries to take part in the process, and developing the advocacy messages that still need to go out. Now there is an increased momentum for this issue -- for the access to drugs in general, and also for mother-to-child transmission. We need to keep this momentum growing, to turn the research findings into reality in developing countries.

A few years ago, when HIV blood screening was advocated, there were difficulties and restrictions and financial problems. Now the blood supply is screened in most countries. We need to keep driving this momentum. It is an effort for all of us.

HIV Treatment Options

by Denny Smith

This is AIDS Treatment News' third annual overview of antiretroviral drugs.

The best use of these drugs is still evolving, but several ideas have become the foundation for the current standard of care:

1. The goal of effective treatment is to slow viral replication to undetectable limits. Today that usually requires at least three drugs.

2. Resistance to these drugs can develop quickly if too many doses are missed. So if a drug is too difficult to tolerate or too complicated to manage, it should be replaced with another choice.

3. Viral loads that rise appreciably above detectable limits suggest that resistance to one or more of the drugs has developed, and a change of treatment should be considered. As with CD4 counts, one lab result is not a dependable trigger for a major decision; at least one more viral load should be drawn. But once a decision is made to change a regimen, all three drugs should be replaced at the same time, since switching or adding just one or two makes it easy for the virus to become resistant again.

Common adult doses are given for the drugs listed below; pediatric dosing and formulations can be found in the Physician's Desk Reference. Also, the side effects described are only the most common or important ones, and everyone should be prepared for less expected effects. If you are having a problem with your medications, or stop taking them for any reason, call your health-care provider immediately.

Nucleoside Analog Reverse Transcriptase Inhibitors

These drugs work by inhibiting an enzyme -- reverse transcriptase -- which the virus needs to take over a cell's machinery.

AZT, also called zidovudine, is marketed under the brand name Retrovir®. AZT can be combined with most other antiretrovirals, but probably should not be used with d4T. It can cause headaches and stomach upset, but these usually go away after a couple weeks. Over extended periods of use, it can cause anemia (low production of red blood cells), neutropenia (low white cells) and myopathy (damage to muscle fibers). These problems resolve if the drug is discontinued. The usual prescription for AZT is two capsules (200 mg) taken three times a day, or one 300 mg capsule taken twice a day. AZT is also marketed in a tablet called Combivir, which also contains 3TC (300 mg of AZT and 150 mg of 3TC). There is a liquid suspension as well, which is easier to manage for children and people who have difficulty swallowing.

ddI, or didanosine, is sold under the brand name VIDEX® and can be combined with most other antiretrovirals. It can cause pancreatitis and peripheral neuropathy, so if you experience abdominal pain, or tingling and numbness in your toes or fingers, call your provider. The usual prescription for ddI is two tablets (125 or 200 mg, depending on body weight) taken twice a day on an empty stomach with water. Many people do not like the chalky texture of the original ddI formulation; the orange-flavored version may be a bit easier to take. It also comes in a powder that can be mixed in water. Some providers feel that ddI is just as effective and more convenient if the entire daily amount is taken in one dose. But in that case, the strength and number of tablets must be calibrated to obtain the correct level of buffering agent in the tablets. A pharmacist can figure that out.

ddC, or zalcitabine, is sold as HIVID®, and can be combined with most other antiretrovirals. Like ddI, ddC can cause pancreatitis and peripheral neuropathy; if you experience abdominal pain or tingling and numbness in your toes or fingers, call your provider. The usual prescription for ddC is one tablet (0.75 mg) taken three times a day.

d4T, or stavudine, is marketed as Zerit®. It can be combined with most other antiretrovirals, but probably should not be used with AZT. Like the other "d" drugs, d4T can cause pancreatitis and peripheral neuropathy, so if you experience abdominal pain, or tingling and numbness in your toes or fingers, call your provider. The usual prescription for d4T is one capsule (30 or 40 mg, depending on body weight) taken twice a day. It also comes in a liquid suspension.

3TC, or lamivudine, is marketed as Epivir®, and can be combined with any other antiretroviral. It can cause headaches and insomnia in some people, but these usually go away after a few weeks. The usual prescription for 3TC is one tablet (150 mg) taken twice a day. It also comes in a tablet called Combivir that has AZT added (300 mg of AZT and 150 mg of 3TC). And it comes in a liquid suspension as well.

Abacavir, also known as 1592 or Ziagen™, is dispensed through an "expanded-access" program, which means it is still experimental but is available for persons who have failed other therapies. Abacavir is an important drug, but users need to know about a potentially serious hypersensitivity reaction that happens in about 3% of patients; this usually begins from a few days to four weeks after starting the drug, and it will go away without further problem if the drug is stopped and not restarted. If you develop fever, nausea, and malaise (and sometimes a rash) while taking this drug -- signs of this reaction -- call your provider immediately. If you stop taking abacavir because of hypersensitivity, NEVER RESTART IT, since restarting after hypersensitivity can cause a more serious and possibly fatal reaction. Dosing for abacavir is 300 mg taken twice a day.

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine is sold under the brand name Viramune®, and has been combined with all other antiretrovirals. Nevirapine can cause a serious rash, but this can usually be avoided by starting with a low dose, one tablet taken once a day for two weeks, and then doubled to the usual prescription: one tablet (200 mg) twice a day. Nevirapine may lower the blood levels of other drugs; when combined with indinavir in particular, the indinavir is usually increased from 800 mg to 1000 mg each dose.

Delavirdine is approved as Rescriptor®, and has been used with all other antiretrovirals. Like nevirapine, it can cause a rash in some people. The usual prescription for delavirdine is four pills (400 mg) taken three times a day.

Efavirenz, also known as DMP-266 or SUSTIVA™, is available under an expanded-access program to people with CD4 counts of 400 or less and a history of failing the approved antiretrovirals. This drug can cause light-headedness when taken with AZT, 3TC or indinavir; it can also cause kidney irritation, so that drinking plenty of water is important. The usual dosing for efavirenz is three pills (600 mg) taken once a day, although the expanded-access protocol allows for one pill taken three times a day. Efavirenz, like nevirapine, may lower the levels of other drugs. If combined with indinavir, each indinavir dose should be increased from 800 mg to 1000 mg. Efavirenz should NOT be taken during pregnancy, since it was reported to cause birth defects in recent monkey studies.

Nucleotide Reverse Transcriptase Inhibitors

Adefovir, also known as bis-POM PMEA or PREVEON™, is available through an expanded-access program for people who have failed at least two nucleoside analogs and one protease inhibitor. Adefovir can cause nausea and vomiting, and may lower levels of carnitine in the body. Dosing for adefovir is one pill (120 mg) taken once a day with 500 mg of carnitine.

Protease Inhibitors

These drugs target a different enzyme of the virus -- protease -- which is essential for HIV to assemble working copies of itself.

Saquinavir is sold under the brand name FORTOVASE®. (An older version, called Invirase, was not absorbed very well; note the new dosing for FORTOVASE.) Saquinavir can be combined with all other antiretrovirals, and may work especially well with ritonavir, using lower doses of both drugs. Saquinavir can cause stomach upset and elevated liver enzymes, and should be used with caution with certain other medications. The usual prescription for saquinavir -- unless combined with ritonavir -- is six capsules (1200 mg) taken three times a day with food. The usual dose when combined with ritonavir is 400 mg of each drug, taken twice a day.

Ritonavir is marketed as Norvir®. Ritonavir can be combined with most other antiretrovirals, and may work especially well in combination with saquinavir, using a low dose. However, there are many drugs, both prescribed and recreational, that should be taken with caution or not at all with ritonavir. Make your provider aware of all drugs you might take. Ritonavir can cause stomach upset, generalized discomfort and tingling or numbness around the mouth. These might be avoided by starting with a low dose, three capsules taken twice a day with food, and adding one capsule each dose every couple days until the usual prescription is tolerated: six capsules (600 mg) taken twice a day. That dose will be lower, 400 mg, if combined with saquinavir. The capsules should be stored in a refrigerator. There is also a liquid formulation of ritonavir.

Indinavir is sold under the brand name Crixivan®, and can be used with most other antiretrovirals. Indinavir can cause stomach upset, kidney stones and generalized discomfort, although drinking plenty of fluids may prevent the kidney stones. It should be used with caution with certain other medications, so make sure your provider knows about everything you are taking. The usual prescription for indinavir is two capsules (800 mg) taken three times a day on an empty stomach with a large glass of water. That dose may be larger, 1000 mg, if indinavir is combined with nevirapine or efavirenz.

Nelfinavir is approved under the trade name Viracept®, and has been combined with all other antiretrovirals. It can cause stomach upset and diarrhea, and should be used with caution with certain other medications. The usual prescription for nelfinavir is three tablets (750 mg) taken three times a day with food. But it may also be effective when taken twice a day, five tablets (1250 mg) each dose. There is a powdered formulation of nelfinavir that can be mixed in water.

Ribonucleotide Reductase Inhibitors

This class targets an enzyme which the virus needs and which is made by blood cells. So far, the only available drug which works this way is hydroxyurea, which was approved years ago to treat certain cancers. But at least one more drug like this is under development.

Hydroxyurea, also called Hydrea, may work especially well with ddI. It can lower white and red cell counts, although that is unlikely at the low doses used for HIV infection: 500 to 1000 mg daily. (It may be more likely, however, when combined with drugs that pose the same problem, such as AZT or ganciclovir.) The effect of hydroxyurea on HIV replication is somewhat indirect, so it should probably be considered only an addition to a standard, three-drug regimen.

Community Organizing by Email

Needle Exchange Mobilization Example

Last week's events around needle exchange provide an example of how email can be used for political mobilization -- and suggest ways to use this medium effectively.

On April 21 -- the day after the U.S. Department of Health and Human Services announced its finding that needle exchange was effective in preventing HIV transmission without increasing drug use, but that Federal funding of these programs would still be banned -- USA Today conducted a reader poll on the funding issue, through its Web site (www.usatoday.com). Such polls are clearly unreliable for estimating public opinion (even when, like this one, they have software to prevent people from voting repeatedly). But they do show the effectiveness of each side in getting its supporters mobilized, which can be at least as important.

Early in the morning only 25% of 4500 votes supported needle exchange, with almost all of the rest opposed. Throughout the day a flurry of emails went out -- we received 20 (not counting duplicates), even though we are not on needle-exchange lists -- and by late evening the vote had completely turned around and was more than 68% in favor.

Apparently no one involved had any advance notice, and yet this entire mobilization took place within a single day. The first email, as far as we can determine, was sent in the morning by Project Inform's Treatment Action Network (TAN), which heard about the poll from a member who saw it in the newspaper or on the Web; this alert went to about 350 members who tend to be very active, and who forwarded it to others.

At about the same time the AIDS Action Council sent its alert on the poll to a fax list of several thousand AIDS organizations. Fax alerts may not work as well as email, because it is much harder for recipients to forward them to their own lists; but in this case the document was short, because those involved already knew the issues, so action alerts could easily be typed from the fax into email, with no need to re-enter long background papers.

An analysis of the changing vote during the day suggests that after the emails were out, the Yes votes outnumbered the No by about seven to one -- compared to three to one the opposite way before the email mobilization.

Here are some conclusions we drew:

• What makes email work is people, not software or massive mailing lists. Almost all of the email we received was from persons or organizations we knew, which made it compelling. Just automating the process and sending to strangers produces spam, not effective mobilization.

• Several individuals who emailed us also sent their entire list of recipients. That is often a bad idea, because people can get unwanted email if the list goes astray. But in this case it showed us that many of the individuals had personal activist lists consisting of several dozen (mostly people, but also including organizations, and addresses of specialized email lists which would further distribute the messages to persons unlikely to have received it already). And the fact that these senders still included their personal activist email list with their message suggests that those involved know and trust each other.

• The structure of this one-day, decentralized, effective mobilization was as follows:

  • The issue was particularly important to many people.

  • It was well known to them, so it needed no lengthy background paper (which would stop many busy recipients).

  • There was an easy way to act -- without needing to compose a letter, without spending money, and without any illusion that one must be some kind of expert in the subject in order to respond.

  • The first organizations and individuals to get the word out were able to move rapidly without advance notice.

  • Then other organizations and individuals (often with personal lists of dozens) carried out the main part of the mobilization, usually quoting the earlier emails but also including their own messages urging their friends and colleagues to vote. Established email distribution lists like AIDSACT allowed further conversation, including those who did not have large activist lists of their own. [For more information on AIDSACT, send email to listproc@critpath.org, with "info aidsact" -- without the quotes -- in the first line.]

  • All these communications were between people who know and respect each other, who already had working relationships.

  • The result is that thousands of interested individuals each received many communications from friends and colleagues urging them to vote that day in the poll. And thousands did vote.

[Any email action alert should have an expiration date, so that copies will not keep being redistributed indefinitely, long after they are useful; here the USA Today poll was only for one day, so the expiration was implicit. Also, requests for a Web or email response should include the entire computer address -- which will provide a "hot link" in most email software, allowing users to vote or otherwise respond without leaving their email session.]

The bottom line is that to respond so effectively on such short notice, the community needed two things. First, one or more major organizations (or possibly unaffiliated individuals) must be paying attention, be able to move quickly, and have large lists of constituents so that they can reach many interested people immediately. Second -- and at least equally important -- there must be many individuals and organizations who can personalize the message and pass it on to their friends and colleagues.

This whole mobilization had essentially zero financial cost. Therefore there were no delays to approve spending, and when an organization could not make a decision immediately, people could act on their own. Without spending any money, thousands of people across the country were mobilized to act together -- in less than a day.

Here is a way for communities to defend themselves in a world of big money, power, and institutions which are often deaf or corrupt, and repeatedly run amuck. Committed individuals are central, not machinery. No matter where they live, individuals and small groups can make a difference through building their own constituencies on issues that matter to them.