S.J. Little, et al. Persistence of Transmitted Drug Resistance among Subjects With Primary HIV Infection Not Receiving Antiretroviral Therapy. 9th Retrovirus Conference, Seattle, 2002. Abstract 95.
A single-dose of the AIDS drug nevirapine when taken at the onset of labor is a proven method for dramatically reducing rates of mother-to-child transmission (MTCT) of HIV. So why does Dr. Joep Lange, President of the International AIDS Society and vocal advocate for expanding the worldwide access to antiretroviral (ARV) drugs, take every opportunity to warn that resistance to nevirapine (NVP) can arise after single-dose use? His purpose is to raise this question: if single-dose NVP brings resistance, then should the drug be reserved exclusively for chronic treatment regimens and never used as a single-dose for preventing MTCT? Such talk causes shivers of alarm to dance through the networks of doctors and advocates working to extend ARV medicines to all corners of the world. But what is the basis for his nervousness?
Dr. Lange is correct that NVP resistance can appear after only one dose, but his conclusion about how to use this valuable drug is exactly wrong. NVP is very well suited for preventing MTCT. It acts quickly to lower viral load in the mother and the effect lasts for more than a day -- enough time to protect a baby during labor and delivery. A single-dose given to the newborn continues the protection for up to a week. The drug crosses the placenta and appears in breast milk during the first critical days when the newborn receives its antibody-rich colostrum. No serious toxicity has ever been reported for single-use nevirapine, although longer-term follow up for children exposed to nevirapine at birth still needs to be performed. Though not as sure as an extended course of AZT or triple therapy to prevent transmission, in settings with limited prenatal care and little money to spend on medicines, single-dose NVP is cheap and effective.
Compare the profile of single-dose nevirapine to that of nevirapine used for chronic HIV infection. Severe rash has occurred in as many as 8% of people who start nevirapine therapy and some cases of liver toxicity have been fatal. These life-threatening side effects may not show up for several weeks or months after starting the drug. While close liver enzyme monitoring and careful medical management may be able to catch most incidents of toxicity before they become serious, this is precisely the kind of care likely to be scarce in resource-poor countries. Furthermore, there is some evidence that women on full-time NVP may suffer liver complications and serious rash at a higher rate than men. The toxicity problems are possibly due to the long half-life of nevirapine in the blood. The slow rate of clearance that makes nevirapine ideal for single-dose use during labor may cause trouble over time if blood concentrations accumulate to toxic levels during daily chronic dosing.
Dr. Lange's concern stems from the ease with which resistance can develop to nevirapine. As little as a single DNA mutation is sufficient to allow HIV to evade suppression by not only nevirapine, but also by efavirenz and delavirdine, the two other currently approved members of the non-nucleoside reverse transcriptase (NNRTI) inhibitor class of antiretroviral drugs. In one study, resistant mutations were observed in 30% of women eight weeks after single-dose nevirapine exposure. Dr. Lange is worried that women with the K103N mutation will never be able to use nevirapine, efavirenz or delavirdine as part of a chronic ARV regimen -- should one become available to them in the future. Yet it's likely that having had resistance previously may not be a problem for women who only use NVP to avoid infecting their newborns. After the single dose has cleared the blood, the body's ecology no longer favors the nevirapine mutant. After a period of weeks to a few months, the wild-type nevirapine-susceptible virus should again overtake the woman's viral population. If she uses nevirapine during her next delivery, the fast acting drug should quickly suppress the dominant viral population and lower her viral load to help insure a safe delivery. Since the nevirapine-resistant virus is now archived in latently infected cells, she may experience a bloom of the resistant strain, but not until the baby has been safely delivered. No reports of a second labor and delivery treated by nevirapine have yet been published, but real-world data should soon become available as several nevirapine MTCT pilot programs enter their third year.
In a study presented at the 9th Retrovirus Conference by Susan Little of the University of California, San Diego, the K103N mutation associated with NNRTI resistance persisted for up to a year in women who had been infected with drug resistant strains of virus. Dr. Lange, a convener of the panel that heard Dr. Little's presentation, was quick to ask if her findings should provoke a "rethinking" of single-dose nevirapine. Dr. Little agreed that the data was "extremely concerning."
Dr. Little found persistent NVP resistance in four of her six study participants. However, there is a crucial distinction that limits applying her observations to women who develop nevirapine resistance from drug exposure. Dr. Little's subjects were infected by sexual contact with partners who had been exposed to nevirapine and then transmitted a resistant strain. This means that her study patients carried a drug resistant clone and lacked an archived copy of a wild-type drug susceptible virus. For the drug resistance phenotype to disappear, a spontaneous N103K mutation had to occur then grow out as the dominant strain. This chain of events is far more dependent on the play of chance and environmental factors than is the process of an archived wild-type strain re-establishing itself after a few days of drug suppression. If anything, the spontaneous loss of N103 in this small group suggests that NVP resistant virus is less fit to replicate than the wild-type and argues for a quick rebound of drug-susceptible virus in most women exposed to single-dose therapy.
Since nevirapine resistance is so quick to develop, perhaps the real concern should be with the impact that widespread NNRTI resistance might have on successful efforts to prevent MTCT. Nevirapine resistance can be expected to rapidly arise in populations that adopt it as part of triple-drug ARV regimens. Even if adherence is near 100%, normal variations in absorption, metabolism and viral dynamics may allow virus replicating in the presence of nevirapine to quickly generate drug-resistant mutants. In resource-poor settings, viral load monitoring is likely to be minimal or non-existent. Therefore individuals failing nevirapine may be more likely continue on their failing regimens, perhaps infecting new individuals with NNRTI resistant strains -- including women who could benefit from single-dose nevirapine when delivering their children. This would be the true tragedy, dimming one of the few therapeutic bright spots in the world AIDS crisis.
It is unquestionable that the best solution for stabilizing a family invaded by HIV is to not only give treatment to prevent MTCT, but also to provide continuing treatment to suppress virus in the mother and in other members of her family, including her children and husband. Indeed a new study of continuing ARV for mothers, called MTCT-Plus, is springing from the foundation of successful mother and infant research programs. These MTCT programs have moved forward because they have had the support and funding to successfully demonstrate results. Sadly, the lack of enthusiasm among drug companies, governments, foundations and the Global Fund for paying for chronic treatment means that the slow pace of bringing therapy to the vast majority of people who need it will continue to drag.
The unique suitability of nevirapine to prevent MTCT may be overshadowed in many minds by another of its attributes, its low cost. Nevirapine, whether supplied by Boeringer-Ingleheim or by a generic manufacturer, is by far the cheapest choice for the potent leg of a three-drug combo -- and cost often looms larger than other issues when access to treatment is discussed. But proponents of universal therapy need to critically ask, is the cheapest drug really the best drug for the job? Despite the low cost of nevirapine itself, the expense for chronic dosing added to a nucleoside backbone, plus viral load and toxicity monitoring, will keep this regimen from being widely deployed for years to come. Meanwhile, the MTCT programs are reaching people, educating them, testing them and increasingly, treating them. Although confirmatory data about single-dose NVP used in subsequent pregnancies are eagerly awaited, it does a disservice to the most successful current efforts to expand HIV treatment in the developing world by promoting entirely theoretical objections.