The Challenge of HIV Drug Resistance

HIV’s ability to develop resistance to drugs has serious implications both for the treatment of individuals and for public health, forcing doctors and researchers in the United States and in resource-scarce nations to grapple with some weighty dilemmas. The issue is complicated by factors such as limited access to drug treatments in parts of the world where HIV prevalence is highest; the public health interest in controlling the spread of drug-resistant HIV; and the rights of individuals to use the treatments available to them in order to survive.

Mutation, Replication Lead to Resistance
Medications used to treat infections by retroviruses such as HIV—known as antiretroviral therapy—work by reducing the amount of HIV, the “viral load,” in the blood, thus holding at bay the damage the virus can do to the immune system and the onset of illnesses that characterize AIDS. HIV has a strong ability to become resistant to medications because of the high rate at which the virus naturally changes or mutates. When a random mutation allows HIV to withstand the effects of an anti-HIV drug, the mutant version continues to multiply, and the drug then becomes ineffective against the virus. Therefore, drug treatments are designed to depress or halt the rate at which HIV can replicate, giving the virus fewer opportunities to acquire resistance to the medications.

Because HIV can mutate quickly to counter the effects of only one antiretroviral drug (monotherapy), a therapy that combines several drugs, requiring the virus to make several changes to counter their effects, is recommended. A combination of three or more drugs in what is known as highly active antiretroviral therapy (HAART) can often keep viral load at very low levels, allowing people living with HIV the opportunity for longer, healthier lives than may have been possible without the treatment.

“Three drugs do a much better job suppressing virus replication than two, or one. That means you get fewer mutations and a lower likelihood that resistance is going to emerge,” says Mark Wainberg, professor and director of the McGill University AIDS Centre, who studies the emergence and control of drug-resistant HIV.

Cross-Resistance Limits Options
Antiretroviral drugs are currently grouped into three classes: nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). Each controls replication rate by interfering with a stage in HIV’s replication process. NRTIs, such as zidovudine (ZDV), and NNRTIs, such as lamivudine (3TC), are so named because they act by interfering with HIV’s reverse transcriptase enzyme, a protein essential to HIV’s process of genome replication. PIs hinder protease’s activity, which is to assist in the assembly of new viruses.

Among the three classes, there are approximately fifteen antiretroviral drugs available to people infected with HIV. However, individuals infected with a resistant strain of HIV often have fewer drugs from which to choose because many of the drugs are cross-resistant.

“Cross-resistance is really our biggest problem,” explains Richard D’Aquila, associate professor of medicine in the Infectious Disease Unit of Massachusetts General Hospital. “Even though there are a number of drugs out there, we often find that when one drug fails, the virus is actually resistant to several drugs within that same class.” If a patient develops multidrug resistance early in the treatment plan, his or her chances of benefiting from long-term therapy can be significantly reduced.

Adherence Is Crucial to Avoiding Drug Resistance
People taking anti-HIV medications must be careful to take every dose of their medicines, to take them at the correct times and in the correct manner, and to store the medicines properly in order to maintain the concentration of drugs in the bloodstream necessary to fully control viral replication. D’Aquila says, “The single most important thing a patient can do to avoid drug resistance is to be faithful to his or her drug regimen.”

There are, however, a number of considerations that may cause people to stop taking medications or to take them inconsistently. “We have to remember that these drugs are usually very toxic,” says Carlos Brites, associate professor of infectious diseases at the Federal University of Bahia in Brazil. Many people discontinue their drug treatment because of the intolerable side effects. In addition, some stop taking the medicines because they find it difficult to follow their regimens without disclosing their HIV status to those around them. And it is not uncommon for people to stop taking medicines when they begin to feel well again or if meeting the cost of the drugs becomes too difficult.

“The best approach,” says D’Aquila, “is to work with the patient to recognize how difficult this process is and to provide some help in figuring out which of the patient’s daily habits might be useful as reminders for taking pills. The other thing that we try to do now is to use medication in combinations that will have fewer side effects and that need to be taken less often.”

Testing for Resistance
Researchers have developed resistance tests that they hope will help improve long-term HIV treatment and lead to the development of more effective drugs. People with HIV who opt for resistance testing can find out which antiretrovirals are no longer effective for them and which might still be useful, using either genotypic or phenotypic tests.

A genotypic test shows the genetic sequence of the virus in an individual’s blood and identifies mutations known to cause resistance to certain drugs. Information from genotypic testing is sometimes used by physicians who want to try to compensate for the virus’s resistance to a particular drug. While some mutations make HIV unrecognizable to a drug, switching drugs may overcome these effects. The key to successful reversal is to modify the virus’s environment so that it responds by mutating in a certain way.

The cost of genotypic testing is relatively low—about US$250. This type of testing, however, tests for mutations, not actual resistance. Because scientists have not identified all of the HIV mutations that cause resistance or deciphered the interactive effects of HIV mutations, a genotypic test may not always provide definitive answers for a person needing to change his or her drug regimen.

A phenotypic test is a direct measure of viral resistance to drugs as determined through laboratory analysis of virus grown in culture, that is, an in vitro analysis. For this type of test, scientists attempt to establish what levels of antiretroviral drugs will suppress the virus’s growth in vitro. If the virus being tested requires unusually large amounts of a drug to achieve viral suppression, that virus is deemed resistant to that drug.

Unlike genotypic tests, phenotypic tests can quantify resistance, showing a virus’s varying levels of sensitivity to each antiretroviral drug on the market. However, conducting a phenotypic test is more complex and time-consuming, and consequently, more expensive, than a genotypic test—between US$800 and US$900.

Transmission of Drug-Resistant HIV
Within the scientific community, there is concern that drug-resistant strains of HIV will spread as more people take antiretrovirals without achieving full viral suppression. In fact, a study published in AIDS in January 2000 showed that nearly 10 percent of 81 newly infected individuals were infected with viral strains resistant to multiple drugs in Canada. Other studies serve to validate these results. In a study of recently infected individuals conducted in May 2000 by the U.S. Military HIV Research Program, 26 percent showed phenotypic resistance to NNRTIs. A study by researchers at the University of California at San Diego showed that among a group of newly infected individuals in the United States, 2.1 percent had been infected with highly resistant HIV and 25.5 percent demonstrated reduced sensitivity to one or more antiretroviral drugs.

Max Essex, Mary Lasker Woodard professor of health sciences at the Harvard School of Public Health and chair of the Harvard AIDS Institute, gives perspective to these results by comparing mutant strains with wild-type or nonmutated HIV. “In the long run, wild-type virus grows better. So while the spread of drug-resistant HIV is a threat, it is unlikely to have an impact at epidemic levels like what we’ve seen with drug-resistant malaria and tuberculosis. Mutated HIV-1B, for example, does not appear to be fit enough to spread through an entire population through multiple transmission cycles.” HIV-1B is the viral subtype that circulates primarily in Europe and the Americas.

Drug Treatment in Resource-Scarce Countries
Despite the emergence of drug-resistant strains, the overall success of antiretroviral therapy in resource-rich countries is undeniable. It is clear that the best way to prevent drug resistance is to keep viral replication low, something that combinations of strong antiretroviral medications can achieve. Approximately 90 percent of the HIV-infected people in the world, however, do not have access to these drug combinations. People living in resource-scarce regions may only be able to afford less powerful drugs, and only occasionally, regimens that may actually increase both their risk of developing drug-resistant HIV and of transmitting it to others.

Rosemary Musonda, head of the Immunology Unit at the Tropical Diseases Research Centre in Ndola, Zambia, is concerned about the potential emergence of drug-resistant HIV in developing countries if antiretroviral drugs are made more widely available. However, she is quick to emphasize that economics drives this issue. “At the moment, people cannot access the triple combinations. Our concern is that if drug prices are not brought down enough, there will be more people on monotherapy. These drugs may be taken in inadequate amounts, and that can produce drug resistance.

“HIV is a matter of life and death, and people are going to take whatever they can get because they want to survive.”

Wainberg would agree. “In developing countries, the vast majority of people who are getting drugs are not getting triple therapy. In some cases they’re probably getting monotherapy, and in many other cases, bi-therapy. And in that setting, we can probably look to the epidemic of drug-resistant viruses in sexual transmission to keep increasing instead of going down.

“In some ways, there’s almost a conflict of interest between the rights of individuals in developing countries who cannot afford more than two drugs to be treated with those two drugs and the greater public health interests in that country. After all, we know that just two drugs are probably enough to extend life for at least some time. But what if we see that the amount of drug resistance in primary infection continues to go up?”

Of further concern in developing countries is the question of how drug resistance will affect the success of perinatal prevention programs. Essex explains, “Much of the use of antiretroviral drugs in Africa is for chemoprevention. If you have drug-resistant virus circulating in areas with perinatal transmission prevention programs, you may find that those programs won’t work anymore.”

Non-B Subtype Resistance-Associated Mutations Are Uncharted Territory
Although a good deal is known about HIV-1B resistance-causing mutations, there are a number of unanswered questions associated with such mutations in other subtypes. Non-B subtypes cause the most HIV infections worldwide and predominate the epidemics in Africa and Asia.

Essex says, “With some of the subtypes, especially C, none of the standard ‘road maps’ of resistance-associated mutations have been developed for the simple reason that not enough people in regions where these subtypes are predominant have been treated with antiretrovirals.”

Indeed, in July 2000, researchers at the U.S. Centers for Disease Control and Prevention published a study in which they acknowledged the need to learn more about mutation patterns in non-B subtypes. Of the 301 sequences they analyzed, 91 percent of samples of non-B subtypes contained at least one genetic change associated with resistance to protease inhibitors compared with 75 percent having such a change in the samples of B subtypes studied.

Researchers at the Botswana–Harvard HIV Reference Laboratory, which opened last year in Gaborone, are working jointly with those at McGill University AIDS Centre to perform specific drug resistance testing of the HIV-1C virus before and during treatment. Says Essex. “The research conducted by scientists in this facility in Botswana will greatly accelerate our understanding of HIV-1C.”

Capacity-Building Is Necessary to Sustain Treatment
Capacity-building in resource-scarce countries will be an important step toward ensuring that antiretroviral treatment is sustainable. “One common thread is the need to have a lab in the developing country setting,” remarks Wainberg, citing the Botswana–Harvard facility as an example. “A lab allows you to recruit people who want to participate in international trials; it allows you to do a lot of AIDS awareness and education. And when we deliver drugs to the developing country settings, we want to accompany them with full education programs to make sure that the drugs are used in the way that they are intended.”

Musonda agrees. “People who are going to take the drugs should have access to laboratory facilities where at least their viral load can be monitored. Then there also might be possibilities of linking up with other facilities for drug-resistance surveillance.”

Resource-scarce countries seeking to provide sustainable antiretroviral treatment can look to Brazil as a model. “The Brazilian Ministry of Health,” says Brites, “provides free drugs to any patient infected with HIV who meets the clinical criteria for receiving antiretrovirals. They provide three drugs.” Companies in Brazil produce generic antiretroviral drugs to save the country the expense of buying them from international pharmaceutical giants.

Poster printed with permission from Vertex Pharmaceuticals.

Says Brites, “One of the most interesting points in the Brazilian experience in providing antiretrovirals is in terms of cost. We estimate that if the Brazilian government bought drugs at the market price, the cost would be twice as much. Then it would be impossible to provide triple therapy for all our patients.”

A Combined Approach Is Needed
Success in controlling the spread of drug-resistant HIV depends on concerted research, clinical, and political efforts. Scientists continue to develop new drug therapies that may further restrain the virus’s ability to replicate and become resistant. But nonmedical approaches must also be solidly in place if these new therapeutics are to have any success at thwarting HIV’s attempts to develop resistance. Adherence, access, and infrastructure are critical behavioral and social components to any treatment regimen. Examples such as Brazil demonstrate that governments can improve access to antiretrovirals for their citizens, while efforts such as those underway in Botswana show how governments can form international partnerships to improve the infrastructure within their countries. Together these approaches may help researchers stay ahead of the rapidly evolving virus.

—Molly Holme is an editor in the Department of Immunology and Infectious Diseases at the Harvard School of Public Health.