The next big challenge: Managing HIV infection in an age of higher resistance
Time may be running out before AIDS deaths rise
Drug-resistant HIV either will be a big problem in coming decades or a manageable obstacle, depending on whether the more optimistic or pessimistic predictions come true. However, researchers say there is no question that resistance has increased dramatically in recent years and that it will continue to rise.
A recently published study that used a mathematical model to understand HIV drug resistance from 1996 to 2001 in San Francisco and then to predict resistance from 2001 to 2005 has found that the current prevalence of resistance is high and will continue to increase.1
"We predict a prevalence of drug-resistant HIV of 42% by 2005," says Sally Blower, PhD, professor of biomathematics at the AIDS Institute at the University of California - Los Angeles School of Medicine. Blower was one of the investigators who wrote about the HIV resistance study, published in the September issue of Nature Medicine.
The mathematical model indicates that antiretroviral resistance among HIV infections in San Francisco currently is about 30%. The study also predicts that the transmission rate of drug-resistant HIV will be about 15% by the year 2005. What is happening in San Francisco likely will be seen across the country, as well as the world.
"I think San Francisco has been on the leading edge of the epidemic in this country," says James Kahn, MD, associate professor of medicine at the University of California - San Francisco. Kahn is a co-author on the HIV drug-resistance study. "It’s not only what this study means in our country, but also in developing countries where there’s been a huge push to bring antiretroviral treatments," Kahn says. "So what is happening in San Francisco is relevant for the country and for the rest of the world."
The key to whether antiretroviral-resistant HIV leads to a rise in AIDS deaths has to do with the fitness of drug-resistant strains relative to drug-sensitive strains, Blower and Kahn say. (To see CDC chart listing AIDS cases and deaths through 2000, click here.) "We don’t know how these resistant viruses will behave," Kahn says. "Will you sustain some immunologic benefit even with resistant virus, or will resistant virus be more pathogenic?" The answer to that question will probably not be known for another year as researchers continue to study antiretroviral-resistant HIV and its impact on viral load, disease progression, and CD4 cell counts, Kahn adds.
Blower says she believes the current research supports the optimistic view that despite a growth in drug-resistant HIV, the current HIV incidence rate and mortality rates will continue to decline, at least in the short term. "It’s complicated, but all the things we’ve looked at in the short term, 10-year predictions in terms of mortality and morbidity, show that the effects are beneficial even with the drugs we have now," Blower says. "Drug resistance in some ways is not so serious in HIV infection because people are going to die from the disease anyway, since we do not have drugs that cure people."
However, the more pessimistic view is that it is only a matter of time before a more virulent drug-resistant virus occurs, and then clinicians will see a sharp rise in AIDS opportunistic infections and deaths.
"So far, the drug-resistant virus is not associated with fast progression to AIDS, although it can still cause AIDS deaths at a lower rate than wild-type, drug-sensitive virus," says Robert Grant, MD, MPH, assistant investigator and assistant professor at the Gladstone Institute of Virology and Immunology in San Francisco.
There is one point about drug-resistant virus that has researchers in agreement: There is no corroborating evidence showing that an individual who already is infected with a particular strain of HIV can become infected with another strain that is drug-resistant. Despite an anecdotal report from Canada about a possible case of super-infection, this has not been documented, Grant says.
"In clade B epidemics like we have in the U.S., where almost everyone is infected with clade B, we haven not yet seen documented cases of where people have acquired a second virus after one has been established," Grant states. "The first virus that enters a person interferes with additional viruses that may challenge the person," Grant explains. "The first virus may use up many of the cells required for viral replication, so the new virus that challenges or attempts to re-infect the person may not find enough target cells to replicate."
While there are many cases in which a person acquired more than one form of HIV initially, there are no confirmed cases of a person who is already infected with one type of HIV becoming re-infected with another, Grant adds. "We don’t know whether or not that can occur." For this reason, researchers are confident in predicting that the majority of antiretroviral resistance cases will continue to involve people who have been treated with highly active antiretroviral therapy whose own virus has begun to show resistance to one or more of the drugs in their regimen.
This means clinicians can do a great deal to slow the growth of antiretroviral-resistant virus by tailoring therapy with that possibility in mind. For example, initial antiretroviral therapy should be delayed as long as possible, Blower suggests. "This is on the basis of what’s best for the individual, but also what’s best at the population level," Blower says.
By delaying the initial treatment, a clinician also can assess the patient’s readiness in starting therapy and commitment to taking the drugs as prescribed, Grant says. "If a patient is not ready to start therapy, it’s inappropriate for them to try, because they’ll be less able to take their medicines well," Grant adds.
Because resistance occurs when there’s some drug selection pressure, but not enough to completely suppress viral replication, it’s very important that patients are committed to taking all of their medications as prescribed or to stopping treatment altogether until a new regimen can be found. "We need to do a better job of keeping people on their medicine, trying to identify reasons why treatment fails our patients," Kahn says. "We need to be more clever in having drug levels monitored in our patients."
It’s important to continually attempt to achieve the safest drug regimen that also has the best potential for suppressing the virus, Kahn adds. "A more toxic drug may not have more added benefit than the patient’s current treatment, because it takes a greater cost in toxicity that may backfire if patients are less inclined to take the medication," Kahn explains. "That’s what we’re struggling with, and that’s the key question."
The second strategy is to shift HIV treatment to specialized HIV physicians and clinics where patients can be given the most up-to-date and effective treatments for suppressing the wild virus as well as drug-resistant strains, Blower says.
It’s becoming increasingly important for clinicians to understand resistance and how to develop a therapy that will produce the best virological response. This includes using resistance tests to predict drug resistance and to prevent the emergence of resistance, Grant says. The Food and Drug Administration approved on Sept. 28, 2001, the genotypic test called TrueGene HIV-1 Genotyping Kit, made by Visible Genetics Inc. in Toronto, Ontario. With the FDA’s approval, the test will be more readily available in clinical labs.
Although transmission of drug-resistant virus to uninfected people will continue to remain relatively low, it can be reduced even further through continued prevention messages targeting HIV-infected people.
Prevention is still best medical strategy
The study found that the number of new infections occurring each year would actually be decreasing, even with the transmission of antiretroviral-resistant strains, if it were not for the fact that risky behavior has been increasing.
Prevention programs should keep in mind that safe sex might mean different things depending on a person’s HIV status and sexual behavior. For example, HIV-positive people who are having sex with a variety of partners should use condoms and other safe-sex strategies to prevent transmitting the virus to their uninfected partners and also to protect themselves against gonorrhea, syphilis, hepatitis, herpes, and other sexually transmitted diseases (STDs), Kahn says.
Alternatively, if an HIV-infected person is in a long-term relationship with another HIV-infected person, it might be better to encourage them to have sex without using condoms, so long as they remain monogamous, Grant says. "It may allow them to stay together and have a more happy sex life," Grant explains. "And the safest thing for them and their potential partners is to encourage mutual monogamy by giving them appropriate information about the risk of superinfection, which may be very low."
Reference
1. Blower SM, Aschenbach AN, Gershengorn HB, Kahn JO. Predicting the unpredictable: Transmission of drug-resistant HIV. Nature Medicine 2001; 9:1016-1020.
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