MTN-009: The HIV Drug Resistance Study
1. What is the aim of MTN-009?
Nowhere in the world is HIV cutting a wider, more destructive swath than in sub-Saharan Africa, and women, who account for 60 percent of those getting infected, are bearing the brunt of the epidemic. The extent that these infections involve drug resistant virus is not known. MTN-009, also called the HIV Drug Resistance Study, aims to provide a reliable assessment of the prevalence of HIV drug resistance in a representative population of women from KwaZulu-Natal, South Africa, where a woman’s HIV risk is among the highest. MTN-009 seeks also to understand if certain risk behaviors are associated with resistance. The study expects to enroll 350 newly diagnosed HIV-positive women and approximately 650 HIV-negative women, all between the ages of 18 and 40. Understanding the prevalence of HIV drug resistance will not only help inform public health decisions concerning the selection of antiretrovirals (ARVs) that should or should not be used as part of antiretroviral therapy (ART), but will also help to guide HIV prevention efforts focused on testing different ARV-based approaches.
2. Why is this study important?
Several African countries are beginning to expand access to ARVs for treatment as well as step up efforts to prevent mother to child transmission of HIV with the use of ARVs. At the same time, several large-scale trials are testing the promise of ARVs for preventing HIV in different at-risk populations. The widespread use of ARVs brings with it an inherent concern: drug resistance. If not recognized and properly managed, high rates of drug resistance could facilitate its spread and eventually compromise the effectiveness of mainstay drugs. As such, information on the prevalence of HIV resistance will have critical bearing on the success of both current and future treatment and prevention programs. For its part, MTN-009 will contribute important data about the prevalence of and risks for HIV drug resistance in women of reproductive age, who face the greatest risk of acquiring HIV, primarily through unprotected sex with a male partner. Importantly, the study will help determine if virus being transmitted to women has strains that are resistant to the ARVs currently being evaluated in HIV prevention trials like VOICE. VOICE – Vaginal and Oral Interventions to Control the Epidemic – is testing daily use of a vaginal microbicide containing the ARV tenofovir and another approach called pre-exposure prophylaxis (PrEP), which involves daily use of an ARV tablet, either tenofovir or Truvada.
3. Who is conducting the study?
MTN-009 is being conducted by a team of researchers working in the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network established and funded in 2006 by the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of the U.S. National Institutes of Health (NIH). The study itself gets its funding from DAIDS/NIAID and the NIH Office of AIDS Research.
Leading the study are Urvi Parikh, Ph.D., of the University of Pittsburgh, and Photini Kiepiela, Ph.D., of the South African Medical Research Council (MRC) in Durban.
4. Where is MTN-009 being conducted?
MTN-009 is being conducted at seven sites affiliated with the MRC HIV Clinical Trials Unit in Durban and the surrounding KwaZulu-Natal region of South Africa. These same sites are also currently conducting the VOICE Study.
5. How is the study designed?
Women who contact one of the MRC sites to inquire about taking part in an HIV prevention trial, including VOICE, will first be offered enrollment in MTN-009, the HIV Drug Resistance Study. Those who voluntarily enroll will be asked to complete a private, computer-assisted questionnaire about behaviors that could potentially increase the risk of drug resistance, such as prior use of ARVs by either the participant or her sexual partner. Participants will then be tested for HIV infection. If a woman tests negative, her participation in MTN-009 concludes at that time and she will be referred to VOICE or another HIV prevention trial for screening. A woman who tests HIV positive will have additional tests of her blood to determine if there is evidence of drug resistant virus and to assess the effect that her HIV is having on the health of her immune system. One test will measure the amount of virus in the blood (viral load). Another test, called CD4+ T cell count, will provide an estimate of the number of healthy immune cells that remain uninfected. At subsequent study visits, participants will be counseled on the results of these tests, told how the results may impact the effectiveness of certain types of ARV medications as well as be referred to appropriate health care and counseling services. Although MTN-009 does not provide HIV treatment, the results of study tests may help doctors who are treating the infection to make better medical choices. With a participant’s permission, study staff will share results of laboratory tests performed as part of the study with her healthcare providers.
6. What is drug resistance?
Drug resistance refers to the ability of some microorganisms, including viruses such as HIV, to adapt so they can survive and multiply in the presence of drugs that would normally weaken or kill them. This happens in HIV because the virus is prone to making mistakes when it multiplies. Some of these mistakes, called mutations, can make HIV resistant to one or more antiretroviral (ARV) drug.
7. How can someone acquire or develop resistance?
ART, the standard treatment for people with HIV infection, consists of at least three ARV drugs from at least two different classes of drugs. For the most part, ART is safe and effective in suppressing the ability of HIV to multiply and in improving the health of people with HIV. However, people being treated with ART can sometimes develop resistance to one or more of the ARVs. When detected, resistance can usually be managed by stopping the ineffective ARV and starting a new combination of drugs. If the ineffective drug continues to be used, drug resistant virus will keep multiplying unchecked and could feasibly be transmitted to others, such as through unprotected sex. Resistance could also happen if people who are unknowingly already infected use ARVs or an ARV-based product intended for HIV prevention. That’s because these approaches involve a single ARV. While one ARV has the potential to prevent HIV in someone who is uninfected, one drug alone is not enough to suppress virus in someone who is infected. If a person who is infected continues taking a single drug, there is greater risk that virus would become resistant to that drug or drugs in the same class, thereby limiting treatment options in the future. HIV prevention trials include several measures, such as frequent HIV testing, to minimize a participant’s risk of drug resistance.
8. How common is drug resistance?
In countries such as the United States, where ART is widely used, about 10 percent of new infections occur with drug-resistant HIV. Where ART use is more limited, new infections are far less likely to be from drug-resistant HIV. According to the Southern African Treatment and Resistance Network, less than 5 percent of newly infected individuals in the sub-Saharan region have drug-resistant virus. These numbers could increase with scale-up of ART, however. It’s also important to understand that there are different genetic subtypes of HIV. In the United States and Canada, most HIV infections are with the B subtype strain, while in most of Africa, the C subtype is most dominant. Resistant virus is categorized according to its subtype, so while drug resistance may become increasingly more common as more people receive ART, it may not necessarily behave or look the same in Africa as elsewhere, and it could involve different ARVs.
9. Does having resistance to one drug mean no other options exist?
A mutation causing resistance to one ARV does not always reduce the effectiveness of every drug in that class of drugs or of other types of drugs used to treat HIV infection. If detected early, most types of drug resistance can be readily managed by stopping the ineffective ARV drug and starting a new combination of drugs. Depending on the type of resistance, however, treatment options may be limited.
10. How is drug resistance detected?
Special laboratory tests can detect drug resistance from just a small sample of blood. These tests look for changes, or mutations, in the genetic makeup of HIV and identify those that have signatures for different types of drug resistant virus. As such, a drug resistance test can indicate a particular drug or drug class that should be avoided as well as those ARVs that may have reduced effectiveness. In recently infected or newly diagnosed people, resistance testing can help determine the best combination of ARVs to consider when treatment is later needed. During the time that a person is being treated with ART, routine resistance testing helps in monitoring the effectiveness of drug combinations so that adjustments can be made promptly as needed.
11. What kind of resistance tests are done in MTN-009?
MTN-009 researchers will be using two types of resistance tests, both to be conducted at the MTN virology laboratory at the University of Pittsburgh, which has special expertise in this area. Two types of resistance tests will be used in MTN-009. The standard test detects resistance by casting a wide net. But this technique cannot always capture every mutation present in a sample, so the sensitive test is used to seek out specific mutations that may have been missed. These tests will be particularly important for characterizing HIV drug resistance within a population for whom there is currently very little data – South African women. Most information about drug resistance involves the HIV B subtype, which is most common in the Americas and Europe. Yet, in Africa, the predominant virus is C subtype, with other subtypes seen as well. This means that the drug resistant varieties that are usually seen in the United States or elsewhere may not necessarily be the same as those that arise in Africa.
12. Do women found to be HIV-positive in MTN-009 receive treatment for their HIV?
Although MTN-009 does not provide HIV treatment, women who test positive for HIV will receive immediate counseling by study staff. Study staff will also refer women to available sources of medical care, counseling, and other services they may need. Because the results of study tests may help doctors who are treating the infection to make better medical choices, with a participant’s permission, study staff will share the results of study tests with her healthcare providers.
13. Do women provide informed consent?
Women who volunteer to join the study are told about all the study procedures, any possible risks and benefits and the time requirements of the study. Study staff also explain that women do not have to join and they can choose to leave the study at any time, without consequence. This process is called “Informed Consent.” Information is provided in understandable terms and translated into local languages. Site community educators and Community Advisory Board (CAB) members also play important roles in helping prospective participants understand the purpose, potential benefits and risks of the study.
14. What kind of approvals were needed before this study could get underway?
MTN-009 underwent extensive and rigorous review by NIAID and the U.S. Food and Drug Administration. Moreover, the study was reviewed by an ethics committee for the MRC that must approve all clinical research being conducted at any MRC site.
15. When did the trial begin and how long will it last?
MTN-009 began enrolling women into the study in September 2010 and is expected to take about two years to complete. Results should be available some time in 2013.
# # #
About the Microbicide Trials Network
The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.
Additional information about MTN-009—the HIV Drug Resistance Study, VOICE and more generally about HIV drug resistance, is available at http://www.mtnstopshiv.org/news/studies/mtn009 and http://www.mtnstopshiv.org/news/studies/mtn003
3-September-10
See Also
