July 2, 1998 GENEVA, Switzerland -- A team of AIDS researchers has reported a case in which a person has become infected with HIV that is resistant to six of the 11 approved HIV anti-retroviral drugs, including protease inhibitors. The investigators are from the University of California San Francisco AIDS Research Institute, ViroLogic, Inc., and the Centers for Disease Control and Prevention
Protease inhibitors have been approved for two years, and as part of triple combination therapies, have contributed to a dramatic decline in AIDS death rates. Protease inhibitors block construction of proteins the virus needs to build more copies of itself.
Transmission of drug resistant HIV has been reported previously, but only to anti-retrovirals known as reverse transcriptase inhibitors, which work by blocking the replication of the virus. They have been in use for more than 10 years, but are less effective treatments.
The transmission of protease inhibitor resistant strains of HIV to a previously uninfected person could represent an emerging clinical and public health problem because protease inhibitors are a powerful weapon in the arsenal against HIV, said Frederick Hecht, MD, assistant clinical professor of medicine at the UCSF-affiliated San Francisco General Hospital, and lead author of the study. The case study was reported by Hecht here today (July 1) at the 12th World AIDS Conference. Research results also will be published in the New England Journal of Medicine, currently in press.
The multi-drug resistant HIV strain is believed to have been transmitted from one person to another through unprotected anal intercourse. Multiple mutations of HIV are required for the virus to become resistant to protease inhibitors, according to Hecht, and it had been thought that those mutations might make it more difficult for the virus to reproduce and make transmission between people less likely.
"We still don't know how frequently resistant strains are transmitted," he said. "But we now know that people can acquire strains with multi-drug resistance, including resistance to protease inhibitor treatment."
The subject of the case study was a middle-aged homosexual man who reported that his only risk encounter in the six months prior to being infected with HIV was receptive anal intercourse without a condom. He said his partner had withdrawn before ejaculation, a behavior that many in the gay community have considered to be a low-risk practice.
"There may be a tendency to feel complacent because of the success of treatment efforts," Hecht said, "but the fact that this transmission occurred by a practice that many consider to be 'safe' highlights the crucial role of continued prevention efforts needed to control the HIV epidemic."
With the patient's consent, the researchers obtained information from his partner. He was diagnosed with HIV infection in 1990, and since then was sporadically treated with nine anti-retroviral drugs, including reverse transcriptase inhibitors and protease inhibitors.
Hecht said that interruptions in the partner's treatment may have contributed to the development of resistant HIV that was transmitted to the patient.
"This study shows that we can do more harm than good if we don't help patients take their medications correctly," said Margaret Chesney, PhD, professor of medicine at UCSF, a co-investigator of the study, and an expert on adherence issues. "The bottom line is that helping patients stick to these difficult regimens is as important as the drugs themselves."
To examine the sensitivity and resistance of the patient's virus to the 11 approved HIV anti-retrovirals, the researchers used a novel phenotypic drug susceptibility assay developed by ViroLogic, Inc., a biotechnology company located in South San Francisco, Calif. The technique uses a retroviral vector that contains a viral gene segment from the patient's virus and an indicator, to measure the sensitivity of the patient's virus to HIV anti-retrovirals.
Virologic's phenotypic analysis showed the patient's virus was resistant to two reverse transcriptase inhibitors: zidovudine (AZT) and lamivudine (3TC), and four protease inhibitors: saquinavir, ritonavir, indinavir, and nelfinavir. In addition, the researchers evaluated the viral genotype of the patient and the partner to determine whether mutations associated with resistance to anti-retrovirals were present. The patient's virus had four mutations associated with resistance to reverse transciptase inhibitors and seven associated with resistance to protease inhibitors.
Evaluation of the partner's virus showed many of the same mutations, while other genetic tests showed the virus in the patient closely matched that of the partner.
Because this patient's virus is resistant to many anti-retrovirals, typical drug combinations are not working as well as for other patients, Hecht said, but other treatment options still exist.
"This case doesn't mean that combination therapy is not a good thing," said Thomas J. Coates, PhD, director of the UCSF AIDS Research Institute. "A lot of people are living longer and better lives due to combination therapies, but it is clearly not the final answer. We have to help the afflicted communities understand that transmission of resistant strains is possible, even by a practice not considered to be very risky."
The patient was a part of the UCSF Options Project, a study evaluating the usefulness of combination therapy started soon after infection. The project is directed by James O. Kahn, MD, of the UCSF AIDS Program at San Francisco General Hospital.
Co-investigators in this study from the UCSF Gladstone Institute of Virology and Immunology are: Robert Grant, MD, MPH, staff research scientist and director of the UCSF/Gladstone Core Virology Lab; Laura Digilia, MD and Nirmala Bandrapalli, MS.
Other co-investigators are Beth Dillon, MSW, MPH, and Bernard Branson, MD, from the Centers for Disease Control and Prevention, and Christos Petropoulos, PhD; Huan Tian, PhD; and Nicholas Hellmann, MD, from ViroLogic.
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