Antiretroviral Therapy Still Effective in Patients Who Develop Drug-Resistant Viruses, Study Says
Patients harboring drug-resistant HIV strains may still benefit from antiretroviral therapy, according to new research published in this week's New England Journal of Medicine. The study, conducted by University of California-San Francisco researchers, indicates that mutations that allow HIV to become resistant to standard antiretroviral therapy may also reduce the virus' "fitness" -- its ability to replicate and cause disease. The study involved HIV-positive male patients who had drug-resistant HIV circulating in their blood for at least one year. Sixteen of these patients were "randomly assigned to continue or discontinue antiretroviral therapy" -- 11 patients stopped therapy and five continued therapy. The remaining seven patients were enrolled in a non-randomized component, and all of them discontinued therapy. Researchers each week measured viral loads, CD4+ cell counts and level of drug resistance; viral fitness was measured at the beginning of the study and 12 weeks after therapy was discontinued.
Drugs Keep Working in Face of Resistance
Researchers found that the five patients who continued antiretroviral therapy had a median increase in viral load counts of 0.31 log copies per milliliter, a median decrease in CD4+ cell counts of 15 cells per cubic millimeter and maintained stable drug resistance levels. These patients also exhibited "markedly reduced" viral fitness throughout the study. Among the 18 patients who discontinued therapy, viral loads increased and CD4+ cell counts decreased "immediately" after therapy was stopped. This finding showed that the drugs "were exerting a moderate antiviral effect against the resistant virus." In addition, eight weeks after therapy was discontinued, "drug susceptible 'wild-type'" virus emerged among study subjects, and replicated at "much higher levels" than the drug-resistant virus. Researchers found that as the wild-type virus emerged in patients' blood, CD4+ cell counts decreased "dramatically," and several patients developed clinical disease "soon after treatment was discontinued." Lead study investigator Dr. Steven Deeks, UCSF assistant professor of medicine in the Positive Health Program at San Francisco General Medical Center, said, "The observation that antiretroviral therapy can select for a poorly fit virus has important clinical implications. Many patients with drug-resistant virus will likely continue to benefit from therapy for several years after the emergence of a drug-resistant virus. Hopefully these patients will remain stable until drugs that are able to suppress resistant virus become available."
Drug-Resistant Virus in Hiding
Researchers also measured drug-resistant viral levels in cellular reservoirs from nine patients, and were able to detect resistant virus in five of these patients "long after resistant virus could no longer be detected using standard tests." Deeks said of this finding, "Based on these observations, we believe that drug-resistant virus will re-emerge once therapy is restarted. This suggests that for patients with drug resistant virus, a strategy of stopping therapy, allowing drug susceptible virus to re-emerge, and then restarting therapy may not necessarily give them a second chance" (UCSF release, 2/13). The study concludes, "Although the long term clinical implications of our findings remain to be determined, continued treatment with a regimen containing protease inhibitors in patients with limited therapeutic options may be associated with sustained clinical benefit" (New England Journal of Medicine, 2/15).
A Temporary Impairment of Viral Fitness?
An accompanying NEJM editorial states, "[W]e believe that the benefit of continued drug therapy in patients with drug-resistant viruses may in large measure be due to the continued suppression of drug-sensitive viruses, as well as to the appreciable time required for the selection of drug-resistant viruses that are as pathogenic as the drug-sensitive viruses." The editorial notes that the "slow but consistent increase in the viral load and decrease in the CD4+ cell count observed by Deeks et al. in the small group of patients who continued therapy suggest that viral adaptation is indeed continuing," speculating that "although it is certainly true that drug resistance develops at a cost to viral fitness, the impairment in viral replication may be temporary." The NEJM editorial concludes, "The strategy of continuing treatment despite the ongoing replication and selection of drug-resistant variants will need to be compared with other strategies, such as those aimed at detecting drug resistance early, at a time when a change of therapy might suppress replication to an undetectable level" (Frankel/Mullins, NEJM, 2/15).