Breaks from antiretroviral treatment are not the answer for HIV patients

Patients who are infected with multi-drug resistant strains of the HIV virus do not benefit from taking “drug holidays”—structured interruptions in their antiretroviral treatment—a new study has found (New England Journal of Medicine 2003;349:837-46).

Drug holidays had been proposed as a method to regain drug sensitivity to antiretrovirals as well as to reduce drug toxicity and are increasingly popular among patients infected with HIV. However, new research indicates that interrupting treatment may actually be harmful, even if sensitive strains of the virus return.

Researchers led by Dr Jody Lawrence of the University of California San Francisco Medical Center enrolled 270 patients with multi-drug resistant HIV from across the United States into a multicentre trial, where they were randomised into two groups. One group had a four month structured interruption of treatment, followed by a change in antiretroviral treatment. The control group took an immediate change in drug regimen.

In the drug holiday group, genotypic reversion from multi-drug resistant strains of HIV occurred in 64% of patients within 16 weeks of stopping antiretroviral treatment. However, contrary to predictions, reversion of viral strains to wild type virus, theoretically more susceptible to treatment, was not accompanied by a better therapeutic response in the long run.

After a median follow up of 11.6 months, 22 of 138 patients who interrupted their treatment either died or got worse, compared with 12 of the 132 patients who didn't stop treatment (P=0.01; hazard ratio in treatment interruption group 2.57 (95% confidence interval 1.2 to 5.5). The patients who took a drug holiday also developed weaker immune systems, with decreases in their CD4 T cells and an increase in infections related to AIDS. Eight patients in each group died during the study period.

Among the 17 patients in the drug holiday group whose disease progressed, oesophageal candidiasis, Pneumocystis carinii pneumonia, and cryptosporidiosis were the most common infections. Study subjects in the drug holiday group also saw their viral titres rise during the first four months of treatment, with a mean HIV viral RNA concentration of 1.2 log copies per ml higher than the concentration in the other group (P<0.11). However, this difference did not persist after four months. Overall quality of life was similar in both groups.

While it is unclear why reversion to antiretroviral sensitive strains did not result in a better therapeutic response, it suggests that wild type virus may be more immunosuppressive than viruses bearing drug resistance markers.

Commenting on the results, Dr Anthony Fauci of the National Institute of Allergy and Infectious Diseases, the agency which funded the study, said: “It is important to remember that the failure of treatment interruption seen in this study pertains only to individuals who had drug resistant HIV and detectable virus in their blood when they entered the study.

“For individuals who are being successfully treated with anti-HIV medications, other studies have shown that cycle of treatment interruptions for shorter periods may be of potential benefit to conserve medications and reduce drug related toxicities.”