Treatment interruption shows no benefit in drug-resistant HIV infection
NIAID news release
Prescribed interruptions in antiretroviral therapy – so-called “drug holidays” – may hasten disease progression in a subset of HIV-positive individuals, namely those whose treatment has been rendered significantly less effective by the development of resistance to multiple anti-HIV drugs (MDR-HIV). This was the finding in a study by researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH).
As reported in the 28 August 2003 issue of The New England Journal of Medicine, researchers found that study participants who underwent a four-month structured treatment interruption had more HIV-related complications and poorer immune response than did individuals who took antiretroviral drugs continuously throughout the study.
“Interruption of treatment has become increasingly common among HIV-positive individuals,” says NIAID Director Anthony S Fauci MD. “This study helps to clarify the effects of treatment interruption in one group of patients and emphasises how important it is for people to join clinical trials to help answer questions that will improve patient care.”
As used in this study, structured treatment interruption involves discontinuing all anti-HIV drugs for a defined period of time to allow the repopulating virus to regain susceptibility to anti-HIV drugs. Previous studies of individuals infected with MDR-HIV have shown that drug-sensitive variants of the virus re-emerge and become predominant after therapy is stopped. Treatment interruptions have also been used to give people time off from multiple medications that may be difficult to take and have toxic side effects.
“We had hoped that a structured treatment interruption would be beneficial for people experiencing treatment failure due to multidrug-resistant HIV,” says study chair Jody Lawrence MD, of the Department of Medicine at the University of California, San Francisco. “However, our results indicate that this strategy does not work and should be avoided by this group of HIV-infected individuals. Continuing therapy guided by HIV drug resistance testing proved to be a better approach.”
Conducted by NIAID’s Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA), the MDR-HIV study by Dr Lawrence and colleagues is the first randomised clinical endpoint study to examine the effectiveness of structured treatment interruption in people with few remaining treatment options. The study enrolled 270 participants with MDR-HIV who had HIV levels of more than 5,000 copies per milliliter of plasma. About one half of the participants were randomised to a four month interruption of treatment before starting a new optimised anti-HIV treatment regimen. The other half (the control group) immediately started a new optimised regimen. Physicians were given the results of two types of HIV drug-resistance tests to help them choose the optimised regimen.
After an average follow-up of nearly 12 months, 22 of the 138 individuals in the treatment-interruption group had either died or experienced disease progression, defined by the occurrence of one or more AIDS-defining condition. In contrast, 12 of the 132 people in the control group (those who received continuous therapy throughout the study) had died or had their disease worsen. Participants in the treatment-interruption group also had persistently fewer CD4 T-cells and showed no benefit in HIV viral load response or quality of life relative to the control group.
“This trial was conducted because community and healthcare providers were interested in finding better treatment strategies for people with treatment failure and multidrug-resistant HIV,” says Sandra Lehrman MD, director of the Therapeutics Research Program in NIAID’s Division of AIDS. “The strengths of the study,” she notes, “are the number of volunteers who participated in the study, the length of follow-up and the fact that there was a randomised comparison with a control group. These features allowed the researchers to study the overall impact of structured treatment interruption, including the effects on AIDS-related illnesses, HIV viral load, CD4 T-cell count and quality of life.”
“It is important to remember,” adds Dr Fauci, “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 cycles of treatment interruptions for shorter periods may be of potential benefit to conserve medications and reduce drug-related toxicities.”
The duration of the treatment break at four months was longer than other researchers have recommended for such experienced patients. However around 25% of the interruption group restarted therapy earlier, after just over two months.
Eight deaths occurred in each arm, so including deaths and disease progression together when presenting the summary confused these results. However a significantly greater number of progressions occurred in the interruption arm (17 vs 4, HR 6.04 95%CI 1.8-20.8). Most of the cases of disease progression in the interruption group also occurred after treatment had been restarted and not during the interruption period. Patients taking an interruption had more new AIDS-defining illnesses.
Median CD4 count at baseline was around 150 cells/mm3 and 125 cells/mm3 in the interruption and continued treatment arms and median CD4 nadir in each group was around 30 cell/mm3. However during the months 0-4 the interruption group dropped to a median of 80 cells/mm3 lower than the continued treatment arm.
An interruption of two months in the French GigaHAART study showed a greater benefit in the interruption arm compared to patients who continued on therapy. The GigaHAART study used regimens with eight or more drugs compared to the median 3.6 drugs in the US study.
Perhaps the key to an interruption relies on individualising the length of the break depending on closely monitoring a patient’s response (every 2-4 weeks). Short-term out growth of resistant virus by wild-type virus show this occurs after two months and several studies have suggested that viral fitness similarly increases at this time.
J. Lawrence et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. The New England Journal of Medicine 349(9):837-46 (2003).