By Liz Highleyman

Recent data from the large SMART study provided evidence that interruption of antiretroviral therapy is a risky strategy. Now, a report from the TIBET Study Group, published in the January 11, 2007 issue of AIDS, casts further negative light on structured treatment interruption.

Colored scanning electron micrograph of a T4 cell (green) infected with HIV (red).

The TIBET Study evaluated the safety of treatment interruption guided by CD4 cell counts and plasma HIV RNA levels. The study included 201 HIV positive adults with sustained CD4 counts above 500 cells/mm3 and viral loads below 50 copies/mL at baseline. Participants were randomly assigned either to continue on standard antiretroviral therapy (n = 101) or to interrupt therapy as long as CD4 count was maintained above 350 cells/mm3 and viral load stayed below 100,000 copies/mL (n = 100). Both groups were followed for 2 years.

Results

• Compared with control subjects, participants who interrupted therapy reduced their total treatment exposure by 67%.

• No AIDS-defining illnesses or deaths occurred in either group.

• Patients in the treatment interruption group suffered significantly more adverse events related to the intake of medication or therapy interruption (relative hazard 2.71; P < 0.001), mainly due to more mononucleosis-like symptoms.

• Subjects in the treatment interruption group experienced improvements in the psychosocial spheres of quality of life and pain reporting.

• However, interruption of therapy had no effect on the physical aspects of quality of life.

• Although both groups had a similar risk of CD4 cell counts falling below 200 cells/mm3, at least 10% of subjects in the treatment interruption group had CD4 counts below 350 cells/mm3 at every time point.

• Drug resistance mutations were detected in 36% of subjects, but new resistance mutations were selected only in patients who interrupted non-nucleoside reverse transcriptase inhibitor (NRTI) therapy.

• Lower nadir (lowest-ever) CD4 count, higher viral load set-point, and prior exposure to sub-optimal regimens were all independent predictors of the need to reinitiate treatment.

Conclusion

"Overall, guided treatment interruptions were not as safe as continuing therapy," the authors concluded. "Despite achieving some improvements in quality of life, guided treatment interruptions did not reduce the overall rate of management-related adverse events."

In an accompanying editorial review, Drs. Jintanata Ananworanich and Bernard Hirschel offered a perspective on the future of structured treatment interruption.

In particular, they noted, it is not yet possible to explain the discrepancies between studies such as SMART, TIBET, and Trivacan, which demonstrated the potential dangers of this strategy, and others such as Staccato and BASTA, which showed no apparent increase in HIV disease progression.

"It is possible, but far from proven," the authors wrote, that factors such as longer duration of prior treatment, shorter length of interruption, and using a higher CD4 cell threshold for restarting therapy (350 vs 250 cells/mm3) might explain the divergent outcomes.

"To put it in a nutshell, in our opinion, the results of SMART suggest: 'Once you have started HAART, you never can stop again'," they said. However, they acknowledged that, "many patients may feel that their quality of life is improved by time off drugs, and the one in 50-100 risk of something bad happening is worth taking."

Moreover, they added, "the need to interrupt therapy for drug toxicities will remain an important issue in HIV treatment. That is why efforts to make [structured treatment interruption] safer will continue," perhaps using higher CD4 cell count thresholds or fixed-length on-and-off cycles, as used in the African DART trial.

Hospital Universitari Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain; Institut Catala de Recerca Avancada (ICREA), Spain; Universitat Politecnica de Catalunya, Barcelona, Spain; Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain; Hospital de Calella, Barcelona, Spain; Hospital Joan XXIII, Universitat Rovira i Virgili, Tarragona, Spain; Ospedale San Raffaele, Milan, Italy; Netherlands Australia Thailand Research Collaboration (HIV-NAT), Bangkok, Thailand; John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu, Hawaii; South East Asia Research Collaboration with Hawaii (SEARCH), Bangkok, Thailand; Geneva University Hospital, Geneva, Switzerland.

1/19/07

References

L Ruiz, R Paredes, G Gomez and others (the TIBET Study Group). Antiretroviral therapy interruption guided by CD4 cell counts and plasma HIV-1 RNA levels in chronically HIV-1-infected patients. AIDS 21(2): 169-178. January 11, 2007.

J Ananworanich, B Hirschel. Intermittent therapy for the treatment of chronic HIV infection. AIDS 21(2): 123-134. January 11, 2007.