The return of treatment interruptions?

By Edwin J Bernard. Reporting by Gus Cairns.

Two and a half years after the SMART study of CD4 count-guided treatment interruption was halted because of a higher risk of death in people who stopped treatment, it seems that the concept of structured treatment breaks refuses to go away. Two new studies on this subject were reported at the Ninth Congress on Drug Therapy in HIV Infection in Glasgow last month.

The LOTTI study

It was with some trepidation that Dr Franco Maggiolo presented four-year results from the LOTTI study, a five-year, Italian, structured-treatment-interruption study that is still ongoing. “My task this morning is not easy: it’s a difficult thing to talk about strategic treatment interruptions since the SMART trial,” he told the conference, “but I’m here to convince you there are some good options for patients.

”In the LOTTI study, 329 individuals were randomised either to receive continuous antiretroviral therapy, or to stop treatment when their CD4 counts reached at least 600 cells/mm³ and to resume when they fell below 350 cells/mm³. To be eligible for the study, however, patients needed to have a current CD4 cell count above 600 cells/mm³, a lowest-ever CD4 count of above 200 cells/mm³, and to have been on stable antiretroviral therapy with a viral load below 50 copies/ml.

After four years, the proportion of participants reaching the study’s primary endpoint (any AIDS-defining event; death from any cause; or hospitalisation) was similar - 12.1% of those who interrupted treatment and 11.6% of those on continuous treatment. During this time, the participants who interrupted therapy were off treatment for two-thirds of the time compared with less than 2% of the time in the continuous-therapy participants.

Unlike the SMART study, in LOTTI significantly more people on continuous treatment experienced a cardiovascular or metabolic event, at a rate of 3.3% per year compared with 0.2% a year in those who interrupted therapy.

Dr Maggiolo commented that the average follow-up time in SMART had been just over a year, compared with four years in his study. If the LOTTI study had been stopped at the same timepoint as SMART, no difference would have been observed in cardiovascular and metabolic events either. He argues that his study demonstrated that it took a long time for the benefits of therapy-sparing regimes to become evident.

He also said that, in his study, 95% of patients had CD4 counts over 350 - compared with 65% on SMART - and 0.5% below 250, compared with 8.6% on SMART. This might explain the higher mortality and illness rates seen in patients off treatment in the SMART study.

The FOTO study

Dr Cal Cohen then presented results from the much smaller FOTO (Five On, Two Off) study, which randomised 60 participants with an average CD4 count of 670 cells/mm³, either to continue treatment with efavirenz (Sustiva) and tenofovir/FTC (Truvada) or to stop taking it at weekends.

After 24 weeks, 80% in the continuous treatment arm and 83% in the weekend-off arm had a viral load under 50 copies/ml, a non-significant difference.

Did participants adhere to the strategy? In the FOTO arm, three patients took over five doses a week at some point and, although eight individuals took three days off, none developed a detectable viral load (viral loads were measured on Mondays). As well as the weekend-off protocol saving 29% on drug costs, Dr Cohen said, his patients strongly preferred to have weekends off treatment. When asked on a scale of 0 to 10 whether they preferred stopping their drugs at weekends, where zero indicated total disapproval and 10 total approval, the average score was 9.5.

Unlike the LOTTI strategy, the FOTO protocol also kept viral loads undetectable, meaning that it did not entail the problem of potentially raising the sexual infectiousness of the participants.

Will either strategy make it into UK HIV clinics? Dr Maggiolo told the conference that doctors might like to see more evidence before recommending structured treatment interruptions, but when asked what further evidence would be required before it is considered to be safe clinical practice, he replied, “It already is mine. It’s not for every clinician or every patient, but it’s a safe option for some.”