The large SMART treatment interruption trial and several other studies have shown that CD4-guided antiretroviral treatment interruption is a potentially hazardous strategy, leading to an increased risk of AIDS-related opportunistic infections and serious non-AIDS-defining disease, without conferring any significant apparent benefits.

Nevertheless, researchers continue to study various intermittent treatment strategies in an effort to reduce the side effects, inconvenience, and costs of continuous, possibly life-long therapy. Data from 2 such studies -- 1 in adults and 1 in children -- were presented last week at the 9th International Congress on Drug Therapy in HIV Infection (HIV9) in Glasgow, Scotland.

LOTTI Study

The Italian LOTTI trial prospectively compared continuous HAART versus a CD4-guided structured treatment interruption strategy. The 329 participants started the study on HAART with undetectable HIV RNA (< 50 copies/mL) and a baseline CD4 count > 700 cells/mm3; furthermore, their nadir (lowest-ever) CD4 count had never fallen below 200 cells/mm3. About three-quarters were men, the mean age was about 40 years, and the average time on antiretroviral therapy was about 6 years.

Participants were randomly assigned either to stay on continuous therapy or else to stop treatment when their CD4 count was above 700 cells/mm3 and resume when it fell to 350 cells/mm3 -- the threshold for starting antiretroviral therapy in the current U.S. and European guidelines. In SMART, by contrast, the 2720 participants in the treatment interruption arm stopped therapy when their CD4 count was above 350 cells/mm3 and did not resume until it fell to 250 cells/mm3, which left them spending considerable time at relatively low levels.

The primary LOTTI endpoint was progression to AIDS (any opportunistic disease), death from any cause, or diseases (other than opportunistic illnesses) requiring hospitalization. Secondary endpoints included less serious illness, major adverse events (AEs), virological failure, and cost of therapy. Interim results from an intent-to-treat analysis at 4 years were presented, representing a total follow-up time of nearly 1400 person-years.

Results

• Patients in the treatment interruption arm were on HAART for 35% of total follow-up time (mean 515 days), compared with 98% of time in the continuous therapy arm (mean 1530 days).

• At 4 years, 12.1% of patients in the treatment interruption arm reached the primary endpoint compared with 11.6% in the continuous therapy arm (odds ratio [OR] 1.05; not a statistically significant difference).

• Serious (grade 3 or 4) AEs were reported in 20.6% of treatment interruption patients versus 27.4% in the continuous therapy arm.

• No patients in the treatment interruption arm experienced major cardiovascular events or diabetes, compared with 4 and 6, respectively, in the continuous therapy arm.

• Overall, just 1% of treatment interruption patients experienced primary or secondary cardiovascular or metabolic AEs, compared with nearly 11% in the continuous therapy arm.

• However, 7 treatment interruption patients -- but none on continuous therapy -- developed bacterial pneumonia.

• 4.8% of patients in the treatment interruption arm and 6.7% in the continuous therapy arm developed drug resistance mutations (OR 0.79).

• Over the entire period, the average daily cost of therapy was less than half as much in the treatment interruption arm compared with the continuous therapy arm: 9 Euros (about US$11) vs 20 Euros (about US$25) (P < 0.0001).

Conclusion

Based on these findings, the investigators concluded that "CD4-guided [structured treatment interruption] may be a possible alternative strategic option for chronically infected individuals responding to HAART provided that CD4 decrements would be steadily maintained above a safe threshold."

"[Structured treatment interruptions] warrant further careful prospective evaluation especially to investigate virologic and clinical outcomes in the very long period," they continued.

In discussing these results, presenter Franco Maggiolo suggested that it may take a long follow-up time before the benefits of intermittent therapy with respect to metabolic adverse events become apparent. No such difference was seen in SMART, but that study was prematurely halted after just over 1 year of follow-up, compared with 4 years in LOTTI.

Ospedali Riuniti, Bergamo, Italy; Ospedale Careggi, Firenze, Italy; Ospedale San Gerardo, Monza, Italy; Ospedale San Paolo, Milano, Italy.

PENTA 11 Study

The international Pediatric European Network for Treatment of AIDS (PENTA) 11 trial looked at CD4-guided treatment interruption in children with HIV. Pediatric patients may particularly benefit from intermittent treatment since they face the prospect of spending their entire life on antiretroviral therapy. Furthermore, the strategy may be less hazardous since children still have good thymus activity and may be better able to regenerate CD4 cells after treatment interruption.

This Phase 2 trial included 109 children from 9 countries with baseline viral load < 50 copies/mL and CD4 percentage > 30% for those age 2-6 years or CD4 percentage > 25% and CD4 cell count > 500 cells/mm3 for those age 7-15 years. The median age was 9 years (range 2-16 years), 55% were girls, and about one-third each were white, black, and Asian. All were on HAART for at least 24 weeks, with an average duration of about 6 years. Overall, the children had well-preserved immune function, with a median baseline CD4 percentage of 36% (nadir 18%) and median CD4 count of 966 (nadir 627) cells/mm3.

Participants were randomly assigned either to receive continuous treatment or to interrupt therapy if their CD4 percentage fell below 20% (age < 7 years), or CD4 percentage below 20% or CD4 count below 350 cells/mm3 (age 7 years or older). Treatment also resumed in the case of AIDS-defining events. After the results of SMART became known, additional precautions were added limiting the allowable duration of treatment interruptions to 48 weeks, with 24 weeks of therapy required before the next interruption.

The primary endpoint was CD4 percentage < 15%, as well as CD4 < 200 cells/mm3 for those age 7 or older, occurrence of CDC class C AIDS events, or death. Patients were followed until the last randomized child completed 72 weeks follow-up. All comparisons were intention-to-treat.

Results

• After a median 130 weeks of follow-up, 4% of total follow-up time was spent off therapy in the continuous treatment arm versus 48% in the treatment interruption arm.

• 98% versus 96% of time, respectively, was spent with a CD4 count ? 350 cells/mm3.

• In the treatment interruption arm, after the first interruption, 38% restarted therapy before the 48-week limit, 57% restarted at week 48, and 3% remained off treatment.

• 16 children underwent a second treatment interruption.

• No participants in either arm died or experienced class C AIDS events.

• However, clinical events overall were about half as frequent in the continuous therapy arm (26 events) compared with the treatment interruption arm (50 events).

• At 72 weeks, 85% of children in the continuous therapy arm and 58% in the treatment interruption arm had HIV RNA < 50 copies/mL (94% vs 81% with < 400 copies/mL) (P = 0.04 and 0.002).

• Among a subset of children who resumed treatment for at least 24 weeks, 68% had HIV RNA < 50 copies/mL (89% < 400 copies/mL).

• 1 of 53 children in the continuous therapy arm and 4 of 56 in the treatment interruption arm reached the CD4 endpoints (not a significant difference; P = 0.4).

• At 72 weeks, CD4 counts declined by a mean 106 and 240 cells/mm3, respectively, in the continuous therapy and treatment interruption arms (P = 0.01).

• Among the children who resumed therapy for at least 24 weeks, the mean CD4 decline was 124 cells/mm3.

• In the treatment interruption arm, CD4 recovery after treatment interruption was more rapid in younger children (P = 0.02).

"In this pilot study we observed no deaths or serious clinical events," the researchers concluded.

Overall, they continued, fewer children in the treatment interruption arm had viral load suppressed < 50 copies/ml at 72 weeks, and CD4 recovery after treatment interruption appeared better in younger children.

They added that "longer-term assessment of all children after restarting antiretroviral therapy will be required to fully assess risks and benefits of [treatment interruption] in this population."

Given the small size of the study, they said they "cannot currently recommend children undergo CD4-guided planned treatment interruptions."

MRC, London, UK; INSERM SC10, Paris, France; Medical Research Council Clinical Trials Unit, London, UK; IRD, Chiang Mai University, Chiang Mai, Thailand; Enice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD; Hôpital de l'Archet, Nice, France; Hospital Materno Infantil, Madrid, Spain; Medical University of Warsaw, Warsaw, Poland; University Children's Hospital of Zurich, Zurich, Switzerland; Universitäts-kinderkliniken, Munich, Germany; Nakornping Hospital, Chiang Mai, Thailand; St Mary's Hospital, London, UK; Universitá di Padova, Padova, Italy.

11/18/08

References

F Maggiolo, M Airoldi, A Callegaro, and others. O213 CD4-guided STI in patients responding to HAART. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):O18. November 10, 2008.

DM Gibb, A Compagnucci, H Green, and others. Treatment interruption in children with chronic HIV-infection: the results of the paediatric European network for treatment of AIDS (PENTA) 11 trial. 9th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 9-13, 2008. Journal of the International AIDS Society 11(Suppl 1):O21. November 10, 2008.