African DART Study Confirms Risk of Strategic Treatment Interruption

Data from the DART (Development of Anti-Retroviral Therapy in Africa) study, presented at the XVI International AIDS Conference last week in Toronto, offered further evidence that strategic treatment interruption can lead to worse HIV disease progression and higher mortality rates.

Researchers enrolled 3316 treatment-naive patients (about 75% women) with CD4 counts below 200 cells/mm3 from two sites in Uganda and one in Zimbabwe. After 48 or 72 weeks on antiretroviral therapy with AZT (Retrovir) plus 3TC (Epivir) plus either tenofovir (Viread), abacavir (Ziagen), or nevirapine (Viramune), 813 participants with CD4 counts above 300 cells/mm3 were randomly assigned to either continue HAART (n = 405) or interrupt and re-initiate therapy in 12-week cycles (n = 408).

At the time of randomization, the median age was 37 years, the median CD4 count was 358 cells/mm3, and the median nadir (lowest ever) CD4 count was 132 cells/mm3. About three-quarters were taking tenofovir or abacavir, and 23% were on nevirapine.

Results

After a median follow-up period of 51 weeks, patients in the continuous therapy arm had received antiretroviral drugs for 99% of the time, compared with 50% in the treatment interruption arm.

A total of 9 patients (1%) died, 4 in the continuous therapy arm and 5 in the treatment interruption arm (hazard ratio [HR] 1.30; P = 0.70).

12 patients in the continuous therapy arm developed a new or recurrent AIDS-defining (WHO stage 4) illness or death, for a rate of 3.2 per 100 person-years (PY).

In the treatment interruption arm, 31 patients experienced disease progression or death, for a rate of 8.2 per 100 PY (HR 2.6; 95% CI 1.4-5.1; P = 0.003).

In multivariate analysis, the treatment interruption arm had:

- 2.73 times higher rate of new AIDS-defining (WHO stage 4) events or death (P = 0.007);

- 2.58 times higher rate of new or recurring AIDS-defining events or death (P = 0.004);

- 2.95 times higher rate of new or recurring WHO stage 3 illness or death (P < 0.001).

The most frequent first AIDS-defining events were:

- esophageal candidiasis (4 cases in the continuous arm vs. 17 in the treatment interruption arm);

- extrapulmonary tuberculosis (1 vs. 4, respectively);

- cryptococcosis (2 vs. 2);

- herpes simplex (1 vs. 2).

Rates of grade 4 adverse events were 7.3 per 100 PY in the continuous therapy arm, compared with 5.9 in the treatment interruption arm (P = 0.46).

More patients changed their regimen due to toxicity in the continuous therapy arm than in the treatment interruption arm (3.1 vs. 0.5 per 100 PY, respectively) (P = 0.02).

Following a review by the Data Safety and Monitoring Committee, randomization was terminated on March 15, 2006, and all patients were offered continuous therapy.

Conclusion

The authors concluded that over a median follow-up of 51 weeks, the majority (92%) of patients in the treatment interruption arm were able to take antiretroviral therapy intermittently without developing AIDS-defining events.

However, the treatment interruption strategy was associated with a 2.6-fold increased risk of disease progression. Although the rate of death was not significantly higher in the treatment interruption arm, the researchers wrote, this strategy "cannot be recommended."

8/25/06

Reference
J Hakim (for the DART Trial Team). A structured treatment interruption (STI) strategy of 12 week cycles on and off ART is clinically inferior to continuous treatment in patients with low CD4 counts before ART: a randomisation within the DART trial. XVI International AIDS Conference. Toronto, August 13-18, 2006. Abstract THLB0207.