The majority of individuals whose lowest-ever CD4 cell count did not fall below 250 cells/mm3 appear able to interrupt treatment safely, for at least one year, according to a mostly prospective United States study published in the November 1st issue of the Journal of Acquired Immune Deficiency Syndromes.
Researchers from Texas undertook an examination of the consequences of interrupting highly active antiretroviral therapy (HAART) for any reason. They questioned clinicians at two large HIV clinics in Dallas regarding patients with a documented CD4 cell count above 250 cells/mm3 who were planning to stop, or had already stopped HAART for at least five consecutive weeks. One hundred and seven patients fulfilled the study criteria and were followed for an mesdian of 252 days (range 24 - 950 days).
Almost 90% of participants had a lowest-ever pre-HAART CD4 cell count greater than 250 cells/mm3. The median lowest-ever CD4 cell count was 377 cells/mm3 (range 120 - 712 cells/mm3). At the time of interrupting therapy, only two individuals had a CD4 cell count below 350 cells/mm3 and 61% had an undetectable viral load (defined as either below 400 or 50 copies/ml depending on the test used).
The researchers used 60 day periods to measure the virological and immunological outcomes of interrupting therapy. They found that CD4 cell count decline was rapid in the first 60 days (a median of 65 cells/mm3 per month) but levelled off to a relatively constant 8 cells/mm3 a month throughout the rest of the follow-up period. Similarly, the increase in HIV viral load was rapid in the first 60 days (2.54 log10) but then remained constant without a significant increase. Most participants had a steady viral load by 60 days, and the researchers comment that many would have likely achieved their viral load set point earlier, but this was not measured.
After 13 months of follow-up, the median CD4 cell count remained above the pre-HAART CD4 cell count, and the median viral load was “slightly less” than pre-HAART levels (22,400 vs. 8320 copies/ml). Six individuals maintained an undetectable viral load whilst off therapy for more than two months, and two individuals lasted 167 and 180 days before their viral loads became detectable. Interestingly, all eight had measurable detectable viral loads pre-HAART.
Two individuals suffered from the effects of increased viral loads. One was confirmed to have 'retroviral rebound syndrome’ and the second had fevers and felt unwell, but did not have the complete syndrome. Symptoms only partially improved after restarting therapy. No AIDS-defining events were recorded during the study.
Forty-one individuals (38%) restarted HAART during the follow-up period. The median CD4 cell count was 388 cells/mm3 after a median interruption of 6.4 months (1.3 - 35 months). Median viral load at the time of restart was 70,800 copies/ml (undetectable to 741,000 copies/ml). The most common reasons for restarting (which were not mutually exclusive) were:
- Health care provider recommended (31).
- Patient- or physician-determined CD4 cell count threshold reached (23).
- Patient- or physician-determined viral load threshold reached (16).
- Patient request (7).
The study had a combined endpoint of either a CD4 cell count below 250 cells/mm3 or restarting HAART or both. Only seven individuals reached one of the endpoints: a CD4 cell count below 250 cells/mm3 (in a median of seven months). The median time to reach the combined endpoint was 8.9 months.
All ten (100%) individuals with a pre-HAART CD4 cell count less than 250 cells/mm3 reached the combined endpoint. This compares with 23 of 82 (28%) of those with a pre-HAART CD4 cell count above 250 cells/mm3.
In univariate analysis, factors which predicted the combined endpoint were found to be:
- Lower pre-HAART CD4 cell count.
- Total number of prior drugs.
- Older age.
There was also a trend towards higher pre-HAART viral load being associated with reaching the endpoint.
In multivariate analysis, the most significant predictors of the combined endpoint were found to be:
- Pre-HAART CD4 cell count less than 250 cells/mm3 vs. greater than 250 cells/mm3 (odds ratio [OR] for > 250 cells/mm3 0.156; 95% confidence interval [CI], 0.025 - 0.861; p = 0.03).
- Total number of prior drugs (OR 1.455; 95% CI 1.080 - 1.959; p = 0.014).
- Older age (OR 1.083; 95% CI 1.001 - 1.172; p = 0.048).
Although follow-up time was limited in those restarting therapy (median 93 days, range 26 - 520 days), the median viral load was ‘undetectable’ and the median CD4 cell count increase was 137 cells/mm3 by 110 days.
The researchers concede that their data may have certain limitations, particularly the exclusion of individuals who restarted HAART earlier than five weeks after interruption, which they estimate as less than 5% of patients at the two sites. This may have resulted in improved outcomes for the study as a whole.
However, they assert that their data suggest that stopping therapy in patients with a pre-HAART CD4 cell count greater than 250 cells/mm3 is “safe and is not associated with any adverse outcomes.”
The safety of treatment interruptions is being tested in a large international study called SMART, which is randomising participants to continue HAART or to interrupt therapy until their CD4 counts fall below 350 cells/mm3. The study will compare the clinical outcomes of patients and their experience of drug toxicity, as well as the development of resistance.
Skiest DJ et al. Is it safe to stop antiretroviral therapy in patients with preantiretroviral CD4 cell counts > 250 cells/µL. JAIDS 37: 1351-1357, 2004.