Study finds smaller CD4 response to successful antiretroviral therapy following treatment interruptions

HIV-positive people who stop taking antiretroviral therapy and then start again are likely to see smaller CD4 cell count increases than they did when they first went on antiretrovirals, according to a study in the December 15^th edition of the Journal of Acquired Immune Deficiency Syndromes. The poorest immunological responses were seen in study participants who were older and whose CD4 counts were lower during treatment interruption.

The observational study used data from CASCADE, a large European research network that is monitoring the health of more than 17,000 HIV-positive individuals. Investigators identified a cohort of 216 CASCADE participants who had stopped taking antiretroviral regimens after an initial treatment period of at least 90 days, then started again after a break of at least 14 days.

The most striking finding was that when people resumed antiretroviral therapy, CD4 cell counts initially increased about as much as they had during the first treatment period, but then increased at a slower rate after three months. In other words, there were smaller long-term CD4 cell count gains following treatment interruption.

The median duration of treatment interruption was 6.2 months, and CD4 cell counts were available for a median (IQR) of 19.4 (8.5-37.8) months following treatment resumption.

When investigators compared the rate of CD4 increase per month in the first treatment period to the rate in the second, they found the equivalent of median increases of 106 (88 to 123) cells/mm³ at the three-month mark during the first treatment period versus 99 (74 to 119) cells/mm³ at the same point after treatment resumption; then, respectively, 119 (101 to 137) versus 107 (88 to 127) cells/mm³ at six months; 145 (126 to 165) versus 125 (105 to 144) cells/mm³ at twelve months; 200 (170 to 230) versus 160 (135 to 185) cells/mm³ at 24 months; and 258 (213 to 302) versus 197 (162 to 231) cells/mm³ at 36 months (all 95% confidence interval [CI]).

Investigators also looked at rates of CD4 increase following treatment interruption in relation to CD4 cell count levels during treatment interruption. They found that only people who had CD4 cell count measures of more than 500 cells/mm³ during treatment interruption could be expected to attain nearly normal CD4 cell count levels within three years.

People older than 40 had smaller CD4 increases during their first three months back on antiretroviral therapy, as did people who returned to the same antiretroviral regimens.

Virologic responses during the two treatment periods were comparable, with viral loads dropping to less than 500 copies/ml for 82% of people newly initiating antiretroviral therapy and for 87% of people resuming antiretroviral therapy after treatment interruption. During the first treatment period, a median time of 13.6 (11.9 to 16.2) weeks was required for the viral load to go below 500 copies/ml, and during the second treatment period, a median time of 12 (11 to 15) weeks was required.

The researchers attribute the initial steep climb in CD4 cell counts after resumption of antiretroviral therapy to the release of CD4 cells that were sequestered in the lymph nodes when viral load was high. The same mechanism accounts for large early increases in CD4 cell counts when people first begin antiretroviral therapy. It takes longer for new CD4 cells be formed, and thus a slower rate of increase can be expected after three months.

However, the researchers note, “The underlying biological mechanism for the observed differences in these subsequent rates of CD4 increase during [treatment resumption] … is mostly unknown.” They do not believe that previously undetected viral resistance from the first treatment period could account for their outcomes because even people who had sustained virologic responses to both rounds of treatment saw poorer CD4 responses after treatment interruption.

Many researchers began to investigate the effects of planned treatment interruptions, also known as structured treatment interruptions, after a 1999 case study raised the possibility that people might continue to see the benefits of antiretroviral therapy while taking time off from the medicines. However, large clinical studies of various treatment interruption strategies have not only failed to confirm their efficacy but also raised safety concerns.

While it seems unlikely that planned treatment interruptions will ever be medically advisable, the complexity and toxicity of antiretroviral regimens lead many HIV-positive people to discontinue treatment. The authors of the CASCADE treatment interruption study advise careful clinical monitoring of treatment interruptions in people who are above age 40 and have had low CD4 cell count levels in the past.