Predictors of HIV RNA Control after Discontinuation of HAART Started at Acute Infection Combined with Treatment Interruptions and Immune-based Therapies

Pathophysiological events occurring at primary HIV type 1 infection (PHI) determine the subsequent course of HIV disease. Treatment with HAART initiated at this stage leads to sustained suppression of plasma virus load in conjunction with immune system recovery.

However, the premature occurrence of dyslipidemia and lipodystrophy in some post PHI-treated patients has led to uncertainties as to the long-term benefit of such strategies. Although international guidelines still recommend treating PHI, an increasing number of physicians are now adopting a more conservative approach and delay initiation of HAART, despite demonstrations by several studies that HIV-specific CD4 T cells can only be preserved when therapy is initiated at PHI.

HAART discontinuation after several months, or short-course therapy, could therefore constitute a valid approach for limiting the long-term effects of therapy while enhancing immune control of viral replication.

The use of structured therapeutic interruptions (STIs) also has been emphasized as a technique for improving viral control after ceasing therapy.

However, because effective control is generally obtained in less than half of cases with STIs, it may be useful to determine the prognostic factors correlated with control, to pinpoint which patients could benefit from this strategy. Researchers in France analyzed this issue in a cohort of patients treated after PHI.

Thirty patients with acute human immunodeficiency virus (HIV) type 1 infection received a combination of 3 antiretroviral drugs (n = 15) or 4 antiretroviral drugs plus hydroxyurea and interleukin-2 (n = 15) for 24 months, followed by 1 - 3 structured therapeutic interruptions (STIs).

Viral control, defined as maintaining plasma viremia <5000 copies/mL without therapy, was achieved in 14 cases. Lymphocyte subsets, plasma HIV-1 RNA loads, proviral DNA loads in peripheral blood mononuclear cells (PBMCs), residual HIV-1 RNA loads in PBMCs and in lymph node cells, and anti-p24 lymphoproliferative response were measured.

In the multivariate analysis, proviral DNA loads in PBMCs and anti-p24 lymphoproliferative response assessed at 24 months were independently correlated with viral control after STI.

These results enabled the researchers to define a subgroup of patients for whom safe discontinuation of therapy initiated at acute infection was suitable and contributed to ascertaining priority for biological parameter assessment in future clinical trials.

Discussion

Taken together, say the investigators, these data argue for early interventions capable of decreasing HIV cellular reservoirs as much as possible at a time when the immune system is less damaged.

The quantitative evaluation of lymphocyte subsets was not predictive of response. Lymphocyte activation markers were low in most patients as a result of the sustained undetectability of plasma viremia with HAART.

The fact that residual levels of cell-associated HIV RNA were not predictive of response in either blood or lymph node tissues is also noteworthy. However, given the small sample size of the trial, the power could have been insufficient to detect lack of association, and further studies are necessary to determine whether other markers could be useful for determining patient evolution after therapy ceased.

In conclusion, the authors write, “In our opinion, these data can contribute to treatment of acute HIV-1 infected patients. At a time when long-term HAART is thwarted by drug-induced side effects and compliance problems, the efficient determination of patient subgroups able to safely interrupt therapy is of utmost importance.

“ Future clinical trials should focus on strategies for reducing proviral reservoirs as much and as quickly as possible while maintaining or reinforcing an HIV-1 specific immune response.”

11/21/03

Reference
A Lafeuillade and others. Predictors of Plasma Human Immunodeficiency Virus Type 1 RNA Control after Discontinuation of Highly Active Antiretroviral Therapy Initiated at Acute Infection Combined with Structured Treatment Interruptions and Immune-Based Therapies. The Journal of Infectious Diseases 188:1426-1432. November 15, 2003.