Factors associated with immunologic stability despite protease inhibitor based HAART “failure”
By Brian Boyle MD, for HIVandhepatitis.com
An accepted principle in the treatment of HIV infection is that unless the patient is on deep salvage antiretroviral therapy — when issues of viral fitness may trump the issue of complete virologic suppression — when virologic failure of an antiretroviral regimen occurs the regimen should be rapidly changed to avoid what is thought to be an inevitable immunologic failure, as well as the development of increasing viral resistance and cross-resistance to antiretrovirals.
This belief appears well founded in most HIV patients, since this is the course many will follow. However, it has been observed that some patients with incomplete viral suppression with protease inhibitor-based antiretroviral therapy — which would usually be considered virologic “failure” — do not immunologically fail, but instead continue to have stable or even rising CD4+ T cell counts.
In a clinic-based cohort study of 291 HIV-infected adults by Steven Deeks and associates, an effort was made to determine both the incidence and the risk factors of patients virologic failing protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) — defined as a viral load >500 copies/mL on two consecutive occasions — returning to pre-therapy CD4+ T cell count levels. The enrolled patients’ median, absolute and change in CD4+ T cell count and viral load at the time of virologic failure were 224 and +90 cells/mm3 and 3.74 and -0.94 log10 copies/mL, respectively.
The patients were observed for a median of 27.9 months. During that time, 128 stopped therapy for at least 16 weeks, 89 switched to a salvage regimen and had a successful virologic response and 47 died, with 31 of these deaths being AIDS-related.
If the data were censored to take into account patients in whom a successful salvage regimen was initiated, the median time to immunologic failure — ie a return to pretherapy CD4+ T cell levels — after the onset of virologic failure, was three years. If patient data were also censored at the time therapy was discontinued, then only 36.8% of the patients experienced immunologic failure after three years of continuous virologic failure.
Using a multivariate analysis, the change in viral load from pre-treatment baseline, and to a lesser extent the absolute level of viremia during virologic failure, were predictors of subsequent immunologic failure. The risk of immunologic failure was most likely in patients who failed to maintain viral suppression of at least 0.69 log10 copies/mL from baseline or had an absolute plasma viremia of > 4.5 log10 copies/mL. Discontinuing therapy was also associated with immunologic failure independent of viral load changes.
The authors conclude: “Immunologic failure of protease inhibitor therapy occurs among patients experiencing long-term virologic failure, but is delayed by the continued use of a partially effective antiretroviral regimen.
“Change in viral load from pre-therapy ‘set point’ is the single most important predictor of maintaining a CD4 cell increase. For patients with limited therapeutic options, strategies based on maintaining some degree of partial viral suppression may be warranted”.
The authors note, however, that the decision is a difficult one, especially in patients with other viable treatment options, and involves the patient and clinician balancing the potential immunologic benefits of “continuing a well-tolerated regimen despite ongoing viral replication” against “the risk of continued viral evolution and the emergence of high-level drug resistance.”
S Deeks et al. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS. 2002; 16:201-207.
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