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What Happens When Failing Therapy Is Stopped?

In patients who have detectable viral loads on a PI-based regimen, stopping therapy is associated with decline of CD4-cell count, increase of viral load, reversion to wild-type virus, and increase of in vitro viral fitness.

Despite high rates of virologic failure seen in clinical practice, most cohort studies have shown ongoing immunologic and clinical benefits from antiretroviral treatment. The data presented in this study help to clarify the mechanism behind this apparent paradox.

In the first part of the study, patients who had detectable viremia (more than 2500 copies/ml) on a PI-containing regimen were randomized 2:1 to stop or continue therapy. In the second part, all patients discontinued treatment. Data from the randomized arm are presented here. All patients had been treated with PI-based antiretroviral therapy for at least 12 months, with no change in regimen during the preceding 4 months, and all had experienced a CD4 count increase of at least 100 cells/mm³ in response to treatment. Clinical and laboratory follow-up was conducted weekly for 12 weeks.

Sixteen patients entered the randomized portion of the study, 11 of whom were assigned to stop treatment. One patient stopped only the PI in his regimen, and was not included in this analysis. Patients who stopped treatment experienced a median decrease in CD4 counts of 128 cells/mm³ at week 12, compared with a decrease of 15 cells/mm³ among those who remained on treatment. Patients who stopped treatment experienced a median increase in viral load of 0.84 log₁₀ compared with an increase of 0.31 log₁₀ for those who continued therapy. Differences in both of these markers were statistically significant.

Using phenotypic resistance testing on in vitro samples, researchers found that there was a shift to wild-type virus by 16 weeks in 9 of the 10 patients randomized to stop therapy; the one exception had no detectable resistance at baseline. This shift in drug susceptibility occurred at various times after therapy was discontinued and was often abrupt. Despite this shift in detected drug resistance in plasma, cultures of peripheral blood mononuclear cells showed that resistant strains persisted in long-lived cellular reservoirs. The increase in viral load and decrease in CD4-cell counts in patients stopping therapy did not occur until after the shift to wild-type susceptibility, at which point the changes were marked. The authors also measured replicative capacity in vitro ("fitness") and found that viral replication was impaired at baseline, but increased more in patients stopping treatment than in those who continued it.

These findings suggest that PI-based regimens continue to have antiretroviral activity, even after resistance has emerged. A likely mechanism explaining at least part of this phenomenon is the continued activity of the regimen against the fittest -- and most pathogenic -- viral strains, namely those that are wild type. An accompanying editorial to this elegant study discusses further implications of these findings, especially for the difficult balance between the virologic, immunologic, and clinical benefits of continuing a "failing" regimen and the cost of gradually accumulating resistance mutations to that regimen. Indeed, further clinical follow-up of this group presented by the first author at the 8th Retrovirus Conference shows that clinical progression will eventually develop after long-term virologic failure (Abstract 428).

— Paul E. Sax, MD

Published in Journal Watch HIV/AIDS Clinical Care April 1, 2001

Citation(s):

Deeks SJ et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001 Feb 15; 344:472-80.

• Original article (Subscription may be required)
• Medline abstract (Free)

Frenkel LM and Mullins JI. Should patients with drug-resistant HIV-1 continue to receive antiretroviral therapy? N Engl J Med 2001 Feb 15; 344:520-1.

• Original article (Subscription may be required)
• Medline abstract (Free)