Outcome of patients with discordant responses to HAART
By Brian Boyle, MD for HIV&Hepatitis.com
A subset of patients receiving highly active antiretroviral therapy (HAART) – a triple drug combination therapy that usually includes a protease inhibitor – exhibits a high CD4 T cell response in the presence of a sustained viral load or have low CD4 cell counts despite a decrease in viral load.
However, there is very little data available on the long-term outcome of patients with such discordant responses to therapy. Therefore, a prospective cohort was analysed to determine the clinical, virologic and immunologic outcomes in 150 patients over a
Patients were enrolled in the study if they were HIV-1 seropositive, protease inhibitor-naïve and antiretroviral-experienced. Plasma virus load and CD4 T cell counts were obtained within 2 weeks prior to starting therapy and every 3 months thereafter. Initial HAART therapy consisted of indinavir combined with 2 nucleoside analogues. An immunologic response to therapy was defined as an increase in CD4 cell count from baseline of at least 100 cells/μL at 12 months and a virologic response was defined as a decrease in plasma HIV RNA of at least 1 log or <500 copies/mL. Long-term immunologic and virologic responses had the same definitions, but at 30 months of follow-up.
Patients were classified in 1 of 4 categories: positive immunologic and virologic responders (I+V+), negative responders to both (I-V-), positive immunologic, but negative virologic responders (I+V-) or the converse – negative immunologic, but positive virologic responders (I-V+). Of note, seven patients were lost to follow-up after 12 months. Also, 82 patients discontinued indinavir treatment during the 30-month follow-up because of side effects, treatment failure or their physician’s decision. Second line HAART included ritonavir and saquinavir, ritonavir, nelfinavir, saquinavir or nevirapine.
At 12 months of therapy, 60% of patients were complete responders, 12% were non-responders, and 28% had discrepant immunologic and virologic responses, specifically 19% had a positive immunologic response and a negative virologic response (I+V-) and 9% were virologic responders without an immunologic response (I-V+). There was no significant difference in response to HAART on the basis of sex, transmission risk group, or baseline CD4 cell count or viral load.
Also, there was no difference in response in terms of mean time receiving NRTIs before protease inhibitor treatment, previous zidovudine monotherapy or changing the nucleoside analogue during the first month of HAART. However, a statistical difference was noted with regard to age with I-V+ responders being older than the other groups. Finally, 92% of full responders remained as such for the entire 30 months and 78% of the non-responders remained non-responders despite changes in therapy.
The following were determined to be risk factors for clinical progression and death: CD4 count <100 cells/μL at baseline, plasma HIV RNA levels at baseline, AIDS defining event prior to enrolment in study, previous zidovudine monotherapy and duration of antiretroviral therapy prior to study. Furthermore, the relative risk of progression was 51-fold higher in I-V- group than in the I+V+. Also, there was a 6.5-fold higher risk in the I+V- group and 9.7-fold higher in the I-V+ relative to the I+V+ group for progression of disease. The I+V- group had a lower risk of progression (0.12-lower) than the I-V- group, as did the I-V+ group (0.2-lower).
The authors assert “the overall efficacy of HAART was reflected by the high percentage of patients (67%) who had an increase in CD4 cell counts >100 cells/μL and a decrease in HIV virus load of >1.0 log/mL or who achieved persistent HIV RNA plasma levels <500 copies/mL.” None of the factors stated previously were predictive of a discrepant response, however, patients with a virologic response in the absence of an immunologic response were statistically older than the other groups.
The authors state these “findings are consistent with reports indicating that the magnitude of immune restoration is dependent on thymic activity, which decreases with age.” Furthermore, the risk of progression of I+V- patients was significantly lower than that of I-V+ patients, such that 86% of I+V- patients were alive and free of AIDS-related events at 30 months whereas this proportion was 79% in the I-V+ patients and 33% in I-V- patients.
The authors conclude: “[these] results support the predominance of the CD4 marker over plasma HIV load for predicting clinical outcome in patients who do not achieve a full immunologic and virologic response. Thus, although it may be tempting to switch therapy in patients with discrepant responsesþthere is a potential risk of using most of the available classes of antiretroviral drugs too early in patients with an overall high rate of clinical responsesþparticularly for patients with an immunologic response in the absence of a virologic response.”
Finally, more research is necessary to “determine the threshold of plasma HIV load above which the risk of immunologic and clinical failure becomes significant.”
Piketty C and others. Long-term Clinical Outcome of Human Immunodeficiency Virus-infected Patients with Discordant Immunologic and Virologic Responses to a Protease Inhibitor-containing Regimen. Journal of Infectious Diseases. 2001; 183:1328-35.
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