The goal of antiretroviral therapy in HIV-positive patients is to suppress the viral replication (to below the limit of detection) and possibly increase the CD4 cell count. The clinical benefit of anti-HIV drugs is largely dependent on the extent of immune reconstitution. In fact, patients having a substantial immune response, despite a virologically failing regimen, perform better clinically than patients with a fully suppressive regimen, but without a significant CD4 cell count increase [1–3]. The immunological benefit resulting from highly active antiretroviral therapy (HAART) is generally considered to be the consequence of viral suppression and a reduction of the pathogenic (immune-depleting) potential of ongoing viral replication. However, recent evidence indicates that patients on failing regimens (detectable viraemia, despite full adherence to treatment), who discontinued their HAART, experienced a rapid decrease in CD4 cell count and an increase in viral load, suggesting that even a partial control of HIV replication may be of benefit in terms of immune preservation [4,5]. Moreover, in both antiretroviral-naive and experienced patients, the immunological and virological effect of anti-HIV medications may not always be concordant. Discrepant responses, either immunological (CD4 cell count improvement, despite persistent viral replication) or virological (undetectable viral load, without any CD4 cell count increase), have often been reported in patients on protease inhibitor (PI)-based regimens [1,2,6–9]. Up to 19% of patients on HAART may experience such a paradoxical response to therapy [1,2].
We describe four patients with discordant immunological responses, out of 67 HIV-positive individuals who started their first non-nucleoside-reverse-transcriptase-inhibitor (NNRTI)-based regimen because of the failure of a PI-containing therapy, and who had at least 8 months of follow-up (range 8–14 months). Discordant immunological response was defined if all the following criteria were present: (i) an increase in CD4 cell count greater than 100 cells/μl from baseline; (ii) an increase or a non-significant decrease (equal to or less than 1 log from baseline) in viraemia; and (iii) stability or a decrease in CD4 cell count during the previous year, when the patient was on his last PI-based regimen.
Twenty-nine patients (43.2%) out of this cohort gained more than 100 CD4 cells/μl after starting the NNRTI-based treatment. However, most of them (22 patients) achieved an undetectable viral load or experienced a reduction in the HIV-RNA level of 1 log from baseline or greater, any time since starting the NNRTI. Only seven patients had a substantial immune reconstitution (CD4 cell count increase of more than 100 cells/μl), despite a non-significant decrease in viraemia. Of these, three patients had experienced an immunological improvement during the previous year when they were on their last PI-based regimen. For these latter patients, it is difficult to assess the relative role of NNRTI- or PI-based treatment in determining the immune recovery. For this reason they were excluded from the analysis. The remaining four patients (Table 1) were considered to be discordant immunological responders, given the increasing CD4 cell count in the presence of an insufficiently suppressive regimen. All of them had had a stable or decreasing CD4 cell count trend during the past 12 months before starting their first NNRTI regimen. It is noteworthy that the first three patients did have an initial immune response (> 100 cells/μl from baseline) on their previous PI-based regimens, before experiencing stability or a decline in their CD4 cell count. All four patients had received at least one PI (mean 1.5) and three were on efavirenz. They were not severely immunosuppressed (baseline CD4 cell count ≥ 180) and their CD4 cell count increase was 148 cells/μl or greater, after 8–14 months of therapy. The baseline viral load was relatively low (< 11 000 copies/μl) as was the highest HIV-RNA value during the follow-up. Only two patients had a genotype test performed before starting their first NNRTI-based regimen, because resistance testings were not routinely available at that time. Neither of the two had an NNRTI resistance-conferring mutation.
Some speculation about the immunological benefit (increasing CD4 cell count under therapy) in patients with insufficient viral suppression has been reported. This finding may be related to reduced viral fitness under selective drug pressure [10,11], to a sort of PI-intrinsic effect [12,13] as all series have been reported in patients on PI-based regimens, or to a higher thymic output in some treated patients . Our observations provide evidence that, if the immune reconstitution is partly caused by an unclear pharmacological effect of anti-HIV medications (other than their antiviral potency), it is not a peculiar response of PI-containing regimens. It may also be seen in patients on NNRTI.
Maria Grazia Finazzi
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