Low level HIV replication despite good virological response may explain CD4+ cell decline in a patient receiving combination nucleoside analogue therapy

A residual, low level of HIV-1 replication may be the cause of a progressive decrease in CD4+ T-cell count in patients who appear to have a complete virologic response to antiretroviral therapy, according to Spanish researchers.

Dr Felipe Garcia and colleagues from the Hospital Clinic in Barcelona describe the treatment of a patient with chronic HIV-1 infection whose CD4+ T-cell count decreased in spite of a plasma viral load of less than 20 copies per mL.

The patient received stavudine plus didanosine therapy for 12 months, which resulted in a steady decline of plasma viral load from an initial level of 21 665 HIV-1 RNA copies per mL. During this same period, the patient’s CD4+ T-cell count decreased from 559 cells per microlitre (µL) to 259 cells per microlitre (µL).

However, at the end of 12 months, analysis of tonsilar biopsies showed a viral load of 125 000 copies per mg of tissue. The patient’s antiretroviral therapy was switched to zidovudine, lamivudine, and the protease inhibitor nelfinavir.

Plasma viral load decreased to less than 5 copies per mL, while CD4+ T-cell count increased to 705 cells/µL after 12 months on the triple-therapy regimen. Similarly, tonsilar load decreased to less than 40 copies per mg.

‘A change to a more potent regimen seems to lead to recovery of immune system function,’ the authors write in the February issue of Clinical Infectious Diseases. This is supported by the fact that ‘the changes in the different immunologic markers (proliferation responses to mitogens and antigens, as well as percentages of CD8+ CD38+ and CD8+ CD28+ T cells) were concordant.’

The authors conclude that lymphoid tissue biopsies may be necessary to detect similar cases of residual replication. In addition, ‘changing or intensifying the therapy with a more potent regimen could prevent a decrease in the CD4+ T-cell count and improve the function of the immune system.’

Comment

There have been previous concerns that combination regimens not containing protease inhibitors may have insufficient potency to suppress HIV replication to the same degree as PI based regimens. Even though HIV was well suppressed in plasma in this patient, replication appeared to be ongoing in the lymphatic tissues. It is, however, encouraging that CD4 reconstitution was salvageable on initiation of a PI containing regimen. Further investigation of the differences in degree of suppression of HIV replication in various tissues and of the qualitative aspects of immune reconstitution between PI containing and non-PI containing regimens is warranted.