Added value of hydroxyurea or IL-2 to STIs remains uncertain
A separate poster presented by Felipe Garcia considered if the use of hydroxyurea (HU) might be associated with added benefit during STIs . Franco Lori and colleagues have hypothesised that this may be the case in their so-called PANDA cohort. It has been further postulated that the use of HU might promote the generation and preservation of HIV-specific immune responses.
Eighteen patients with chronic HIV-infection and a similar profile to those from the EARTH study were treated with d4T/3TC/indinavir for 52 weeks before being randomised to add HU (HU group) for 6 months or to continue with their triple combination (non-HU group). All patients had a plasma viral load of <20 copies/mL for at least 32 weeks prior to randomisation. After these 6 months they then undertook 3 treatment interruptions separated by periods of 2 months treatment with their triple combination +/- HU. Therapy was reintroduced when VL increased above 200 copies/mL in the first interruption and after 2 weeks in the second and third interruptions irrespective of viral load. Fourth and fifth interruptions are planned with the HU group continuing on HU only during the antiretroviral interruptions.
Rebound of plasma viral load was detected in all cases after the first interruption. There was no difference in mean doubling time between the HU and non-HU groups (2.08±0.38 vs 2.67±0.8, p=0.52). Viral load rebounded to a mean between 1,000 and 10,000 copies/mL after the first, second and third interruptions and was similar in both groups. CD4+ proliferative response to HIV p24 antigen was detected in 3/18 subjects during the first interruption, 8/18 during the second interruption and 12/18 during the third interruption. There were no differences between the HU and non-HU groups.
As in the previous study known resistance mutations associated with antiretroviral drug resistance were not detected after the first, second and third interruptions and virological response to <20 copies/mL was quickly achieved after reintroduction of therapy after each interruption.
It was concluded that HU associated with antiretroviral therapy neither prevents viral load rebound nor changes viral load rebound dynamics after treatment interruption. Hydroxyurea also appeared to be neither effective in increasing the control of viraemia after 3 interruptions of therapy, nor in inducing a higher proportion of specific immune responses against HIV-1 antigens. However, as with the previous study, after the second and third interruptions about half of the patients developed a strong specific CD4+ T-lymphocyte proliferative response against HIV p24 antigen (irrespective of exposure to HU).
Preliminary observations on the 5 patients who have reached the planned fourth and fifth interruptions suggests that maintaining HU during interruption of antiretrovirals might help to further control viraemia.
The kinetics of viral rebound and T-cell dynamics after a single treatment interruption in patients on HAART +/- IL-2 (the COSMIC trial) were presented by Jan van Lunzen of the University Hospital Eppendorf, Hamburg . Fifty six patients with a mean CD4+ T-cell count and viral load of 484 cells/mm3 and 4.42 log copies/mL respectively were randomised to receive d4T/3TC/nelfinavir/saquinavir with or without adjuvant IL-2. Therapy was ceased in 10 patients (5 receiving IL-2, 5 on ARV’s only) according to strict criteria:
- Very low to undetectable viral burden in lymph node by in situ hybridisation.
- Viral load undetectable in CNS (<25 copies/mL).
- Viral load undetectable (<25 copies/mL) in plasma for 13 to 23 months (median 16 months).
All patients had a rebound in plasma viral load after treatment interruption which was detectable after 1.5 to 6 weeks (median 3 weeks). Maximum viral load was reached after 2 to 12 weeks (median 4.5 weeks) and an ‘overshoot’ of viral load compared to baseline was observed. 6 of 10 patients regardless of IL-2 had therapy reintroduced after a median 3 months when their viral loads reached pretreatment levels. 4 of 10 patients are not receiving therapy up to 6, 12, 13 and 14 months after discontinuation and continue to experience low viral loads.
The group concluded that on a single interruption pretreatment levels of plasma viraemia are reached regardless of previous IL-2 treatment and that CD4+ and CD8+ activation and proliferation shows a strong correlation with viral load. T-cell responses tended to be reduced during the peak of rebound and increased again during steady state. No influence of adjuvant IL-2 on the parameters studied was observed.
More interesting observations on strategic therapy interruptions were presented but as always the caveats on small numbers warrant caution in interpretation. More data is needed from a wider variety of patients. Large prospective trials of continuous versus intermittent HAART are planned and should provide valuable insight into the utility of this approach.
The hydroxyurea study varies from other STI studies in that there were set 2 week periods off treatment after the second and third interruptions. Viral load may not have rebounded sufficiently during these 2 week interruptions. Additionally viral load was not allowed to reach set-point. It may be that hydroxyurea might display an effect on the set-point. Lori’s PANDA cohort were on 2 NAs + HU only, and low level viraemia (and therefore antigen exposure) in the presence of HU was prolonged. Might this be a further requisite for a beneficial effect of HU on immune response & viral set-point?
It is unknown what the dosage and administration of IL-2 was in the above study. A single interruption may not reveal added benefit. Additionally, maintenance of IL-2 during ART interruption may be necessary so that IL-2 stimulated cells are encountering antigen. This may, however, carry the risk of IL-2 stimulating viral replication while ARV’s are suspended.
- Garcia F, Plana M, Ortiz GM et al. Hydroxyurea neither prevents viral load rebound nor facilitates further control of viral replication after three consecutive cyclic interruptions of therapy in chronic HIV infection: a randomised trial. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 190.
- van Lunzen J, Frahm N, Hoffman C et al. Rapid rebound of viral replication, T cell activation, proliferation and dysfunction after discontinuation of HAART with or without interleukins 2. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 194.