Protease inhibitor (PI) and NNRTI-based regimens appear to be equally able to bring about immune reconstitution in people who start treatment early, even though a PI based regimen achieves better reductions in viral load and increase in the number of CD4-T cells, according to Spanish research published in the 15 April edition of the Journal of Acquired Immune Deficiency Syndromes. However neither treatment regimen can bring about a return of an HIV-specific CD4-T cell response.
The Spanish trial, which ran between 1998 and 2000 monitored the effectiveness of antiretroviral treatment in 20 people with chronic HIVinfection, each of whom had a CD4-T cell count of above 500 with a detectable viral load above 5000 copies/ml. Nine people were treated with an antiretroviral regimen containing the PI indinavir, plus the NRTIs d4T (stavudine) and ddI (didanosine). Eleven people were treated with the NNRTI nevirapine, plus d4T and ddI. There were no significant differences in CD4 T-cell count or plasma and lymphatic viral load between the two groups at the start of the trial.
Over a period of twelve months the effectiveness of the PI and NNRTI-based regimens was assessed, with CD4 T-cell counts and standard and ultra sensitive viral load tests performed on two occasions during the trial and at its conclusion. Biopsies were also taken from the lymphatic tissue in the tonsils to monitor viral load and test reaction to pathogens. Detailed analyses of the immune profiles of both the PI and NNRTI group were also performed.
The researchers found that after twelve months the PI group had achieved a better reduction in viral load, with 83% experiencing a drop in viral load below 200 copies ml and 71% below 50 copies/ml, compared to 73% and 45% respectively for the NNRTI group, which was statistically significant. In addition, the results from the tonsil biopsy also suggested better viral suppression amongst the PI group, with 100% having a viral load below 40 copies/mL against 54% in the PI group. It was also noticed that the percentage of CD4 T-cells in PI group increased “significantly” from 35% to 52%, whilst remaining at baseline in those treated with nevirapine at approximately 44%.
However, detailed analysis of the immune profiles of both treatment groups, indicated that other markers suggested that their immune systems had experienced comparable reconstitution. In particular, researchers found that there was a comparable drop in CD8-positive T cells, an increase in the mean percentage of the CD28-positive subset of CD8-positive-T cells and “a high and significant decrease” in both CD8-positive and CD38-positive T cells. Both groups also saw an increase in naïve and memory T cell production.
The lymphocyte biopsy taken from the tonsils proved equally responsive to a tetanus and CMV in both groups.
Even though treatment was initiated whilst the immune systems of the trial participants was still largely intact, neither the PI nor NNRTI group experienced any restoration of HIV-specific CD4 response. The researchers also point out that further studies are needed to assess if an NNRTI-based regimen would bring about a similar degree of immune reconstitution in people who had experienced more advanced immune damage.
Evidence from a US study which appears to support the findings of this research was also published in a letter the same edition of the Journal of Acquired Immune Deficiency Syndromes. Doctors at St Luke’s Medical Center in Chicago compared viral suppression and immune reconstitution in 24 patients with viral load below 80 copies/ml and similar baseline CD4 counts and age, thirteen of whom were taking a PI-based treatment regimen, the other eleven a PI-sparing regimen. Overall they noticed few differences in immune reconstitution between the two groups, although they did notice that the PI group had lower levels of immune activation. The letter’s authors believe that this warrants further investigation as high levels of immune activation of CD4-positive and CD8-positive T cells were associated with an increased risk of developing an AIDS-defining illness before the availability of HAART.
Plana M et al. Immunologic reconstitution after 1 year of highly active antiretroviral therapy, with or without protease inhibitors. Journal of Acquired Immune Deficiency Syndromes 29(5):429-434, 2002.
Smith KY et al. Immune reconstitution after successful treatment with protease inhibitor-based and protease inhibitor-sparing antiretroviral regimens. Journal of Acquired Immune Deficiency Syndromes 29(5): 544-545, 2002.