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IAS 2015: Many People with Long-term HIV Infection Do Not Achieve Full CD4 Cell Recovery

One-third of people who started combination antiretroviral therapy (ART) many years ago using first-generation protease inhibitors did not achieve complete immunological recovery with normal CD4 T-cell counts despite good viral suppression, according to a French study presented at the recent 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention in Vancouver.

It is well known that effective combination ART for people with HIV can suppress viral replication and prevent disease progression and immune deficiency. Among people who have already sustained substantial immune deficiency at the time they start ART, CD4 cell counts usually rise, but may never reach normal levels.

Francois Raffi from Université de Nantes in France and colleagues evaluated immune recovery over 10 years among more than 600 participants in the APROCO-COPILOTE cohort who started combination ART containing a first-generation protease inhibitor (PI) in 1997-1999, not long after this new class of drugs became widely available.

This analysis focused on 399 participants who had no clinical disease progression, undetectable viral load (HIV RNA <50 copies/mL) at the last visit, and sustained virological suppression with no more than 1 viral "blip" (50-500 copies/mL) during the last 18 months of follow-up.

Most participants (81%) were men and the median age at baseline was 39 years. The median baseline CD4 count was 254 cells/mm³ and 39% had <200 cells/mm³, indicating advanced immune suppression. Three-quarters used unboosted indinavir (Crixivan) or nelfinavir (Viramune) as their initial PI, while a smaller number used saquinavir (Invirase) or full-dose ritonavir (Norvir).

The researchers looked at CD4 response, defined as a CD4 count >500 cells/mm³, and complete immunological response, defined as both a CD4 count >500 cells/mm³ and a CD4:CD8 ratio >1.

Results

• 132 of the 399 patients (33%) did not experience CD4 response.
• 319 patients (80%) did not achieve complete immunologic response.
• In a multivariate analysis, factors associated with incomplete CD4 response included:

o   Older age (over 40 years) at baseline (odds ratio [OR] 2.55);

o   Absence of CD4 recovery (still <500 cells/mm³) after 4 months or 1 year on ART (OR 2.79 and 3.56, respectively);

o   Longer total duration (>3 months) of ART interruption (OR 2.32).

• Factors associated with incomplete immunological response included:

o   Low CD4:CD8 ratio (<0.8) after 8 or 12 months on ART (OR 6.14 and 5.53, respectively);

o   Longer total duration of ART interruption (OR 4.44);

o   Having used >3 ART regimens (OR 2.97).

o   Having used a larger number of treatment sequences, or changing regimens more times (OR 0.33 for 4-6, 0.58 for 6-9, and 0.19 for >10 sequences compared to 0-4 changes).

• Baseline CD4 count and CD4:CD8 ratio, however, were not significant predictors of 10-year immunological outcomes.

"In this population having started ART with first-generation PI, long-term immunologic recovery was rarely complete after 10 years of antiretroviral therapy despite clinical and virological success," the researchers concluded. "Failure to achieve long-term immunologic response was not associated with baseline immunological parameters, but with immunologic response during the first year of treatment."

"This study confirms the deleterious effect of treatment interruption on long-term immunologic recovery on combination ART," they continued.

They added that the beneficial effect of multiple antiretroviral regimens needs further study, but the positive impact might be due to more frequent ART optimization, such as changing a failing regimen sooner or switching to more potent and better-tolerated new drugs as they became available.

9/2/15

Reference

F Raffi, A Perrier, V Le Moing, et al. Factors associated with incomplete immunologic recovery in HIV-infected patients with clinical and virologic success after 10 years of antiretroviral therapy: a prospective cohort study. 8th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Vancouver, July 19-22, 2015. Abstract MOPEB149.