Immune restoration during HAART: 8-year follow-up in HIV-positive patients with sustained virological suppression

Abstract

Durable virological suppression during HAART is associated with immunological recovery in patients with HIV infection. Current guidelines recommend to initiate HAART when CD4+ cell count falls <350/μl. However, recent studies have shown a higher immune restoration when HAART was started at CD4+ baseline level > 350 cells/μl. We retrospectively assessed the long-term immunological outcome in patients with sustained virological suppression during HAART, for up to 8 years. MethodsHIV-infected consecutive patients attending to our clinic were included, with the following inclusion criteria: follow-up >1 year while on HAART and sustained virologic suppression (HIV-RNA <400 copies/ml) for at least 6 consecutive months. We analyzed the immunological outcome by of annual determination of: 1) CD4+ cell count; and 2) change in CD4+ cell count from baseline. Complete immunological recovery was defined as CD4+ cell count ≥700/μl. Patients were stratified according to baseline CD4+ cell (counts of <200/μl, 200-350/μl and >350/ μl), age, HIV risk group, HCV co-infection, HAART regimen, sex, and race. A statistical analysis was performed by linear regression. Summary of results352 patients were observed: 172, 85 and 95 patients had baseline CD4+ cell count <200/μl, 200-350/μl and >350/ μl, respectively. After 5 years of therapy, 29%, 69% and 82% of patients with baseline CD4+ cell count, respectively, <200/μl, 200-350/μl and >350/μl, exceeded the threshold of 500 cells/μl (p = 0.034).Among patients with baseline CD4+ cell count >350/μl, mean CD4+ cell count reached a plateau with a complete immunological recovery by 4 years of suppressive HAART. CD4+ cell count increased even after 8 years without ever reaching a full immunological recovery in patients with baseline CD4+ cell count <200/μl. Patients aged ≥50 years had a slower but similar immune recovery (p > 0.05). We found no significant differences in immunological response according to baseline viral load, HIV risk factor, sex, HCV co-infection and HAART regimen. ConclusionIn our study, patients with sustained viral suppression experienced a significant immune recovery over 8 years of HAART. We found that complete immune recovery was achieved only in patients with baseline CD4+ cell count >350/μl. This observation strengthens the hypothesis that starting HAART at CD4+ cell counts < 50/μl could not be adequate to obtain a complete immunological recovery.

The pattern of immunologic and virologic responses to Highly Active Antiretroviral Treatment (HAART): Does success bring further challenges?

“…Although, it varies in different settings, ART should be started when CD4+ count is 201-350, or <= 200/µl for developed and resource-poor settings, respectively (21). However, given the observed lower morbidity, mortality and fewer adverse events associated with the initiation of HAART at higher CD4 cell counts (23,24), WHO recommends CD4+ count <= 350 cells/µl to initiate ART as a universal guideline (5).…”

“…Overall, the long-term shape of CD4+ count after HAART depends on the baseline CD4+ count, control of viral replication overtime, the stage of the disease at baseline, duration on treatment (39,40), as well as on baseline patient factors including higher HIV RNA level, co-morbidities, presence of drug resistant viruses, sub-optimal pharmacokinetics, and potency of the ARV regimen (17). The time required to reach to normal value of CD4+ counts ranges from two to eight years (24,41).…”

“…HCV, HIV-2, HTLV-1, HTLV-2), medications (ZDV, TDF+DDI), and persistent immune activation (17). However, others have reported no difference in immunological response related to baseline viral load, HIV risk factor, sex, HCV coinfection and HAART regimen (24). Several explanations have been given about the mechanisms by which inadequate immune CD4+ recovery occurred in response to HAART.…”

“…Moreover, although the rate of CD4+ recovery depends on several factors including baseline CD4+ count, control of viral replication overtime, the stage of the disease at baseline, duration on treatment (17,40), the time required for CD4+ cells to reach the normal values ranges from two to eight years (24,41). However, the fact that there is significant reduction in the frequency of OIs, and in morbidity and mortality, irrespective of the slow recovery rate as well as low absolute number of CD4+ cells post-HAART, raises a research question "how strong is the restoration of the functional immune response specific to variety of OIs post-HAART irrespective the low number of CD4+ cells in the periphery?…”

Factors associated with long‐term CD4 cell recovery in HIV‐infected patients on successful antiretroviral therapy

“…However, there are patients who show an early CD4 cell recovery even with positive plasma HIV viral load, while others have a slow CD4 cell gain in spite of having a long‐term suppressed HIV viral load. The mechanisms underlying this immunovirological discordance are not fully understood . Some studies have shown that efficient thymopoiesis is key to the natural maintenance and ART‐mediated recovery of naïve and total CD4 cell counts in HIV‐infected individuals .…”