Immunological predictors of CD4+ T cell decline in antiretroviral treatment interruptions

<p>Abstract</p> <p>Background</p> <p>The common response to stopping anti-HIV treatment is an increase of HIV-RNA load and decrease in CD4⁺, but not all the patients have similar responses to this therapeutic strategy. The aim was to identify predictive markers of CD4⁺cell count declines to < 350/μL in CD4-guided antiretroviral treatment interruptions.</p> <p>Methods</p> <p>27 HIV-infected patients participated in a prospective multicenter study in with a 24 month follow-up. Patients on stable highly active antiretroviral therapy (HAART), with CD4⁺count > 600/μL, and HIV-RNA < 50 copies/ml for at least 6 months were offered the option to discontinue antiretroviral therapy. The main outcome was a decline in CD4⁺cell count to < 350/μL.</p> <p>Results</p> <p>After 24 months of follow-up, 16 of 27 (59%) patients (who discontinued therapy) experienced declines in CD4⁺cell count to < 350/μL. Patients with a CD4⁺nadir of < 200 cells/μL had a greater risk of restarting therapy during the follow-up (RR (CI95%): 3.37 (1.07; 10.36)). Interestingly, lymphoproliferative responses to <it>Mycobacterium tuberculosis </it>purified protein derivative (PPD) below 10000 c.p.m. at baseline (4.77 (1.07; 21.12)), IL-4 production above 100 pg/mL at baseline (5.95 (1.76; 20.07)) in PBMC cultured with PPD, and increased IL-4 production of PBMC with p24 antigen at baseline (1.25 (1.01; 1.55)) were associated to declines in CD4⁺cell count to < 350/μL.</p> <p>Conclusion</p> <p>Both the number (CD4⁺nadir) and the functional activity of CD4⁺(lymphoproliferative response to PPD) predict the CD4⁺decrease associated with discontinuation of ART in patients with controlled viremia.</p

Impact of long-term viral suppression in CD4+ recovery of HIV-children on Highly Active Antiretroviral Therapy

BACKGROUND: The effects of HAART may differ between children and adults because children have a developing immune system, and the long-term immunological outcome in HIV-infected children on HAART is not well-known. A major aim of our study was to determine CD4+ evolution associated with long-term VL control during 4 years of observation on HAART. METHODS: We carried out a retrospective study on a cohort of 160 vertically HIV-infected children. It was carried out from 1996 to 2004 in six large Spanish pediatric referral hospitals. We compared 33 children who had long-term VL suppression (VL ≤400 copies/ml) in the first 12 months of follow-up and maintained that level throughout follow-up (Responders-group), and 127 children with persistently detectable VL in spite of ART switches (Non-Responders-group). RESULTS: We observed a quick initial and significant increase in CD4(+ )counts from the baseline to 12 months on HAART in both groups (p < 0.01). The Non-Responders group sustained CD4+ increases and most of these children maintained high CD4(+ )level counts (≥25%). The Non-Responders group reached a plateau between 26% and 27% CD4(+ )at the first 12 months of follow-up that remained stable during the following 3 years. However, the Responders group reached a plateau between 30% and 32% CD4(+ )at 24, 36 and 48 months of follow-up. We found that the Responders group had higher CD4(+ )count values and higher percentages of children with CD4(+ )≥25% than the Non-Responders group (p < 0.05) after month 12. CONCLUSION: Long-term VL suppression in turn induces large beneficial effects in immunological responses. However, it is not indispensable to recover CD4(+ )levels

Clinical Predictors of Immune Reconstitution following Combination Antiretroviral Therapy in Patients from the Australian HIV Observational Database

A small but significant number of patients do not achieve CD4 T-cell counts >500 cells/µl despite years of suppressive cART. These patients remain at risk of AIDS and non-AIDS defining illnesses. The aim of this study was to identify clinical factors associated with CD4 T-cell recovery following long-term cART.Patients with the following inclusion criteria were selected from the Australian HIV Observational Database (AHOD): cART as their first regimen initiated at CD4 T-cell count <500 cells/µl, HIV RNA<500 copies/ml after 6 months of cART and sustained for at least 12 months. The Cox proportional hazards model was used to identify determinants associated with time to achieve CD4 T-cell counts >500 cells/µl and >200 cells/µl.501 patients were eligible for inclusion from AHOD (n = 2853). The median (IQR) age and baseline CD4 T-cell counts were 39 (32-47) years and 236 (130-350) cells/µl, respectively. A major strength of this study is the long follow-up duration, median (IQR) = 6.5(3-10) years. Most patients (80%) achieved CD4 T-cell counts >500 cells/µl, but in 8%, this took >5 years. Among the patients who failed to reach a CD4 T-cell count >500 cells/µl, 16% received cART for >10 years. In a multivariate analysis, faster time to achieve a CD4 T-cell count >500 cells/µl was associated with higher baseline CD4 T-cell counts (p<0.001), younger age (p = 0.019) and treatment initiation with a protease inhibitor (PI)-based regimen (vs. non-nucleoside reverse transcriptase inhibitor, NNRTI; p = 0.043). Factors associated with achieving CD4 T-cell counts >200 cells/µl included higher baseline CD4 T-cell count (p<0.001), not having a prior AIDS-defining illness (p = 0.018) and higher baseline HIV RNA (p<0.001).The time taken to achieve a CD4 T-cell count >500 cells/µl despite long-term cART is prolonged in a subset of patients in AHOD. Starting cART early with a PI-based regimen (vs. NNRTI-based regimen) is associated with more rapid recovery of a CD4 T-cell count >500 cells/µl

The risk of AIDS-defining events is decreasing over time in the German HIV-1 Seroconverter Cohort

<p>Abstract</p> <p>Background</p> <p>With ageing of the HIV-infected population, long-term exposure to treatment, varying adherence, emerging resistance and complications to therapies, effectiveness of Highly Active Antiretroviral Therapy (HAART) needs to be monitored continuously at the population level. The German HIV-1 Seroconverter Cohort is a multi-centre, open, long-term observational cohort including patients with a known or reliably estimated date of HIV-infection i.e. last negative and first positive HIV antibody test within a maximum three-year interval or laboratory evidence of seroconversion. Our study aims to investigate survival improvements and changes in AIDS risk over calendar periods in the German HIV-1 Seroconverter Cohort.</p> <p>Methods</p> <p>Retrospective (for the pre-1997 period) and prospective (since 1997) data from the German HIV-1 Seroconverter Cohort were used. Time from seroconversion to first AIDS-defining event over calendar periods was analysed by using Cox models adjusting for age at seroconversion, sex, transmission groups and short HIV test interval. Kaplan-Meier methods were used to determine expected survival (remaining AIDS-free) by calendar period.</p> <p>Results</p> <p>2162 seroconverters with 8976 person-years of observation were included in our analysis (up to 31.12.2010). A total of 196 first AIDSdefining events were reported. Two periods i.e. 19972000 and 2007-2010 were statistically associated with a reduction in the risk of AIDS, accounting for an overall reduction of 80%. Compared to1997-2000, hazard ratios were 2.6 (95%CI, 1.6-4.8; p=0.000) in pre-1997 and 0.5 (95%CI, 0.3-0.8; p=0.007) in 20072010. Independent risk factor for AIDS progression was age at seroconversion (HR, 1.3 per 10year-increase; p=0.001).</p> <p>Conclusion</p> <p>HAART effectiveness has improved in the German HIV-1-Seroconverter Cohort. The risk to develop AIDS decreased significantly in 19972000 and in 20072010. However, elderly may require particular monitoring in view of their faster progression to AIDS.</p