CD4-guided Treatment Interruption Research Articles

CD4+ T-cell differentiation, regulatory T cells and gag-specific T lymphocytes are unaffected by CD4-guided treatment interruption and therapy resumption

Despite limiting exposure to antiretroviral drugs, structured treatment interruptions can influence multiple aspects of T-cell immunity, particularly those regarding CD4(+) T lymphocytes. We evaluated the impact of CD4-guided treatment interruption (CD4-GTI) and treatment resumption on regulatory T cells (Tregs), T-lymphocyte activation, differentiation and polyfunctional gag-specific response. Patients were analyzed just prior to treatment interruption, at 2 and 6 months after treatment interruption, just prior to treatment resumption and at 2 and 6 months after treatment resumption. Thawed peripheral blood mononuclear cells were stained immediately for phenotype analysis or stimulated with HIV-gag peptides and analyzed by polychromatic flow cytometry. Treatment interruption resulted in a CD4(+) cell count decrease and plasma viral load (pVL) increase, but did not preclude a good immune reconstitution and a complete suppression of pVL after treatment resumption. Treatment interruption did not influence CD4(+) T-cell differentiation and Treg subsets. During treatment interruption, gag-specific CD4(+) T cells were not lost, although the frequency of HIV-specific CD8(+) cells increased. Most gag-specific CD4(+) T cells were potentially cytotoxic (CD107a(+)) and were not influenced by pVL or by HAART. Most helper (CD154(+)) gag-specific CD4(+) T lymphocytes did not produce interferon-γ or interleukin-2. CD4-GTI did not cause depletion of memory cells, Tregs or HIV-specific CD4(+) cells and, on the contrary, could induce HIV-specific responses. If guided by CD4(+) T-cell count, treatment interruption does not provoke irreversible immune damages.

NK-cell phenotype at interruption underlies widely divergent duration of CD4+-guided antiretroviral treatment interruption

Long-term side effects may represent a relevant burden of antiretroviral treatment (ART) in HIV-infected patients with good CD4 immune reconstitution over extended time spans. CD4-guided treatment interruption (TI) has been evaluated to address this point and may result in a wide spectrum of time off ART in different patient cohorts. We studied whether differences in innate immune responses, in particular NK cells, are associated to patterns of longer (LoTI) or a shorter (ShTI) TI. Clinical cohort parameters were analyzed on a group of patients widely diverging for TI duration (<9 versus >18 months) on samples before TI, including NK-cell analysis and function by natural cytotoxicity receptor (NCR)-triggered γ-IFN production. Although persistently reduced NCR expression (NKp30) and function were observed in both LoTI and ShTI patients on ART compared with healthy donors, relevant differences were observed at baseline TI in those patients who subsequently developed LoTI course. Lower expression of NKG2D and NKp46 on NK cells. This also translates in reduced γ-IFN production in redirected functional assays. Thus, differences in innate immune balance exist during ART, may be associated to differential control of HIV infection and their understanding could explain clinical differences in individual patients that are not reflected by CD4(+) cell counts alone.

Predictive Value of Intracellular HIV-1 DNA Levels During CD4-Guided Treatment Interruption in HIV+Patients

The amount of HIV-1 DNA within peripheral blood mononuclear cells is an important marker of viral activity. We studied intracellular HIV-1 DNA content in purified CD4(+) T cells from 28 chronically HIV-1-infected adults with sustained CD4(+) T cell counts (>500 cells/microl) and undetectable plasma viral load (<50 copies/ml), who underwent CD4-guided treatment interruption (TI). Patients were followed up for 18 months during TI, and for 6 months after treatment resumption (TR). Six naïve HIV(+) patients starting therapy were also enrolled and followed up for 6 months. All patients were studied every 2 months; HIV-1 DNA copy number was quantified with real-time PCR. Considering all patients remaining off-treatment, in the first 18 months of TI, intracellular HIV-1 DNA levels (expressed as Log(10) copies/million cells) remained stable (mean, 3.82 and 3.77 at time 0 and after 18 months, respectively). Similarly, HIV-1 DNA values, either in patients who restarted treatment after TI (time 0, 4.90) or in naïve patients who started treatment for the first time (time 0, 4.37), did not change significantly in the first 6 months of therapy (4.42 and 3.67, respectively). Evaluating HIV-1 DNA variations during the first 2 months of TI, we found that patients with a stable level had a lower risk to reach a CD4(+) T cell count <350 cells/microl, and thus to restart therapy, whereas this risk was significantly higher in those with a marked increase of HIV-1 DNA. In conclusion, intracellular HIV-1 DNA is a predictive marker for the length of CD4-guided TI.

Lipid and Apoprotein Profile in HIV-1-Infected Patients After CD4-Guided Treatment Interruption

The aims of the present study were to determine if metabolic abnormalities and cytokine derangements are modified in HIV-1-infected patients after 12 months on treatment interruption (TI). The design of this study was prospective randomized study. Longitudinal multicenter study in HIV-1-infected patients with a 12-month follow-up. Patients on stable highly active antiretroviral therapy, with CD4 count >600/microL and HIV RNA <50 copies/mL for at least 6 months, were randomized to interrupt therapy or continue ongoing highly active antiretroviral therapy. Lipids (total cholesterol, triglycerides), apoproteins (A1, B, and E), and adipocytokines (leptin, adiponectin, plasminogen activator inhibitor-1, monocyte chemotactic protein-1, Interleukin-6, Interleukin-8, and tumor necrosis factor-alpha) were measured at baseline and at month 12. Multiplex suspension bead array immunoassay was performed using the Luminex 100 analyzer to identify protein expression in plasma. Patients who underwent TI (n = 19) had a significant decrease in median cholesterol levels (P < 0.001), while median triglyceride levels remained unchanged. There was a significant decrease in Apo-A1 levels (P = 0.048) and Apo-B levels (P < 0.001) and an increase in tumor necrosis factor-alpha levels (P = 0.034). Given the greater decrease in Apo-B, the ratio Apo-A1/Apo-B increased after 12 months of TI (from 3.4 to 5.1, P = 0.008). We did not find significant variations in leptin or adiponectin levels. In patients who continued on highly active antiretroviral therapy (n = 18), there were no significant changes in any of the measured parameters. The lipid profile and apoproteins levels change toward a less atherogenic profile after TI, arguing against a lipid-mediated mechanism to explain the increased cardiovascular risk in patients who interrupt treatment.

HIV-1 genotype after interruption of non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy and virological response after resumption of the same regimen

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a longer half-life than nucleoside reverse transcriptase inhibitor (NRTIs). Simultaneous interruption of all drugs exposes the patients to NNRTI monotherapy. This study evaluated HIV-1 genotype after treatment interruption (TI) of NNRTI-based antiretroviral therapy (ART) and virological response after resumption of the same ART regimen. A prospective study was conducted in HIV-1-infected patients who enrolled into a CD4-guided TI study. All patients continued dual NRTIs for a further 7-10 days at NNRTI TI. HIV-1 genotypic assay was performed prior to resumption of the same ART regimen. Forty-three patients required ART resumption after TI from NNRTI-based regimens. Mean age was 42.7 years; 44% were men. Median CD4 and HIV-1 RNA at the time of ART resumption were 178 cell/mm(3) and 5.78 log copies/mL, respectively. HIV-1 genotype revealed no mutations contributed to NRTI or NNRTI resistance. Of all, 56% and 100% patients achieved undetectable HIV-1 RNA at three and six months, respectively. Median CD4 were 386 and 419 cells/mm(3) at the corresponding periods. In conclusion, continuation of dual NRTIs for 7-10 days after TI of NNRTI-based regimens can minimize the risk of acquired NNRTI resistance. With this strategy, the same regimen can be used for resumption and also yield good virological and immunological outcomes.

Treatment interruption in children with HIV infection

To review studies evaluating the role of planned/structured treatment interruptions in the management of HIV-infected children. Randomized controlled treatment interruption trials in adults have reported varying results. Three trials were stopped early by their data safety and monitoring boards because of inferiority of the interruption arm, based on differences in the risk of clinical events between randomized arms. Although the risk in the treatment interruption arms relative to continuous treatment was substantial, the absolute risks of AIDS/death were low in both arms. Little research has been carried out evaluating treatment interruptions in children, even though their role may be more critical as children frequently start antiretroviral therapy at an early age with the expectation that they will need to take it for life. In addition to observational studies, two ongoing randomized paediatric trials in chronic infection are based on CD4-guided treatment interruption strategies, using higher CD4 thresholds for restart/stop of antiretroviral therapy than in adult trials. Three trials are evaluating strategies of interruption following treatment of primary infection in infancy. It is vital that this research continues as antiretroviral therapy is rolled out to increasing numbers of young children in resource-limited settings.

Snapshots for May 2006

Snapshots for May 2006

New antiretroviral drugs and approaches to HIV treatment.

New antiretroviral drugs and approaches to HIV treatment.