Immunological and virological consequences of patient-directed antiretroviral therapy interruption during chronic HIV-1 infection (original) (raw)
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Structured antiretroviral treatment interruptions in chronically HIV1-infected subjects
Proceedings of The National Academy of Sciences, 2001
The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4 ؉ T cells >400 per l. CD4 ؉ T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-␥-producing HIV-1-specific CD8 ؉ and CD4 ؉ T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8 ؉ T cell responses in all eight STI subjects (P ؍ 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4 ؉ T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P ؍ 0.001 and 0.34, respectively). CD4 ؉ T cell counts were regained on return to HAART. Control subjects (n ؍ 4) maintained VL <400 copies per ml and stable CD4 ؉ T cell counts, and showed no enhancement of antiviral CD8 ؉ T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.
Immunological Analysis of Treatment Interruption After Early Highly Active Antiretroviral Therapy
Viral Immunology, 2010
We longitudinally evaluated HIV-specific T-cell immunity after discontinuation of highly active antiretroviral therapy (HAART). After treatment interruption (TI), some individuals could maintain a low plasma viral load (<15,000 copies/mL), whereas others could not (>50,000 copies/mL). Before HAART was initiated, plasma viral load was similar. After TI, the numbers of CD8 þ T cells increased more in individuals without viral control, whereas individuals maintaining a low viral load showed a more pronounced increase in HIV-specific CD8 þ T-cell numbers. No differences were seen in the number or percentage of cytokine-producing HIV-1specific CD4 þ T cells, or in proliferative capacity of T cells. Four weeks after TI, the magnitude of the total HIV-1-specific CD8 þ T-cell response (IFN-g þ and/or IL-2 þ and/or CD107a þ) was significantly higher in individuals maintaining viral control. Degranulation contributed more to the overall CD8 þ T-cell response than cytokine production. Whether increased T-cell functionality is a cause or consequence of low viral load remains to be elucidated.
AIDS, 2000
Objective: To analyse the immunological and virological effects of treatment interruptions in HIV-1-infected patients with treatment failure and multidrug-resistant virus. Methods: Drug susceptibility was assessed using Antivirogram and genotypic analysis was based on population and clonal sequencing for 48 patients who had interrupted treatment (> 2 months). Results: Treatment interruption resulted in viral load increases (mean 0.7 log 10 copies/ ml; P 0.0001) and CD4 cell count decreases (mean 89 3 10 6 cells/l; P 0.0001). A complete shift to wild-type virus at the phenotypic, genotypic and clonal level was observed in 28/45 patients. These patients differed from those that did not show a shift to wild type in baseline CD4 cell counts (192 versus 59 3 10 6 cells/l; P 0.007) and in the relationship between baseline viral load and CD4 cell count (no correlation versus a signi®cant negative correlation; P 0.008). Response to re-initiation of treatment fell with increasing viral load [relative hazard (RH) 0.33; P 0.001] and with increasing total number of drugs with reduced susceptibility (RH 0.51; P 0.0003); it improved with the number of new drugs received (RH 2.12; P 0.0002) and a shift to wild type (RH 5.22, P 0.006). Conclusions: Changes in surrogate markers suggest that treatment provided bene®t in spite of virological failure and resistant virus. Although patients with a shift to wildtype virus responded better in the short term to treatment re-initiation, the long-term effects are not known and the risk of immune deterioration needs to be carefully considered.
Sustained HIV Viral Suppression following Treatment Interruption: An Observational Study
AIDS Research and Human Retroviruses, 2006
, with a potential for significant loss of CD4 ϩ cells. Patients who maintain virologic suppression despite interrupting treatment have not been well described. All patients with a pretreatment viral load (VL) Ն5000 copies/ml, who had been on therapy for Ն2 weeks, and who underwent a TI lasting Ն180 days were analyzed. Patients whose maximum VL did not exceed 5000 copies/ml Ն6 months after starting TI ("nonrebounders") were compared with those whose VL exceeded 5000 copies/ml (rebounders). Seventy-one patients were included in the analysis. Nineteen (27%) were nonrebounders. Ninety-four percent of patients in each group interrupted treatment for reasons unrelated to virologic response. Median change in CD4 count during TI was not significantly different between the nonrebounder and rebounder groups (؊20.5/l vs. ؊64.0/l; p Ͻ 0.086). In a multivariate logistic regression analysis, the following factors predicted nonrebounder status: peak VL before TI (log 10 copies/ml) (OR ؍ 0.14, 95% CI ؍ 0.04-0.48, p ؍ 0.0016); having received HAART (vs. mono/dual therapy) as initial regimen (OR: 11.0, 95% CI: 2.04-59.8, p ؍ 0.0054); and female gender (OR ؍ 4.8, 95% CI ؍ 1.09-21.5, p ؍ 0.0384). The large majority of chronically infected HIV patients with a TI Ն180 days interrupted treatment for reasons unrelated to virologic response. Almost 30% did not have a significant virologic rebound. Those patients were more likely to be female, had a lower peak VL prior to treatment, and their initial regimen was more likely to be HAART. Examining the immune responses of nonrebounders may contribute to the understanding of protective immunity to HIV.
Long-term consequences of treatment interruptions in chronically HIV-1-infected patients
PubMed, 2005
Objective: To evaluate the long-term effects of antiretroviral treatment (ART) interruptions on metabolic, immunological, virological and clinical outcomes in chronically HIV-1 infected patients. Methods: Multi-centric, prospective, controlled 24-month cohort study in HIV-1 infected patients interrupting ART once or several times and for at least two weeks. Patients were compared to a frequency-matched control group continuing on ART. Results: A total of 399 HIV-1 infected patients were included, among them 133 patients with treatment interruption (TI) and 266 control patients. Baseline characteristics were well matched. Median baseline CD4 cell count was 379/microl in TI-patients and 410/microl in control patients (p = ns). Median duration of the first TI was 1.1 months, and 37 % of patients had two or further TI's. Whereas CD4 cell count in control patients had increased significantly by a median of 67/microl at month 24 (p<0.0001), median CD4 cell count at month 24 in the TI-patients did not differ significantly from baseline. However, two-year AIDS-free survival was not significantly different between TI- and control patients. Liver enzymes and blood lipids improved significantly during TI. Conclusion: TI was associated with a significant immunological disadvantage at 24-month follow-up compared to continued ART. In this relatively immunocompetent cohort, however, TI's did not lead to an increased risk of disease progression within two years of follow-up.
Treatment interruptions in HIV-infected subjects
Journal of Antimicrobial Chemotherapy, 2006
Despite a high antiviral efficacy, the use of highly active antiretroviral therapy (HAART) in clinical practice is often impaired by the long-term toxicity of antiretroviral treatment, the increased rate of human immunodeficiency virus-1 (HIV-1) drug resistance in treated patients and the cost of therapies, so that possible interruption of HAART has to be considered as part of the current clinical practice. However, this strategy is usually followed by a rapid viral rebound with a substantial loss of CD4 T lymphocytes because the HIV suppression with HAART does not result in reconstitution of the HIV-specific immune response. Structured treatment interruption (STI) has already been investigated in HIV-infected subjects with well-controlled viral replication (initiating treatment during primary or chronic HIV infection) and in those with multiple treatment failures. A clear benefit of STI in patients with chronic infection remains controversial and these benefits are more often observed in patients starting treatment during primary HIV infection.