Immunological and virological responses to highly active antiretroviral therapy in a non-clinical trial setting in a developing Caribbean country

OBJECTIVE: Few data exist on the efficacy of antiretroviral therapy in individuals infected with HIV in the Caribbean. We evaluated the virological and immunological responses of HIV-infected adults starting highly active antiretroviral therapy (HAART). DESIGN: This was a prospective observational cohort study. METHODS: A total of 158 antiretroviral-naive patients who initiated HAART between January 2002 and March 2003, and completed at least 6 months of treatment and follow up, were included in the analysis. The response to therapy was assessed by changes in CD4 cell counts and viral loads from baseline. The mean increase in CD4 cell count, the rate of virological success (a viral load of <50 HIV-1 RNA copies/mL) and the rate of immunological success (an increase in CD4 cell count of > or =50 cells/microL over the baseline value) after commencing HAART were measured. RESULTS: In total, 82% of patients (123 of 150) achieved viral loads of <50 copies/mL after 6 months of therapy. Viral success rate after 6 months of HAART was similar irrespective of gender, pre-HAART CD4 cell count and pre-HAART viral load. However, patients older than 40 years were significantly more likely to achieve virological success than those younger than 40 years. At 6 months after starting HAART, 79.5% of patients were estimated to have achieved immunological success and 17.9% had an increase in CD4 cell count of > or =200 cells/microL over the baseline value. The median increase in CD4 cell count for the 156 patients who had CD4 cell counts at baseline and at 6 months of therapy was 122 cells/microL. CONCLUSION: In this cohort of antiretroviral-naive HIV-infected adults, there was a high rate of virological and immunological success after 6 months of HAART, irrespective of the pre-HAART viral load and CD4 cell count.     

Diagnostic accuracy of CD4 cell count increase for virologic response after initiating highly active antiretroviral therapy

OBJECTIVE: To derive and internally validate a clinical prediction rule for virologic response based on CD4 cell count increase after initiation of HAART in a resource-limited setting. DESIGN AND METHODS: A retrospective cohort study at two HIV care clinics in Gaborone, Botswana. The participants were previously treatment-naive HIV-1-infected individuals initiating HAART. The main outcome measure was a plasma HIV-1 RNA level (viral load) < or = 400 copies/ml (i.e. undetectable) 6 months after initiating HAART. RESULTS: The ability of CD4 cell count increase to predict an undetectable viral load was significantly better in those with baseline CD4 cell counts < or = 100 cells/microl [area under the ROC curve (AUC), 0.78; 95% confidence interval (CI), 0.67-0.89; versus AUC, 0.60; 95% CI, 0.48-0.71; P = 0.018]. The sensitivity, specificity, and positive and negative predictive values of a CD4 cell count increase of > or = 50 cells/microl for an undetectable viral load in those with baseline CD4 cell counts < or = 100 cells/microl were 93.1, 61.3, 92.5 and 63.3%, respectively. Alternatively, these values were 47.8, 87.1, 95.0 and 24.5%, respectively, if a increase in CD4 cell count of > or = 150 cells/microl was used. CONCLUSIONS: CD4 cell count increase after initiating HAART has only moderate discriminative ability in identifying patients with an undetectable viral load, and the predictive ability is higher [corrected] in patients with lower baseline CD4 cell counts. Although HIV treatment programs in resource-constrained settings could consider the use of CD4 cell count increases to triage viral load testing, more accurate approaches to monitoring virologic failure are urgently needed.     

Prognostic value of plasma HIV RNA among highly active antiretroviral therapy users

BACKGROUND: The study objective was to compare the prognostic value of plasma HIV RNA and CD4 cell count at baseline and as time-updated variables in highly active antiretroviral therapy (HAART) users for two outcomes: development of AIDS and change in CD4 cell count. METHODS: The study population comprised 387 men enrolled in the Multicenter AIDS Cohort Study who were AIDS-free and initiated HAART between 1996 and 2001. Follow-up until AIDS diagnosis (n=36, 9%) or the last AIDS-free visit was included. To determine the predictive value of combining HIV RNA and CD4 cell count, regression tree methods using recursive partitioning at pre-specified cut points for both variables were used. RESULTS: Low CD4 cell count was a strong predictor of AIDS among HAART users. However, HIV RNA showed strong prognostic value for AIDS development among those with CD4 cell counts > 250 x 10(6) cells/l, in whom an HIV RNA level > 1000 copies/ml carried a 4.6-fold greater risk of developing AIDS. HIV RNA < 5000 copies/ml was also predictive of subsequent increase in CD4 cell count with significantly higher increases among those with initial CD4 counts > 300 x 10(6) cells/l. CONCLUSION: Although, in HAART users, CD4 cell count was the primordial prognostic marker, an HIV RNA > 1000 copies/ml attained after HAART initiation was a strong predictor of the rate of subsequent CD4 cell count increase and of developing AIDS in patients whose CD4 cell counts were > 250 x 10(6) cells/l.     

Impact of baseline viral load and adherence on survival of HIV-infected adults with baseline CD4 cell counts > or = 200 cells/microl

BACKGROUND: Baseline plasma HIV RNA levels > 100 000 copies/ml have been associated with elevated mortality rates after the initiation of HAART. There is uncertainty regarding the optimal strategy for patients with high plasma HIV RNA but CD4 cell count > or = 200 cells/microl. OBJECTIVE: To evaluate the impact of baseline plasma HIV RNA on survival among patients with CD4 cell counts > or = 200 cells/microl. METHODS: Patients were stratified by plasma HIV RNA, CD4 cell count and adherence level. Mortality rates were evaluated using Kaplan-Meier methods and Cox regression. RESULTS: Among 1166 patients initiating HAART with a CD4 cell count > or = 200 cells/microl, a baseline HIV RNA > or = 100 000 copies/ml was statistically associated with elevated mortality among non-adherent patients (log-rank P = 0.032), but not for adherent patients (log-rank P = 0.690). In a multivariate Cox model comparing patients with a baseline CD4 cell count > or = 200 cells/microl and a baseline plasma HIV RNA < 100 000 copies/ml, the mortality rate was statistically similar among patients with a baseline CD4 cell count > or = 200 cells/microl and a baseline plasma HIV RNA > or = 100 000 copies/ml (relative hazard, 1.21; 95% confidence interval, 0.89-1.65; P = 0.232). CONCLUSION: HIV RNA > or = 100 000 copies/ml was only associated with mortality among HIV-infected patients initiating HAART with CD4 cell counts > or= 200 cells/microl if the patients were non-adherent.     

Immunophenotype of HIV+ patients during CD4 cell-monitored treatment interruption: role of the IL-7/IL-7 receptor system

OBJECTIVE: To investigate immunological changes during CD4-guided therapy interruption in HIV(+) patients who suspended HAART. PATIENTS: Seventeen patients aged > 18 years, who had received HAART for at least 12 months, and had a pre-interruption CD4+ cell count > 500 cells/microl, interrupted treatment. Median nadir CD4(+) cell count was 288 cells/microl. HIV plasma viral load at discontinuation was < 50 or > 50 copies/ml. Criteria for restarting treatment were: a CD4(+) T-lymphocyte count < 350 cells/microl on two separate occasions, a clinical manifestation of AIDS, and the patient's desire to resume HAART. Eleven patients were still off therapy after 12 months (group A); according to the first criterion, six patients restarted therapy within 12 months (group B). METHODS: Haematological, viro-immunological, cytofluorimetic and molecular assays were performed at baseline and every 2 months following standard methods. Statistical analysis was performed under Stata 7.0. RESULTS: In the first 2 months of treatment interruption, a significant increase in viral load and CD8(+) lymphocyte activation occurred. Then such parameters decreased and remained stable. In all patients, a decrease in CD4(+) lymphocytes took place as well, that affected in a similar manner naive, central memory, effector memory and terminally differentiated cells. Group B always presented lower amounts of CD4(+) effector memory lymphocytes. The expression of CD127 was always higher in group A. CONCLUSIONS: The loss of CD4(+) lymphocytes upon viral rebound is equal among naive and memory subsets. Patients with higher expression of CD127, who are likely to exert a better capacity to utilize endogenous interleukin-7 by T cells, could remain off therapy for longer periods.     

CD4 lymphocyte count as a predictor of the duration of highly active antiretroviral therapy-induced suppression of human immunodeficiency virus load.

The association between CD4 cell count and duration of virus load suppression was investigated in 558 patients in the Frankfurt HIV Clinic Cohort who had begun highly active antiretroviral therapy and who had virus load declines to 500 copies/mL; P=.0001). Baseline virus load was not associated with virus load rebound. Lower baseline CD4 cell counts were associated with increased risk of viral rebound; however, this risk was significantly reduced in persons with low baseline CD4 cell counts who experienced substantial increases in CD4 cell counts during follow-up.     

Rapid activation of lymph nodes and mononuclear cell HIV expression upon interrupting highly active antiretroviral therapy in patients after prolonged viral suppression

OBJECTIVE: To compare the architecture and HIV-1 RNA and Gag p24 protein expression in lymph nodes (LN) excised from individuals during chronic highly active antiretroviral therapy (HAART) with LN removed from the same patient after plasma virus rebound following the interruption of HAART. MATERIALS AND METHODS: Six HIV-1-infected patients on HAART, with CD4 cell counts greater than 350 cells/microl, and plasma HIV-1 RNA less than 50 copies/ml, underwent inguinal LN excision upon discontinuation of HAART, and again after rebound of plasma virus. Lymph nodes were evaluated by immunohistochemical staining for Gag p24 antigen and Ki67, in-situ hybridization for HIV-1 RNA and H3-histone, and transmission electron microscopy (TEM). RESULTS: LN at baseline were quiescent to mildly hyperplastic and generally contained more primary than secondary follicles. Only one LN had detectable follicular dendritic cell (FDC)-associated p24 antigen, none had HIV RNA. Few mononuclear cells (MNC) expressed RNA or p24 antigen. Plasma virus at the second biopsy ranged from 329 to 3.2 x 10(6) copies/ml. CD4 cell count decline ranged from 5 to 51% during drug hiatus, and was greatest in patients with highest viral rebound. Four of six of the second LN were more hyperplastic than the initial LN, two showed paracortical hyperplasia. MNC expression of HIV RNA in the second LN paralleled the level of plasma viremia. Increased Ki67 and H3-histone signal occurred in the second LN. CONCLUSION: Quiescent LN from individuals on HAART rapidly become hyperplastic and activated within 1-2 months after treatment interruption. As in acute HIV infection, virus expression by LN MNC parallels the rebound in plasma viremia and fall in CD4 cell count.     

Slower CD4 cell decline following cessation of a 3 month course of HAART in primary HIV infection: findings from an observational cohort

OBJECTIVE: To investigate the effect of a short course of HAART during primary HIV infection (PHI) on rate of CD4 cell and viral load change. METHODS: Data following HAART cessation from 89 individuals (seroconverting 1999-2003) who chose to take a 3 month course of HAART at PHI were compared with 179 untreated controls in CASCADE, using linear and nonlinear random effects models. Participants were non-randomized but frequency matched for age, sex, risk factor, year of seroconversion and presentation within the first 6 months of seroconversion. Time to CD4 cell count < 350 cells/microl and initiation of clinically indicated antiretroviral therapy (ART) were also compared as competing risks. RESULTS: The rate of CD4 cell decline following therapy cessation appeared significantly slower among treated participants than untreated controls: losses of 51 cells/microl [95% confidence interval (CI), 32-69] and 77 cells/microl (95% CI, 65-89), respectively, 3 years after seroconversion (P = 0.011). Based on extrapolated data, viral loads also differed significantly at this point (4.09 and 4.53 copies/ml, respectively). At 2 years, there was no significant difference in mean viral load levels: 4.31 copies/ml (95% CI, 4.14-4.48) and 4.47 copies/ml (95% CI, 4.28-4.66), respectively. CASCADE seroconverters were more likely to reach CD4 cell count < 350 cells/microl or initiate clinically indicated ART (hazard ratio, 1.45; 95% CI, 1.02-2.05; P = 0.039). CONCLUSION: A short course of ART at PHI may delay CD4 cell decline. Confirmation of this requires a randomized clinical trial powered to address definitively the role of ART intervention in PHI (currently underway through SPARTAC).     

Spontaneous remission of cytomegalovirus retinitis in a patient infected with the human immunodeficiency virus

BACKGROUND: We report a case of CMV retinitis cured in an AIDS patient after two months of regular HAART therapy without CMV medications. CASE REPORT: A 37-year-old patient (baseline CD4 count 47/ml) receiving HAART (2 NRTI and 1 IP) showed poor compliance and had increased his CD4 count for two months reaching 263/ml although HIV viral load remained high (71,840 copies/ml). His fundus was normal. He was evaluated 8 months after a period of loss to follow-up: his CD4 count was 65/ml, HIV viral load was 123,000 copies/ml, CMV serology for IgV and viruria were positive, viremia was negative, his fundus revealed a healed CMV retinitis. Six months later and without any CMV therapy, no relapse has been observed while regularly taking HAART medications. CONCLUSION: Few cases have been reported in which HAART therapy with good immune response and reduced HIV viral load lead to complete regression of CMV retinitis without specific CMV medication. This case suggests that, even with an uncontrolled HIV viral load, HAART via transient immune restoration may contribute to resolving CMV retinitis.     

Gender differences in clinical progression of HIV-1-infected individuals during long-term highly active antiretroviral therapy

OBJECTIVE: To assess gender differences in the long-term clinical, virological and immunological outcomes during highly active antiretroviral therapy (HAART). METHODS: This longitudinal observational multicentre study followed 2460 HIV-infected patients who had begun a protease inhibitor-based regimen for a median period of 43 months. Outcome measures were virological suppression (< 500 copies/ml), confirmed virological rebound after suppression, and death or new AIDS-defining illness (ADI). RESULTS: At baseline, 690 female patients (28.0%) had significantly lower age, higher prevalence of heterosexual contact and lower prevalence of intravenous drug use as risk factors for HIV infection compared with males. Furthermore, females had a lower number of AIDS-defining illnesses, higher CD4 cell counts and lower viral loads.No gender differences were reported in terms of proportion of patients achieving viral suppression or exhibiting rebound after achieving viral suppression. Female patients experienced reduced clinical progression during follow-up compared with males (P = 0.008) by Kaplan-Meier analysis; however this difference was not significant in an adjusted analysis. In a multivariate model, the interaction between gender and risk factor for HIV or viral load showed that female drug users and female patients with a baseline HIV RNA viral load of 10(4)-10(5) copies/ml had a favourable clinical outcome compared with males (P = 0.035 and P = 0.015, respectively). CONCLUSION: No differences were found between genders in terms of virological and immunological outcomes during long-term HAART. Nevertheless, a lower risk of clinical progression was reported among female patients with intermediate baseline viral load than in males.     

Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection

Therapeutic immunization with autologous monocyte-derived dendritic cells (DCs) loaded with heat-inactivated autologous human immunodeficiency virus type 1 (HIV-1) in 12 patients with chronic HIV-1 infection who were receiving highly active antiretroviral therapy (HAART) was feasible, safe, and well tolerated. Virus was obtained during an initial interruption of HAART (hereafter, "stop 1") so that DCs could be pulsed. After immunization and a second interruption of HAART (hereafter, "stop 2"), set-point plasma viral load (PVL; 24 weeks after stop 2) decreased > or =0.5 log(10) copies/mL relative to baseline PVL in 4 of 12 patients. We observed a significant lengthening in mean doubling time of PVL rebound and significant decreases in the area under the curve and the mean peak of PVL rebound after stop 2, compared with those after stop 1. This response was associated with changes in HIV-1-specific CD4(+) lymphoproliferative and CD8(+) T cell responses. These changes were not observed in a group of nonimmunized control patients.     

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

OBJECTIVE: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. DESIGN: Cohort study. PARTICIPANTS: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load 1000 copies/ml. MAIN OUTCOME MEASURE: CD4 count changes. RESULTS: Among patients who maintained plasma HIV RNA levels /= 350 x 10(6)/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 x 10(6)/l, 88% achieved a CD4 cell count of >/= 200 x 10(6)/l and 59% achieved a count of >/= 350 x 10(6)/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). CONCLUSIONS: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune system's capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.     

CD8+ cell noncytotoxic anti-HIV response: restoration by HAART in the late stage of infection

Highly active antiretroviral therapy (HAART) is currently the best HIV infection management strategy. However, its effects on the CD8+ T cell noncytotoxic anti-HIV response (CNAR) are not well known. We investigated if HAART has different effects on CNAR in patients at the intermediate and late stages of HIV infection. Untreated healthy HIV-infected subjects with a mean CD4+ T cell count of 606 cells/microl were examined as a reference group. Plasma viral load, CD4+ T cell count, and CNAR activity were measured at baseline and regular intervals for at least 48 weeks following initiation of HAART. Baseline CNAR activity in all subjects correlated inversely with viral load and directly with CD4 T+ cell counts. The level of CNAR in the latestage group was significantly lower than in the intermediate-stage and the healthy reference group (p < 0.01). Following initiation of HAART, substantial increases in CD4+ T cell counts and decreases in viral loads were observed in both groups, indicating treatment success. CNAR activity was found to be increased significantly during HAART, but only in the late-stage group (p < 0.01). This increase in CD8+ cell function was seen within 4 weeks of treatment initiation and resulted in levels of CNAR activity almost equal to those observed in the healthy reference subjects. Our findings suggest a beneficial effect on CNAR in those individuals with reduced activity, typically in late-stage infection.     

Higher risk of AIDS or death in patients with lower CD4 cell counts after virally suppressive HAART

Background The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain.
Methods We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/μL before HAART initiation; ≥2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50–1000 copies/mL.
Results One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/μL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs . 39 among those who did not meet either endpoint ( P =0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of ≤200 vs . >350 cells/μL was 10.7 ( P =0.013), and at CD4 cell count of 201–350 vs . >350 cells/μL was 8.54 ( P =0.014).
Conclusion In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.     

Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level

OBJECTIVES: To evaluate the impact on CD4 cell count and HIV-1 DNA level in peripheral blood mononuclear cells (PBMC) of long-term highly active antiretroviral therapy (HAART) in the setting of maximal success, i.e., constant plasma HIV-1 RNA load suppression. DESIGN: Retrospective analysis of patients selected for a constantly undetectable plasma HIV-1 RNA load since HAART initiation. METHODS: HIV-1 DNA was measured in PBMC using a real-time polymerase chain reaction assay. Loess estimates and regression analysis were used for modelling the variations of the CD4 cell count and HIV DNA level over time. RESULTS: The study included 41 patients chronically infected with HIV-1 who had been taking HAART for a median duration of 60.4 months and had an undetectable plasma HIV RNA load ever since the first 6 months of HAART; 25 were tested for HIV-1 DNA. The mean CD4 cell count increase was high during the first 18 months on therapy (168 x 10 cells/l per year), much lower afterwards (38 x 10 cells/l per year), independently of the baseline CD4 cell count. Most of the patients (73.2%) reached a CD4 cell count constantly > or = 400 x 10/l during follow-up. HIV-1 DNA showed a mean decrease of 0.48 log10 copies/10 PBMC during the first year, of 0.18 log10 copies/10 PBMC per year during the 2nd and 3rd years, but no significant decrease afterwards. CONCLUSIONS: These results question the benefit of very long-term maintenance of HAART in terms of CD4 gain and HIV-1 DNA reduction.     

Benefit of viral load testing for confirmation of immunological failure in HIV patients treated in rural Malawi

Objective Viral load testing is used in the HIV programme of Chiradzulu, Malawi, to confirm the diagnosis of immunological failure to prevent unnecessary switching to second‐line therapy. Our objective was to quantify the benefit of this strategy for management of treatment failure in a large decentralized HIV programme in Africa. Methods Retrospective analysis of monitoring data from adults treated with first‐line antiretroviral regimens for >1 year and meeting the WHO immunological failure criteria in an HIV programme in rural Malawi. The positive predictive value of using immunological failure criteria to diagnose virological failure (viral load >5000 copies/ml) was estimated. Results Of the 227 patients with immunological failure (185 confirmed with a repeat CD4 measurement), 155 (68.2%) had confirmatory viral load testing. Forty‐four (28.4%) had viral load >5000 copies/ml and 57 (36.8%) >1000 copies/ml. Positive predictive value was 28.4% (95% CI 21.4–36.2%). Repeat CD4 count testing showed that 41% of patients initially diagnosed with immunological failure did no longer meet failure criteria. Conclusions Our results support the need for confirming all cases of immunological failure with viral load testing before switching to second‐line ART to optimize the use of resources in developing countries.     

Cytomegalovirus-specific IFN-gamma production is associated with protection against cytomegalovirus reactivation in HIV-infected patients on highly active antiretroviral therapy

OBJECTIVES: To identify the predictors of cytomegalovirus reactivation in AIDS patients on highly active antiretroviral therapy (HAART). DESIGN: This prospective study enrolled cytomegalovirus-seropositive AIDS patients on or about to start HAART, who were not receiving anti-cytomegalovirus prophylaxis. Clinical and laboratory data were collected over 3.5 years at clinic visits, which coincided with the study visits. METHODS: Blood was obtained at every study visit and was used for measurements of cytomegalovirus cell-mediated immunity (lymphocyte proliferation, IFN-gamma, IL-2, and IL-10 production), cytomegalovirus viral load, CD4 cell count, and HIV viral load. A logistic-normal model was used to analyse outcome data with repeated observations. RESULTS: Twenty-six patients had 40 episodes of cytomegalovirus reactivation (positive cytomegalovirus viral load) during the study. Their immunological and virological parameters were compared with 26 randomly selected control individuals from the same cohort. The risk of cytomegalovirus reactivation significantly decreased with every 6-month increase in HAART duration [odds ratio (OR) 0.5; P = 0.02] and marginally increased with every log10 RNA copies/ml HIV viral load (OR 2; P = 0.07). CD4 cell counts, cytomegalovirus lymphocyte proliferation, IL-2, and IL-10 did not reach significance as predictors of cytomegalovirus reactivation. However, cytomegalovirus IFN-gamma production significantly decreased the risk of cytomegalovirus reactivation (OR 0.03; P = 0.04). CONCLUSION: Cytomegalovirus-specific IFN-gamma has a unique value as an immunological predictor of cytomegalovirus reactivation, demonstrating the importance of cellular immune responses in the control of cytomegalovirus replication in HAART recipients.     

Expansion of pre-terminally differentiated CD8 T cells in chronic HIV-positive patients presenting a rapid viral rebound during structured treatment interruption

OBJECTIVE: The influence of structured treatment interruption on effector/memory CD8 T cell dynamics was analysed in chronic HIV-infected patients showing a rapid or delayed viral rebound. DESIGN: Structured treatment interruption consisted of at least one month of discontinuation, followed by highly active antiretroviral therapy (HAART) resumption. Two groups of HIV structured treatment interruption patients were selected on the basis of plasma viral HIV-RNA value (> 30 000 copies/ml, branched DNA): group A (n = 14), patients with a rapid viral rebound (within one month) and group B (n = 6), patients with a delayed or no viral rebound (after a minimum of 4 months). METHODS: A clinical and immunological follow-up was performed at HAART suspension (t 0), one month from suspension (t 1), at HAART resumption (t 2), and 30 days from resumption (t 3). RESULTS: A sustained viral rebound was observed in group A patients, showing a rapid expansion of circulating CD8 T lymphocytes. In this group, the frequencies of CD8 T cells releasing IFN-gamma after mitogen-induced or Gag-specific stimulation were highly increased after HAART discontinuation. Nevertheless, these CD8 T lymphocytes were mainly composed of pre-terminally differentiated cytotoxic T lymphocytes (CTL) expressing a CCR7 CD27 CD45RA phenotype and a reduced amount of perforin. In contrast, group B patients showed no significant changes in immunological parameters during a prolonged drug-free period. CONCLUSION: These data indicate that monitoring CD8 T cell dynamics during structured treatment interruption could be clinically relevant, and new therapeutic strategies should aim qualitatively to restore CTL effector functions.