Everything fine so far? Physical and mental health in HIV-infected patients with virological success and long-term exposure to antiretroviral therapy.

INTRODUCTION: Little is known about the well-being on long-term exposure to antiretroviral therapy. The ACTG Augmented Symptoms Distress Module (ASDM) is a validated tool which measures the presence of a total of 22 symptoms seen with HIV and quantifies the extent to which they cause distress to the patient. METHODS: ELBE was a cross-sectional study that consecutively included adult HIV-infected patients presenting with viral suppression (<50 HIV RNA copies/mL) and ART exposure for at least five years. Patients were evaluated by four different questionnaires, including ASDM. RESULTS: Of a total of 894 patients included in the three participating ELBE centres, complete data on ASDM were available for 698 patients (626 male, 69 female, 3 transsexual). Median age was 49.7 years (range, 23.3-82.5 years) and median exposure to ART was 11.5 years (range, 5-28 years). Median CD4 T-cell counts had increased from a CD4 nadir of 180 to currently 640 cells/µL. Despite immunological and virological success, a high degree of symptom-related distress was noted in this patient population. In total, 63.8% and 36.3% of the patients had at least one "bothersome" or one "very bothersome" symptom, respectively. The symptoms most frequently reported to be "bothersome" or "very bothersome" were fatigue and energy loss (18.5% and 11.0% respectively), insomnia (12.8% and 11.6%), sadness and depression (13.0% and 10.0%), sexual dysfunction (12.0% and 10.0%), and changes in body appearance (11.0% and 10.9%). There was no association between the degree of symptom-related distress and gender, age or CD4 T-cell nadir. However, the history of AIDS-defining illnesses, comorbidities such as depression but also the duration of ART were significantly associated with a higher overall symptom summary score and with a higher frequency of symptoms. For example, in patients with at least 15 years of ART exposure, only 27.3% of the patients did not report at least one "bothersome" or "very bothersome" symptom. CONCLUSIONS: In this large group of positively selected HIV+ patients with virological success and long-term exposure to ART, a high degree of symptom-related distress was found. Medical care of HIV-infected patients should not only focus on optimal virological outcome. More data on quality of life in patients with long-term exposure to ART is needed.

Intermittent viraemia and immune reconstitution in patients with more than 10-15 years of antiretroviral therapy: baseline values still matter.

INTRODUCTION: Data on patients with long-term exposure to ART is scarce because controlled studies usually do not follow up patients for more than five to seven years. We were interested whether baseline parameters such as CD4 T-cell nadir or pre-treatment viraemia do have an impact on ART success after more than a decade of treatment. METHODS: ELBE is a cross-sectional study on adult HIV+ patients presenting consecutively with viral suppression (<50 HIV RNA copies/mL) and with ART exposure of at least five years. In this sub-analysis, all patients with more than 10 years of ART exposure were evaluated for immune reconstitution and for intermittent transient viraemia (50-1000 copies/mL, defined as "blips") during the last five years. RESULTS: From a total of 894 patients included in the three participating ELBE centres, 524 patients had an ART exposure of at least 10 years and had been treated continuously during the last 5 years. Of these, 33.4% had at least one "blip" while 63.5% did not show any transient viraemia of more than 50 copies/mL. Patients with at least one blip had a higher pre-treatment viraemia compared to patients without blips (5.30 versus 5.06 log copies/mL, p=0.0003). In patients with a pre-treatment viraemia of more than 100,000, 50,000-100,000 and less than 50,000 copies/mL, the proportions of patients with blips during the last five years were 39.5%, 30.5% and 21.8% (p=0.007), respectively. The history of an AIDS-defining illness or the CD4 T-cell nadir was not associated with a higher frequency of blips. However, CD4 T-cell nadir was a strong predictor for current CD4 T-cell counts. In patient groups with a CD4 T-cell nadir of 0-99, 100-199, 200-349, 350+ cells/µL, the median current CD4 T cells were 571, 667, 710 and 890 cells/µL, respectively. These differences remained significant when the analysis was restricted to patients with more than 15 years of ART exposure (n=268). CONCLUSIONS: In this large group of positively selected HIV+ patients with long-term exposure to ART of at least 10-15 years, high pre-treatment viraemia was still associated with a higher frequency of intermittent transient viraemia ("blip"). A low CD4 T-cell nadir remained associated with a lower CD4 cell recovery. The clinical implications of these findings remain to be evaluated.

Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma are associated with nonprogressive HIV-1 infection.

BACKGROUND: Long-term survival of HIV-1 infected individuals is usually achieved by continuous administration of combination antiretroviral therapy (ART). An exception to this scenario is represented by HIV-1 infected nonprogressors (NP) which maintain relatively high circulating CD4+ T cells without clinical symptoms for several years in the absence of ART. Several lines of evidence indicate an important role of the T-cell response in the modulation of HIV-1 infection during the acute and chronic phase of the disease. RESULTS: We analyzed the functional and the differentiation phenotype of Nef- and Tat-specific CD8+ T cells in a cohort of HIV-1 infected NP in comparison to progressors, ART-treated seropositive individuals and individuals undergoing a single cycle of ART interruption. We observed that a distinctive feature of NP is the presence of Nef-specific CD45RA+ CD8+ T cells secreting MIP-1beta but not IFN-gamma. This population was present in 7 out of 11 NP. CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells were not detected in HIV-1 infected individuals under ART or withdrawing from ART and experiencing a rebounding viral replication. In addition, we detected Nef-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cells in only 1 out of 10 HIV-1 infected individuals with untreated progressive disease. CONCLUSION: The novel antigen-specific CD45RA+ IFN-gammaneg MIP-1beta+ CD8+ T cell population represents a new candidate marker of long-term natural control of HIV-1 disease progression and a relevant functional T-cell subset in the evaluation of the immune responses induced by candidate HIV-1 vaccines.

The intracellular detection of MIP-1beta enhances the capacity to detect IFN-gamma mediated HIV-1-specific CD8 T-cell responses in a flow cytometric setting providing a sensitive alternative to the ELISPOT.

BACKGROUND: T-cell mediated immunity likely plays an important role in controlling HIV-1 infection and progression to AIDS. Several candidate vaccines against HIV-1 aim at stimulating cellular immune responses, either alone or together with the induction of neutralizing antibodies, and assays able to measure CD8 and CD4 T-cell responses need to be implemented. At present, the IFN-gamma-based ELISPOT assay is considered the gold standard and it is broadly preferred as primary assay for detection of antigen-specific T-cell responses in vaccine trials. However, in spite of its high sensitivity, the measurement of the sole IFN-gamma production provides limited information on the quality of the immune response. On the other hand, the introduction of polychromatic flow-cytometry-based assays such as the intracellular cytokine staining (ICS) strongly improved the capacity to detect several markers on a single cell level. RESULTS: The cumulative analysis of 275 samples from 31 different HIV-1 infected individuals using an ICS staining procedure optimized by our laboratories revealed that, following antigenic stimulation, IFN-gamma producing T-cells were also producing MIP-1beta whereas T-cells characterized by the sole production of IFN-gamma were rare. Since the analysis of the combination of two functions decreases the background and the measurement of the IFN-gamma+ MIP-1beta+ T-cells was equivalent to the measurement of the total IFN-gamma+ T-cells, we adopted the IFN-gamma+ MIP-1beta+ data analysis system to evaluate IFN-gamma-based, antigen-specific T-cell responses. Comparison of our ICS assay with ELISPOT assays performed in two different experienced laboratories demonstrated that the IFN-gamma+ MIP-1beta+ data analysis system increased the sensitivity of the ICS up to levels comparable to the sensitivity of the ELISPOT assay. CONCLUSION: The IFN-gamma+ MIP-1beta+ data evaluation system provides a clear advantage for the detection of low magnitude HIV-1-specific responses. These results are important to guide the choice for suitable highly sensitive immune assays and to build reagent panels able to accurately characterize the phenotype and function of responding T-cells. More importantly, the ICS assay can be used as primary assay to evaluate HIV-1-specific responses without losing sensitivity in comparison to the ELISPOT assay.

HIV-1 specific CD8+ T cells with an effector phenotype and control of viral replication.

Most people infected with HIV-1 cannot control viral replication despite the presence of virus-specific CD8+ T cells. It has been postulated that this inability is related to the failure of these cells to mature into fully differentiated effector cells. We tested this hypothesis by comparing the maturation phenotype of virus-specific CD8+ T cells in people who could control viral replication off anti-retroviral therapy with those who could not. In five patients with treated acute HIV-1-infection, structured treatment interruption (STI) induced control of viral replication was associated with expansion of virus-specific CD8+ T cells with a fully differentiated effector phenotype. These effector cells were also expanded in treatment-naive chronically infected individuals who spontaneously controlled viral replication, and augmented expression of perforin was noted in both settings. Our data show that full maturation of virus-specific CD8+ T cells is possible in the context of HIV-1-infection, and suggest that such maturation might be important in viral control.