Chronic HIV Disease Research Articles

The effect of short-course antiretroviral therapy initiated in primary HIV-1 infection on interleukin-6 and D-dimer levels.

Interruption of antiretroviral therapy (ART) in chronic HIV disease is associated with increased mortality, predicted by elevations in interleukin-6 (IL-6) and D-dimer. The effect of ART interruption in primary HIV-1 infection on these biomarkers is unknown. Plasma samples from 200 HIV seroconverters enrolled in the Short Pulse Anti-Retroviral Therapy At HIV Seroconversion trial of deferred ART (standard of care) - 12 or 48 week ART (ART12 or ART48, respectively) - were analysed for IL-6 and D-dimer at weeks 0, 12, 16, 48, 52, 60 and 108 after randomization. Changes in log10 levels from weeks 0 to 12 were analysed using linear regression, as were changes from baseline to 4 weeks after stopping ART. Areas under the biomarker-time curves (AUC) to week 108 were adjusted for baseline values, and compared across all arms. Median (inter-quartile range) baseline IL-6 and D-dimer were 1.45 (0.88, 2.41) pg/ml and 0.34 (0.20, 0.50) mg/l, respectively. At week 12, D-dimer levels were significantly lower among treated compared to untreated individuals (P < 0.001), whereas IL-6 levels were similar (P = 0.23). Within 4 weeks from stopping ART, IL-6 and D-dimer levels rose by 22 and 18%, reaching pre-ART levels. Over 108-week follow-up, there was no difference between arms in IL-6 AUC (P = 0.53), but D-dimer AUC was significantly lower for ART12 and ART48 compared to standard of care (overall P = 0.008). Stopping ART in primary HIV-1 infection leads to inflammatory biomarker rebound to pre-treatment levels. However, over 108-week follow-up, we found no evidence that biomarker levels were higher for those interrupting ART, compared to those remaining ART-naïve, and D-dimer levels were significantly lower.

Chronic alcohol abuse and HIV disease progression: studies with the non-human primate model.

The populations at risk for HIV infection, as well as those living with HIV, overlap with populations that engage in heavy alcohol consumption. Alcohol use has been associated with high-risk sexual behavior and an increased likelihood of acquiring HIV, as well as poor outcome measures of disease such as increased viral loads and declines in CD4+ T lymphocytes among those living with HIV-infections. It is difficult to discern the biological mechanisms by which alcohol use affects the virus:host interaction in human populations due to the numerous variables introduced by human behavior. The rhesus macaque infected with simian immunodeficiency virus has served as an invaluable model for understanding HIV disease and transmission, and thus, provides an ideal model to evaluate the effects of chronic alcohol use on viral infection and disease progression in a controlled environment. In this review, we describe the different macaque models of chronic alcohol consumption and summarize the studies conducted with SIV and alcohol. Collectively, they have shown that chronic alcohol consumption results in higher levels of plasma virus and alterations in immune cell populations that potentiate SIV replication. They also demonstrate a significant impact of chronic alcohol use on SIV-disease progression and survival. These studies highlight the utility of the rhesus macaque in deciphering the biological effects of alcohol on HIV disease. Future studies with this well-established model will address the biological influence of alcohol use on susceptibility to HIV, as well as the efficacy of anti-retroviral therapy.

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART.Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.

Relationship of plasma cytokines and clinical biomarkers to memory performance in HIV

Chronic systemic immune activation and inflammatory processes have been linked to brain dysfunction in medically stable HIV-infected people. We investigated the association between verbal memory performance and plasma concentrations of 13 cytokines measured using multiplexed bead array immunoassay in 74 HIV-seropositive individuals and 50 HIV-seronegative controls. Memory performance was positively related to levels of IL-8 and IFN-γ, and negatively related to IL-10 and IL-18 and to hepatitis C infection. Memory performance was not significantly related to HIV disease markers. The results indicate the importance of systemic immune and inflammatory markers to neurocognitive function in chronic and stable HIV disease.

Chronic HIV disease and activation of the coagulation system

With current effective antiretroviral treatment, the spectrum of morbidity and mortality during chronic HIV disease has shifted away from AIDS defining clinical events. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications, including, but not limited to, venous and arterial thrombotic disease. Mechanisms specific to HIV disease, antiretroviral therapy, and lifestyle or behavioral factors contribute to a pro-coagulant state, in part, through increased tissue factor activity coupled with a paradoxical decline in the anti-coagulant response. Alterations in coagulation biology in the context of HIV disease appear to be largely a consequence of persistent systemic immune activation, micro- and macro-vascular disease, and, potentially, impaired hepatic synthesis of coagulation factors. The clinical consequences of HIV-related changes in coagulation biology, the degree to which they are unique to HIV disease, and whether they can be mitigated through adjunct treatments, remains a focus of current research.

Ask the Experts: Management of HIV-associated cognitive impairment

Alan Winston is a consultant physician in HIV and genitourinary medicine at St Mary’s Hospital (London, UK) and a clinical senior lecturer at Imperial College London (UK). Dr Winston’s research includes work on understanding the pathogenesis and epidemiology of comorbidities in relation to chronic HIV-disease with a focus on CNS pathology. He sits both on the British HIV Association and European AIDS Clinical Society writing groups on the management of cognitive impairment in HIV-disease. Simon Rackstraw is a consultant physician in HIV and genitourinary medicine at the Royal London Hospital (UK) and medical director at Mildmay Mission Hospital UK (London, UK). Dr Rackstraw’s research includes work on understanding the epidemiology of cognitive impairment in HIV-infected patients and strategies for rehabilitation in those with HIV-related cognitive disorders.

Lipodystrophy and adrenal insufficiency: Potential mediators of peripheral neuropathy in HIV infection?

The mechanisms behind certain co-morbid conditions associated with chronic HIV disease still remain elusive. HIV-associated peripheral neuropathy is one among those rarely studied manifestations in HIV-1 infection. Numerous underlying factors associated with peripheral neuropathy have been described in HIV disease. Herein, we hypothesized certain heretofore undescribed potential mechanisms that lead to HIV associated neuropathy. Being a multifactoral manifestation, HIV-associated neuropathy is presumed to have an association with physiological factors namely, adrenal inadequacy/steroid resistance and lipodystrophy-induced cushion-effect loss in peripheral nerves. Therefore, management of the adrenals with steroids at the time-point of high inflammatory burden thereby preventing lipodystrophy by selecting the optimum treatment regimen could markedly alleviate the severity of HIV-associated neuropathic manifestations.

Special features of quantification of CD8&lt;sup&gt;+&lt;/sup&gt;CD38&lt;sup&gt;+ &lt;/sup&gt;T-cells by flow cytometry does not represent a good biomarker to monitor the reactivation of cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

CD38 also known as cyclic ADP ribose hydrolase is a surface glycoprotein expressed by several leukocytes, in particular CD4+ and CD8+ T-cells, B-lymphocytes and natural killer cells.(1) CD38 is part of a large family of nucleotide-metabolizing ectoenzymes that also includes CD26, CD39 and CD73. These molecules are clustered in specialized areas of the cell membrane, playing roles as receptor signaling molecules thus regulating cell activation, defense from pathogens, cell migration, immune synapse formation and also life cycle.(2) CD38 is a powerful disease biomarker for several human disorders, including leukemias and myelomas, and also directly involved in the pathogenesis and prognosis of human virus infections. Several potential clinical applications of CD38 as a putative laboratorial biomarker in the diagnosis, prognosis and therapy of viral infections have been previously reported.(2) Elevated CD38 antigen expression on CD8+ T cells has been pointed out as a stronger marker for the risk of chronic HIV disease progression to AIDS.(3) Moreover, recent studies have demonstrated that a parallel decline of CD8+CD38+ lymphocytes and viremia may occur in treated hepatitis B patients, suggesting its role as a biomarker for active infection.(4) It has been proposed that monitoring of the CD8+CD38+ T-cell subset in peripheral blood represents a powerful approach to detect cytomegalovirus (CMV) infections in kidney transplant recipients.(5) More recently, it has been reported that in fact, the monitoring of CD38 high expression in peripheral blood CD8+ lymphocytes is a useful additional diagnostic marker for CMV infection in patients after kidney transplantation, especially when they are at risk of tissue-invasive disease when CMV DNA copies may not be detectable in peripheral blood.(6) The questions surrounding CD38 are still fascinating and continue to prompt novel investigations. One important matter to be clarified is whether the overexpression of the CD38 molecule by circulating T cells may represent a universal biomarker for CMV infection after all modalities of organ transplantation. In order to address this issue, Lino et al.(7) performed a prospective investigation to clarify the applicability of flow cytometric enumeration of CD8+CD38+ T-cells in peripheral blood as a laboratorial indicator of CVM infection/reactivation in allogeneic hematopoietic stem cell (HSCT) recipients. The data presented in this study revealed that, in contrast to those previously published in kidney transplantation, the overexpression of CD38 in circulating CD8+ T cells does not correlate with the presence on CMV antigenemia. The authors present a plausible explanation for this phenomenon, discussing the particularities of CD38 expression during bone marrow repopulation and immune system reconstitution after HSCT. The cyclic nature of CD38 expression during hematopoietic ontogeny may explain the presence of CD38 overexpression even in those HSCT recipients with undetectable antigenemia. It has been reported that CD38 is expressed early in hematopoietic cells, with downregulation during the cell maturation process and re-expression upon cell activation. This knowledge is relevant to aware flow cytometry readers and medical professionals working in the clinical management of transplant recipients that overexpression of CD38 may not be considered a universal biomarker of CMV infection following organ transplantation. The article is well organized, presenting the technical details necessary to ensure its reproducibility, excellent scientific quality and promises a fruitful reading.

MS233 DYSLIPIDEMIA AND CARDIOVASCULAR RISK IN NORTHERN GREECE. ATHOS CARDIO GREECE STUDY

Mechanisms of functional impairment of dendritic cells (DCs) during chronic HIV-1 infection are not well understood. In order to understand this phenomenon, we aimed to study the expression of negative regulators of cytokine signaling and correlate with DC exhaustion during chronic HIV-1 disease. Monocyte-derived DCs (mo-DCs) from 27 HIV-1 infected patients (CD4+ T-cell counts: 429 ± 44 cells/μL, plasma viral load: Log10 3.9 ± 1.0 copies/ml) and 19 healthy controls (HCs) were stimulated ex vivo with TLR4 agonist, lipopolysaccharide (LPS) for 2 days to evaluate their functional fitness. The expression of a set of genes associated with cytokine signaling was evaluated in a custom designed PCR array by Real-Time PCR. The mo-DCs from HIV-1 infected patients depicted functional exhaustion as evident by decreased allo-stimulation index (mean ± SD: 10 ± 6 vs. 24 ± 16) (p < 0.05), decreased cytokine production (pg/ml) (IL-12: 4.6 ± 16 vs. 25 ± 85; TNF-α: 128 ± 279 vs. 286 ± 544; IL-10: 6 ± 12 vs. 13 ± 20; IL-8: 10,688 ± 11,748 vs. 17,470 ± 125,049) and retained endocytosis (1.1 ± 0.3 vs. 1.0 ± 0.29) (p < 0.05) even after LPS-stimulation, as compared to HCs. Significantly upregulated expression of SOCS-1 (mean ± SD fold change: 2.2 ± 2vs.0.8 ± 0.6), SOCS-3 (6.3 ± 7.4vs.1.4 ± 0.4), PIAS-1 (1.6 ± 0.1vs.1.0 ± 0.3) and SHP-1 (0.8 ± 0.4vs.0.4 ± 0.2) correlated positively with PD-L1 expression in these DCs (Spearman's coefficient, SOCS-1: 0.63, SOCS-3: 1.0 and PIAS-1: 0.7) (p < 0.05). The expression of these molecules trended positively with plasma viral load and negatively with CD4+ T-cell counts. These findings suggest that the upregulation of negative regulatory factors during chronic HIV disease have profound down-modulatory effects on DC functions and establishment of an overall exhausted state. Understanding mechanisms causing upregulation of these factors may lead to the design of new generation therapeutics based on silencing of their gene expression.

Everything Changed: Spiritual Transformation in People with HIV

Spiritual Transformation (ST) is accompanied by dramatic changes in spiritual beliefs along with major changes in behaviors, self-view, and attitudes. This study examined types of ST, as well as its antecedents and consequences in people with HIV. Qualitative content analysis was used to analyze interviews about ST in people's lives in two samples: people with chronic HIV-disease (chronic disease sample, n = 74) and people with HIV who identified themselves as spiritual (spiritual sample, n = 73). ST occurred in 39% of the chronic disease and 75% of the spiritual sample. These STs were generally positive (95%) and enduring (M = 8.71 +/- 7.43 years). ST was most frequently associated with spiritual experience (in particular near-death experience), substance-use recovery, and HIV/AIDS-diagnosis. Main antecedents were substance-use disorder, education/upbringing, and desire to change. Further themes were depression/helplessness, confrontation with illness/death, social support, and lifestyle. The top six consequences include spiritual intensification, more spiritual practices, positive feelings toward self, recovery from substance-use, finding new meaning and purpose in life, and increased self-knowledge. In the spiritual sample, there was a common pattern of hitting rock bottom with drugs, having a spiritual experience (in particular a near-death experience), and joining a drug program. Positive ST occurs in a sizable proportion of people with HIV. Importantly, ST often results in an enduring substance-use recovery, and an improved quality of life as indicated by enhanced gratitude, appreciation, joy, sense of peace, and reduced fear of death.

Dendritic Cell Function in HIV Infection

Dendritic cells (DCs) are antigen-presenting cells that serve as critical links between innate and adaptive immunity. Recent advances have revealed that DC interactions with HIV are pleiotropic. As direct antimicrobial effector cells, DCs may play a role in whether HIV infection is established upon mucosal exposure. As potent antigen-presenting cells, DCs probably modulate control of chronic HIV disease through the priming of adaptive immune responses. By contrast, DCs may contribute to HIV pathogenesis through the enhancement of T-cell infection, production of inflammatory cytokines that lead to chronic immune activation (and a proapoptotic state) and the formation of suppressive T-regulatory cells. In this article, recent progress in the field of HIV–DC interactions, including mucosal infection and HIV transmission to T cells, DC infection and activation, DC number and function in acute and chronic HIV infection, and DC immunoregulatory effects are discussed.

Venous Thromboembolism (VTE) Characteristics among White- and Black-Americans: a Cross Sectional Study

Background: Compared to Whites, Black-Americans may have a 40% higher incidence of idiopathic VTE. However, whether other VTE characteristics vary by race is uncertain.Objective: To compare demographic and baseline characteristics among White- and Black-Americans with VTE.Methods: Using a standardized data-collection form, demographic and baseline characteristics were prospectively collected from consecutive consenting patients enrolled in seven Thrombosis and Hemostasis Centers from August 2003 to March 2008. For patients with objectively diagnosed VTE, demographic and baseline characteristics were compared among White- and Black-American VTE patients, both overall, and by age and gender.Results: Among 1960 White- and 368 Black-Americans with VTE, compared to Whites, Blacks had significantly less isolated DVT (73.9% vs. 86.5%, p<0.001) and significantly more PE ± DVT (45.1 vs. 39.6%, p=0.05). Blacks and Whites did not differ in mean age (43.4 vs. 44.3 years), but a significantly higher proportion of Black men VTE patients were in age groups 20–39 and 80+ years. Blacks and Whites differed significantly by gender, with a significantly higher proportion of Black women with VTE (69.8% vs. 59.1%, p=0.0001). Blacks had a significantly higher mean BMI (32.3 vs. 29.4 kg/m2, p<0.0001), a significantly lower proportion with recent surgery or trauma, active cancer and infection, and a significantly lower proportion with a family history of VTE or documented thrombophilia (solely due to reduced Factor V Leiden and Prothrombin G20210A prevalence). Conversely, Blacks had a significantly higher proportion with hypertension, hyperlipidemia, diabetes mellitus, chronic renal disease and dialysis, HIV and sickle cell disease. The two races did not differ significantly regarding the proportion with idiopathic VTE, CHF, CAD/MI, peripheral artery disease, stroke or other chronic neurological disease (i.e., cerebral palsy), chronic liver disease or autoimmune disease, including antiphospholipid syndrome. Compared to White women VTE patients, Black women VTE patients had a significantly lower proportion with recent surgery, trauma, infection, oral contraceptive use and possibly hormone therapy; and a significantly higher proportion with idiopathic VTE, hypertension, diabetes mellitus, chronic renal disease, HIV and sickle cell disease. Compared to White men VTE patients, Black men VTE patients did not differ significantly regarding recent surgery, trauma, cancer, infection or autoimmune disease, but Black men had a significantly higher proportion with hypertension, diabetes mellitus, HIV and sickle cell disease. Black and White men with VTE did not differ significantly regarding idiopathic VTE, CHF, CAD/MI, stroke, peripheral arterial disease and chronic renal disease.Conclusion: White- and Black-Americans with VTE differ significantly regarding demographic and baseline characteristics that may be risk factors for VTE.

Abstract CN09-02: Cancer and infection: lessons from immune deficient populations

Abstract CN09-02 Immune deficiency offers an informative window through which to examine the infection-cancer relationship. Simply stated, if a cancer is caused by infection, then it is likely to occur at increased rates in people with immune deficiency. The HIV epidemic, and the expansion of organ transplantation programs, have led to the creation of large cohorts with immune deficiency. In this talk, I will review recent findings on cancer occurrence in these populations. People with HIV are at increased risk for a wide range of cancers, but there has been debate about whether this is due to immune deficiency, or due to exposure to cancer risk factors such as smoking, alcohol intake, and sexually transmitted and blood-borne pathogens. New light has been shed on these relationships by work on cancer in kidney transplant recipients. As transplant recipients have little in common with people with HIV apart from immune deficiency, shared patterns of cancer occurrence would likely be explained by immune deficiency. We conducted a retrospective cohort study of 28,855 end stage renal disease patients in Australia. Incident cancers diagnosed between 1982 and 2003 were ascertained by record linkage. Standardised incidence ratios (SIRs) were calculated in transplant recipients. Cancer rates were increased after transplantation for all infection-related cancers, including those related to KSHV (KS); EBV (NHL, Hodgkin lymphoma); HPV (anogenital cancers and head and neck cancers); HBV and HCV (liver cancer) and helicobacter pylori (stomach cancer). Rates were not increased for most epithelial cancers common in the general population. We also conducted a meta-analysis comparing cancer risks in population-based studies of solid organ transplant recipients and in people with HIV infection. This revealed that the pattern of increased cancer incidence was strikingly similar in the two populations. These data suggest that most infection-associated cancers occur at increased rates related to immune deficiency in people with HIV and in transplant recipients. A key question that remains is whether reversal of immune deficiency can reduce cancer risk. Our analysis of cancer risk in people who cease immune suppression because their kidney transplant fails suggests that cancer risk does rapidly return to baseline. In chronic HIV disease, reversal of immune suppression due to treatment is more gradual and less complete, and the increased rates of some but not all infection-related cancers appear to decrease towards normal levels. Describing cancer rates by current level of immune function is an important research priority among people with HIV. Infection-related cancer is caused by the interplay between immune function and infection. For many of these cancers, the raised risk associated with immune deficiency can be reversed by a return to normal immunity. These findings have implications for the management of long term mild immune deficient states, and also for the prevention of infection-related cancer in the general population. Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN09-02.

Treatment interruption strategies: how great are the risks?

This review brings together the results of recent definitive trials of treatment interruption strategies in order to evaluate the risks and to examine whether there is evidence to support this approach in clinical practice. Recent studies confirm that there is no clear benefit of treatment interruption in the settings of virological failure or acute infection. The most important recent data relate to the use of structured treatment interruption in the setting of chronic HIV disease. The SMART and Trivacan trials found that a CD4 lymphocyte count guided interruption strategy was clearly inferior to continuous therapy, but Staccato (using a higher threshold for treatment re-initiation) did not. The largest fixed-schedule treatment interruption trial also reported inferior clinical outcomes with interruption, although the evidence of harm was less clear in other smaller studies. A broad spectrum of clinical effects of treatment interruption was highlighted by this research. Overall, recent studies indicate that treatment interruption is associated with a variable degree of net harm. Continuous treatment should remain the strongly preferred approach, although, if it is carefully managed, there may be some clinical situations in which the benefits of a short period of interruption may potentially outweigh the risks.

Prevalence and Characteristics of Left Ventricular Noncompaction in a Community Hospital Cohort of Patients with Systolic Dysfunction

Left ventricular noncompaction (LVNC) is felt to be a rare form of cardiomyopathy, although its prevalence in a nonreferred population is unknown. We examined the prevalence and clinical characteristics of LVNC in a community hospital cohort of adult patients with echocardiographic evidence of left ventricular (LV) systolic dysfunction. All adult echocardiograms with global LV dysfunction and an LVEF < or = 45% over a 1-year period were reviewed for signs of LV noncompaction. Its presence was confirmed by the consensus of at least 2/3 readers specifically searching for this using standard criteria for noncompaction. A 3.7% prevalence of definite or probable LVNC was found in those with LVEF < or = 45% and a 0.26% prevalence for all patients referred for echocardiography during this period. This is appreciably higher than prior reports from tertiary centers. Noncompaction may not be a rare phenomenon and is comparable to other more widely recognized but less common causes of heart failure such as peripartum myopathy, connective tissue diseases, chronic substance abuse and HIV disease.

Disease severity, self-reported experience of workplace discrimination and employment loss during the course of chronic HIV disease: differences according to gender and education

Objectives:Evidence for the existence of a harmful effect of chronic disease on employment status has been provided. Although this effect of chronic illness on employment has been reported to be...

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

AbstractAlthough generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation“set point” is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4+ and CD8+ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviral-treated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8+ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8+ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8+ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4+ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4+ T cells are lost over time.

Chronic disease self-management and adherence to HIV medications.

Although it is widely recognized that potent antiretroviral therapies have transformed HIV from an acute to a chronic illness, it is less often recognized that with this change, a different model of care is appropriate. People living with chronic HIV must function independently, taking personal long-term, day-to-day responsibility for care. The role of doctors and the healthcare system is to help them do this. The authors present a conceptual framework for the self-management of chronic HIV disease and discuss the components of an HIV self-management program. The ability to take antiretroviral medications well and consistently is a key part of self-management but should be nested within an array of important skills, including symptom-management skills, goal setting and planning, communication, and accessing information and resources.

Validation of the Medical Outcomes Study HIV Health Survey as a measure of quality of life in HIV-infected patients in Singapore.

Measurement of quality of life is crucial to assess the full impact of antiretroviral therapy on patient morbidity. No quality of life instruments have been validated in an Asian HIV-infected patient population, but it is important to do so given the increasing involvement of the region in clinical trials. We set out to validate the Medical Outcomes Study HIV Health Survey (MOS-HIV) in HIV infected patients in Singapore. Clinically stable outpatients were asked to complete the 30-item MOS-HIV (English or Chinese translation). Patients were also asked about the frequency of selected disease symptoms, and clinical and demographic data were recorded from the case sheet. 163 patients (90% Chinese, 96% male, mean age 38 years, mean CD4 count 159 cells/mm(3)) participated in the study and completed the questionnaire to a satisfactory standard. The questionnaire showed good internal consistency (Cronbach's alpha >0.7 in all cases). There were significant differences in quality of life scores between Centers for Disease Control disease stages, and significant correlations with CD4 count and symptom score, confirming the discriminant validity of the MOS-HIV. Factor analysis revealed two components corresponding to physical and mental health which were similar to those of studies in Western countries except that pain was more closely related to mental than physical health. Linear regression analysis identified symptom burden as the major predictor of physical and mental health. We concluded that the MOS-HIV is a valid measure of quality of life in this HIV patient population in Singapore, and is therefore likely to be useful in future clinical trials in the region. In the era of chronic HIV disease, close attention to symptoms (disease or drug-related) is warranted due to their major adverse influence on mental and physical aspects of quality of life.

Persistent HIV-1-specific cellular responses despite prolonged therapeutic viral suppression.

Antiretroviral therapy (ART) currently represents the best way to avert the lethal consequences of chronic persistent HIV-1 infection. It leads to significant reductions of plasma viremia, often to undetectable levels, but it can also be linked with the reduction and disappearance of detectable HIV-specific CD8 T-cell responses. Here we describe a group of patients in whom ongoing replication of HIV, particularly transcription of Nef mRNA species, was detected despite prolonged and clinically successful antiretroviral treatment. Modest, but significant, numbers of HIV-specific CD8 T cells and CD4 T-cell responses were found in these subjects, with the strongest responses directed towards Nef epitopes. Detailed phenotypic analysis of the HIV-specific CD8 cells demonstrated low perforin levels and persistent expression of CD27, a phenotype associated with incomplete differentiation of cytotoxic T lymphocytes (CTL). This immature CTL phenotype has been described previously in association with chronic HIV disease, but its continued persistence is surprising in the setting of prolonged viral suppression on therapy and the presence of HIV-specific CD4 cell activity.