Minimal interference: A basis for selecting ART for prevention with positives.

Given international interest in "treatment as prevention" (TasP) and the pertinence of optimizing antiretroviral treatment (ART) regimens for TasP, 19 French HIV experts were interviewed on their criteria for ART if used specifically for prevention with HIV-positive persons. Through content analysis of the interview material, nine criteria were identified. The most endorsed criteria, collectively, suggest a choice of treatment based on "minimal interference" where negative impacts of ART are minimized and ease of treatment integration maximized in the lives of people living with HIV/AIDS (PLHIV) for both the short and long term. These criteria were the tolerance, side effects, and/or toxicity profile of ART, simplicity (e.g., of treatment schedule, dosage form) and the individualization of treatment (e.g., adapted to lifestyle). While virologic efficacy (i.e., a durable, undetectable viral load) was also deemed important, several experts specified that it was virtually assured with current treatments. To a much lesser extent, experts endorsed diffusion of ART into the genital compartments, a strong genetic barrier (against resistance), validated treatments (as opposed to new classes of ART), a rapid reduction in HIV viral load, and treatment cost. Pharmacologically, minimal interference calls for further improvements in the tolerance, side effects and toxicity profile of ART and in the simplicity of ART administration. Clinically, it means avoiding a one-size-fits-all approach to ART in TasP and engagement with and of PLHIV in ART selection and side effects management. Strategically, it emphasises keeping the health and quality of life of PLHIV at the forefront of a TasP-oriented public health intervention.

Regulatory T cells in HIV infection: can immunotherapy regulate the regulator?

Regulatory T cells (Tregs) have a dominant role in self-tolerance and control of autoimmune diseases. These cells also play a pivotal role in chronic viral infections and cancer by limiting immune activation and specific immune response. The role of Tregs in HIV pathogenesis remains poorly understood as their function, changes according to the phases of infection. Tregs can suppress anti-HIV specific responses and conversely can have a beneficial role by reducing the deleterious impact of immune activation. We review the frequency, function and homing potential of Tregs in the blood and lymphoid tissues as well as their interaction with dendritic cells in the context of HIV infection. We also examine the new insights generated by recombinant IL-2 and IL-7 clinical trials in HIV-infected adults, including the immunomodulatory effects of Tregs. Based on their detrimental role in limiting anti-HIV responses, we propose Tregs as potential targets for immunotherapeutic strategies aimed at decreasing Tregs frequency and/or immunosuppressive function. However, such approaches require a better understanding of the time upon infection when interfering with Treg function may not cause a deleterious state of hyperimmune activation.

Impact of dyslipidemia associated with Highly Active Antiretroviral Therapy (HAART) on cardiovascular risk and life expectancy.

We investigated the effect of dyslipidemia associated with highly active antiretroviral therapy on cardiovascular risk and life expectancy among patients who had the human immunodeficiency virus. Dyslipidemia estimates were based on results from a phase 2 randomized trial that compared lipid changes after 32 weeks of therapy with atazanavir with those with nelfinavir (each in combination with stavudine and lamivudine). The resultant increased coronary risk was estimated using Framingham risk equations, and change in life expectancy (after adjustment for mortality due to human immunodeficiency virus) was based on the cardiovascular life expectancy model, which is based on a published Markov's model. Levels of total cholesterol and low-density lipoprotein cholesterol increased significantly more among patients who used nelfinavir (+24% and +28%) than among those who used atazanavir (+4% and +1%). This dyslipidemia increased the risk of coronary disease by 50% over 10 years. The absence of dyslipidemia was estimated to preserve life expectancy 0.15 to 1.53 additional years depending on a patient's age, gender, and other risk factors. There are increasing reports of dyslipidemia and cardiovascular events associated with highly active antiretroviral therapy. Significant increases in blood lipid levels observed with some protease inhibitors are associated with an increase in calculated 10-year coronary risk. Accordingly, minimizing dyslipidemia associated with highly active antiretroviral therapy may preserve life expectancy among adults who have the human immunodeficiency virus.

Incidence and predictors of hepatic steatosis and fibrosis by serum biomarkers in a large cohort of human immunodeficiency virus mono-infected patients.

Background. Longitudinal data on liver disease in human immunodeficiency virus (HIV) mono-infection are scarce. We used noninvasive serum biomarkers to study incidence and predictors of hepatic steatosis and fibrosis. Methods. Hepatic steatosis was diagnosed by hepatic steatosis index ≥36. Advanced liver fibrosis was diagnosed by fibrosis-4 index >3.25. Kaplan-Meier analysis was used to estimate incidences. Cox regression analysis was used to explore predictors of hepatic steatosis and fibrosis development. Results. In this retrospective observational study, 796 consecutive HIV mono-infected patients were observed for a median of 4.9 (interquartile range, 2.2-6.4) years. Incidence of hepatic steatosis was 6.9 of 100 per person-years (PY) (95% confidence interval [CI], 5.9-7.9). Incidence of advanced liver fibrosis was 0.9 of 100 PY (95% CI, 0.6-1.3). Development of hepatic steatosis was predicted by black ethnicity (adjusted hazard ratio [aHR] = 2.18; 95% CI, 1.58-3; P < .001) and lower albumin (aHR = 0.94; 95% CI, 0.91-0.97; P < .001). Development of advanced liver fibrosis was predicted by higher glucose (aHR = 1.22; 95% CI, 1.2-1.3; P < .001) and lower albumin (aHR = 0.89; 95% CI, 0.84-0.93; P < .001). Conclusions. Incident hepatic steatosis is frequent in HIV mono-infected patients, particularly in those of black ethnicity. These patients can also develop advanced liver fibrosis. Identification of at-risk individuals can help early initiation of hepatological monitoring and interventions, such as targeting euglycemia.

The cost-effectiveness of highly active antiretroviral therapy, Canada 1991-2001.

AIM: To estimate the cost-effectiveness ratio of highly-active antiretroviral therapy (HAART) in Canada. DESIGN: A before-and-after analysis to calculate incremental cost of life year gained (LYG) between 1991 and 1995 (pre-HAART period) and between 1997 and 2001 (HAART period) for non-AIDS and AIDS groups (CDC stage of HIV infection). METHODS: For two Quebec HIV hospital clinics, mean inpatient (IP) days, outpatient (OP) visits and direct health care costs per patient-year (PPY) were calculated. Cox's proportional hazards models calculated disease progression, stratified by study periods and adjusted for gender, age at cohort entry, sexual orientation, injecting drug use and baseline CD4 cell count. RESULTS: For non-AIDS patients, mean IP days was 1.6 (pre-HAART period) compared with 0.8 PPY (HAART period); mean OP visits increased from 2.8 to 5.5 PPY. Total cost was US$ 4265 (pre-HAART period) and US$ 9445 PPY (HAART period) of which 66 and 84%, respectively were spent on antiretroviral drugs. Median progression time was 6.3 years in the pre-HAART period compared with 12.5 years in HAART period (log rank chi = 270, P < 0.0001). Incremental cost per LYG between periods was US$ 14 587. For AIDS patients, mean IP days decreased from 13.3 to 4.4 PPY between periods; OP visits increased from 8.3 to 9.2 PPY. Total costs increased from US$ 9099 to US$ 11 754 PPY, while expenditure on antiretroviral drugs increased from 29 to 72% of total cost. Median progression time was 3.8 years in the pre-HAART period, which increased to 13.3 years in the HAART period (log rank chi = 158, P < 0.0001); incremental cost per LYG between periods was US$ 12 813. CONCLUSION: HAART appeared a cost-effective intervention in Canada.

French HIV experts on early antiretroviral treatment for prevention: uncertainty and heterogeneity.

Early use of highly active antiretroviral treatment (ART) in people living with HIV for HIV prevention has gained legitimacy but remains controversial. Nineteen French HIV experts with diverse specializations (over half of whom were clinicians) were qualitatively interviewed on their views about ART irrespective of CD4 count of more than 500 cells/mm3 for purposes of HIV prevention, which is not systematically recommended in France. Content analysis identified 2 broad categories: individual considerations (subcategories: patient health and well-being; patient preparedness and choice) and collective considerations (subcategories:HIV transmission risk; impact on the epidemic; cost). Uncertainty surrounded many experts' considerations, and unity was lacking on key issues (eg, candidacy for early preventive treatment, expected clinical- and population-level effects). An umbrella theme labeled "Weighing the merits of early ART in the face of uncertainties was identified. Our analyses raise doubts about the current acceptability of widespread implementation of early ART for HIV prevention in France.

Impact of autologous dendritic cell-based immunotherapy (AGS-004) on B- and T-cell subset changes and immune activation in HIV-infected patients receiving antiretroviral therapy.

We previously reported that a combination of antiretroviral therapy with 4 monthly injections of each patient's own autologous dendritic cells (AGS-004) electroporated with CD40 ligand and with HIV RNA antigens obtained from each patient's own pre-antiretroviral therapy plasma induced HIV-specific CD8 T-cell responses in 10 patients. To assess other AGS-004-induced immune changes, we evaluated the modifications in B- and T-cell subsets and the level of immune activation in these patients. The proportion of Bm1 naive cells was increased along with an augmentation of the proliferation marker Ki67. Memory B-cell frequency, CD4 and CD8 T-cell subsets, regulatory T-cell frequency, and CD38/HLA-DR/PD-1 T-cell activation levels remained unchanged after AGS-004 dendritic cell immunotherapy.

Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers.

Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-α and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.

CD4 T cell nadir independently predicts the magnitude of the HIV reservoir after prolonged suppressive antiretroviral therapy.

BACKGROUND: The level of HIV-1 integrated DNA in CD4 T cells was reported to predict the evolution of untreated HIV-1 infection independently of CD4 cell counts or plasma HIV-1 RNA levels. However, the relevance of reservoir level while on efficient antiretroviral therapy (ART) is still unknown. OBJECTIVES: To evaluate factors that may contribute to the establishment and maintenance of HIV-1 reservoir size in ART-treated HIV-1-infected adults with complete suppression of viremia. STUDY DESIGN: 35 subjects receiving ART with plasma HIV-1 RNA below the limit of detection for an average duration of 3.2 years were studied. A highly sensitive PCR was used to assess HIV-1 integrated DNA levels in sorted CD4 T cells. RESULTS: The mean HIV-1 integrated DNA was 300±7copies/10(6) CD4 cells (range 10-1408). In univariate analysis, the levels of HIV-1 proviral DNA appeared to be independent of duration of HIV-1-infection, duration on ART, time since HIV-1 viral load was undetectable, delay between HIV-1 infection and starting ART, or viral load before starting ART. Conversely, CD4 T cell nadir, CD4/CD8 ratio and, to lesser degree, CD4 T cell counts were inversely associated with HIV-1 proviral DNA levels. In multivariate analysis, only CD4 T cell nadir significantly predicted levels of HIV-1 proviral DNA (P=0.025). CONCLUSIONS: CD4 T cell nadir strongly predicted reservoir size independently of other factors in HIV-1-infected adults with complete suppression of viremia. Collectively, these results indicate that the extent of CD4 T cell depletion before ART drives the size of the viral reservoir after prolonged therapy.

A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy.

Antiretroviral-naive HIV-1-infected volunteers received zidovudine/lamivudine plus either lopinavir/ritonavir (n=104) or efavirenz (n=51). Lopinavir/ritonavir-treated subjects demonstrating 3 consecutive monthly HIV-1 RNA levels <50 copies/mL started lopinavir/ritonavir monotherapy. In previous-failure=failure analysis, 48% (lopinavir/ritonavir) and 61% (efavirenz) maintained HIV-1 RNA at <50 copies/mL through week 96, (P= .17; 95% confidence interval [CI] for the difference, -29% to 4%); in noncompletion=failure analysis, 60% (lopinavir/ritonavir) and 63% (efavirenz) maintained HIV-1 RNA at <50 copies/mL at week 96 (P= .73; 95% CI for the difference, -19% to 13%). Significant sparing of peripheral lipoatrophy was noted in the lopinavir/ritonavir simplification strategy. This study has provided important information for future studies using treatment simplified to lopinavir/ritonavir monotherapy.

Immunophenotypic patterns of CD8+ T cell subsets expressing CD8alphaalpha and IL-7Ralpha in viremic, aviremic and slow progressor HIV-1-infected subjects.

Evidence from animal models suggests that the expression of CD8alphaalpha homodimer on CD8(+) T cells plays a key role in the generation of long-lived memory cells. Here, we studied the quantitative alterations of CD8(+) T cell subsets expressing CD8alphaalpha, interleukin-7 receptor (IL-7Ralpha) and activation markers in HIV-1-infected individuals including aviremic, viremic and slow progressor subjects using eight-color flow cytometry. Compared to slow progressor subjects, expression of CD8alphaalpha was significantly reduced in aviremic and viremic patients and this reduction occurred mainly within central memory cell subsets and not in naive and effector memory compartments. Persistence of antigenemia leads to IL-7Ralpha loss mainly on central and pre-terminal memory CD8(+) T cell subsets in viremic patients but not in slow progressor subjects. Compared to aviremic and viremic patients, slow progressor subjects had lower levels of IL-7 and reduced activated cells. The expression of CD8alphaalpha was not significantly related to IL-7Ralpha although negative associations were evidenced within all CD8(+) T cell subsets. Collectively, these results further advance the characterization of immunophenotypic patterns of CD8(+) T cell subsets expressing CD8alphaalpha/IL-7Ralpha and provide new insights into the ability of HIV-1 infection to alter memory cell population.