Antiretroviral Therapy For HIV Infection Research Articles

P2 Audit of clinical stage at presentation and factors contributing to antiretroviral therapy delay, in HIV patients in rural Kenya

BackgroundThe 2010 WHO guideline, “Antiretroviral Therapy for HIV Infection in Adults and Adolescents” states that those with HIV and CD4 counts ≤350 cells/mm3, should start antiretroviral therapy (ART), regardless of...

Chemotherapy for thymic carcinoma in an adult patient with HIV infection

A 69-year-old man was referred to our hospital in June 2010 after the diagnosis of an anterior mediastinal tumor and HIV infection. Histopathological examination of a CT-guided needle biopsy specimen showed undifferentiated thymic carcinoma. Chest CT revealed pleural dissemination, bone invasion, and left lung metastases. The final diagnosis was Masaoka stage IVb. Surgery was considered inappropriate. Instead, the patient first underwent highly active antiretroviral therapy for HIV infection, followed by four courses of cisplatin, doxorubicin, vincristine, and cyclophosphamide chemotherapy for thymic carcinoma. A partial response was achieved. To our knowledge, this is the first report of thymic carcinoma in an adult patient with HIV infection.

A quantitative basis for antiretroviral therapy for HIV-1 infection

Highly active antiretroviral therapy (HAART)1–3 has dramatically decreased mortality from HIV-1 infection4 and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication3,5–9, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines10,11 are based on empirical results of clinical trials in which other factors like regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear.Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretrovirals exhibit previously unappreciated complex non-linear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, combined effects can be understood with a novel approach that considers the degree of independence of drug effects.This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success, and provides a rational basis for treatment simplification and optimization.

Toxoplasmosis Hospitalizations in the United States, 2008, and Trends, 1993-2008

Toxoplasmosis-related hospitalizations often occur in persons with human immunodeficiency virus (HIV) infection and other causes of immunosuppression. Using the National Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project, we examined trends in toxoplasmosis-related hospitalizations by HIV infection status from 1993 through 2008, and rates by sex and race or ethnicity in 2008. The NIS is designed to represent a 20% sample of US community hospitals and currently includes information on up to 8 million discharges per year from ∼1000 hospitals. We used International Classification of Diseases, Ninth Revision, Clinical Modification codes 130-130.9 for toxoplasmosis and 042-044/795.8/795.71/V08 for HIV infection. Estimated HIV-associated toxoplasmosis hospitalizations increased from 9395 in 1993 to 10583 in 1995 (P = .0002), then dropped to 3643 in 2001 (P < .0001), with similar levels thereafter. The rate of HIV-associated toxoplasmosis hospitalizations among all HIV-related hospitalizations decreased from 3.33% in 1993 to 1.25% in 2008 (P < .0001). Estimated non-HIV-associated toxoplasmosis hospitalizations were less variable from 1993 to 2008 (range, 386-819; 0.0020% in 1993, 0.0015% in 2008). In 2008, the rates of both HIV- and non-HIV-associated toxoplasmosis hospitalizations were higher in Hispanic persons than in white persons. HIV-associated toxoplasmosis hospitalizations dropped markedly after 1995 when highly active antiretroviral therapy was introduced; however, hospitalizations decreased relatively little after 2000, suggesting late diagnosis of some HIV-infected persons or antiretroviral therapy failure. Non-HIV-associated toxoplasmosis hospitalizations have been more stable. The rates of toxoplasmosis-related hospitalizations varied markedly among racial and ethnic groups.

Prevalence of HIV Drug Resistance Mutations in HIV Type 1 Isolates in Antiretroviral Therapy Naïve Population from Northern India

Objective. The increased use of antiretroviral therapy (ART) has reduced the morbidity and mortality associated with HIV, adversely leading to the emergence of HIV drug resistance (HIVDR). In this study we aim to evaluate the prevalence of HIVDR mutations in ART-naive HIV-1 infected patients from northern India. Design. Analysis was performed using Viroseq genotyping system based on sequencing of entire protease and two-thirds of the Reverse Transcriptase (RT) region of pol gene. Results. Seventy three chronic HIV-1 infected ART naïve patients eligible for first line ART were enrolled from April 2006 to August 2008. In 68 patients DNA was successfully amplified and sequencing was done. 97% of HIV-1 strains belonged to subtype C, and one each to subtype A1 and subtype B. The overall prevalence of primary DRMs was 2.9% [2/68, 95% confidence interval (CI), 0.3%–10.2%]. One patient had a major RT mutation M184V, known to confer resistance to lamivudine, and another had a major protease inhibitor (PI) mutation D30N that imparts resistance to nelfinavir. Conclusion. Our study shows that primary HIVDR mutations have a prevalence of 2.9% among ART-naive chronic HIV-1 infected individuals.

Efficacy of first-line antiretroviral therapy: differences between hospital-based outpatient units and private practices in Germany

Purpose of the study : The efficacy of highly active antiretroviral therapy of HIV-infection (HAART) is influenced by factors like potency of applied drugs, adherence of the patient, or resistance-associated mutations. Up to now, there is little evidence about the impact of the therapeutic setting. Methods: Since 2001, the prospective multicenter study RESINA examines the epidemiology of primary HIV drug resistance in Nordrhein-Westfalen, the biggest federal state of Germany. Longitudinal data of all participants are followed in a cohort. Parameters of patients treated in hospital-based outpatient units were compared to those of participants treated in private practices. All 36 centers were specialized in the care for HIV and AIDS patients. Summary of results: Altogether, 1591 patients were enrolled from 2001 to 2009 with a follow-up until the end of 2010. 1099 cases were treated in hospital-based units, 492 were treated in private practices. Significant differences were found considering baseline characteristics. Patients with further progressed disease and more non-European individuals were cared for in hospital units. Only median age and the rate of primary drug resistance were not significantly different. After 48 weeks, 81.9% of patients in hospital units and 85.9% in private practices had a viral load below the limit of detection (p=0.12). A similar result was seen after 96 weeks (p=0.54). A comparable increase of CD4 cell-count was determined in both groups. Conclusions : The RESINA study covers a large cohort treated in different specialized facilities. We found significant differences in baseline characteristics with more unfavourable parameters in cases at hospital-based units compared to private practices. Nevertheless, treatment outcome was similar up to 2 years after therapy initiation. In conclusion, adminstration of HAART is highly efficacious regardless of treatment setting in Germany.

Utility of routine viral load, CD4 cell count, and clinical monitoring among adults with HIV receiving antiretroviral therapy in Uganda: randomised trial

Objective To evaluate the use of routine laboratory monitoring in terms of clinical outcomes among patients receiving antiretroviral therapy (ART) in Uganda.Design Randomised clinical trialSetting A home based ART programme...

Decreases in IL-7 levels during antiretroviral treatment of HIV infection suggest a primary mechanism of receptor-mediated clearance

AbstractIL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV+ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV− controls and 43 untreated HIV+ patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4+ and CD8+ T cells was driven by increases in CD127+ naive and central memory T cells. CD4+ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127+ cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance.

Implementing operational research to scale-up access to antiretroviral therapy for HIV infection: lessons learned from the Cameroonian experience

Given the lack of evidence on how to best design and implement antiretroviral therapy (ART) scaling-up policies, operational research has seen a surge in interest. There is, however, little published information on the contribution of operational research in ART programs' implementation or in improvement of associated outcomes. The article focuses therefore on how operational research may contribute to such improvements and what the key enabling factors are for its integration into program frameworks. One of the most systematic operational research linked to a national ART program on the African continent was conducted in Cameroon between 2006 and 2010. Along with operational research carried out elsewhere in Africa, it helped demonstrate that a strategy of decentralizing HIV care can increase treatment coverage and improve early access to care, while maintaining good clinical outcomes. Multipartnership between local researchers, national authorities, healthcare professionals and the civil society is the key enabling factor for the relevance of operational research and the translation of its results into policy and practice. In spite of a dramatic increase in access to ART during recent years in low-income countries, the fight against HIV remains a failure in terms of the goal of breaking the pandemic dynamic. Operational research is needed more than ever to face this challenge.

Paediatric European Network for Treatment of AIDS response to 2010 revision of World Health Organization recommendations on ‘Antiretroviral therapy for HIV infection in infants and children’

Paediatric European Network for Treatment of AIDS response to 2010 revision of World Health Organization recommendations on ‘Antiretroviral therapy for HIV infection in infants and children’

Epicardial adipose tissue is an independent marker of cardiovascular risk in HIV-infected patients

Epicardial adipose tissue (EAT) is increased in HIV-infected patients. The aim of this study was to evaluate the association between EAT and coronary artery calcium (CAC) a marker of atherosclerosis; furthermore, we investigated the association of EAT with HIV infection, antiretroviral therapy (ART), and lipodystrophy. This was a cross-sectional study of 876 consecutive HIV-infected ART experienced patients. Patients underwent CAC imaging with multidetector computed tomography (CT) for atherosclerosis screening and risk of cardiovascular events (CAC score >100); EAT was measured in the same CT images. Factors independently associated with EAT were explored in a multivariable backward stepwise linear regression analysis. Multivariable logistic regression was used to evaluate the association of EAT and CAC score greater than 100. Patients' mean age was 47.2 ± 8 years, 68% were men. EAT was associated with central fat accumulation and mixed lipodystrophy phenotypes. Factors independently associated with EAT were: age [β = 0.6, confidence interval (CI) 0.2-1.0], male sex (β = 6.6, CI 0.5-12.7), visceral adipose tissue (β = 0.12, CI 0.08-0.17), waist circumference (β = 0.7, CI 0.04-1.3), current CD4⁺ (β = 0.6, CI 0.1-1.2, per 50 cells), total cholesterol (β = 0.1, CI 0.02-0.15), and cumulative exposure to ART (months) (β = 0.05, CI 0.00-0.11). EAT (per 10 cm³) was associated with CAC greater than 100 (odds ratio = 1.10, CI 1.02-1.19) after adjustment for age, male sex, and diabetes. We showed an association between EAT and central fat accumulation and mixed form lipodystrophy phenotypes as well as traditional risk factors for atherosclerosis. EAT may be a useful marker of cardiovascular risk as shown by its association with CAC greater than 100.

A case of tuberculosis showing immune reconstitution syndrome after the initiation of antiretroviral therapy for HIV infection

Abstract A 27-year-old man admitted for high fever, wet cough and abnormality on his chest radiograph. He was diagnosed as pulmonary tuberculosis, and started treatment with INH, RFP, EB, and PZA. After other examinations, he was diagnosed as having a acquired immunodeficiency syndrome, too. We gave him zidovudine and lamivudine/ abacavir sulfate to treat HIV infection. After starting treatment with anti-tuberculosis drugs his fever alleviated, but after 10 days from the start of anti-HIV drugs, he showed high fever, and abnormality of his chest radiograph exacervated. We diagnosed him as immune reconstitution syndrome, and gave him prednisolone 30 mg/day. His symptoms improved gradually.

Antiretroviral use during pregnancy for treatment or prophylaxis

Introduction: Antiretrovirals are recommended for all pregnant women either for treatment of HIV-1 infection or for prevention of mother-to-child transmission. Distinguishing between HIV-1-infected pregnant women who meet treatment criteria and those who do not (who use antiretrovirals during pregnancy for prophylaxis) is accomplished by assessing the HIV-1 disease stage and has important implications regarding when antiretroviral drugs are initiated during pregnancy, what drugs are used and antiretroviral use after delivery.Areas covered: This review addresses antiretroviral use by HIV-1-infected women during pregnancy. Specifically, the review focuses on antiretroviral therapy for HIV-1-infected pregnant women who meet criteria for treatment and antiretroviral prophylaxis for HIV-1-infected pregnant women (to prevent mother-to-child transmission of HIV-1). The review primarily addresses antiretroviral use in resource-rich settings, but use in resource-poor settings is briefly addressed.Expert opinion:Antiretrovirals represent only one component of the overall management of HIV-1 infected pregnant women and, therefore, cannot be viewed in isolation from other components of optimal care for HIV-1-infected women and from other efficacious interventions to prevent mother-to-child transmission of HIV-1. Antiretrovirals can be used safely and effectively during pregnancy. We concur with current guidelines regarding the threshold that differentiates which women need antiretroviral therapy for HIV-1 infection for their own health versus those who need prophylaxis to prevent transmission of HIV-1 infection to their child. We thus recommend that lifelong antiretroviral therapy be initiated in patients with an AIDS-defining illness, a CD4 count < 350 cells/mm3 or other co-morbid conditions such as acute opportunistic infections, HIV-1-associated nephropathy or hepatitis B co-infection. Irrespective of whether or not antiretrovirals are used during pregnancy, or whether antiretrovirals during pregnancy are used for treatment or prophylaxis, all infants of HIV-1-infected women should receive antiretroviral post-exposure prophylaxis.

Clinical Management of HIV Drug Resistance

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Biomarkers of Immune Dysfunction Following Combination Antiretroviral Therapy for HIV Infection

Combination antiretroviral therapy (cART) has significantly reduced morbidity and mortality of HIV-infected patients, yet their life expectancy remains reduced compared with the general population. Most HIV-infected patients receiving cART have some persistent immune dysfunction characterized by chronic immune activation and premature aging of the immune system. Here we review biomarkers of T-cell activation (CD69, -25 and -38, HLA-DR, and soluble CD26 and -30); generalized immune activation (C-reactive protein, IL-6 and D-dimer); microbial translocation (lipopolysaccharide, 16S rDNA, lipopolysaccharide-binding protein and soluble CD14); and immune dysfunction of specific cellular subsets (T cells, natural killer cells and monocytes) in HIV-infected patients on cART and their relationship to adverse clinical outcomes including impaired CD4 T-cell recovery, as well as non-AIDS clinical events, such as cardiovascular disease.

Inflammation et VIH

Although antiretroviral therapy for HIV infection prevents AIDS-related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at a higher-than-expected risk of complications, including cardiovascular disease, cancer, osteoporosis and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly demonstrated by the immune activation and inflammation that persist despite effective suppression of HIV replication.

HIV Infection, Inflammation, Immunosenescence, and Aging

Although antiretroviral therapy for HIV infection prevents AIDS-related complications and prolongs life, it does not fully restore health. Long-term treated patients remain at higher than expected risk for a number of complications typically associated with aging, including cardiovascular disease, cancer, osteoporosis, and other end-organ diseases. The potential effect of HIV on health is perhaps most clearly exhibited by a number of immunologic abnormalities that persist despite effective suppression of HIV replication. These changes are consistent with some of the changes to the adaptive immune system that are seen in the very old ("immunosenescence") and that are likely related in part to persistent inflammation. HIV-associated inflammation and immunosenescence have been implicated as causally related to the premature onset of other end-organ diseases. Novel therapeutic strategies aimed at preventing or reversing these immunologic defects may be necessary if HIV-infected patients are to achieve normal life span.

Monitoring of highly active antiretroviral therapy in HIV infection

Patients on antiretroviral therapy (ART) in high-income countries have routine laboratory tests to monitor ART efficacy/toxicity. We review studies describing the outcomes and costs of different monitoring approaches, predominantly in low-income countries. CD4 cell counts, HIV RNA viral load and clinical events are frequently discordant; viral load suppression occurs with WHO-defined CD4 failure and, as expected, viral load failure often occurs before CD4 failure. Routine CD4 monitoring provides small but significant mortality/morbidity benefits over clinical monitoring, but, at current prices, is not yet cost-effective in many sub-Saharan African countries. Viral load monitoring is less cost-effective with modelling studies reporting variable results. More research into point-of-care tests, methods for targeting monitoring and thresholds for defining failure is needed. Most laboratory monitoring for toxicity is neither effective nor cost-effective. In terms of models for delivery of care, task-shifting with nurse-led and decentralized care appear as effective as doctor-led or centralized care. Recent studies have improved the evidence base for monitoring on ART. Future research to increase cost-effectiveness by better targeting of monitoring and/or evaluating implementation of less costly point-of-care tests will contribute to long-term success of ART while continuing to increase ART coverage.

Establishment of reference CD4+ T cell values for adult Indian population.

BackgroundCD4+ T lymphocyte counts are the most important indicator of disease progression and success of antiretroviral treatment in HIV infection in resource limited settings. The nationwide reference range of CD4+ T lymphocytes was not available in India. This study was conducted to determine reference values of absolute CD4+ T cell counts and percentages for adult Indian population.MethodsA multicentric study was conducted involving eight sites across the country. A total of 1206 (approximately 150 per/centre) healthy participants were enrolled in the study. The ratio of male (N = 645) to female (N = 561) of 1.14:1. The healthy status of the participants was assessed by a pre-decided questionnaire. At all centers the CD4+ T cell count, percentages and absolute CD3+ T cell count and percentages were estimated using a single platform strategy and lyse no wash technique. The data was analyzed using the Statistical Package for the Social Scientist (SPSS), version 15) and Prism software version 5.ResultsThe absolute CD4+ T cell counts and percentages in female participants were significantly higher than the values obtained in male participants indicating the true difference in the CD4+ T cell subsets. The reference range for absolute CD4 count for Indian male population was 381-1565 cells/μL and for female population was 447-1846 cells/μL. The reference range for CD4% was 25-49% for male and 27-54% for female population. The reference values for CD3 counts were 776-2785 cells/μL for Indian male population and 826-2997 cells/μL for female population.ConclusionThe study used stringent procedures for controlling the technical variation in the CD4 counts across the sites and thus could establish the robust national reference ranges for CD4 counts and percentages. These ranges will be helpful in staging the disease progression and monitoring antiretroviral therapy in HIV infection in India.

Usefulness of hemoglobin and albumin as prognostic markers for highly active antiretroviral therapy for HIV-1 infection

Usefulness of hemoglobin and albumin as prognostic markers for highly active anti-retroviral therapy for HIV-1 infection. Anemia and hypoalbuminemia are common complications in human immunodeficiency virus (HIV) infection. We aimed to investigate the changes in hemoglobin and albumin levels in response to highly active antiretroviral therapy (HAART). Further, we evaluated the appropriateness of using hemoglobin and albumin as HIV disease progression markers. A prospective longitudinal study of 122 subjects was carried out. Pre-treatment, one year, and two year post-treatment hemoglobin, and albumin levels were correlated with respective CD4+ T cell counts. The sensitivity, specificity, and positive predictive value of each marker against CD4+ T cell counts were calculated in order to establish the appropriateness of use of these parameters as surrogate disease progression and prognostic markers. Mean hemoglobin and albumin levels pre-, one, and two year post HAART were 9.7 g/dL, 12.1 g/dL, and 13.1 g/dL, respectively, P = 0.001; albumin: 3.7 gm%, 4.4 gm%, and 4.7 gm%, respectively, P = 0.001. There was a positive correlation between hemoglobin, albumin, and CD4+ T cell count at pre-treatment, one year, and two year post-treatment visit. Both albumin and hemoglobin had high sensitivity when compared to CD4+ T cell counts. Hemoglobin and albumin levels were found to increase after initiation of HAART. Hemoglobin and albumin were seen to be a strong prognostic marker of HIV disease progression at pre-, one, and two year post-treatment. Therefore, hemoglobin and albumin may be used together along with CD4 + T cell counts in HIV management, particularly in resource-poor settings.