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1.  Relationship between total bilirubin, endothelial function, inflammation and oxidative stress in HIV-infected adults on stable antiretroviral therapy 
HIV medicine  2012;13(10):609-616.
Objective
Enhanced inflammation is evident in HIV, even with virologic suppression. Outside HIV, studies show an independent association between higher total bilirubin and better endothelial function as well as lower prevalence of coronary heart disease possibly due to the anti-inflammatory and antioxidant effect of bilirubin.
Methods
A cross-sectional study was performed in HIV-1 infected adults on stable antiretroviral therapy (ART) to determine if a relationship exists between total bilirubin and endothelial function (flow mediated dilation (FMD) of the brachial artery), inflammation (interleukin-6 (IL-6), soluble tumor necrosis factor receptors, C-reactive protein, adhesion molecules), coagulation markers (fibrinogen and D-Dimer) and oxidative stress (F2-Isoprostanes). Endpoints were compared based on total bilirubin levels and atazanavir status using distributionally-appropriate, two-sample tests. Correlation coefficients were determined between total bilirubin and end points. Linear regression was used to model the relationship between total bilirubin (and atazanavir status) and FMD.
Results
98 adults were included. Total bilirubin was higher in atazanavir group (median (IQR) 1.8 (1.1–2.6) vs. 0.6 (0.4–1.4) mg/dL; p<0.01) as was insulin, HOMA-IR and fibrinogen. Total bilirubin was positively correlated with fibrinogen and was not correlated with other outcomes. After adjustment, neither total bilirubin nor atazanavir status was associated with FMD.
Conclusions
In virologically-suppressed, HIV-infected adults on stable ART, neither total bilirubin nor atazanavir use was associated with improved endothelial function as measured by FMD, inflammation or oxidative stress as measured by biomarkers.
doi:10.1111/j.1468-1293.2012.01026.x
PMCID: PMC3430799  PMID: 22624591
2.  Markers of inflammation and coagulation indicate a prothrombotic state in HIV-infected patients with long-term use of antiretroviral therapy with or without abacavir 
Background
Abacavir (ABC) treatment has been associated with an increased incidence of myocardial infarction. The pathophysiological mechanism is unknown. In this study markers of inflammation and coagulation in HIV-infected patients using antiretroviral therapy with or without ABC were examined to pinpoint a pathogenic mechanism. Given the important role of high sensitivity C-reactive protein (hsCRP) levels in predicting cardiovascular risk, patient groups were also analyzed according to hsCRP levels.
Methods
Patients treated with ABC and a matched control group treated without ABC were selected retrospectively. Vascular endothelial growth factor (VEGF) and markers of endothelial cell activation (von Willebrand factor (vWF), factor VIII), fibrin formation (fibrinogen, D-dimer, prothrombin fragment 1+2 (F1+2), endogenous thrombin potential (ETP)), anticoagulation markers (protein C and S, activated protein C sensitivity ratio (APCsr)) and inflammation markers (IL-6, hsCRP) were measured in citrated plasma.
Results
A total of 81 patients were included of whom 27 patients used an ABC-containing regimen and 54 used a non-ABC-containing regimen. Patient characteristics were not significantly different between the groups except for longer duration of use of the current antiretroviral regimen in the ABC group (p = 0.01). The median time on ABC was 68 months (interquartile range 59-80 months). No differences in coagulation and inflammation markers according to ABC use were observed. For the whole patient group elevated vWF and F1+2 levels were observed in 23% and 37%, respectively. Compared to the reference ranges for the general population increased APCsr was found in 79% and lower protein C and VEGF levels in 40% and 43%, respectively. Patients in the high-risk category for cardiovascular disease with hsCRP levels > 3 mg/L had significantly higher fibrinogen, D-dimer, F1+2 and ETP levels compared to patients from the low-risk category with hsCRP levels < 1 mg/L.
Conclusion
HIV-infected patients using ABC showed no specific abnormalities in coagulation or inflammation markers that might explain the increased risk of myocardial infarction. For the whole group, regardless of ABC use, evidence of a prothrombotic state was observed. Thirty-three percent of patients with long-term use of antiretroviral treatment had hsCRP levels above 3 mg/L, which is strongly associated with cardiovascular disease in HIV-uninfected individuals.
doi:10.1186/1742-6405-7-9
PMCID: PMC2873236  PMID: 20398387
3.  Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment 
Background
Inflammation and hemostasis perturbation may be involved in vascular complications of HIV infection. We examined atherogenic biomarkers and subclinical atherosclerosis in HIV-infected adults before and after beginning highly-active antiretroviral therapy (HAART).
Methods
In the Women's Interagency HIV Study (WIHS), 127 HIV-infected women studied pre- and post-HAART were matched to HIV-uninfected controls. Six semi-annual measurements of soluble CD14, tumor necrosis factor (TNF)-alpha, soluble interleukin (IL)-2 receptor, IL-6, IL-10, monocyte chemoattractant protein (MCP)-1, D-dimer, and fibrinogen were obtained. Carotid artery intima-media thickness (CIMT) was measured by B-mode ultrasound.
Results
Relative to HIV-uninfected controls, HAART-naïve HIV-infected women had elevated levels of soluble CD14 (1945 vs 1662 ng/mL, Wilcoxon signed rank P<0.0001), TNF-alpha (6.3 vs 3.4 pg/mL, P<0.0001), soluble IL-2 receptor (1587 vs 949 pg/mL, P<0.0001), IL-10 (3.3 vs 1.9 pg/mL, P<0.0001), MCP-1 (190 vs 163 pg/mL, P<0.0001) and D-dimer (0.43 vs 0.31 µg/mL, P<0.01). Elevated biomarker levels declined after HAART. While most biomarkers normalized to HIV-uninfected levels, in women on effective HAART, TNF-alpha levels remained elevated compared to HIV-uninfected women (+0.8 pg/mL, P=0.0002). Higher post-HAART levels of soluble IL-2 receptor (P=0.02), IL-6 (P=0.05), and D-dimer (P=0.03) were associated with increased CIMT.
Conclusions
Untreated HIV infection is associated with abnormal hemostasis (e.g., D-dimer), and pro-atherogenic (e.g., TNF-alpha) and anti-atherogenic (e.g., IL-10) inflammatory markers. HAART reduces most inflammatory mediators to HIV-uninfected levels. Increased inflammation and hemostasis are associated with subclinical atherosclerosis in recently treated women. These findings have potential implications for long-term risk of cardiovascular disease in HIV-infected patients, even with effective therapy.
doi:10.1097/QAI.0b013e31825b03be
PMCID: PMC3400505  PMID: 22592585
antiretroviral therapy; cardiovascular diseases; cytokines; hemostasis; HIV; inflammation
4.  Biomarkers of Vascular Dysfunction in Children Infected with Human Immunodeficiency Virus-1 
Background
We compared biomarkers of vascular dysfunction among HIV-infected children to a demographically-similar group of uninfected children and determined factors associated with these biomarkers.
Methods and Results
We measured several biomarkers of vascular dysfunction: C-Reactive Protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein -1 (MCP1) [inflammation]; fibrinogen and P-selectin [coagulant dysfunction]; soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin [endothelial dysfunction]; and leptin [metabolic dysfunction]. Anthropometry, body composition, CD4%, HIV viral load, and antiretroviral therapy were recorded. Mean age was 14.8y [106 HIV-infected children] and 12.3y [55 control children]. Sex and body mass index Z-scores were similar. Infected children had higher sICAM, sVCAM, MCP1, IL-6, and fibrinogen levels. E-selectin (p=0.07), and CRP (p=0.08) trended to be greater in the HIV group, yet leptin, and P-selectin were similar. In multivariable analyses in the HIV-infected children alone, each 1-standard-deviation increase in waist:hip ratio was associated with increases in sICAM (17%), MCP1 (19%), IL6 (18%), and CRP (59%). CD4% was inversely associated with sVCAM, MCP1, IL6, fibrinogen, and CRP.
Conclusion
HIV-infected children have higher levels of biomarkers of vascular dysfunction than healthy children. Risk factors associated with these biomarkers include higher waist:hip ratios and HIV disease severity.
doi:10.1097/QAI.0b013e3181e222c9
PMCID: PMC2943965  PMID: 20531209
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
5.  Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy 
AIDS (London, England)  2008;22(10):1153-1161.
Objective
We investigated the effect of short viremic episodes on soluble markers associated with endothelial stress and cardiovascular disease risk in chronically HIV-1-infected patients followed during continuous antiretroviral therapy, antiretroviral therapy interruption and antiretroviral therapy resumption.
Design and methods
We assessed changes in plasma levels of von Willebrand factor, soluble vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 by enzyme-linked immunosorbent assay, as well as T-cell activation (CD8+/CD38+, CD8+/HLA-DR+ and CD3+/CD95+) by flow cytometry, in 36 chronically HIV-1-infected patients participating in a randomized study. Patients were divided into the following three groups: a, on continuous antiretroviral therapy; b, on a 6-week antiretroviral therapy interruption; or c, on antiretroviral therapy interruption extended to the achievement of viral set point.
Results
Although all measurements remained stable over a 40-week follow-up on antiretroviral therapy, plasma levels of soluble vascular cell adhesion molecule-1 (P < 0.0001) and soluble intercellular adhesion molecule-1 (P = 0.003) increased during treatment interruption in correlation with viral rebound and T-cell activation. No significant changes in von Willebrand factor were observed in any of the groups. After resuming antiretroviral therapy, soluble vascular cell adhesion molecule-1 levels remained elevated even after achievement of viral suppression to less than 50 copies/ml.
Conclusion
The prompt rise in plasma soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1 upon viral rebound suggests an acute increase in endothelial stress upon treatment interruption, which may persists after viral resuppression of virus. Thus, viral replication during short-term treatment interruption may increase the overall cardiovascular risk during and beyond treatment interruption.
doi:10.1097/QAD.0b013e328303be2a
PMCID: PMC2726750  PMID: 18525261
cardiovascular risk; endothelial stress; HIV-1; treatment interruption
6.  Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort 
Objective
To determine the association of inflammatory markers, fibrinogen and C-reactive protein (CRP), with 5-year mortality risk.
Methods
Vital status was ascertained in 922 HIV-infected participants from the Study of Fat Redistribution and Metabolic Change in HIV infection. Multivariable logistic regression estimated odds ratios (OR) after adjustment for demographic, cardiovascular and HIV-related factors.
Results
Over a 5-year period, HIV-infected participants with fibrinogen levels in the highest tertile(>406mg/dL) had 2.6-fold higher adjusted odds of death than those with fibrinogen in the lowest tertile(<319mg/dL). Those with high CRP(>3mg/L) had 2.7-fold higher adjusted odds of death than those with CRP<1mg/L. When stratified by CD4 count category, fibrinogen (as a linear variable) remained independently associated [OR(95% confidence intervals) per 100mg/dL increase in fibrinogen: 1.93(1.57,2.37);1.43(1.14,1.79);1.43(1.14,1.81);and 1.30(1.04,1.63) for CD4 <200,200–350,>350–500, and >500cells/μL, respectively. Higher CRP also remained associated with higher odds of death overall and within each CD4 subgroup.
Conclusion
Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults. Our findings suggest that even in those with relatively preserved CD4 counts >500cells/μL, inflammation remains an important risk factor for mortality. Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals.
doi:10.1097/QAI.0b013e3181e66216
PMCID: PMC2955817  PMID: 20581689
HIV; inflammation; C-reactive protein; fibrinogen; mortality
7.  Associations of HIV infection with insulin and glucose levels in antiretroviral-naïve Rwandan women: a cross-sectional analysis 
BMJ Open  2013;3(12):e003879.
Objectives
The purpose of these analyses was to determine the associations of HIV infection and related immune dysfunction with a glucose homeostasis in the population of antiretroviral-naïve HIV-infected and uninfected Rwandan women. We hypothesise that insulin resistance and its consequences in the developing countries may be further elevated with HIV infection itself regardless of antiretroviral therapy.
Study design
Cross-sectional analysis of a longitudinal cohort.
Setting
Community-based women's associations.
Participants
In 2005, 710 HIV-infected (HIV positive) antiretroviral naïve and 226 HIV-uninfected (HIV negative) women were enrolled in the Rwanda Women's Interassociation Study and Assessment (RWISA). Clinical and demographic parameters, CD4 count, fasting insulin and glucose levels, anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were obtained. Linear models were fit to log-transformed Homeostasis Model Assessment (HOMA) with results exponentiated back to a multiplicative effect on the original scale.
Primary outcome measures
The outcome, insulin resistance, was measured by the HOMA, calculated as fasting insulin (μU/mL)×fasting glucose (mmol/L)⁄22.5.
Results
In adjusted models, HIV-positive women were less insulin resistant than HIV-negative; an HIV-positive woman tended to have 0.728 times as much (95% CI 0.681 to 0.861) HOMA than a comparable HIV-negative woman. Among the HIV-positive women, those with CD4 <200 cells/µL tended to have 0.741 times as much HOMA (95% CI 0.601 to 0.912) as did comparable women with CD4 >350 cells/µL. The older age was independently associated with a lower HOMA insulin resistance. After adjusting for body mass index, fat and fat-free mass were not independently associated with HOMA.
Conclusions
This study found that HIV infection and more advanced HIV infection (CD4 counts <200 cells/µL) were associated with greater insulin sensitivity in antiretroviral naïve African women. These findings provide baseline information for the interpretation of future studies on the effect of antiretroviral therapy on metabolic insulin sensitivity derangements in African population.
doi:10.1136/bmjopen-2013-003879
PMCID: PMC3855496  PMID: 24319275
Diabetes & Endocrinology; Epidemiology
8.  Correlation between HIV disease and lipid metabolism in antiretroviral-naïve HIV-infected patients in Japan 
Antiretroviral therapy alters lipid metabolism in HIV-infected patients. However, interpreting the impact of HIV infection on lipid metabolism is difficult because of various associated factors, including antiretroviral drugs and demographic characteristics. A few studies have associated HIV infection with lipid metabolism in antiretroviral-naïve HIV-infected patients. Because there were no data in this regard from Japan, the present study examined the impact of HIV infection, as well as demographic and clinical features, on lipid metabolism in antiretroviral-naïve HIV-infected patients in Japan. We performed a cross-sectional study to examine the impact of HIV disease, demographic and clinical characteristics on lipid metabolism among 168 HIV-infected Japanese men who were antiretroviral naïve and who did not have hemophilia, including patients who took medication for dyslipidemia. The mean age of the patients was 45.7 years; 0.6% of the patients took medication to dyslipidemia. The mean CD4 lymphocyte count was 289/μL, the mean baseline log10 HIV viral load was 4.2 HIV-1 RNA copies/mL, and 22% of the patients had a history of AIDS-defining events. A higher HDL-C concentration was associated with a higher CD4 lymphocyte count (p = 0.043). Also, a higher LDL-C concentration was associated with a higher CD4 lymphocyte count (p = 0.003). Infection with HIV was associated with dyslipidemia in antiretroviral-naïve patients. More advanced HIV disease was associated with less favorable lipid homeostatic profiles. These results are similar to findings from other countries.
doi:10.1007/s10156-011-0275-5
PMCID: PMC3278606  PMID: 21735099
Lipids; HIV infection; Antiretroviral naïve
9.  Human Immunodeficiency Virus (HIV) Latency: The Major Hurdle in HIV Eradication 
Molecular Medicine  2012;18(1):1096-1108.
Failure of highly active antiretroviral therapy to eradicate the human immunodeficiency virus (HIV), even in patients who suppress the virus to undetectable levels for many years, underscores the problems associated with fighting this infection. The existence of persistent infection in certain cellular and anatomical reservoirs appears to be the major hurdle in HIV eradication. The development of therapeutic interventions that eliminate or limit the latent viral pools or prevent the reemergence of the viruses from producing cells will therefore be required to enhance the effectiveness of current antiretroviral strategies. To achieve this goal, there is a pressing need to understand HIV latency at the molecular level to design novel and improved therapies to either eradicate HIV or find a functional cure in which patients could maintain a manageable viral pool without AIDS in the absence of antiretroviral therapy. The integrated proviral genome remains transcriptionally silent for a long period in certain subsets of T cells. This ability to infect cells latently helps HIV to establish a persistent infection despite strong humoral and cellular immune responses against the viral proteins. The main purpose of this report is to provide a general overview of the HIV latency. We will describe the hurdles being faced in eradicating latent HIV proviruses. We will also briefly discuss the ongoing strategies aimed toward curing HIV infection.
doi:10.2119/molmed.2012.00194
PMCID: PMC3475336  PMID: 22692576
10.  Development and Validation of a Composite Programmatic Assessment Tool for HIV Therapy 
PLoS ONE  2012;7(11):e47859.
Background
We developed and validated a new and simple metric, the Programmatic Compliance Score (PCS), based on the IAS-USA antiretroviral therapy management guidelines for HIV-infected adults, as a predictor of all-cause mortality, at a program-wide level. We hypothesized that non-compliance would be associated with the highest probability of mortality.
Methods and Findings
3543 antiretroviral-naive HIV-infected patients aged ≥19 years who initiated antiretroviral therapy between January 1, 2000 and August 31, 2009 in British Columbia (BC), Canada, were followed until August 31, 2010. The PCS is composed by six non-performance indicators based on the IAS-USA guidelines: (1) having <3 CD4 count tests in the first year after starting antiretroviral therapy; (2) having <3 plasma viral load tests in the first year after starting antiretroviral therapy; (3) not having drug resistance testing done prior to starting antiretroviral therapy; (4) starting on a non-recommended antiretroviral therapy regimen; (5) starting therapy with CD4 <200 cells/mm3; and (6) not achieving viral suppression within 6 months since antiretroviral therapy initiation. The sum of these six indicators was used to develop the PCS score - higher score indicates poorer performance. The main outcome was all-cause mortality. Each PCS component was independently associated with mortality. In the mortality analysis, the odds ratio (OR) for PCS ≥4 versus 0 was 22.37 (95% CI 10.46–47.84).
Conclusions
PCS was strongly associated with all-cause mortality. These results lend independent validation to the IAS-USA treatment guidelines for HIV-infected adults. Further efforts are warranted to enhance the PCS as a means to further improve clinical outcomes. These should be specifically evaluated and targeted at healthcare providers and patients.
doi:10.1371/journal.pone.0047859
PMCID: PMC3501505  PMID: 23185244
11.  The relation of price of antiretroviral drugs and foreign assistance with coverage of HIV treatment in Africa: retrospective study 
Objective To determine the association of reductions in price of antiretroviral drugs and foreign assistance for HIV with coverage of antiretroviral treatment.
Design Retrospective study.
Setting Africa.
Participants 13 African countries, 2003-8.
Main outcome measures A price index of first line antiretroviral therapy with data on foreign assistance for HIV was used to estimate the associations of prices and foreign assistance with antiretroviral coverage (percentage of people with advanced HIV infection receiving antiretroviral therapy), controlling for national public health spending, HIV prevalence, governance, and fixed effects for countries and years.
Results Between 2003 and 2008 the annual price of first line antiretroviral therapy decreased from $1177 (£733; €844) to $96 and foreign assistance for HIV per capita increased from $0.4 to $13.8. At an annual price of $100, a $10 decrease was associated with a 0.16% adjusted increase in coverage (95% confidence interval 0.11% to 0.20%; 0.19% unadjusted, 0.14% to 0.24%). Each additional $1 per capita in foreign assistance for HIV was associated with a 1.0% adjusted increase in coverage (0.7% to 1.2%; 1.4% unadjusted, 1.1% to 1.6%). If the annual price of antiretroviral therapy stayed at $100, foreign assistance would need to quadruple to $64 per capita to be associated with universal coverage. Government effectiveness and national public health expenditures were also positively associated with increasing coverage.
Conclusions Reductions in price of antiretroviral drugs were important in broadening coverage of HIV treatment in Africa from 2003 to 2008, but their future role may be limited. Foreign assistance and national public health expenditures for HIV seem more important in expanding future coverage.
doi:10.1136/bmj.c6218
PMCID: PMC2987231  PMID: 21088074
12.  Neurologic Complications of HIV Disease and Their Treatment 
Substantial work on the peripheral and central nervous system complications of HIV was presented at the 16th Conference on Retroviruses and Opportunistic Infections. Six studies of more than 4500 volunteers identified that distal sensory polyneuropathy remains common, ranging from 19% to 66%, with variation based on disease stage, type of antiretroviral therapy, age, and height. Eight studies of more than 2500 volunteers identified that neurocognitive disorders are also common, ranging from 25% to 69%, with variation based on stage of disease, antiretroviral use, diabetes mellitus, and coinfection with hepatitis viruses. Therapy-focused studies identified that resistance testing of cerebrospinal fluid (CSF)-derived HIV may improve management of people with HIV-associated neurologic complications, that poorly penetrating antiretroviral therapy is associated with persistent low-level HIV RNA in CSF, and that efavirenz concentrations in CSF are low but in the therapeutic range in most individuals. Neuroimaging reports identified that people living with HIV had abnormal findings on magnetic resonance imaging (gray matter atrophy, abnormal white matter), magnetic resonance spectroscopy (lower neuronal metabolites), and blood-oxygen-level dependent functional magnetic resonance imaging (lower cerebral blood flow). Other important findings on the basic neuroscience of HIV and diagnosis and management of neurologic opportunistic infections are discussed.
PMCID: PMC3065886  PMID: 19401607
13.  Differences in Serum Levels of Magnesium, Phosphate, and Albumin for HAART-Experienced and HAART-Naïve Female Patients Attending Parirenyatwa Opportunistic Infections Clinic in Harare, Zimbabwe 
ISRN AIDS  2013;2013:383214.
Antiretroviral therapy inhibits HIV replication, maintains health, and preserves life. However, both antiretroviral therapy and HIV infection have been reported to have short- and long-term effects on bone metabolism. A cross-sectional study was performed to compare serum bone profiles in HIV positive patients on highly active antiretroviral therapy and compare them to therapy-naïve patients. Serum levels of calcium, magnesium, phosphate, and albumin were measured in 40 female participants on highly active antiretroviral therapy, recruited sequentially from Parirenyatwa Opportunistic Infections Clinic, Harare, Zimbabwe. The 40 women were matched for age with 40 antiretroviral therapy-naïve women. Magnesium, phosphate, and albumin levels were significantly higher in the therapy-naïve than in therapy-experienced patients. There was no statistically significant difference in calcium levels of the two groups of women. Evidence from this study suggests that highly active antiretroviral therapy lowers levels of magnesium, phosphate, and albumin but has no effect on levels of serum calcium.
doi:10.1155/2013/383214
PMCID: PMC3777213  PMID: 24093073
14.  Evaluating the Effect of Early Versus Late ARV Regimen Change if Failure on an Initial Regimen: Results From the AIDS Clinical Trials Group Study A5095 
The current goal of initial antiretroviral (ARV) therapy is suppression of plasma human immunodeficiency virus (HIV)-1 RNA levels to below 200 copies per milliliter. A proportion of HIV-infected patients who initiate antiretroviral therapy in clinical practice or antiretroviral clinical trials either fail to suppress HIV-1 RNA or have HIV-1 RNA levels rebound on therapy. Frequently, these patients have sustained CD4 cell counts responses and limited or no clinical symptoms and, therefore, have potentially limited indications for altering therapy which they may be tolerating well despite increased viral replication. On the other hand, increased viral replication on therapy leads to selection of resistance mutations to the antiretroviral agents comprising their therapy and potentially cross-resistance to other agents in the same class decreasing the likelihood of response to subsequent antiretroviral therapy. The optimal time to switch antiretroviral therapy to ensure sustained virologic suppression and prevent clinical events in patients who have rebound in their HIV-1 RNA, yet are stable, is not known. Randomized clinical trials to compare early versus delayed switching have been difficult to design and more difficult to enroll. In some clinical trials, such as the AIDS Clinical Trials Group (ACTG) Study A5095, patients randomized to initial antiretroviral treatment combinations, who fail to suppress HIV-1 RNA or have a rebound of HIV-1 RNA on therapy are allowed to switch from the initial ARV regimen to a new regimen, based on clinician and patient decisions. We delineate a statistical framework to estimate the effect of early versus late regimen change using data from ACTG A5095 in the context of two-stage designs.
In causal inference, a large class of doubly robust estimators are derived through semiparametric theory with applications to missing data problems. This class of estimators is motivated through geometric arguments and relies on large samples for good performance. By now, several authors have noted that a doubly robust estimator may be suboptimal when the outcome model is misspecified even if it is semiparametric efficient when the outcome regression model is correctly specified. Through auxiliary variables, two-stage designs, and within the contextual backdrop of our scientific problem and clinical study, we propose improved doubly robust, locally efficient estimators of a population mean and average causal effect for early versus delayed switching to second-line ARV treatment regimens. Our analysis of the ACTG A5095 data further demonstrates how methods that use auxiliary variables can improve over methods that ignore them. Using the methods developed here, we conclude that patients who switch within 8 weeks of virologic failure have better clinical outcomes, on average, than patients who delay switching to a new second-line ARV regimen after failing on the initial regimen. Ordinary statistical methods fail to find such differences. This article has online supplementary material.
doi:10.1080/01621459.2011.646932
PMCID: PMC3545451  PMID: 23329858
Causal inference; Double robustness; Longitudinal data analysis; Missing data; Rubin causal model; Semiparametric efficient estimation
15.  Hepatitis C Infection Is Associated with Lower Lipids and High-Sensitivity C-Reactive Protein in HIV-Infected Men 
AIDS patient care and STDs  2007;21(7):479-491.
Increased cardiovascular risk has been linked to HIV infection and combination antiretroviral therapy, but the impact of hepatitis C virus (HCV) status on indices of cardiovascular risk has not been routinely assessed in the HIV-infected population. The objective of this study was to analyze associations of HCV, HIV, and combination antiretroviral therapy with lipid levels and C-reactive protein (CRP) among older men. We measured fasting total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and high-sensitivity CRP serum levels in a cross-sectional study of 108 HIV-infected and 74 HIV-uninfected at-risk older men. One hundred ten men (60%) had detectable HCV RNA, with no difference by HIV status (p = 0.25). The majority (88%) of men with HCV infection had a history of injection drug use. Among all men, HCV infection was independently associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), triglycerides (p = 0.01), and CRP (p < 0.001). Among HIV-infected men, HCV infection was associated with lower total cholesterol (p < 0.001), LDL-C (p < 0.001), and CRP (p = 0.004). HCV infection was associated with lower triglycerides among men on protease inhibitors (PI) (p = 0.02) and non-PI combination antiretroviral therapy (p = 0.02), but not among antiretroviral-naïve men. These findings demonstrate an association of lower serum lipid and CRP levels with HCV infection and suggest that HCV status should be assessed as an important correlate of cardiovascular risk factors in studies of older men with or at risk for HIV.
doi:10.1089/apc.2006.0150
PMCID: PMC2423809  PMID: 17651029
16.  Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery 
BJA: British Journal of Anaesthesia  2010;104(5):555-562.
Background
Normalization of plasma fibrinogen levels may be associated with satisfactory haemostasis and reduced bleeding. The aim of this retrospective study was to assess fibrinogen recovery parameters after administration of fibrinogen concentrate (Haemocomplettan® P) to patients with diffuse bleeding in cardiovascular surgery. Data on transfusion and patient outcomes were also collected.
Methods
Patient characteristic and clinical data were obtained from patient records. Results of the thromboelastometry (FIBTEM®) and of the standard coagulation tests, including plasma fibrinogen level, measured before surgery, before and after haemostatic therapy, and on the following day, were retrieved from laboratory records.
Results
Thirty-nine patients receiving fibrinogen concentrate for diffuse bleeding requiring haemostatic therapy after cardiopulmonary bypass were identified. The mean fibrinogen concentrate dose administered was 6.5 g. The mean fibrinogen level increased from 1.9 to 3.6 g litre−1 (mean increment of 0.28 g litre−1 per gram of concentrate administered); maximum clot firmness increased from 10 to 21 mm. The mean fibrinogen increase was 2.29 (sd 0.7) mg dl−1 per mg kg−1 bodyweight of concentrate administered. Thirty-five patients received no transfusion of fresh-frozen plasma (FFP) or platelet concentrate after receiving fibrinogen concentrate; the remaining four patients received platelet concentrate intraoperatively. Eleven patients received platelets, FFP, or both during the first postoperative day. No venous thromboses, arterial ischaemic events, or deaths were registered during hospitalization.
Conclusions
In this retrospective study, fibrinogen concentrate was effective in increasing plasma fibrinogen level, and contributed to the correction of bleeding after cardiovascular surgery.
doi:10.1093/bja/aeq058
PMCID: PMC2855672  PMID: 20348140
blood, coagulation; fibrinogen concentrate; pharmacokinetics, uptake; surgery, cardiovascular
17.  Growth hormone and tesamorelin in the management of HIV-associated lipodystrophy 
HIV-infected patients on highly active antiretroviral therapy (HAART) develop a complex of body composition changes known, including peripheral fat loss (lipoatrophy) and central fat accumulation (lipohypertrophy). These changes may cause significant patient distress, which could in turn interfere with adherence to antiretroviral therapy. Treatment options – including antiretroviral switch, insulin sensitizers, and surgical approaches – have been associated with limited success and potential complications. The observation that low growth hormone levels are associated with central fat accumulation among HIV patients has led to the development of tesamorelin (a growth hormone releasing hormone analog) for the management of central fat accumulation. Randomized controlled trials have shown that administration of tesamorelin is safe and effective in reducing central fat accumulation among HIV-infected patients. This effect is transient, however, and its association with improved cardiovascular risk remains unclear.
doi:10.2147/HIV.S14561
PMCID: PMC3218714  PMID: 22096409
HAART; HIV; tesamorelin; lipodystrophy
18.  Knowledge and adherence to antiretroviral therapy among adult people living with HIV/AIDS treated in the health care centers of the association "Espoir Vie Togo" in Togo, West Africa 
Background
The efficiency of antiretroviral therapy (ART) depends on a near perfect level of patients' adherence. The level of adherence of adults HIV-infected patients treated in the HIV/AIDS health care centres of the association "Espoir Vie Togo" in Togo, West Africa is not properly documented. The aim of the present study was to examine by means of self-reports the knowledge, the adherence level and associated factors to antiretroviral therapy (ART) among these patients.
Methods
We conducted a cross-sectional survey among adult people living with HIV/AIDS (PLWHA) through a structured questionnaire.
Results
A total of 99 patients were enrolled. Among them, 55.6% knew the name of antiretroviral agents of regimens prescribed. All patients had a good knowledge of treatment schedule. The treatment regimens based on 2 NRTIs + 1 NNRTI were used in 90% of patients. The average adherence rate was 89.8% of the total doses prescribed while 62.62% of patients showed an adherence rate of 95% or above. The treated groups were similar in term of median % of medication doses taken according to PLWHA epidemiological characteristics. However, patients reported forgetting (34.9%), travel (25.6%), cost of treatment (13.9%) and side effects (11.6%) as the main factors of missing at least once a dose intake.
Conclusion
These results should encourage the association and all the involved actors in the HIV/AIDS's program to strengthen counseling, education and information interventions for HIV-infected patients in order to overcome the potential barriers of poor adherence.
doi:10.1186/1472-6904-10-11
PMCID: PMC2949664  PMID: 20849595
19.  Prevalence of reverse transcriptase and protease mutations associated with antiretroviral drug resistance among drug-naïve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions, Tanzania 
Background
Access to antiretroviral drugs for HIV-1 infection has increased in sub-Saharan Africa (SSA) during the past few years. Mutations in the HIV-1 genome are often associated with treatment failure as indicated by viral replication and elevated levels of virus in the blood. Mutations conferring resistance to antiretroviral drugs are based on comparing gene sequences with corresponding consensus sequences of HIV-1 subtype B that represents only 10% of the AIDS pandemic. The HIV pandemic in SSA is characterized by high viral genetic diversity. Before antiretroviral drugs become more widely available, it is important to characterize baseline naturally occurring genetic mutations and polymorphisms associated with antiretroviral drug resistance among circulating HIV-1 subtypes.
Methods
The prevalence of mutations associated with antiretroviral drug resistance in protease (PR) and reverse transcriptase (RT) regions among antiretroviral treatment-naïve HIV-1 infected pregnant women was investigated in Bukoba (Kagera) and Moshi (Kilimanjaro) municipalities, Tanzania, between September and December 2005. The HIV-1 pol gene was amplified using primers recognizing conserved viral sequences and sequenced employing BigDye chemistry from 100 HIV-1 seropositive treatment-naïve pregnant women and 61 HIV-1 seropositive women who had received a single dose of Nevirapine (sdNVP). Positions 1–350 of the RT and 1–99 of the PR genes were analyzed for mutations based on the Stanford University HIV Drug Resistance Database.
Results
HIV-1 subtypes A, C, D, CRF10_CD and Unique Recombinant Forms (URF) were detected. Primary mutations associated with NRTI and NNRTI resistance were detected among 3% and 4% of treatment-naïve strains, respectively. Primary mutations associated with NRTI and NNRTI resistance were detected in 1.6% and 11.5% of women who had received sdNVP, respectively. None of the primary mutations associated with PI resistance was found. Polymorphisms detected in RT and PR sequences were mainly mutations that are found in the consensus sequences of non-B subtypes
Conclusion
Based on the WHO HIV Drug Resistance Research Network Threshold of less than 5%, the baseline prevalence of primary mutations among treatment-naïve HIV-1 infected pregnant women in Kagera and Kilimanjaro regions was low. The significance of HIV-1 subtype B polymorphic positions with respect to antiretroviral resistance identified among the prevalent HIV-1 subtypes is unknown. More studies addressing the correlation between polymorphic mutations, antiretroviral resistance and clinical outcome are warranted in regions where non-B subtypes are prevalent.
doi:10.1186/1742-6405-5-13
PMCID: PMC2443165  PMID: 18570675
20.  Treating HIV-1 Infection: What Might the Future Hold? 
Advances in antiretroviral combination therapy lasting the past two decades have transformed HIV-1 infection from a fatal disease into a chronic medical condition that in many cases does not compromise life quality. There are 25 different antiretroviral agents available currently, allowing for patient-centered, individualized management of HIV-1 infection, and ongoing progress in HIV-1 virology and antiretroviral pharmacology is likely to expand treatment options further in the future. Nevertheless, antiretroviral therapy continues to have limitations, including insufficient immunological reconstitution, selection of drug resistance, ongoing abnormal immune activation despite effective suppression of HIV-1 viremia, and the inability to target latently infected cells that are responsible for long-term viral persistence. Owing to these shortcomings, the theoretical ability of antiretroviral therapy to extend life expectancy to normal levels is not realized in many cases. Strategies to address these limitations are a matter of active ongoing research and will be summarized in this article.
doi:10.1177/2040622311411601
PMCID: PMC3513891  PMID: 23251756
antiretroviral drugs; chronic disease; drug resistance; HIV-1 infection; immune activation; latent infection
21.  Persistent intrathecal immune activation in HIV-1-infected individuals on antiretroviral therapy 
Background
Neopterin is a well-established marker of macrophage activation. The cerebrospinal fluid (CSF) neopterin levels are elevated in most HIV-1-infected individuals, and decrease significantly after initiation of antiretroviral therapy (ART). Unexpectedly, CSF concentrations often remain mildly abnormal even in patients treated for a long time with suppressive ART. The aims of this study were to analyse if persistently elevated CSF neopterin levels were associated with either the type of antiretroviral regimen or with low-level CSF HIV-1 concentrations, and to evaluate if plasma HIV-1 RNA levels correlated to lingering CSF neopterin concentrations in patients with effective ART.
Methods
One hundred and fifty-seven chronically HIV-1-infected patients with stable ART for ≥ 6 months and no neurological symptoms were included, and 193 HIV-1-infected patients without ART served as controls. Neopterin was analysed with either a radio-immunoassay or an enzyme-linked immunosorbent assay. HIV-1 RNA quantification was performed with the Roche Amplicor assay, version 1.5. Two quantitative HIV-1 RNA assays with sensitivities ≤ 2.5 copies/ml were used in 40 samples.
Results
As anticipated, HIV-1 RNA and CSF neopterin levels were markedly lower in patients on ART compared to untreated controls. No significant difference in CSF neopterin concentrations was found between those treated with protease inhibitor- and non-nuceloside reverse transcriptase-based regimens in combination with 2 nucleoside analogues. Subjects with CSF HIV-1 RNA loads < 2.5 copies/ml had the lowest CSF neopterin levels. Plasma viral load had no impact on intrathecal immune activation in cases with CSF viral loads < 50 copies/ml.
Conclusions
The persistent intrathecal cell-mediated immune response was associated with CSF viral load, but not with treatment regimen in individuals on ART.
doi:10.1097/QAI.0b013e31815ace97
PMCID: PMC2628632  PMID: 17971711
HIV-1 RNA; cerebrospinal fluid; neopterin; antiretroviral therapy
22.  Quality of Life Among HIV-Infected Patients in Brazil after Initiation of Treatment 
Clinics (Sao Paulo, Brazil)  2009;64(9):867-875.
INTRODUCTION
Despite improvement in clinical treatment for HIV-infected patients, the impact of antiretroviral therapy on the overall quality of life has become a major concern.
OBJECTIVE
To identify factors associated with increased levels of self-reported quality of life among HIV-infected patients after four months of antiretroviral therapy.
METHODS
Patients were recruited at two public health referral centers for AIDS, Belo Horizonte, Brazil, for a prospective adherence study. Patients were interviewed before initiating treatment (baseline) and after one and four months. Quality of life was assessed using a psychometric instrument, and factors associated with good/very good quality of life four months after the initiation of antiretroviral therapy were assessed using a cross-sectional approach. Logistic regression was used for analysis.
RESULTS
Overall quality of life was classified as ‘very good/good’ by 66.4% of the participants four months after initiating treatment, while 33.6% classified it as ‘neither poor nor good/poor/very poor’. Logistic regression indicated that >8 years of education, none/mild symptoms of anxiety and depression, no antiretroviral switch, lower number of adverse reactions and better quality of life at baseline were independently associated with good/very good quality of life over four months of treatment.
CONCLUSIONS
Our results highlight the importance of modifiable factors such as psychiatric symptoms and treatment-related variables that may contribute to a better quality of life among patients initiating treatment. Considering that poor quality of life is related to non-adherence to antiretroviral therapy, careful clinical monitoring of these factors may contribute to ensuring the long-term effectiveness of antiretroviral regimens.
doi:10.1590/S1807-59322009000900007
PMCID: PMC2745298  PMID: 19759880
Antiretroviral therapy; Anxiety; Depression; Adverse reactions; Antiretroviral therapy switch
23.  METHADONE MAINTENANCE THERAPY PROMOTES INITIATION OF ANTIRETROVIRAL THERAPY AMONG INJECTION DRUG USERS 
Addiction (Abingdon, England)  2010;105(5):907-913.
Aims
Despite proven benefits of antiretroviral therapy (ART), many HIV-infected injection drug users (IDU) do not access treatment even in settings with free health care. We examined whether methadone maintenance therapy (MMT) increased initiation and adherence to ART among an IDU population with free health care.
Design
We prospectively examined a cohort of opioid-using antiretroviral-naïve HIV-infected IDU and investigated factors associated with initiation of antiretroviral therapy as well as subsequent adherence. Factors independently associated with time to first initiation of antiretroviral therapy were modelled using Cox proportional hazards regression.
Findings
Between May 1996 and April 2008, 231 antiretroviral-naïve HIV-infected opioid using IDU were enrolled, among whom 152 (65.8%) initiated ART, for an incidence density of 30.5 (95% confidence interval [CI]: 25.9–35.6) per 100 person-years. After adjustment for time-updated clinical characteristics and other potential confounders, use of MMT was independently associated with more rapid uptake of antiretroviral therapy (relative hazard = 1.62 [95% CI: 1.15–2.28]; p = 0.006). Those prescribed methadone also had higher rates of ART adherence after first antiretroviral initiation (odds ratio = 1.49 [95% CI: 1.07–2.08]; p = 0.019).
Conclusion
These results demonstrate that MMT contributes to more rapid initiation and subsequent adherence to ART among opioid-using HIV-infected IDU. Addressing international barriers to the use and availability of methadone may dramatically increase uptake of HIV treatment among this population.
doi:10.1111/j.1360-0443.2010.02905.x
PMCID: PMC2857602  PMID: 20331553
HIV; AIDS; methadone; ART; Vancouver; Canada
24.  Differential adherence to combination antiretroviral therapy is associated with virological failure with resistance 
AIDS (London, England)  2008;22(1):75-82.
Objectives
To investigate the occurrence of differential adherence to components of combination antiretroviral therapy and assess its predictors and association with virological failure and antiretroviral medication resistance.
Design
A secondary analysis of prospective clinical trial data.
Methods
The Flexible Initial Retrovirus Suppressive Therapies study (Community Programs for Clinical Research on AIDS 058) was a randomized trial comparing non-nucleoside reverse transcriptase inhibitor (NNRTI) versus protease inhibitor (PI) versus NNRTI plus PI-based (three-class) antiretroviral therapy in treatment-naive HIV-1-infected individuals. Adherence was assessed at months 1 and 4, and then every 4 months. Differential adherence, defined as any difference in self-reported level of adherence to individual antiretroviral medications at the same timepoint, was evaluated as a binary time-updated variable in multivariate Cox regression analyses of time to initial virological failure (HIV-RNA >1000 copies/ml) and initial virological failure with genotypic antiretroviral resistance.
Results
Differential adherence was reported at least once by 403 of 1379 participants (29%), over 60 months median follow-up. Differential adherence was more commonly reported by participants randomly assigned to the three-class strategy (35%) than the NNRTI (28%) or PI (25%) strategies (P = 0.005), but was not associated with demographic or baseline disease-specific factors. Of those reporting differential adherence, 146 (36%) reported it before initial virological failure. These participants had an increased risk of initial virological failure and initial virological failure with antiretroviral resistance compared with participants without differential adherence before initial virological failure.
Conclusion
Differential adherence was commonly reported and was associated with an increased risk of initial virological failure and initial virological failure with antiretroviral resistance.
doi:10.1097/QAD.0b013e3282f366ff
PMCID: PMC2405889  PMID: 18090394
adherence; antiretroviral resistance; differential adherence; HIV; virological failure
25.  Short-course raltegravir intensification does not reduce persistent low-level viremia in patients with HIV-1 suppression during receipt of combination antiretroviral therapy 
Background
Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short (28d) course antiretroviral intensification of standard combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma viremia in patients on suppressive antiretroviral therapy.
Methods
Subjects (N=10) with long term HIV-1 suppression on combination antiretroviral regimens were intensified for 4 weeks with raltegravir. Plasma viremia was determined prior to, during, and following the 4-week intensification period using a sensitive HIV-1 RNA assay (limit of detection of 0.2 copies HIV-1 RNA/ml plasma). A four week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (c. 1-14 d) half-lives.
Results
There was no evidence in any subject of decline in HIV-1 RNA levels during the period of raltegravir intensification or rebound after discontinuation. Median levels of HIV-1 RNA prior to (0.17 log10 copies/ml), during (0.04 log10 copies/ml), and following (0.04 log10 copies/ml) raltegravir intensification (p >0.1 for all comparisons in parametric analyses). HPLC/mass spectroscopy studies confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification.
Conclusions
Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects on suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches.
doi:10.1086/650749
PMCID: PMC2897152  PMID: 20156060

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