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1.  Peripheral Neuropathy in ART-Experienced Patients: Prevalence and Risk Factors 
Journal of neurovirology  2013;19(6):557-564.
Peripheral neuropathy (PN) is a common neurological complication of HIV infection that has debilitating effects on quality-of-life. While there has been a comprehensive evaluation of the prevalence of neuropathic signs/symptoms and risk factors (RFs) for PN or symptomatic PN (SPN) with initiation of combination antiretroviral therapy (cART) in ART-naïve patients, similar evaluation in ART-experienced patients is limited. This study investigated the prevalence and RFs for PN/SPN in ART-experienced patients enrolled in clinical salvage therapy studies. Between February 2000 and June 2007, five hundred and twenty-two ART-experienced participants who experienced virologic failure with a prior regimen and started new regimens were followed longitudinally and annually screened for signs and symptoms of PN. Rates of PN/SPN at 3 years since parent study entry were 52.8% and 24.0%, respectively. Aging, taller height, protease inhibitor use, and female sex were significant RFs for PN/SPN. The use of statin drugs was significantly associated with lower odds of SPN, and it may prevent progression from no SPN to SPN.
PMCID: PMC3965352  PMID: 24297499
peripheral neuropathy; symptomatic peripheral neuropathy; risk factors; HIV infection
2.  HIV peripheral neuropathy progression: protection with glucose-lowering drugs? 
Journal of neurovirology  2012;18(5):428-433.
The purpose of this study is to evaluate risk factors for progression from asymptomatic peripheral neuropathy (APN) to symptomatic peripheral neuropathy (SPN). Antiretroviral therapy (ART)-naïve patients initiating combination ART were followed longitudinally and screened for signs/ symptoms of PN. Having APN was associated with higher odds of future SPN (odds ratio (OR)=1.58, 95 % confidence interval (CI)=(1.08, 2.29), p=0.027). Neurotoxic ART use was associated with increased odds of progression to SPN (OR= 2.16, 95 % CI=(1.21, 3.85), p=0.009) while use of glucose-lowering drugs (non-insulin) was protective (OR=0.12, 95 % CI=(0.02, 0.83), p=0.031). Use of glucose-lowering drugs (non-insulin) may prevent progression from APN to SPN.
PMCID: PMC3485691  PMID: 22806348
Peripheral neuropathy; Symptomatic peripheral neuropathy; Risk factors; HIV; Glucose-lowering drugs
3.  Peripheral neuropathy in HIV: prevalence and risk factors 
AIDS (London, England)  2011;25(7):919-928.
To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART.
AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally.
Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations.
Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use.
Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN.
PMCID: PMC3196556  PMID: 21330902
aging; antiretroviral therapy; HIV; neurological; peripheral neuropathy; risk factors
4.  Factors Associated with Remaining on Initial Randomized Efavirenz-containing Regimens in the AIDS Clinical Trials Group 
AIDS (London, England)  2013;27(12):1887-1897.
Efavirenz (EFV) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is a recommended initial antiretroviral (ARV) regimen. Understanding characteristics related to EFV success is clinically useful.
Data from 2,220 ARV-naïve participants randomized to EFV + 2/3 NRTIs in 4 ACTG trials plus a long-term cohort, were analyzed.
Logistic regression, using inverse probability of censoring weighting to address selective-followup bias, was used to identify factors associated with EFV success (no treatment interruptions of >30 days, HIV RNA<200 copies/mL) 1 year (yr) post initiation and at yrs 2-5 if successful at yr 1.
Pre-treatment characteristics were: median age 38 yrs, 82% male, 40% white, 10% history of injection drug use (HxIDU), median CD4+ T-lymphocyte 227 cells/uL and 33% HIV RNA>100,000 copies/mL. In a multivariable model, factors associated with yr 1 EFV success were: race (white OR: 1.5; p<0.001; Hispanic OR: 1.5; p=0.003 vs. black), no pre-treatment sign/symptom ≥grade 3 (OR: 1.7; p=0.008) and no HxIDU (OR: 1.7; p=0.001). Predictors of EFV success at yrs 2-5 were: no HxIDU (yrs 2-5; ORs 1.9-2.2); self-reported complete (4-days prior to study visit) adherence during yr 1 (yrs 2-4; ORs 1.6-1.9); fewer missed visits during yr 1 (yrs 2,4,5; ORs 0.92-0.98/1% increase); HIV RNA <50 copies/mL at yr 1 (yrs 2,3; ORs 1.9-2.2); and older age (>50 v. ≤ 30 yrs) (yrs 2,3,4: ORs 2.3-3.7).
Characteristics predictive of EFV success in the short-and longer-term differed except for HxIDU. Behaviors occurring during yr 1 were associated with EFV success over 5 years.
PMCID: PMC4204654  PMID: 23925417
Efavirenz; human immunodeficiency virus; highly active antiretroviral therapy; cohort study; clinical trials
5.  Hepatitis C Viremia and the Risk of Chronic Kidney Disease in HIV-Infected Individuals 
Lucas, Gregory M. | Jing, Yuezhou | Sulkowski, Mark | Abraham, Alison G. | Estrella, Michelle M. | Atta, Mohamed G. | Fine, Derek M. | Klein, Marina B. | Silverberg, Michael J. | Gill, M. John | Moore, Richard D. | Gebo, Kelly A. | Sterling, Timothy R. | Butt, Adeel A. | Kirk, Gregory D. | Benson, Constance A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Carey, John T. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Horberg, Michael A. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Rico, Puerto | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Patel, Pragna | Brooks, John T. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Althoff, Keri N. | Abraham, Alison G. | Lau, Bryan | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
The Journal of Infectious Diseases  2013;208(8):1240-1249.
Background. The role of active hepatitis C virus (HCV) replication in chronic kidney disease (CKD) risk has not been clarified.
Methods. We compared CKD incidence in a large cohort of HIV-infected subjects who were HCV seronegative, HCV viremic (detectable HCV RNA), or HCV aviremic (HCV seropositive, undetectable HCV RNA). Stages 3 and 5 CKD were defined according to standard criteria. Progressive CKD was defined as a sustained 25% glomerular filtration rate (GFR) decrease from baseline to a GFR < 60 mL/min/1.73 m2. We used Cox models to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Results. A total of 52 602 HCV seronegative, 9508 HCV viremic, and 913 HCV aviremic subjects were included. Compared with HCV seronegative subjects, HCV viremic subjects were at increased risk for stage 3 CKD (adjusted HR 1.36 [95% CI, 1.26, 1.46]), stage 5 CKD (1.95 [1.64, 2.31]), and progressive CKD (1.31 [1.19, 1.44]), while HCV aviremic subjects were also at increased risk for stage 3 CKD (1.19 [0.98, 1.45]), stage 5 CKD (1.69 [1.07, 2.65]), and progressive CKD (1.31 [1.02, 1.68]).
Conclusions. Compared with HIV-infected subjects who were HCV seronegative, both HCV viremic and HCV aviremic individuals were at increased risk for moderate and advanced CKD.
PMCID: PMC3778973  PMID: 23904290
HIV; hepatitis C virus; chronic kidney disease; hepatitis C RNA; cohort study; glomerular filtration rate; injection drug use
6.  Higher Expression of Several Interferon-Stimulated Genes in HIV-1-Infected Females After Adjusting for the Level of Viral Replication 
The Journal of Infectious Diseases  2013;208(5):830-838.
Background. Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1–infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1–induced interferon-alpha (IFN-α) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1–associated immune activation observed.
Methods. T-cell and dendritic cell populations were isolated from treatment-naive chronically HIV-1–infected individuals enrolled in the Adult Clinical Trials Group 384 by fluorescence-activated cell sorting. The expression of 98 genes involved in Toll-like receptor and type I IFN signaling pathways were quantified using Nanostring technology.
Results. Several ISGs were significantly correlated with HIV-1 viral load and/or CD4+ T-cell count. Higher expression levels of a subset of these ISGs were observed in cells derived from females as compared to males after adjusting for viral load and were correlated to higher levels of T-cell activation.
Conclusion. These data show that higher IFN-α production is associated with higher ex vivo expression of several ISGs in females. This might contribute to higher levels of immune activation and the observed faster HIV-1 disease progression in females for a given level of viral replication.
PMCID: PMC3733517  PMID: 23757341
HIV-1; innate immunity; type I Interferon; Toll-like receptors; T cells; sex differences; immune activation; dendritic cells; pathogenesis
7.  The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy 
AIDS (London, England)  2013;27(13):2101-2110.
To assess whether CD8+ T-cell activation predicts risk of AIDS and non-AIDS morbidity during suppressive antiretroviral therapy (ART).
Post-hoc analyses of ART-naïve subjects in prospective ART studies. Subjects with HIV-RNA levels ≤ 200 copies/mL and CD8+ T-cell activation data (%CD38+HLA-DR+) at year-one of ART were selected to determine years 2–5 incidence of AIDS and non-AIDS events.
We censored data at time of ART interruption or virologic failure. Inverse probability of censoring weighted logistic regression was used to correct for informative censoring.
We included 1025 subjects; 82% were men, median age 38 years, pre-ART CD4 count 255 cells/mm3, and year-one activated CD8+ T-cells 24%. Of these, 752 had 5 years of follow-up; 379 remained on ART and had no confirmed plasma HIV-RNA >200 copies/mL. The overall probability of an AIDS or non-AIDS event in years 2–5 was estimated at 13% (95%-confidence interval [CI] 10–15%), had everyone remained on suppressive ART. Higher year-one activated CD8+ T-cell percentage increased the probability of subsequent events (Odds-Ratio 1.22 per 10% higher [95%-CI 1.04–1.44]); this effect was not significant after adjusting for age. Among those age ≥ 50 years (n=108 at year 1), the probability of an event in years 2–5 was 37% and the effect of CD8+ T-cell activation was more apparent (Odds-Ratio=1.42, p=0.02 unadjusted and adjusted for age).
CD8+ T-cell activation is prognostic of clinical events during suppressive ART although this association is confounded by age. The consequences of HIV-associated immune activation may be more important in those age ≥50 years.
PMCID: PMC3933027  PMID: 24326304
Antiretroviral Therapy; HIV/AIDS; CD8+T-cell activation; virologic suppression; loss to follow-up; observational data
8.  CD4 trajectory adjusting for dropout among HIV-positive patients receiving combination antiretroviral therapy in an East African HIV care centre 
Estimates of CD4 response to antiretroviral therapy (ART) obtained by averaging data from patients in care, overestimate population CD4 response and treatment program effectiveness because they do not consider data from patients who are deceased or not in care. We use mathematical methods to assess and adjust for this bias based on patient characteristics.
We examined data from 25,261 HIV-positive patients from the East Africa IeDEA Consortium.
We used inverse probability of censoring weighting (IPCW) to represent patients not in care by patients in care with similar characteristics. We address two questions: What would the median CD4 be “had everyone starting ART remained on observation?” and “were everyone starting ART maintained on treatment?”
Routine CD4 count estimates were higher than adjusted estimates even under the best-case scenario of maintaining all patients on treatment. Two years after starting ART, differences between estimates diverged from 30 cells/µL, assuming similar mortality and treatment access among dropouts as patients in care, to over 100 cells/µL assuming 20% lower survival and 50% lower treatment access among dropouts. When considering only patients in care, the proportion of patients with CD4 above 350 cells/µL was 50% adjusted to below 30% when accounting for patients not in care. One-year mortality diverged 6–14% from the naïve estimates depending on assumptions about access to care among lost patients.
Ignoring mortality and loss to care results in over-estimation of ART response for patients starting treatment and exaggerates the efficacy of treatment programs administering it.
PMCID: PMC4136415  PMID: 25131801
HIV/AIDS; IPCW; Resource-limited setting; CD4 count; Mathematical modeling; sub-Saharan Africa
9.  A Randomized Trial of Interleukin-2 During Withdrawal of Antiretroviral Treatment 
In HIV-infected individuals on antiretroviral treatment with viral suppression, structured treatment interruptions are designed to allow exposure to endogenous HIV antigens and to thereby boost HIV-specific immunity. AIDS Clinical Trials Group A5132 was an exploratory 2-arm randomized trial that evaluated two 4-week treatment interruptions in combination with 2 strategies for administering interleukin-2 (IL-2): 2.0 million international units of IL-2 subcutaneously daily during the final 2 weeks of treatment interruption and the first week of treatment reinitiation (arm A), or 4.5 million international units of IL-2 subcutaneously twice a day during the first 5 days of treatment reinitiation (arm B). Twenty-one subjects with HIV-1 RNA <50 copies/mL and CD4+ T cell counts ≥300 (median 615) cells/mm3 were randomized. The primary endpoint was the viral setpoint measured 11–12 weeks after a third treatment interruption (observed for 7 Arm A and 9 Arm B). The median HIV-1 RNA setpoints were 4.3 and 4.5 log10 copies/mL for Arm A and Arm B, respectively; there was no evidence of a difference between arms (P = 0.50, rank-sum test, worst rank for unobserved viral setpoint). The current study, the first to evaluate IL-2 during repeated short-term treatment interruptions, revealed no evidence for augmentation of HIV immunity. Viral setpoints were similar to historical controls, emphasizing the need for new strategies to enhance HIV-specific immunity.
PMCID: PMC3104401  PMID: 21291323
10.  CD8+ T-cell Activation in HIV-1-Infected Patients Experiencing Transient Low-level Viremia During Antiretroviral Therapy 
Transient low-level viremia of 50–400 HIV RNA copies/mL (TLLV) is common during antiretroviral therapy, but its pathogenesis, consequences and optimal management are unclear. Heightened immune activation is associated with detrimental outcomes, including impaired CD4+ T-cell reconstitution. Using CD38/HLA-DR expression on CD8+ T-cells measured in two large studies, we determined associations between TLLV and immune activation levels before, during, and after TLLV. We found that TLLV does not significantly change CD8+ T-cell activation, and that higher CD8+ T-cell activation during viral suppression <50 copies/mL is associated with a modest increase in the risk of a subsequent TLLV.
PMCID: PMC3632289  PMID: 23392463
low-level; viremia; blip; immune; activation; CD8+
11.  Trends and Disparities in Antiretroviral Therapy Initiation and Virologic Suppression Among Newly Treatment-Eligible HIV-Infected Individuals in North America, 2001–2009 
Hanna, David B. | Buchacz, Kate | Gebo, Kelly A. | Hessol, Nancy A. | Horberg, Michael A. | Jacobson, Lisa P. | Kirk, Gregory D. | Kitahata, Mari M. | Korthuis, P. Todd | Moore, Richard D. | Napravnik, Sonia | Patel, Pragna | Silverberg, Michael J. | Sterling, Timothy R. | Willig, James H. | Lau, Bryan | Althoff, Keri N. | Crane, Heidi M. | Collier, Ann C. | Samji, Hasina | Thorne, Jennifer E. | Gill, M. John | Klein, Marina B. | Martin, Jeffrey N. | Rodriguez, Benigno | Rourke, Sean B. | Gange, Stephen J. | Benson, A. | Bosch, Ronald J. | Collier, Ann C. | Boswell, Stephen | Grasso, Chris | Mayer, Ken | Hogg, Robert S. | Harrigan, Richard | Montaner, Julio | Cescon, Angela | Brooks, John T. | Buchacz, Kate | Gebo, Kelly A. | Moore, Richard D. | Rodriguez, Benigno | Horberg, Michael A. | Silverberg, Michael J. | Thorne, Jennifer E. | Goedert, James J. | Jacobson, Lisa P. | Klein, Marina B. | Rourke, Sean B. | Burchell, Ann | Rachlis, Anita R. | Hunter-Mellado, Robert F. | Mayor, Angel M. | Gill, M. John | Deeks, Steven G. | Martin, Jeffrey N. | Saag, Michael S. | Mugavero, Michael J. | Willig, James | Eron, Joseph J. | Napravnik, Sonia | Kitahata, Mari M. | Crane, Heidi M. | Justice, Amy C. | Dubrow, Robert | Fiellin, David | Sterling, Timothy R. | Haas, David | Bebawy, Sally | Turner, Megan | Gange, Stephen J. | Anastos, Kathryn | Moore, Richard D. | Saag, Michael S. | Gange, Stephen J. | Kitahata, Mari M. | McKaig, Rosemary G. | Justice, Amy C. | Freeman, Aimee M. | Moore, Richard D. | Freeman, Aimee M. | Lent, Carol | Platt, Aaron | Kitahata, Mari M. | Van Rompaey, Stephen E. | Crane, Heidi M. | Webster, Eric | Morton, Liz | Simon, Brenda | Gange, Stephen J. | Abraham, Alison G. | Lau, Bryan | Althoff, Keri N. | Zhang, Jinbing | Jing, Jerry | Golub, Elizabeth | Modur, Shari | Hanna, David B. | Rebeiro, Peter | Wong, Cherise | Mendes, Adell
In the last decade, timely initiation of antiretroviral therapy and resulting virologic suppression have greatly improved in North America concurrent with the development of better tolerated and more potent regimens, but significant barriers to treatment uptake remain.
Background. Since the mid-1990s, effective antiretroviral therapy (ART) regimens have improved in potency, tolerability, ease of use, and class diversity. We sought to examine trends in treatment initiation and resulting human immunodeficiency virus (HIV) virologic suppression in North America between 2001 and 2009, and demographic and geographic disparities in these outcomes.
Methods. We analyzed data on HIV-infected individuals newly clinically eligible for ART (ie, first reported CD4+ count <350 cells/µL or AIDS-defining illness, based on treatment guidelines during the study period) from 17 North American AIDS Cohort Collaboration on Research and Design cohorts. Outcomes included timely ART initiation (within 6 months of eligibility) and virologic suppression (≤500 copies/mL, within 1 year). We examined time trends and considered differences by geographic location, age, sex, transmission risk, race/ethnicity, CD4+ count, and viral load, and documented psychosocial barriers to ART initiation, including non–injection drug abuse, alcohol abuse, and mental illness.
Results. Among 10 692 HIV-infected individuals, the cumulative incidence of 6-month ART initiation increased from 51% in 2001 to 72% in 2009 (Ptrend < .001). The cumulative incidence of 1-year virologic suppression increased from 55% to 81%, and among ART initiators, from 84% to 93% (both Ptrend < .001). A greater number of psychosocial barriers were associated with decreased ART initiation, but not virologic suppression once ART was initiated. We found significant heterogeneity by state or province of residence (P < .001).
Conclusions. In the last decade, timely ART initiation and virologic suppression have greatly improved in North America concurrent with the development of better-tolerated and more potent regimens, but significant barriers to treatment uptake remain, both at the individual level and systemwide.
PMCID: PMC3657490  PMID: 23315317
antiretroviral therapy; healthcare disparities; HIV; time factors; viral load
12.  HIV-1 RNA Levels and Antiretroviral Drug Resistance in Blood and Non-Blood Compartments from HIV-1–Infected Men and Women enrolled in AIDS Clinical Trials Group Study A5077 
PLoS ONE  2014;9(4):e93537.
Detectable HIV-1 in body compartments can lead to transmission and antiretroviral resistance. Although sex differences in viral shedding have been demonstrated, mechanisms and magnitude are unclear. We compared RNA levels in blood, genital-secretions and saliva; and drug resistance in plasma and genital-secretions of men and women starting/changing antiretroviral therapy (ART) in the AIDS Clinical Trials Group (ACTG) 5077 study.
Blood, saliva and genital-secretions (compartment fluids) were collected from HIV-infected adults (≥13 years) at 14 United-States sites, who were initiating or changing ART with plasma viral load (VL) ≥2,000 copies/mL. VL testing was performed on all compartment fluids and HIV resistance genotyping on plasma and genital-secretions. Spearman rank correlations were used to evaluate concordance and Fisher’s and McNemar’s exact tests to compare VL between sexes and among compartments.
Samples were available for 143 subjects; 36% treated (23 men, 29 women) and 64% ‘untreated’ (40 men, 51 women). RNA detection was significantly more frequent in plasma (100%) than genital-secretions (57%) and saliva (64%) (P<0.001). A higher proportion of men had genital shedding versus women (78% versus 41%), and RNA detection was more frequent in saliva versus genital-secretions in women when adjusted for censoring at the limit of assay detection. Inter-compartment fluid VL concordance was low in both sexes. In 22 (13 men, 9 women) paired plasma-genital-secretion genotypes from treated subjects, most had detectable resistance in both plasma (77%) and genital-secretions (68%). Resistance discordance was observed between compartments in 14% of subjects.
HIV shedding and drug resistance detection prior to initiation/change of ART in ACTG 5077 subjects differed among tissues and between sexes, making the gold standard blood-plasma compartment assessment not fully representative of HIV at other tissue sites. Mechanisms of potential sex-dependent tissue compartmentalization should be further characterized to aid in optimizing treatment and prevention of HIV transmission.
Trial Registration NCT00007488
PMCID: PMC3974754  PMID: 24699474
13.  Study Design Issues in Evaluating Immune Biomarkers 
Current opinion in HIV and AIDS  2013;8(2):147-154.
Purpose of review
The dramatic increase in the number and type of immune biomarkers that can be measured, particularly those assessing immune activation, has led to numerous investigations in HIV-infected individuals to explore pathogenesis and to assess therapeutic interventions that aim to attenuate immune activation. An overview is provided on study designs and related statistical and operational issues relevant to these investigations.
Recent findings
Cohort studies and nested case-control studies within these cohorts have identified multiple biomarkers that are associated with increased risk of disease. Early-stage clinical trials of therapies to address these risks in HIV-infected individuals with viral suppression on antiretroviral therapy are a substantial focus of current HIV research.
Appropriate study design is essential in biomarker research.
PMCID: PMC3777851  PMID: 23380656
Observational research; clinical trials; biomarker; measurement error; surrogate marker
14.  Residual Plasma Viremia and Infectious HIV-1 Recovery from Resting Memory CD4 Cells in Patients on Antiretroviral Therapy: Results from ACTG A5173 
Antiviral therapy  2013;18(4):10.3851/IMP2543.
In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viremia and ex vivo recovery of infectious virus from latently-infected CD4 cells is uncertain.
We measured residual viremia (HIV-1 RNA copies/mL) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T cells.
Ten patients who initiated ART and maintained a plasma HIV-1 RNA level <200 copies/mL had residual viremia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24–96; the remainder had IUPM measured 1–3 times over 24–72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viremia and IUPM (0.56 higher log10 HIV-1 RNA copies/mL per 1 log10 higher IUPM, p=0.005). Residual viremia level was positively associated with CD38 density and percentage on CD8+ T-cells in concurrent samples and with pre-ART HIV-1 RNA levels.
In patients with HIV-1 RNA levels <200 copies/mL 24–96 weeks after initiating ART, the level of viremia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viremia measured by SCA reflects the size of the latent reservoir in patients who have had virologic suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.
PMCID: PMC3887470  PMID: 23411421
HIV-1; reservoir; residual viremia; single-copy assay
15.  Innovations in nutrition education and global health: the Bangalore Boston nutrition collaborative 
India has a wide range of nutrition and health problems which require professionals with appropriate skills, knowledge and trans-disciplinary collaborative abilities to influence policy making at the national and global level.
The Bangalore Boston Nutrition Collaborative (BBNC) was established as collaboration between St. John’s Research Institute (SJRI), Harvard School of Public Health and Tufts University, with a focus on nutrition research and training. The goals of the BBNC were to conduct an interdisciplinary course, develop web-based courses and identify promising Indian students and junior faculty for graduate training in Boston.
From 2010, an annual two-week short course in nutrition research methods was conducted on the SJRI campus taught by international faculty from Indian and US universities. More than 100 students applied yearly for approximately 30 positions. The course had didactic lectures in the morning and practical hands-on sessions in the afternoon. Student rating of the course was excellent and consistent across the years. The ratings on the design and conduct of the course significantly improved (p <0.001) from 2010 to 2012. Through open-ended questions, students reported the main strengths of the course to be the excellent faculty and practical “hands-on” sessions. A web based learning system TYRO, was developed, which can be used for distance learning. Four faculty members/graduate students from SJRI have visited Boston for collaborative research efforts.
The BBNC has become a well-established capacity building and research training program for young professionals in nutrition and global health. Efforts are ongoing to secure long term funding to sustain and expand this collaboration to deliver high quality nutrition and global health education enabled by information and communication technologies.
PMCID: PMC3897915  PMID: 24400811
Nutrition; Global Health; Education; Training; Research
16.  Predictors of Residual Viremia in Patients on Long-term Suppressive Antiretroviral Therapy 
Antiviral therapy  2012;18(1):39-43.
HIV-1-infected individuals with plasma RNA <50 copies/mL on antiretroviral therapy (ART) may have residual, low-level viremia detectable by PCR assays which can detect a single copy of viral RNA (single-copy assay, SCA). The clinical predictors of residual viremia in patients on long-term suppressive ART are incompletely understood.
We evaluated factors associated with residual viremia in patients on suppressive ART who underwent screening for a raltegravir intensification trial (ACTG A5244). The screened population was HIV-1-infected adults receiving ART for ≥12 months with pre-ART HIV-1 RNA >100,000 copies/mL and on-therapy RNA levels below detection limits of commercial assays for ≥6 months.
Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. Sixty-two percent had detectable viremia (>0.2 copies/mL) by SCA (median 0.2 copies/mL; quartile [Q] 1, Q3 [<0.2, 1.8]). Younger patients had lower HIV-1 RNA levels than older individuals (r=0.27, p=0.005). Patients with virologic suppression on ART for 2 years or less had higher residual viremia than those with suppression for more than 2 years (median 2.3 vs. 0.2 copies/mL, p=0.016).
Among HIV-1-infected patients with pre-ART HIV-1 RNA >100,000 copies/mL, residual viremia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viremia was associated with older age and less than 2 years of virologic suppression on ART. These findings should help in selection of candidates for clinical trials of interventions designed to eliminate residual viremia.
PMCID: PMC3578982  PMID: 22914318
HIV-1; Single-copy assay; residual viremia
17.  Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada 
PLoS ONE  2013;8(12):e81355.
Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000–2007 in the U.S. and Canada.
Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables.
The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000–2002 to 2006–2007. Men and women had comparable life expectancies in all periods except the last (2006–2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm3.
A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.
PMCID: PMC3867319  PMID: 24367482
18.  Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells 
AIDS (London, England)  2008;22(10):10.1097/QAD.0b013e3282fd6df4.
Valproic acid and intensified antiretroviral therapy may deplete resting CD4+ T-cell HIV infection. We tested the ability of valproic acid to deplete resting CD4+ T-cell infection in patients receiving standard antiretroviral therapy.
Resting CD4+ T-cell infection was measured in 11 stably aviremic volunteers twice prior to, and twice after Depakote ER 1000 mg was added to standard antiretroviral therapy. Resting CD4+ T-cell infection frequency was measured by outgrowth assay. Low-level viremia was quantitated by single copy plasma HIV RNA assay.
A decrease in resting CD4+ T-cell infection was observed in only four of the 11 patients. Levels of immune activation and HIV-specific T-cell response were low and stable. Valproic acid levels ranged from 26 to 96 μg/ml when measured near trough. Single copy assay was performed in nine patients. In three patients with depletion of resting CD4+ T-cell infection following valproic acid, single copy assay ranged from less than 1–5 copies/ml. Continuous low-level viremia was observed in three patients with stable resting CD4+ T-cell infection (24–87, 8–87, and 1–7 copies/ml respectively) in whom multiple samples were analyzed.
The prospective addition of valproic acid to stable antiretroviral therapy reduced the frequency of resting CD4+ T-cell infection in a minority of volunteers. In patients in whom resting CD4+ T-cell infection depletion was observed, viremia was rarely detectable by single copy assay.
PMCID: PMC3863687  PMID: 18525258
antiretroviral therapy; HIV; latency; resting CD4+ T cells; valproic acid
19.  HIV-1 Amino Acid Changes Among Participants With Virologic Failure: Associations With First-line Efavirenz or Atazanavir Plus Ritonavir and Disease Status 
The Journal of Infectious Diseases  2012;206(12):1920-1930.
Background. Although specific human immunodeficiency virus type 1 (HIV-1) drug resistance mutations are well studied, little is known about cumulative amino acid changes, or how regimen and participant characteristics influence these changes.
Methods. In the AIDS Clinical Trials Group randomized study A5202 of treatment-naive HIV-infected participants, cumulative HIV-1 amino acid changes from pretreatment to virologic failure were evaluated in protease and reverse transcriptase (RT) gene sequences.
Results. Among 265 participants with virologic failure, those assigned atazanavir plus ritonavir (ATV/r) did not have significantly more protease changes compared with those assigned efavirenz (EFV) (P ≥ .13). In contrast, participants with virologic failure assigned EFV had more RT changes, including and excluding known resistance codons (P < .001). At pretreatment, lower CD4 cell count, major resistance, more amino acid mixtures (all P < .001), hepatitis C antibody negativity (P = .05), and black race/ethnicity (P = .02) were associated with more HIV-1 amino acid changes.
Conclusions. Virologic failure following EFV-containing treatment was associated with more HIV-1 amino acid changes compared to failure of ATV/r-containing treatment. Furthermore, we show that non–drug resistance mutations occurred more frequently among those failing EFV, the clinical relevance of which warrants further investigation. Pretreatment immunologic status may play a role in viral evolution during treatment, as evidenced by increased amino acid changes among those with lower pretreatment CD4 count.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3502379  PMID: 23148287
21.  Vitamin D status and TB treatment outcomes in adult patients in Tanzania: a cohort study 
BMJ Open  2013;3(11):e003703.
Vitamin D is an immunomodulator and can alter response to tuberculosis (TB) treatment, though randomised trials have been inconclusive to date. We present one of the first comprehensive analysis of the associations between vitamin D status and TB treatment, T-cell counts and nutritional outcomes by HIV status.
Cohort study.
Outpatient clinics in Tanzania.
25-hydroxyvitamin D levels were assessed in a cohort of 677 patients with TB (344 HIV infected) initiating anti-TB treatment at enrolment in a multivitamin supplementation (excluding vitamin D) trial ( identifier: NCT00197704).
Primary and secondary outcome measures
Information on treatment outcomes such as failure and relapse, HIV disease progression, T-cell counts and anthropometry was collected routinely, with a median follow-up of 52 and 30 months for HIV-uninfected and HIV-infected patients, respectively. Cox and binomial regression, and generalised estimating equations were used to assess the association of vitamin D status with these outcomes.
Mean 25-hydroxyvitamin D concentrations at enrolment were 69.8 (±21.5) nmol/L (27.9 (±8.6) ng/mL). Vitamin D insufficiency (<75 nmol/L) was associated with a 66% higher risk of relapse (95% CI 4% to 164%; 133% higher risk in HIV-uninfected patients). Each unit higher 25-hydroxyvitamin D levels at baseline were associated with a decrease of 3 (p=0.004) CD8 and 3 (p=0.01) CD3 T-cells/µL during follow-up in patients with HIV infection. Vitamin D insufficiency was also associated with a greater decrease of body mass index (BMI; –0.21 kg/m2; 95% CI −0.39 to −0.02), during the first 8 months of follow-up. No association was observed for vitamin D status with mortality or HIV disease progression.
Adequate vitamin D status is associated with a lower risk of relapse and with improved nutritional indicators such as BMI in patients with TB, with or without HIV infection. Further research is needed to determine the optimal dose of vitamin D and effectiveness of daily vitamin D supplementation among patients with TB.
PMCID: PMC3840339  PMID: 24247327
HIV; Africa; Vitamin D
22.  Immune Activation While on Potent Antiretroviral Therapy Can Predict Subsequent CD4+ T-Cell Increases Through 15 Years of Treatment 
HIV clinical trials  2013;14(2):61-67.
While persistent T-cell activation has been cross-sectionally associated with poor CD4+ T-cell restoration in HIV-infected individuals maintaining antiretroviral treatment (ART)–mediated viral suppression, it remains unclear whether CD8+ T-cell activation is of predictive effect on CD4+ T-cell recovery.
We assessed whether the extent of persistent CD8+ T-cell activation (% CD38+/HLA-DR+) in the fi rst few years of ART-mediated viral suppression predicted subsequent CD4+ T-cell recovery in 95 subjects with up to 15 years of observation on suppressive ART.
Lower CD8+ T-cell activation and higher naïve CD4+ T-cell frequencies (CD45RA+/CD62L+) measured at year 3 to 5 after starting ART independently predicted greater subsequent CD4+ T-cell increases. The mean CD4 count increase from year 0 to year 5 and the increase to the average of year 10 to 15 in the low CD8 activation group (≤18.5%; mean = 13%) were 342 and 458 cells/mm,3 and the increases were 248 and 349 cells/mm3 for the high CD8 activation group (>18.5%; mean = 29%) (P = .002 and P = .016, respectively, comparing groups). At years 10 to 15, the mean CD4 counts in the groups were 579 and 484 cells/mm3, respectively (P = .026).
These fi ndings support the need to identify approaches to reduce immune activation in treated HIV disease.
PMCID: PMC3788605  PMID: 23611826
antiretroviral therapy; CD4+ T-cell counts; HIV; immune activation
23.  Predictors and consequences of anaemia among antiretroviral-naïve HIV-infected and HIV-uninfected children in Tanzania 
Public health nutrition  2009;13(2):289-296.
Predictors and consequences of childhood anaemia in settings with high HIV prevalence are not well known. The aims of the present study were to identify maternal and child predictors of anaemia among children born to HIV-infected women and to study the association between childhood anaemia and mortality.
Prospective cohort study. Maternal characteristics during pregnancy and Hb measurements at 3-month intervals from birth were available for children. Information was also collected on malaria and HIV infection in the children, who were followed up for survival status until 24 months after birth.
Dar es Salaam, Tanzania.
The study sample consisted of 829 children born to HIV-positive women.
Advanced maternal clinical HIV disease (relative risk (RR) for stage ≥2 v. stage 1: 1.31, 95% CI 1.14, 1.51) and low CD4 cell counts during pregnancy (RR for <350 cells/mm3 v. ≥350 cells/mm3: 1.58, 95% CI 1.05, 2.37) were associated with increased risk of anaemia among children. Birth weight <2500 g, preterm birth (<34 weeks), malaria parasitaemia and HIV infection in the children also increased the risk of anaemia. Fe-deficiency anaemia in children was an independent predictor of mortality in the first two years of life (hazard ratio 1.99, 95 % CI 1.06, 3.72).
Comprehensive care including highly active antiretroviral therapy to eligible HIV-infected women during pregnancy could reduce the burden of anaemia in children. Programmes for the prevention of mother-to-child transmission of HIV and antimalarial treatment to children could improve child survival in settings with high HIV prevalence.
PMCID: PMC3775572  PMID: 19650963
HIV; Malaria; Anaemia; Child mortality; Sub-Saharan Africa
24.  Multivitamin supplementation improves haematologic status in children born to HIV-positive women in Tanzania 
Anaemia is prevalent among children born to HIV-positive women, and it is associated with adverse effects on cognitive and motor development, growth, and increased risks of morbidity and mortality.
To examine the effect of daily multivitamin supplementation on haematologic status and mother-to-child transmission (MTCT) of HIV through breastfeeding.
A total of 2387 infants born to HIV-positive women from Dar es Salaam, Tanzania were enrolled in a randomized, double-blind, placebo-controlled trial, and provided a daily oral supplement of multivitamins (vitamin B complex, C and E) or placebo at age 6 weeks for 24 months. Among them, 2008 infants provided blood samples and had haemoglobin concentrations measured at baseline and during a follow-up period. Anaemia was defined as haemoglobin concentrations<11 g/dL and severe anaemia<8.5 g/dL.
Haemoglobin concentrations among children in the treatment group were significantly higher than those in the placebo group at 12 (9.77 vs. 9.64 g/dL, p=0.03), 18 (9.76 vs. 9.57 g/dL, p=0.004), and 24 months (9.93 vs. 9.75 g/dL, p=0.02) of follow-up. Compared to those in the placebo group, children in the treatment group had a 12% lower risk of anaemia (hazard ratio (HR): 0.88; 95% CI: 0.79–0.99; p=0.03). The treatment was associated with a 28% reduced risk of severe anaemia among children born to women without anaemia (HR: 0.72; 95% CI: 0.56–0.92; p=0.008), but not among those born to women with anaemia (HR: 1.10; 95% CI: 0.79–1.54; p=0.57; p for interaction=0.007). One thousand seven hundred fifty three infants who tested HIV-negative at baseline and had HIV testing during follow-up were included in the analysis for MTCT of HIV. No association was found between multivitamin supplements and MTCT of HIV.
Multivitamin supplements improve haematologic status among children born to HIV-positive women. Further trials focusing on anaemia among HIV-exposed children are warranted in the context of antiretroviral therapy.
PMCID: PMC3744818  PMID: 23948440
multivitamins; haemoglobin; anaemia; mother-to-child transmission; randomized controlled trial; Tanzania
25.  HIV Infection and the Incidence of Malaria Among HIV-Exposed Children from Tanzania 
The Journal of Infectious Diseases  2012;205(10):1486-1494.
To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children.
Newborn infants of HIV-infected mothers were enrolled at 6 weeks and followed for 2 years. HIV status was assessed by enzyme-linked immunosorbant assay and confirmed by HIV DNA polymerase chain reaction. Malaria was defined as (1) physician-diagnosed clinical malaria; (2) probable malaria, in which laboratory testing is requested for parasitemia; and (3) blood smear–confirmed malaria. Cox proportional hazards models estimated hazard ratios (HRs) for development of first and second malaria episodes, and generalized estimating equation models estimated malaria rate differences per 100-child-years in relation to time-updated HIV status.
Child HIV infection was associated with clinical (HR, 1.34; 95% confidence interval [CI], 1.12–1.61), probable (HR, 1.47; 95% CI, 1.19–1.81), and confirmed (HR, 1.67; 95% CI, 1.18–2.36) malaria episodes. Per 100 child-years, HIV-infected children experienced 88 (95% CI, 65–113), 36 (95% CI, 19–53), and 20 (95% CI, 9–31) more episodes of clinical, probable, and confirmed malaria episodes, respectively, than HIV-uninfected children. Among children with ≥1 malaria episodes, those with HIV infection developed second clinical (HR, 1.28; 95% CI, 1.04–1.57), probable (HR, 1.60; 95% CI, 1.26–2.14), and confirmed (HR, 2.27; 95% CI, 1.06–3.89) malaria sooner than HIV-uninfected children.
HIV infection is a risk factor for the development of malaria. Proactive malaria disease prevention and treatment is warranted for all children, particularly those with HIV infection in settings of coendemicity.
PMCID: PMC3415816  PMID: 22457274

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