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To characterize the prevalence of anemia and risk factors between 2007 and 2017 for moderate/severe anemia among people with HIV (PWH) in North America who have initiated antiretroviral therapy (ART).Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).We estimated the annual prevalence between 1 January 2007 and 31 December 2017 of mild (11.0-12.9 g/dl men, 11.0-11.9 g/dl women), moderate (8.0-10.9 g/dl regardless of sex) and severe (8.0 g/dl regardless of sex) anemia. Poisson regression models with robust variance and general estimating equations estimated crude and adjusted prevalence ratios (aPR) with 95% confidence intervals ([-]) comparing risk factors for moderate/severe vs. no/mild anemia between 2007 and 2017.Among 73 898 PWH we observed 366 755 hemoglobin measurements following ART initiation, 37 301 (50%) had one or more measures of anemia during follow-up (mild = 17 743 [24%]; moderate = 13 383[18%]; severe = 6175 [8%]). Moderate/severe anemia was more prevalent among women, non-Hispanic Black and Hispanic PWH (vs. non-Hispanic white), those with underweight body mass index (18.5 kg/m2) and with comorbidities and coinfections. Older age had increased prevalence of moderate/severe anemia among males and decreased prevalence among females. Prevalence of moderate/severe anemia was greater among those with lower CD4+ cell count (≤200 cells/μl) [aPR = 2.11 (2.06-2.17)] unsuppressed HIV viral load (200 copies/ml) [aPR = 1.26 (1.23-1.29)] and within the first 6 months of ART initiation (vs.1 year of ART) [aPR = 1.66 (1.61-1.72)].The prevalence of anemia among PWH is reduced after ART initiation but remains high. Risk factors differ by sex and include comorbidities and HIV disease severity. The persistent, substantial prevalence of anemia among PWH merits further investigation, targeted screening, and clinical interventions.

Background Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. Objective To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. Design Observational cohort study. Setting Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. Participants 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. Measurements Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. Results Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. Limitation Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. Conclusion Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. Primary funding source National Institutes of Health.

Objective(s)The short-term safety of treatment interruptions, a necessary part of cure studies, is not well established, particularly in women. We explored viral rebound kinetics and safety in a group of postpartum women discontinuing ART and compared results to men in historical interruption trials.DesignProspective evaluation of time to virologic rebound.MethodsOne thousand and seventy-six asymptomatic, virally suppressed, postpartum women living with HIV enrolled in the PROMISE trial with baseline CD4 cell counts at least 350 cells/μl underwent antiretroviral treatment (ART) discontinuation. Proportion with virologic suppression at weeks 4 and 12 were compared with participants in ACTG treatment interruption trials (91% male population).ResultsIn PROMISE, using interval censored methods, the estimated median time to HIV viral rebound was 2 weeks. An estimated 6% of women would remain virally suppressed at 30 weeks. Of those who had viral rebound by 30 weeks (N = 993), less than 4% experienced grade 3 or higher laboratory events, and 1% experienced WHO stage 2 or higher clinical events. Overall, less than 1% of participants progressed from WHO Stage 1 to Stage 2 or higher after discontinuation of ART, and 3.9% experienced a decline in CD4 cell count to less than 350 cells/μl or local treatment guidelines. A significantly higher proportion of women in PROMISE (25.4%) were virologically suppressed (

Background The updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)–specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality. Methods Because complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count Results Among 37230 PWH in VACS and 8061 PWH in the NA-ACCORD subset, median age was 53 and 44 years; 3% and 19% were women; and 48% and 39% were black. Discrimination in NA-ACCORD (C-statistic = 0.842 [95% confidence interval {CI}, .830–.854]) was better than in VACS (C-statistic = 0.813 [95% CI, .809–.817]). Predicted and observed mortality largely overlapped in VACS and the NA-ACCORD subset, overall and within subgroups. Conclusions Based on this validation, VACS Index 2.0 can reliably estimate probability of all-cause mortality, at various follow-up times, among PWH in North America.

Background Statins exert pleiotropic anti-inflammatory and immune-modulatory effects, which might translate into antiviral activity. We evaluated whether reported current statin exposure is associated with lower levels of markers of HIV persistence and immune activation/inflammation. Methods We compared levels of markers of HIV viral persistence [cell-associated HIV RNA (CA-RNA), CA-DNA, and single copy assay plasma HIV RNA] and immune activation/inflammation (IL-6, IP-10, neopterin, sCD14, sCD163, and TNF-alpha) between statin users and nonusers among participants of ACTG A5321 who initiated antiretroviral therapy (ART) during chronic infection and maintained virologic suppression (HIV-1 RNA levels ≤50 copies/mL) for ≥3 years. Results A total of 303 participants were analyzed. Median time on the current statin was 2.9 years (1.2-5.1). There were no differences between statin users and nonusers in levels of CA-DNA (median 650 vs. 540 copies/10 CD4 T cells; P = 0.58), CA-RNA (53 vs. 37 copies/10 CD4 T cells; P = 0.12), or single copy assay (0.4 vs. 0.4 copies/mL; P = 0.45). Similarly, there were no significant differences between statin users and nonusers in markers of inflammation/activation, except for IP-10 (137 vs. 118 pg/mL; P = 0.028). Findings were unchanged after adjustment for factors including pre-ART CD4 and HIV RNA, and years on ART. Conclusions In this cohort of persons on long-term suppressive ART, current statin use was not associated with lower levels of HIV persistence or immune activation/inflammation. These results do not support a major role for statins in reducing HIV persistence, although an early transient effect cannot be excluded. Prospective, randomized studies are needed to confirm these findings.

While increased CD8 counts and low CD4/CD8 ratio during treated HIV correlate with immunosenescence, their additional predictive values to identify individuals with HIV at higher risk of clinical events remain controversial.We selected treatment-naive individuals initiating ART from ACTG studies 384, 388, A5095, A5142, A5202, and A5257 who had achieved viral suppression at year 2. We examined the effect of CD8+ T cell counts and CD4/CD8 at year 2 on the probability of AIDS and serious non-AIDS events in years 3-7. We used inverse probability weighting methods to address informative censoring, combined with multivariable logistic regression models.We analyzed 5133 participants with a median age of 38 years; 959 (19%) were female, pre-ART median CD4 counts were 249 (Q1-Q3 91-372) cell/µL. Compared to participants with CD8 counts between 500/µL and 1499/µL, those with1500/µL had a higher risk of clinical events during years 3-7 (aOR 1.75; 95%CI 1.33-2.32). CD4/CD8 ratio was not predictive of greater risk of events through year 7. Additional analyses revealed consistent CD8 count effect sizes for the risk of AIDS events and noninfectious non-AIDS events, but opposite effects for the risk of severe infections, which were more frequent among individuals with CD8 counts500/µL (aOR 1.70; 95%CI 1.09-2.65).The results of this analysis with pooled data from clinical trials support the value of the CD8 count as a predictor of clinical progression. People with very high CD8 counts during suppressive ART might benefit from closer monitoring and may be a target population for novel interventions.This research was supported by NIH/NIAID awards UM1 AI068634, UM1 AI068636, and UM1 AI106701 and Carlos III Health Institute and FEDER funds (BA21/00017 and BA21/00022).

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

Background HIV-1 proviruses persist in people on antiretroviral therapy (ART) but most are defective and do not constitute a replication-competent reservoir. The decay of infected cells carrying intact compared with defective HIV-1 proviruses has not been well defined in people on ART. Methods We separately quantified intact and defective proviruses, residual plasma viremia, and markers of inflammation and activation in people on long-term ART. Results Among 40 participants tested longitudinally from a median of 7.1 years to 12 years after ART initiation, intact provirus levels declined significantly over time (median half-life, 7.1 years; 95% confidence interval [CI], 3.9–18), whereas defective provirus levels did not decrease. The median half-life of total HIV-1 DNA was 41.6 years (95% CI, 13.6–75). The proportion of all proviruses that were intact diminished over time on ART, from about 10% at the first on-ART time point to about 5% at the last. Intact provirus levels on ART correlated with total HIV-1 DNA and residual plasma viremia, but there was no evidence for associations between intact provirus levels and inflammation or immune activation. Conclusions Cells containing intact, replication-competent proviruses are selectively lost during suppressive ART. Defining the mechanisms involved should inform strategies to accelerate HIV-1 reservoir depletion.

Background Although adipose tissue has been proposed to harbor part of the human immunodeficiency virus 1 (HIV-1) reservoir, the influence of host characteristics, including sex and body mass index (BMI), on measures of HIV-1 persistence during antiretroviral therapy (ART) are incompletely understood. Methods We evaluated age, sex, BMI, waist circumference, years on ART, pre-ART HIV-1 RNA, pre-ART CD4+ T-cell count, and initial ART regimen with measures of HIV-1 persistence in blood (residual viremia, cellular HIV-1 DNA and RNA) in a cohort of 295 individuals with well-documented long-term virologic suppression (HIV-1 RNA Results Men were more likely than women to have detectable plasma HIV-1 RNA by single-copy assay (52% vs 29%; P = .003), and the proportion of participants with detectable residual viremia increased in a stepwise fashion by BMI category (normal weight or underweight, 38%; overweight, 50%; and obese, 55%). ART regimen type was not associated with measures of HIV-1 persistence after controlling for ART duration. Conclusions Sex and obesity are independently associated with residual viremia in people on long-term ART. Additional studies to confirm these relationships and to define the mechanisms by which sex and obesity affect HIV-1 persistence are needed to inform HIV-1 cure strategies.

OBJECTIVE. We evaluated frequencies of T cells with high PD-1 expression (PD-1(HI)) before and after long-term effective antiretroviral therapy (ART), and determined if frequencies on-ART correlated positively with measures of HIV persistence and negatively with HIV-specific responses. METHODS. We enrolled individuals who started ART during chronic infection and had durable suppression of viremia for ≥4 years (N=99). We assessed PD-1(HI) T cell frequencies at timepoints pre- and on-ART using flow cytometry, and evaluated how frequencies on-ART are associated with measures of HIV persistence, HIV-specific immune responses, and immune activation levels. RESULTS. Pre-ART, PD-1(HI) CD4(+) T cells correlated positively with viremia and negatively with CD4(+) T cell count. At year 1 on-ART, %PD-1(HI) CD4(+) T cells decreased but then remained stable at 4 and 6-15 years on-ART, while %PD-1(HI) CD8(+) T cells on-ART remained similar to pre-ART. PD-1(HI) CD4(+) T cells correlated positively with HIV DNA pre- and on-ART, and with CD4(+) T cell activation on-ART. PD-1(HI) CD4(+) T cells negatively correlated with HIV Gag- and Env-specific T cell responses but not with CMV- or EBV-specific responses. PD-1(HI) CD8(+) T cells trended towards a negative correlation with responses to Gag and Env, but not to CMV and EBV. CONCLUSIONS. PD-1(HI) T cells persist in blood despite prolonged suppression on ART, correlate with HIV DNA levels, and are associated with lower HIV-specific T cell responses but not CMV- or EBV-specific responses, suggesting that these cells are HIV-specific. The findings support evaluating PD-1 blockade strategies for their effect on HIV persistence and HIV-specific immunity.

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.

Objectives To examine the effects of oral maternal vitamin B12 supplementation during pregnancy and early lactation on cognitive development in children. Method We studied 218 children born to mothers enrolled in a placebo-controlled, randomized trial of vitamin B12 supplementation during pregnancy through 6 weeks post-partum. Cognitive functions were assessed at 30 months using the Bayley Scales of Infant Development- 3rd edition (BSID III). The association of maternal sociodemographic characteristics, maternal biochemical status during pregnancy, birth weight and home environment with each sub-domain of BSID-III was examined using linear regression analysis. Separate multiple linear regression analyses for each of the BSID-III sub-domains with maternal trimester specific nutritional biomarker status was conducted. Results Children of mothers who received oral vitamin B12 supplementation had significantly higher scores on expressive language compared to children of mothers who received placebo (β = 0.14, P = 0.03). Children of mothers with elevated serum total homocysteine (tHcy) in the second and third trimesters of pregnancy had significantly lower scores on expressive language (β = - 0.18, P = 0.03 and β = - 0.19, P = 0.02, respectively) and gross motor domains (β = - 0.23, P = 0.008 and β = - 0.30, P = 0.001, respectively) of BSID-III adjusted for treatment arm and multiple confounders, compared with children whose mothers did not have elevated tHcy. Conclusions for practice Maternal B12 supplementation during pregnancy was associated with higher expressive language scores in children at 30 months. Elevated maternal tHcy levels during pregnancy had negative associations with expressive language and gross motor domains of BSID-III. Larger trials of maternal B12 supplementation are needed to confirm these findings.

BACKGROUND Understanding the flow of patients through the continuum of HIV care is critical to determine how best to intervene so that the proportion of HIV-infected persons who are on antiretroviral treatment and virally suppressed is as large as possible. METHODS Using immunological and virological data from the Centers for Disease Control and Prevention and the North American AIDS Cohort Collaboration on Research and Design from 2009 to 2012, we estimated the distribution of time spent in and dropout probability from each stage in the continuum of HIV care. We used these estimates to develop a queueing model for the expected number of patients found in each stage of the cascade. RESULTS HIV-infected individuals spend an average of about 3.1 months after HIV diagnosis before being linked to care, or dropping out of that stage of the continuum with a probability of 8%. Those who link to care wait an additional 3.7 months on average before getting their second set of laboratory results (indicating engagement in care) or dropping out of care with probability of almost 6%. Those engaged in care spent an average of almost 1 year before achieving viral suppression on antiretroviral therapy or dropping out with average probability 13%. For patients who achieved viral suppression, the average time suppressed on antiretroviral therapy was an average of 4.5 years. CONCLUSIONS Interventions should be targeted to more rapidly identifying newly infected individuals, and increasing the fraction of those engaged in care that achieves viral suppression.

Kaposi sarcoma (KS) remains common among HIV-infected persons. To better understand KS etiology and to help target prevention efforts, we comprehensively examined a variety of CD4 T-cell count and HIV-1 RNA viral load (VL) measures, as well as antiretroviral therapy (ART) use, to determine independent predictors of KS risk.North American AIDS Cohort Collaboration on Research and Design.We followed HIV-infected persons during 1996-2009 from 18 cohorts. We used time-updated Cox regression to model relationships between KS risk and recent, lagged, trajectory, and cumulative CD4 count or VL measures, as well as ART use. We used Akaike's information criterion and global P values to derive a final model.In separate models, the relationship between each measure and KS risk was highly significant (P0.0001). Our final mutually adjusted model included recent CD4 count [hazard ratio (HR) for50 vs. ≥500 cells/μL = 12.4; 95% confidence interval (CI): 6.5 to 23.8], recent VL (HR for ≥100,000 vs. ≤500 copies/mL = 3.8; 95% CI: 2.0 to 7.3), and cumulative (time-weighted mean) VL (HR for ≥100,000 vs. ≤500 copies/mL = 2.5; 95% CI: 1.0 to 5.9). Each P-trend was0.0001. After adjusting for these measures, we did not detect an independent association between ART use and KS risk.Our results suggested a multifactorial etiology for KS, with early and late phases of development. The cumulative VL effect suggested that controlling HIV replication promptly after HIV diagnosis is important for KS prevention. We observed no evidence for direct anti-KS activity of ART, independent of CD4 count and VL.

Background Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART. Design The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation. Methods All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count. Results The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age. Conclusion Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.

Author(s): Hoenigl, Martin; Moser, Carlee B; Funderburg, Nicholas; Bosch, Ronald; Kantor, Amy; Zhang, Yonglong; Eugen-Olsen, Jesper; Finkelman, Malcolm; Reiser, Jochen; Landay, Alan; Moisi, Daniela; Lederman, Michael M; Gianella, Sara; Adult Clinical Trials Group NWCS 411 study team | Abstract: BackgroundDespite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) infection remains associated with higher morbidity and mortality, driven, in part, by increased inflammation. Our objective was to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, with occurrence of non-AIDS events.MethodsParticipants (141 cases, 310 matched controls) were selected from a longitudinal observational trial; all were virally suppressed on ART at year 1 and thereafter. Soluble urokinase plasminogen activator receptor (suPAR), lipopolysaccharide binding protein (LBP), beta-D-glucan (BDG), intestinal fatty-acid binding protein, oxidized low-density lipoproteins, and soluble CD163 were measured pre-ART, after 1-year of ART, and pre-event. At each time point, conditional logistic regression analysis assessed associations of the biomarkers with events and adjusted for relevant covariates to calculate odds ratios (ORs) according to 1 interquartile range (IQR) difference.ResultsAt all time points, higher levels of suPAR were associated with increased risk of non-AIDS events (OR per 1 IQR was 1.7 before ART-initiation, OR per 1 IQR was 2.0 after 1 year of suppressive ART, and OR 2.1 pre-event). Higher levels of BDG and LBP at year 1 and pre-event (but not at baseline) were associated with increased risk of non-AIDS events. No associations were observed for other biomarkers.ConclusionsElevated levels of suPAR were strongly, consistently, and independently predictive of non-AIDS events at every measured time point. Interventions that target the suPAR pathway should be investigated to explore its role in the pathogenesis of non-AIDS-related outcomes in HIV infection.

Herpes zoster (HZ) has high morbidity in people living with HIV (PLHIV). We investigated immunological factors that correlated with the development of HZ in PLHIV with controlled HIV replication on antiretroviral therapy (ART). PLHIV who developed HZ on ART (cases), with undetectable plasma HIV RNA, and CD4 counts ≥200 cells/μL were matched 1:1 to controls by CD4 count, age, gender, race, and duration of ART. Varicella-zoster virus (VZV)-specific T cells and circulating regulatory T cells (Treg) were measured by flow cytometry before and after HZ. Differences between cases and controls were assessed by paired t-tests and longitudinal changes by Wilcoxon signed rank test. HZ cases (N = 31) had higher CD4(+)FOXP3(+)CD25(+)% Treg before HZ compared with 31 controls. After VZV ex vivo restimulation, cases had lower T cell responses, including CD8(+)perforin(+)% cytotoxic T lymphocytes (CTLs), CD4(+)IL10(+)%, and CD4(+)TGFβ(+)% compared with controls. Overall, Treg negatively correlated with VZV-specific Th1 responses. Moreover, Treg decreased over time on ART in HZ cases, VZV-CTLs were stable and did not increase even after HZ. Increased circulating Treg and decreased VZV-specific T cell immune responses were associated with the risk of HZ in PLHIV. The kinetics of Treg over time, but not of VZV-CTLs, paralleled the natural history of HZ, whose incidence decreases over time on effective ART.

BackgroundResearch is needed to better understand relations between immunosuppression and HIV viraemia and risk for non-Hodgkin lymphoma, a common cancer in people living with HIV. We aimed to identify key CD4 count and HIV RNA (viral load) predictors of risk for non-Hodgkin lymphoma, overall and by subtype.MethodsWe studied people living with HIV during 1996-2014 from 21 Canadian and US cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. To determine key independent predictors of risk for non-Hodgkin lymphoma, we assessed associations with time-updated recent, past, cumulative, and nadir or peak measures of CD4 count and viral load, using demographics-adjusted, cohort-stratified Cox models, and we compared models using Akaike's information criterion.FindingsOf 102 131 people living with HIV during the study period, 712 people developed non-Hodgkin lymphoma. The key independent predictors of risk for overall non-Hodgkin lymphoma were recent CD4 count (ie, lagged by 6 months

BACKGROUNDPersistence of HIV in sanctuary sites despite antiretroviral therapy (ART) presents a barrier to HIV remission and may affect neurocognitive function. We assessed HIV persistence in cerebrospinal fluid (CSF) and associations with inflammation and neurocognitive performance during long-term ART.METHODSParticipants enrolled in the AIDS Clinical Trials Group (ACTG) HIV Reservoirs Cohort Study (A5321) underwent concurrent lumbar puncture, phlebotomy, and neurocognitive assessment. Cell-associated HIV DNA and HIV RNA (CA-DNA, CA-RNA) were measured by quantitative PCR (qPCR). in peripheral blood mononuclear cells (PBMCs) and in cell pellets from CSF. In CSF supernatant and blood plasma, cell-free HIV RNA was quantified by qPCR with single copy sensitivity, and inflammatory biomarkers were measured by enzyme immunoassay.RESULTSSixty-nine participants (97% male, median age 50 years, CD4 696 cells/mm3, plasma HIV RNA

BACKGROUND Prior studies found overweight or obese HIV-infected individuals had greater early CD4 cell recovery on antiretroviral therapy (ART), but the results have been inconsistent. We assessed the longitudinal relationship between body mass index (BMI) and CD4 cell recovery on ART in a large, multisite cohort to identify potential physiologic links between adiposity and CD4 cell expansion. METHODS We modeled the relationship of time-updated BMI with CD4 count in patients starting ART from 17 North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) cohorts. The primary analysis used a linear mixed effects model incorporating up to 13 years of data per patient and adjusted for age, sex, race, ART regimen, baseline CD4 count and other covariates. Sensitivity analyses limited the cohort to patients with sustained viral suppression or censored at virologic failure. RESULTS Fourteen thousand eighty-four HIV-infected individuals initiating ART contributed data between 1998 and 2010. Time-updated BMI was significantly associated with CD4 cell recovery over time (P < 0.001). After 5 years of ART, the mean CD4 count at a BMI of 30 kg/m was 22% higher than at a BMI of 22 kg/m (606 vs. 498 cells per microliter) and 34% higher at a BMI of 40 kg/m (665 vs. 498 cells per microliter). Results were similar in the sensitivity analyses. DISCUSSION Higher BMI is associated with long-term advantages in immune recovery on ART. Although it is unclear if this impacts health outcomes, including balancing the negative health effects of obesity, elucidating the underlying mechanism could identify therapies for patients with suboptimal immune reconstitution.

In HIV-1-infected patients, variation at the HLA class I locus is associated with disease progression, but few studies have assessed the influence of HLA alleles on HIV-1 CRF01_AE infection, which is dominant in Thailand. We hypothesized that alleles predicted to confer more effective immune responses, such as HLA-B*46, would protect against disease progression. HLA typing was performed on HIV-1 incident cases surviving until 1998-1999 and HIV-1-negative matched controls from Thai army cohorts enrolled between 1991 and 1995. We assessed associations between class I alleles and disease progression subsequent to HLA typing. Ninety-nine HIV-1-incident cases were followed for a median of 3.7 years after HLA typing; during this time, 58 participants died. Two alleles were associated with mortality: HLA B*51 was protective (3-year survival B*51(pos) vs. B*51(neg): 75% vs. 52%; p = 0.034) whereas Cw*04 was deleterious (3-year survival Cw*04(pos) vs. Cw*04(neg): 39% vs. 60%; p = 0.027). HLA-B*46 was not associated with disease progression. Alleles present at different frequencies in HIV-1-incident compared with HIV-1-negative men included HLA-A*02:03, B*35, B*15, and C*08. 1. In conclusion in this Thai army cohort, HLA-B*51 was associated with lower mortality, confirming that this allele, which is protective in clade B HIV-1 infection, has a similar effect on HIV CRF01_AE infection. The deleterious effect of HLA-Cw*04 must be interpreted with caution because it may be in linkage disequilibrium with disease-susceptible HLA-B alleles. We did not find that HLA-B*46 was protective. These findings may inform vaccine development for areas of the world in which HIV-1 CRF01_AE infection is prevalent.

Background Maternal macronutrient intake is likely to play a pivotal role in fetoplacental growth. Male fetuses grow faster and their growth is more responsive to maternal size. Objective We assessed the role of fetal sex in modifying the effect of maternal macronutrient intake on the risk of small-for-gestational-age (SGA) birth. Design This was a prospective, observational cohort study of 2035 births from an urban South Asian Indian population. Maternal intakes of total energy and macronutrients were recorded by validated food-frequency questionnaires. The interaction of trimester 1 macronutrient intake with fetal sex was tested on the outcome of SGA births. Results The prevalence of SGA was 28%. Trimester 1 macronutrient composition was high in carbohydrate and low in fat (means ± SDs-carbohydrate: 64.6% ± 5.1%; protein: 11.5% ± 1.1%; and fat: 23.9% ± 4.4% of energy). Higher carbohydrate and lower fat consumption were each associated with an increased risk of SGA [adjusted OR (AOR) per 5% of energy (95% CI): carbohydrate: 1.15 (1.01, 1.32); fat: 0.83 (0.71, 0.97)] specifically among male births (males: n = 1047; females: n = 988). Dietary intake of >70% of energy from carbohydrate was also associated with increased risk (AOR: 1.67; 95% CI: 1.00, 2.78), whereas >25% of energy from fat intake was associated with decreased risk (AOR: 0.61; 95% CI: 0.41, 0.90) of SGA in male births. Conclusions Higher carbohydrate and lower fat intakes early in pregnancy were associated with increased risk of male SGA births. Therefore, we speculate that fetal sex acts as a modifier of the role of maternal periconceptional nutrition in optimal fetoplacental growth.

Author(s): Namazi, Golnaz; Fajnzylber, Jesse M; Aga, Evgenia; Bosch, Ronald J; Acosta, Edward P; Sharaf, Radwa; Hartogensis, Wendy; Jacobson, Jeffrey M; Connick, Elizabeth; Volberding, Paul; Skiest, Daniel; Margolis, David; Sneller, Michael C; Little, Susan J; Gianella, Sara; Smith, Davey M; Kuritzkes, Daniel R; Gulick, Roy M; Mellors, John W; Mehraj, Vikram; Gandhi, Rajesh T; Mitsuyasu, Ronald; Schooley, Robert T; Henry, Keith; Tebas, Pablo; Deeks, Steven G; Chun, Tae-Wook; Collier, Ann C; Routy, Jean-Pierre; Hecht, Frederick M; Walker, Bruce D; Li, Jonathan Z | Abstract: BackgroundHIV posttreatment controllers are rare individuals who start antiretroviral therapy (ART), but maintain HIV suppression after treatment interruption. The frequency of posttreatment control and posttreatment interruption viral dynamics have not been well characterized.MethodsPosttreatment controllers were identified from 14 studies and defined as individuals who underwent treatment interruption with viral loads ≤400 copies/mL at two-thirds or more of time points for ≥24 weeks. Viral load and CD4+ cell dynamics were compared between posttreatment controllers and noncontrollers.ResultsOf the 67 posttreatment controllers identified, 38 initiated ART during early HIV infection. Posttreatment controllers were more frequently identified in those treated during early versus chronic infection (13% vs 4%, P l .001). In posttreatment controllers with weekly viral load monitoring, 45% had a peak posttreatment interruption viral load of ≥1000 copies/mL and 33% had a peak viral load ≥10000 copies/mL. Of posttreatment controllers, 55% maintained HIV control for 2 years, with approximately 20% maintaining control for ≥5 years.ConclusionsPosttreatment control was more commonly identified amongst early treated individuals, frequently characterized by early transient viral rebound and heterogeneous durability of HIV remission. These results may provide mechanistic insights and have implications for the design of trials aimed at achieving HIV remission.

Author(s): Chow, Felicia C; Wilson, Michael R; Wu, Kunling; Ellis, Ronald J; Bosch, Ronald J; Linas, Benjamin P | Abstract: OBJECTIVE:To investigate the incidence of first-ever stroke/transient ischemic attack (TIA) and associated risk factors in a cohort of persons living with HIV infection (PLWH). DESIGN:Observational cohort study METHODS:We determined incidence rates of first-ever stroke/TIA in PLWH after ART initiation from the AIDS Clinical Trials Group ALLRT cohort and its parent trials. Poisson regression models evaluated baseline and time-varying covariates as risk factors for stroke/TIA. RESULTS:The incidence rate of stroke/TIA was 1.69 per 1000 person-years. Incidence rates were highest in women (2.88 stroke/TIAs per 1000 person-years compared with 1.40 per 1000 person-years in men) and non-Hispanic Blacks (2.51 stroke/TIAs per 1000 person-years compared with 0.77 per 1000 person-years in Hispanic/other race/ethnicities and 1.56 per 1000 person-years in whites). In a multivariable model, we found a significant age-by-sex interaction (P = 0.01). The higher risk of stroke/TIA in women was more pronounced at younger ages, whereas older age conferred a greater increase in stroke/TIA risk in men than women. Other risk factors for stroke/TIA included hypertension, higher LDL, and HIV RNA greater than 200 copies/ml. Overweight/obese BMI and higher CD4+:CD8+ ratio protected against stroke/TIA. CONCLUSION:Women and non-Hispanic Blacks living with HIV had the highest incidence rates of stroke/TIA. A concerted effort must be made to include PLWH from these at-risk groups in observational and interventional studies aimed at understanding stroke mechanisms and reducing stroke risk in HIV infection. Strategies to modify stroke risk in PLWH should employ a multipronged approach targeting vascular risk factors and engaging and retaining patients in HIV care.

Background We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study. Methods Cases were 143 human immunodeficiency virus (HIV)-infected adults who developed a non-AIDS event; 315 controls remained event-free. Specimens were tested pre-ART, year 1 post-ART, and at the visit preceding the event. Conditional logistic regression evaluated the associations of biomarker changes with non-AIDS events. Results Inflammatory and most activation biomarkers declined from pre-ART to year 1 for cases and controls. Subsequently, inflammatory biomarkers remained mostly stable in controls but not cases. Cellular activation markers generally declined for both cases and controls between year 1 and the pre-event sampling. Controls with greater pre-ART RNA levels or lower CD4+ levels had higher biomarker levels while also experiencing greater biomarker declines in the first year of ART. Changes in biomarkers to year 1 showed no significant associations with non-AIDS events. Cases, however, had significantly greater increases in all plasma biomarkers (but not cellular activation) from year 1 to the visit preceding the event. Conclusions Inflammation increases prior to non-AIDS events in treated HIV-infected adults. These biomarker changes may reflect subclinical disease processes or other alterations in the inflammatory environment that causally contribute to disease. Clinical trials registration NCT00001137.

Background: There is persistent confusion as to whether abacavir (ABC) increases the risk of myocardial infarction (MI), and whether such risk differs by type 1 (T1MI) or 2 (T2MI) MI in adults with HIV. Methods: Incident MIs in North American Cohort Collaboration on Research and Design participants were identified from 2001 to 2013. Discrete time marginal structural models addressed channeling biases and time-dependent confounding to estimate crude hazard ratio (HR) and adjusted hazard ratio (aHR) and 95% confidence intervals; analyses were performed for T1MI and T2MI separately. A sensitivity analysis evaluated whether Framingham risk score (FRS) modified the effect of ABC on MI occurrence. Results: Eight thousand two hundred sixty-five adults who initiated antiretroviral therapy contributed 29,077 person-years and 123 MI events (65 T1MI and 58 T2MI). Median follow-up time was 2.9 (interquartile range 1.4-5.1) years. ABC initiators were more likely to have a history of injection drug use, hepatitis C virus infection, hypertension, diabetes, impaired kidney function, hyperlipidemia, low (,200 cells/mm3) CD4 counts, and a history of AIDS. The risk of the combined MI outcome was greater for persons who used ABC in the previous 6 months [aHR = 1.84 (1.17-2.91)]; and persisted for T1MI (aHR = 1.62 [1.01]) and T2MI [aHR = 2.11 (1.08-4.29)]. FRS did not modify the effect of ABC on MI (P = 0.14) and inclusion of FRS in the MSM did not diminish the effect of recent ABC use on the combined outcome. Conclusions: Recent ABC use was associated with MI after adjustment for known risk factors and for FRS. However, screening for T1MI risks may not identify all or even most persons at risk of ABC use-associated MIs.

UNLABELLED We measured plasma human immunodeficiency virus type 1 (HIV-1) RNA levels by means of single-copy assay in 334 participants receiving virologically suppressive antiretroviral therapy (ART). A residual viremia load of ≥1 copy/mL after 4 years of ART was predicted by a higher pre-ART HIV-1 RNA level, higher CD8(+) T-cell count during treatment, and a lower ratio of CD4+ T cells to CD8+ T cells during treatment but not by initial ART regimen. In a longitudinal subset of 64 individuals, continued decay of the plasma HIV-1 RNA level was observed, with an average annual decrease of 6% and an estimated half-life of 11.5 years. In contrast to prior reports, the persistent viremia level continues to slowly decline during years 4-12 of suppressive ART. CLINICAL TRIALS REGISTRATION NCT00001137.

To examine the utility of waist-to-height ratio to identify risk of high blood pressure when compared to body mass index and waist circumference in South Indian urban school children.Secondary data analysis from a cross-sectional study.Urban schools around Bangalore, India.1913 children (58.1% males) aged 6-16 years with no prior history of chronic illness (PEACH study).Height, weight, waist circumference and of blood pressure were measured. Children with blood pressure ?90th percentile of age-, sex-, and height-adjusted standards were labelled as having high blood pressure.13.9% had a high waist-to-height ratio, 15.1% were overweight /obese and 21.7% had high waist circumference. High obesity indicators were associated with an increased risk of high blood pressure. The adjusted risk ratios (95% CI) of high systolic blood pressure with waist-to-height ratio, body mass index and waist circumference were 2.48 (1.76, 3.47), 2.59 (1.66, 4.04) and 2.38 (1.74, 3.26), respectively. Similar results were seen with high diastolic blood pressure.Obesity indicators, especially waist-to-height ratio due to its ease of measurement, can be useful initial screening tools for risk of high blood pressure in urban Indian school children.

Iron in high doses or when given to non-anaemic women may have adverse effects on pregnancy outcomes. This study aimed to estimate the supplemental iron intake in non-anaemic pregnant women attending an urban antenatal care setting in South India and examine the association of supplemental iron intake with birth outcomes.A cohort of 1196 non-anaemic pregnant women was studied. Daily supplemental iron intake was calculated as total supplemental iron consumed (mg) during pregnancy divided by the total number of days the supplement was recommended. Association of tertiles of supplemental iron intake with term low birth weight (tLBW), preterm delivery and small for gestational age (SGA) was examined using log-binomial regression, adjusting for maternal age, height, body mass index at recruitment, parity, education and type of delivery.Mean haemoglobin in trimester 1 was 12.4 ± 0.9 g/dl and mean supplemental iron intake was 37.7 ± 4.0 mg/day. Women in the highest tertile (39.2 mg/day) of supplemental iron intake had an increased risk of tLBW as compared with the lowest tertile (⩽ 36.6 mg/day) (adjusted risk ratio: 1.89; 95% confidence interval: 1.26, 2.83). Although supplemental iron intake was negatively correlated with gestational age (r=-0.20, P0.001) and birth weight (r=-0.07, P=0.011), there was no association between preterm delivery or SGA and supplemental iron intake.It appears that iron supplementation in non-anaemic pregnant women may not be beneficial, as we have observed the adverse effects with a prescribed dose of 45 mg/day. This may warrant the consideration of an individualized approach for antenatal iron supplementation, especially in non-anaemic women.

Data on the relationship of antiretroviral exposure to measures of human immunodeficiency virus (HIV) persistence are limited. To address this gap, multiple viral, immunologic, and pharmacologic measures were analyzed from individuals with sustained virologic suppression on therapy (median 7 years) in the AIDS Clinical Trials Group A5321 cohort. Among 110 participants on tenofovir-(TFV)-disoproxil-fumarate (TDF)/emtricitabine (FTC)-containing regimens, we found no significant correlation between hair concentrations of individual antiretrovirals (ARVs) in the regimen and measures of HIV persistence (plasma HIV-1 RNA by single copy assay, cell-associated-DNA, cell-associated RNA) or soluble markers of inflammation. These findings suggest that higher systemic ARV exposure may not impact HIV persistence or inflammation.

The rise in prevalence rates of Type 2 Diabetes among Indians is well recognized. The research focus has been primarily to understand the changes in insulin sensitivity and beta cell dysfunction among Indians with Type 2 Diabetes. However, no data are available on the role of peripheral tissue, in particular intramyocellular lipid (IMCL) content and its impact on glucose homeostasis among Indians with prediabetes. 28 male subjects (20–40 year) were studied. 13 with prediabetes (BMI ranging from 25.4 ± 2.9 kg/m2) and 15 controls (BMI ranging from 24.6 ± 2.8 kg/m2) were recruited. Body composition by dual energy X-ray absorptiometry (DXA), insulin sensitivity, insulin secretion rates were derived using the minimal model of C-peptide secretion and kinetics rates and skeletal muscle strength of the lower limb (quadriceps) was assessed using Isokinetic dynamometry. From muscle biopsy samples of the vastus lateralis, IMCL fat content (Oil red O staining) was determined. The prediabetes group were older compared to controls (P

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load

Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART., Author summary HIV-infected individuals who are receiving antiretroviral therapy continue to have low but persistent amounts of virus in blood as well as high levels of immune activation. Elevated immune activation has been linked to medical complications, like heart disease. Whether activation is being driven by or driving HIV persistence is not known. To answer this question, we measured levels of HIV, inflammation and immune activation in 101 HIV-infected individuals before and during long-term antiretroviral therapy. We found that pre-treatment levels of HIV correlated with on-treatment measures of HIV persistence. HIV levels correlated with inflammation and activation before starting therapy but not during long-term treatment, suggesting that virus persistence is not driving or driven by immune activation or inflammation. Higher levels of activation and inflammation before therapy were associated with higher levels during treatment, indicating that immune events that occurred before treatment initiation had long-lasting effects despite sustained control of the virus. These findings should stimulate studies of genetic or viral factors that affect levels of virus, activation and inflammation prior to treatment, and should inform the design of strategies to reduce HIV persistence and dampen harmful immune activation and inflammation in people who are on long-term treatment.

Background. Human immunodeficiency virus type 1 (HIV-1) DNA dynamics during long-term antiretroviral therapy (ART) are not defined. Methods. Blood mononuclear cells obtained during 7–12 years of effective ART were assayed for total HIV-1 DNA and 2-long terminal repeat (LTR) circles by quantitative polymerase chain reaction (qPCR). Slopes of HIV-1 DNA were estimated by participant-specific linear regressions. Plasma was assayed for residual viremia (HIV-1 RNA) by qPCR. Results. Thirty participants were studied. HIV-1 DNA decreased significantly from years 0–1 and 1–4 of ART with median decay slopes of −0.86 (interquartile range, −1.05, −0.59) and −0.11 (−0.17, −0.06) log10(copies/106 CD4+ T-cells)/year, respectively (P < .001). Decay was not significant for years 4–7 (−0.02 [−0.06, 0.02]; P = .09) or after year 7 of ART (−0.006 [−0.030, 0.015]; P = .17). All participants had detectable HIV-1 DNA after 10 years (median 439 copies/106 CD4+ T-cells; range: 7–2074). Pre-ART HIV-1 DNA levels were positively associated with pre-ART HIV-1 RNA levels (Spearman = 0.71, P < .001) and with HIV-1 DNA at years 4, 7, and 10 on ART (Spearman ≥ 0.75, P < .001). No associations were found (P ≥ .25) between HIV-1 DNA slopes or levels and % activated CD8+ T-cells (average during years 1–4) or residual viremia (n = 18). 2-LTR circles were detected pre-ART in 20/29 and in 8/30 participants at last follow-up. Conclusions. Decay of HIV-1 DNA in blood is rapid in the first year after ART initiation (86% decline), slows during years 1–4 (23% decline/year), and subsequently plateaus. HIV-1 DNA decay is not associated with the levels of CD8+ T-cell activation or persistent viremia. The determinants of stable HIV-1 DNA persistence require further elucidation. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT00001137","term_id":"NCT00001137"}}NCT00001137.

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.

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.

With the advent of effective antiretroviral therapy (ART), the spectrum of disease experienced by those with HIV infection has changed. Viral suppression is common1 and incident AIDS defining events are rare.2 Yet, those with HIV infection continue to experience excess mortality 3;4 which is incompletely described by age, CD4 count, and HIV-1 RNA alone.5 Despite ART, chronic HIV infection appears to exacerbate generic pathophysiologic processes associated with aging which increase physiologic vulnerability relative to demographically similar uninfected individuals.6–8 Consistent with current treatment guidelines9, HIV providers routinely monitor general indicators of organ system injury including hemoglobin, platelets, aspartate and alanine transaminase (AST and ALT), creatinine, and viral hepatitis C infection (HCV) but have no index with which to integrate these data into an overall estimate of disease burden or mortality risk. Such a comprehensive measure would be useful as a means of more effectively motivating behavior change in the clinical setting10, improved risk stratification in the analysis of observational data11 and more effective randomized trials12. For example, indices such as the Framingham Risk Index has enhanced research and care in cardiovascular disease13 and several geriatric risk indices are enhancing research and care for those aging without HIV infection.14 While the cumulative evidence supporting the accuracy and generalizability of the VACS Index exceeds that for any prior HIV risk index, the VACS Index builds upon important prior research.15–22 Most prior indices emphasized AIDS defining conditions, CD4 cell count, and HIV-1 RNA. Some recognized the importance of age and anemia16;20. However much has changed since these indices were developed and validated. Specifically, the increasing role of multi-organ system injury (reflected by FIB 4, eGFR, and hemoglobin) and of hepatitis C infection (HCV), and the decreasing role of AIDS Defining Illnesses, CD4 count, and HIV-1 RNA. By including FIB-4, HCV, eGFR, hemoglobin and age, and placing less weighting upon CD4 count and HIV-1 RNA, the VACS Index better reflects more of the major common pathways of physiologic injury among those on antiretroviral therapy. As a result, the Veterans Aging Cohort Study Index (VACS Index) discriminates risk of mortality more effectively than an index restricted to CD4 count, HIV-1 RNA and age (Restricted Index).23 24 Importantly, the discrimination of the VACS Index rivals that of indices in clinical use including the Framingham Index13 and those recommended for use among geriatric patients.14 Nevertheless, prognostic indices developed in one sample (those within the Veterans Affairs Healthcare System (VA)) may not generalize to a new sample or important subgroups.25 Further, indices effective at one particular point in clinical care (ART initiation) may not generalize beyond treatment initation.25 We use data from the North American AIDS Cohort Collaboration (NA-ACCORD) to test the generalizability of the VACS Index outside the VA and at differing intervals of exposure to ART. We then combine data from NA-ACCORD and VA to translate index scores to an estimated absolute risk of mortality and compare predicted to observed mortality by cohort and subgroups defined by sex, age, race, and HIV-1 RNA titer.

Background HIV-1-infected individuals with plasma RNAMethods We evaluated factors associated with residual viraemia 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. Results Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. 62% had detectable viraemia (>0.2 copies/ml) by SCA (median 0.2 copies/ml, IQR 2 years (median 2.3 versus 0.2 copies/ml; P=0.016). Conclusions Among HIV-1-infected patients with pre-ART HIV-1 RNA>100,000 copies/ml, residual viraemia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viraemia was associated with older age and

Background: Multiple micronutrients (vitamin B complex and vitamins C and E) were effective at reducing infectious disease morbidity, HIV disease progression, and poor pregnancy outcomes in HIV-infected women. Objective: The objective was to evaluate whether direct supplementation of these micronutrients to HIV-exposed infants reduces mortality and morbidity. Design: Infants born to HIV-infected women from Dar es Salaam, Tanzania, were randomly assigned to receive daily oral supplementation of multiple multivitamins (vitamin B complex and vitamins C and E) or placebo from age 6 wk for 24 mo. All-cause mortality, hospitalizations, and unscheduled clinic visits were recorded. Morbidities were recorded during monthly follow-up visits. All mothers received multiple micronutrients throughout the study. Results: A total of 1193 infants were randomly assigned to receive micronutrients and 1194 to receive placebo. There were 138 child deaths in the multivitamin group and 124 deaths in the placebo group (HR: 1.13; 95% CI: 0.88, 1.44; P = 0.33). Hospitalizations (RR: 0.83; 95% CI: 0.62, 1.13; P = 0.23), unscheduled clinic visits (RR: 0.97; 95% CI: 0.85, 1.10; P = 0.59), and maternal reports of diarrhea (RR: 0.97; 0.87, 1.10; P = 0.64) were not significantly different between the 2 groups. Fever (P = 0.02) and vomiting (P = 0.007) were significantly lower in the multivitamin group. Among 429 children whose mothers received antiretroviral (ARV) therapy, multivitamin use had no effect on mortality but was associated with a significant reduction in hospitalizations (P = 0.035), episodes of fever (P = 0.005), and episodes of fever and cough (P = 0.019). Conclusions: In the setting of maternal micronutrient supplementation, supplementation of HIV-exposed infants with vitamin B and vitamins C and E does not reduce mortality. Studies of nutrition supplementation in ARV-exposed infants may be warranted. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00197730","term_id":"NCT00197730"}}NCT00197730.

More than 5 million individuals are receiving chronic antiretroviral therapy (ART) to suppress the replication of human immunodeficiency virus type 1 (HIV-1). Current US guidelines recommend monitoring of ART with measurement of HIV-1 RNA every 3–6 months to assess virologic response [1]. Virologic suppression with ART results in profound long-term clinical benefits including decrease in immunodeficiency and an increase in life span [2, 3]. Virologic failure reverses each of these benefits, and the recrudescence of viral replication, is associated with the selection of drug-resistant viruses and CD4 cell count decline [4–6]. Upon rebound of viremia on ART, recommendations include reinforcement of adherence and drug resistance testing of plasma HIV-1 to determine the optimal regimen to achieve virologic suppression. In AIDS Clinical Trials Group (ACTG) Study A5202, treatment-naive participants were randomized to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) with either tenofovir DF/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC). The major drug resistance mutations detected by sequencing and consensus alignment at the time of virologic failure were previously reported, where reverse transcriptase (RT) resistance-associated mutations were found to be more frequent among participants with virologic failure assigned to EFV-containing than ATV/r-containing treatment arms [7–9]. Here we present a thorough assessment of HIV-1 major and nonmajor mutations, and cumulative amino acid changes from pretreatment to virologic failure, to provide additional evidence for selection pressures and evolution of drug resistance in response to the different combinations of antiretrovirals.

Background Persistent immune activation and inflammation in virologically suppressed human immunodeficiency virus (HIV) infection are linked to excess cardiovascular risk. Objective To evaluate atorvastatin as a strategy to reduce cardiovascular risk. Methods A5275 was a multicenter, prospective, randomized, double-blind, placebo-controlled, cross-over pilot study of atorvastatin (10 mg/day for 4 weeks then 20 mg/day for 16 weeks) with a planned enrollment of 97 HIV-infected participants ≥18 years old, receiving boosted protease inhibitor–based antiretroviral therapy for ≥6 months, with plasma HIV-1 RNAs below limits of quantification ≥180 days, and fasting low-density lipoprotein (LDL) cholesterol ≥70 and + /DR + ) and plasma levels of IL-6 and D-dimer. Arms were compared using the Wilcoxon rank-sum tests and also summarized changes pre-to-post atorvastatin treatment. Analyses were as-treated. Results Ninety-eight participants were enrolled at 31 U S sites and 73 completed study treatment. Atorvastatin treatment did not decrease T-lymphocyte or monocyte activation, circulating biomarker levels (interleukin-6, D-dimer, soluble CD14, soluble CD163, monocyte chemoattractant protein-1, interferon-gamma–induced protein-10, high-sensitivity C-reactive protein, CD40L, and P-selectin) or white blood cell Kruppel-like Factor 2/4 messenger RNA levels. Pre-to-post atorvastatin reductions in calculated LDL (−38%), oxidized-LDL (−33%), and lipoprotein-associated phospholipase A2 (−31%) were significant ( P Conclusion In virologically suppressed individuals with HIV infection, atorvastatin did not significantly decrease levels of soluble or cellular biomarkers of immune activation and inflammation but resulted in robust reductions in LDL cholesterol, oxLDL, and lipoprotein-associated phospholipase A 2 , biomarkers associated with cardiovascular risk.

The jury on transmission of HIV through breast-feeding is still on. Data from a clinical trial in children born to HIV-positive mothers were evaluated with respect to their relationship to mother-to-child transmission. A total of 1629 infants who were not infected at age 6 weeks, had HIV results available at 12 months and who were breast-fed were included in this study. Exclusive breast feeding (EBF) rates declined from 85% at 2 months to < 30% by 4 months. EBF was associated with a sustained and significant reduction in HIV infection. With every incremental month of EBF, HIV infection was reduced by 16% [multivariable (risk ratio) RR: 0.84, CI: 0.72-0.98, p = 0.03] from enrollment to 6 months of age and by 18% (multivariable RR: 0.82, CI: 0.72-0.94, p = 0.005) from enrollment to 12 months of age. EBF significantly reduces the risk of vertical HIV transmission through 12 months of age.

Background: There remains concern regarding the occurrence of noncommunicable diseases (NCDs) among individuals aging with human immunodeficiency virus (HIV), but few studies have described whether disparities between demographic subgroups are present among individuals on antiretroviral therapy (ART) with access to care. Methods: We assessed the first documented occurrence of type 2 diabetes mellitus (DM), chronic kidney disease (CKD), and treated hypertension (HTN) by age, sex, and race within the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). HIV-infected adults (≥18 years) who initiated ART were observed for first NCD occurrence between 1 January 2000 and 31 December 2013. Cumulative incidences as of age 70 were estimated accounting for the competing risk of death; Poisson regression was used to compare rates of NCD occurrence by demographic subgroup. Results: We included >50000 persons with >250000 person-years of follow-up. Median follow-up was 4.7 (interquartile range, 2.4–8.1) years. Rates of first occurrence (per 100 person-years) were 1.2 for DM, 0.6 for CKD, and 2.6 for HTN. Relative to non-black women, the cumulative incidences were increased in black women (68% vs 51% for HTN, 52% vs 41% for DM, and 38% vs 35% for CKD; all P < .001); this disparity was also found among men (73% vs 60% for HTN, 44% vs 34% for DM, and 30% vs 25% for CKD; all P < .001). Conclusions: Racial disparities in the occurrence of DM, CKD, and HTN emphasize the need for prevention and treatment options for these HIV populations receiving care in North America.

Viral load (VL) rebound timing and set point were analyzed in 235 participants undergoing analytic treatment interruption (ATI) in 6 AIDS Clinical Trials Group studies. There was no significant association between rebound timing and ATI VL set point for those who rebounded ≤12 weeks. VL set points were lower in participants with rebound >12 weeks (P < 0.001) and participants treated during early infection (P < 0.001). Pre-antiretroviral therapy VL correlated with set point, though 68% of participants had a set point lower than pre-antiretroviral therapy VL. These results illustrate complex relationships between post-ATI virologic outcomes and the potential presence of biological factors mediating rebound timing and set point.

Children born to human immunodeficiency virus (HIV)-infected women are susceptible to undernutrition, but modifiable risk factors and the time course of the development of undernutrition have not been well characterized. The objective of this study was to identify maternal, socioeconomic and child characteristics that are associated with stunting, wasting and underweight among Tanzanian children born to HIV-infected mothers, followed from 6 weeks of age for 24 months. Maternal and socioeconomic characteristics were recorded during pregnancy, data pertaining to the infant's birth were collected immediately after delivery, morbidity histories and anthropometric measurements were performed monthly. Multivariate Cox proportional hazards methods were used to assess the association between potential predictors and the time to first episode of stunting, wasting and underweight. A total of 2387 infants (54.0% male) were enrolled and followed for a median duration of 21.2 months. The respective prevalence of prematurity (

Objective. To determine whether human immunodeficiency virus (HIV) infection is associated with increased risk of malaria incidence and recurrence in children. Methods. 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. Results. 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. Conclusions. 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.

BACKGROUND: Patients with tuberculosis (TB) often suffer from profound malnutrition. OBJECTIVE: To examine the patterns and predictors of change in nutritional and hemoglobin status during and after TB treatment. METHODS: A total of 471 human immunodeficiency virus (HIV) positive and 416 HIV-negative adults with pulmonary TB were prospectively followed in Dar es Salaam, Tanzania. All patients received 8 months' TB treatment following enrollment. RESULTS: About 40% of HIV-positive and 47% of HIV negative TB patients had body mass index (BMI) < 18.5 kg/m 2 at baseline, while about 94% of HIV-positive and 84% of HIV-negative participants were anemic at baseline. Both HIV-positive and HIV-negative patients experienced increases in BMI and hemoglobin concentrations over the course of TB treatment. Among HIV-positive patients, older age, low CD4 cell counts, and high viral load were independently associated with a smaller increase in BMI from baseline to 8 months. Female sex, older age, low CD4 cell counts, previous TB infection and less money spent on food were independently associated with a smaller improvement in hemoglobin levels among HIV-positive patients during treatment. CONCLUSION: HIV-positive TB patients, especially those with low CD4 cell counts, showed poor nutritional recovery during TB treatment. Adequate nutritional support should be considered during TB treatment.

Background & Aims While the majority of HCV-infected patients progress to chronic hepatitis, a small fraction of individuals are able to clear the virus. Resolution of infection occurs within the first few weeks to months of infection, suggesting that innate immune functions may be critical for early control. Epidemiologic data support a role for particular NK cell receptor bearing populations in this control, yet the mechanism by which NK cells respond to HCV early in infection is unknown. Methods Changes in the phenotype and function of NK cells were investigated in a cohort of 43 individuals identified during various stages of HCV infection with different clinical outcomes. Results Acute, chronic, and resolved HCV infections were characterized by an expansion of CD56 neg NK cells. Furthermore, increased levels of HLA-C-binding KIR + NK cells were observed in HCV resolvers, while all stages of HCV infection were associated with reduced percentages of NKG2D + , NKp30 + , and NKp46 + NK cells, and a slight increase in the ability of NK cells to respond to target cells bearing the ligands for these receptors. In contrast, NKG2A + and CD94 + NK cells were elevated in acute and chronic HCV infection, but not in resolved infection. Most importantly, in acute infection, lower frequencies of NKp30 + , NKp46 + , CD161 + , and NKG2D + NK cells were observed in patients who were subsequently able to clear HCV infection than in those becoming chronically infected. Conclusions These data implicate particular populations of NK cells in the early control and clearance of HCV infection.

Examine incidence and factors associated with loss to follow-up (LTFU) in the AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trials (ALLRT) cohort.ALLRT is a prospective cohort of HIV-infected persons randomized to antiretroviral (ARV) regimens/strategies in ACTG trials and followed long-term after the trial ends. Person-years were calculated from ALLRT entry until loss to follow-up (LTFU; defined using off-study reasons or ≥ 3 consecutive missed visits), death/ severe debilitation/site closures, or June 2009 (censored). Poisson regression was used to examine LTFU factors separately among participants who were ARV naïve or ARV experienced at trial entry.Among 4,630 participants (22,524 person-years), 1,140 were lost to follow-up, 237 died, 29 were severely debilitated, and 443 were at sites that closed. The LTFU incidence was 5.5 and 4.2 per 100 person-years among previously ARV-naïve and ARV-experienced participants, respectively. In both groups, age ≤ 50, site location, being off ARVs, and viral load ≥ 400 copies/mL were associated with a higher risk of LTFU. Among ARV-naïve participants, male sex, education16 years, intravenous drug use, and cigarette smoking were also associated with LTFU.Knowledge of differential LTFU can help researchers identify participants at risk of LTFU in longitudinal HIV cohorts and design retention strategies, thereby limiting study bias. The identified factors should be included in inverse probability of weighting models to account for LTFU.

Objectives: 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), recoveryfromperipheral neuropathy/SPNafterneurotoxicART(nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design: 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. Methods: 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. Results: 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 400copies/ml or less and 70.3% with CD4 greater than 350cells/ml. 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. Conclusion: Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for peripheral neuropathy/SPN. 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins AIDS 2011, 25:919‐928