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1.  Effects of Smoking on Non-AIDS-Related Morbidity in HIV-Infected Patients 
Smoking is common in the human immunodeficiency virus–infected population and may interact adversely with chronic systemic inflammation to promote end-organ disease. This article reviews the non-AIDS-related effects of smoking.
Tobacco smoking has many adverse health consequences. Patients with human immunodeficiency virus (HIV) infection smoke at very high rates, and many of the comorbidities associated with smoking in the general population are more prevalent in this population. It is likely that a combination of higher smoking rates along with an altered response to cigarette smoke throughout the body in persons with HIV infection leads to increased rates of the known conditions related to smoking. Several AIDS-defining conditions associated with smoking have been reviewed elsewhere. This review aims to summarize the data on non-AIDS-related health consequences of smoking in the HIV-infected population and explore evidence for the potential compounding effects on chronic systemic inflammation due to HIV infection and smoking.
PMCID: PMC3689343  PMID: 23572487
smoking; tobacco; HIV; comorbidity
2.  Pathogenesis and Treatment of HIV Lipohypertrophy 
Purpose of Review
This review addresses our current understanding of the pathogenesis of HIV associated lipohypertrophy, and describes an evidence-based approach to treatment.
Recent Findings
Although the pathogenesis of HIV associated lipohypertrophy remains elusive, recent clinical and laboratory investigations in fatty acid metabolism and growth hormone dynamics have furthered our understanding of the condition. These findings have also paved the way for new therapeutic interventions, of which tesamorelin, an analogue of growth hormone-releasing hormone, has gained recognition as a promising treatment strategy against visceral fat accumulation. Recent randomized placebo-controlled trials of tesamorelin demonstrated significant reductions in visceral adipose tissue, improvement in lipid parameters, and no adverse effects on glucose tolerance. Optimal therapeutic dosing and treatment duration, though, are not yet known. Whether treatment with GHRH-analogues will translate into improved long-term metabolic and cardiovascular outcomes also remains to be seen.
Although the pathogenesis of HIV lipohypertrophy remains unclear, several theories and observations have led to the development of treatment strategies to counter fat accumulation and its accompanying metabolic complications. Based on clinical trials, analogues of the GH/GHRH axis appear to be most effective in reducing visceral adipose tissue.
PMCID: PMC3671942  PMID: 21124215
lipohypertrophy; visceral adipose tissue; HIV; lipodystrophy; tesamorelin
3.  Testosterone Replacement Therapy and Polycythemia in HIV-infected Patients 
AIDS (London, England)  2012;26(2):243-245.
We conducted a case-control study to assess testosterone use as a primary risk factor for polycythemia in 21 HIV-infected men. Any testosterone use within two months of first elevated hemoglobin was associated with polycythemia (matched odds ratio 6.55; 95% CI 1.83-23.4; P=0.004) and intramuscular administration demonstrated a stronger association than topical use. No adverse cardiovascular or thrombotic events were observed. HIV-infected patients taking testosterone should undergo routine hematologic monitoring with adjustment of therapy when appropriate.
PMCID: PMC3670149  PMID: 22008652
4.  Clinical Manifestations in Individuals with Recent Diagnosis of HTLV Type I Infection 
Human T-lymphotropic virus type 1 (HTLV-1) is known to cause HTLV-associated myelopathy (HAM)/tropical spastic paraparesis and adult T cell leukemia. A growing body of evidence links HTLV-1 infection with an increasing spectrum of disease, including uveitis, periodontal disease, arthropathy, sicca syndrome, and neurologic deficits.
Despite recent findings, the natural history of HTLV-1 infection remains poorly defined. This study was designed to better characterize initial clinical and neurological findings in individuals diagnosed with HTLV-1 infection.
Study Design
We conducted a cross-sectional study of 71 individuals recently diagnosed with HTLV-1 and 71 uninfected age- and sex-matched blood donors in Salvador, Brazil. Subjects were administered a standardized questionnaire and underwent physical exam.
HTLV-1 infected subjects were significantly more likely than controls to report complaints of hand and foot numbness (OR=5.3; 95% CI: 1.8-15.3; p=0.002 and OR=4.0; 95% CI: 1.3-12; p=0.013 respectively), difficulty running (OR=4.0; 95% CI: 1.1-14.2, p=0.032), nocturia (OR=5.0, 95% CI: 1.1-22.8, p=0.038), arthralgia (OR 3.3, 95% CI: 1.4-7.7, p=0.006), and photophobia (OR 3.3, 95% CI: 1.4-7.7, p=0.006).
Neurologic, ocular and rheumatologic complaints may be the first manifestations of HTLV-1 infection. Therefore, all patients presenting with initial diagnosis should be rigorously screened for these symptoms.
PMCID: PMC3074002  PMID: 21388871
HTLV-1; neurologic manifestations; clinical manifestations; neuropathy; natural history
5.  Safety and Antiviral Activity of the HCV Entry Inhibitor ITX5061 in Treatment-Naive HCV-Infected Adults: A Randomized, Double-Blind, Phase 1b Study 
The Journal of Infectious Diseases  2013;209(5):658-667.
Background. Hepatitis C virus (HCV) entry involves scavenger receptor B1 (SRB1). In vitro, SRB1 inhibition by ITX5061 impedes HCV replication.
Methods. Multicenter study to assess safety/activity of ITX5061 in previously untreated, noncirrhotic, HCV genotype 1 infected adults. Design included sequential cohorts of 10 subjects with ITX5061 (n = 8) or placebo (n = 2) to escalate duration (3 to 14 to 28 days) or deescalate dose (150 to 75 to 25 mg) based on predefined criteria for safety and activity (≥4 of 8 subjects with HCV RNA decline ≥1 log10 IU/mL).
Results. Thirty subjects enrolled in 3 cohorts: ITX5061 150 mg/day by mouth for 3 (A150), 14 (B150), and 28 (C150) days. Six subjects had grade ≥3 adverse events (one in placebo); none were treatment related. One of the 7 C150 subjects (14.3%, 95% confidence interval [CI], .7%–55.4%) had ≥1 log10 IU/mL decline in HCV RNA (1.49 log10 IU/mL), whereas none of the 6 placebo, 8 A150 or 8 B150 subjects showed such decline.
Conclusions. Oral ITX5061 150 mg/day for up to 28 days was safe and well tolerated. In the 28-day cohort, 1 of 7 subjects showed antiviral activity; however, predefined criteria for antiviral activity were not met at the doses and durations studied.
PMCID: PMC3923538  PMID: 24041792
HCV; SRB1; entry inhibitors
6.  Pilot Study of Pioglitazone Prior to HCV Re-treatment in HIV/HCV Genotype 1-Infected Subjects with Insulin Resistance and Prior Nonresponse to Peginterferon and Ribavirin Therapy: A5239 
Insulin resistance (IR) is associated with nonresponse to HCV treatment. In this multicenter, single-arm pilot study, adult, HIV/HCV genotype 1 coinfected prior nonresponders to peginterferon/ribavirin (PegIFN/RBV) with homeostatic model assessment-IR >2.5 were treated with pioglitazone(PIO) for 24 weeks followed by PegIFN/RBV/PIO. 3/19 subjects (15.8%) achieved undetectable HCV RNA at week 24 of PegIFN/RBV/PIO which was not significantly different than the historical null rate of 10% (p=0.29, lower limit of the exact 1-sided 90% confidence interval 5.9%). Over the 24 weeks of PIO monotherapy, ALT and AST declined significantly and correlated with improved metabolic parameters.
PMCID: PMC3998202  PMID: 24525470
hepatitis C; HIV; insulin resistance; pegylated interferon; nonresponder; metabolic
7.  Glycemic Control in HIV-Infected Patients with Diabetes Mellitus and Rates of Meeting American Diabetes Association Management Guidelines 
AIDS Patient Care and STDs  2011;25(1):5-12.
Limited data exist on the prevalence of inadequate glycemic control and rates of meeting American Diabetic Association (ADA) management guidelines in HIV-infected adults with diabetes mellitus. We conducted a retrospective cross-sectional study of 142 HIV-infected adults with type 2 diabetes at an urban academic HIV clinic during 2008. We estimated the prevalence of and assessed associations with inadequate glycemic control, defined as hemoglobin A1c ≥7.5% for ≥50% of quarters over the year, and determined rates of meeting ADA clinical goals. Ninety-two percent of patients received antiretroviral therapy. The prevalence of inadequate glycemic control was 33% (95% confidence interval [CI] 25%–42%). Compared to patients with adequate control, those with inadequate control had fewer years since HIV diagnosis (12.7 versus 15.1, p = 0.01), increased use of insulin (60% versus 20%, p < 0.001) or any diabetic medication (98% versus 85%, p = 0.02), and higher triglyceride levels (238 versus 168 mg/dL, p = 0.008). Rates of achieving ADA goals were 42% for blood pressure, 66% for low-density lipoprotein cholesterol (LDL-C), 33% for high-density lipoprotein cholesterol, and 31% for triglycerides. Thirty-six percent of patients who did not meet the LDL-C goal received statin therapy. Forty-seven percent of patients were screened for retinopathy and 19% of patients without preexisting renal disease were screened for nephropathy. In conclusion, the prevalence of inadequate glycemic control in HIV-infected patients with diabetes is similar to published data from the general population. Suboptimal rates of meeting ADA blood pressure and lipid goals and adherence to screening guidelines demonstrate need for further clinician and patient education.
PMCID: PMC3030908  PMID: 21214374
8.  Factors Associated with Poor Immunologic Response to Virologic Suppression by Highly Active Antiretroviral Therapy in HIV-Infected Women 
Virologic response to highly active antiretroviral therapy (HAART) typically results in a substantial rise in CD4 cell counts. We investigated factors associated with poor CD4 response among HIV-infected women followed at 6-monthly intervals in the Women’s Interagency HIV Study. Women with nadir CD4 counts <350 cells/mm3 who achieved at least 6 months of plasma HIV RNA < 400 copies/ml were studied. Demographic, clinical, and treatment factors were compared between immunologic nonresponders, defined as the lower quartile of CD4 count change after two visits with virologic suppression (<56 cell/mm3; n = 38), and the remaining group of responders (n = 115). Immunologic nonresponders had lower baseline HIV RNA levels and higher CD4 counts, more frequently used HAART 6 months prior to achieving consistent viral suppression, and more commonly had HIV RNA levels >80 but <400 copies/mL at both suppressive visits (21 vs. 7.8%, p = 0.024). In multivariate analysis, higher CD4 count and lower HIV RNA level at the last presuppressive visit were associated with immune nonresponse. We conclude that higher baseline CD4 count and lower HIV RNA level were associated with poor immunologic response to HAART in women with virologic suppression for at least 6 months. Persistent low level viremia may also contribute.
PMCID: PMC3126664  PMID: 16545008
9.  HIV/AIDS and lipodystrophy: Implications for clinical management in resource-limited settings 
Lipodystrophy is a term used to describe a metabolic complication of fat loss, fat gain, or a combination of fat loss and gain, which is associated with some antiretroviral (ARV) therapies given to HIV-infected individuals. There is limited research on lipodystrophy in low- and middle-income countries, despite accounting for more than 95% of the burden of HIV/AIDS. The objective of this review was to evaluate the prevalence, pathogenesis and prognosis of HIV-related lipoatrophy, lipohypertrophy and mixed syndrome, to inform clinical management in resource-limited settings.
We conducted a structured literature search using MEDLINE electronic databases. Relevant MeSH terms were used to identify published human studies on HIV and lipoatrophy, lipohypertrophy, or mixed syndrome in low-, low-middle- and upper-middle-income countries through 31 March 2014. The search resulted in 5296 articles; after 1599 studies were excluded (958 reviews, 641 non-human), 3697 studies were extracted for further review. After excluding studies conducted in high-income settings (n=2808), and studies that did not meet inclusion criteria (n=799), 90 studies were included in this review.
Results and Discussion
Of the 90 studies included in this review, only six were from low-income countries and eight were from lower middle-income economies. These studies focused on lipodystrophy prevalence, risk factors and side effects of antiretroviral therapy (ART). In most studies, lipodystrophy developed after the first six months of therapy, particularly with the use of stavudine. Lipodystrophy is associated with increased risk of cardiometabolic complications. This is disconcerting and anticipated to increase, given the rapid scale-up of ART worldwide, the increasing number and lifespan of HIV-infected patients on long-term therapy, and the emergence of obesity and non-communicable diseases in settings with extensive HIV burden.
Lipodystrophy is common in resource-limited settings, and has considerable implications for risk of metabolic diseases, quality of life and adherence. Comprehensive evidence-based interventions are urgently needed to reduce the burden of HIV and lipodystrophy, and inform clinical management in resource-limited settings.
PMCID: PMC4297925  PMID: 25598476
HIV; AIDS; lipodystrophy; fat redistribution; antiretroviral therapy
10.  Glycated Hemoglobin in Diabetic Women with and Without HIV Infection: Data from the Women's Interagency HIV Study 
Antiviral therapy  2010;15(4):571-577.
Limited data suggest that glycated hemoglobin (hemoglobin A1c; A1C) values may not reflect glycemic control accurately in HIV-infected individuals with diabetes.
We evaluated repeated measures of paired fasting glucose and A1C values in 315 HIV-infected and 109 HIV-uninfected diabetic participants in the Women's Interagency HIV Study. Generalized estimating equations used log A1C as the outcome variable, with adjustment for log fasting glucose concentration in all models.
An HIV-infected woman on average had 0.9868 times as much A1C (that is, 1.32% lower; 95% confidence interval 0.9734-0.9904) as an HIV-uninfected woman with the same log fasting glucose concentration. In multivariate analysis, HIV serostatus was not associated, but white, other non-black race, and higher red blood cell mean corpuscular volume (MCV) were statistically associated with lower A1C values. Use of diabetic medication was associated with higher A1C values. In multivariate analysis restricted to HIV-infected women, white and other race, higher MCV, and HCV viremia were associated with lower A1C values whereas older age, use of diabetic medications and higher CD4 cell count were associated with higher A1C values. Use of combination antiretroviral therapy, protease inhibitors, zidovudine, stavudine, or abacavir was not associated with A1C values.
We conclude that A1C values were modestly lower in HIV-infected diabetic women relative to HIV-uninfected diabetic women after adjustment for fasting glucose concentration. The difference was abrogated by adjustment for MCV, race, and diabetic medication use. Our data suggest that in clinical practice A1C gives a reasonably accurate refection of glycemic control in HIV-infected diabetic women.
PMCID: PMC2943237  PMID: 20587850
11.  Brief Report: Plasma Homocysteine is Not Associated with HIV Serostatus or Antiretroviral Therapy in Women 
The effects of HIV serostatus and combination antiretroviral therapy (cART) on plasma homocysteine (Hcy) are uncertain.
Plasma Hcy was assayed in a cross-sectional study of 249 HIV-infected and 127 HIV-uninfected women at the Bronx Women’s Interagency HIV Study site.
Mean plasma Hcy was 7.42 ± 2.68 in HIV-infected and 7.18 ± 2.66 µmol/L in HIV-uninfected women (P = 0.40). Hyperhomocysteinemia (defined as Hcy > 10 µmol/L) was seen in 16.9% and 13.4 % of HIV-infected and HIV-uninfected women, respectively (P=0.45). Among HIV-infected women, cART use was not associated with Hcy level. Compared to the lowest quartile, women with Hcy in the highest quartile had lower mean serum vitamin B12 and RBC folate levels. In multivariate analysis that did not include micronutrient levels, age, serum creatinine and lower CD4% were significantly associated with plasma Hcy level in HIV-infected women.
Plasma Hcy was not associated with HIV serostatus or use of cART in this cross-sectional study. Reduced availability of folate cofactors for Hcy remethylation in HIV-infected women with lower folate intake and decreased health status may influence Hcy levels.
PMCID: PMC2755615  PMID: 19333128
Homocysteine; HIV; women; vitamin B12; folate
12.  HCV/HIV Co-infection and Responses to Initial Antiretroviral Treatment 
AIDS (London, England)  2013;27(17):2725-2734.
To explore the relationship between HCV/HIV co-infection and responses to initial antiretroviral treatment (ART)
Four AIDS Clinical Trials Group HIV treatment studies' data were combined to compare initial ART responses between HCV/HIV co-infected and HIV mono-infected patients as evaluated by virologic failure, CD4 measures, occurrence of AIDS/death and Grade 3/4 safety events, using Kaplan-Meier estimates and proportional hazard, regression and mixed effects models, adjusting for baseline covariates.
Of the 3041 included subjects, 81% were male, 19% had prior history of AIDS, the median (25th, 75th percentile) baseline HIV RNA was 4.72 (4.38, 5.18) log10 copies/mL and the median (25th, 75th percentile) baseline CD4 was 216.0 (76.5, 327.0) cells/μL. The 279 HCV/HIV co-infected were older (44 vs. 37 years), more likely to be black non-Hispanic (47% vs. 36%) and history/current intravenous drug user (52% vs. 5%) than the 2762 HIV mono-infected subjects (All P-values < 0.001). HCV/HIV co-infection was associated with earlier virologic failure, hazard ratio (HR) (95% confidence interval): 1.43 (1.07, 1.91); smaller mean CD4 increase and CD4% increase (-33.8 (-52.2, -15.4) cells/μL and -1.16% (-1.43%, -0.89%), respectively) over a median of 132 weeks follow-up; earlier occurrence of Grade 3/4 safety event, HR 1.51 (1.26, 1.81); and increased AIDS/mortality, HR 2.10 (1.31, 3.37). Treatment effects comparing antiretroviral regimens were not significantly different by HCV/HIV co-infection status.
HCV/HIV co-infection is associated with attenuated response to ART. Results support earlier initiation of HIV therapy and increased monitoring of those initiating ART with HCV/HIV co-infection.
PMCID: PMC4214386  PMID: 23921611
HCV/HIV Co-infection; ART; Treatment Naïve; Early Virologic Failure; CD4 Responses
13.  Factors Associated with Smoking in HIV-Infected Patients and Potential Barriers to Cessation 
AIDS Patient Care and STDs  2013;27(11):604-612.
Smoking is common in patients with HIV and is associated with increased morbidity and mortality. With the goal of targeting future cessation interventions, we sought to identify factors associated with smoking status, readiness and confidence in cessation, and success in quitting. As part of a larger study in New York City assessing predictors of chronic obstructive pulmonary disease (COPD), we enrolled HIV-infected subjects at least 35 years of age without known asthma or COPD. Current smokers received detailed tobacco history, and smoking status was assessed by chart review at 3 and 6 months post-enrollment. Two hundred subjects were enrolled (29% current smokers, 31.5% never smokers, 39.5% former smokers, mean age of 49, 84% male, 64% had AIDS, and 97% were receiving antiretroviral therapy). Current smokers had higher unemployment and increased rates of other substance use than former smokers or never smokers. In multivariate analysis, being unemployed and having used inhalant drugs were associated with current smoking. Substance abuse history was not correlated with readiness to quit or patient estimated cessation. Lower education was associated with decreased readiness to quit. Follow-up smoking status for baseline current smokers was available for 47/58 enrollees at 6 months; 4 (9%) stopped smoking completely, and 17 (36%) decreased the number of packs-per-day. Smoking and concomitant substance abuse is common in HIV, and special attention should be given to this issue, in addition to a patient's readiness to quit, when implementing tobacco cessation protocols, especially in busy urban HIV care centers.
PMCID: PMC3820122  PMID: 24138488
14.  Forecasting Temporal Dynamics of Cutaneous Leishmaniasis in Northeast Brazil 
Cutaneous leishmaniasis (CL) is a vector-borne disease of increasing importance in northeastern Brazil. It is known that sandflies, which spread the causative parasites, have weather-dependent population dynamics. Routinely-gathered weather data may be useful for anticipating disease risk and planning interventions.
Methodology/Principal Findings
We fit time series models using meteorological covariates to predict CL cases in a rural region of Bahía, Brazil from 1994 to 2004. We used the models to forecast CL cases for the period 2005 to 2008. Models accounting for meteorological predictors reduced mean squared error in one, two, and three month-ahead forecasts by up to 16% relative to forecasts from a null model accounting only for temporal autocorrelation.
These outcomes suggest CL risk in northeastern Brazil might be partially dependent on weather. Responses to forecasted CL epidemics may include bolstering clinical capacity and disease surveillance in at-risk areas. Ecological mechanisms by which weather influences CL risk merit future research attention as public health intervention targets.
Author Summary
Cutaneous leishmaniasis (CL) is a disease resulting from infection by the Leishmania parasites, which humans may acquire when bitten by an infected sandfly. From a public health standpoint, it is important to identify cases early and monitor patients' clinical outcomes because unsuccessfully-treated patients are at risk for severe complications. Since weather conditions affect survival and reproduction of sandflies that transmit Leishmania, routinely-gathered weather and climate data may be useful for anticipating CL outbreaks, bolstering clinical capacity for high-risk periods, and initiating interventions such as active case-finding during these periods to limit disease burden. Here we assessed whether the number of CL cases occurring per month in a rural region of Bahía, Brazil was associated temperature, humidity, precipitation, and El Niño sea surface temperature oscillation patterns observed during preceding seasons. We formulated models that improved accuracy of one, two, and three month-ahead CL predictions by accounting for weather. Forecasts of this nature can contribute to reducing CL burden by informing resource allocation and intervention planning in preparation for epidemics.
PMCID: PMC4214672  PMID: 25356734
15.  Oxidant Stress in HIV-Infected Women from the Women’s Interagency HIV Study 
Antiviral therapy  2009;14(6):763-769.
Oxidant stress contributes to the pathogenesis of multiple conditions and can be assessed by measuring plasma F2-isoprostane concentrations. We hypothesized that oxidant stress is associated with plasma homocysteine concentration and risk factors for atherosclerosis in HIV-infected women.
We measured plasma F2-isoprostane concentrations in a cross-sectional study of 249 HIV-infected women attending the Bronx site of the Women’s Interagency HIV Study and assessed associations with plasma homocysteine concentration and other metabolic parameters by linear regression.
In multivariate analysis, HCV viremia, waist circumference, homocysteine concentration, and serum aspartate transanimase level were positively associated with log F2-isoprostane concentration (all P < 0.005). There was a trend for an inverse association between log F2-isoprostane and CD4% (P = 0.06). Among women with HCV infection, the FIB-4 index, an indirect marker of liver fibrosis derived from routine laboratory tests, was positively associated with log F2-isoprostane concentration.
In this cross-sectional study of HIV-infected women, plasma F2-isoprostane concentration was positively associated with homocysteine concentration, as well as HCV infection, abdominal obesity, and aspartate transaminase level.
PMCID: PMC2760028  PMID: 19812438
Oxidant stress; oxidative stress; F2-isoprostanes; homocysteine; HIV; HCV
16.  Vitamin D and Insulin Resistance in Non-Diabetic Women's Interagency HIV Study Participants 
AIDS Patient Care and STDs  2013;27(6):320-325.
We explored the relationship between vitamin D levels and insulin resistance (IR) among 1082 nondiabetic (754 HIV-infected) women enrolled in the Women's Interagency HIV study (WIHS), a large and well-established cohort of HIV infected and uninfected women in the US. Vitamin D levels 20–29 ng/mL were considered insufficient and <20 ng/mL deficient. IR was estimated using the homeostasis model assessment (HOMA) and a clinically significant cut-off ≥2.6 was used for HOMA-IR. In the unadjusted analysis, women who were vitamin D insufficient or deficient were 1.62 (95% CI: 1.01–2.61, p=0.05) and 1.70 (95% CI: 1.11–2.60, p=0.02) times more likely to have HOMA values≥2.6 compared to women with sufficient vitamin D. The association did not remain significant after adjustment for factors associated with IR. Among the 754 HIV-infected women, current PI use (OR 1.61, 95% CI: 1.13–2.28, p=0.008) remained independently associated with HOMA ≥2.6 while vitamin D insufficiency (OR 1.80, 95% CI: 0.99–3.27, p=0.05) was marginally associated with HOMA ≥2.6 after adjustment. Ethnicity, body mass index, smoking status, and hepatitis C status were independently associated with insulin resistance in HIV-infected and uninfected women. We found a marginally significant association between vitamin D insufficiency and insulin resistance among nondiabetic HIV-infected WIHS women.
PMCID: PMC3671624  PMID: 23675750
17.  Pregnancy Differentially Impacts Performance of Latent Tuberculosis Diagnostics in a High-Burden Setting 
PLoS ONE  2014;9(3):e92308.
Targeted screening for latent TB infection (LTBI) in vulnerable populations is a recommended TB control strategy. Pregnant women are at high risk for developing TB and likely to access healthcare, making pregnancy an important screening opportunity in developing countries. The sensitivity of the widely-used tuberculin skin test (TST), however, may be reduced during pregnancy.
We performed a cross-sectional study comparing the TST with the QuantiFERON Gold In-tube (QGIT) in 401 HIV-negative women presenting antepartum (n = 154), at delivery (n = 148), or postpartum (n = 99) to a government hospital in Pune, India. A subset of 60 women enrolled during pregnancy was followed longitudinally and received both tests at all three stages of pregnancy.
The QGIT returned significantly more positive results than the TST. Of the 401 women in the cross-sectional study, 150 (37%) had a positive QGIT, compared to 59 (14%) for the TST (p<0.005). Forty-nine (12%) did not have their TST read. Of 356 who had both results available, 46 (13%) were concordant positive, 91 (25%) were discordant (12 (3%) TST+/QGIT-; 79 (22%) TST−/QGIT+), and 206 (57%) concordant negative. Comparison by stage of pregnancy revealed that QGIT percent positivity remained stable between antepartum and delivery, unlike TST results (QGIT 31–32% vs TST 11–17%). Median IFN-γ concentration was lower at delivery than in antepartum or postpartum (1.66 vs 2.65 vs 8.99 IU/mL, p = 0.001). During postpartum, both tests had significantly increased positives (QGIT 31% vs 32% vs 52%, p = 0.01; TST 17% vs 11% vs 25%, p<0.005). The same trends were observed in the longitudinal subset.
Timing and choice of LTBI test during pregnancy impact results. QGIT was more stable and more closely approximated the LTBI prevalence in India. But pregnancy stage clearly affects both tests, raising important questions about how the complex immune changes brought on by pregnancy may impact LTBI screening.
PMCID: PMC3962385  PMID: 24658103
18.  Vitamin D insufficiency may impair CD4 recovery among Women’s Interagency HIV Study participants with advanced disease on HAART 
AIDS (London, England)  2013;27(4):573-578.
Recent studies in HIV-infected men report an association between low vitamin D (25OH-D) and CD4 recovery on HAART. We sought to test this relationship in the Women’s Interagency HIV Study (WIHS).
We examined 204 HIV-infected women with advanced disease, who started HAART after enrollment in the WIHS. We measured vitamin D (25OH-D) levels about 6 months prior to HAART initiation. The relationship between CD4 recovery (defined as increases of ≥50, 100, and 200 cells at 6, 12, and 24 months) and exposure variables was examined using logistic regression models at 6, 12 and 24 months post-HAART initiation in unadjusted and adjusted analyses, and using multivariable longitudinal Generalized Estimating Equations (GEE). Vitamin D insufficiency was defined as 25OH-D levels at least 30 ng/ml.
The majority were non-Hispanic black (60%) and had insufficient vitamin D levels (89%). In adjusted analyses, at 24 months after HAART, insufficient vitamin D level (OR 0.20, 95% CI 0.05–0.83) was associated with decreased odds of CD4 recovery. The undetectable viral load (OR 11.38, 95% CI 4.31–30.05) was associated with CD4 recovery. The multivariable GEE model found that average immune reconstitution attenuated significantly (P <0.01) over time among those with insufficient vitamin D levels compared with those with sufficient vitamin D levels.
Vitamin D insufficiency is associated with diminished late CD4 recovery after HAART initiation among US women living with advanced HIV. The mechanism of this association on late CD4 recovery may be late vitamin D-associated production of naive CD4 cells during immune reconstitution.
PMCID: PMC3902982  PMID: 23095316
antiretroviral therapy; HIV; immune reconstitution; vitamin D; women
19.  Effects of highly active antiretroviral therapy and its adherence on herpes zoster incidence: a longitudinal cohort study 
Herpes zoster (HZ) is common among HIV-infected individuals, but the impacts of highly active antiretroviral therapy (HAART) and HAART adherence on HZ risk have not been well studied.
The effects of HAART and HAART adherence on HZ incidence were evaluated by comparing HIV-infected women on HAART (HAART use group) with the HIV-infected women remaining HAART naïve (HAART naïve group) in the Women’s Interagency HIV Study (WIHS). A 1:1 matching with propensity score for predicting HAART initiation was conducted to balance background covariates at index visit, including HIV disease stage. Kaplan-Meier method was used to compare the risk of HZ development between the matched pairs. Cox proportional hazard models were used to assess the effects of HAART and HAART adherence on HZ incidence.
Through propensity score matching, 389 pairs of participants were identified and they contributed 3,909 person years after matching. The background covariates were similar between the matched pairs at the index visit. The participants had a mean age around 39 years old, and about 61% of them were Black and 22% were Latina. No significant difference in HZ risk was observed between the HAART use group and the HAART naïve group during the first year of follow-up in any analyses. In the univariate analysis, the HAART use group had marginally lower HZ risk (Hazard Ratio (HR): 0.72; 95% Confidence Interval (CI): 0.48-1.1) over the entire follow-up period. However, women with a HAART adherence level of ≥95% had significantly lower HZ risk (HR: 0.54; 95% CI: 0.31, 0.94) compared to the HAART naïve women. The association remained significant after adjusting for quality of life score and acyclovir use, but it attenuated and was no longer statistically significant after adjusting for an intermediate variable, either CD4+ T cell counts or HIV viral load.
Among adult women, we observed a significant preventive effect of long-term HAART use on HZ incidence when a HAART adherence level of ≥95% was attained, and this effect was mediated through reduction of HIV viral load and improvement of CD4+ T cell counts.
PMCID: PMC3904465  PMID: 24373482
HAART; Adherence; Herpes zoster; Incidence; Propensity score
20.  Lower Liver-Related Death in African American Women With HIV/HCV Co-Infection Compared to Caucasian and Hispanic Women 
Hepatology (Baltimore, Md.)  2012;56(5):1699-1705.
Among individuals with and without concurrent human immunodeficiency virus (HIV), racial/ethnic differences in the natural history of hepatitis C virus (HCV) have been described. African-Americans have lower spontaneous HCV clearance than Caucasians, yet slower rates of liver fibrosis once chronically infected. It is not clear how these differences in the natural history of hepatitis C affect mortality, in either HIV positive or negative individuals. We conducted a cohort study of HIV/HCV co-infected women followed in the multicenter, NIH-funded Women’s Interagency HIV Study (WIHS) to determine the association of self-reported race/ethnicity with all-cause and liver-related mortality. Survival analyses were performed using Cox proportional hazards models. The eligible cohort (n=794) included 140 Caucasians, 159 Hispanics, and 495 African Americans. There were 438 deaths and 49 liver-related deaths during a median follow-up of 8.9 years and maximum follow-up of 16 years. African American co-infected women had significantly lower liver-related mortality compared to Caucasian (HR 0.41 95% CI 0.19–0.88, p=0.022) and Hispanic co-infected women (HR 0.38 95% CI 0.19–0.76, p=0.006). All-cause mortality was similar between racial/ethnic groups (HRs for all comparisons 0.82–1.03, logrank p=0.8).
African American co-infected women were much less likely to die from liver disease as compared to Caucasians and Hispanics, independent of other causes of death. Future studies are needed to investigate the reasons for this marked racial/ethnic discrepancy in liver-related mortality.
PMCID: PMC3440547  PMID: 22618868
race; ethnicity; viral hepatitis; mortality; gender
21.  Immunological and Viral Features in Patients with Overactive Bladder Associated with Human T-Cell Lymphotropic Virus Type 1 Infection 
Journal of medical virology  2012;84(11):1809-1817.
The majority of patients infected with human T-cell lymphotropic virus-type 1 (HTLV-1) are considered carriers, but a high frequency of urinary symptoms of overactive bladder, common in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) have been documented in these patients. The aim of this study was to determine if immunological and viral factors that are seen in HAM/TSP are also observed in these patients. Participants were classified as HTLV-1 carriers (n=45), HTLV-1 patients suffering from overactive bladder (n=45) and HAM/TSP (n=45). Cells from HTLV-1 overactive bladder patients produced spontaneously more proinflammatory cytokines than carriers. TNF-α and IL-17 levels were similar in HAM/TSP and HTLV-1 overactive bladder patients. High proviral load was found in patients with overactive bladder and HAM/TSP and correlated with proinflammatory cytokines. In contrast with findings in patients with HAM/TSP, serum levels of Th1 chemokines were similar in HTLV-1 overactive bladder and carriers. Exogenous addition of regulatory cytokines decreased spontaneous IFN-γ production in cell cultures from HTLV-1 overactive bladder patients. The results show that HTLV-1 overactive bladder and HAM/TSP patients have in common some immunological features as well as similar proviral load profile. The data show that HTLV-1 overactive bladder patients are still able to down regulate their inflammatory immune response. In addition, these patients express levels of chemokines similar to carriers, which may explain why they have yet to develop the same degree of spinal cord damage as seen in patients with HAM/TSP. These patients present symptoms of overactive bladder, which may be an early sign of HAM/TSP.
PMCID: PMC3457650  PMID: 22997085
HTLV-1; immune response; cytokines; chemokines; proviral load
22.  Association of HIV infection with Incident Diabetes Mellitus: Impact of using Hemoglobin A1C as a Criterion for Diabetes 
Data regarding the association between HIV and DM are conflicting, with little known regarding the impact of including hemoglobin A1C (A1C) as a criterion for DM.
Pooled logistic regression was used to quantify the association between HIV and DM in 1501 HIV-infected and 550 HIV-uninfected participants from the Women’s Interagency HIV Study. Incident DM was defined using three DM definitions: (I) fasting glucose (FG) ≥126mg/dl, anti-DM medication, or reporting DM diagnosis (with confirmation by FG≥126mg/dl or anti-DM medication); (II) confirmation with a second FG≥126mg/dl; and (III) addition of A1C≥6.5% confirmed by FG≥126mg/dl or anti-DM medication.
DM incidence per 100 person-years was 2.44, 1.55, and 1.70 for HIV-infected women; 1.89, 0.85, and 1.13 for HIV-uninfected women, using definition I, II, and III, respectively. After adjustment for traditional DM risk factors, HIV infection was associated with 1.23, 1.90, and 1.38-fold higher risk of incident DM, respectively; the association reached statistical significance only when confirmation with a second FG≥126mg/dl was required. Older age, obesity, and a family history of DM were each consistently and strongly associated with increased DM risk.
HIV infection is consistently associated with greater risk of DM. Inclusion of an elevated A1C to define DM increases the accuracy of the diagnosis and only slightly attenuates the magnitude of the association otherwise observed between HIV and DM. By contrast, a DM diagnosis made without any confirmatory criteria for FG ≥126mg/dl overestimates the incidence, while also underestimating the effects of HIV on DM risk, and should be avoided.
PMCID: PMC3480977  PMID: 22878421
Diabetes mellitus; HIV; Women; Hemoglobin A1C
23.  Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis 
AIDS (London, England)  2012;26(5):599-607.
Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART.
HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women’s Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed.
Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death.
Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV.
PMCID: PMC3698040  PMID: 22156972
fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality
24.  Effects of a Reduced Dose of Stavudine on the Incidence and Severity of Peripheral Neuropathy in HIV-Infected Adults in South Africa 
Antiviral therapy  2012;17(4):737-743.
Although recent WHO guidelines recommend withdrawing stavudine (d4T) from first-line ART therapy, it remains commonly used in resource-constrained settings. In 2006, WHO recommended decreasing the dose of d4T from 40mg to 30mg to mitigate toxicities. We compared the incidence and severity of peripheral neuropathy (PN) by d4T dose in a retrospective cohort study.
Patients’ charts from an ART-naïve population at a rural clinic in KZN, South Africa were retrospectively reviewed for signs and symptoms of incident PN and were graded for severity using the DAIDs scale. Patients enrolled prior to the WHO guideline change were enrolled if they were on d4T 40mg for at least 6 months. After the guideline change all patients were initiated on d4T 30mg.
A total of 475 patients were analyzed; 235 in the 40mg cohort (152.7 person-years [py]) and 240 in the 30mg cohort (244.7py). Incidence of peripheral neuropathy was 90.4/100 py (95% CI:75.9–106.8) in the 40mg cohort versus 40.5/100py (95% CI:32.9–49.3) in the 30mg group (incidence rate ratio [IRR]=0.45, p <0.0001). There was no difference in proportion of severe peripheral neuropathy cases (grade 3/4) between the cohorts; 8.3% in the 40mg group and 8.9% in the 30mg group (p=1.0). In a multivariate analysis risk of peripheral neuropathy was associated with increasing age (HR=1.65 95% CI:1.24–2.19), 40 mg dose (HR=2.1, 95% CI:1.61–2.74) and concurrent tuberculosis therapy (HR= 1.41 95% CI:1.06–1.87).
Incidence of peripheral neuropathy in the 40mg cohort was extremely high and though lower in the 30mg cohort, the rate was nonetheless unacceptably high.
PMCID: PMC3662496  PMID: 22414588
25.  Fractures after antiretroviral initiation 
AIDS (London, England)  2012;26(17):2175-2184.
Bone mineral density declines by 2–6% within 1–2 years after initiation of antiretroviral therapy (ART); however, it is uncertain whether this results in an immediate or cumulative increase in fracture rates.
We evaluated the incidence and predictors of fracture in 4640 HIV-positive participants from 26 randomized ART studies followed in the AIDS Clinical Trials Group (ACTG) Longitudinal-Linked Randomized Trial study for a median of 5 years. Fragility and nonfragility fractures were recorded prospectively at semiannual visits. Incidence was calculated as fractures/total person-years. Cox proportional hazards models evaluated effects of traditional fracture risks, HIV disease characteristics, and ART exposure on fracture incidence.
Median (interquartile range) age was 39 (33, 45) years; 83% were men, 48% white, and median nadir CD4 cell count was 187 (65, 308) cells/μl. Overall, 116 fractures were reported in 106 participants with median time-to-first fracture of 2.3 years. Fracture incidence was 0.40 of 100 person-years among all participants and 0.38 of 100 person-years among 3398 participants who were ART naive at enrollment into ACTG parent studies. Among ART-naive participants, fracture rates were higher within the first 2 years after ART initiation (0.53/100 person-years) than subsequent years (0.30/100 person-years). In a multivariate analysis of ART-naive participants, increased hazard of fracture was associated with current smoking and glucocorticoid use but not with exposure to specific antiretrovirals.
Fracture rates were higher within the first 2 years after ART initiation, relative to subsequent years. However, continuation of ART was not associated with increasing fracture rates in these relatively young HIV-positive individuals.
PMCID: PMC3652631  PMID: 22951635
antiretroviral initiation; bone loss; fracture; fracture incidence; HIV

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