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1.  Population-based Surveillance of HIV Drug Resistance Emerging on Treatment and Associated Factors at Sentinel Antiretroviral Therapy Sites in Namibia 
World Health Organization (WHO) prospective surveys of acquired HIV drug resistance (HIVDR) evaluate HIVDR emerging after the first year of antiretroviral therapy (ART) and associated factors.
Consecutive ART starters in 2009 were enrolled at three sentinel sites in Namibia. Genotyping was performed at start and after 12 months in patients with HIV viral load (VL) >1000 copies/mL. HIVDR outcomes were: HIVDR Prevention (VL ≤1000 copies/mL), Possible HIVDR (VL>1000 copies/mL without detectable HIVDR or loss to follow-up (LTFU) or ART stop), and HIVDR (VL>1000 copies/mL with detectable HIVDR). Adherence was assessed using medication possession ratio (MPR).
Of 394 starters, at 12 months 80% were on first-line ART, 1% died, 4% transferred out, 1% stopped ART, <1% switched to second-line and 15% were LTFU. Among patients on first-line, 77% had VL testing. 94% achieved VL ≤1000 copies/mL. At baseline, 7% had HIVDR. After 12 months, among patients with VL testing, 5% had HIVDR. A majority of patients failing therapy had high level resistance to non-nucleoside reverse transcriptase inhibitors but none to protease inhibitors. All sites achieved WHO target of ≥70% HIVDR Prevention. Factors associated with not achieving HIVDR Prevention were: baseline resistance to non-nucleoside reverse transcriptase inhibitors (OR 3.0, p=0.023), WHO stage 3 or 4 at baseline (OR 2.0, p=0.012), and MPR<75% (OR 4.9, p=0.021).
Earlier ART initiation and removal of barriers to on-time drug pickups may help to prevent HIVDR. These data inform decisions at national and global levels on the effectiveness of first- and second-line regimens.
PMCID: PMC4334707  PMID: 25564107
HIV; AIDS; Africa; anti-retroviral agents; drug resistance; adherence
2.  Household Food Insecurity Associated with Antiretroviral Therapy Adherence Among HIV-infected Patients in Windhoek, Namibia 
Food insecurity is emerging as an important barrier to antiretroviral therapy (ART) adherence. The objective of this study was to determine if food insecurity is associated with poor ART adherence among HIV-positive adults in a resource-limited setting that utilizes the public health model of delivery.
A cross-sectional study using a one-time questionnaire and routinely collected pharmacy data.
Participants were HIV-infected adults on ART at the public ART clinics in Windhoek, Namibia: Katutura State Hospital, Katutura Health Centre, and Windhoek Central Hospital. Food insecurity was measured by the Household Food Insecurity Access Scale (HFIAS). Adherence was assessed by the pharmacy adherence measure medication possession ratio (MPR). Multivariate regression was used to assess whether food insecurity was associated with ART adherence.
Among 390 participants, 7% were food secure, 25% were mildly or moderately food insecure and 67% were severely food insecure. In adjusted analyses, severe household food insecurity was associated with MPR <80% (OR 3.84, 1.65 to 8.95). Higher household healthcare spending (OR 1.92, 1.02 to 3.57) and longer duration of ART (OR 0.82, 0.70 to 0.97) were also associated with <80% MPR.
Severe household food insecurity is present in more than half of the HIV-positive adults attending a public ART clinic in Windhoek, Namibia, and is associated with poor ART adherence as measured by MPR. Ensuring reliable access to food should be an important component of ART delivery in resource-limited settings using the public health model of care.
PMCID: PMC4215168  PMID: 25356779
HIV; AIDS; Namibia; antiretroviral adherence; food insecurity
3.  High-Fat Meals Do Not Impair Postprandial Endothelial Function in HIV-Infected and Uninfected Men 
Prior studies have demonstrated impaired endothelium-dependent flow-mediated dilation (FMD) in healthy subjects following a high-fat meal. Compared to uninfected individuals, HIV-infected persons have been shown to have impaired FMD. We examined the effect of two different high-fat meals on endothelial function in HIV-infected and uninfected men. We performed a randomized, parallel group crossover study comparing 47 white men [18 HIV-uninfected, 9 HIV-infected and antiretroviral therapy (ART)-naïve, and 20 HIV-infected men on ART]. Fasting participants consumed one of two randomly assigned high-fat meals of either saturated or polyunsaturated fat, followed at least 24 h later by the other meal. Brachial artery ultrasound measurements to assess vascular reactivity were performed before and 3 h after each dietary challenge. There was no significant difference in mean baseline or postprandial FMD between HIV-infected and HIV-uninfected participants (mean baseline FMD±SD, 9.0%±5 vs. 9.2%±5, p=0.9; mean postprandial FMD±SD, 9.0%±4.7 vs. 9.1%±4.7, p=0.96, respectively). No significant difference in baseline or postprandial change in FMD was found between meals or HIV treatment groups. Fasting lipids and glucose, CD4+ count, and viral load did not predict FMD in HIV-infected participants. In contrast to previous reports, this study did not demonstrate impaired endothelium-dependent vasodilation after high-fat meals in either HIV-infected or HIV-uninfected men. Moreover, HIV infection itself may not be the primary explanation for the abnormal endothelial function reported in HIV-infected individuals.
PMCID: PMC4151053  PMID: 24892462
4.  Short Communication: Effects of Omega-3 Fatty Acids on Triglycerides and High-Density Lipoprotein Subprofiles in HIV-Infected Persons with Hypertriglyceridemia 
Hypertriglyceridemia and low high-density lipoprotein (HDL)-cholesterol (HDL-C) may contribute to a presumed accelerated risk for cardiovascular disease in HIV-infected individuals. We evaluated the effect of omega-3 fatty acid treatment on triglycerides, low-density lipoprotein (LDL)-C, HDL-C, and HDL subpopulations. Forty-one HIV-seropositive subjects with hypertriglyceridemia (≥150 mg/dl) on active antiretroviral therapy were enrolled in this placebo-controlled, double-blind, randomized, crossover trial comparing the effects of omega-3 fatty acid treatment (1.9 g EPA and 1.5 g DHA) on triglycerides, LDL-C, HDL-C, and HDL subpopulations. An independent sample t-test was used to assess the study start to posttreatment change for all components. After omega-3 fatty acid treatment, triglyceride levels decreased 63.2±86.9 mg/dl (p<0.001). No significant changes in total cholesterol, LDL-C, or HDL-C were found. Within HDL subpopulations, significant changes were seen in the most atheroprotective HDL particles, α-1, which increased by 2.5±5.6 mg/dl (p<0.05), and preα-1, which increased by 0.6±1.0 mg/dl (p<0.001). Preα-3, a presumably atherogenic HDL particle, decreased by 0.5±0.9 mg/dl (p<0.01). Omega-3 fatty acid treatment significantly lowered triglyceride levels in HIV-positive patients with moderate hypertriglyceridemia. While no study-wide improvements in LDL-C or HDL-C were detected, the HDL subpopulation profile changed in a beneficial way suggesting more cardioprotection after treatment.
PMCID: PMC4118719  PMID: 24988179
5.  Switch to Raltegravir Decreases Soluble CD14 in Virologically Suppressed Overweight Women: The Women, Integrase, and Fat Accumulation Trial 
HIV medicine  2014;15(7):431-441.
Soluble CD14 (sCD14) is a monocyte activation marker associated with increased mortality in HIV. We assessed 48-week changes in sCD14 and other inflammatory biomarkers in virologically suppressed, HIV-infected women switching to raltegravir (RAL) from PI or NNRTI.
HIV-infected women with central adiposity and HIV-1 RNA <50 copies/mL continued their thymidine-sparing NRTI backbone and were randomized to switch to open-label RAL at week 0 (immediate) or 24 (delayed). In an exploratory analysis, inflammatory biomarkers were measured on stored fasting plasma.
Thirty-seven evaluable subjects were 78% non-White and had median age 43 years, BMI 32 kg/m2 and CD4+ T cell count 558 cells/µL. At baseline, biomarker values were similar between groups. After 24 weeks, median sCD14 significantly declined in subjects switching to RAL (−21% (p<0.001) vs. PI/NNRTI −5% (p=0.49), between group p<0.01). After 48 weeks, immediate switch subjects maintained this decline and delayed switch subjects experienced a similar decline following switch to RAL (−10%, within-group p<0.01). Immediate switch subjects also experienced an initial increase in TNF-α that was neither maintained after 48 weeks nor seen in delayed switch subjects. After adjustment for multiple testing, only declines in sCD14 remained significant.
In this randomized trial of women with central adiposity, switch to RAL from PI or NNRTI was associated with a statistically significant decline in sCD14. Further studies are needed to determine whether integrase inhibitors have improved monocyte activation profiles compared to PIs and/or NNRTIs, and whether measured differences between antiretroviral agents translate to demonstrable clinical benefit.
PMCID: PMC4107004  PMID: 24506429
raltegravir; sCD14; monocyte activation; inflammation; women
6.  Cardiovascular Disease-Risk Markers in HIV Patients 
HIV-positive patients have an increased risk for CVD; however, the underlying mechanisms are not well understood. Our goal was to assess traditional and emerging CVD-risk factors in the CARE Study, a well-described cohort of HIV-infected adults.
We analyzed demographic and clinical (viral load, CD4 count, ART regimen, cIMT) data including markers of lipid and glucose homeostasis in 176 HIV-positive subjects receiving regular care for HIV infection.
No significant association between cIMT and LDL-C level was observed. HIV patients had significantly lower level of the large α-1 HDL particles and about 3-fold higher level of the small pre β-1 HDL particles than the normal population, but these parameters were not significantly associated with cIMT. Components of the metabolic syndrome, high TG/low HDL-C, insulin resistance and high BMI, as well as viral load were significant but moderate contributors to increased cIMT.
The major lipid disorder was low HDL-C and high TG level in this HIV-positive cohort. LDL-C was not elevated. These and previously published data indicate that HIV infection and HIV medications influence CVD risk by impairing cholesterol removal (efflux) via ABCA1 from macrophages. Decreasing CVD risk in HIV patients, with impaired cholesterol efflux from macrophages, may require a lower LDL-C goal than recommended for HIV-negative patients and also a better control of TG level.
PMCID: PMC4439003  PMID: 26005590
HIV; CVD risk; ART
7.  Switch to Raltegravir From Protease Inhibitor or Nonnucleoside Reverse-Transcriptase Inhibitor Does not Reduce Visceral Fat In Human Immunodeficiency Virus-Infected Women With Central Adiposity 
Open Forum Infectious Diseases  2015;2(2):ofv059.
Human immunodeficiency virus-infected women with central adiposity switched to raltegravir-based antiretroviral therapy immediately or after 24 weeks. No statistically significant changes in computed tomography-quantified visceral adipose tissue (VAT) or subcutaneous fat were observed, although 48 weeks of raltegravir was associated with a 6.4% VAT decline. Raltegravir for 24 weeks was associated with improvements in lipids.
PMCID: PMC4567084  PMID: 26380350
antiretroviral therapy; fat; HIV; raltegravir; visceral; women
8.  Immune Response and Intestinal Permeability in Children With Acute Gastroenteritis Treated With Lactobacillus rhamnosus GG: A Randomized, Double-Blind, Placebo-Controlled Trial 
Supplementation with the probiotic Lactobacillus rhamnosus GG (LGG) is safe, decreases repeated episodes of diarrhea, improves intestinal permeability, and increases IgG antibody response in rotavirus diarrhea in Indian children.
Background. Probiotics have a possible role in the treatment of pediatric acute gastroenteritis. We report the effect of the probiotic Lactobacillus rhamnosus GG (LGG) on intestinal function, immune response, and clinical outcomes in Indian children with cryptosporidial or rotavirus diarrhea.
Methods. Children with gastroenteritis aged 6 months to 5 years, testing positive for either rotavirus or Cryptosporidium species in stool (coinfections were excluded), were randomized to LGG (ATCC 53103) or placebo, once daily for 4 weeks. Baseline demographic and clinical details were obtained. Sera were tested for immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to Cryptosporidium and rotavirus, and the lactulose to mannitol ratio for intestinal permeability was determined at baseline and at the end of follow-up.
Results. Of the 124 children enrolled, 82 and 42 had rotavirus and cryptosporidial diarrhea, respectively. Median diarrheal duration was 4 days; one-third of the children had severe diarrhea. Baseline and clinical parameters were comparable between children receiving LGG and placebo. At the end of follow-up, fewer children with rotavirus diarrhea on LGG had repeated diarrheal episodes (25% vs 46%; P = .048) and impaired intestinal function (48% vs 72%; P = .027). Significant increase in IgG levels postintervention (456 vs 2215 EU; P = .003) was observed in children with rotavirus diarrhea receiving LGG. Among children with cryptosporidial diarrhea, those receiving LGG showed significant improvement in intestinal permeability.
Conclusions. LGG has a positive immunomodulatory effect and may be useful in decreasing repeated episodes of rotavirus diarrhea. Improvement in intestinal function in children with rotavirus and cryptosporidial gastroenteritis emphasizes the role of probiotics in treating intestinal impairment after infection.
Clinical Trials Registration. CTRI/2010/091/000339.
PMCID: PMC3967829  PMID: 24501384
probiotics; LGG; gastroenteritis; immune response; intestinal function
9.  Lipoprotein-Associated Phospholipase A2, a Novel Cardiovascular Inflammatory Marker, in HIV-Infected Patients 
Lipoprotein-associated phospholipase A2, an emerging biomarker of cardiovascular disease that is highly abnormal in HIV-infected patients and associated with several cardiometabolic and treatment-specific risk factors, may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification.
Background. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging biomarker of cardiovascular disease. This study was conducted to describe the distribution of Lp-PLA2 in a cohort of human immunodeficiency virus (HIV)–infected adults and to determine associations between Lp-PLA2, cardiometabolic risk factors, and subclinical atherosclerosis in this population.
Methods. Lp-PLA2 was assessed in 341 (25% women, 52% white, 74% on highly active antiretroviral therapy [HAART]) participants of a cohort with detailed characterization of atherogenic risk factors, including surrogate markers of carotid and coronary atherosclerosis.
Results. Mean Lp-PLA2 mass was 313 ± 105 ng/mL and activity 173 ± 49 nmol/minute/mL. Seventy-five percent of participants had abnormal Lp-PLA2. Those in the highest Framingham Risk Score tertile had significantly higher Lp-PLA2 activity. Participants with abnormal carotid intima-media thickness (cIMT) had higher Lp-PLA2 mass and activity. Those with coronary artery calcium (CAC) scores >100 had significantly higher Lp-PLA2 mass than those with lower or nondetectable calcium. Those on HAART and protease inhibitor (PI)–based treatment had significantly higher Lp-PLA2 mass and activity than those who were treatment-naive or not on PIs. In multivariate regression, HAART and PI use were positively associated with Lp-PLA2 activity and mass after adjusting for age, race, sex, low-density and high-density lipoprotein cholesterol levels, triglyceride level, and smoking. Adding Lp-PLA2 activity tertiles to the model improved the predictive value for abnormal common cIMT, but not internal cIMT or CAC score.
Conclusions. Lp-PLA2 is highly abnormal in HIV-infected patients and is associated with several cardiovascular and HIV treatment-specific risk factors. Lp-PLA2 may be used as an additional and more vascular specific biomarker for cardiovascular risk stratification in HIV-positive patients.
PMCID: PMC3935500  PMID: 24336757
HIV; cardiovascular; inflammation; LpPLA2; atherosclerosis
10.  HIV Drug Resistance Profiles and Clinical Outcomes in Patients with Viremia Maintained at Very Low Levels 
World journal of AIDS  2013;3(2):71-78.
We describe an observational study of clinical, virologic and drug resistance profiles in HIV-positive antiretroviral adherent subjects with stable low level viremia (LLV) 50–1,000 copies/mL for more than 12 months. Subjects were followed from time of first detectable viral load (VL). In total, 102 episodes of LLV were detected among 80 individuals. The median (mean, range) HIV copy number at genotyping was 250 (486, <50–3900) copies/mL after 14 (17.9, 0–58) months of LLV. Few patients maintained LLV for the entire 9 year period of observation, with half (52%) experiencing viremic progression following a stable period of LLV either spontaneously or after treatment interruption or failed regimen intensification. In the setting of prolonged periods of sustained LLV, mean duration 22 (range 8 – 106) months, drug resistance (DR) was almost universal. Resistance to ≥1 on-treatment drugs was defined in 97% of specimens and DR to all drugs in the treatment regimen in over half of all patients. Evolution of DR mutations during the period of LLV was observed in 20/28 (71%) subjects with specimens available for follow-up testing. This evolution was associated with viremic progression to levels >1000 copies/mL (p=0.03).
Our data suggest that DR present in patients with LLV is likely to impact long term clinical outcomes, highlighting the importance of optimizing techniques to detect the presence of drug resistant HIV in the setting of LLV and the need for larger prospective studies to assess the emergence of DR in the setting of sustained LLV and the impact of this DR on treatment outcomes.
PMCID: PMC4319662  PMID: 25664219
HIV; low level viremia; treatment experienced patients; HIV drug resistance
11.  Progression of Carotid Intima-Media Thickness and Coronary Artery Calcium over Six Years in an HIV-infected Cohort 
Journal of acquired immune deficiency syndromes (1999)  2013;64(1):10.1097/QAI.0b013e31829ed726.
To evaluate changes in cardiovascular disease risk surrogate markers in a longitudinal cohort of HIV-infected adults over 6 years.
Internal and common carotid artery intima-media thickness, coronary artery calcium, vascular and HIV risk factors were prospectively examined over 6 years in HIV-infected adults from 2002 to 2010.
Longitudinal cohort study with participants from urban center and surrounding communities.
Subjects, participants
345 HIV-infected participants were recruited from a longitudinal cohort study. 211 participants completed the study and were included in this analysis.
Main Outcome Measures
Total and yearly internal and common carotid artery intima-media thickness change; coronary artery calcium score progression.
Participants were 27% female and 49% non-white; mean age at start was 45 ± 7 years. The median change in internal and common carotid arteries over six years was 0.15mm (0.08,0.28) and 0.12mm (0.09,0.15), respectively. Age, baseline triglycerides ≥ 150mg/dL, and pack-years smoking were associated with internal carotid artery intima-media thickness change; age, cholesterol, nadir CD4+ count, and protease inhibitor use were associated with common carotid artery intima-media thickness change. Diabetes, HIV viral load, and HAART duration were associated with coronary artery calcium progression.
Carotid intima-media thickness and coronary artery calcium progressed in this HIV-infected cohort. Some HIV-specific characteristics were associated with surrogate marker changes, but the majority of risk factors continue to be traditional. Aggressive identification and management of modifiable risk factors may reduce progression of cardiovascular disease risk in this population.
PMCID: PMC3815556  PMID: 23945252
12.  Changes in HIV-1 Subtypes B and C Genital Tract RNA in Women and Men After Initiation of Antiretroviral Therapy 
Fiscus, Susan A. | Cu-Uvin, Susan | Eshete, Abel Tilahun | Hughes, Michael D. | Bao, Yajing | Hosseinipour, Mina | Grinsztejn, Beatriz | Badal-Faesen, Sharlaa | Dragavon, Joan | Coombs, Robert W. | Braun, Ken | Moran, Laura | Hakim, James | Flanigan, Timothy | Kumarasamy, N. | Campbell, Thomas B. | Klingman, Karin L. | Nair, Apsara | Walawander, Ann | Smeaton, Laura M. | De Gruttola, Victor | Martinez, Ana I. | Swann, Edith | Barnett, Ronald L. | Brizz, Barbara | Delph, Yvette | Gettinger, Nikki | Mitsuyasu, Ronald T. | Eshleman, Susan | Safren, Steven | Andrade, Adriana | Haas, David W. | Amod, Farida | Berthaud, Vladimir | Bollinger, Robert C. | Bryson, Yvonne | Celentano, David | Chilongozi, David | Cohen, Myron | Collier, Ann C. | Currier, Judith Silverstein | Eron, Joseph | Firnhaber, Cynthia | Flexner, Charles | Gallant, Joel E. | Gulick, Roy M. | Hammer, Scott M. | Hoffman, Irving | Kazembe, Peter | Kumwenda, Johnstone | Kumwenda, Newton | Lama, Javier R. | Lawrence, Jody | Maponga, Chiedza | Martinson, Francis | Mayer, Kenneth | Nielsen, Karin | Pendame, Richard B. | Ramratnam, Bharat | Rooney, James F. | Sanchez, Jorge | Sanne, Ian | Schooley, Robert T. | Snowden, Wendy | Solomon, Suniti | Tabet, Steve | Taha, Taha | Uy, Jonathan | van der Horst, Charles | Wanke, Christine | Gormley, Joan | Marcus, Cheryl J. | Putnam, Beverly | Ntshele, Smanga | Loeliger, Edde | Pappa, Keith A. | Webb, Nancy | Shugarts, David L. | Winters, Mark A. | Descallar, Renard S. | Sharma, Jabin | Poongulali, S. | Cardoso, Sandra Wagner | Faria, Deise Lucia | Berendes, Sima | Burke, Kelly | Kanyama, Cecelia | Kayoyo, Virginia | Samaneka, Wadzanai P. | Chisada, Anthony | Santos, Breno | La Rosa, Alberto | Infante, Rosa | Balfour, Henry H. | Mullan, Beth | Kim, Ge-Youl | Klebert, Michael K. | Mildvan, Donna | Revuelta, Manuel | Jan Geiseler, P. | Santos, Bartolo | Daar, Eric S. | Lopez, Ruben | Frarey, Laurie | Currin, David | Haas, David H. | Bailey, Vicki L. | Tebas, Pablo | Zifchak, Larisa | Sha, Beverly E. | Fritsche, Janice M.
Women with human immunodeficiency virus (HIV)–1 subtype C had significantly higher genital tract viral loads compared to women with HIV-1 subtype B and men with HIV-1 subtype C or B. Women in general were significantly less likely to have genital tract viral load below the lower limit of quantification compared to men.
Background. Combination antiretroviral therapy (cART) reduces genital tract human immunodeficiency virus type 1 (HIV-1) load and reduces the risk of sexual transmission, but little is known about the efficacy of cART for decreasing genital tract viral load (GTVL) and differences in sex or HIV-1 subtype.
Methods. HIV-1 RNA from blood plasma, seminal plasma, or cervical wicks was quantified at baseline and at weeks 48 and 96 after entry in a randomized clinical trial of 3 cART regimens.
Results. One hundred fifty-eight men and 170 women from 7 countries were studied (men: 55% subtype B and 45% subtype C; women: 24% subtype B and 76% subtype C). Despite similar baseline CD4+ cell counts and blood plasma viral loads, women with subtype C had the highest GTVL (median, 5.1 log10 copies/mL) compared to women with subtype B and men with subtype C or B (4.0, 4.0, and 3.8 log10 copies/mL, respectively; P < .001). The proportion of participants with a GTVL below the lower limit of quantification (LLQ) at week 48 (90%) and week 96 (90%) was increased compared to baseline (16%; P < .001 at both times). Women were significantly less likely to have GTVL below the LLQ compared to men (84% vs 94% at week 48, P = .006; 84% vs 97% at week 96, P = .002), despite a more sensitive assay for seminal plasma than for cervical wicks. No difference in GTVL response across the 3 cART regimens was detected.
Conclusions. The female genital tract may serve as a reservoir of persistent HIV-1 replication during cART and affect the use of cART to prevent sexual and perinatal transmission of HIV-1.
PMCID: PMC3689341  PMID: 23532477
HIV-1 genital tract RNA; HIV-1 subtypes B and C; antiretroviral drugs
13.  Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons 
Rotger, Margalida | Glass, Tracy R. | Junier, Thomas | Lundgren, Jens | Neaton, James D. | Poloni, Estella S. | van 't Wout, Angélique B. | Lubomirov, Rubin | Colombo, Sara | Martinez, Raquel | Rauch, Andri | Günthard, Huldrych F. | Neuhaus, Jacqueline | Wentworth, Deborah | van Manen, Danielle | Gras, Luuk A. | Schuitemaker, Hanneke | Albini, Laura | Torti, Carlo | Jacobson, Lisa P. | Li, Xiuhong | Kingsley, Lawrence A. | Carli, Federica | Guaraldi, Giovanni | Ford, Emily S. | Sereti, Irini | Hadigan, Colleen | Martinez, Esteban | Arnedo, Mireia | Egaña-Gorroño, Lander | Gatell, Jose M. | Law, Matthew | Bendall, Courtney | Petoumenos, Kathy | Rockstroh, Jürgen | Wasmuth, Jan-Christian | Kabamba, Kabeya | Delforge, Marc | De Wit, Stephane | Berger, Florian | Mauss, Stefan | de Paz Sierra, Mariana | Losso, Marcelo | Belloso, Waldo H. | Leyes, Maria | Campins, Antoni | Mondi, Annalisa | De Luca, Andrea | Bernardino, Ignacio | Barriuso-Iglesias, Mónica | Torrecilla-Rodriguez, Ana | Gonzalez-Garcia, Juan | Arribas, José R. | Fanti, Iuri | Gel, Silvia | Puig, Jordi | Negredo, Eugenia | Gutierrez, Mar | Domingo, Pere | Fischer, Julia | Fätkenheuer, Gerd | Alonso-Villaverde, Carlos | Macken, Alan | Woo, James | McGinty, Tara | Mallon, Patrick | Mangili, Alexandra | Skinner, Sally | Wanke, Christine A. | Reiss, Peter | Weber, Rainer | Bucher, Heiner C. | Fellay, Jacques | Telenti, Amalio | Tarr, Philip E.
We show in human immunodeficiency virus–positive persons that the coronary artery disease effect of an unfavorable genetic background is comparable to previous studies in the general population, and comparable in size to traditional risk factors and antiretroviral regimens known to increase cardiovascular risk.
Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection.
Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort.
Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD.
Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.
PMCID: PMC3669528  PMID: 23532479
HIV infection; coronary artery disease; genetics; traditional risk factors; antiretroviral therapy
14.  Pharmacy and self-report adherence measures to predict virological outcomes for patients on free antiretroviral therapy in Tamil Nadu, India 
AIDS and behavior  2013;17(6):2253-2259.
Over 480,000 individuals receive free antiretroviral therapy (ART) in India yet data associating ART adherence with HIV viral load for populations exclusively receiving free ART are not available. Additionally estimates of adherence using pharmacy data on ART pick-up are not available for any population in India. After 12-months ART we found self-reported estimates of adherence were not associated with HIV viral load. Individuals with < 100% adherence using pharmacy data predicted HIV viral load, and estimates combining pharmacy data and self-report were also predictive. Pharmacy adherence measures proved a feasible method to estimate adherence in India and appear more predictive of virological outcomes than self-report. Predictive adherence measures identified in this study warrant further investigation in populations receiving free ART in India to allow for identification of individuals at risk of virological failure and in need of adherence support.
PMCID: PMC3674125  PMID: 23435750
HIV; adherence; antiretroviral therapy; India; virological outcomes
15.  Urinary Eicosanoid Metabolites in HIV-Infected Women with Central Obesity Switching to Raltegravir: An Analysis from the Women, Integrase, and Fat Accumulation Trial 
Mediators of Inflammation  2014;2014:803095.
Chronic inflammation is a hallmark of HIV infection. Eicosanoids reflect inflammation, oxidant stress, and vascular health and vary by sex and metabolic parameters. Raltegravir (RAL) is an HIV-1 integrase inhibitor that may have limited metabolic effects. We assessed urinary F2-isoprostanes (F2-IsoPs), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB2) in HIV-infected women switching to RAL-containing antiretroviral therapy (ART). Thirty-seven women (RAL = 17; PI/NNRTI = 20) with a median age of 43 years and BMI 32 kg/m2 completed week 24. TxB2 increased in the RAL versus PI/NNRTI arm (+0.09 versus −0.02; P = 0.06). Baseline PGI-M was lower in the RAL arm (P = 0.005); no other between-arm cross-sectional differences were observed. In the PI/NNRTI arm, 24-week visceral adipose tissue change correlated with PGI-M (rho = 0.45; P = 0.04) and TxB2 (rho = 0.44; P = 0.005) changes, with a trend seen for PGE-M (rho = 0.41; P = 0.07). In an adjusted model, age ≥ 50 years (N = 8) was associated with increased PGE-M (P = 0.04). In this randomized trial, a switch to RAL did not significantly affect urinary eicosanoids over 24 weeks. In women continuing PI/NNRTI, increased visceral adipose tissue correlated with increased PGI-M and PGE-M. Older age (≥50) was associated with increased PGE-M. Relationships between aging, adiposity, ART, and eicosanoids during HIV-infection require further study.
PMCID: PMC4058804  PMID: 24991090
16.  Metabolic Syndrome Predicts All-Cause Mortality in Persons with Human Immunodeficiency Virus 
AIDS Patient Care and STDs  2013;27(5):266-271.
We examined the association between metabolic syndrome (MS) and its individual defining criteria on all-cause mortality in human immunodeficiency virus (HIV)-infected persons. We used data from 567 HIV-infected participants of the Nutrition for Healthy Living study with study visits between 9/1/2000 and 1/31/2004 and determined mortality through 12/31/2006. MS was defined using modified National Cholesterol Education Program guidelines. Cox proportional hazards for all-cause mortality were estimated for baseline MS status and for its individual defining criteria. There were 83 deaths with median follow-up of 63 months. Baseline characteristics associated with increased risk of mortality were: older age in years (univariate hazard ratio [HR] 1.04, p<0.01), current smoking (HR 1.99, p=0.02), current heroin use (HR 1.97, p=0.02), living in poverty (HR 2.0, p<0.01), higher mean HIV viral load (HR 1.81, p<0.01), and having a BMI <18 (HR 5.84, p<0.01). For MS and its criteria, only low HDL was associated with increased risk of mortality on univariate analysis (HR 1.84, p=0.01). However, metabolic syndrome (adjusted HR 2.31, p=0.02) and high triglycerides (adjusted HR 3.97, p<0.01) were significantly associated with mortality beyond 36 months follow-up. MS, low HDL, and high triglycerides are associated with an increased risk of mortality in HIV-infected individuals.
PMCID: PMC3651687  PMID: 23651103
17.  Development of a nutrient-dense food supplement for HIV-infected women in rural Kenya using qualitative and quantitative research methods 
Public health nutrition  2012;16(4):721-729.
Formative research to facilitate the development, packaging and delivery of a culturally acceptable nutrition intervention for HIV-infected women in rural Kenya for an intervention trial.
Focus group discussion on three areas: (i) ingredients and form of the nutrition intervention, (ii) packaging and delivery and (iii) monitoring of adherence. Two single-blind taste tests with eleven different porridge formulations of various combinations of maize flour, soyabeans, peanuts, sorghum, mung beans, dried fish, raisins and dried whole milk. Follow-up acceptability focus group discussion was also conducted.
Voi, Kenya, community based.
Focus group discussion and two taste tests (twenty-one women aged 16–55 years). Follow-up acceptability focus group discussion (four women enrolled in intervention trial).
The preferred porridge for taste consisted of maize, soyabeans and peanuts. For animal protein, dried whole milk and dried fish were used. Although the women disliked the taste of dried fish, it was acceptable if added in small undetectable quantities. Sugar over lime was favoured for taste. Women believed they could consume at least two cups of porridge per day without displacing their usual meals. The optimal delivery interval was believed to be every two weeks in individual serving packages. Women who had been consuming porridge for several weeks felt the taste was acceptable for long-term consumption.
This formative research resulted in the development, packaging and delivery of a nutrient-dense food supplement using local ingredients to meet the dietary needs of the population and acceptable for daily consumption by women in Kenya for evaluation in an intervention trial.
PMCID: PMC3984962  PMID: 22974548
HIV; Africa; Kenya; Nutrition therapy
18.  Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations 
Journal of virological methods  2010;168(0):114-120.
To compare standard PCR/cloning and single genome sequencing (SGS) in their ability to reflect actual intra-patient polymorphism of HIV-1 populations, a total of 530 HIV-1 pro-pol sequences obtained by both sequencing techniques from a set of 17 ART naïve patient specimens was analyzed. For each specimen, 12 and 15 sequences, on average, were characterized by the two techniques. Using phylogenetic analysis, tests for panmixia and entropy, and Bland-Altman plots, no difference in population structure or genetic diversity was shown in 14 of the 17 subjects. Evidence of sampling bias by the presence of subsets of identical sequences was found by either method. Overall, the study shows that neither method was more biased than the other, and providing that an adequate number of PCR templates is analyzed, and that the bulk sequencing captures the diversity of the viral population, either method is likely to provide a similar measure of population diversity.
PMCID: PMC3949620  PMID: 20451557
HIV; Single genome sequencing (SGS); pro-pol diversity; cloning and sequencing; treatment naïve
19.  Drug Use and Other Risk Factors Related to Lower Body Mass Index among HIV-Infected Individuals 
Drug and alcohol dependence  2008;95(0):10.1016/j.drugalcdep.2007.12.004.
Malnutrition is associated with morbidity and mortality in HIV infected individuals. Little research has been conducted to identify the roles that clinical, illicit drug use and socioeconomic characteristics play in the nutritional status of HIV-infected patients. This cross-sectional analysis included 562 HIV-infected participants enrolled in the Nutrition for Healthy Living study conducted in Boston, MA and Providence, RI. The relationship between body mass index (BMI) and several covariates (type of drug use, demographic, and clinical characteristics) were examined using linear regression.
Overall, drug users had a lower BMI than non-drug users. The BMI of cocaine users was 1.4 kg/m2 less than that of patients who did not use any drugs, after adjusting for other covariates (p= 0.02). The BMI of participants who were over the age of 55 years was 2.0 kg/m2 less than that of patients under the age of 35, and BMI increased by 0.3 kg/m2 with each 100 cells/mm3 increase in CD4 count. HAART use, adherence to HAART, energy intake, AIDS status, hepatitis B and hepatitis C co-infections, cigarette smoking and depression were not associated with BMI in the final model.
In conclusion, BMI was lower in drug users than non-drug users, and was lowest in cocaine users. BMI was also directly associated with CD4 count and inversely related to age more than 55 years old. HIV infected cocaine users may be at higher risk of developing malnutrition, suggesting the need for anticipatory nutritional support.
PMCID: PMC3837518  PMID: 18243579
drug users; cocaine users; BMI; HIV; CD4 count
20.  HIV-1 Sero-Prevalence and Awareness of Mother-to-Child Transmission Issues Among Women Seeking Antenatal Care in Tamil Nadu, India 
Despite increasing availability of HIV-1 testing, education, and methods to prevent transmission, Indian women and their children remain at risk of acquiring HIV. We assessed the sero-prevalence and awareness about HIV among pregnant women presenting to a private tertiary care hospital in South India.
Sero-prevalence was determined via enzyme-linked immunosorbent assay (ELISA) testing, and questionnaires were analyzed using chi-square statistics and odds ratios to look for factors associated with HIV positivity.
A total of 7956 women who presented for antenatal care were interviewed. Fifty-one women of the 7235 women who underwent HIV testing (0.7%) were found to be HIV positive. Awareness of mother-to-child transmission (MTCT) of HIV (64%), HIV transmission through breast milk (42%), and prevention of MTCT (13%) was low.
There is a need to educate South Indian women about HIV to give them information and the means to protect themselves and their unborn children from acquiring HIV.
PMCID: PMC3652013  PMID: 20530464
HIV; sero-prevalence; awareness; pregnancy; antenatal; India
21.  Knowledge of HIV Transmission and Associated Factors among HIV-Positive and HIV-Negative Patients in Rural Kenya 
Knowledge of HIV transmission is a prerequisite to practicing safer behaviors to prevent HIV infections and may be expected to vary by region because of cultural and socioeconomic determinants. A cross-sectional study was conducted in rural Kenya using a standardized questionnaire assessing HIV transmission knowledge, socio-demographic and other characteristics. Participants were recruited from the voluntary counseling and testing clinic and the general hospital population of Moi District Hospital. “High” HIV transmission knowledge scorers (≥ 81%) (Mean score) were compared with “low” scorers (<81%). Bivariate and multivariate logistic regression analyses were performed to examine factors associated with HIV transmission knowledge. Of 214 participants, 70 (33%) were HIV-positive, 104 (49%) were HIV-negative, and 40 (19%) did not know. Factors associated with low knowledge in multivariate analyses were lower education (OR 2.36, CI 1.03–5.46), lower household money on healthcare (OR 2.03, CI 1.28–3.21), higher clinic transportation costs (OR 3.14, CI 1.20–9.82), sex without a condom (OR 2.18, CI 1.12–4.26), positive HIV status vs. negative (OR 2.50, CI 1.22–5.26) and positive HIV status vs. unknown (OR 3.57, CI 1.33–9.09). Mean HIV transmission knowledge score was relatively high; however, a large proportion of patients demonstrated low knowledge. Identifying individuals at risk for low knowledge will support targeted HIV education and prevention programs.
PMCID: PMC3595060  PMID: 23495369
22.  Medication Possession Ratio Associated with Short-Term Virologic Response in Individuals Initiating Antiretroviral Therapy in Namibia 
PLoS ONE  2013;8(2):e56307.
The visual-analogue scale (VAS), Likert item (rating scale), pills identification test (PIT), and medication possession ratio (MPR) provide estimates of antiretroviral therapy (ART) adherence which correlate with HIV viral suppression. These simple adherence measures are inexpensive and easy to administer; however, require validation and adjustment prior to implementation. The objective of this study was to define the optimal adherence assessment measure in Namibia to identify patients at risk for sub-optimal adherence and poor virologic response 6 months after ART initiation. We conducted a cross-sectional survey in HIV-infected adults receiving ART for 6–12 months prior to the adherence assessment. Adherence measures included 30-day VAS, 30-day Likert item, self-reported treatment interruptions, PIT, and MPR. Association of adherence measures with 6-month HIV-1 RNA level was assessed using two thresholds (1000 copies/mL and 5000 copies/mL). Adherence was assessed in 236 patients, mean age 37.3 years, 54% female. Mean adherence was 98.1% by 30-day VAS, 84.7% by 30-day Likert item, 97.0% by self-reported treatment interruptions, 90.6% by PIT, and 98.8% by MPR. Agreement between adherence measures was poor using kappa statistic. 76% had HIV-1 RNA <1000 copies/ml, and 88% had HIV-1 RNA <5000 copies/ml. MPR (continuous) was associated with viral suppression <5000 copies/ml (p = 0.036). MPR <75% was associated with virologic failure at ≥5000 copies/ml with OR 3.89 (1.24, 12.21), p = 0.013. Adherence was high with all measures. Only MPR, was associated with short-term virologic response, suggesting its cross-culturally utility for early identification of patients at high risk for virologic failure.
PMCID: PMC3585291  PMID: 23509605
23.  Antimicrobial Prescribing in the U.S. for Adult Acute Pharyngitis in Relation to Treatment Guidelines 
i. Rationale, aims and objectives
American College of Physicians (ACP) published guidelines for the diagnosis and treatment of acute pharyngitis in adults in 2001. The objective of this study is to characterize antibiotic prescribing patterns in the United States for acute pharyngitis and evaluate concordance with the 2001 ACP pharyngitis treatment guidelines
ii. Methods
Patients aged ≥18 years identified with acute pharyngitis via (ICD-9 CM) diagnosis codes were identified from data collected annually (1996-2006) by the National Center for Health Statistics (NCHS) and Centers for Disease Control and Prevention (CDC) from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Medical Care Survey (NHAMCS). Total US office visits for acute pharyngitis were estimated. Logistic regression was performed to determine whether antibiotic prescribing was associated with the publishing of the ACP guidelines.
iii. Results
3,791 office visits met study criteria. We extrapolated 78.0 million visits for acute pharyngitis from 1996-2006. Antibiotics were prescribed in 62.6% of cases and 7.5% of cases received ACP-recommended antibiotics. There was a significant decrease in the rate of antibiotic prescriptions from 66.5% to 59.1% after publication of ACP guidelines. Univariate analysis showed that antibiotic prescribing decreased by 27%, OR=0.73 (0.55-0.95), p=0.021. Multivariate analyses confirmed this finding, OR=0.72 (0.56-0.94), p=0.014. The prescribing of ACP-recommended antibiotics did not significantly change, 8.5% to 6.6% p=0.519.
iv. Conclusions
Publishing of ACP guidelines for the diagnosis and treatment of pharyngitis was associated with a decrease in the overall prescribing of antibiotics but not the prescribing of ACP-recommended antibiotics.
PMCID: PMC2978269  PMID: 20586844
guidelines; infectious disease; pharmacoepidemiology; physician behavior; health education
24.  Malnutrition in a population of HIV-positive and HIV-negative drug users living in Chennai, South India 
Drug and alcohol dependence  2011;118(1):73-77.
Malnutrition is a strong predictor of poor outcomes in people living with HIV (PLHIV). Drug users are at increased risk of malnutrition regardless of whether or not they are infected with HIV. Little data exists on the nutritional status of drug users (with or without HIV infection) in India.
We describe and compare the nutrition and metabolic status of 107 HIV-positive and 193 HIV-negative male clients of a community-based drop-in center for injection drug users in Chennai, India. Measures of nutrition and metabolic status include body composition, dietary intake, food insecurity, and serum lipid levels.
We found poor overall nutritional status in both the HIV-positive and HIV-negative clients, with HIV-positive men faring worse on some parameters. Both groups had extremely low percent body fat, but levels in HIV-positive participants were significantly lower (6.5% vs. 7.9%, p=.01). HIV-positive men also had significantly lower total caloric and fat intakes compared to HIV-negative men. A considerable proportion (70%) of both HIV-positive and HIV-negative drug users were food insecure. HDL cholesterol levels were significantly lower and below normal range in the HIV-positive compared to HIV-negative men.
The high levels of food insecurity and poor nutritional status in this population, regardless of HIV status, indicates critical need for intervention. Improving nutritional status in those who are infected with HIV prior to initiation of antiretroviral treatment may help patients to reap the full benefits of therapy.
PMCID: PMC3130882  PMID: 21420798
Nutritional status; injection drug users; India; HIV-infection
25.  Repeated assessments of food security predict CD4 change in the setting of antiretroviral therapy 
Food insecurity is highly prevalent in HIV-infected populations, and analyses utilizing multiple assessments of food security to predict CD4 change are lacking. 592 patients with ≥ 4 food security assessments were followed prospectively. In the final model, for patients using antiretroviral therapy, increases in CD4 counts were on average 99.5 cells less for individuals with at least one episode of food insecurity compared to those consistently food secure (P < 0.001). Other sociodemographic factors were not predictive. Repeated assessments of food security are potent predictors of treatment response notwithstanding antiretroviral therapy use. Potential mechanisms for this association are proposed.
PMCID: PMC3159819  PMID: 21694604
Food security; Immunological response; Antiretroviral therapy

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