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1.  A Phase III Comparative Study of the Efficacy and Tolerability of Three Non-Nucleoside Reverse Transcriptase Inhibitor-Sparing Antiretroviral Regimens for Treatment-Naïve HIV-1-Infected Volunteers: A Randomized, Controlled Trial 
Annals of internal medicine  2014;161(7):461-471.
Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naïve HIV-infected persons.
Perform a rigorous evaluation of three NNRTI-sparing initial antiretroviral regimens to demonstrate equivalence for virologic efficacy and tolerability.
Phase-III, 1:1:1 randomized, open label, >96 week study.
Fifty-seven sites in United States and Puerto Rico.
Treatment naïve, ≥18 years, HIV-1 RNA >1000 copies/mL, no nucleoside reverse transcriptase or protease inhibitor resistance.
Atazanavir 300 mg with ritonavir 100 mg, daily; or raltegravir 400 mg twice daily; or darunavir 800 mg with ritonavir 100 mg, daily; plus emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg daily.
Virologic failure defined as confirmed HIV-1 RNA >1000 copies/mL between 16 and 24 weeks, or >200 copies/mL at or after 24 weeks; tolerability failure defined as discontinuation of atazanavir, raltegravir or darunavir for toxicity. A secondary endpoint was a combination of virologic efficacy and tolerability.
Among 1,809 participants all pairwise comparisons of incidence of virologic failure over 96-weeks demonstrated equivalence within ±10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and a 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir respectively, primarily due to hyperbilirubinemia. For combined virologic efficacy and tolerability ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at time of virologic failure was rare but more likely with raltegravir.
Open label; ritonavir not provided
Over 2 years all three regimens attain high and equivalent rates of virologic control. Regimens containing raltegravir or ritonavir-boosted darunavir have superior tolerability compared to the ritonavir-boosted atazanavir regimen.
Primary Funding Source
National Institute of Allergy and Infectious Diseases
PMCID: PMC4412467  PMID: 25285539
2.  Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257 
In this randomized trial, raltegravir had more of a favorable lipid profile than ritonavir-boosted atazanavir or ritonavir-boosted darunavir–based regimens. Metabolic syndrome rates increased to the same degree for all 3 regimens. There was no relationship between ritonavir exposure and lipid levels.
Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24).
Methods. Treatment-naive adult subjects were randomized to ritonavir-boosted atazanavir or darunavir, or raltegravir-based cART. Changes in lipids and other metabolic outcomes over time were estimated. Differences between arms were estimated with 97.5% confidence intervals and compared using pairwise Student t tests. Associations between ritonavir C24 and lipid changes at week 48 were evaluated via linear regression.
Results. Analyses included 1797 subjects with baseline fasting data. Baseline lipid profiles and metabolic syndrome rates (approximately 21%) were similar across arms. Comparable increases occurred in total cholesterol, triglycerides, and low-density lipoprotein cholesterol with the boosted protease inhibitors (PIs); each PI had greater increases relative to raltegravir (all P ≤ .001 at week 96). Metabolic syndrome incident rates by week 96 (approximately 22%) were not different across arms. Ritonavir C24 was not different by arm (P = .89) (median, 69 ng/mL and 74 ng/mL in the atazanavir and darunavir arms, respectively) and were not associated with changes in lipid measures (all P > .1).
Conclusions. Raltegravir produced the most favorable lipid profile. Metabolic syndrome rates were high at baseline and increased to the same degree in all arms. Ritonavir C24 was not different in the PI arms and had no relationship with the modest but comparable increases in lipids observed with either atazanavir or darunavir. The long-term clinical significance of the lipid changes noted with the PIs relative to raltegravir deserves further evaluation.
Clinical Trials Registration. NCT 00811954.
PMCID: PMC4660025  PMID: 25767256
HIV/AIDS; cART; lipids; metabolic syndrome
3.  Clinical Practice Guideline for the Management of Chronic Kidney Disease in Patients Infected With HIV: 2014 Update by the HIV Medicine Association of the Infectious Diseases Society of America 
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
PMCID: PMC4271038  PMID: 25234519
HIV-1; chronic kidney disease; clinical practice guideline; HIV-associated nephropathy; kidney transplantation
4.  Effect of Protein Binding on Unbound Atazanavir and Darunavir Cerebrospinal Fluid Concentrations 
Journal of clinical pharmacology  2014;54(9):1063-1071.
HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.
PMCID: PMC4396178  PMID: 24691856
HIV/AIDS; central nervous system; clinical pharmacology
Journal of Critical Care  2011;27(1):51-57.
With the advent of Highly Active Antiretroviral Therapy (HAART), sepsis has become a more frequent ICU diagnosis for patients with HIV infections. Yet, little is known about the etiologies of acute infections in critically ill patients with HIV and the factors that affect in-hospital mortality.
Cases of patients with HIV requiring intensive care specifically for severe sepsis were identified over 27 months. Demographic information, variables related to acute illness severity, variables related to HIV infection, and all acute infections contributing to ICU stay were recorded.
Of 990 patients admitted to the ICU with severe sepsis, 136 (13.7%) were HIV-infected. There were 194 acute infections among the 125 patients with full data available; 112 of the infections were nosocomial/healthcare-associated, 55 were AIDS-related, and 27 were community-acquired. Patients with nosocomial/healthcare-associated and AIDS-related infections had lower CD4 counts and were less likely to be on HAART (p<0.05). The inpatient mortality was 42%. In a multivariable logistic regression model, only the APACHE II score (odds ratio, OR 1.12, 95% CI 1.02–1.23) was significantly associated with hospital mortality, although any HAART use (OR 0.53, 95% CI 0.22–1.33, p=0.18) approached statistical significance.
In this large cohort study, nosocomial/healthcare-associated infections were common in ICU patients with HIV and severe sepsis. Hospital mortality was associated with acute illness severity, but not clearly associated with variables related to HIV infection. Interventions that aim to prevent or more effectively treat nosocomial infections in critically ill patients with HIV may favorably impact clinical outcomes.
PMCID: PMC3269533  PMID: 22033058
6.  Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia 
Open Forum Infectious Diseases  2015;2(3):ofv085.
Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257.
Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated.
Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%–36%) in Black, 60% (CI, 32%–84%) in White, and 29% (CI, 8%–58%) in Hispanic participants; negative predictive values were 97% (CI, 93%–99%), 95% (CI, 90%–98%), and 97% (CI, 90%–100%), respectively.
Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat.
PMCID: PMC4498287  PMID: 26180834
atazanavir; HIV; pharmacogenomics; pharmacokinetics; UGT1A1
7.  Integrated Population Pharmacokinetic/Viral Dynamic Modeling of Lopinavir/Ritonavir in HIV-1 Treatment Naïve Patients 
Clinical pharmacokinetics  2014;53(4):361-371.
Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI) based regimen to treat HIV-infection. As with all PIs, the trough concentration (Ctrough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein (AAG) and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters.
Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry.
LPVt typical value of clearance (CLLPVt/F) was 4.73 L/h and distribution volume (VLPVt/F) was 55.7 L. Clearance (CLLPVf/F) and distibution volume (Vf/F) for LPVf were 596 L/h and 6370 L, respectively. Virion clearance rate was 0.0350 h-1. Simulated LPVLPVt Ctrough at 90% (EC90) and 95% (EC95) maximum response were 316 and 726 ng/mL, respectively.
The pharmacokinetic/pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modeling and simulation approach could be used as a surrogate assessment of ARV where adequate early phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.
PMCID: PMC3962720  PMID: 24311282
8.  Dysregulated B Cell Expression of RANKL and OPG Correlates with Loss of Bone Mineral Density in HIV Infection 
PLoS Pathogens  2014;10(11):e1004497.
HIV infection is associated with high rates of osteopenia and osteoporosis, but the mechanisms involved are unclear. We recently reported that bone loss in the HIV transgenic rat model was associated with upregulation of B cell expression of the key osteoclastogenic cytokine receptor-activator of NF-κB ligand (RANKL), compounded by a simultaneous decline in expression of its physiological moderator, osteoprotegerin (OPG). To clinically translate these findings we performed cross-sectional immuno-skeletal profiling of HIV-uninfected and antiretroviral therapy-naïve HIV-infected individuals. Bone resorption and osteopenia were significantly higher in HIV-infected individuals. B cell expression of RANKL was significantly increased, while B cell expression of OPG was significantly diminished, conditions favoring osteoclastic bone resorption. The B cell RANKL/OPG ratio correlated significantly with total hip and femoral neck bone mineral density (BMD), T- and/or Z-scores in HIV infected subjects, but revealed no association at the lumbar spine. B cell subset analyses revealed significant HIV-related increases in RANKL-expressing naïve, resting memory and exhausted tissue-like memory B cells. By contrast, the net B cell OPG decrease in HIV-infected individuals resulted from a significant decline in resting memory B cells, a population containing a high frequency of OPG-expressing cells, concurrent with a significant increase in exhausted tissue-like memory B cells, a population with a lower frequency of OPG-expressing cells. These data validate our pre-clinical findings of an immuno-centric mechanism for accelerated HIV-induced bone loss, aligned with B cell dysfunction.
Author Summary
HIV infection causes significant bone loss and skeletal deterioration, leading to fractures that are often devastating and incur significant financial burden on patients and their families. HIV-infected individuals have up to a five-fold higher risk of bone fractures, and the increasing average age of people living with HIV/AIDS has triggered fears of an impending epidemic of bone fractures in this population. Antiretroviral therapy, used to manage HIV infection, fails to prevent, but rather paradoxically accelerates skeletal decline. The underlying mechanisms of HIV-induced bone loss are poorly understood. The aim of this study was to clarify the mechanisms of bone loss in HIV-infected patients, in an effort to better understand how bone loss and fractures occur, and consequently how it can be prevented in this population. The cytokine RANKL (Receptor Activator of Nuclear Factor kappa-B Ligand) helps induce bone loss. We show that RANKL expression was increased in immune cells in HIV-infected individuals. Another cytokine, osteoprotegerin (OPG), counteracts the activity of RANKL, and therefor helps prevent bone loss. OPG expression by the same immune cells was decreased in HIV-infected individuals. We conclude that disrupted immune cell expression of RANKL and OPG in HIV-infected patients contributes to bone loss.
PMCID: PMC4231117  PMID: 25393853
9.  Global HIV/AIDS Medicine 
Emerging Infectious Diseases  2008;14(6):1006-1007.
PMCID: PMC2600274
10.  Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T cell activation 
Initiation of ART during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful ART, and maintained viral suppression through 96 weeks. Pre-therapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and while this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, p=0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.
PMCID: PMC3683110  PMID: 23314410
acute HIV infection; antiretroviral therapy; immune activation; viral dynamics; NNRTIs
11.  A Switch in Therapy to a Reverse Transcriptase Inhibitor Sparing Combination of Lopinavir/Ritonavir and Raltegravir in Virologically Suppressed HIV-Infected Patients: A Pilot Randomized Trial to Assess Efficacy and Safety Profile: The KITE Study 
AIDS Research and Human Retroviruses  2012;28(10):1196-1206.
A nucleoside reverse transcriptase inhibitor (NRTI) backbone is a recommended component of standard highly active antiretroviral therapy (sHAART). However, long-term NRTI exposure can be limited by toxicities. NRTI class-sparing alternatives are warranted in select patient populations. This is a 48-week single-center, open-label pilot study in which 60 HIV-infected adults with plasma HIV-1 RNA (<50 copies/ml) on sHAART were randomized (2:1) to lopinavir/ritonavir (LPV/r) 400/100 mg BID+raltegravir (RAL) 400 mg BID switch (LPV-r/RAL arm) or to continue on sHAART. The primary endpoint was the proportion of subjects with HIV-RNA<50 copies/ml at week 48. Secondary efficacy and immunologic and safety endpoints were evaluated. Demographics and baseline lipid profile were similar across arms. Mean entry CD4 T cell count was 493 cells/mm3. At week 48, 92% [95% confidence interval (CI): 83–100%] of the LPV-r/RAL arm and 88% (95% CI: 75–100%) of the sHAART arm had HIV-RNA<50 copies/ml (p=0.70). Lipid profile (mean±SEM, mg/dl, LPV-r/RAL vs. sHAART) at week 24 was total-cholesterol 194±5 vs. 176±9 (p=0.07), triglycerides 234±30 vs. 133±27 (p=0.003), and LDL-cholesterol 121±6 vs. 110±8 (p=0.27). There were no serious adverse events (AEs) in either arm. Regimen change occurred in three LPV-r/RAL subjects (n=1, due to LPV-r/RAL-related AEs) vs. 0 in sHAART. There were no differences between arms in bone mineral density, total body fat composition, creatinine clearance, or CD4 T cell counts at week 48. In virologically suppressed patients on HAART, switching therapy to the NRTI-sparing LPV-r/RAL combination produced similar sustained virologic suppression and immunologic profile as sHAART. AEs were comparable between arms, but the LPV-r/RAL arm experienced higher triglyceridemia.
PMCID: PMC3448110  PMID: 22364141
12.  Immune Activation Mediated Change in Alpha-1-Acid Glycoprotein: Impact on Total and Free Lopinavir Plasma Exposure 
Journal of clinical pharmacology  2011;51(11):1539-1548.
Immune mediated changes in circulating α-1-acid glycoprotein (AAG), a type 1 acute phase protein, which binds protease inhibitors (PI), may alter protein binding and contribute to PI's pharmacokinetic (PK) variability.
In a prospective, 2-phase intensive PK study on antiretroviral naive human immunodeficiency virus (HIV)-infected subjects treated with a lopinavir-/ritonavir-based regimen, steady state PK sampling and AAG assays were performed at weeks 2 and 16 of treatment.
Median entry age was 43 years (n = 16). Median plasma log10 HIV-1 RNA, CD4 T-cell counts, and AAG were 5.16 copies/mL, 28 cells/μL, and 143 mg/dL, respectively.The total lopinavir area under the concentration time curve (AUC12_total) and maximum concentration (Cmax_total) changed linearly with AAG at mean rates of 16±7 mg*hr/L (slope ± SE); P = .04, and 1.6 ± 0.6 mg/L, P = .02, per 100 mg/dL increase in AAG levels, respectively (n = 15).A 29% drop in AAG levels between week 2 and week 16 was associated with 14% (geometric mean ratio [GMR] = 0.86; 90% confidence interval [CI] = 0.74-0.98) and 13% (GMR = 0.87; 90% CI = 0.79-0.95) reduction in AUC12_total and Cmax_total, respectively. Neither free lopinavir PK parameters nor antiviral activity (HIV-1 RNA average AUC minus baseline) was affected by change in plasma AAG.
Changes in plasma AAG levels alter total lopinavir concentrations, but not the free lopinavir exposure or antiviral activity. This observation may have implications in therapeutic drug monitoring.
PMCID: PMC3128238  PMID: 21209245
antiretroviral drugs; pharmacokinetics; protein binding
13.  Tuberculosis Biomarker and Surrogate Endpoint Research Roadmap 
The Centers for Disease Control and Prevention and National Institutes of Health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. The goals were to assess recent surrogate marker research and to provide specific recommendations for (1) the qualification and validation of biomarkers of treatment outcome; (2) the standardization of specimen and data collection for future clinical trials, including a minimum set of samples and collection time points; and (3) the creation of a specimen repository to support biomarker testing. This article summarizes these recommendations and provides a roadmap for their implementation.
PMCID: PMC3208659  PMID: 21737585
14.  HIV-1 RNA Rectal Shedding Is Reduced in Men With Low Plasma HIV-1 RNA Viral Loads and Is Not Enhanced by Sexually Transmitted Bacterial Infections of the Rectum 
The Journal of Infectious Diseases  2011;204(5):761-767.
Background. Among human immunodeficiency virus (HIV)–infected men who have sex with men (MSM) taking combination antiretroviral therapy (cART), the impact of rectal sexually transmitted infections (STIs) on rectal HIV-1 shedding is unknown.
Methods. Human immunodeficiency virus type 1 (HIV-1) RNA was quantified from rectal swabs collected for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) screening of HIV-1-infected MSM. Correlations of STIs with rectal viral load were explored using multinomial regression modeling. HIV-1 coreceptor tropism was predicted from sequencing in a subset of men.
Results. Thirty-one (39%) of 80 men (59 prescribed combination antiretroviral therapy [cART]) had HIV detected in 38 (42%) of 91 rectal swabs. Rectal HIV detection was associated with plasma virus loads above 3.15 log10 copies/mL (95% confidence limit [CL] 2.73, 3.55) and paired rectal viral loads and plasma viral loads were correlated (Kendall’s tau [τ] 0.68, Spearman rho [P] = .77). Rectal STIs and abnormal anal cytology were not associated with rectal viral load. HIV coreceptor distribution was very similar between the plasma and rectum in 3 of 4 men.
Conclusions. Plasma and rectal viral load were correlated, and rectal STIs did not increase the likelihood of detecting HIV in the rectal secretions in MSM, including those with low or undetectable plasma viral load. Suppressing plasma viral load is likely to reduce risk of HIV transmission to insertive partners.
PMCID: PMC3156109  PMID: 21844302
15.  Liver Enzymes Elevation and Immune Reconstitution Among Treatment-Naïve HIV-Infected Patients Instituting Antiretroviral Therapy 
Because liver enzymes elevation (LEE) complicates antiretroviral (ARV) therapy, and because the strongest risk factor for ARV-related LEE is HBV/HCV coinfection, it is speculated that ARV-related LEE may be a form of immune reconstitution disease. This study summarizes the relation between immune reconstitution, ARV-induced LEE, and HBV/HCV coinfection.
Medical records of ARV-naïve HIV-infected patients initiating ARV were reviewed for hepatitis coinfection, LEE (grade ≥2 AST/ALT) and changes in CD4 T-cell counts over time in an urban HIV clinic. Risk factors for LEE were statistically evaluated, and changes in CD4 T-cell counts were estimated by a mixed-effects linear model.
Predictors of LEE included HBV/HCV coinfection (OR = 6.44) and stavudine use (OR = 2.33). Nelfinavir use was protective (OR = 0.45). The mean rate of change in CD4 T-cell counts was higher in HBV/HCV coinfected subjects who developed LEE (99 cells/μL per month) compared with non-coinfected subjects who did not develop LEE (59 cells/μL per month, P = 0.03), non-coinfected subjects who developed LEE (36 cells/μL per month, P = 0.01), and coinfected subjects who did not develop LEE, 38% higher (62 cells/μL per month; P = 0.11)
A more robust immune restoration was observed among HBV/HCV coinfected subjects who developed liver enzyme elevation after antiretroviral initiation compared with other groups. This finding suggests that ARV-related liver enzyme elevation may be related in part to immune reconstitution, as measured by changes in CD4 T-cell counts.
PMCID: PMC3075308  PMID: 18004087
Hepatotoxicity; Liver enzymes elevation; Antiretroviral drugs; Immune reconstitution; HIV/AIDS
16.  High Prevalence of Persistent Parasitic Infections in Foreign-Born, HIV-Infected Persons in the United States 
Foreign-born, HIV-infected persons are at risk for sub-clinical parasitic infections acquired in their countries of origin. The long-term consequences of co-infections can be severe, yet few data exist on parasitic infection prevalence in this population.
Methodology/Principal Findings
This cross-sectional study evaluated 128 foreign-born persons at one HIV clinic. We performed stool studies and serologic testing for strongyloidiasis, schistosomiasis, filarial infection, and Chagas disease based on the patient's country of birth. Eosinophilia and symptoms were examined as predictors of helminthic infection. Of the 128 participants, 86 (67%) were male, and the median age was 40 years; 70 were Mexican/Latin American, 40 African, and 18 from other countries or regions. Strongyloides stercoralis antibodies were detected in 33/128 (26%) individuals. Of the 52 persons from schistosomiasis-endemic countries, 15 (29%) had antibodies to schistosome antigens; 7 (47%) had antibodies to S. haematobium, 5 (33%) to S. mansoni, and 3 (20%) to both species. Stool ova and parasite studies detected helminths in 5/85 (6%) persons. None of the patients tested had evidence of Chagas disease (n = 77) or filarial infection (n = 52). Eosinophilia >400 cells/mm3 was associated with a positive schistosome antibody test (OR 4.5, 95% CI 1.1–19.0). The only symptom significantly associated with strongyloidiasis was weight loss (OR 3.1, 95% CI 1.4–7.2).
Given the high prevalence of certain helminths and the potential lack of suggestive symptoms and signs, selected screening for strongyloidiasis and schistosomiasis or use of empiric antiparasitic therapy may be appropriate among foreign-born, HIV-infected patients. Identifying and treating helminth infections could prevent long-term complications.
Author Summary
Undiagnosed and untreated parasitic infections can have severe consequences for human immunodeficiency virus (HIV)-infected persons. An estimated 2 billion people worldwide are infected with soil-transmitted helminths and schistosomiasis, yet there are few data on the prevalence in HIV-infected immigrants to more developed countries. This information could help clinicians determine what testing is needed and what signs or symptoms to expect. We performed serologic, stool, and urine testing for selected parasites in 128 foreign-born persons receiving care at an HIV clinic in Atlanta, Georgia. We found that 26% had serologic evidence of infection with Strongyloides stercoralis and 29% had serologic evidence of schistosomiasis. Because these were likely chronic processes, symptoms and signs were often absent; only weight loss was significantly associated with strongyloidiasis. High eosinophil counts were also associated with parasitic infection. This study suggests the need for targeted screening of foreign-born, HIV-infected persons for parasitic infections (mainly strongyloidiasis and schistosomiasis) or the use of empiric antiparasitic therapy, particularly among those with unexplained eosinophilia. Although there are established guidelines for screening of refugees, health care providers should consider the risk of these organisms in patients who have entered the United States through other pathways.
PMCID: PMC3075235  PMID: 21532747
17.  Lopinavir/Ritonavir Pharmacokinetic Profile: Impact of Sex and Other Covariates Following a Change From Twice-Daily to Once-Daily Therapy 
Journal of clinical pharmacology  2007;47(8):970-977.
The aim of this study was to determine the impact of sex on the pharmacokinetics of lopinavir/ritonavir. Interaction between lopinavir/ritonavir and tenofovir was also evaluated. Steady-state plasma samples were obtained from virologically suppressed HIV-infected patients on lopinavir/ritonavir 800/200-mg soft gel capsule taken once daily. Drug assays were performed by high-performance liquid chromatography. Pharmacokinetic parameters estimated by noncompartmental method were reported as 90% confidence intervals (CIs) about the geometric mean ratio (GMR). There were 9 males and 11 females. No sex differences were observed in lopinavir/ritonavir pharmacokinetics profile. The GMRsex (women compared with men) for lopinavir area under the concentration–time curve (AUC24), maximum concentration (Cmax), and minimum concentration (Cmin) was 0.95 (90% CI, 0.70–1.29), 0.88 (90% CI, 0.67–1.15), and 1.27 (90% CI, 0.60–2.66), respectively. Similarly, the GMRsex for ritonavir AUC24, Cmax, and Cmin was 0.84 (90% CI, 0.57–1.24), 0.79 (90% CI, 0.50–1.22), and 1.02 (90% CI, 0.58–1.80), respectively. Tenofovir coadministration led to a reduction in lopinavir/ritonavir plasma exposure, giving a lopinavir GMRtenofovir for Cmax of 0.72 (90% CI, 0.57–0.93) and AUC24 of 0.74 (90% CI, 0.56–0.98), respectively. No difference in lopinavir/ritonavir plasma concentrations between sexes was demonstrated in this study. However, tenofovir coadministration lowered lopinavir/ritonavir plasma exposure.
PMCID: PMC3073482  PMID: 17615254
Gender- or sex-related differences; lopinavir pharmacokinetics
18.  Pharmacokinetics of an Indinavir-Ritonavir-Fosamprenavir Regimen in Patients with Human Immunodeficiency Virus 
Pharmacotherapy  2008;28(1):74-81.
Study Objective
To evaluate the pharmacokinetic compatibility of a ritonavir-boosted indinavir-fosamprenavir combination among patients with human immunodeficiency virus (HIV).
Single-center, nonrandomized, prospective, multiple-dose, two-phase pharmacokinetic study.
University research center.
Eight adult patients with HIV infection who had been receiving and tolerating indinavir 800 mg–ritonavir 100 mg twice/day for at least 2 weeks.
After 12-hour pharmacokinetic sampling was performed on all patients (period A), fosamprenavir (a prodrug of amprenavir) 700 mg twice/day was coadministered for 5 days, with a repeat 12-hour pharmacokinetic sampling performed on the fifth day (period B).
Measurements and Main Results
Pharmacokinetic parameters were determined for indinavir, ritonavir, and amprenavir: area under the concentration-time curve from time 0 to 12 hours after dosing (AUC0–12), maximum plasma concentration (Cmax), and 12-hour plasma concentration (C12). For each parameter, the geometric mean, as well as the geometric mean ratio (GMR) comparing period B with period A, were calculated. Indinavir Cmax was lowered by 20% (GMR 0.80, 95% confidence interval [CI] 0.67–0.96), AUC0–12 was lowered by 6% (GMR 0.94, 95% CI 0.74–1.21), and C12 was increased by 28% (GMR 1.28, 95% CI 0.78–2.10). Ritonavir AUC0–12 was 20% lower (GMR 0.80, 95% CI 0.54–1.19), Cmax was 15% lower (GMR 0.85, 95% CI 0.55–1.32), and C12 was 7% lower (GMR 0.93, 95% CI 0.49–1.76). With the exception of indinavir Cmax, the changes in indinavir and ritonavir pharmacokinetic parameters observed after fosamprenavir coadministration were not statistically significant. The geometric means of amprenavir AUC0–12, Cmax, and C12 were 41,517 ng•hour/ml (95% CI 30,317–56,854 ng•hr/ml), 5572 ng/ml (95% CI 4330–7170 ng/ml), and 2421 ng/ml (95% CI 1578–3712 ng/ml), respectively.
The combination of indinavir 800 mg–ritonavir 100 mg–fosamprenavir 700 mg twice/day appears to be devoid of a clinically significant drug-drug interaction and should be evaluated as an alternative regimen in salvage HIV treatment. This combination may be suitable as part of a background regimen to optimize the therapeutic benefit of newer classes of antiretroviral agents such as the integrase and coreceptor inhibitors in the treatment of multidrug-resistant viruses.
PMCID: PMC3073489  PMID: 18154477
antiretroviral pharmacokinetics; ritonavir-boosted double–protease inhibitor combination; indinavir; fosamprenavir
19.  Culturally-adapted and audio-technology assisted HIV/AIDS awareness and education program in rural Nigeria: a cohort study 
HIV-awareness programs tailored toward the needs of rural communities are needed. We sought to quantify change in HIV knowledge in three rural Nigerian villages following an integrated culturally adapted and technology assisted educational intervention.
A prospective 14-week cohort study was designed to compare short-term changes in HIV knowledge between seminar-based education program and a novel program, which capitalized on the rural culture of small-group oral learning and was delivered by portable digital-audio technology.
Participants were mostly Moslem (99%), male (53.5%), with no formal education (55%). Baseline HIV knowledge was low (<80% correct answers for 9 of the 10 questions). Knowledge gain was higher (p < 0.0001 for 8 of 10 questions) in the integrated culturally adapted and technology-facilitated (n = 511) compared with the seminar-based (n = 474) program.
Baseline HIV-awareness was low. Culturally adapted, technology-assisted HIV education program is a feasible cost-effective method of raising HIV awareness among low-literacy rural communities.
PMCID: PMC2834647  PMID: 20181073
20.  Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection▿  
Journal of Virology  2008;82(20):9808-9822.
A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.
PMCID: PMC2566282  PMID: 18667503
21.  Diversity, Divergence, and Evolution of Cell-Free Human Immunodeficiency Virus Type 1 in Vaginal Secretions and Blood of Chronically Infected Women: Associations with Immune Status 
Journal of Virology  2005;79(15):9799-9809.
Most human immunodeficiency virus type 1 (HIV-1) infections are believed to be the result of exposure to the virus in genital secretions. However, prevention and therapeutic strategies are usually based on characterizations of HIV-1 in blood. To understand better the dynamics between HIV-1 quasispecies in the genital tract and blood, we performed heteroduplex assays on amplified env products from cell-free viral RNA in paired vaginal secretion (VS) and blood plasma (BP) samples of 14 women followed for 1.5 to 3.5 years. Diversity and divergence were less in VS than in BP (P = 0.03 and P < 0.01, respectively), and divergence at both sites was correlated with blood CD4+ cell levels (VS, P = 0.05; BP, P = 0.01). Evolution of quasispecies was observed in 58% of the women; the loss or gain of quasispecies in VS or BP was always accompanied by such changes at the other site. In addition, sustained compartmentalization of quasispecies in VS was found for four women, even as CD4+ cell levels decreased to low levels (<50 cells/μl). Quasispecies changes over time were associated with fluctuations in CD4+ cell levels; concordant increases or decreases in VS and BP divergence had greater CD4+ cell level changes than intervals with discordant changes (P = 0.05), and women with evolving quasispecies had greater decreases in CD4+ cell levels compared to that for women who maintained the same quasispecies (P < 0.05). Thus, diversity, divergence, and evolution of cell-free HIV-1 in VS can be different from that in BP, and dynamics between their respective quasispecies are associated with changes in CD4+ cell levels.
PMCID: PMC1181596  PMID: 16014941
22.  Specificity of the Antibody Response to the Pneumococcal Polysaccharide and Conjugate Vaccines in Human Immunodeficiency Virus-Infected Adults 
Nonspecific antibodies, which are thought to be nonprotective, have been shown to contribute a substantial proportion of the measured concentration in the standardized immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) for pneumococcal polysaccharide capsular antibodies. The presence of such antibodies in human immunodeficiency virus (HIV)-infected persons has not been evaluated. The amount of nonspecific antibodies is proportional to the reduction in IgG antibody concentration that occurs with serum absorption with the heterologous polysaccharide 22F. We measured the amount of nonspecific antibodies before and after vaccination with the pneumococcal conjugate vaccine (PCV; n = 33) or the pneumococcal polysaccharide vaccine (PPV; n = 34) in HIV-infected adults with CD4 counts of ≥200 cells/mm3. Blood was drawn before and 2 months after vaccination. For prevaccination sera, we found a substantial amount of nonspecific antibodies for serotypes 4, 6B, 9V, and 23F (23 to 47% of measured IgG concentration), but not for serotype 14. There tended to be proportionately less nonspecific antibodies in postvaccine sera than prevaccine sera for PCV, but not for PPV. Subjects with a low HIV viral load (≤400 copies/ml) had proportionately more nonspecific antibodies than those with higher viral load before and after both vaccines. After 22F absorption, the geometric mean concentrations of antibodies were significantly higher post-PCV than post-PPV for the high viral load group for all five serotypes, but for no serotypes in the low viral load group. These findings confirm that absorption with a heterologous pneumococcal polysaccharide (e.g., 22F) is necessary to remove nonspecific antibodies in a standardized IgG ELISA for pneumococcal capsular antibodies in HIV-infected adults.
PMCID: PMC321324  PMID: 14715560
23.  Detection of Infectious Human Immunodeficiency Virus Type 1 in Female Genital Secretions by a Short-Term Culture Method 
Journal of Clinical Microbiology  2003;41(9):4081-4088.
Infectious human immunodeficiency virus type 1 (HIV-1) is difficult to detect in female genital secretions by standard virus culture techniques. To improve detection of cell-free HIV-1 in female genital secretions, we adapted a short-term assay that uses the multinuclear-activation galactosidase indicator (MAGI) assay. When vaginal lavages from HIV-1-infected women were tested with the adapted MAGI assay, 25 (64%) of 39 lavages with detectable, cell-free HIV-1 RNA were shown to have infectious virus. No infectious virus was found in 10 vaginal lavages from HIV-1-infected women with undetectable vaginal viral loads. Significantly (P < 0.01) more lavages from HIV-1-infected women tested positive for infectious virus by the MAGI assay than by standard peripheral blood mononuclear cell (PBMC) coculture, which detected infectious virus in only 6 (17%) of 35 vaginal lavages. Lavages with viral loads of >10,000 copies per lavage yielded significantly (P < 0.01) more positive cultures than those with <10,000 copies by using the MAGI assay. Detection of infectious HIV-1 in vaginal lavages was not associated with the presence of genital tract infections or CD4+-T-cell counts. However, although the results were not significant (P = 0.08), the MAGI assay detected infectious virus from more vaginal lavages at a vaginal pH of ≥4.5 than at a pH of <4.5. These results indicate that the MAGI assay is more sensitive than PBMC culture methods for detecting infectious virus in female genital secretions. Accurate measurements of infectious virus in genital secretions will improve studies that evaluate sexual transmission of HIV-1.
PMCID: PMC193780  PMID: 12958229
24.  Clinical Comparison of an Enhanced-Sensitivity Branched-DNA Assay and Reverse Transcription-PCR for Quantitation of Human Immunodeficiency Virus Type 1 RNA in Plasma 
Journal of Clinical Microbiology  1998;36(3):716-720.
The performance characteristics of an enhanced-sensitivity branched-DNA assay (bDNA) (Quantiplex HIV-1 version 2.0; Chiron Corp., Emeryville, Calif.) and a reverse transcription (RT)-PCR assay (AMPLICOR HIV-1 Monitor; Roche Diagnostic Systems, Inc., Branchburg, N.J.) were compared in a molecular diagnostic laboratory. Samples used in this evaluation included linearity and reproducibility panels made by dilution of a human immunodeficiency virus type 1 (HIV-1) stock culture of known virus particle count in HIV-1-negative plasma, a subtype panel consisting of HIV-1 subtypes A through F at a standardized level, and 64 baseline plasma specimens from HIV-1-infected individuals. Plots of log10 HIV RNA copies per milliliter versus log10 nominal virus particles per milliliter demonstrated that both assays were linear over the stated dynamic ranges (bDNA, r = 0.98; RT-PCR, r = 0.99), but comparison of the slopes of the regression lines (bDNA, m = 0.96; RT-PCR, m = 0.83) suggested that RT-PCR had greater proportional systematic error. The between-run coefficients of variation for bDNA and RT-PCR were 24.3 and 34.3%, respectively, for a sample containing 1,650 nominal virus particles/ml and 44.0 and 42.7%, respectively, for a sample containing 165 nominal virus particles/ml. Subtypes B, C, and D were quantitated with similar efficiencies by bDNA and RT-PCR; however, RT-PCR was less efficient in quantitating subtypes A, E, and F. One non-B subtype was recognized in our clinical specimens based on the ratio of values obtained with the two methods. HIV-1 RNA was quantitated in 53 (83%) baseline plasma specimens by bDNA and in 55 (86%) specimens by RT-PCR. RT-PCR values were consistently greater than bDNA values, with population means of 142,419 and 67,580 copies/ml, respectively (P < 0.01). The results were highly correlated (r = 0.91), but the agreement was poor (mean difference in log10 copies per milliliter ± 2 standard deviations, 0.45 ± 0.61) for the 50 clinical specimens that gave discrete values with both methods.
PMCID: PMC104614  PMID: 9508301

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