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1.  Silymarin for hepatitis C virus infection 
Antiviral therapy  2012;18(2):141-147.
Silymarin, an extract of milk thistle seeds, and silymarin-derived compounds have been considered hepatoprotective since the plant was first described in ancient times. Hepatoprotection is defined as several non-mutually exclusive biological activities including antiviral, antioxidant, anti-inflammatory and immunomodulatory functions. Despite clear evidence for silymarin-induced hepatoprotection in cell culture and animal models, evidence for beneficial effects in humans has been equivocal. This review will summarize the current state of knowledge on silymarin in the context of hepatitis C virus infection. The information was collated from a recent workshop on silibinin in Germany.
PMCID: PMC4076489  PMID: 23011959
2.  Resistance to tenofovir-based regimens during treatment failure of subtype C HIV-1 in South Africa 
Antiviral therapy  2013;18(7):915-920.
Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principle TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV.
Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virologic failure (defined as an HIV RNA >1000 c/mL) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors.
Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major NNRTI mutations in 24 (57%), and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA log10 3.3 versus 4.2 c/mL) and prior stavudine exposure. An additional 5 patients had minority K65R populations identified by allele-specific PCR.
These data suggest that the K65R prevalence at virologic failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype C infected patients with up to 6 months of failure of a TDF-containing regimen.
PMCID: PMC4046272  PMID: 23751421
3.  Does HIV infection promote early kidney injury in women? 
Antiviral therapy  2013;19(1):79-87.
In HIV-infected women, urine concentrations of novel tubulointerstitial injury markers, interleukin-18 (IL-18) and kidney injury marker-1 (KIM-1) are associated with kidney function decline and all-cause mortality. We hypothesized that HIV-infected individuals with preserved kidney filtration function would have more extensive kidney injury, as determined by urine injury markers, compared to the uninfected controls, and that risk factors for tubulointerstitial injury would differ from risk factors for albuminuria.
In this cross-sectional study, we compared urine concentrations of IL-18, KIM-1, and ACR in 908 HIV-infected and 289 HIV-uninfected women enrolled in the Women’s Interagency HIV Study, utilizing stored urine specimens from visits between 1999 and 2000.
After multivariate-adjusted linear regression analysis, mean urine concentrations were higher in HIV-infected individuals by 38% for IL-18 (p<0.0001), 12% for KIM-1 (p=0.081), and 47% for ACR (p<0.0001). Higher HIV RNA level (15% per 10-fold increase, p<0.0001), lower CD4 count (8% per doubling, p=0.0025), HCV infection (30%, p=0.00018), and lower HDL (5% per 10 mg/dL, p=0.0024) were each associated with higher IL-18 concentrations. In contrast, hypertension (81%, p<0.0001) and diabetes (47%, p=0.018) were among the strongest predictors of higher ACR, though HIV RNA level (15% per 10-fold increase, p=0.0004) was also associated with higher ACR.
HIV-infected women had more extensive tubulointerstitial and glomerular injury than uninfected women, but the associated factors differed among the urine biomarkers. Combinations of urinary biomarkers should be investigated to further characterize early kidney injury in HIV-infected women.
PMCID: PMC3933452  PMID: 23970313
4.  An Association Between Adiposity and Serum Levels of Macrophage Inflammatory Protein-1α and Soluble CD14: Results from a Cross-Sectional Study 
Antiviral therapy  2013;18(5):729-733.
Greater adipose tissue is associated with increased circulating high-sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well characterized.
We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) receptor 1 & 2, macrophage inflammatory protein-1α (MIP-1α), macrophage chemotactic protein-1 (MCP-1), soluble CD14, and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4+ count, smoking status, PI use, and daily use of either NSAIDs or aspirin.
The majority (77%) of the 85 study participants were male, median CD4+ cell count was 500 cells/µl (IQR 315, 734) and median BMI was 25.1 kg/m2 (IQR 22.7, 28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (β=1.82, p<0.01) and MIP-1α (β=1.36, p<0.01), but negatively associated with soluble CD14 (β=0.90, p<0.01). Results were similar for trunk fat, limb fat, and serum leptin level. The positive relationship between DXA measurements and TNF-α receptor 1 approached significance (p≤0.07 for all). There was no consistent relationship between adiposity and serum IL-6, TNF-α receptor 2, or MCP-1 levels.
Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1α and lower soluble CD14 levels possibly reflecting an important role for cells of the monocyte/macrophage lineage.
PMCID: PMC3923367  PMID: 23748193
HIV; antiretroviral therapy; inflammation; obesity; adipose tissue; nutrition
5.  Bone turnover, OPG/RANKL, and inflammation with antiretroviral initiation: comparison of tenofovir- vs. non-tenofovir regimens 
Antiviral therapy  2011;16(7):1063-1072.
Bone mineral density decreases with antiretroviral therapy (ART)-initiation, although the pathogenesis, including the role of tenofovir (TDF), is unclear. This study assessed changes in bone-turnover markers, osteoprotegerin (OPG), soluble receptor activator for nuclear factor kappa β ligand (sRANKL), and inflammation in subjects initiating TDF- vs. non-TDF-containing regimens, and determined the relationship between bone turnover, OPG/sRANKL, and inflammation.
This was a longitudinal, observational study comparing levels of bone-turnover markers (C-terminal telopeptide of type I collagen, CTX; osteocalcin (OC)), OPG, sRANKL, and inflammatory cytokines (soluble tumor necrosis factor-α receptor-I, -II (sTNFR-I,-II), interleukin-6) prior to ART and 6–12 months after ART-initiation with a TDF- vs. non-TDF-containing regimen in HIV-infected subjects 18–50 years old.
87 subjects were enrolled (TDF=44; non-TDF=43). Groups were similar except subjects on TDF had a lower CD4 nadir (P<0.01) and were more likely to receive a protease inhibitor (PI) (P=0.03). At pre-ART, 35% and 1% of subjects had CTX and OC above normal range, respectively. Both increased with ART initiation, whereas OPG, sRANKL, and inflammatory markers significantly decreased. In multivariate models, increases in OC were associated with TDF-use, PI-use, and pre-ART levels of sTNFR-I, while increases in CTX were associated with CD4 nadir <50 cell/mm3. Increases in bone markers were unrelated to pre-ART levels of OPG/sRANKL and changes in OPG/sRANKL after ART-initiation.
TDF-use, PI-use, TNF-α activity, and advanced HIV disease are associated with changes in bone-turnover markers, underscoring the complicated interaction between ART, bone turnover, inflammation, and immune status, which extend beyond the OPG/RANKL system.
PMCID: PMC3915418  PMID: 22024522
HIV; osteoporosis; antiretroviral therapy; bone-turnover; inflammation
6.  Haemoglobin and anaemia in the SMART study 
Antiviral therapy  2011;16(3):329-337.
Data from randomized trials on the development of anaemia after interruption of therapy is not well described.
2248 patients from the SMART study were included. We used Cox proportional hazards models to investigate development of new (≤12 mg/dl for females, ≤14 mg/dl for males) or worsening (≤8 mg/dl if anaemic at randomization) anaemia and poisson regression analyses to explore the relationship between anaemia and the development of AIDS, death or non-AIDS events.
759 patients developed new or worsening anaemia; 420/1106 (38.0%) in the drug conservation (DC) arm and 339/1127 (30.1%) in the virologic suppression (VS) arm; p<0.0001. At 4 months after randomization, patients in the DC arm had a significantly increased risk of developing new or worsening anaemia (adjusted relative hazard 1.56, 95% CI 1.28–1.89). Currently anaemic patients had an increased incidence of AIDS (adjusted IRR 2.31; 95% CI 1.34–3.98), death (2.19; 95% CI 1.23–3.87) and non-AIDS events (2.98; 95% CI 2.01–4.40) compared to non-anaemic patients.
Patients who interrupted cART had a higher risk of new or worsening anaemia. Anaemic patients had a higher incidence of AIDS, non-AIDS defining events or deaths, possibly due to deteriorating health and subclinical disease.
PMCID: PMC3909832  PMID: 21555815
Anaemia; treatment interruption; haemoglobin; AIDS; death; non-AIDS events
7.  Combination therapy with amantadine, oseltamivir and ribavirin for influenza A infection: safety and pharmacokinetics 
Antiviral therapy  2012;18(3):377-386.
Antiviral resistance among influenza A viruses is associated with high morbidity and mortality in immunocompromised hosts. However, treatment strategies for drug-resistant influenza A are not established. A triple-combination antiviral drug (TCAD) regimen consisting of amantadine (AMT), oseltamivir (OSL) and ribavirin (RBV) demonstrated good efficacy in an animal model.
We first analysed the pharmacokinetics (PKs) of TCAD therapy in healthy volunteers. We then performed a pilot study of TCAD therapy in patients undergoing chemotherapy or haematopoietic cell transplantation. AMT (75 mg), OSL (50 mg) and RBV (200 mg) were administered three times a day for 10 days. The safety and PKs of TCAD therapy were monitored.
The PKs of TCAD therapy in healthy volunteers was shown to be similar to the PKs of each drug individually from a single dose. In the pilot study, six immunocompromised patients received TCAD therapy and one patient received OSL monotherapy. All but one patient completed 10 days of TCAD therapy without side effects; one patient receiving TCAD was withdrawn from the study because of respiratory failure and ultimately recovered. Viral load was decreased after TCAD therapy, despite the presence of either AMT- or OSL-resistant virus in two cases. One patient with 2009 influenza A/H1N1 receiving OSL monotherapy developed confirmed OSL resistance during treatment.
TCAD therapy had similar PKs to each individual antiviral during monotherapy following a single dose and can be administered safely in immunocompromised patients.
PMCID: PMC3912210  PMID: 23264438
8.  Immune deficiency could be an early risk factor for altered insulin sensitivity in antiretroviral-naive HIV-1-infected patients: the ANRS COPANA cohort 
Antiviral Therapy  2012;17(1):91-100.
The relationships between immunovirological status, inflammatory markers, insulin resistance and fat distribution have not been studied in recently diagnosed (<1 year) antiretroviral-naïve HIV-1-infected patients.
We studied 214 antiretroviral-naïve patients at enrolment in the metabolic sub-study of the ANRS COPANA cohort. We measured clinical, immunovirological and inflammatory parameters, glucose/insulin during oral glucose tolerance test (OGTT), adipokines, subcutaneous and visceral fat surfaces (SAT and VAT, assessed by computed tomography) and the body fat distribution based on dual-energy X-ray absorptiometry (DEXA).
Median age was 36 years; 28% of the patients were female and 35% of sub-Saharan origin; 20% had low CD4 counts (≤200/mm3). Patients with low CD4 counts were older and more frequently of sub-Saharan Africa origin, had lower BMI but not different SAT/VAT ratio and fat distribution than other patients. They also had lower total, LDL- and HDL-cholesterolemia, higher triglyceridemia and post-OGTT glycemia, higher markers of insulin resistance (insulin during OGTT and HOMA-IR) and of inflammation (hsCRP, IL-6, TNFα, sTNFR1 and sTNFR2). After adjustment for age, sex, geographic origin, BMI and waist circumference, increased insulin resistance was not related to any inflammatory marker. In multivariate analysis, low CD4 count was an independent risk factor for altered insulin sensitivity (β-coefficient for HOMA-IR: +0.90; p=0.001; CD4>500/mm3 as the reference), in addition to older age (β: +0.26 for a 10-year increase; p=0.01) and higher BMI (β: +0.07 for a 1-kg/m2 increase; p=0.003).
In ART-naive patients, severe immune deficiency but not inflammation could be an early risk factor for altered insulin sensitivity.
PMCID: PMC3893638  PMID: 22267473
Adipokines; blood; Adult; Africa South of the Sahara; ethnology; Blood Glucose; analysis; Body Fat Distribution; Body Mass Index; C-Reactive Protein; analysis; CD4 Lymphocyte Count; Cohort Studies; Cytokines; blood; European Continental Ancestry Group; Female; France; epidemiology; Glucose Tolerance Test; HIV Infections; blood; ethnology; immunology; virology; Humans; Insulin; blood; Insulin Resistance; immunology; Lipoproteins; blood; Male; RNA, Viral; analysis; Risk Factors
9.  Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial 
Antiviral therapy  2011;17(4):613-621.
Studies suggest that vitamin D deficiency is a risk factor for cardiovascular disease and diabetes. Vitamin D deficiency is prevalent in HIV patients but the effect of vitamin D supplementation on cardiovascular risk in this population is unknown.
We conducted a randomized, double-blind, placebo-controlled trial among 45 HIV-infected adults in Cleveland (OH, USA) on stable antiretroviral therapy with durable virological suppression and a baseline serum 25-hydroxyvitamin D level of ≤20 ng/ml. Participants were randomized 2:1 to vitamin D3 4,000 IU daily or placebo for 12 weeks. The primary outcome was a change in flow-mediated brachial artery dilation (FMD).
Baseline demographics were similar except for age (vitamin D versus placebo, mean ±SD 47 ±8 versus 40 ±10 years; P=0.009). Both groups had reduced FMD at baseline (median values 2.9% [IQR 1.6–4.8] for vitamin D versus 2.5% [IQR 1.7–6.4] for placebo; P=0.819). Despite an increase in the concentration of serum 25-hydroxyvitamin D from baseline to 12 weeks (5.0 ng/ml [IQR −0.9–7.4] versus −1.9 ng/ml [IQR −4.0–0.1] for vitamin D versus placebo, respectively; P=0.003), there was no difference in FMD change (0.55% [IQR −1.05–2.13] versus 0.29% [IQR −1.61–1.77]; P=0.748). Vitamin D supplementation was associated with a decrease in total and non-high-density lipoprotein cholesterol, and an increase in indices of insulin resistance.
Among HIV-infected individuals with vitamin D deficiency, supplementation with 4,000 IU vitamin D3 daily for 12 weeks modestly improved vitamin D status and cholesterol but worsened insulin resistance without change in endothelial function. The mechanisms of resistance to standard doses of vitamin D and the complex role of vitamin D in glucose metabolism in this population require further investigation.
PMCID: PMC3898848  PMID: 22293363
10.  Vitamin D is linked to carotid intima-media thickness and immune reconstitution in HIV-positive individuals 
Antiviral therapy  2011;16(4):555-563.
Patients with HIV infection are at increased risk of cardiovascular disease (CVD). Vitamin D insufficiency has been associated with increased CVD risk in non-HIV populations. This study sought to determine the relationship between vitamin D status and markers of CVD and HIV-related factors in HIV-positive patients.
Patients with HIV infection on antiretroviral therapy and healthy controls were prospectively enrolled. Fasting lipids, glucose, insulin, inflammatory markers (soluble tumour necrosis factor-α receptor I, interleukin-6 and high-sensitivity C-reactive protein) and endothelial markers (soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1) were measured. Fasting 25-hydroxyvitamin D (25(OH)D) was measured from stored serum samples. The internal carotid artery and common carotid artery (CCA) intima-media thickness (IMT) were measured in a subset of HIV-positive patients. Baseline cross-sectional data were analysed.
A total of 149 HIV-positive patients (56 with carotid IMT) and 34 controls were included. Controls had higher adjusted mean 25(OH)D levels than HIV-positive patients (P=0.02). In multivariable linear regression among the HIV-positive patients, 25(OH)D was positively associated with CD4+ T-cell restoration after antiretroviral therapy (ΔCD4 = current - nadir CD4+ T-cell; P<0.01), but was not associated with inflammatory or endothelial markers. In multivariable logistic regression, odds of having CCA IMT above the median were more than 10× higher in those with lower 25(OH)D levels (OR=10.62, 95% CI 1.37–82.34; P<0.01).
Vitamin D status in HIV-positive patients was positively associated with improved immune restoration after antiretroviral therapy and negatively associated with CCA IMT. These findings suggest that vitamin D may play a role in HIV-related CVD and in immune reconstitution after antiretroviral therapy.
PMCID: PMC3895475  PMID: 21685543
11.  Could Early Antiretroviral Therapy Entail More Risks than Benefits in sub-Saharan African HIV-Infected Adults? A Model-Based Analysis 
Antiviral therapy  2012;18(1):45-55.
Initiation of antiretroviral therapy (ART) in all HIV-infected adults, regardless of count, is a proposed strategy for reducing HIV transmission. We investigated the conditions under which starting ART early could entail more risks than benefits for patients with high CD4 counts.
We used a simulation model to compare ART initiation upon entry to care (“immediate ART”) to initiation at CD4 ≤350 cells/μL (“WHO 2010 ART”) in African adults with CD4 counts >500 cells/μL. We varied inputs to determine the combination of parameters (population characteristics, conditions of care, treatment outcomes) that would result in higher 15-year mortality with immediate ART.
Fifteen-year mortality was 56.7% for WHO 2010 and 51.8% for immediate ART. In one-way sensitivity analysis, lower 15-year mortality was consistently achieved with immediate ART unless the rate of fatal ART toxicity was >1.0/100PY, the rate of withdrawal from care was >1.2-fold higher or the rate of ART failure due to poor adherence was >4.3-fold higher on immediate ART. In multi-way sensitivity analysis, immediate ART led to higher mortality when moderate rates of fatal ART toxicity (0.25/100PY) were combined with rates of withdrawal from care >1.1-fold higher and rates of treatment failure >2.1-fold higher on immediate ART than on WHO 2010 ART.
In sub-Saharan Africa, ART initiation at entry into care would improve long-term survival of patients with high CD4 counts, unless it is associated with increased withdrawal from care and decreased adherence. In early ART trials, a focus on retention and adherence will be critical.
PMCID: PMC3893045  PMID: 22809695
12.  Residual Plasma Viremia and Infectious HIV-1 Recovery from Resting Memory CD4 Cells in Patients on Antiretroviral Therapy: Results from ACTG A5173 
Antiviral therapy  2013;18(4):10.3851/IMP2543.
In HIV-1-infected patients receiving antiretroviral therapy (ART), the relationship between residual viremia and ex vivo recovery of infectious virus from latently-infected CD4 cells is uncertain.
We measured residual viremia (HIV-1 RNA copies/mL) by single-copy assay (SCA) and the latent reservoir by infectious virus recovery from resting memory CD4 cells (infectious units per million cells [IUPM]) in patients who initiated ART. We assessed immune activation by measuring CD38 expression on T cells.
Ten patients who initiated ART and maintained a plasma HIV-1 RNA level <200 copies/mL had residual viremia and IUPM measured every 24 weeks. Five of 10 patients had longitudinal IUPM measured at weeks 24–96; the remainder had IUPM measured 1–3 times over 24–72 weeks. Analyses of 29 paired measurements revealed a positive association between level of residual viremia and IUPM (0.56 higher log10 HIV-1 RNA copies/mL per 1 log10 higher IUPM, p=0.005). Residual viremia level was positively associated with CD38 density and percentage on CD8+ T-cells in concurrent samples and with pre-ART HIV-1 RNA levels.
In patients with HIV-1 RNA levels <200 copies/mL 24–96 weeks after initiating ART, the level of viremia is positively associated with infectious virus recovery from resting memory CD4 cells. Whether this association persists after longer-term suppressive ART needs to be determined. If additional studies show that residual viremia measured by SCA reflects the size of the latent reservoir in patients who have had virologic suppression for longer periods of time, this could facilitate testing of potentially curative strategies to reduce this important reservoir.
PMCID: PMC3887470  PMID: 23411421
HIV-1; reservoir; residual viremia; single-copy assay
13.  Predictors of Residual Viremia in Patients on Long-term Suppressive Antiretroviral Therapy 
Antiviral therapy  2012;18(1):39-43.
HIV-1-infected individuals with plasma RNA <50 copies/mL on antiretroviral therapy (ART) may have residual, low-level viremia detectable by PCR assays which can detect a single copy of viral RNA (single-copy assay, SCA). The clinical predictors of residual viremia in patients on long-term suppressive ART are incompletely understood.
We evaluated factors associated with residual viremia in patients on suppressive ART who underwent screening for a raltegravir intensification trial (ACTG A5244). The screened population was HIV-1-infected adults receiving ART for ≥12 months with pre-ART HIV-1 RNA >100,000 copies/mL and on-therapy RNA levels below detection limits of commercial assays for ≥6 months.
Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. Sixty-two percent had detectable viremia (>0.2 copies/mL) by SCA (median 0.2 copies/mL; quartile [Q] 1, Q3 [<0.2, 1.8]). Younger patients had lower HIV-1 RNA levels than older individuals (r=0.27, p=0.005). Patients with virologic suppression on ART for 2 years or less had higher residual viremia than those with suppression for more than 2 years (median 2.3 vs. 0.2 copies/mL, p=0.016).
Among HIV-1-infected patients with pre-ART HIV-1 RNA >100,000 copies/mL, residual viremia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viremia was associated with older age and less than 2 years of virologic suppression on ART. These findings should help in selection of candidates for clinical trials of interventions designed to eliminate residual viremia.
PMCID: PMC3578982  PMID: 22914318
HIV-1; Single-copy assay; residual viremia
14.  Increased FDG uptake in Association with Reduced Extremity Fat in HIV Patients 
Antiviral therapy  2012;18(2):243-248.
HIV lipodystrophy - characterized by peripheral lipoatrophy, with or without central fat accumulation - confers increased metabolic risk. However, the functional activity of HIV lipodystrophic tissue in relation to metabolic risk has yet to be fully explored in vivo through the use of non-invasive imaging techniques. This study assesses the relationship between FDG uptake in various fat depots and metabolic/immune parameters among subjects with HIV lipodystrophy.
Lipodystrophic men on anti-retroviral therapy (ART) underwent whole-body 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) scans and detailed metabolic/immune phenotyping.
FDG uptake in the subcutaneous adipose tissue (SAT) of the extremities (mean standardized uptake value, or SUV, of the arm and leg SAT) was found to correlate with the degree of peripheral lipoatrophy (r = 0.7, p = 0.01). Extremity SAT FDG uptake was positively associated with HOMA-IR (r = 0.6, p = 0.02) and fasting hyperinsulinemia (r = 0.7, p 0.01), while fat percentage of extremities was not. Further, extremity SAT FDG uptake was significantly associated with CD4 count (r = 0.6, p = 0.05). In multivariate modeling for HOMA-IR, extremity SAT FDG uptake remained significant after controlling for BMI and TNF-α (R2 for model = 0.71, p = 0.02; SUV in the extremity SAT β-estimate 12.3, p = 0.009).
In HIV lipodystrophic patients, extremity SAT FDG uptake is increased in association with reduced extremity fat and may contribute to insulin resistance. Noninvasive assessments of in situ inflammation using FDG-PET may usefully complement histological and gene expression analyses of metabolic dysregulation in peripheral fat among HIV+ patients.
PMCID: PMC3670757  PMID: 23041595
HIV; lipodystrophy; FDG-PET/CT; insulin resistance
15.  Cost-effectiveness Analysis of UGT1A1 Genetic Testing to Inform Antiretroviral Prescribing in HIV Disease 
Antiviral therapy  2012;18(3):399-408.
Homozygosity for UGT1A1*28/*28 (Gilbert’s variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually.
Initiating atazanavir-based ART at CD4 <500/µl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinemia by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario.
Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
PMCID: PMC3744167  PMID: 23264445
16.  Antiretroviral-based HIV-1 Prevention: Antiretroviral Treatment and Pre-Exposure Prophylaxis 
Antiviral therapy  2012;17(8):1483-1493.
Antiretroviral-based HIV-1 prevention strategies – including antiretroviral treatment (ART) to reduce the infectiousness of HIV-1 infected persons and oral and topical pre-exposure prophylaxis (PrEP) for uninfected persons to prevent HIV-1 acquisition – are the most promising new approaches for decreasing HIV-1 spread. Observational studies among HIV-1 serodiscordant couples have associated ART initiation with a reduction in HIV-1 transmission risk of 80–92%, and a recent randomized trial demonstrated that earlier initiation of ART (i.e., at CD4 counts between 350 and 550 cells/mm3), in the context of virologic monitoring and adherence support, resulted in a 96% reduction in HIV-1 transmission. A number of ongoing and recently-completed clinical trials have assessed the efficacy of PrEP for HIV-1 prevention as peri-coitally administered or daily-administered 1% tenofovir gel and daily oral tenofovir and combination emtricitabine/tenofovir. Completed studies have demonstrated HIV-1 protection efficacies ranging from 39% to 75%. However, two trials in African women have shown no HIV-1 protection with PrEP; the reasons for lack of efficacy in those trials are being investigated. Adherence is likely key to efficacy of antiretrovirals for HIV-1 prevention, both as ART and PrEP. Critical unanswered questions for successful delivery of antiretroviral-based HIV-1 prevention include how to target ART and PrEP to realize maximum population benefits, whether HIV-1 infected persons at earlier stages of infection would accept ART to reduce their risk for transmitting HIV-1 and highest-risk HIV-1 negative persons would use PrEP, and whether high adherence could be sustained to achieve high effectiveness.
PMCID: PMC3531985  PMID: 23221365
17.  A 72-week randomized study of the safety and efficacy of a d4T to AZT switch at 24 weeks compared to AZT or TDF when given with 3TC and NVP 
Antiviral therapy  2012;17(8):1521-1531.
Due to superior long-term toxicity profile, AZT and TDF are preferred to d4T for first-line antiretroviral regimens. However, short-term d4T use could be beneficial in avoiding AZT-induced anemia.
We randomized (1:1:1) 150 treatment-naive Thai HIV-infected adults with CD4 count <350 cells/mm3 to arm 1: 24-week GPO-VIR S30® (d4T+3TC+NVP) followed by 48-week GPO-VIR Z250® (AZT+3TC+NVP); arm 2: 72-week GPO-VIR Z250®; or arm 3: 72-week TDF+FTC+NVP. Hemoglobin (Hb), dual energy x-ray absorptiometry, neuropathic signs, estimated glomerular filtration rate (eGFR), CD4 count, plasma HIV RNA, and adherence were assessed.
In ITT analysis, mean Hb decreased from baseline to week 24 in arm 2 compared to arm 1 (-0.19 vs 0.68 g/dL, P=0.001) and arm 3 (0.48 g/dL, P=0.010). Neuropathic signs were more common in arm 2 compared to arm 3 (20.4 vs 4.2%, P=0.028) at week 24. There were no differences in changes in peripheral fat and eGFR from baseline to weeks 24 and 72 among arms. CD4 count increased more in arm 1 than arms 2 and 3 from baseline to week 24 (168 vs 117 and 118 cells/mm3, P=0.01 and 0.02, respectively) but the increase from baseline to week 72 was similar among arms.
A 24-week d4T lead-in therapy caused less anemia and greater initial CD4 count rise than initiating treatment with AZT. This strategy could be considered in patients with baseline anemia or low CD4 count. If confirmed in a larger study, this may guide global recommendations on antiretroviral initiation where AZT is more commonly used than TDF.
PMCID: PMC3715552  PMID: 23220732
18.  The effect of rifampicin-based antitubercular therapy and cytochrome P450 2B6 genotype on efavirenz mid-dosing interval concentrations in a South African HIV-infected population 
Antiviral therapy  2009;14(5):687-695.
Rifampicin may decrease efavirenz concentrations by inducing expression of cytochrome P450 isoenzyme 2B6 (CYP2B6), which metabolises efavirenz. The CYP2B6 516G>T polymorphism impairs efavirenz metabolism and occurs more commonly in Africans than Caucasians. We explored the effect of concomitant rifampicin-based antitubercular therapy and the 516G>T polymorphism on efavirenz mid-dosing interval plasma concentrations, and investigated risk factors for efavirenz concentrations outside 1-4mg/L, in a South African population.
Mid-dosing interval efavirenz plasma concentrations were measured in adults on antiretroviral therapy (efavirenz 600 mg daily throughout) with and without antitubercular therapy, using validated LC/MS/MS methods. Between patient and within patient comparisons were made.
There were 142 participants: 40 on antitubercular therapy and 102 controls; mean weight 66 kg. Median efavirenz concentration was 2.4mg/L (IQR 1.3, 3.1) and 1.8mg/L (IQR 1.4, 4.4) in participants on antitubercular therapy and controls, respectively (p=0.734). Paired efavirenz concentrations during and after antitubercular therapy in 17 participants were also similar (p=0.113). In 122 participants genotyped, 60 (49%) had G/G genotype, 46 (38%) were G/T heterozygotes and 16 (13%) were T/T homozygotes. In a multivariate logistic regression model, adjusted for sex, weight and concomitant antitubercular therapy, the 516G>T polymorphism was strongly associated with high efavirenz concentrations (>4 mg/L): odds ratios 4.4 (95%CI 1.3-14.9) for G/T versus G/G and 31.1 (95%CI 6.6-146.6) for T/T versus G/G. High efavirenz concentrations were associated with severe sleep disturbance (p=0.048). Low efavirenz concentrations (<1mg/L) were associated with virological failure (odds ratio 12.5; 95% CI 2.7-57.3).
Efavirenz can be used together with rifampicin-based antitubercular therapy without dose adjustment in this population. The 516G>T polymorphism occurred commonly and was associated with high efavirenz concentrations.
PMCID: PMC3837290  PMID: 19704172
19.  Pharmacokinetic study of once–daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3–<36 months 
Antiviral therapy  2010;15(3):10.3851/IMP1532.
Once-daily dosing of abacavir and lamivudine has been approved for adults, but paediatric data are insufficient. We conducted a pharmacokinetic study of once-daily and twice-daily abacavir and lamivudine in children aged 3–<36 months.
Children with stable HIV type-1 (HIV-1) RNA levels after 12 weeks treatment with twice-daily abacavir (8 mg/kg) with or without lamivudine (4 mg/kg) underwent plasma pharmacokinetic sampling. Children then switched to once-daily abacavir (16 mg/kg) with or without lamivudine (8 mg/kg), and sampling was repeated 4 weeks later. The area under the plasma concentration–time curve over 24 h (AUC0–24) and the maximum concentration (Cmax) were compared using geometric mean ratios (GMRs); 90% confidence intervals (CIs) within the range of 0.80–1.25 were considered bioequivalent.
A total of 18 children (4, 6 and 8 in the 3–<12, 12–<24 and 24–<36 month age ranges, respectively) provided pharmacokinetic data for abacavir (17 for lamivudine). The GMR of AUC0–24, once-daily versus twice-daily, was 1.07 (90% CI 0.92–1.23) for abacavir and 0.91 (90% CI 0.79–1.06) for lamivudine. Cmax almost doubled on once-daily versus twice-daily dosing: abacavir and lamivudine GMRs were 2.04 (90% CI 1.73–2.42) and 1.78 (90% CI 1.52–2.09), respectively. At baseline, 12, 24 and 48 weeks, 89%, 94%, 100% and 89% of children had HIV-1 RNA<400 copies/ml, respectively.
Bioequivalence was demonstrated on AUC0–24 between twice-daily and once-daily abacavir; very similar AUC0–24 values were seen for twice-daily and once-daily lamivudine. Given that viral load suppression rates were maintained, these data suggest that once-daily abacavir and lamivudine might be an option for children aged 3–<36 months.
PMCID: PMC3827580  PMID: 20516550
20.  Genotypic HIV type-1 drug resistance among patients with immunological failure to first-line antiretroviral therapy in south India 
Antiviral therapy  2009;14(7):10.3851/IMP1411.
HIV type-1 (HIV-1) monitoring in resource limited settings relies on clinical and immunological assessment. The objective of this study was to study the frequency and pattern of reverse transcriptase (RT) drug resistance among patients with immunological failure (IF) to first-line therapy.
A cross-sectional study of 228 patients with IF was done, of which 126 were drug-naive (group A) when starting highly active antiretroviral therapy (HAART) and 102 were exposed to mono/dual therapy prior to HAART initiation (group B). A validated in-house genotyping method and Stanford interpretaion was used. Means, sd, median and frequencies (as percentages) were used to indicate the patient characteristics in each group. The χ2 test and Fisher's exact test were used to compare categorical variables as appropriate. All analyses were performed using SPSS software, version 13.0. P-values <0.05 were considered to be statistically significant.
RT drug resistance mutations were found in 92% and 96% of patients in groups A and B, respectively. Median (interquartile range) CD4+ T–cell count at failure was 181cells/ml (18–999) and time to failure was 40 months (2–100). M184V (80% versus 75%), thymidine analogue mutations (63% versus 74%), Y181C (39% versus 39%) and K103N (29% versus 39%) were predominant RT mutations in both groups. Extensive nucleoside reverse transcriptase inhibitor cross-resistance mutations were observed in 51% and 26%of patients in group B and A, respectively.
Alternative strategies for initial therapy and affordable viral load monitoring could reduce resistance accumulations and preserve available drugs for future options in resource-limited settings.
PMCID: PMC3816397  PMID: 19918105
21.  New Approaches to Prophylactic Human Papillomavirus Vaccines for Cervical Cancer Prevention 
Antiviral therapy  2011;17(3):10.3851/IMP1941.
The currently licensed human papillomavirus (HPV) vaccines are safe and highly effective at preventing HPV infection for a select number of papillomavirus types, thus decreasing the incidence of precursors to cervical cancer. It is expected that vaccination will also ultimately reduce the incidence of this cancer. However, the licensed HPV vaccines are type-restricted and expensive, and also require refrigeration, multiple doses, and intramuscular injection. Second generation vaccines are currently being developed to address these shortcomings. New expression systems, viral and bacterial vectors for HPV L1 capsid protein delivery, and use of the HPV L2 capsid protein will hopefully aid in decreasing cost and increasing ease of use and breadth of protection. These second generation vaccines also could allow affordable immunization of women in developing countries, where the incidence of cervical cancer is high.
PMCID: PMC3815710  PMID: 22293302
22.  Mathematical modeling of HCV infection: what can it teach us in the era of direct antiviral agents? 
Antiviral therapy  2012;17(6 0 0):1171-1182.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and affects nearly 170 million people worldwide. Whereas the previous standard of care with pegylated interferon and ribavirin had a modest effectiveness, the recent approval of two highly potent protease inhibitors and the ongoing development of dozens of direct acting antivirals (DAAs) constitute a major milestone for HCV therapy. Mathematical modeling of viral kinetics under treatment has played an instrumental role in improving our understanding of virus pathogenesis and in guiding drug development. Here, we review the current state of HCV kinetic modeling, and challenges to the standard biphasic viral decline model that arise when fitting viral kinetic models to data obtained with DAAs.
PMCID: PMC3641583  PMID: 23186606
23.  Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV–HCV coinfection 
Antiviral therapy  2012;18(2):237-242.
Fractures and cirrhosis are major causes of morbidity and mortality among HIV–HCV-coinfected individuals. It is not known whether vitamin D deficiency is associated with these outcomes.
Between 2005 and 2007, 116 HIV–HCV- coinfected individuals underwent dual-energy X-ray absorptiometry within 1 year of a liver biopsy. 25-Hydroxy-vitamin D (25OHD) and parathyroid hormone were measured from archived samples. Low bone mineral density (BMD) was defined as BMD≥2 standard deviations lower than age-, sex- and race-matched controls (Z-score ≤−2.0) at the total hip, femoral neck or lumbar spine. Histological fibrosis staging was assessed according to the METAVIR system (0 [no fibrosis] to 4 [cirrhosis]).
The cohort was 87% African-American and 63% male. The median age (IQR) was 49.9 years (46.5–53.3). A total of 89% had a CD4+ T-cell count >200 cells/mm3 and 64% were receiving HAART. The median 25OHD was 19 ng/ ml (IQR 11.0–26.0). Hypovitaminosis D (25OHD≤15 ng/ml) was present in 41% and secondary hyperparathyroidism, defined by parathyroid hormone >65 pg/ml, was present in 24%. In total, 27% had low BMD (Z-score ≤−2) at the spine, femoral neck or total hip, and 39% had significant hepatic fibrosis (METAVIR≥2). In multivariate analysis, vitamin D deficiency was not associated with significant fibrosis or with BMD at any site.
Vitamin D deficiency was highly prevalent in this mostly African-American HIV–HCV-coinfected population, but was not related to BMD or liver disease severity. These data suggest that efforts to increase vitamin D levels in this population may not improve bone or liver outcomes.
PMCID: PMC3790468  PMID: 22910231
24.  Second-line protease inhibitor-based highly active antiretroviral therapy after failing non-nucleoside reverse transcriptase inhibitors-based regimens in Asian HIV-infected children 
Antiviral therapy  2013;18(4):591-598.
The WHO recommends boosted protease inhibitor (bPI)-based highly active antiretroviral therapy (HAART) after failing non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment. We examined outcomes of this regimen in Asian HIV-infected children.
Children from five Asian countries in the TREAT Asia Pediatric HIV Observational Database (TApHOD) with ≥24 weeks of NNRTI-based HAART followed by ≥24 weeks of bPI-based HAART were eligible. Primary outcomes were the proportions with virologic suppression (HIV-RNA <400 copies/ml) and immune recovery (CD4% ≥25% if age <5 years and CD4 count ≥500 cells/mm3 if age ≥5 years) at 48 and 96 weeks.
Of 3422 children, 153 were eligible; 52% were female. At switch, median age was 10 years, 26% were in WHO stage 4. Median weight-for-age z-score (WAZ) was −1.9 (n=121), CD4% was 12.5% (n=106), CD4 count was 237 (n=112) cells/mm3, and HIV-RNA was 4.6 log10copies/ml (n=61). The most common PI was lopinavir/ritonavir (83%).
At 48 weeks, 61% (79/129) had immune recovery, 60% (26/43) had undetectable HIV-RNA and 73% (58/79) had fasting triglycerides ≥130mg/dl. By 96 weeks, 70% (57/82) achieved immune recovery, 65% (17/26) virologic suppression, and hypertriglyceridemia occurred in 66% (33/50).
Predictors for virologic suppression at week 48 were longer duration of NNRTI-based HAART (p=0.006), younger age (p=0.007), higher WAZ (p=0.020), and HIV-RNA at switch <10,000 copies/ml (p=0.049).
In this regional cohort of Asian children on bPI-based second-line HAART, 60% of children tested had immune recovery by one year, and two-thirds had hyperlipidemia, highlighting difficulties in optimizing second-line HAART with limited drug options.
PMCID: PMC3715593  PMID: 23296119
Asian HIV-infected children; protease inhibitor; second-line HAART
25.  HIV infection and obesity: Where did all the wasting go? 
Antiviral therapy  2012;17(7):1281-1289.
The success of antiretroviral therapy (ART) has led to dramatic changes in causes of morbidity and mortality in HIV-infected individuals. As chronic diseases rates have increased in HIV+ populations, modifiable risk factors such as obesity have increased in importance. Our objective was to evaluate factors associated with weight change among patients receiving ART.
ART-naïve patients initiating therapy at the University of Alabama - Birmingham 1917 HIV/AIDS Clinic from 2000– 2008 were included. Body Mass Index (BMI) was categorized as: underweight (<18.5), normal weight (18.5–24.9), overweight (25–29.9) and obese (≥30). Linear regression models were used to evaluate overall change in BMI and factors associated with increased BMI category 24 months following ART initiation.
Among 681 patients, the mean baseline BMI was 25.4 ± 6.1; 44% of patients were overweight/obese. At 24 months, 20% of patients moved from normal to overweight/obese or overweight to obese BMI categories. Greater increases in BMI were observed in patients with baseline CD4 count < 50 cells/μl (3.4 ± 4.1, P<0.01) and boosted protease inhibitor use (2.5±4.1 P=0.01), but did not account for all of the variation observed in weight change.
The findings that almost half of patients were overweight or obese at ART initiation, and 1 in 5 patients moved to a deleterious BMI category within 2 years of ART initiation are alarming. ART therapy provides only a modest contribution to weight gain in patients. Obesity represents a highly prevalent condition in patients with HIV infection and an important target for intervention.
PMCID: PMC3779137  PMID: 22951353
obesity; HIV; body mass index

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