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1.  Association between systemic inflammation and obstructive sleep apnea in men with or at risk for HIV infection 
Antiviral therapy  2014;19(8):725-733.
To determine whether markers of systemic inflammation are associated with the presence of moderate-to-severe obstructive sleep apnea (OSA), and whether this association differs based on HIV and HIV treatment status.
HIV-uninfected men (HIV−; n=60), HIV-infected men receiving HAART (HIV+/HAART; n=58), and HIV-infected men not receiving HAART (HIV+/ No HAART; n=41) underwent polysomnograpy and measurement of plasma levels of TNF-alpha, soluble TNF-alpha receptors I and II (sTNFRI and sTNFRII) and IL-6. The relationship between moderate-severe OSA (respiratory disturbance index ≥15 apnea/hypopnea events/hour) and inflammatory markers was assessed with multivariable regression models.
Compared to the HIV− men, HIV+/HAART men and HIV+/No HAART men had higher levels of TNF-alpha, sTNFRI, and sTNFRII, independent of age, race, smoking status, obstructive lung disease (OLD), and BMI. Moderate-to-severe OSA was present in 48% of the sample (HIV−:57%; HIV+/HAART: 41%; HIV+/No HAART: 44%). Among the HIV+/No HAART men, but not in the other groups, TNF-alpha, sTNFRII, and IL-6 levels were higher in those with moderate-severe OSA compared to men with no-to-mild OSA after adjustment for age, race, smoking status, OLD, and BMI. Within this group, the association of high TNF-alpha concentrations with moderate-severe OSA was also independent of CD4 cell count and plasma HIV RNA concentration.
Compared to HIV-infected men on HAART and HIV-uninfected men, markers of systemic inflammation were higher in HIV-infected men not receiving HAART. In these men, TNF-alpha was significantly related to obstructive sleep apnea, independent of HIV-related covariates.
PMCID: PMC4130807  PMID: 24518040
2.  Active pharmaceutical ingredients for antiretroviral treatment in low- and middle-income countries: a survey 
Antiviral therapy  2014;19(0 3):15-29.
Active pharmaceutical ingredients (APIs) are the molecular entities that exert the therapeutic effects of medicines. This article provides an overview of the major APIs that are entered into antiretroviral therapy (ART), outlines how APIs are manufactured, and examines the regulatory and cost frameworks of manufacturing ART APIs used in low- and middle-income countries (LMICs). Almost all APIs for ART are prepared by chemical synthesis. Roughly 15 APIs account for essentially all of the ARTs used in LMICs. Nearly all of the ART APIs purchased through the Global Fund for AIDS, TB and Malaria (GFATM) or the United States President’s Emergency Plan for AIDS Relief (PEPFAR) are produced by generic companies. API costs are very important because they are the largest contribution to the overall cost of ART. Efficient API production requires substantial investment in chemical manufacturing technologies and the ready availability of raw materials and energy at competitive prices. Generic API production is practiced in only a limited number of countries; the API market for ART is dominated by Indian companies. The quality of these APIs is ensured by manufacturing under good manufacturing practice (GMP), including process validation, testing against previously established specifications and the demonstration of clinical bioequivalence. The investment and personnel costs of a quality management system for GMP contribute significantly to the cost of API production. Chinese companies are the major suppliers for many advanced intermediates in API production. Improved chemistry of manufacturing, economies of scale and optimization of procurement have enabled drastic cost reductions for many ART APIs. The available capacity for global production of quality-assured APIs is likely adequate to meet forecasted demand for 2015. The increased use of ART for paediatric treatment, for second-line and salvage therapy, and the introduction of new APIs and combinations are important factors for the future of treatment in LMICs. The introduction of new fixed-dose combinations for ART and use of new drug delivery technologies could plausibly provide robust, durable ART for all patients in need, at an overall cost that is only moderately higher than what is presently being spent.
PMCID: PMC4318528  PMID: 25310430
3.  Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post partum: results of the BAN Study 
Antiviral therapy  2014;19(6):587-595.
An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral, and Nutrition study was performed to describe drug exposure and antiviral response.
Women using Combivir®[zidovudine (ZDV)+ lamivudine (3TC)]+Aluvia®[lopinavir/ritonavir(LPV/RTV)] were enrolled. Breast milk (BM) and mother and infant plasma (MP, IP) samples were obtained over 6hrs after observed dosing at 6, 12, or 24wks post-partum for drug concentrations and HIV RNA.
30 mother/infant pairs (10 each at 6, 12,and 24wks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, while LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24wks. The majority (98.3%) of BM concentrations were >HIVwt IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA.
ZDV and 3TC concentrated in BM while LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low ARV concentrations in IP suggests prevention of transmission while breast feeding may be due to ARV effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early.
PMCID: PMC4110187  PMID: 24464632
4.  Hepatic Safety and Tolerability of Raltegravir among HIV Patients Coinfected with Hepatitis B and/or C 
Antiviral therapy  2014;19(4):415-422.
Potential liver toxicity is an important consideration for antiretroviral selection among patients coinfected with HIV and viral hepatitis (B and/or C). We sought to describe the hepatic safety profile of raltegravir in this population.
Using data from HIV clinical cohorts at Johns Hopkins University and the University of North Carolina at Chapel Hill, we evaluated factors associated with liver enzyme elevations (LEEs) and calculated adverse event incidence rates for patients initiated on raltegravir-containing regimens prior to January 1, 2010. LEEs were graded according to Division of AIDS definitions.
During the study period, 456 patients received raltegravir – of whom 36% were hepatitis-coinfected (138 HCV, 17 HBV, 11 HBV+HCV). Coinfected patients were more likely to have baseline abnormal LEEs, and developed severe (grade 3–4) LEEs at a rate 3.4 times that of HIV-monoinfected patients (95% confidence interval (CI), 1.28, 9.61). Among all participants, the incidence rate for first occurrence of severe LEEs was 5 per 100 person-years (95% CI, 3, 7). In adjusted analyses, coinfected patients had a 2.7-fold increased hazard of severe LEEs (95% CI, 1.03, 7.04). Sixty percent of severe abnormalities occurred within 6 months after starting raltegravir; the drug was discontinued in 3 coinfected patients (1.3%) and 18 monoinfected patients (6.2%).
Compared to HIV-monoinfected patients, those with HIV-hepatitis coinfection are at increased hazard of developing LEEs on raltegravir, at a level similar to other antiretrovirals. Severe events were uncommon, rarely leading to raltegravir discontinuation. With appropriate monitoring, raltegravir-based therapy is safe in hepatitis-coinfected patients.
PMCID: PMC4108567  PMID: 24458137
integrase strand transfer inhibitors; hepatotoxicity; clinical cohort; United States
5.  [No title available] 
PMCID: PMC4295493  PMID: 23052978
6.  Long-Term Changes in Carotid Intima-Media Thickness among HIV-Infected Children and Young Adults 
Antiviral therapy  2013;19(1):61-68.
HIV+ patients are at increased risk of cardiovascular disease (CVD). This study assessed long-term changes in carotid intima-media thickness (IMT) as a surrogate marker for CVD risk in HIV-infected children and young adults.
This was a longitudinal, observational study comparing carotid IMT in HIV-infected subjects 2–21 years old to matched controls over 144 weeks.
34 HIV-infected and 29 controls were included in the analysis. Among the HIV-infected group, median age was 10 years, 74% black, and 65% female. 91% were perinatally-infected with 82% on antiretroviral therapy and a median CD4 count of 681 cells/mm3. At baseline, HIV-infected had increased internal carotid artery (ICA) and common carotid artery (CCA) IMT (mm) [ICA- HIV+: 0.90, controls: 0.73 (P<0.01); CCA- HIV+: 1.00, controls: 0.90 (P=0.02)]. Relatively large changes in ICA and CCA IMT were seen from year to year in both groups. However, by week 144, there were no net changes in ICA or CCA IMT within the HIV-infected group. In the controls, CCA increased 0.1 mm and ICA increased 0.17 mm from baseline to week 144. ICA and CCA IMT were similar between groups by 144 weeks.
Despite variations from year to year in carotid IMT in HIV-infected children and healthy controls, likely due to arterial growth and/or luminal diameter change, little or no net change occurred in carotid IMT over the entire 144-week study period. This suggests that only small net changes occur over time in HIV-infected children despite an increased long-term risk of CVD.
PMCID: PMC3938569  PMID: 23985545
HIV; atherosclerosis; cardiovascular disease; intima-media thickness; pediatrics; adolescents
7.  Changes to antiretroviral drug regimens during integrated TB-HIV treatment: Results of the SAPiT trial 
Antiviral therapy  2013;19(2):161-169.
Frequency of drug changes in combination antiretroviral therapy among patients starting both tuberculosis (TB) and human immunodeficiency virus (HIV) therapy, as a result of treatment-limiting toxicity or virological failure, is not well established.
Patients in the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) trial were randomized to initiate antiretroviral therapy either early or late during TB treatment or after completion of TB treatment. Drug changes due to toxicity (defined as due to grade 3 or 4 adverse events) or virological failure (defined as viral load > 1000 copies/ml on two occasions, taken at least 4 weeks apart) were assessed in these patients.
A total of 501 TB-HIV co-infected patients were followed for a mean of 16.0 (95% confidence interval (CI): 15.5 to 16.6) months after antiretroviral therapy (ART) initiation. The standard first-line ARVs used, were efavirenz, lamivudine and didanosine. Individual drug switches for toxicity occurred in 14 patients (incidence rate: 2.1 per 100 person-years; 95% (CI): 1.1 to 3.5), and complete regimen changes due to virological failure in 25 patients (incidence rate: 3.7 per 100 person-years; CI: 2.4 to 5.5). The most common treatment limiting toxicities were neuropsychiatric effects (n=4; 0.8%), elevated transaminase levels and hyperlactatemia (n= 3; 0.6%), and peripheral neuropathy (n=2; 0.4%). Complete regimen change due to treatment failure was more common in patients with CD4+ cell count <50cells/mm3 (p<0.001) at ART initiation and body mass index greater than 25 kg/m2 (p=0.01) at entry into the study.
Both drug switches and complete regimen change were uncommon in patients co-treated for TB-HIV with the chosen regimen. Patients with severe immunosuppression need to be monitored carefully, as they were most at risk for treatment failure requiring regimen change.
PMCID: PMC3984627  PMID: 24176943
8.  Tenofovir or zidovudine in second-line antiretroviral therapy after stavudine failure in southern Africa 
Antiviral therapy  2013;19(5):521-525.
There is debate over using tenofovir or zidovudine alongside lamivudine in second-line antiretroviral therapy (ART) following stavudine failure. We analyzed outcomes in cohorts from South Africa, Zambia and Zimbabwe
Patients aged ≥16 years who switched from a first-line regimen including stavudine to a ritonavir-boosted lopinavir-based second-line regimen with lamivudine or emtricitabine and zidovudine or tenofovir in seven ART programs in southern Africa were included. We estimated the causal effect of receiving tenofovir or zidovudine on mortality and virological failure using Cox proportional hazards marginal structural models. Its parameters were estimated using inverse probability of treatment weights. Baseline characteristics were age, sex, calendar year and country. CD4 cell count, creatinine and hemoglobin levels were included as time-dependent confounders.
1,256 patients on second-line ART, including 958 on tenofovir, were analyzed. Patients on tenofovir were more likely to have switched to second-line ART in recent years, spent more time on first-line ART (33 vs. 24 months) and had lower CD4 cell counts (172 vs. 341 cells/μl) at initiation of second-line ART. The adjusted hazard ratio comparing tenofovir with zidovudine was 1.00 (95% confidence interval 0.59-1.68) for virologic failure and 1.40 (0.57-3.41) for death.
We did not find any difference in treatment outcomes between patients on tenofovir or zidovudine; however, the precision of our estimates was limited. There is an urgent need for randomized trials to inform second-line ART strategies in resource-limited settings.
PMCID: PMC4043936  PMID: 24296645
HIV infection; second-line ART; cohort studies; causal modeling; sub-Saharan Africa
10.  Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youth treated with tenofovir disoproxil fumarate 
Antiviral therapy  2014;19(6):613-618.
Tenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biologic activity, and is elevated in persons with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youth treated with combination antiretroviral therapy (cART) containing or not containing TDF.
A randomized controlled trial in HIV+ youth ages 18–25 years enrolled participants based on cART treatment with TDF (TDF, N=118) or without TDF (no-TDF, N=85) and randomized within those groups to VITD (50,000 IU every four weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.
At baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was +7.7 pg/mL in the TDF/VITD group, compared to −1.7 (no-TDF/VITD, p=0.010); −1.3 (TDF/PL, p=0.006); and +1.1 (no-TDF/PL, p=0.035).
These results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youth.
PMCID: PMC4135028  PMID: 24535626
11.  Plasma lopinavir concentrations predict virological failure in a cohort of South African children initiating a protease-inhibitor-based regimen 
Antiviral therapy  2014;19(4):399-406.
Poor adherence to antiretroviral therapy contributes to pharmacokinetic variability and is the major determinant of virological failure. However, measuring treatment adherence is difficult, especially in children. We investigated the relationship between plasma lopinavir concentrations, pretreatment characteristics and viral load >400 copies/ml.
A total of 237 HIV-infected children aged 4–42 months on lopinavir/ritonavir oral solution were studied prospectively and followed for up to 52 weeks. Viral load and lopinavir concentration were measured at clinic visits 12, 24, 36 and 52 weeks after starting treatment. Cox multiple failure events models were used to estimate the crude and adjusted effect of lopinavir concentrations on the hazard of viral load >400 copies/ml.
The median (IQR) pretreatment CD4+ T-lymphocyte percentage was 18.80% (12.70–25.35) and 53% of children had a pretreatment viral load >750,000 copies/ml. The median (IQR) weight-for-age and height-for-age z-scores were −2.17 (−3.35–−2.84) and −3.34 (−4.57–−3.41), respectively. Median (IQR) lopinavir concentrations were 8.00 mg/l (4.11–12.42) at median (IQR) 3.50 h (2.67–4.25) after the dose. The hazard of viral load >400 copies/ml was increased with lopinavir concentrations <1 mg/l versus ≥1 mg/l (adjusted hazard ratio 2.3 [95% CI 1.63, 3.26]) and lower height-for-age z-scores.
Low lopinavir concentrations (<1 mg/l) are associated with viraemia in children. This measure could be used as a proxy for adherence and to determine which children are more likely to fail.
PMCID: PMC4229495  PMID: 24518130
12.  Treatment of hepatitis C with an interferon-based lead-in phase: A perspective from mathematical modeling 
Antiviral therapy  2014;19(5):469-477.
The standard of care for hepatitis C virus (HCV) genotype 1 is a protease inhibitor (telaprevir or boceprevir) combined with pegylated interferon and ribavirin (P/R). A lead-in phase of P/R therapy before addition of the protease inhibitor has been used, with the aim of improving response rates by reducing the development of protease inhibitor resistance. However, whether such a strategy can bring benefit to patients is unclear.
A viral dynamic model was used to compare in silico HCV dynamics in patients treated with a period of P/R lead-in therapy followed by the addition of a protease inhibitor versus immediate triple therapy without lead-in.
The model predicts that both regimens result in a similar end of treatment viral load change (viral decline or breakthrough). Thus, the current lead-in strategy may not decrease the rate of viral breakthrough/relapse or increase the rate of sustained virologic response. This agrees with available data from clinical trials of several HCV protease inhibitors, such as telaprevir, boceprevir, and faldaprevir.
These results suggest that current P/R lead-in strategies may not improve treatment outcomes. However, virus kinetics during a period of P/R therapy, combined with other factors such as the IL28B polymorphism and baseline viral load, can identify interferon-sensitive patients and help develop response-guided therapies.
PMCID: PMC4101064  PMID: 24434478
13.  Effects of HIV type-1 immune selection on susceptability to integrase inhibitor resistance 
Antiviral therapy  2009;14(7):953-964.
All site-specific interactions between HIV type-1 (HIV-1) subtype, human leukocyte anti-gen (HLA)-associated immune selection and integrase inhibitor resistance are not completely understood. We examined naturally occurring polymorphisms in HIV-1-integrase sequences from 342 antiretroviral-naive individuals from the Western Australian HIV Cohort Study and the Swiss HIV Cohort Study.
Standard bulk sequencing and sequence-based typing were used to generate integrase sequences and high-resolution HLA genotypes, respectively. Viral residues were examined with respect to drug resistance mutations and CD8+ T-cell escape mutations.
In both predominantly subtype B cohorts, 12 of 38 sites that mediate integrase inhibitor resistance mutations were absolutely conserved, and these included the primary resistance mutations. There were 18 codons with non-primary drug resistance-associated substitutions at rates of up to 58.8% and eight sites with alternative polymorphisms. Five viral residues were potentially subject to dual-drug and HLA-associated immune selection in which both selective pressures either drove the same amino acid substitution (codons 72, 157 and 163) or HLA alleles were associated with an alternative polymorphism that would alter the genetic barrier to resistance (codons 125 and 193). The common polymorphism T125A, which was characteristic of non-subtype B and was also associated with carriage of HLA-B*57/*5801, increased the mutational barrier to the resistance mutation T125K.
Primary integrase inhibitor resistance mutations were not detected in the absence of drug exposure in keeping with sites of high constraint. Viral polymorphisms caused by immune selection and/or associated with non-subtype B might alter the genetic barrier to some non-primary resistance-associated mutations.
PMCID: PMC4155129  PMID: 19918099
14.  Use of glomerular filtration rate estimating equations for drug dosing in HIV-positive patients 
Antiviral therapy  2013;18(6):793-802.
Current HIV treatment guidelines recommend using the Cockcroft-Gault equation for drug dosing adjustments. The use of newer glomerular filtration rate (GFR) estimating equations for drug dosing and the appropriateness of physician antiretroviral dosing based on estimated kidney function have not been studied in an HIV-positive population.
We evaluated concordance between measured and estimated GFR for the assignment of kidney function categories designated by the Food and Drug Administration (FDA) Guidance for Industry for pharmacokinetic studies, and appropriateness of physician antiretroviral drug dosing for level of kidney function in 200 HIV-positive patients on stable antiretroviral therapy. Estimated kidney function was determined using the Chronic Kidney Disease-Epidemiology collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD) Study and Cockcroft-Gault equations.
For assignment of FDA-designated kidney function categories, concordance rates between measured and estimated GFR using the CKD-EPI, MDRD Study and Cockcroft-Gault equations were 79%, 71% and 77%, respectively. This pattern was consistent across most subgroups. When actual prescribed dosages were compared to recommended dosages based on the level of estimated kidney function, 3% to 19% of study participants were prescribed higher than recommended dosages. The largest discordance between prescribed and recommended dosages was observed for the Cockcroft-Gault equation.
The CKD-EPI equation has the highest concordance with measured GFR for the assignment of FDA-designated kidney function categories. Its use may lead to lower dosing related errors in HIV-infected US adults on stable antiretroviral therapy. More education is required with respect to dose adjustment for level of kidney function.
PMCID: PMC4018994  PMID: 23963249
15.  Single and Multiple Dose Pharmacokinetics of Dolutegravir in the Genital Tract of HIV Negative Women 
Antiviral therapy  2013;18(8):1005-1013.
Antiretrovirals (ARV) that achieve adequate concentrations in anatomical sites of transmission are of interest for HIV prevention. A Phase 1, open label, pharmacokinetic (PK) study was performed to describe first dose and steady-state PK of the integrase inhibitor dolutegravir (DTG) in blood plasma (BP), cervicovaginal fluid (CVF), cervical tissue (CT), and vaginal tissue (VT) in HIV-1 negative women.
Eight healthy females given DTG 50mg daily for 5–7d had eleven paired BP and CVF samples collected over 24h following the first dose (PK1) and multiple dosing (PK2). Each woman underwent CT and VT biopsies at 1/4 time points at PK1 and PK2 to generate composite PK profiles. DTG concentrations were analyzed by validated LC-MS/MS methods. Noncompartmental PK analysis was performed and Spearman Rank Correlations determined between matrices.
BP AUCs were similar to previous reports and concentrations remained greater than the protein-adjusted IC90 for wild-type HIV (64 ng/mL). CVF exposures were ~6% of BP with low interindividual variability. CT and VT exposures were 7% of BP at PK1, and 9–10% of BP at PK2 with 94% of samples >PA-IC90. CT and VT concentrations were correlated to each other (rho=0.70, p=0.003), and to CVF at steady state (rho=0.52, p=0.04). Accumulation of DTG from PK1 to PK2 occurred in BP, CT, and VT, but only marginally in CVF.
DTG BP PK were consistent with previously published values. CVF, CT and VT exposures were highly correlated. At PK2, DTG accumulated to a greater extent in tissue than in BP or CVF, suggesting increased tissue affinity.
PMCID: PMC4038682  PMID: 23899439
dolutegravir; pharmacokinetics; cervicovaginal fluid; cervical tissue; vaginal tissue; female genital tract
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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