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1.  Protease Inhibitor Levels in Hair Samples Strongly Predict Virologic Responses to HIV Treatment 
AIDS (London, England)  2009;23(4):471-478.
Objective
Antiretroviral (ARV) therapies fail when behavioral or biologic factors lead to inadequate medication exposure. Currently available methods to assess ARV exposure are limited. Levels of ARVs in hair reflect plasma concentrations over weeks to months and may provide a novel method for predicting therapeutic responses.
Design/methods
The Women's Interagency HIV Study, a prospective cohort of HIV-infected women, provided the basis for developing and assessing methods to measure commonly-prescribed protease inhibitors (PIs) - lopinavir (LPV) and atazanavir (ATV) - in small hair samples. We examined the association between hair PI levels and initial virologic responses to therapy in multivariate logistic regression models.
Results
ARV concentrations in hair were strongly and independently associated with treatment response for 224 women starting a new PI-based regimen. For participants initiating LPV/RTV, the odds ratio (OR) for virologic suppression was 39.8 (95%CI 2.8–564) for those with LPV hair levels in the top tertile (>1.9ng/mg) compared to the bottom (≤0.41ng/mg) when controlling for self-reported adherence, age, race, starting viral load and CD4, and prior PI experience. For women starting ATV, the adjusted OR for virologic success was 7.7 (95%CI 2.0-29.7) for those with hair concentrations in the top tertile (>3.4ng/mg) compared to the lowest (≤1.2ng/mg).
Conclusions
PI levels in small hair samples were the strongest independent predictor of virologic success in a diverse group of HIV-infected adults. This noninvasive method for determining ARV exposure may have particular relevance for the epidemic in resource-poor settings due to the ease of collecting and storing hair.
doi:10.1097/QAD.0b013e328325a4a9
PMCID: PMC2654235  PMID: 19165084
Hair levels; therapeutic drug monitoring; antiretroviral exposure; virologic response; protease inhibitors; atazanavir; lopinavir; WIHS cohort
2.  Short Communication: A Low-Cost Method for Analyzing Nevirapine Levels in Hair as a Marker of Adherence in Resource-Limited Settings 
Abstract
The measurement of antiretroviral concentrations in hair is emerging as an important technology to objectively quantify adherence to combination antiretroviral therapy. Hair levels of antiretrovirals are the strongest independent predictor of virologic success in large prospective cohorts of HIV-infected patients and surpass self-report in predicting outcomes. Hair is easy to collect and store, but validated methods to analyze antiretroviral levels in hair using liquid chromatography tandem mass spectrometry (LC-MS/MS) are expensive. We report here on the development of a thin-layer chromatography (TLC) assay for the semiquantitative analysis of nevirapine in hair. TLC assay results from 11 samples were consistent with results using LC-MS/MS [Spearman correlation coefficient 0.99 (95% CI 0.95–0.996)]. This simple, low-cost method of analyzing nevirapine concentrations in hair may provide a novel monitoring tool for antiretroviral adherence in resource-limited settings and merits further study in clinical settings.
doi:10.1089/aid.2013.0239
PMCID: PMC3887402  PMID: 24164410
3.  Pharmacy Refill Adherence Compared with CD4 Count Changes for Monitoring HIV-Infected Adults on Antiretroviral Therapy 
PLoS Medicine  2008;5(5):e109.
Background
World Health Organization (WHO) guidelines for monitoring HIV-infected individuals taking combination antiretroviral therapy (cART) in resource-limited settings recommend using CD4+ T cell (CD4) count changes to monitor treatment effectiveness. In practice, however, falling CD4 counts are a consequence, rather than a cause, of virologic failure. Adherence lapses precede virologic failure and, unlike CD4 counts, data on adherence are immediately available to all clinics dispensing cART. However, the accuracy of adherence assessments for predicting future or detecting current virologic failure has not been determined. The goal of this study therefore was to determine the accuracy of adherence assessments for predicting and detecting virologic failure and to compare the accuracy of adherence-based monitoring approaches with approaches monitoring CD4 count changes.
Methodology and Findings
We conducted an observational cohort study among 1,982 of 4,984 (40%) HIV-infected adults initiating non-nucleoside reverse transcriptase inhibitor-based cART in the Aid for AIDS Disease Management Program, which serves nine countries in southern Africa. Pharmacy refill adherence was calculated as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last refill prior to the endpoint of interest, expressed as a percentage. The main outcome measure was virologic failure defined as a viral load > 1,000 copies/ml (1) at an initial assessment either 6 or 12 mo after cART initiation and (2) after a previous undetectable (i.e., < 400 copies/ml) viral load (breakthrough viremia). Adherence levels outperformed CD4 count changes when used to detect current virologic failure in the first year after cART initiation (area under the receiver operating characteristic [ROC] curves [AUC] were 0.79 and 0.68 [difference = 0.11; 95% CI 0.06 to 0.16; χ2 = 20.1] respectively at 6 mo, and 0.85 and 0.75 [difference = 0.10; 95% CI 0.05 to 0.14; χ2 = 20.2] respectively at 12 mo; p < 0.001 for both comparisons). When used to detect current breakthrough viremia, adherence and CD4 counts were equally accurate (AUCs of 0.68 versus 0.67, respectively [difference = 0.01; 95% CI −0.06 to 0.07]; χ2 = 0.1, p > 0.5). In addition, adherence levels assessed 3 mo prior to viral load assessments were as accurate for virologic failure occurring approximately 3 mo later as were CD4 count changes calculated from cART initiation to the actual time of the viral load assessments, indicating the potential utility of adherence assessments for predicting future, rather than simply detecting current, virologic failure. Moreover, combinations of CD4 count and adherence data appeared useful in identifying patients at very low risk of virologic failure.
Conclusions
Pharmacy refill adherence assessments were as accurate as CD4 counts for detecting current virologic failure in this cohort of patients on cART and have the potential to predict virologic failure before it occurs. Approaches to cART scale-up in resource-limited settings should include an adherence-based monitoring approach.
Analyzing pharmacy and laboratory records from 1,982 patients beginning HIV therapy in southern Africa, Gregory Bisson and colleagues find medication adherence superior to CD4 count changes in identifying treatment failure.
Editors' Summary
Background.
Globally, more than 30 million people are infected with the human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Combinations of antiretroviral drugs that hold HIV in check (viral suppression) have been available since 1996. Unfortunately, most of the people affected by HIV/AIDS live in developing countries and cannot afford these expensive drugs. As a result, life expectancy has plummeted and economic growth has reversed in these poor countries since the beginning of the AIDS pandemic. Faced with this humanitarian crisis, the lack of access to HIV treatment was declared a global health emergency in 2003. Today, through the concerted efforts of governments, international organizations, and funding bodies, about a quarter of the HIV-positive people in developing and transitional countries who are in immediate need of life-saving, combination antiretroviral therapy (cART) receive the drugs they need.
Why Was This Study Done?
To maximize the benefits of cART, health-care workers in developing countries need simple, affordable ways to monitor viral suppression in their patients—a poor virologic response to cART can lead to the selection of drug-resistant HIV, rapid disease progression, and death. In developed countries, virologic response is monitored by measuring the number of viral particles in patients' blood (viral load) but this technically demanding assay is unavailable in most developing countries. Instead, the World Health Organization recommends that CD4+ T cell (CD4) counts be used to monitor patient responses to cART in resource-limited settings. HIV results in loss of CD4 cells (a type of immune system cell), so a drop in a patient's CD4 count often indicates virologic failure (failure of treatment to suppress the virus). However, falling CD4 counts are often a result of virologic failure and therefore monitoring CD4 counts for drops is unlikely to prevent virologic failure from occurring. Rather, falling CD4 counts are often used only to guide a change to new medicines, which may be even more expensive or difficult to take. On the other hand “adherence lapses”—the failure to take cART regularly—often precede virologic failure, so detecting them early provides an opportunity for improvement in adherence that could prevent virologic failure. Because clinics that dispense cART routinely collect data that can be used to calculate adherence, in this study the researchers investigate whether assessing adherence might provide an alternative, low-cost way to monitor and predict virologic failure among HIV-infected adults on cART.
What Did the Researchers Do and Find?
The Aid for AIDS Disease Management Program provides cART to medical insurance fund subscribers in nine countries in southern Africa. Data on claims for antiretroviral drugs made through this program, plus CD4 counts assessed at about 6 or 12 months after initiating cART, and viral load measurements taken within 45 days of a CD4 count, were available for nearly 2,000 HIV-positive adults who had been prescribed a combination of HIV drugs including either efavirenz or nevirapine. The researchers defined adherence as the number of months of cART claims submitted divided by the number of complete months between cART initiation and the last pharmacy refill before a viral load assessment was performed. Virologic failure was defined in two ways: as a viral load of more than 1,000 copies per ml of blood 6 or 12 months after cART initiation, or as a rebound of viral load to similar levels after a previously very low reading (breakthrough viremia). The researchers' statistical analysis of these data shows that at 6 and 12 months after initiation of cART, adherence levels indicated virologic failure more accurately than CD4 count changes. For breakthrough viremia, both measurements were equally accurate. Adherence levels during the first 3 months of cART predicted virologic failure at 6 months as accurately as did CD4 count changes since cART initiation. Finally, the combination of adherence levels and CD4 count changes accurately identified patients at very low risk of virologic failure.
What Do These Findings Mean?
These findings suggest that adherence assessments (based in this study on insurance claims for pharmacy refills) can identify the patients on cART who are at high and low risk of virologic failure at least as accurately as CD4 counts. In addition, they suggest that adherence assessments could be used for early identification of patients at high risk of virologic failure, averting the health impact of treatment failure and the cost of changing to second-line drug regimens. Studies need to be done in other settings (in particular, in public clinics where cART is provided without charge) to confirm the generalizability of these findings. These finding do not change that fact that monitoring CD4 counts plays an important role in deciding when to start cART or indicating when cART is no longer protecting the immune system. But, write the researchers, systematic monitoring of adherence to cART should be considered as an alternative to CD4 count monitoring in patients who are receiving cART in resource-limited settings or as a way to direct the use of viral load testing where feasible.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050109.
This study is discussed further in a PLoS Medicine Perspective by David Bangsberg
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on all aspects of HIV/AIDS, including an article about adherence to antiretroviral therapy
Information is available from Avert, an international AIDS charity, on HIV and AIDS in Africa and on providing AIDS drug treatment for millions
The World Health Organization provides information about universal access to HIV treatment (in several languages) and on its recommendations for antiretroviral therapy for HIV infection in adults and adolescents
The US Centers for Disease Control and Prevention also provides information on global efforts to deal with the HIV/AIDS pandemic (in English and Spanish)
doi:10.1371/journal.pmed.0050109
PMCID: PMC2386831  PMID: 18494555
4.  Atazanavir Pharmacokinetics With and Without Tenofovir during Pregnancy 
Background
Plasma concentrations of several protease inhibitors are decreased during pregnancy. Few data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.
Design
IMPAACT 1026s is an on-going, prospective, non-blinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included two cohorts receiving atazanavir/ritonavir 300mg/100mg once daily during the third trimester through 6-12 weeks postpartum either with or without tenofovir.
Methods
Intensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase HPLC with a detection limit of 0.13 mcg/mL. Pharmacokinetic targets were the estimated 10th percentile atazanavir AUC (29.4 mcg*hr/mL) in non-pregnant historical controls taking the standard dose (mean AUC=57 mcg*hr/mL) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs. Infant bilirubin concentrations were measured at 24-48 hours and 4-6 days after birth.
Results
Atazanavir pharmacokinetic data were available for 38 women (18 without tenofovir, 20 with tenofovir. Median atazanavir AUC was reduced during the third trimester compared to postpartum for subjects not receiving tenofovir (41.9 vs 57.9 mcg*hr/mL, p=.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg*hr/mL, p=.04). During the third trimester, AUC was below the target in 33% (6/18) of women not receiving tenofovir and 55% (11/20) of women receiving tenofovir. Trough concentration was below the target in 6% (1/18) of women not receiving tenofovir and 15% (3/20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29 paired samples was 0.18 (0 - 0.45). No excessive infant bilirubin concentrations were observed.
Conclusions
Atazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400mg/100mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults, especially for pregnant women who are antiretroviral-experienced and/or who are also receiving tenofovir.
doi:10.1097/QAI.0b013e31820fd093
PMCID: PMC3125419  PMID: 21283017
atazanavir; tenofovir; pharmacokinetics; pregnancy; HIV; mother to child transmission
5.  Atazanavir Plus Ritonavir or Efavirenz as Part of a 3-Drug Regimen for Initial Treatment of HIV-1 
Annals of internal medicine  2011;154(7):445-456.
Background
Limited data compare once-daily options for initial therapy for HIV-1.
Objective
To compare time to virologic failure; first grade-3 or -4 sign, symptom, or laboratory abnormality (safety); and change or discontinuation of regimen (tolerability) for atazanavir plus ritonavir with efavirenz-containing initial therapy for HIV-1.
Design
A randomized equivalence trial accrued from September 2005 to November 2007, with median follow-up of 138 weeks. Regimens were assigned by using a central computer, stratified by screening HIV-1 RNA level less than 100 000 copies/mL or 100 000 copies/mL or greater; blinding was known only to the site pharmacist. (ClinicalTrials.gov registration number: NCT00118898)
Setting
59 AIDS Clinical Trials Group sites in the United States and Puerto Rico.
Patients
Antiretroviral-naive patients.
Intervention
Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine.
Measurements
Primary outcomes were time to virologic failure, safety, and tolerability events. Secondary end points included proportion of patients with HIV-1 RNA level less than 50 copies/mL, emergence of drug resistance, changes in CD4 cell counts, calculated creatinine clearance, and lipid levels.
Results
463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir–lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF–emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and and the group that received efavirenz and did not differ according to whether abacavir–lamivudine or tenofovir DF–emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir–lamivudine but not with tenofovir DF–emtricitabine.
Limitations
Neither HLA-B*5701 nor resistance testing was the standard of care when A5202 enrolled patients. The third drugs, atazanavir plus ritonavir and efavirenz, were open-label; the nucleoside reverse transcriptase inhibitors were prematurely unblinded in the high viral load stratum; and 32% of patients modified or discontinued treatment with their third drug.
Conclusion
Atazanavir plus ritonavir and efavirenz have similar antiviral activity when used with abacavir–lamivudine or tenofovir DF–emtricitabine.
Primary Funding Source
National Institutes of Health.
doi:10.1059/0003-4819-154-7-201104050-00316
PMCID: PMC3430716  PMID: 21320923
6.  Effects of the H2-Receptor Antagonist Famotidine on the Pharmacokinetics of Atazanavir-Ritonavir With or Without Tenofovir in HIV-Infected Patients 
AIDS Patient Care and STDs  2011;25(9):509-515.
Abstract
Significant pharmacokinetic interactions can result between acid-suppressing agents and some protease inhibitors (PIs) in the management of HIV infection. In healthy subjects, famotidine, an H2-receptor antagonist, reduces exposures of atazanavir by 4–28% at doses of 20–40 mg twice daily. This study evaluated the effect of famotidine 20–40 mg twice daily on the pharmacokinetics of atazanavir/ritonavir 300/100 mg once daily with and without tenofovir disoproxil fumarate (TDF) 300 mg in HIV-infected patients (n=40; 87.5% male; mean age 42, range 26–63 years; 55% white). Coadministration of famotidine 40 mg and atazanavir/ritonavir to HIV-infected patients reduced exposures of atazanavir by approximately 20%. This is comparable to reductions seen in HIV-uninfected subjects. Coadministration of famotidine 20 mg had less impact on atazanavir exposures, with no reduction of atazanavir geometric mean plasma concentration at 24 h postdose (Cmin). In the presence of TDF, administration of famotidine 20–40 mg twice daily 2 h after and 10 h before atazanavir/ritonavir reduced exposures of atazanavir by 19–25%. However, all individual atazanavir Cmin values remained at least five-fold above the population mean protein-binding adjusted 90% maximum effect (EC90) against wild-type HIV (14 ng/mL). No viral load rebound was observed at end of study. The results confirmed that coadministration of an H2-receptor antagonist with atazanavir/ritonavir in HIV-infected patients resulted in similar magnitude of reductions in atazanavir exposures as in healthy subjects. This supports the current dose recommendations for coadministration of an H2-receptor antagonist with atazanavir/ritonavir.
doi:10.1089/apc.2011.0113
PMCID: PMC3157302  PMID: 21770762
7.  Pharmacokinetics of an Increased Atazanavir Dose with and without Tenofovir During the Third Trimester of Pregnancy 
Background
Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy.
Methods
IMPAACT 1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including two cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the 2nd trimester (2nd trim), 400/100 mg during the 3rd trimester (3rd trim) and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by HPLC. Pharmacokinetic targets were the 10th percentile atazanavir AUC (29.4 mcg*hr/mL) in non-pregnant adults on standard dose and 0.15 mcg/mL, minimum trough concentration.
Results
Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; Median (range) pharmacokinetic parameters are presented for 2nd, 3rd trim and PP and number who met target/total. * indicates p<0.05 compared to PP.
Atazanavir without tenofovir
AUC 30.5 (9.19–93.8), 45.7 (11–88.3), and 48.8 (9.9–112.2) mcg-hr/mL, and 8/14, 29/37 and 27/34 met target. C24h was 0.49 (0.09–4.09), 0.71 (0.14–2.09), and 0.90 (0.05–2.73) mcg/mL; 13/14, 36/37 and 29/34 met target.
Atazanavir with tenofovir
AUC 26.2 (6.8–60.9)*, 37.7 (0.72–88.2)*, and 58.6 (6–149) mcg-hr/mL, and 7/17, 23/32 and 27/29 met target. C24h was 0.44 (0.12–1.06)*, 0.57 (0.02–2.06)*, and 1.26 (0.09–5.43) mcg/mL; 7/17, 23/32 and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events.
Conclusions
Atazanavir/ritonavir increased to 400/100mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.
doi:10.1097/QAI.0b013e318289b4d2
PMCID: PMC3625451  PMID: 23392467
atazanavir; tenofovir; pharmacokinetics; pregnancy; HIV; mother to child transmission
8.  Microanalysis of the antiretroviral nevirapine in human hair from HIV-infected patients by liquid chromatography-tandem mass spectrometry 
Analytical and bioanalytical chemistry  2011;401(6):1923-1933.
Sufficient drug exposure is crucial for maintaining durable responses to HIV treatments. However, monitoring drug exposure using single blood samples only provides short-term information and is highly subject to intra-individual pharmacokinetic variation. Drugs can accumulate in hair over a long period of time, so hair drug levels can provide drug exposure information over prolonged periods. We now report on a specific, sensitive and reproducible LC-MS/MS method for measuring nevirapine (NVP), a widely used antiretroviral drug, levels in human hair using even a single short strand of hair. Hair samples are cut into small segments and drug is extracted in methanol/trifluoroacetic acid (v/v, 9:1) shaken at 37°C in a water bath overnight, followed by liquid-liquid extraction under alkaline conditions. The extracted samples are then separated on a BDS-C18 column with mobile phase composed as 50% acetonitrile containing 0.15% acetic acid and 4 mM ammonium acetate with an isocratic elution for a total run time of 3 min. and detected by triple quadrupole electrospray multiple reaction mode at precursor/product ion at 267.0>225.9 m/z. Deuterated nevirapine-d5 was used as internal standard. This method was validated from 0.25 to 100 ng/mg using 2 mg hair samples. The accuracies for spiked NVP hair control samples were 98–106% with coefficients of variation (CV) less than 10%. The CV for incurred hair control samples was less than 7%. The extraction efficiency for incurred control hair samples was estimated at more than 95% by repeated extractions. This method has been successfully applied to analyze more than 1000 hair samples from participants in a large ongoing cohort study of HIV-infected participants. We also showed that nevirapine in human hair can easily be detected in a single short strand of hair. This method will allow us to identify drug non-adherence using even a single strand of hair.
doi:10.1007/s00216-011-5278-7
PMCID: PMC3477620  PMID: 21847531
Antiretroviral drug; Nevirapine; Hair; LC-MS/MS; TDM; Adherence
9.  Factors affecting antiretroviral pharmacokinetics in HIV-infected women with virologic suppression on combination antiretroviral therapy: a cross-sectional study 
BMC Infectious Diseases  2013;13:256.
Background
Although some studies show higher antiretroviral concentrations in women compared to men, data are limited. We conducted a cross-sectional study of HIV-positive women to determine if protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin and Cmax values were significantly different than historical general population (predominantly male) averages and to evaluate correlates of higher concentrations.
Methods
HIV-positive women with virologic suppression (viral load < 50copies/mL) on their first antiretroviral regimen were enrolled. Timed blood samples for Cmin and Cmax were drawn weekly for 3 weeks. The ratio of each individual’s median Cmin and Cmax to the published population mean values for their PI or NNRTI was calculated and assessed using Wilcoxon sign-rank. Intra- and inter-patient variability of antiretroviral drug levels was assessed using coefficient of variation and intra-class correlation. Linear regression was used to identify correlates of the square root-transformed Cmin and Cmax ratios.
Results
Data from 82 women were analyzed. Their median age was 41 years (IQR=36-48) and duration of antiretrovirals was 20 months (IQR=9-45). Median antiretroviral Cmin and Cmax ratios were 1.21 (IQR=0.72-1.89, p=0.003) (highest ratios for nevirapine and lopinavir) and 0.82 (IQR=0.59-1.14, p=0.004), respectively. Nevirapine and efavirenz showed the least and unboosted atazanavir showed the most intra- and inter-patient variability. Higher CD4+ count correlated with higher Cmin. No significant correlates for Cmax were found.
Conclusions
Compared to historical control data, Cmin in the women enrolled was significantly higher whereas Cmax was significantly lower. Antiretroviral Cmin ratios were highly variable within and between participants. There were no clinically relevant correlates of drug concentrations.
Trial registration
NCT00433979
doi:10.1186/1471-2334-13-256
PMCID: PMC3679788  PMID: 23732043
HIV; Women; Antiretroviral therapy; Pharmacokinetics
10.  Antenatal Atazanavir: A Retrospective Analysis of Pregnancies Exposed to Atazanavir 
Introduction. There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. Methods. A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. Results. There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), “preconception” atazanavir exposure; 27 started atazanavir-based cART as “first-line” during the pregnancy; and 29 “switched” to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. Conclusions. These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy.
doi:10.1155/2014/961375
PMCID: PMC4190692  PMID: 25328370
11.  Low lopinavir plasma or hair concentrations explain second line protease inhibitor failures in a resource-limited setting 
Background
In resource-limited settings, many patients, with no prior PI treatment on a second-line, high genetic barrier, ritonavir boosted protease inhibitor (PI) containing regimen have virologic failure.
Methods
We conducted a cross-sectional survey to investigate the aetiology of virologic failure in two public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load > 500 copies/ml) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study.
Results
Ninety three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients 37(40%) had virological failure, only 2 of which had had major protease inhibitor mutations. The negative predictive values: probability of failure with lopinavir plasma concentration > 1μg/mL or hair concentrations > 3.63ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies/ml, of patients without protease inhibitor resistance, could be explained by either having a low lopinavir concentration in plasma or hair.
Conclusions
Most patients who fail a LPV/r regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent LPV/r use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing.
doi:10.1097/QAI.0b013e31820dc0cc
PMCID: PMC3073814  PMID: 21239995
Lopinavir; medication adherence; resource-limited settings; protease inhibitor resistance mutations; plasma concentration; hair concentration
12.  Predictors of Suboptimal Virologic Response to Highly Active Antiretroviral Therapy Among Human Immunodeficiency Virus-Infected Adolescents 
Objective
To examine the prevalence and biopsychosocial predictors of sub-optimal virologic response to highly active antiretroviral therapy (HAART) among human immunodeficiency virus (HIV)-infected adolescents.
Design
Population-based cohort study.
Setting
Sixteen academic medical centers across thirteen cities in the United States.
Participants
One hundred and fifty four HIV-infected adolescents who presented for at least two consecutive visits after initiation of HAART.
Main Outcome Measures
Viral load (plasma concentration of HIV RNA), CD4+ T-lymphocyte count.
Results
Of the 154 adolescents enrolled in the study, 50 (32.5%) demonstrated early and sustained virologic suppression while receiving HAART. The remaining 104 adolescents (67.5%) had a poor virologic response. Adequate adherence (>50%) to HAART—reported by 70.8% of respondents—was associated with a 60% reduced odds of suboptimal virologic suppression in a multivariable logistic regression model (adjusted odds ratio = 0.4; 95% confidence interval : 0.2 – 1.0). Exposure to sub-optimal antiretroviral therapy (ART) prior to HAART, on the other hand, was associated with more than a two-fold increased odds of sub-optimal virologic response (adjusted odds ratio = 2.6; 95% confidence interval: 1.1 – 5.7).
Conclusions
Fully two-thirds of HIV-infected adolescents in the current study demonstrated a sub-optimal virologic response to HAART. Non-adherence and prior single or dual ART were associated with subsequent poor virologic responses to HAART. These predictors of HAART failure echo findings in pediatric and adult populations. Given the unique developmental stage of adolescence, age-specific interventions are indicated to address high rates of non-adherence and therapeutic failure.
doi:10.1001/archpediatrics.2009.204
PMCID: PMC3739292  PMID: 19996046
HIV; Adolescent; Antiretroviral Therapy; Highly Active; Adherence; Viral Load; CD4 Lymphocyte Count
13.  Evaluation of multiple measures of antiretroviral adherence in the Eastern European country of Georgia 
Introduction
There is little information on adherence to antiretroviral therapy (ART) in the Eastern European region. This prospective study evaluated multiple measures of adherence and their association with viral suppression among HIV patients in Georgia.
Methods
A prospective cohort study enrolled 100 consecutive antiretroviral-naïve adult (age ≥18 years) patients, who were followed for three months. Adherence was assessed by medication refill and three self-report measures (an AIDS Clinical Trial Group [ACTG] tool for four-day adherence, a visual analogue scale [VAS] and a rating task for 30-day adherence). The VAS represented a line anchored by 0 and 100% corresponding to the percentage of prescribed doses taken. The rating task asked patients to rate their ability to take all medications as prescribed, with responses categorized into six levels of adherence: very poor (0%), poor (20%), fair (40%), good (60%), very good (80%) and excellent (100%). Patients with adherence of ≥95% by medication refill, ACTG and VAS, and ≥80% by rating task, were defined as adherent.
Results
Of 100 patients enrolled, eight had missing data and were excluded from analysis. Among the remaining 92 patients, the median age was 39 years, and 70% were men. Major modes of HIV acquisition were injection drug use (IDU; 47.3%) and heterosexual contact (44.1%). The proportions of adherent patients were as follows: 68% by medication refill, 90% by ACTG questionnaire, 38% by VAS and 42% by rating task. On average, four months after commencing ART, 52 (56.5%) patients had a viral load <400 copies/ml and 26 (28.3%) patients had a viral load <50 copies/ml. Of 43 persons with a history of IDU, 22 (51.2%) reached a viral load of <400 copies/ml. In multivariate analysis, only refill adherence was a statistically significant predictor of viral suppression of <400 copies/ml: the risk ratio was 1.7 (95% CI: 1.1–2.8). Refill adherence, VAS and rating task were associated with viral suppression of <50 copies/ml. Non-IDUs were twice as likely to achieve viral load <50 copies/ml compared to IDUs. Refill adherence had the largest area under the receiver-operating characteristic curve for predicting viral suppression.
Conclusions
Medication refill adherence was the strongest predictor of viral suppression. IDUs can achieve optimal virologic outcomes, but may require additional adherence support.
doi:10.7448/IAS.17.1.18885
PMCID: PMC3983475  PMID: 24721464
antiretroviral therapy; adherence; Eastern Europe; injection drug use; viral suppression
14.  French 2013 guidelines for antiretroviral therapy of HIV-1 infection in adults 
Introduction
These guidelines are part of the French Experts’ recommendations for the management of people living with HIV/AIDS, which were made public and submitted to the French health authorities in September 2013. The objective was to provide updated recommendations for antiretroviral treatment (ART) of HIV-positive adults. Guidelines included the following topics: when to start, what to start, specific situations for the choice of the first session of antiretroviral therapy, optimization of antiretroviral therapy after virologic suppression, and management of virologic failure.
Methods
Ten members of the French HIV 2013 expert group were responsible for guidelines on ART. They systematically reviewed the most recent literature. The chairman of the subgroup was responsible for drafting the guidelines, which were subsequently discussed within, and finalized by the whole expert group to obtain a consensus. Recommendations were graded for strength and level of evidence using predefined criteria. Economic considerations were part of the decision-making process for selecting preferred first-line options. Potential conflicts of interest were actively managed throughout the whole process.
Results
ART should be initiated in any HIV-positive person, whatever his/her CD4 T-cell count, even when >500/mm3. The level of evidence of the individual benefit of ART in terms of mortality or progression to AIDS increases with decreasing CD4 cell count. Preferred initial regimens include two nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a non-nucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine), or a ritonavir-boosted protease inhibitor (atazanavir or darunavir). Raltegravir, lopinavir/r, and nevirapine are recommended as alternative third agents, with specific indications and restrictions. Specific situations such as HIV infection in women, primary HIV infection, severe immune suppression with or without identified opportunistic infection, and person who injects drugs are addressed. Options for optimization of ART once virologic suppression is achieved are discussed. Evaluation and management of virologic failure are described, the aim of any intervention in such situation being to reduce plasma viral load to <50 copies/ml.
Conclusion
These guidelines recommend that any HIV-positive individual should be treated with ART. This recommendation was issued both for the patient’s own sake and for promoting treatment as prevention.
doi:10.7448/IAS.17.1.19034
PMCID: PMC4062879  PMID: 24942364
antiretroviral treatment; guidelines; first-line therapy; virologic failure; cost of treatment.
15.  Impact of Baseline HIV-1 Tropism on Viral Response and CD4 Cell Count Gains in HIV-Infected Patients Receiving First-line Antiretroviral Therapy 
The Journal of Infectious Diseases  2011;204(1):139-144.
Background. Viral tropism influences the natural history of human immunodeficiency type 1 (HIV-1) disease: X4 viruses are associated with faster decreases in CD4 cell count. There is scarce information about the influence of viral tropism on treatment outcomes.
Methods. Baseline plasma samples from patients recruited to the ArTEN (Atazanavir/ritnoavir vs. Nevirapine on a background of Tenofovir and Emtricitabine) trial were retrospectively tested for HIV-1 tropism using the genotypic tool geno2phenoFPR=5.75%. ArTEN compared nevirapine with atazanavir-ritonavir, both along with tenofovir-emtricitabine, in drug-naïve patients.
Results. Of 569 ArTEN patients, 428 completed 48 weeks of therapy; 282 of these received nevirapine and 146 of these received atazanavir-ritonavir. Overall, non-B subtypes of HIV-1 were recognized in 96 patients (22%) and X4 viruses were detected in 55 patients (14%). At baseline, patients with X4 viruses had higher plasma HIV RNA levels (5.4 vs 5.2 log copies/mL, respectively; P = .044) and lower CD4 cell counts (145 vs 188 cells/μL, respectively; P < .001) than those with R5 strains. At week 48, virologic responses were lower in patients with X4 viruses than in patients with R5 viruses (77% vs 92%, respectively; P = .009). Multivariate analysis confirmed HIV-1 tropism as an independent predictor of virologic response at week 24 (P = .012). This association was extended to week 48 (P = .007) in clade B viruses. Conversely, CD4 cell count recovery was not influenced by baseline HIV-1 tropism.
Conclusions. HIV-1 tropism is an independent predictor of virologic response to first-line antiretroviral therapy. In contrast, it does not seem to influence CD4 cell count recovery.
Clinical Trials Registration. NCT00389207.
doi:10.1093/infdis/jir218
PMCID: PMC3307159  PMID: 21628668
16.  Durability of antiretroviral therapy and predictors of virologic failure among perinatally HIV-infected children in Tanzania: a four-year follow-up 
BMC Infectious Diseases  2014;14(1):567.
Background
In Tanzania, HIV-1 RNA testing is rarely available and not standard of care. Determining virologic failure is challenging and resistance mutations accumulate, thereby compromising second-line therapy. We evaluated durability of antiretroviral therapy (ART) and predictors of virologic failure among a pediatric cohort at four-year follow-up.
Methods
This was a prospective cross-sectional study with retrospective chart review evaluating a perinatally HIV-infected Tanzanian cohort enrolled in 2008-09 with repeat HIV-1 RNA in 2012-13. Demographic, clinical, and laboratory data were extracted from charts, resistance mutations from 2008-9 were analyzed, and prospective HIV RNA was obtained.
Results
161 (78%) participants of the original cohort consented to repeat HIV RNA. The average age was 12.2 years (55% adolescents ≥12 years). Average time on ART was 6.4 years with 41% receiving second-line (protease inhibitor based) therapy. Among those originally suppressed on a first-line (non-nucleoside reverse transcriptase based regimen) 76% remained suppressed. Of those originally failing first-line, 88% were switched to second-line and 72% have suppressed virus. Increased level of viremia and duration of ART trended with an increased number of thymidine analogue mutations (TAMs). Increased TAMs increased the odds of virologic failure (p = 0.18), as did adolescent age (p < 0.01).
Conclusions
After viral load testing in 2008-09 many participants switched to second-line therapy. The majority achieved virologic suppression despite multiple resistance mutations. Though virologic testing would likely hasten the switch to second-line among those failing, methods to improve adherence is critical to maximize durability of ART and improve virologic outcomes among youth in resource-limited settings.
doi:10.1186/s12879-014-0567-3
PMCID: PMC4225040  PMID: 25373425
Pediatric HIV; HIV resistance; Thymidine analogue mutations; ART adherence; HIV RNA; Durability of antiretroviral therapy; Viral load
17.  A Randomized Controlled Trial Comparing the Effects of Counseling and Alarm Device on HAART Adherence and Virologic Outcomes 
PLoS Medicine  2011;8(3):e1000422.
Michael Chung and colleagues show that intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure, whereas use of an alarm device had no effect.
Background
Behavioral interventions that promote adherence to antiretroviral medications may decrease HIV treatment failure. Antiretroviral treatment programs in sub-Saharan Africa confront increasing financial constraints to provide comprehensive HIV care, which include adherence interventions. This study compared the impact of counseling and use of an alarm device on adherence and biological outcomes in a resource-limited setting.
Methods and Findings
A randomized controlled, factorial designed trial was conducted in Nairobi, Kenya. Antiretroviral-naïve individuals initiating free highly active antiretroviral therapy (HAART) in the form of fixed-dose combination pills (d4T, 3TC, and nevirapine) were randomized to one of four arms: counseling (three counseling sessions around HAART initiation), alarm (pocket electronic pill reminder carried for 6 months), counseling plus alarm, and neither counseling nor alarm. Participants were followed for 18 months after HAART initiation. Primary study endpoints included plasma HIV-1 RNA and CD4 count every 6 months, mortality, and adherence measured by monthly pill count. Between May 2006 and September 2008, 400 individuals were enrolled, 362 initiated HAART, and 310 completed follow-up. Participants who received counseling were 29% less likely to have monthly adherence <80% (hazard ratio [HR] = 0.71; 95% confidence interval [CI] 0.49–1.01; p = 0.055) and 59% less likely to experience viral failure (HIV-1 RNA ≥5,000 copies/ml) (HR 0.41; 95% CI 0.21–0.81; p = 0.01) compared to those who received no counseling. There was no significant impact of using an alarm on poor adherence (HR 0.93; 95% CI 0.65–1.32; p = 0.7) or viral failure (HR 0.99; 95% CI 0.53–1.84; p = 1.0) compared to those who did not use an alarm. Neither counseling nor alarm was significantly associated with mortality or rate of immune reconstitution.
Conclusions
Intensive early adherence counseling at HAART initiation resulted in sustained, significant impact on adherence and virologic treatment failure during 18-month follow-up, while use of an alarm device had no effect. As antiretroviral treatment clinics expand to meet an increasing demand for HIV care in sub-Saharan Africa, adherence counseling should be implemented to decrease the development of treatment failure and spread of resistant HIV.
Trial registration
ClinicalTrials gov NCT00273780
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Adherence to HIV treatment programs in poor countries has long been cited as an important public health concern, especially as poor adherence can lead to drug resistance and inadequate treatment of HIV. However, two factors have recently cast doubt on the poor adherence problem: (1) recent studies have shown that adherence is high in African HIV treatment programs and often better than in Western HIV clinics. For example, in a meta-analysis of 27 cohorts from 12 African countries, adequate adherence was noted in 77% of subjects compared to only 55% among 31 North America cohorts; (2) choice of antiretroviral regimens may impact on the development of antiretroviral resistance. In poor countries, most antiretroviral regimens contain non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine or efavirenz, which remain in the patient's circulation for weeks after single-dose administration. This situation means that such patients may not experience antiretroviral resistance unless they drop below 80% adherence—contrary to the more stringent 95% plus adherence levels needed to prevent resistance in regimens based on unboosted protease inhibitors—ultimately, off-setting some treatment lapses in resource-limited settings where NNRTI-based regimens are widely used.
Why Was This Study Done?
Given that adherence may not be as crucial an issue as previously thought, antiretroviral treatment programs in sub-Saharan Africa may be spending scarce resources to promote adherence to the detriment of some potentially more effective elements of HIV treatment and management programs. Although many treatment programs currently include adherence interventions, there is limited quality evidence that any of these methods improve long-term adherence to HIV treatment. Therefore, it is necessary to identify adherence interventions that are inexpensive and proven to be effective in resource-limited settings. As adherence counseling is already widely implemented in African HIV treatment programs and inexpensive alarm devices are thought to also improve compliance, the researchers compared the impact of adherence counseling and the use of an alarm device on adherence and biological outcomes in patients enrolled in HIV programs in rural Kenya.
What Did the Researchers Do and Find?
The researchers enrolled 400 eligible patients (newly diagnosed with HIV, never before taken antiretroviral therapy, aged over 18 years) to four arms: (1) adherence counseling alone; (2) alarm device alone; (3) both adherence counseling and alarm device together; and (4) a control group that received neither adherence counseling nor alarm device. The patients had blood taken to record baseline CD4 count and HIV-1 RNA and after starting HIV treatment, returned to the study clinic every month with their pill bottles for the study pharmacist to count and recorded the number of pills remaining in the bottle, and to receive another prescription. Patients were followed up for 18 months and had their CD4 count and HIV-1 RNA measured at 6, 12, and 18 months.
Patients receiving adherence counseling were 29% less likely to experience poor adherence compared to those who received no counseling. Furthermore, those receiving intensive early adherence counseling were 59% less likely to experience viral failure. However, there was no significant difference in mortality or significant differences in CD4 counts at 18 months follow-up between those who received counseling and those who did not. There were no significant differences in adherence, time to viral failure, mortality, or CD4 counts in patients who received alarm devices compared to those who did not.
What Do These Findings Mean?
The results of this study suggest that intensive adherence counseling around the time of HIV treatment initiation significantly reduces poor adherence and virologic treatment failure, while using an alarm device has no effect. Therefore, investment in careful counseling based on individual needs at the onset of HIV treatment initiation, appears to have sustained benefit, possibly through strengthening the relationship between the health care provider and patient through communication, education, and trust. Interactive adherence counseling supports the bond between the clinic and the patient and may result in fewer patients needing to switch to expensive second-line medications and, possibly, may help to decrease the spread of resistant HIV. These findings define an adherence counseling protocol that is effective and are highly relevant to other HIV clinics caring for large numbers of patients in sub-Saharan Africa.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000422.
UNAIDS provides information about HIV treatment strategies
The American Public Health Association has information about adherence to HIV treatment regimens
The US Department of Health and Human Services has information for patients about adherence to HIV treatment
The World Health Organization provides information about HIV treatment pharmacovigilance
doi:10.1371/journal.pmed.1000422
PMCID: PMC3046986  PMID: 21390262
18.  Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients 
AIDS Research and Human Retroviruses  2013;29(12):1541-1546.
Abstract
Physiological effects of aging make the older population more susceptible to adverse drug events and drug–drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks. Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r therapy, and proportion treated with tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced creatinine clearance (91 versus 76 ml/min). The older group had a higher atazanavir exposure with median AUC0–24 71.2 vs. 53.1 mg·h/liter, Cmax 8.5 vs. 5.5 mg/liter, and Ctrough 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV Ctrough levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower body weight (BW) (46 versus 63 kg) than the males, but atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher atazanavir concentrations. Parameter estimate for age and atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01–3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing atazanavir pharmacokinetics. Patients from the aging group appeared to have higher atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.
doi:10.1089/aid.2013.0069
PMCID: PMC3848483  PMID: 24088045
19.  Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP) 
PLoS ONE  2014;9(1):e83736.
Background
Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.
Methods
A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).
Results
Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.
Conclusions
This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.
Trial Registration
ClinicalTrials.gov +NCT00903084.
doi:10.1371/journal.pone.0083736
PMCID: PMC3885443  PMID: 24421901
20.  Relationship between total bilirubin, endothelial function, inflammation and oxidative stress in HIV-infected adults on stable antiretroviral therapy 
HIV medicine  2012;13(10):609-616.
Objective
Enhanced inflammation is evident in HIV, even with virologic suppression. Outside HIV, studies show an independent association between higher total bilirubin and better endothelial function as well as lower prevalence of coronary heart disease possibly due to the anti-inflammatory and antioxidant effect of bilirubin.
Methods
A cross-sectional study was performed in HIV-1 infected adults on stable antiretroviral therapy (ART) to determine if a relationship exists between total bilirubin and endothelial function (flow mediated dilation (FMD) of the brachial artery), inflammation (interleukin-6 (IL-6), soluble tumor necrosis factor receptors, C-reactive protein, adhesion molecules), coagulation markers (fibrinogen and D-Dimer) and oxidative stress (F2-Isoprostanes). Endpoints were compared based on total bilirubin levels and atazanavir status using distributionally-appropriate, two-sample tests. Correlation coefficients were determined between total bilirubin and end points. Linear regression was used to model the relationship between total bilirubin (and atazanavir status) and FMD.
Results
98 adults were included. Total bilirubin was higher in atazanavir group (median (IQR) 1.8 (1.1–2.6) vs. 0.6 (0.4–1.4) mg/dL; p<0.01) as was insulin, HOMA-IR and fibrinogen. Total bilirubin was positively correlated with fibrinogen and was not correlated with other outcomes. After adjustment, neither total bilirubin nor atazanavir status was associated with FMD.
Conclusions
In virologically-suppressed, HIV-infected adults on stable ART, neither total bilirubin nor atazanavir use was associated with improved endothelial function as measured by FMD, inflammation or oxidative stress as measured by biomarkers.
doi:10.1111/j.1468-1293.2012.01026.x
PMCID: PMC3430799  PMID: 22624591
21.  The spectrum of HIV mother-to-child transmission risk 
Journal of the International AIDS Society  2014;17(4Suppl 3):19703.
Introduction
With the implementation of combined antiretroviral therapy (cART) and prevention of mother-to-child transmission (MTCT) we observed dramatic decreases in rates of perinatal MTCT of HIV, 0.3% in France in women with plasma viral load (pVL) <50 c/mL at delivery. We describe a case of MTCT which occurred despite virologic suppression of the mother at delivery, the first case in our centre since 2002.
Description of the case
A 26-year-old black woman, Guinea-native, living in France since 2007, was diagnosed with HIV-1 CRF02 in 2008 and lost to follow-up since November 2012 after second delivery (2 female born in March 2009 and October 2012, uninfected). Third pregnancy began in July 2013 and baseline characteristics in September were as follows: week 13 of gestational age (GA), CDC stage A, CD4 317/mm3, pVL 4.89 log c/mL. cART with abacavir/lamivudine and atazanavir/ritonavir 300/100 mg daily (qd) was introduced. VL decreased to 2.4 log c/mL in 4 weeks and CD4 increased to 456/mm3. In December, at week 22 of GA, viral rebound at 4.14 log c/mL due to sub-optimal maternal adherence was observed. After counselling, pVL decreased to 1.69 log c/mL in March 2014, at week 35 of GA and 1.3 log c/mL at delivery. As pVL was <400 c/mL at week 36 of GA, vaginal delivery with IV zidovudine was decided. However, because of poor/uncertain maternal adherence to cART, the neonate was treated with a combination of 2 drugs (lamivudine-nevirapine) with the 4-week zidovudine regimen, until the result of delivery pVL. This combination was stopped at day 2 when maternal delivery pVL (22 c/mL) was received and standard oral zidovudine prophylaxis was continued. Infant was tested for HIV infection at baseline (day 3) and found to be HIV-infected (HIV-RNA 60 c/mL) attesting in-utero HIV transmission. On day 15, zidovudine prophylaxis was discontinued and treatment for HIV infection initiated with standard cART according to the French Paediatric Antiretroviral Guidelines.
Conclusions
The risk of HIV acquisition is low in infants born to women who receive standard cART during pregnancy and labour and achieve undetectable VL at delivery. However, transmission remains a hazard, with possibility of in-utero infection during episodes of non-adherence, and the risk of a possible MTCT has to be mentioned to all pregnant women.
doi:10.7448/IAS.17.4.19703
PMCID: PMC4225373  PMID: 25397451
22.  Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients 
Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h−1; P = 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter−1; P = 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.
doi:10.1128/AAC.01822-12
PMCID: PMC3535925  PMID: 23147727
23.  Atazanavir–bilirubin interaction: a pharmacokinetic–pharmacodynamic model 
Purpose
The aim of this work was to analyze the atazanavir–bilirubin relationship, using a new mathematical approach to pharmacokinetic–pharmacodynamic models, for competitive drug interactions based on Michaelis–Menten equations.
Patients and methods
Because atazanavir induces an increase of plasma bilirubin levels, in a concentration-dependent manner, we developed a mathematical model, based on increments of atazanavir and bilirubin concentrations at steady state, in HIV infected (HIV+) patients, and plotted the corresponding nomogram for detecting suboptimal atazanavir exposure.
Results
By applying the obtained model, the results indicate that an absolute value or an increment of bilirubin at steady state below 3.8 μmol/L, are predictive of suboptimal atazanavir exposure and therapeutic failure.
Conclusion
We have successfully implemented a new mathematical approach to pharmacokinetic–pharmacodynamic model for atazanavir–bilirubin interaction. As a result, we found that bilirubin plasma levels constitute a good marker of exposure to atazanavir and of viral suppression.
doi:10.2147/CPAA.S48377
PMCID: PMC3792011  PMID: 24106429
atazanavir; bilirubin; HIV/AIDS; pharmacodynamics; pharmacokinetics
24.  HIV: prevention of mother-to-child transmission  
Clinical Evidence  2011;2011:0909.
Introduction
Over 2 million children are thought to be living with HIV/AIDS worldwide, of whom over 80% live in sub-Saharan Africa. Without antiretroviral treatment, the risk of HIV transmission from infected mothers to their children is 15% to 30% during gestation or labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding. HIV-1 infection accounts for most infections; HIV-2 is rarely transmitted from mother to child. Transmission is more likely in mothers with high viral loads, advanced disease, or both, in the presence of other sexually transmitted diseases, and with increased exposure to maternal blood. Mixed feeding practices (breast milk plus other liquids or solids) and prolonged breastfeeding are also associated with increased risk of mother-to-child transmission of HIV.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of measures to reduce mother-to-child transmission of HIV? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed a GRADE evaluation of the quality of evidence for interventions.
Results
We found 53 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiretroviral drugs, different methods of infant feeding, elective caesarean section, immunotherapy, micronutrient supplements, vaginal microbicides, and vitamin supplements.
Key Points
Without active intervention, the risk of mother-to-child transmission (MTCT) of HIV-1 is high, especially in populations where prolonged breastfeeding is the norm. Without antiviral treatment, the risk of transmission of HIV from infected mothers to their children is approximately 15% to 30% during pregnancy and labour, with an additional transmission risk of 10% to 20% associated with prolonged breastfeeding.HIV-2 is rarely transmitted from mother to child.Transmission is more likely in mothers with high viral loads, advanced HIV disease, or both.Without antiretroviral treatment (ART), 15% to 35% of vertically infected infants die within the first year of life.The long-term treatment of children with ART is complicated by multiple concerns regarding the complications associated with life-long treatment, including adverse effects of antiretroviral drugs, difficulties of adherence across the developmental trajectory of childhood and adolescence, and the development of resistance.From a paediatric perspective, successful prevention of MTCT and HIV-free survival for infants remain the most important focus.
Antiretroviral drugs given to the mother during pregnancy or labour, to the baby immediately after birth, or to the mother and baby reduce the risk of intrauterine and intrapartum MTCT of HIV-1 and when given to the infant after birth and to the mother or infant during breastfeeding reduce the risk of postpartum MTCT of HIV-1.
Reductions in MTCT are possible using multidrug ART regimens. Longer courses of ART are more effective, but the greatest benefit is derived from treatment during late pregnancy, labour, and early infancy.Suppression of the maternal viral load to undetectable levels (below 50 copies/mL) using highly active antiretroviral therapy (HAART) offers the greatest risk reduction, and is currently the standard of care offered in most resource-rich countries, where MTCT rates have been reduced to 1% to 2%. Alternative short-course regimens have been tested in resource-limited settings where HAART is not yet widely available. There is evidence that short courses of antiretroviral drugs have confirmed efficacy for reducing MTCT. Identifying optimal short-course regimens (drug combination, timing, and cost effectiveness) for various settings remains a focus for ongoing research.The development of viral resistance in mothers and infants after single-dose nevirapine and other short-course regimens that include single-dose nevirapine is of concern. An additional short-course of antiretrovirals with a different regimen during labour and early postpartum, and the use of HAART, may decrease the risk of viral resistance in mothers, and in infants who become HIV-infected despite prophylaxis.World Health Organization guidelines recommend starting prophylaxis with antiretroviral drugs from as early as 14 weeks' gestation, or as soon as possible if women present late in pregnancy, in labour, or at delivery.
Elective caesarean section at 38 weeks may reduce vertical transmission rates (apart from breast-milk transmission). The potential benefits of this intervention need to be balanced against the increased risk of surgery-associated complications, high cost, and feasibility issues. These reservations are particularly relevant in resource-limited settings.
Immunotherapy with HIV hyperimmune globulin seems no more effective than immunoglobulin without HIV antibody at reducing HIV-1 MTCT risk.
Vaginal microbicides have not been demonstrated to reduce HIV-1 MTCT risk.
There is no evidence that supplementation with vitamin A reduces the risk of HIV-1 MTCT, and there is concern that postnatal vitamin A supplementation for mother and infant may be associated with increased risk of mortality.
We don't know whether micronutrients are effective in prevention of MTCT of HIV as we found no RCT evidence on this outcome.
Avoidance of breastfeeding prevents postpartum transmission of HIV, but formula feeding requires access to clean water and health education. The risk of breastfeeding-related HIV transmission needs to be balanced against the multiple benefits that breastfeeding offers. In resource-poor countries, breastfeeding is strongly associated with reduced infant morbidity and improved child survival. Exclusive breastfeeding during the first 6 months may reduce the risk of HIV transmission compared with mixed feeding, while retaining most of its associated benefits.In a population where prolonged breastfeeding is usual, early, abrupt weaning may not reduce MTCT or HIV-free survival at 2 years compared with prolonged breastfeeding, and may be associated with a higher rate of infant mortality for those infants diagnosed as HIV-infected at <4 months of age. Antiretrovirals given to the mother or the infant during breastfeeding can reduce the risk of HIV transmission in the postpartum period. World Health Organization guidelines recommend that HIV-positive mothers should exclusively breastfeed for the first 6 months, after which time appropriate complementary foods can be introduced. Breastfeeding should be continued for the first 12 months of the infant's life, and stopped only when an adequate diet without breast milk can be provided. Heat- or microbicidal-treated expressed breast milk may offer value in particular settings.
PMCID: PMC3217724  PMID: 21477392
25.  External Validation of the Bilirubin–Atazanavir Nomogram for Assessment of Atazanavir Plasma Exposure in HIV-1-Infected Patients 
The AAPS Journal  2012;15(2):308-315.
Atazanavir increases plasma bilirubin levels in a concentration-dependent manner. Due to less costly and readily available assays, bilirubin has been proposed as a marker of atazanavir exposure. In this work, a previously developed nomogram for detection of suboptimal atazanavir exposure is validated against external patient populations. The bilirubin nomogram was validated against 311 matching bilirubin and atazanavir samples from 166 HIV-1-infected Norwegian, French, and Italian patients on a ritonavir-boosted regimen. In addition, the nomogram was evaluated in 56 Italian patients on an unboosted regimen. The predictive properties of the nomogram were validated against observed atazanavir plasma concentrations. The use of the nomogram to detect non-adherence was also investigated by simulation. The bilirubin nomogram predicted suboptimal exposure in the patient populations on a ritonavir-boosted regimen with a negative predictive value of 97% (95% CI 95–100). The bilirubin nomogram and monitoring of atazanavir concentrations had similar predictive properties for detecting non-adherence based on simulations. Although both methods performed adequately during a period of non-adherence, they had lower predictive power to detect past non-adherence episodes. Using the bilirubin nomogram for detection of suboptimal atazanavir exposure in patients on a ritonavir-boosted regimen is a rapid and cost-effective alternative to routine measurements of the actual atazanavir exposure in plasma. Its application may be useful in clinical settings if atazanavir concentrations are not available.
doi:10.1208/s12248-012-9440-8
PMCID: PMC3618856  PMID: 23224752
atazanavir; bilirubin; nomogram

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