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1.  Association between Efavirenz as Initial Therapy for HIV-1 Infection and Increased Risk of Suicidal Ideation, Attempted, or Completed Suicide 
Annals of internal medicine  2014;161(1):1-10.
The relationship between efavirenz use and suicidality is not well defined.
Compare time to suicidality with efavirenz-containing versus efavirenz-free antiretroviral regimens for initial treatment of HIV.
Participant-level data were analyzed from four AIDS Clinical Trials Group (ACTG) antiretroviral-naïve studies conducted from 2001 to 2010. Within each study, participants were randomly assigned to an efavirenz-containing (n=3241) or efavirenz-free regimen (n=2091).
ACTG sites; 74% enrolled in the United States.
Antiretroviral-naïve participants.
Efavirenz versus efavirenz-free regimens.
Suicidality was defined as suicidal ideation, attempted or completed suicide. Groups were compared with a hazard ratio (HR) and 95% confidence interval (CI) estimated from a Cox model stratified by study.
73% were men, median age was 37 years; 32% had documented psychiatric history or received psychoactive medication within 30 days prior to study entry. Median follow-up was 96 weeks. Suicidality incidence per 1000 person-years was 8.08 (47 events) in the efavirenz group and 3.66 (15 events) in the efavirenz-free group, HR: 2.28 (95% CI: 1.27 to 4.10, p=0.006). Incidence of attempted or completed suicide was 2.90 (17 events) and 1.22 (5 events) in the efavirenz and efavirenz-free groups, respectively, HR: 2.58 (95% CI: 0.94 to 7.06, p=0.065). Eight suicide deaths in the efavirenz group and one in the efavirenz-free group were reported.
There was not a standardized questionnaire regarding suicidal ideation or attempt. Efavirenz was open-label in three of four studies.
Initial treatment with an efavirenz-containing antiretroviral regimen was associated with a two-fold increased hazard of suicidality compared to a regimen without efavirenz.
PMCID: PMC4204642  PMID: 24979445
efavirenz; suicide; suicidal ideation; suicidal behavior; HIV; adverse event; psychiatry
2.  HIV Cure Strategies: How Good Must They Be to Improve on Current Antiretroviral Therapy? 
PLoS ONE  2014;9(11):e113031.
We examined efficacy, toxicity, relapse, cost, and quality-of-life thresholds of hypothetical HIV cure interventions that would make them cost-effective compared to life-long antiretroviral therapy (ART).
We used a computer simulation model to assess three HIV cure strategies: Gene Therapy, Chemotherapy, and Stem Cell Transplantation (SCT), each compared to ART. Efficacy and cost parameters were varied widely in sensitivity analysis. Outcomes included quality-adjusted life expectancy, lifetime cost, and cost-effectiveness in dollars/quality-adjusted life year ($/QALY) gained. Strategies were deemed cost-effective with incremental cost-effectiveness ratios <$100,000/QALY.
For patients on ART, discounted quality-adjusted life expectancy was 16.4 years and lifetime costs were $591,400. Gene Therapy was cost-effective with efficacy of 10%, relapse rate 0.5%/month, and cost $54,000. Chemotherapy was cost-effective with efficacy of 88%, relapse rate 0.5%/month, and cost $12,400/month for 24 months. At $150,000/procedure, SCT was cost-effective with efficacy of 79% and relapse rate 0.5%/month. Moderate efficacy increases and cost reductions made Gene Therapy cost-saving, but substantial efficacy/cost changes were needed to make Chemotherapy or SCT cost-saving.
Depending on efficacy, relapse rate, and cost, cure strategies could be cost-effective compared to current ART and potentially cost-saving. These results may help provide performance targets for developing cure strategies for HIV.
PMCID: PMC4232561  PMID: 25397616
3.  Potential savings by reduced CD4 monitoring in stable HIV patients on antiretrovirals 
JAMA internal medicine  2013;173(18):1746-1748.
PMCID: PMC3980729  PMID: 23978894
HIV; CD4; antiretrovirals; costs
4.  Test Performance of Blood Beta-Glucan for Pneumocystis Jirovecii Pneumonia in Patients with AIDS and Respiratory Symptoms 
AIDS (London, England)  2013;27(6):967-972.
To define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia in AIDS patients with respiratory symptoms.
Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms.
Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if ≥80 pg/mL and negative if <80 pg/mL.
Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% (95% CI: 87.2%–96.5%), and specificity 75.0% (50.9%–91.3%). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (91.5%–98.8%). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (38.7%–78.9%).
Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool based on the pretest probability of PCP in such patients.
PMCID: PMC4181577  PMID: 23698062
Beta-glucan; HIV; Acquired Immunodeficiency Syndrome; Pneumocystis; Pneumonia; Predictive Value of Tests
5.  Abacavir/Lamivudine Versus Tenofovir DF/Emtricitabine as Part of Combination Regimens for Initial Treatment of HIV: Final Results 
The Journal of Infectious Diseases  2011;204(8):1191-1201.
(See the editorial commentary by Hull and Montaner, on pages 1154–6.)
Background. AIDS Clinical Trials Group A5202 compared blinded abacavir/lamivudine (ABC/3TC) to tenofovir DF/emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in human immunodeficiency virus (HIV)-infected treatment-naive patients, stratified by screening HIV RNA (< or ≥105 copies/mL). Due to higher virologic failure with ABC/3TC in the high HIV RNA stratum, blinded treatment was stopped in this group, but study follow-up continued for all patients.
Methods. Primary endpoints were times to virologic failure, regimen modification, and safety event.
Results. In the low HIV RNA stratum, time to virologic failure was similar for ABC/3TC vs TDF/FTC with ATV/r (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.76, 2.05) or EFV (HR 1.23, 95% CI 0.77, 1.96), with significantly shorter times to regimen modification for ABC/3TC with EFV or ATV/r and to safety events with EFV. Prior to stopping blinded treatment in the high stratum, higher virologic failure rates were seen with ABC/3TC with EFV (HR 2.46, 95% CI 1.20, 5.05) or ATV/r (HR 2.22, 95% CI 1.19, 4.14).
Conclusions. In the low HIV RNA stratum, times to virologic failure for ABC/3TC or TDF/FTC were not different with EFV or ATV/r. In the high stratum, virologic failure rate was significantly higher for ABC/3TC than for TDF/FTC when given with either EFV or ATV/r.
PMCID: PMC3173503  PMID: 21917892
6.  Blood (1→3)-β-D-Glucan as a Diagnostic Test for HIV-Related Pneumocystis jirovecii Pneumonia 
In a large group of HIV-infected clinical trial participants with diverse opportunistic infections, blood beta-glucan was a more sensitive noninvasive test for PCP than serum LDH; sensitivity was also higher than that frequently reported for induced sputum examinations.
(See the editorial commentary by Morris and Masur, on pages 203–204.)
Background. Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1→3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs).
Methods. The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites.
Results. A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209–500 pg/mL), compared with 37 pg/mL (IQR, 31–235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%–96%), and the specificity was 65% (95% CI, 53%–75%); positive and negative predictive values were 85% (95% CI, 79%–90%) and 80% (95% CI, 68%–89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP.
Conclusions. Blood (1→3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.
PMCID: PMC3165964  PMID: 21690628
7.  Early virologic response to abacavir/lamivudine and tenofovir/emtricitabine during ACTG A5202 
HIV clinical trials  2013;14(6):284-291.
ACTG A5202 randomized treatment-naive individuals to tenofovir-emtricitabine (TDF/FTC) or abacavir-lamivudine (ABC/3TC) combined with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). Individuals in the high screening viral load (VL) stratum (≥100,000 copies/mL) had increased rates of virologic failure with ABC/3TC.
Compare regimen-specific early virologic response.
Using Wilcoxon rank-sum tests, we compared regimen-specific VL changes from entry to week 4 in A5202 subjects (n=1813) and from entry to week 1, 2 and 4 in a 179-patient substudy. We evaluated associations between week 4 VL change and time to virologic failure with Cox proportional-hazards models.
TDF/FTC- and ABC/3TC produced similar Week 4 viral load declines in the entire study population and in the high VL stratum. EFV produced greater VL declines from baseline at week 4 than ATV/r (median −2.1 vs. −1.9 log10 copies/mL; p<0.001). In the substudy of subjects with week 1, 2 and 4 VL data, there was no difference in viral load decline in those randomized to TDF/FTC versus ABC/3TC, but EFV resulted in greater VL decline from entry at each of these timepoints than ATV/r. Smaller Week 4 viral load decline was associated with increased risk of virologic failure.
Within all treatment arms, a less robust week 4 virologic response was associated with higher risk for subsequent virologic failure. However, between-regimen differences in week 4 VL declines did not parallel the previously reported differences in longer term virologic efficacy in A5202, suggesting that between-regimen differences in responses were not due to intrinsic differences in antiviral activity.
PMCID: PMC4060613  PMID: 24334181
Anti-HIV Agents; HIV Infections/drug therapy/*virology; Treatment Outcome
8.  Early Antiretroviral Therapy for Patients With Acute AIDS-Related Opportunistic Infections: A Cost-Effectiveness Analysis of ACTG A5164 
HIV clinical trials  2010;11(5):248-259.
ACTG A5164 demonstrated that early antiretroviral therapy (ART) in HIV-infected patients with acute opportunistic infections (OIs) reduced death and AIDS progression compared to ART initiation 1 month later. We project the life expectancies, costs, and incremental cost-effectiveness ratios (ICERs) of these strategies.
Using an HIV simulation model, we compared 2 strategies for patients with acute OIs: (1) an intervention to deliver early ART, and (2) deferred ART. Parameters from ACTG A5164 included initial mean CD4 count (47/µL), linkage to outpatient care (87%), and immune reconstitution inflammatory syndrome 1 month after ART initiation (7%). The estimated intervention cost was $1,650/patient.
Early ART lowered projected 1-year mortality from 10.4% to 8.2% and increased life expectancy from 10.07 to 10.39 quality-adjusted life-years (QALYs). Lifetime costs increased from $385,220 with deferred ART to $397,500 with early ART, primarily because life expectancy increased, producing an ICER of $38,600/QALY. Results were most sensitive to increased intervention cost and decreased virologic efficacy in the early ART strategy.
An intervention to initiate ART early in patients with acute OIs improves survival and meets US cost-effectiveness thresholds. Programs should be developed to implement this strategy at sites where HIV-infected patients present with OIs.
PMCID: PMC3183461  PMID: 21126955
antiretroviral therapy; HIV; cost; cost-effectiveness; opportunistic infection
9.  Weight and Lean Body Mass Change with Antiretroviral Initiation and Impact on Bone Mineral Density: AIDS Clinical Trials Group Study A5224s 
AIDS (London, England)  2013;27(13):2069-2079.
To compare the effect initiating different antiretroviral therapy (ART) regimens have on weight, body mass index (BMI), and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD).
A5224s was a substudy of A5202, a prospective trial of 1857 ART-naïve participants randomized to blinded abacavir-lamivudine (ABC/3TC) or tenofovir DF-emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV/r). All subjects underwent dual-energy absorptiometry (DXA) and abdominal CT for body composition. Analyses used 2-sample t-tests and linear regression.
A5224s included 269 subjects: 85% male, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/mL, and CD4 233 cells/µL. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks post randomization (all p<0.001). Assignment to ATV/r (vs EFV) resulted in significantly greater weight (mean difference 3.35 kg) and BMI gain (0.88 kg/m2; both p=0.02), but not LBM (0.67 kg; p=0.15), while ABC/3TC and TDF/FTC were not significantly different (p≥0.10). In multivariable analysis, only lower baseline CD4 count and higher HIV-1 RNA were associated with greater increase in weight, BMI, or LBM. In multivariable analyses, increased LBM was associated with an increased hip BMD.
ABC/3TC vs. TDF/FTC did not differ in change in weight, BMI, or LBM; ATV/r vs. EFV resulted in greater weight and BMI gain but not LBM. A positive association between increased LBM and increased hip BMD should be further investigated through prospective interventional studies to verify the impact of increased LBM on hip BMD.
PMCID: PMC3966569  PMID: 24384588
antiretroviral therapy; HIV; body composition; body weight; lean body mass; bone mineral density; randomized clinical trial
10.  Changes in Fat Mitochondrial DNA and Function in Subjects Randomized to Abacavir-Lamivudine or Tenofovir DF–Emtricitabine With Atazanavir-Ritonavir or Efavirenz: AIDS Clinical Trials Group Study A5224s, Substudy of A5202 
The Journal of Infectious Diseases  2012;207(4):604-611.
Background. The effect of nonthymidine nucleoside reverse-transcriptase inhibitors (NRTIs) on fat mitochondrial DNA (mtDNA) content and function is unclear.
Methods. A5202 randomized antiretroviral therapy–naive human immunodeficiency virus–infected subjects to abacavir-lamivudine (ABC/3TC) versus tenofovir DF–emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir-ritonavir (ATV/r). A5224s, substudy of A5202, enrolled 269 subjects with fat measurements by dual-energy x-ray absorptiometry and computed tomography. A subset of subjects underwent fat biopsies at baseline and week 96 for mtDNA content (real-time polymerase chain reaction) and oxidative phosphorylation nicotinamide adenine dinucleotide (reduced) dehydrogenase (complex I) and cytochrome c oxidase (complex IV) activity levels (immunoassays). Intent-to-treat analyses were performed using analysis of variance and paired t tests.
Results. Fifty-six subjects (87% male; median age, 39 years) were included; their median body mass index, CD4 cell count, and fat mtDNA level were 26 kg/m2, 227 cells/μL, and 1197 copies/cell, respectively. Fat mtDNA content decreased within the ABC/3TC and TDF/FTC groups (combining EFV and ATV/r arms; median change, −341 [interquartile range, −848 to 190; P = .03] and −400 [−661 to −221; P < .001] copies/cell, respectively), but these changes did not differ significantly between the 2 groups (P = .57). Complex I and IV activity decreased significantly in the TDF/FTC group (median change, −12.45 [interquartile range, −24.70 to 2.90; P = .003] and −8.25 [−13.90 to −1.30; P < .001], optical density × 103/µg, respectively) but not the ABC/3TC group. Differences between the ABC/3TC and TDF/FTC groups were significant for complex I (P = .03).
Conclusions. ABC/3TC and TDF/FTC significantly and similarly decreased fat mtDNA content, but only TDF/FTC decreased complex I and complex IV activity levels.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3549598  PMID: 23204164
lipoatrophy; lipodystrophy; metabolic disease; mitochondrial dysfunction; mitochondrial toxicity; oxidative phosphorylation
11.  Impact of UGT1A1 Gilbert Variant on Discontinuation of Ritonavir-Boosted Atazanavir in AIDS Clinical Trials Group Study A5202 
The Journal of Infectious Diseases  2012;207(3):420-425.
The UGT1A1*28 variant has been associated with hyperbilirubinemia and atazanavir discontinuation. Protocol A5202 randomly assigned human immunodeficiency virus type 1 (HIV-1)–infected patients to receive atazanavir/ritonavir (atazanavir/r) or efavirenz, with tenofovir/emtricitabine or abacavir/lamivudine. A total of 646 atazanavir/r recipients were evaluable for UGT1A1. Homozygosity for *28/*28 was present in 8% of whites, 24% of blacks, and 18% of Hispanics and was associated with increased bilirubin concentrations. There was an association between *28/*28 and increased atazanavir/r discontinuation among Hispanic participants (P = .005) but not among white or black participants (P = .79 and P = .46, respectively). The positive predictive value of 28*/28* for atazanavir/r discontinuation among Hispanic participants was only 32% (95% confidence interval, 16%–52%).
PMCID: PMC3537445  PMID: 23148286
Gilbert syndrome; pharmacogenetics; atazanavir; UGT1A1; HIV therapy
12.  Lower Pill Burden and Once-Daily Antiretroviral Treatment Regimens for HIV Infection: A Meta-Analysis of Randomized Controlled Trials 
Once-daily compared with twice-daily antiretroviral therapy regimens increased adherence; however, the difference was modest and not associated with a difference in virological suppression. In addition, higher pill burden was associated with lower rates of virological suppression, whether once- or twice-daily regimens.
Background. Contemporary antiretroviral treatment regimens are simpler than in the past, with lower pill burden and once-daily dosing frequency common. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the impact of pill burden and once-daily vs twice-daily dosing on ART adherence and virological outcomes.
Methods. A literature search of 4 electronic databases through 31 March 2013 was used. RCTs comparing once-daily vs twice-daily ART regimens that also reported on adherence and virological suppression were included. Study design, study population characteristics, intervention, outcome measures, and study quality were extracted. Study quality was rated using the Cochrane risk-of-bias tool.
Results. Nineteen studies met our inclusion criteria (N = 6312 adult patients). Higher pill burden was associated with both lower adherence rates (P = .004) and worse virological suppression (P < .0001) in both once-daily and twice-daily subgroups, although the association with adherence in the once-daily subgroup was not statistically significant. The average adherence was modestly higher in once-daily regimens than twice-daily regimens (weighted mean difference = 2.55%; 95% confidence interval [CI], 1.23 to 3.87; P = .0002). Patients on once-daily regimens did not achieve virological suppression more frequently than patients on twice-daily regimens (relative risk [RR] = 1.01; 95% CI, 0.99 to 1.03; P = .50). Both adherence and viral load suppression decreased over time, but adherence decreased less with once-daily dosing than with twice-daily dosing.
Conclusions. Lower pill burden was associated with both better adherence and virological suppression. Adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.
PMCID: PMC3982838  PMID: 24457345
randomized controlled trials; ART; fixed-dose combination; once-daily; twice-daily
13.  Cost-effectiveness Analysis of UGT1A1 Genetic Testing to Inform Antiretroviral Prescribing in HIV Disease 
Antiviral therapy  2012;18(3):399-408.
Homozygosity for UGT1A1*28/*28 (Gilbert’s variant) has been reported to be associated with atazanavir-associated hyperbilirubinemia and premature atazanavir discontinuation. We assessed the potential cost-effectiveness of UGT1A1 testing to inform choice of an initial protease inhibitor-containing regimen in antiretroviral therapy (ART)-naïve individuals.
We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC) computer simulation model to project quality-adjusted life years (QALYs) and lifetime costs (2009 US dollars) for atazanavir-based ART with or without UGT1A1 testing, using darunavir rather than atazanavir when indicated. We assumed UGT1A1-associated atazanavir discontinuation rates reported in the Swiss HIV Cohort Study, a *28/*28 frequency of 14.9%, equal efficacy and cost of atazanavir and darunavir, and genetic assay cost of $107. Sensitivity analyses varied these parameters and hyperbilirubinemia impact on quality of life and loss to follow-up (LTFU). Costs and QALYs were discounted at 3% annually.
Initiating atazanavir-based ART at CD4 <500/µl without UGT1A1 testing had an average discounted life expectancy of 16.02 QALYs and $475,800 discounted lifetime cost. Testing for UGT1A1 increased QALYs by 0.49 per 10,000 patients tested, and was not cost-effective (>$100,000/QALY). Testing for UGT1A1 was cost-effective (<$100,000/QALY) if assay cost decreased to $10, or if avoiding hyperbilirubinemia by UGT1A1 testing reduced LTFU by 5%. If atazanavir and darunavir differed in cost or efficacy, testing for UGT1A1 was not cost-effective under any scenario.
Testing for UGT1A1 may be cost-effective if assay cost is low and if testing improves retention in care, but only if the comparator ART regimens have the same drug cost and efficacy.
PMCID: PMC3744167  PMID: 23264445
14.  HIV-1 Amino Acid Changes Among Participants With Virologic Failure: Associations With First-line Efavirenz or Atazanavir Plus Ritonavir and Disease Status 
The Journal of Infectious Diseases  2012;206(12):1920-1930.
Background. Although specific human immunodeficiency virus type 1 (HIV-1) drug resistance mutations are well studied, little is known about cumulative amino acid changes, or how regimen and participant characteristics influence these changes.
Methods. In the AIDS Clinical Trials Group randomized study A5202 of treatment-naive HIV-infected participants, cumulative HIV-1 amino acid changes from pretreatment to virologic failure were evaluated in protease and reverse transcriptase (RT) gene sequences.
Results. Among 265 participants with virologic failure, those assigned atazanavir plus ritonavir (ATV/r) did not have significantly more protease changes compared with those assigned efavirenz (EFV) (P ≥ .13). In contrast, participants with virologic failure assigned EFV had more RT changes, including and excluding known resistance codons (P < .001). At pretreatment, lower CD4 cell count, major resistance, more amino acid mixtures (all P < .001), hepatitis C antibody negativity (P = .05), and black race/ethnicity (P = .02) were associated with more HIV-1 amino acid changes.
Conclusions. Virologic failure following EFV-containing treatment was associated with more HIV-1 amino acid changes compared to failure of ATV/r-containing treatment. Furthermore, we show that non–drug resistance mutations occurred more frequently among those failing EFV, the clinical relevance of which warrants further investigation. Pretreatment immunologic status may play a role in viral evolution during treatment, as evidenced by increased amino acid changes among those with lower pretreatment CD4 count.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3502379  PMID: 23148287
15.  Economic savings versus health losses: The cost-effectiveness of generic antiretroviral therapy in the United States 
Annals of internal medicine  2013;158(2):84-92.
US HIV treatment guidelines recommend branded once-daily, one-pill efavirenz/emtricitabine/tenofovir as preferred first-line antiretroviral treatment (ART). With the anticipated approval of generic efavirenz in 2012 in the US, the cost of a once-daily, three-pill alternative (generic efavirenz, generic lamivudine, tenofovir) will decrease, but adherence and virologic suppression may be reduced.
To assess the clinical impact, costs, and cost-effectiveness of the generic-based three-pill regimen compared to the branded, co-formulated regimen. To project the potential national savings in the first year of a switch to generic-based ART.
Mathematical simulation of HIV disease.
Data Sources
Published data from US clinical trials and observational cohorts.
Target Population
HIV-infected patients eligible to start on or switch to an efavirenz-based generic ART regimen.
Time Horizon
Lifetime, One-year
US health system
No ART (for comparison), Three-pill Generic ART, and Branded ART
Outcome Measures
Quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratios (ICER, $/quality-adjusted life expectancy [QALY]).
Results of Base-Case Analysis
Compared to No ART, Generic ART has an ICER of $21,100/QALY. Compared to Generic ART, Branded ART increases lifetime costs by $42,500, and per-person survival gains by 0.37 QALYs, for an ICER of $114,800/QALY. Estimated first-year savings, if all eligible US patients start on or switch to Generic ART, are $920 million.
Results of Sensitivity Analysis
Most plausible assumptions about Generic ART efficacy and costs lead to Branded ART ICERs >$100,000/QALY.
The efficacy and price reduction associated with generics are unknown; estimates are intended to be conservative.
Compared to a slightly less effective generic-based regimen, the cost-effectiveness of first-line Branded ART exceeds $100,000/QALY. Generic-based ART in the US could yield substantial budgetary savings to HIV programs.
PMCID: PMC3664029  PMID: 23318310
17.  Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir: ACTG A5224 s, A5202 substudy 
AIDS (London, England)  2012;26(11):1371-1385.
The effect of specific antiretrovirals on inflammation is unclear.
A5224 s was a substudy of A5202, which randomized HIV-infected treatment-naïve subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or atazanavir/ritonavir (ATV/r) in a factorial design. Our analysis compared changes in inflammation markers from baseline to week 24 between ABC/3TC and TDF/FTC. Secondary analyses included changes at week 96 and comparisons of EFV vs. ATV/r.
Analyses included 244 subjects (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/mL, CD4 240 cells/µL. TNF-α, sTNFR-I and -II, sVCAM-1 and sICAM-1 decreased significantly at weeks 24 and 96, without significant differences between components (p ≥ 0.44). At week 24, ABC/3TC had a greater hsCRP mean fold change than TDF/FTC (1.43 vs. 0.88, estimated mean fold change percent difference (Δ) 61.5% [95% CI 13.6%, 129.5%]; p = 0.008). Similar results were seen at week 96 (p = 0.021). At week 24 (but not 96), EFV had a greater hsCRP mean fold change than ATV/r (1.41 vs. 0.88; Δ = 60.2% [12.6%, 127.7%]; p = 0.009). IL-6 decreased significantly at week 24 with TDF/FTC but not with ABC/3TC (between-components p = 0.019). At week 96, IL-6 decreased significantly in both NRTI components (between-components p = 0.11). IL-6 changes were not significantly different between ATV/r and EFV at either time point (p ≥ 0.89).
Soluble TNF-receptors and adhesion molecules decreased following treatment initiation and did not differ by regimens. Differences were seen on hsCRP and IL-6 changes with ABC/3TC vs. TDF/FTC and on hsCRP with EFV vs. ATV/r.
PMCID: PMC3560932  PMID: 22546988
abacavir; C-reactive protein; endothelial activation markers; Inflammation markers; interleukin-6; TNF alpha
18.  Untreated HIV: harmful even at high CD4 cell counts 
Lancet  2010;376(9738):306-308.
PMCID: PMC3523325  PMID: 20638117
19.  Metabolic Effects of Darunavir/Ritonavir Versus Atazanavir/Ritonavir in Treatment-Naive, HIV Type 1-Infected Subjects over 48 Weeks 
AIDS Research and Human Retroviruses  2012;28(10):1184-1195.
We assessed metabolic changes for darunavir/ritonavir (DRV/r) once daily (qd) versus atazanavir/ritonavir (ATV/r) qd with fixed-dose tenofovir/emtricitabine. This was a phase 4, multicenter, open-label, randomized exploratory study. Treatment-naive, HIV-1-infected adults received DRV/r 800/100 mg qd or ATV/r 300/100 mg qd, both with emtricitabine/tenofovir 200/300 mg qd. Primary end point: change in triglyceride levels from baseline to week 12. Secondary end points: week 12 and week 48 changes in lipid parameters, insulin sensitivity, inflammatory/coagulation/bacterial translocation biomarkers, viral load, CD4+ cell count, and week 48 changes in adipose tissue distribution and subjects' perceptions of body changes. In the DRV/r arm, 32/34 and 29/34 subjects completed weeks 12 and 48, respectively; in the ATV/r arm, 30/31 and 25/31 subjects completed weeks 12 and 48, respectively. Small changes in lipid parameters from baseline to weeks 12 and 48 were observed in both arms. Differences were noted between arms in mean changes in total cholesterol (DRV/r, 20.3 mg/dl; ATV/r, 4.6 mg/dl) and apolipoprotein A1 (DRV/r, 10.7 mg/dl; ATV/r, –0.7 mg/dl) at week 12. At week 48, no clinically relevant differences between arms were noted for changes in any lipid parameter, fasting glucose, or insulin sensitivity. Biomarkers generally decreased and efficacy parameters improved in both arms over 48 weeks. Changes in adipose tissue were small and comparable between arms. Subjects' perceptions of body changes generally improved in both study arms. This first pilot comparison in HIV-1-infected subjects suggests that DRV/r has a metabolic profile similar to ATV/r over 48 weeks of treatment. Further randomized studies are warranted.
PMCID: PMC3448095  PMID: 22352336
20.  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.
Limited data compare once-daily options for initial therapy for HIV-1.
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.
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. ( registration number: NCT00118898)
59 AIDS Clinical Trials Group sites in the United States and Puerto Rico.
Antiretroviral-naive patients.
Open-label atazanavir plus ritonavir or efavirenz, each given with with placebo-controlled abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine.
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.
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.
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.
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.
PMCID: PMC3430716  PMID: 21320923
21.  Peripheral and Central Fat Changes in Subjects Randomized to Abacavir-Lamivudine or Tenofovir-Emtricitabine With Atazanavir-Ritonavir or Efavirenz: ACTG Study A5224s 
A5224s compared fat changes with abacavir/lamivudine (ABC/3TC) or TenofovirDF/Emtricitabine (TDF/FTC) with efavirenz (EFV) or atazanavir/ritonavir (ATV/r). TDF/FTC- and ABC/3TC-regimens similarly increased limb and visceral fat. ATV/r led to greater gains in limb fat, and a trend towards greater gains in visceral fat than EFV.
Background. We compare the effect of 4 different antiretroviral regimens on limb and visceral fat.
Methods. A5224s was a substudy of A5202, a trial of human immunodeficiency virus type 1 (HIV-1)–infected, treatment-naive subjects randomized to blinded abacavir-lamivudine (ABC-3TC) or tenofovir DF-emtricitabine (TDF-FTC) with open-label efavirenz (EFV) or atazanavir-ritonavir (ATV-r). The primary endpoint was the presence of lipoatrophy (≥10% loss of limb fat) at week 96 by intent-to-treat (ITT) analysis. Secondary endpoints included changes in limb and visceral fat. Statistical tests included linear regression, binomial, two-sample t test, and Fisher's exact test.
Results. A5224s enrolled 269 subjects; 85% were male, and 47% were white non-Hispanic. The subjects had a median baseline HIV-1 RNA level of 4.6 log10 copies/mL, a median age of 38 years, a median CD4+ cell count of 233 cells/μL, median limb fat of 7.4 kg, median visceral adipose tissue (VAT) of 84.1 cm2, and VAT: total adipose tissue (TAT) ratio of 0.31. At week 96, estimated prevalence of lipoatrophy (upper 95% confidence interval [CI]) was 18% (25%) for ABC-3TC and 15% (22%) for TDF-FTC (P = .70); this was not significantly less than the hypothesized 15% for both (P ≥ .55 for both). The secondary as-treated (AT) analysis showed similar results. At week 96, the estimated mean percentage change from baseline in VAT was higher for the ATV-r group than for the EFV group (26.6% vs 12.4%; P = .090 in ITT analysis and 30.0% vs 14.5%; P = .10 in AT analysis); however, the percentage change in VAT:TAT was similar by ITT and AT analysis (P ≥ .60 for both). Results were similar for absolute changes in VAT and VAT:TAT.
Conclusions. ABC-3TC– and TDF-FTC–based regimens increased limb and visceral fat at week 96, with a similar prevalence of lipoatrophy. Compared to the EFV group, subjects assigned to ATV-r had a trend towards higher mean percentage increase in VAT.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3165963  PMID: 21690627
22.  Cost-effectiveness of Adding an Agent That Improves Immune Responses to Initial Antiretroviral Therapy (ART) in HIV-Infected Patients: Guidance for Drug Development 
HIV Clinical Trials  2012;13(1):1-10.
Adding an immune-enhancing agent to initial antiretroviral therapy (ART) for HIV is a potential strategy to ensure that patients achieve optimal immune response.
Using a mathematical model of HIV disease and treatment, we evaluated the treatment benefits and cost-effectiveness of adding a hypothetical immune-enhancing agent to the initial 6 months of ART. We assumed that the additional agent would result in a higher CD4 increase that would provide clinical benefit. The additional cost ($1,900/month) was based on the cost of a drug currently under investigation for immune enhancement. Outcomes included projected life expectancy and cost-effectiveness in 2009 US dollars/quality-adjusted life year (QALY) with costs and QALYs discounted at 3% annually.
Compared to standard ART, immune-enhanced ART resulting in an additional 40 CD4 cell/μL increase at 6 months yields a 2.4 month projected undiscounted life expectancy increase with a cost-effectiveness ratio of $107,600/QALY. Achieving a cost-effectiveness ratio <$100,000/QALY requires a >43 CD4 cell/μL improvement, or >19 cells/μL if immune-enhancing agent costs are halved.
In addition to showing clinical efficacy, investigational immune enhancement agents need to increase CD4 counts more than has been previously observed or have a lower cost to be considered cost-effective in the United States.
PMCID: PMC3321257  PMID: 22306583
ART-naïve; HIV; immune-enhanced
23.  Bone Mineral Density and Fractures in Antiretroviral-Naive Persons Randomized to Receive Abacavir-Lamivudine or Tenofovir Disoproxil Fumarate-Emtricitabine Along With Efavirenz or Atazanavir-Ritonavir: AIDS Clinical Trials Group A5224s, a Substudy of ACTG A5202 
The Journal of Infectious Diseases  2011;203(12):1791-1801.
(See the editorial commentary by Yin and Overton, on pages 1705-7.)
Background.  Long-term effects of abacavir (ABC)–lamivudine (3TC), compared with tenofovir (TDF)–emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed.
Methods.  A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests.
Results.  Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-1 RNA load was 4.6 log10 copies/mL, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/μL. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -1.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P = .035) and -3.1% and -3.4% (P = .61), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components.
Conclusions. Compared with ABC-3TC, TDF-FTC–treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV.
Clinical Trials Registration. NCT00118898.
PMCID: PMC3100514  PMID: 21606537
24.  Projected Survival Gains from Revising State Laws Requiring Written Opt-in Consent for HIV Testing 
Although the Centers for Disease Control and Prevention recommends HIV testing in all settings unless patients refuse (opt-out consent), many state laws require written opt-in consent.
To quantify potential survival gains from passing state laws streamlining HIV testing consent.
We retrieved surveillance data to estimate the current annual HIV diagnosis rate in states with laws requiring written opt-in consent (19.3%). Published data informed the effect of removing that requirement on diagnosis rate (48.5% increase). These parameters then served as input for a model-driven projection of survival based on consent method. Other inputs included undiagnosed HIV prevalence (0.101%); and annual HIV incidence (0.023%).
Hypothetical cohort of adults (>13 years) living in written opt-in states.
Life years gained (LYG).
In the base-case, of the 53,036,383 adult persons living in written opt-in states, 0.66% (350,040) will be infected with HIV. Due to earlier diagnosis, revised consent laws yield 1.5 LYG per HIV-infected person, corresponding to 537,399 LYG among this population. Sensitivity analyses demonstrate that diagnosis rate increases of 24.8-72.3% result in 304,765–724,195 LYG. Net survival gains vanish if the proportion of HIV-infected persons refusing all testing in response to revised laws exceeds 18.2%.
The potential survival gains of increased testing are substantial, suggesting that state laws requiring opt-in HIV testing should be revised.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-011-1637-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3101973  PMID: 21286837
HIV; AIDS; screening; modeling; survival analysis
25.  Adherence to Antiretroviral Treatment and Correlation with Risk of Hospitalization among Commercially Insured HIV Patients in the United States 
PLoS ONE  2012;7(2):e31591.
A lower daily pill burden may improve adherence to antiretroviral treatment (ART) and clinical outcomes in patients with human immunodeficiency virus (HIV). This study assessed differences in adherence using the number of pills taken per day, and evaluated how adherence correlated with hospitalization.
Commercially insured patients in the LifeLink database with an HIV diagnosis (International Classification of Diseases, 9th Revision, Clinical Modification code 042.xx) between 6/1/2006 and 12/31/2008 and receipt of a complete ART regimen were selected for inclusion. Patients were grouped according to their daily pill count and remained on ART for at least 60 days. Outcomes included adherence and rates of hospitalization. Adherence was measured as the proportion of days between the start and end of the regimen in which the patient maintained supply of all initiated ART components. Logistic regressions assessed the relationship between pills per day, adherence, and hospitalization, controlling for demographics, comorbidities, and ART-naïve (vs. experienced) status.
7,073 patients met the study inclusion criteria, and 33.4%, 5.8%, and 60.8% received an ART regimen comprising one, two, or three or more pills per day, respectively. Regression analysis showed patients receiving a single pill per day were significantly more likely to reach a 95% adherence threshold versus patients receiving three or more pills per day (odds ratio [OR] = 1.59; P<0.001). Regardless of the number of pills received per day, patients were over 40% less likely to have a hospitalization if they were adherent to therapy (OR = 0.57; P<0.001). Patients receiving a single pill per day were 24% less likely to have a hospitalization versus patients receiving three or more pills per day (OR = 0.76; P = 0.003).
ART consisting of a single pill per day was associated with significantly better adherence and lower risk of hospitalization in patients with HIV compared to patients receiving three or more pills per day.
PMCID: PMC3286454  PMID: 22384040

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