Background

The effect of specific antiretrovirals on inflammation is unclear.

Methods

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.

Results

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).

Conclusions

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.

(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.

Abstract

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.

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.

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.

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.

Purpose

Adding an immune-enhancing agent to initial antiretroviral therapy (ART) for HIV is a potential strategy to ensure that patients achieve optimal immune response.

Method

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.

Results

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.

Conclusions

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.

(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.

Background

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.

Objective

To quantify potential survival gains from passing state laws streamlining HIV testing consent.

Design

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%).

Patients

Hypothetical cohort of adults (>13 years) living in written opt-in states.

Measurements

Life years gained (LYG).

Results

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%.

Conclusions

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.

Purpose

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.

Methodology

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.

Results

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).

Conclusions

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.

Background

The effects of immunologic and virologic factors on AMI rates in HIV patients are unclear.

Methods

HIV-infected patients in a U.S. health care system were assessed for AMI.

Results

Of 6,517 HIV patients, 273 (4.2%) had an AMI. In a model adjusting for cardiovascular risk factors, antiretroviral medications, and HIV parameters, CD4 count less than 200/mm3 (OR 1.74, 95% CI 1.07-2.81, P=0.02) predicted AMI. Increased HIV viral load was associated with AMI accounting for CVD risk factors and antiretroviral medications but was not significant when CD4 count was considered.

Conclusions

Immunologic control appears to be the most important HIV-related factor associated with AMI.

Purpose

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.

Method

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.

Results

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.

Conclusions

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.

Background

We sought to use data captured in the electronic health record (EHR) to develop and validate a prediction rule for virologic failure in patients being treated for HIV infection.

Methods

We used EHRs at two Boston tertiary care hospitals, Massachusetts General Hospital and Brigham and Women's Hospital, to identify HIV-infected patients who were virologically suppressed (HIV RNA ≤400 copies/mL) on antiretroviral therapy between 1/1/05 and 12/31/06. We used a multivariable logistic model with data from Massachusetts General Hospital to derive a one-year virologic failure prediction rule. The model was validated using data from the Brigham and Women's Hospital. We then simplified the scoring scheme to develop a clinical prediction rule.

Results

The one-year virologic failure prediction model, using data from 712 Massachusetts General Hospital patients, demonstrated good discrimination (c-statistic 0.78) and calibration (χ2 =6.6, p =0.58). The validation model, based on 362 Brigham and Women's Hospital patients, also showed good discrimination (c-statistic 0.79) and calibration (χ2 =1.9, p =0.93). The clinical prediction rule included seven predictors, Sub-optimal Adherence, CD4 count <100/μL, Drug and/or Alcohol Abuse, Heavily ART Experienced, Missed ≥1Appointment, Prior Virologic Failure, and Suppressed ≤12 months, and appropriately stratified patients in the validation dataset into low, medium and high risk groups, with one-year virologic failure rates of 3.0%, 13.0% and 28.6%.

Conclusions

A risk score based on seven variables available in the EHR predicts HIV virologic failure at one year and could be used for targeted interventions to improve outcomes in HIV disease.

Background

Model-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model.

Methods and Findings

We describe a series of exercises involved in adapting a computer-based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the ‘clinical effectiveness’ of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS.

Conclusions

The model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models.

BACKGROUND

The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known.

METHODS

In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily anti retroviral regimens as initial therapy for HIV-1 infection: abacavir–lamivudine or tenofovir disoproxil fumarate (DF)–emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level ≥1000 copies per milliliter at or after 16 weeks and before 24 weeks, or ≥200 copies per milliliter at or after 24 weeks).

RESULTS

A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir–lamivudine group than in the tenofovir DF–emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir–lamivudine group versus 26 (7%) in the tenofovir DF–emtricitabine group. The time to the first adverse event was also shorter in the abacavir–lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48.

CONCLUSIONS

In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir–lamivudine than in those assigned to tenofovir DF–emtricitabine. (ClinicalTrials.gov number, NCT00118898.)

Background

The combination of tenofovir and emtricitabine (TDF/FTC) shows promise as HIV pre-exposure prophylaxis (PrEP). We sought to forecast clinical, epidemiologic, and economic outcomes of PrEP, taking into account uncertainties regarding efficacy, risk of resistance and toxicity, behavioral disinhibition, and drug costs.

Methods

We adapted a computer simulation of HIV acquisition, detection, and care to model PrEP in high-risk (1.6% average annual HIV incidence) men who have sex with men (MSM) in the United States. Base case assumptions included: 50% PrEP efficacy and $753 monthly TDF/FTC costs. We used sensitivity analyses to examine the stability of results and to identify critical input parameters.

Results

In a cohort with mean age 34 years, PrEP reduced lifetime HIV infection risk from 44% to 25% and increased average life expectancy from 39.9 to 40.7 years (21.7 to 22.2 discounted, quality-adjusted life-years or QALYs). Discounted mean lifetime treatment costs increased from $81,100 to $232,700 per person, indicating an incremental cost-effectiveness ratio (ICER) of $298,000 per QALY gained. Markedly larger reductions in lifetime infection risk (from 43.5% to 5.8%) were observed assuming greater (90%) PrEP efficacy. More favorable ICERs were obtained by targeting younger, higher-incidence populations and with improvements in the efficacy and cost of PrEP.

Conclusions

PrEP could substantially reduce HIV transmission in high-risk populations in the United States. Although it is unlikely to confer sufficient benefits to justify current TDF/FTC costs, price reductions and/or increases in efficacy could make PrEP a cost-effective option in younger or higher-risk populations. Given recent disappointments in HIV prevention and vaccine development, further study of PrEP-based HIV prevention is warranted.

Background

An effective therapeutic vaccine that could augment immune control of HIV-1 replication may abrogate or delay the need for antiretroviral therapy. AIDS Clinical Trials Group (ACTG) A5187 was a phase I/II, randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of an HIV-1 DNA vaccine (VRC-HVDNA 009-00-VP) in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. (clinicaltrials.gov NCT00125099)

Methods

Twenty healthy HIV-1 infected subjects who were treated with antiretroviral therapy during acute/early HIV-1 infection and had HIV-1 RNA<50 copies/mL were randomized to receive either vaccine or placebo. The objectives of this study were to evaluate the safety and immunogenicity of the vaccine. Following vaccination, subjects interrupted antiretroviral treatment, and set-point HIV-1 viral loads and CD4 T cell counts were determined 17–23 weeks after treatment discontinuation.

Results

Twenty subjects received all scheduled vaccinations and discontinued antiretroviral therapy at week 30. No subject met a primary safety endpoint. No evidence of differences in immunogenicity were detected in subjects receiving vaccine versus placebo. There were also no significant differences in set-point HIV-1 viral loads or CD4 T cell counts following treatment discontinuation. Median set-point HIV-1 viral loads after treatment discontinuation in vaccine and placebo recipients were 3.5 and 3.7 log10 HIV-1 RNA copies/mL, respectively.

Conclusions

The HIV-1 DNA vaccine (VRC-HIVDNA 009-00-VP) was safe but poorly immunogenic in subjects treated with antiretroviral therapy during acute/early HIV-1 infection. Viral set-points were similar between vaccine and placebo recipients following treatment interruption. However, median viral load set-points in both groups were lower than in historical controls, suggesting a possible role for antiretroviral therapy in persons with acute or early HIV-1 infection and supporting the safety of discontinuing treatment in this group.

Trial Registration

Clinicaltrials.gov NCT00125099

Background

Expectations regarding receipt of medications and medical care after clinical trials conclude may inform decisions about trial participation. We describe the frequency with which these posttrial services are described in the protocols and informed consent forms (ICFs) of antiretroviral drug (ARV) trials.

Method

We systematically reviewed protocols and ICFs from Phase 3 and 4 antiretroviral trials in adults (≥12 years) from 1987 to 2006. Pharmaceutical industry-sponsored trials were selected from US Food and Drug Administration (FDA) documentation and Clinicaltrials.gov. Trials administered by the AIDS Clinical Trials Group (ACTG) were selected from the ACTG online registry. ACTG- and industry-provided protocols and ICFs were reviewed in full. The primary outcome was any mention of posttrial services, defined as any text regarding posttrial medications or medical care.

Results

Complete trial documents were available for 31 (48%) of 65 trials meeting inclusion criteria. Documents from 14 trials (45%) mentioned any posttrial service: 12 (39%) mentioned medications, and 5 (16%) mentioned medical care. Payment for trial participation (74%) and for care for trial-related injury (94%) were mentioned more often than were posttrial services.

Conclusions

Posttrial medications or medical care was mentioned in the trial documents of <50% of reviewed antiretroviral trials. Improved efforts are needed to clearly describe posttrial services in clinical trial protocols and ICFs. and ICFs.

Objective

To evaluate the clinical impact and cost-effectiveness of HLA-B*5701 testing to guide selection of first-line HIV regimens in the United States.

Design

Cost-effectiveness analysis using a simulation model of HIV disease. The prevalence of HLA-B*5701 and the probabilities of confirmed and unconfirmed severe systemic hypersensitivity reaction (HSR) among patients taking abacavir testing HLA-B*5701 positive and negative were from the PREDICT-1 trial. The monthly costs of abacavir and tenofovir-based regimens were $1,135 and $1,139; similar virologic efficacy was assumed and this assumption was varied in sensitivity analysis.

Subjects

Simulated cohort of patients initiating HIV therapy.

Interventions

1) first-line abacavir, lamivudine, and efavirenz without pre-treatment HLA-B*5701 testing; 2) the same regimen with HLA-B*5701 testing; 3) first-line tenofovir, emtricitabine, and efavirenz.

Main Outcome Measures

Quality-adjusted life expectancy (QALYs) and lifetime medical costs discounted at 3% p.a., cost-effectiveness ratios ($/QALY).

Results

Abacavir-based treatment without HLA-B*5701 testing resulted in a projected 30.93 years life expectancy, 16.23 discounted QALYs, and $472,200 discounted lifetime cost per person. HLA-B*5701 testing added 0.04 quality-adjusted months at an incremental cost of $110, resulting in a cost-effectiveness ratio of $36,700/QALY compared to no testing. Initiating treatment with a tenofovir-based regimen increased costs without improving QALYs. HLA-B*5701 testing remained the preferred strategy only if abacavir-based treatment had equal efficacy and cost less per month than tenofovir-based treatment. Results were also sensitive to the cost of HLA-B*5701 testing and the prevalence of HLA*B5701.

Conclusions

Pharmacogenetic testing for HLA-B*5701 is cost-effective only if abacavir-based treatment is as effective and costs less than tenofovir-based treatment.

Background

In recent studies, subjects who had achieved suppression of the human immunodeficiency virus (HIV) RNA level while receiving an initial 3-drug antiretroviral regimen successfully maintained suppression while receiving treatment with a “boosted” protease inhibitor (PI) alone. We projected the long-term outcomes of this treatment simplification strategy to inform the design of a proposed multicenter, randomized clinical trial.

Methods

We used published studies to estimate the efficacy, adverse effects, and cost of a sequence of HIV drug regimens for the simplification strategy, compared with those outcomes for the current standard-of-care (SOC) strategy. Using a published simulation model of HIV disease, we projected life expectancy, discounted quality-adjusted life expectancy (QALE), and discounted lifetime medical costs for each strategy.

Results

Subjects who have not developed PI-resistant HIV infection at the time of failure of the simplification regimen have a greater life expectancy (27.9 vs. 27.1 years) and QALE (14.9 vs. 14.7 years), compared with SOC subjects, because they receive an additional line of therapy without negative consequences for future treatment options. The QALE for the simplification strategy remains higher than that for the SOC, unless a large proportion of patients experiencing virologic failure while receiving the simplification regimen develop PI resistance. Depending on the probability of simplification regimen failure, the advantage is maintained even if HIV develops PI resistance in 42%–70% of subjects. Projected lifetime costs are $26,500–$72,400 per person lower for the simplification strategy than for the SOC strategy.

Conclusions

An HIV treatment simplification strategy involving use of a boosted PI alone may lead to longer survival overall at lower cost, compared with the SOC combination therapy, because the simplification strategy potentially adds an additional line of therapy. The risk of emergence of PI resistance during treatment with a simplified regimen is a critical determinant of the viability of this strategy.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infection and will play an important part in therapeutic and prophylactic HIV-1 vaccines. The identification of virus-specific epitopes that are efficiently recognized by CTL is the first step in the development of future vaccines. Here we describe the immunological characterization of a number of novel HIV-1-specific, HLA-A2-restricted CTL epitopes that share a high degree of conservation within HIV-1 and a strong binding to different alleles of the HLA-A2 superfamily. These novel epitopes include the first reported CTL epitope in the Vpr protein. Two of the novel epitopes were immunodominant among the HLA-A2-restricted CTL responses of individuals with acute and chronic HIV-1 infection. The novel CTL epitopes identified here should be included in future vaccines designed to induce HIV-1-specific CTL responses restricted by the HLA-A2 superfamily and will be important to assess in immunogenicity studies in infected persons and in uninfected recipients of candidate HIV-1 vaccines.