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Background The US National HIV/AIDS Strategy (NHAS) aims for 72% (90% diagnosed times 80% of those virally suppressed) viral suppression among persons with human immunodeficiency virus (HIV) by 2020. We examined the clinical and economic impact of reaching this target, in the general US population and among black men who have sex with men (MSM), the group with the highest HIV prevalence. Methods Using a mathematical simulation, we project the 5- and 20-year clinical outcomes, costs, and incremental cost-effectiveness ratios for (1) Current Pace of detection, linkage, retention, and virologic suppression and (2) NHAS investments in expanded testing ($24-$74 per test) and adherence ($400 per person-year), calibrated to achieve 72% suppression by 2020. We examined alternative rates of testing, retention, and suppression and the efficacy and cost of adherence interventions. Results Compared with Current Pace over 20 years, NHAS averted 280000 HIV transmissions (80000 in black MSM) and 199000 (45000) deaths and saved 2138000 (453000) years of life, while increasing costs by 23%. The incremental cost-effectiveness ratio for NHAS compared with Current Pace was $68900 per quality-adjusted life-year ($38300 for black MSM) and was most sensitive to antiretroviral therapy costs. Conclusions Reaching NHAS targets would yield substantial clinical benefits and be cost-effective in both the general US and black MSM populations.

Background Current guidelines recommend genotype resistance testing at diagnosis to guide initial selection of antiretroviral therapy (ART). Many standard resistance genotypes exclude testing for resistance to integrase inhibitors ("IR testing"), although this class of drugs is a component of most recommended first-line regimens. Methods We compared the 96-week clinical outcomes and cost-effectiveness of 2 strategies: no IR testing vs IR testing performed at human immunodeficiency virus (HIV) diagnosis. The base case prevalence of transmitted integrase strand transfer inhibitor (INSTI)-resistant (INSTI-R) virus is estimated at 0.1%. With no IR testing, all patients start dolutegravir (DTG)-based ART after genotype; 12-week suppression rates are 90% (INSTI-susceptible [INSTI-S] virus) and 35% (INSTI-R virus). Those not suppressed at 12 weeks undergo IR testing; if diagnosed with INSTI-R virus, they change to ritonavir-boosted darunavir (DRV/r)-based ART. With IR testing, all patients are diagnosed with INSTI-S/INSTI-R virus prior to ART initiation and start DTG- or DRV/r-based regimens, respectively. Costs include IR tests (175 US dollars [USD]) and ART (41100-44900 USD/year). We examined the impact of key parameters in sensitivity analyses. Results IR testing resulted in worse clinical outcomes compared to no IR testing and increased costs by 200 USD/person/year. Prevalence of transmitted INSTI-R virus did not affect the favored strategy. No IR testing remained clinically preferred unless DTG suppression of INSTI-R virus was 92%. If quality of life was worse with DRV/r- than DTG-based ART, no IR testing was clinically preferred over an even broader range of parameters. Conclusions In patients with newly diagnosed HIV, IR testing is projected to result in worse outcomes and is not cost-effective. Pretreatment assessment for INSTI resistance should not be recommended in treatment guidelines.

OBJECTIVES To evaluate the safety and efficacy of the novel tenofovir prodrug, tenofovir alafenamide (TAF), as part of a single-tablet regimen (STR) for the initial treatment of HIV-1 infection. DESIGN Phase 2, randomized, double-blind, double-dummy, multicenter, active-controlled study. METHODS Antiretroviral naive adults with HIV-1 RNA ≥5000 copies per milliliter and a CD4 count ≥50 cells per microliter were randomized 2:1 to receive an STR of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF), plus placebo for 48 weeks. RESULTS Patients on both E/C/F/TAF (n = 112) and E/C/F/TDF (n = 58) had high rates of virologic suppression (

OBJECTIVES It is uncertain whether HIV-1 antiretroviral exposure and clinical response varies between males and females or different race/ethnic groups. We describe ritonavir-enhanced atazanavir pharmacokinetics in relation to virological failure, safety and tolerability in treatment-naive individuals to investigate potential differences. METHODS Plasma samples were collected from participants in AIDS Clinical Trials Group Study A5202 for measurement of antiretroviral concentrations. Individual estimates of apparent oral clearance of atazanavir (L/h) were calculated from a one-compartment model and divided into tertiles as slow (

Background. Virologic failure (VF) on a first-line ritonavir-boosted protease inhibitor (PI/r) regimen is associated with low rates of resistance, but optimal management after failure is unknown. Methods. The analysis included participants in randomized trials who experienced VF on a first-line regimen of PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) and had at least 24 weeks of follow-up after VF. Antiretroviral management and virologic suppression (human immunodeficiency virus type 1 [HIV-1] RNA

Background DOR is a novel NNRTI that has shown noninferior efficacy to DRV+r- and EFV-based regimens in phase 3 trials (DRIVE-FORWARD [NCT02275780] and DRIVE-AHEAD [NCT02403674]). A prespecified integrated analysis of those trials plus a completed phase 2 trial (P007; NCT01632345) was performed to evaluate the overall safety and tolerability of DOR. Methods In this integrated analysis, DOR (100 mg QD) arms from P007, DRIVE-FORWARD, and DRIVE-AHEAD were compared with DRV+r in DRIVE-FORWARD and EFV in P007 and DRIVE-AHEAD for treatment of HIV-1 in ART-naïve adults. The NRTI background included FTC/TDF in P007, ABC/3TC or FTC/TDF in DRIVE-FORWARD, and 3TC/TDF for DOR and FTC/TDF for EFV in DRIVE-AHEAD. The primary safety endpoint was the proportion of participants discontinuing due to adverse events (AEs) through Week 48. Results A total of 1,710 treated participants were included in the analysis (table). Similar proportions of DOR− and DRV+r-treated participants, and fewer of those treated with DOR than with EFV discontinued due to AEs (2.5% vs. 3.1%, DOR vs. DRV+r; 2.5% vs. 6.6%, DOR vs. EFV). Drug-related AEs (DRAEs) were similar for DOR (30.9%) and DRV+r (32.1%), and higher for EFV (61.4%). The most common DRAEs (≥10% any group, any grade) were dizziness (4.9%, 1.8%, and 30.7%) diarrhea (4.0%, 12.8%, and 5.7%), and abnormal dreams (3.2%, 0.3%, and 10.6%) for DOR, DRV+r, and EFV, respectively. Higher rates of central nervous system (CNS) AEs were reported for DOR when EFV was the comparator, while similar low rates of CNS AEs were reported for DOR when DRV+r was the comparator. In two prespecified analyses combining the DOR 100-mg arms and EFV arms from P007 and DRIVE-AHEAD, 2.8% vs. 6.1% discontinued due to AEs on the DOR- and EFV-treated arms, respectively, for a treatment difference of −3.4% (95% CI: −6.2, −0.8; P = 0.012); 25.0% vs. 55.9% of participants experienced ≥1 neuropsychiatric AE in DOR and EFV arms, respectively. Conclusion At Week 48, DOR was generally safe and well tolerated in ART-naïve adults with HIV-1. Statistically significantly lower proportions of DOR- than EFV-treated participants discontinued due to AEs supported by a lower proportion that discontinued due to DRAEs. Those on DOR had fewer CNS AEs compared with those on EFV, and less diarrhea than those on DRV+r. Disclosures M. Thompson, Merck & Co., Inc.: Research funding to AIDS Research Consortium of Atlanta; no funds to me personally, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. Bristol Myers Squibb: Research funding to AIDS Research Consortium of Atlanta; no funds to me personally, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. CytoDyn, Inc.: Research funding to AIDS Research Consortium of Atlanta; no funds to me personally, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. Gilead Sciences, Inc.: Research funding to AIDS Research Consortium of Atlanta; no funds to me personally, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. GlaxoSmithKline: Research funding to AIDS Research Consortium of Atlanta; no funds to me personally, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. Roche Laboratories: Research Funding, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally and Research grant. TaiMed, Inc.: Research Funding, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally and Research grant. ViiV Healthcare: Research Funding, Research funding to AIDS Research Consortium of Atlanta; no funds to me personally. C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Ad Board, Grant Investigator and Research Contractor, Research grant and Research support. J. M. Molina, Merck GIlead ViiV Janssen Teva: Ad Board and Speaker’s Bureau, Consulting fee. Gilead Sciences: Grant Investigator, Research support. J. Gatell, Gilead Sciences: Grant and Independent Contractor, Consulting fee and Educational grant. Janssen: Grant and Independent Contractor, Consulting fee. ViiV Healthcare: Grant and Independent Contractor, Consulting fee. MSD: Grant and Independent Contractor, Consulting fee. P. Sax, Gilead: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Merck: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Janssen: Consultant, Consulting fee. BMS, Gilead, Merck, GSK/ViiV: Grant Investigator, Grant recipient and Research grant. P. Cahn, Abbvie: Grant, Research grant. Merck: Grant, Advisory Board. ViiV Healthcare: Grant, Advisory Board. K. Squires, Merck & Co., Inc.: Ad Board, Ad Board. Gilead Sciences: Grant, Ad Board. VIIV: Ad Board, Ad Board. Bristol Myers Squibb: Ad Board, Ad Board. Janssen: Ad Board, Ad Board. Y. Zhou, Merck & Co., Inc.: Employee, Salary. X. Xu, Merck & Co., Inc.: Employee, Salary. A. Rodgers, Merck & Co., Inc.: Employee and Shareholder, Salary. S. Kumar, Merck & Co., Inc.: Employee and Shareholder, Salary. H. Teppler, Merck & Co., Inc.: Employee and Shareholder, Salary. E. Martin, Merck & Co., Inc.: Employee and Shareholder, Salary. G. Hanna, Merck & Co., Inc.: Employee and Shareholder, Salary. C. Hwang, Merck & Co., Inc.: Employee and Shareholder, Salary.

Slower gait speed is a well-established indicator for increased risk of morbidity and mortality. However, gold standard measurement methods like the six-minute walk test (6MWT), are difficult to use in a clinical setting and may not capture important differences in free-living, volitional activity. We enrolled 46 men (23 HIV+, 23 HIV-) from a prospective observational study (MATCH) of men and women, 50–65 years old. Participants wore an activity tracker (i.e., Nokia Pulse Ox) for three weeks. Tracker data was used to create average gait speed and a measure of percent time at quartiles of maximum observed gait speed. Lab-based, 6MWT gait speed did not differ significantly by HIV status. Free-living, tracker assessed gait speed was significantly slower among HIV+ compared to uninfected participants. HIV+ participants also spent more time at lower activity levels. Free-living gait speed may provide an important digital biomarker of risks not detected by traditional lab-based measures.

Background Prior studies have reported improved adherence, persistency, virologic outcomes and lower risk of hospitalizations with single tablet (STR) vs. multi-tablet regimens (MTR) in HIV treatment. However, most studies were conducted using prescription and medical claims data limited to EFV-based therapies. In this study, we utilized EMR, prescription, and pharmacy dispensing data to assess STR and MTR adherence and persistency as observed in a network of clinical practices. Methods Data were collected for HIV-infected patients in care at six US-based HIV treatment centers. Patients eligible for the study initiated their first ARV between January 2015 and December 2016. First ARV regimen was assigned based on absence of prior ARV prescriptions and a 30-day pre-treatment period with no ARV dispensed or for rapid starts, a high baseline viral load (≥10,000 copies/mL). Adherence was assessed using proportion of days covered (PDC). Follow-up was ≥365 days with duration capped at 365 days for persistency comparisons. Results A total of 1,499 patients met the criteria for the study; 66% (982/1,499) received STR and 34% (517/1,499) MTR. Top STRs were EVG/c/TDF/FTC (265/982, 27%), EVG/c/TAF/FTC (250/982, 26%), and DTG/ABC/3TC (171/982, 17%). Top MTRs were DTG + TDF/FTC (69/517, 13%), DRV + RTV + TDF/FTC (60/517, 12%), and DRV/c + TDF/FTC (40/517, 8%). Average persistency for STRs was significantly longer at 252 days vs. 233 days for MTRs (P = 0.002). Average PDC adherence rates were significantly higher for STRs at 91% vs. 83% for MTRs (P < 0.001). Within the STR group, older age was significantly associated with greater adherence (average age: 45 in 80%+ adherent group vs. 42 in

Background Because of progress in antiretroviral therapy (ART), fewer people with HIV experience virologic failure with multiclass resistance. We sought to estimate the prevalence of multiclass resistance since the introduction of INSTI-based regimens using a systematic literature review. Methods A systematic literature search using PubMed, Embase, and the Cochrane Library was conducted of articles published since 2008, the year when INSTI-based regimens for treatment-experienced people with HIV became widely used. Bibliographies of existing literature reviews, websites of European and International organizations reporting data on HIV and AIDS, and abstracts presented from 2016–2018 at conferences were searched to identify additional relevant studies. Using predefined criteria, two reviewers independently reviewed studies reporting multiclass (three-class or greater) resistance in persons with HIV infection who are treatment experienced and were either perinatally infected or infected as adults. Studies from Western Europe, Australia, Canada and the United States (US) using any type of resistance definitions and resistance tests were included. Results A total of 441 unique articles were identified, 343 were excluded during level 1 screening and 98 articles were included for full-text review. A total of 34 articles (11 US studies, 3 from Canada, 1 from Australia, and 19 from Western European countries.) met the inclusion criteria and were included in data extraction analysis. Over the past decade, a modest decrease in the prevalence of three-class (NNRTI, NRTI, PI) resistance was observed in studies from the United States and Canada, ranging from 8.3% in 2009 to 6.7% in 2014 (Figure 1). Western European countries and Australia showed similar trends. The prevalence of 4-class resistance (including INSTIs) with virologic failure in the current treatment era is low, less than 2% (Figure 2). Conclusion The prevalence of multiclass resistance has decreased over the past decade, with three-class resistance continuing to decline and four-class resistance rare. Although the population with treatment failure and no viable options for a suppressive regimen is currently small, this group of people with HIV are in urgent need of novel treatment options. Disclosures All authors: No reported disclosures.

A Disturbing Decline A 29-year-old woman with a history of systemic lupus erythematosus presented with diarrhea that had been ongoing for several days and had initially been accompanied by nausea a...

OBJECTIVE To compare the effect that initiating different antiretroviral therapy (ART) regimens has on weight, BMI, and lean body mass (LBM) and explore how changes in body composition are associated with bone mineral density (BMD). METHODS A5224s was a sub-study of A5202, a prospective trial of 1857 ART-naive 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 participants underwent dual-energy absorptiometry (DXA) and abdominal computed tomography for body composition. Analyses used two-sample t-tests and linear regression. RESULTS A5224s included 269 participants: 85% men, 47% white non-Hispanic, median age 38 years, HIV-1 RNA 4.6 log10 copies/ml, and CD4 cell count 233 cells/μl. Overall, significant gains occurred in weight, BMI, and LBM at 96 weeks post-randomization (all P

We report week 96 results from a phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, n = 348) vs efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF, n = 352). At week 48, EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% confidence interval: -1.6% to 8.8%). Virologic success (HIV-1 RNA

BackgroundReports of a single case of human immunodeficiency virus (HIV) eradication suggest that elimination of HIV from individuals is possible. Anticipating both increased research funding and the development of effective, durable cure technologies, we describe the circumstances under which a cure might improve survival and be cost-effective in South Africa.MethodsWe adapted a simulation model comparing a hypothetical cure strategy (“Cure”) to the standard of care, lifetime antiretroviral therapy (“LifetimeART”) among adherent South Africans (58% female; mean age 33.8 years; mean CD4 257/µL; virologic suppression ≥1 year). We portrayed cure as a single intervention, producing sustained viral eradication without ART. We considered both a plausible, more imminently achievable “Baseline Scenario” and a more aspirational “Optimistic Scenario”. Inputs (Baseline/Optimistic) included the following: 50%/75% efficacy; 0.6%/0.0% fatal toxicity; 0.37%/0.085% monthly relapse over 5 years (0.185%/0.0425% per month thereafter); and $2000/$500 cost. These inputs were varied extensively in sensitivity analysis.ResultsAt baseline, Cure was “dominated,” yielding lower discounted life expectancy (19.31 life-years [LY] vs 19.37 LY) and greater discounted lifetime costs ($13 800 vs $13 700) than LifetimeART. Under optimistic assumptions, Cure was “cost-saving,” producing greater survival (19.91 LY) and lower lifetime costs ($11 000) than LifetimeART. Findings were highly sensitive to data assumptions, leaving little middle ground where a tradeoff existed between improved survival and higher costs.ConclusionsOnly under the most favorable performance assumptions will an HIV cure strategy prove clinically and economically justifiable in South Africa. The scientific pursuit of a cure should not undermine continued expansions of access to proven, effective, and cost-effective ART.

Introduction Chronic hepatitis C virus (HCV) infection is prevalent among patients with inherited bleeding disorders and is a leading cause of mortality in those with haemophilia. Aim We evaluated the efficacy and safety of ledipasvir–sofosbuvir and sofosbuvir plus ribavirin in patients with chronic HCV genotype 1–4 infection and an inherited bleeding disorder. Methods Ledipasvir–sofosbuvir was administered for 12 weeks to patients with genotype 1 or 4 infection and for 12 or 24 weeks to treatment-experienced cirrhotic patients with genotype 1 infection. Patients with genotype 2 and 3 infection received sofosbuvir plus ribavirin for 12 and 24 weeks respectively. Results The majority of the 120 treated patients had a severe bleeding disorder (55%); overall, 65% of patients had haemophilia A and 26% of patients had haemophilia B; 22% were HIV coinfected. Sustained virologic response at 12 weeks posttreatment was 99% (98/99) in patients with genotype 1 or 4 infection; 100% (5/5) in treatment-experienced cirrhotic patients with genotype 1 infection; 100% (10/10) in patients with genotype 2 infection; and 83% (5/6) in patients with genotype 3 infection. There were no treatment discontinuations due to adverse events (AEs). The most frequent non-bleeding AEs were fatigue, headache, diarrhoea, nausea and insomnia. Bleeding AEs occurred in 22 patients, of which all but one were considered unrelated to treatment. Conclusion Treatment with ledipasvir–sofosbuvir for patients with HCV genotype 1 or 4 infection or sofosbuvir plus ribavirin for patients with genotype 2 or 3 infection was highly effective and well tolerated among those with inherited bleeding disorders.

Over the past two decades we have seen dramatic improvements in the efficacy, safety and availibity of antiretroviral therapy (ART). In the USA and Europe, life expectancy in people living with HIV disease approaches that of the HIV-uninfected.1 Even in regions hardest hit by the HIV epidemic, effective HIV therapy has reversed more than a decade of HIV-related decreased survival. Despite these advances in ART, motivations to pursue HIV cure remain strong due to the toxicity, adherence challenges, cost and access to care issues associated with HIV therapy, as well as the persistant stigma associated with having HIV infection. Further and renewed motivation comes from a single case of HIV cure after stem cell transplantation for acute leukaemia. Given the tremendous improvements in ART, it is important to assess how effective and safe an HIV cure would need to be in order to be a viable option compared to ART. We argue that this should be done prior to the availability of a cure to provide realistic goals for researchers and policy makers. One methodology that has been increasingly popular over the past decade is the use of mathematical simulation modelling to assess the clinical impact, cost-effectiveness and clinical role of different treatment strategies in HIV disease, as well as in medicine broadly.2 Such models provide a framework and approach for using the best available data at any point in time, and assessing the potential impact of emerging innovations. Further, unlike individual trials focused on a single endpoint, these models can integrate multiple data sources to project beyond the timeline or outcomes of individual studies and project long-term outcomes in many domains, including virologic, immunologic, clinical and cost.3 Mathematical models have particular value in their ability to assess uncertainty in clinical care. Examples include parameters determined in …

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.

More than 5 million individuals are receiving chronic antiretroviral therapy (ART) to suppress the replication of human immunodeficiency virus type 1 (HIV-1). Current US guidelines recommend monitoring of ART with measurement of HIV-1 RNA every 3–6 months to assess virologic response [1]. Virologic suppression with ART results in profound long-term clinical benefits including decrease in immunodeficiency and an increase in life span [2, 3]. Virologic failure reverses each of these benefits, and the recrudescence of viral replication, is associated with the selection of drug-resistant viruses and CD4 cell count decline [4–6]. Upon rebound of viremia on ART, recommendations include reinforcement of adherence and drug resistance testing of plasma HIV-1 to determine the optimal regimen to achieve virologic suppression. In AIDS Clinical Trials Group (ACTG) Study A5202, treatment-naive participants were randomized to atazanavir plus ritonavir (ATV/r) or efavirenz (EFV) with either tenofovir DF/emtricitabine (TDF/FTC) or abacavir/lamivudine (ABC/3TC). The major drug resistance mutations detected by sequencing and consensus alignment at the time of virologic failure were previously reported, where reverse transcriptase (RT) resistance-associated mutations were found to be more frequent among participants with virologic failure assigned to EFV-containing than ATV/r-containing treatment arms [7–9]. Here we present a thorough assessment of HIV-1 major and nonmajor mutations, and cumulative amino acid changes from pretreatment to virologic failure, to provide additional evidence for selection pressures and evolution of drug resistance in response to the different combinations of antiretrovirals.

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%).

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.

The effect of specific antiretrovirals on inflammation is unclear.A5224s was a substudy of A5202, which randomized HIV-infected treatment-naïve patients 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 patients (85% male, 48% white non-Hispanic), median age 39 years, HIV-1 RNA 4.6 log10 copies/ml, CD4 240 cells/μl. TNF-α, soluble receptors of TNF-α (sTNFR)-I and II, soluble vascular cellular adhesion molecule (sVCAM)-1 and soluble intercellular adhesion molecule (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 high-sensitivity C-reactive protein (hsCRP) mean fold change than TDF/FTC {1.43 vs. 0.88, estimated mean fold change percentage difference [Δ] 61.5% [95% confidence interval (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 nucleoside reverse transcriptase inhibitor 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.

Summary Background The integrase inhibitor elvitegravir (EVG) has been co-formulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) in a single tablet given once daily. We compared the efficacy and safety of EVG/COBI/FTC/TDF with standard of care—co-formulated efavirenz (EFV)/FTC/TDF—as initial treatment for HIV infection. Methods In this phase 3 trial, treatment-naive patients from outpatient clinics in North America were randomly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF, once daily, plus matching placebo. Patients and study staff involved in giving study treatment, assessing outcomes, and collecting and analysing data were masked to treatment allocation. Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more, and susceptibility to efavirenz, emtricitabine, and tenofovir. The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48. The study is registered with ClinicalTrials.gov, number NCT01095796. Findings 700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87·6%) versus 296/352 (84·1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3·6%, 95% CI −1·6% to 8·8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 μmol/L, IQR 5 to 20 vs 1 μmol/L, −6 to 8; p Interpretation If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection. Funding Gilead Sciences.

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 a43 CD4 cell/µL improvement, or19 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.

Background Integrase strand transfer inhibitors (INSTIs) are widely recommended for initial HIV-1 treatment. Bictegravir (BIC, B) is a novel, once-daily INSTI with potent antiviral activity being developed in coformulation with emtricitabine and tenofovir alafenamide (F/TAF). Methods In this Phase 2 study, treatment naïve, HIV-infected adults were randomized 2:1 to receive blinded treatment with BIC or dolutegravir (DTG) coadministered with open label F/TAF (200/25 mg). After all participants completed 48 weeks, they were unblinded and switched to a single fixed-dose combination tablet of B/F/TAF 50/200/25 mg. The proportion of participants with HIV-1 RNA Results Of 98 participants enrolled in the blinded treatment phase, 65 were randomized to BIC+F/TAF and 33 to DTG+F/TAF. Most were male, had asymptomatic HIV infection, with median HIV-1 RNA 4.4–4.5 log10 c/mL. The proportion of subjects with HIV-1 RNA Conclusion All participants switched from DTG+F/TAF to open-label B/F/TAF maintained virologic suppression, with none discontinuing due to adverse events. During 72 weeks of follow-up, no treatment-emergent resistance to any components was detected in participants taking B/F/TAF. B/F/TAF demonstrated durable virologic suppression in naïve patients through W72 and was safe and effective after switching from DTG + F/TAF, further study in treatment naïve and experienced populations is warranted. Disclosures P. E. Sax, Gilead: Consultant and Investigator, Consulting fee, Research grant and Research support; BMS: Consultant and Investigator, Consulting fee, Research grant and Research support; GlaxoSmithKline/ViiV: Consultant and Investigator, Consulting fee, Research grant and Research support; AbbVie: Consultant, Consulting fee; Janssen: Consultant, Consulting fee; Merck: Consultant, Consulting fee; E. Dejesus, Gilead Sciences: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; Janssen: Consultant, Investigator and Speaker’s Bureau, Consulting fee and Speaker honorarium; G. Crofoot, Gilead: Investigator and Scientific Advisor, Advisory honorarium and Research grant; ViiV: Investigator and Scientific Advisor, Advisory honorarium, Research grant and Research support; D. Ward, Gilead: Investigator, Research support; P. Benson, Gilead Sciences: Investigator, Shareholder and Speaker’s Bureau, Research support and Speaker honorarium; ViiV Healthcare: Investigator, Research support; L. Wei, Gilead: Employee and Shareholder, Salary; K. White, Gilead Sciences, Inc.: Employee and Shareholder, Salary; S. Collins, Gilead: Employee and Shareholder, Salary; H. Martin, Gilead Sciences: Employee, Salary; A. Cheng, Gilead: Employee and Shareholder, Salary; E. Quirk, Gilead: Employee and Shareholder, Salary

(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.

poor, and largely African American population. In that study, only 37% achieved virologic suppression (defined as a viral load ,500 copies/mL) 1 year after initiation of therapy. Of importance, this was approximately half the rate of treatment success achieved in contemporaneous clinical trials [3]. The authors cited several potential explanations for this difference, most prominently poor adherence to clinic visits, a phenomenon strongly linked to demographic factors that were highly prevalent in their clinic. One group in the cohort was an extreme example of the discordance between clinical trials results and what was happening in actual patient care: younger, non-white patients had a 1-year virologic suppression rate of only 25%. The results of this study were sobering and had a major impact on clinical

(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.

(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 intentto-treat. Statistical tests used the factorial design and included linear regression, 2-samplet, 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/lL. 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 5 .004) and -2.6% and -4.0% (P 5 .024), respectively; and for EFV versus ATV/r were -1.7% and -3.1% (P 5 .035) and -3.1% and -3.4% (P 5 .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.

While post-exposure prophylaxis (PEP) is commonly prescribed in the setting of occupational and non-occupational HIV-1 exposures [1,2], there is limited evidence documenting efficacy in the setting of transfusion with infected blood. Furthermore, there are a paucity of data regarding blood-borne exposures that lead to passive transfer of antibodies against HIV [3,4]. We describe the efficacy of PEP in such a situation using highly-sensitive assays for HIV-1 DNA and low-level residual viremia. We report the case of a 12 year old girl with sickle-cell disease admitted for management of a vaso-occlusive crisis who inadvertently received HIV-infected packed red blood cells (PRBCs). She required intermittent PRBC transfusions since the age of 2, with the last transfusion 5 years ago. Her white blood cell count was 10,100 per uL, and hemoglobin 9.6 g/dL. Hemoglobin electrophoresis revealed 57% hemoglobin S. During her admission, she was transfused with one PRBC unit that was collected 32 hours prior to administration. Despite the standard practice of pre-screening blood products, the laboratory at the public hospital in the Kingdom of Saudi Arabia became aware that the PRBCs were contaminated with HIV-1 within hours of her transfusion as a result of human error involving mixing an unscreened bag with screened bags. The donor blood was discovered to be HIV-1 antibody positive and subsequently determined to have a viral load of 9740 copies/mL (subtype C); the donor was not receiving antiretroviral therapy (ART). The Ministry of Health conducted an in-depth investigation and halted blood transfusions at the responsible blood blank. Approximately 24 hours after transfusion, the patient was started on tenofovir, emtricitabine, ritonavir-boosted darunavir (subsequently changed to lopinavir) and raltegravir. Blood tests were positive 24 hours after transfusion for HIV antibodies by ELISA and confirmatory western blot (WB), but negative for HIV-1 DNA and plasma HIV-1 RNA by PCR. The pattern of reactive bands on WB was identical for samples obtained from the donor and patient (gp120, gp41, gp31, p24 and p17). Genotyping revealed that she was CCR5 wild-type. The patient demonstrated no signs or symptoms of acute infection during 13 weeks of ART in a tertiary care center. Testing of donor blood revealed no HIV-1 resistance to the antiretrovirals chosen. Longitudinal testing of the patient’s plasma and peripheral blood mononuclear cells (PBMCs) was performed by both clinical laboratories and by sensitive research assays with thresholds of detection down to 0.06 HIV-1 DNA copies/106 PBMCs and 0.4 RNA copies/mL of plasma during and after ART. All tests were negative prior to and 8 months after ART interruption. She continued to have declining but detectable HIV-1 antibodies with positive confirmatory line immunoassay up to 5 months after transfusion, but confirmatory testing was negative by month 6. Viral load testing 8 months following exposure remained negative. See Table 1. Table 1 HIV-1 DNA, plasma RNA and antibody tests results before and after infected blood transfusion We report the successful use of combination ART PEP following large-volume transfusion of HIV-infected blood from a viremic donor with passive transfer of antibodies to HIV-1. The observation that no HIV was detected in her blood after stopping ART and that antibody levels disappeared over time, strongly suggests that PEP successfully prevented HIV acquisition. The overall transmission rate from HIV-1 antibody positive blood transfusions was 89% in one study with non-transmission attributed to lower viral load and prolonged blood-product storage [5]. HIV-1 transmission from transfusion of PRBCs stored for

Objectives The aim of the study was to quantify the benefits (life expectancy gains) and risks (efavirenz-related teratogenicity) associated with using efavirenz in HIV-infected women of childbearing age in the USA. Methods We used data from the Women's Interagency HIV Study in an HIV disease simulation model to estimate life expectancy in women who receive an efavirenz-based initial antiretroviral regimen compared with those who delay efavirenz use and receive a boosted protease inhibitor-based initial regimen. To estimate excess risk of teratogenic events with and without efavirenz exposure per 100 000 women, we incorporated literature-based rates of pregnancy, live births, and teratogenic events into a decision analytic model. We assumed a teratogenicity risk of 2.90 events/100 live births in women exposed to efavirenz during pregnancy and 2.68/100 live births in unexposed women. Results Survival for HIV-infected women who received an efavirenz-based initial antiretroviral therapy (ART) regimen was 0.89 years greater than for women receiving non-efavirenz-based initial therapy (28.91 vs. 28.02 years). The rate of teratogenic events was 77.26/100 000 exposed women, compared with 72.46/100 000 unexposed women. Survival estimates were sensitive to variations in treatment efficacy and AIDS-related mortality. Estimates of excess teratogenic events were most sensitive to pregnancy rates and number of teratogenic events/100 live births in efavirenz-exposed women. Conclusions Use of non-efavirenz-based initial ART in HIV-infected women of childbearing age may reduce life expectancy gains from antiretroviral treatment, but may also prevent teratogenic events. Decision-making regarding efavirenz use presents a trade-off between these two risks; this study can inform discussions between patients and health care providers.

Background Doravirine (DOR) is a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI). In the phase 3 DRIVE-AHEAD trial in HIV-1-infected treatment-naïve adults, DOR demonstrated noninferior efficacy to efavirenz (EFV) and favorable profiles for neuropsychiatric tolerability and lipids at 48 weeks. We present data through week 96. Methods DRIVE- AHEAD (Clinical Trials Registration: NCT02403674) is a phase 3, multicenter, double-blind, noninferiority trial that compared DOR with EFV. Eligible participants were HIV-1-infected treatment-naïve adults with pre-treatment HIV-1 RNA ≥1,000 copies/mL. Participants were randomized (1:1) to a fixed-dose regimen of DOR 100 mg, lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) QD or EFV 600 mg, emtricitabine 200 mg and TDF 300 mg (EFV/FTC/TDF) QD for up to 96 weeks. Randomization was stratified by screening HIV-1 RNA (≤/>100,000 copies/mL) and hepatitis B/C co-infection (yes/no). The efficacy endpoint of interest at week 96 was HIV-1 RNA Results Of 734 participants randomized, 728 received study drug and were included in analyses (mean age 33 years, 85% male, 48% white, 19% black, 34% Hispanic). At week 96, HIV-1 RNA Conclusion Week 96 results support non-inferiority of DOR/3TC/TFD to EFV/FTC/TDF established at Week 48 with no additional DOR resistance between week 48 and 96. DOR/3TC/TDF was safe and well-tolerated with fewer neuropsychiatric and rash events and favorable lipid profile compared with EFV/FTC/TDF. Disclosures C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Grant Investigator and Research Contractor, Research grant and Research support. K. Squires, Merck & Co., Inc.: Ad Board, Ad Board. Gilead Sciences: Grant, Ad Board. VIIV: Ad Board, Ad Board. Bristol Myers Squibb: Ad Board, Ad Board. Janssen: Ad Board, Ad Board. J. M. Molina, Gilead: Scientific Advisor, Consulting fee. Merck: Scientific Advisor, Consulting fee. ViiV: Scientific Advisor, Consulting fee. Teva: Scientific Advisor, Consulting fee. P. Sax, Gilead: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Merck: Consultant and Grant Investigator, Consulting fee, Grant recipient and Research grant. Janssen: Consultant, Consulting fee. BMS: Grant Investigator, Grant recipient and Research grant. W. Wong, Merck & Co., Inc.: Research Contractor, Research grant. G. Lin, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc.: Employee and Shareholder, May hold stock/stock options in the company and Salary. S. Kumar, Merck & Co., Inc.: Employee and Shareholder, Salary. G. Hanna, Merck & Co., Inc.: Employee and Shareholder, Salary. C. Hwang, Merck & Co., Inc.: Employee and Shareholder, Salary. E. Martin, Merck & Co., Inc.: Employee and Shareholder, Salary. H. Teppler, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA: Employee, May hold stock/stock options in the company and Salary.

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/microL), 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.

Importance Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. Objective To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. Evidence Review New evidence collected since the International Antiviral Society–USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences. A volunteer panel of experts in HIV research and patient care considered these data and updated previous recommendations. Findings ART is recommended for virtually all HIV-infected individuals, as soon as possible after HIV diagnosis. Immediate initiation (eg, rapid start), if clinically appropriate, requires adequate staffing, specialized services, and careful selection of medical therapy. An integrase strand transfer inhibitor (InSTI) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is generally recommended for initial therapy, with unique patient circumstances (eg, concomitant diseases and conditions, potential for pregnancy, cost) guiding the treatment choice. CD4 cell count, HIV RNA level, genotype, and other laboratory tests for general health and co-infections are recommended at specified points before and during ART. If a regimen switch is indicated, treatment history, tolerability, adherence, and drug resistance history should first be assessed; 2 or 3 active drugs are recommended for a new regimen. HIV testing is recommended at least once for anyone who has ever been sexually active and more often for individuals at ongoing risk for infection. Preexposure prophylaxis with tenofovir disoproxil fumarate/emtricitabine and appropriate monitoring is recommended for individuals at risk for HIV. Conclusions and Relevance Advances in HIV prevention and treatment with antiretroviral drugs continue to improve clinical management and outcomes for individuals at risk for and living with HIV.

Objectives To estimate the prevalence of transmitted antiretroviral (ARV) drug resistance, and to assess whether resistance testing influences first-line ARV regimen selection. Methods Data on patients' characteristics were collected through questionnaires. ARV drug resistance was tested by genotypic methods and defined by Quest–Stanford classification rule. Physicians reported the intended and actual treatments and the factors considered in treatment selection. Results Two hundred and twenty-eight patients were included. The prevalence of ARV drug resistance was 12.1%, with 9.8% for non-nucleoside reverse transcriptase inhibitors (NNRTIs), 4.5% for nucleoside reverse transcriptase inhibitors and 1.8% for protease inhibitors (PIs). Pill burdens, dosing frequency and physicians' experience with regimens were the major factors considered in treatment selection. The intended and actual treatment differed for 73 and 44% of the patients with and without ARV drug resistance, respectively [odds ratio (95% confidence interval, CI)=3.6 (1.5–9.0), P=0.006]. NNRTI-based regimens were intended for 10 patients with resistance to NNRTIs; these patients were prescribed PI-based regimens after genotypic testing. Conclusions Transmitted ARV drug resistance was detected in 12.1% of treatment-naive patients, with resistance to NNRTIs the most common. Resistance-testing results played a partial role in first-line treatment selection. However, resistance to NNRTIs pre-empted NNRTI use.

Value of Information (VOI) analysis examines whether to acquire information before making a decision. We introduced VOI to the HIV audience, using the example of generic antiretroviral therapy (ART) in the US.We used a mathematical model and probabilistic sensitivity analysis (PSA) to generate probability distributions of survival (in quality-adjusted life years, QALYs) and cost for three potential first-line ART regimens: three-pill generic, two-pill generic, and single-pill branded. These served as input for a comparison of two hypothetical two-arm trials: three-pill generic versus single-pill branded; and two-pill generic versus single-pill branded. We modeled pre-trial uncertainty by defining probability distributions around key inputs, including 24-week HIV-RNA suppression and subsequent ART failure. We assumed that, without a trial, patients received the single-pill branded strategy. Post-trial, we assumed that patients received the most cost-effective strategy. For both trials, we quantified the probability of changing to a generic-based regimen upon trial completion and the expected VOI in terms of improved health outcomes and costs. Assuming a willingness to pay (WTP) threshold of $100 000/QALY, the three-pill trial led to more treatment changes (84%) than the two-pill trial (78%). Estimated VOI was $48 000 (three-pill trial) and $35 700 (two-pill trial) per future patient initiating ART.A three-pill trial of generic ART is more likely to lead to post-trial treatment changes and to provide more value than a two-pill trial if policy decisions are based on cost-effectiveness. Value of Information analysis can identify trials likely to confer the greatest impact and value for HIV care.

Background. Recommended human immunodeficiency virus (HIV) treatment regimens in the United States contain 3 antiretroviral agents, costing >$30 000/person/year. Pilot studies are evaluating the efficacy of dual therapy with dolutegravir (DTG) and lamivudine (3TC). We examined the potential cost-effectiveness and budget impact of DTG + 3TC regimens in the United States. Methods. Using a mathematical model, we projected the clinical and economic outcomes of antiretroviral therapy (ART)–naive patients under 4 strategies: (1) no ART (for modeling comparison); (2) 2-drug: initial regimen of DTG + 3TC; (3) induction-maintenance: 48-week induction regimen of 3 drugs (DTG/abacavir [ABC]/3TC), followed by DTG + 3TC maintenance if virologically suppressed; and (4) standard of care: 3-drug regimen of DTG/ABC/3TC. Strategy-dependent model inputs, varied widely in sensitivity analyses, included 48-week virologic suppression (88%–93%), subsequent virologic failure (0.1%–0.6%/month), and Medicaid-discounted ART costs ($15 200–$39 600/year). A strategy was considered cost-effective if its incremental cost-effectiveness ratio (ICER) was $500 000/QALY for standard of care. Two-drug was the preferred strategy only when DTG + 3TC 48-week virologic suppression rate exceeded 90%. With 50% uptake of either induction-maintenance or 2-drug for ART-naive patients, cost savings totaled $550 million and $800 million, respectively, within 5 years; savings reached >$3 billion if 25% of currently suppressed patients were switched to DTG + 3TC maintenance. Conclusions. Should DTG + 3TC demonstrate high rates of virologic suppression, this regimen will be cost-effective and would save >$500 million in ART costs in the United States over 5 years.

Cutaneous leishmaniasis is a parasitic infection caused by protozoa of the Leishmania genus that presents as asymptomatic pink papules that may ulcerate. There are several species of Leishmania found in 98 endemic countries and whereas all are associated with cutaneous disease, only specific species can cause mucocutaneous or visceral disease. Although the diagnosis of cutaneous leishmaniasis can be confirmed with Giemsa staining of a biopsy or "touch prep" specimen, only speciation at specialized centers such as the Centers for Disease Control (CDC) can determine the risk of mucocutaneous or visceral disease. Treatment of cutaneous leishmaniasis is varied and depends on the extent of cutaneous disease and the risk of mucocutaneous or visceral disease.

BACKGROUND Among patients with HIV infection, changes in the kidney filtration marker cystatin C after initiation of antiretroviral therapy (ART) may be related to changes in body composition or biomarkers of inflammation. METHODS ACTG A5224s was a substudy of A5202, which randomly assigned ART-naive HIV-infected subjects to blinded abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) with open-label efavirenz (EFV) or ritonavir-boosted atazanavir. This analysis explored changes in cystatin C from 0 to 96 weeks. RESULTS Of the 269 subjects, 85% were male and 66% white non-Hispanics; baseline mean CD4 count was 236 cells per cubic millimeter and cystatin C was 0.89 mg/L. Cystatin C decreased significantly within each arm; however, ritonavir-boosted atazanavir attenuated the beneficial effects of ART on cystatin C compared to EFV. Compared to ABC/3TC, TDF/FTC led to a marginally significant attenuation for percent change analyses only. Higher baseline body mass index and HIV RNA were associated with larger reductions in cystatin C in multivariable models. At baseline, cystatin C was positively correlated with high-sensitivity C-reactive protein (Spearman r = 0.25), interleukin 6 (r = 0.34), soluble intercellular adhesion molecule (r = 0.36), soluble vascular cell adhesion molecule (r = 0.54), tumor necrosis factor α (r = 0.57), and soluble TNF-α receptor I (r = 0.70, all P < 0.001). Reductions in cystatin C from 0 to 96 weeks correlated with reductions in all inflammatory biomarkers (r = 0.39-0.58, P < 0.001) except for high-sensitivity C-reactive protein (r = 0.01, P = 0.89) and IL-6 (r = 0.08, P = 0.24). CONCLUSIONS The beneficial effect of ART on cystatin C concentrations is attenuated by boosted ATV when compared to EFV. Reductions in cystatin C after ART are associated with reductions in systemic inflammation.