BACKGROUND:VH3810109 (N6LS) is a CD4-binding site antibody with broad and potent neutralizing activity in vitro. Here, we present efficacy, safety, and pharmacokinetic results from the phase 2a BANNER study in people with HIV-1. METHODS:BANNER was a randomized, open-label, 2-part, multicenter study of N6LS in adults naive to antiretroviral therapy (ART) with HIV-1 RNA ≥5000 copies/mL. N6LS was evaluated during monotherapy after a single intravenous (IV) infusion at various doses or subcutaneous (SC) injection, followed by 48 weeks of standard-of-care ART. Antiviral activity, safety, pharmacokinetics, and antidrug antibodies (ADAs) were evaluated. RESULTS:Sixty-two participants completed the monotherapy phase and 58 completed the standard-of-care phase. Most participants were male (94%), Hispanic (82%), and White (61%). Virologic response (reduction in HIV-1 RNA ≥0.5 log10 copies/mL from baseline) was achieved in 8/8 (100%; 40 mg/kg IV), 14/15 (93%; 700 mg IV), 5/6 (83%; 280 mg IV), 7/16 (44%; 70 mg IV), and 8/16 (50%; 700 mg SC) participants. Administered IV or SC, N6LS was well tolerated with few drug-related adverse events (n = 13) and no serious adverse events reported during monotherapy. Pharmacokinetic parameters increased proportionally with dose. Incidence of ADAs was dose-dependent and ranged from 6% to 83% in the IV groups; incidence was 19% in the SC group, with no indication that route of administration impacts incidence of ADAs. CONCLUSIONS:N6LS was efficacious and generally safe, supporting further development of N6LS dosed IV or SC for the treatment of HIV-1 (ClinicalTrials.gov, NCT04871113).

The CD4-binding site antibody VH3810109 (N6LS) demonstrated broad and potent neutralization activity in vitro and robust antiviral activity in people with HIV-1. We report safety, tolerability, pharmacokinetics, and anti-drug antibody (ADA) incidence for subcutaneous (SC) and intravenous (IV) N6LS. Safety and pharmacokinetics of a single dose of VH3810109 (also known as GSK3810109), administered either subcutaneously (SC) with rHuPH20 or intravenously (IV) [SPAN]) was an open-label, three-part, phase 1 study evaluating single-dose N6LS in adults without HIV (part 1, 20 mg/kg SC + recombinant human hyaluronidase PH20 [rHuPH20] 2,000 U/mL; part 2, 60 mg/kg IV; part 3, 3,000 mg SC + rHuPH20 2,000 U/mL). Over 24 weeks, adverse events (AEs), injection site reactions (ISRs), pharmacokinetics, and ADAs were monitored. Twenty-four participants (8/part) were enrolled and received a single N6LS dose. Overall AE incidence between SC doses was similar and higher compared with IV, driven by ISRs. No ISRs were reported for IV N6LS; for SC, 15/16 participants reported ISRs, and 17/32 events were grade 3 (all injection site erythema). All ISRs resolved without sequelae or treatment. All participants rated local reactions and pain as acceptable. No serious AEs or deaths occurred. Pharmacokinetics were as expected for a broadly neutralizing antibody; median terminal half-life ranged from 43 to 47 days. No ADAs were observed after IV N6LS (0/8); 5/16 participants had treatment-emergent ADAs after SC N6LS; however, a clear impact on pharmacokinetics was observed in only one participant. N6LS administered IV or SC + rHuPH20 had a favorable safety profile and was well tolerated. Results support the ongoing development of N6LS 3,000 mg SC + rHuPH20 and 60 mg/kg IV into phase 2b.CLINICAL TRIALSRegistered at ClinicalTrials.gov (NCT05291520).

In 2001, the primary and secondary syphilis incidence rate in rural Columbus County, North Carolina was the highest in the nation. To understand the development of syphilis outbreaks in rural areas, we developed and used the Bayesian Maximum Entropy Graphical User Interface (BMEGUI) to map syphilis incidence rates from 1999-2004 in seven adjacent counties in North Carolina. Using BMEGUI, incidence rate maps were constructed for two aggregation scales (ZIP code and census tract) with two approaches (Poisson and simple kriging). The BME maps revealed the outbreak was initially localized in Robeson County and possibly connected to more urban endemic cases in adjacent Cumberland County. The outbreak spread to rural Columbus County in a leapfrog pattern with the subsequent development of a visible low incidence spatial corridor linking Roberson County with the rural areas of Columbus County. Though the data are from the early 2000s, they remain pertinent, as the combination of spatial data with the extensive sexual network analyses, particularly in rural areas gives thorough insights which have not been replicated in the past two decades. These observations support an important role for the connection of micropolitan areas with neighboring rural areas in the spread of syphilis. Public health interventions focusing on urban and micropolitan areas may effectively limit syphilis indirectly in nearby rural areas.

Abstract Background We assessed the efficacy and safety of dolutegravir/lamivudine (DTG/3TC) in a US test-and-treat setting at a secondary 48-week time point of the multicenter, single-arm, phase IIIb STAT study. Methods Participants were eligible adults newly diagnosed with human immunodeficiency virus (HIV)-1 and had started once-daily DTG/3TC within 14 days of diagnosis, before laboratory results were available. Antiretroviral therapy (ART) was modified if baseline testing indicated DTG or 3TC resistance, hepatitis B virus (HBV) coinfection, or creatinine clearance <30 mL/min per 1.73 m2, and these participants remained in the study. A proportion with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48 was calculated among all participants (intention-to-treat-exposed [ITT-E] missing = failure analysis) and those with available data (observed analysis). Results At Week 48, 82% of all participants regardless of ART (107 of 131; ITT-E missing = failure) and 97% with available data (107 of 110; observed analysis) achieved HIV-1 RNA <50 copies/mL. High proportions of virologic response were seen overall, including in participants with high viral load (≥500 000 copies/mL; 89%) or low CD4+ cell count (<200 cells/mm3; 78%) at baseline. Ten participants had treatment modification (baseline HBV coinfection, n = 5; participant/proxy decision, n = 2; baseline M184V resistance mutation, adverse event [AE; rash], and pregnancy, n = 1 each) before Week 48. Two participants met confirmed virologic failure criteria. No treatment-emergent resistance was observed. Ten participants reported drug-related AEs (all grade 1–2); no serious drug-related AEs occurred. Conclusions Results demonstrated high proportions of participants with sustained virologic suppression, no treatment-emergent resistance, and good safety over 48 weeks, supporting first-line use of DTG/3TC in a test-and-treat setting.

Switching to dolutegravir/lamivudine (DTG/3TC), versus continuing tenofovir alafenamide-based regimens, showed durable efficacy and safety through 144 weeks, with no virologic failure or resistance detected, supporting the use of DTG/3TC in virologically suppressed individuals with human immunodeficiency virus type 1. Background Switching to dolutegravir/lamivudine (DTG/3TC) was noninferior to continuing tenofovir alafenamide (TAF)-based regimens for maintaining virologic suppression at week 48 of the TANGO study. Here we present week 144 outcomes (efficacy, safety, weight, and biomarkers). Methods TANGO is a randomized (1:1, stratified by baseline third agent class), open-label, noninferiority phase 3 study. Virologically suppressed (>6 months) adults with human immunodeficiency virus type 1 (HIV-1) switched to once-daily DTG/3TC or continued TAF-based regimens. Results A total of 741 participants received study treatment (DTG/3TC, n = 369; TAF-based regimen, n = 372). At week 144, the proportion of participants with an HIV-1 RNA level >= 50 copies/mL (primary end point, Snapshot; intention-to-treat-exposed population) after switching to DTG/3TC was 0.3% (1 of 369) versus 1.3% (5 of 372) for those continuing TAF-based regimens, demonstrating noninferiority (adjusted treatment difference, -1.1 [95% confidence interval, -2.4 to .2), with DTG/3TC favored in the per-protocol analysis (adjusted treatment difference, -1.1 [-2.3 to -.0]; P = .04). Few participants met confirmed virologic withdrawal criteria (none in the DTG/3TC and 3 in the TAF-based regimen group), with no resistance observed. Drug-related adverse events were more frequent with DTG/3TC (15%; leading to discontinuation in 4%) than TAF-based regimens (5%; leading to discontinuation in 1%) through week 144, but rates were comparable after week 48 (4%; leading to discontinuation in 1% in both groups). Changes from baseline in lipid values generally favored DTG/3TC; no clinical impact on renal function and comparable changes in inflammatory and bone biomarkers across groups were observed. Conclusions Switching to DTG/3TC demonstrated noninferior and durable efficacy compared with continuing TAF-based regimens in treatment-experienced adults with HIV-1, with good safety and tolerability, and no resistance through 144 weeks.

Dolutegravir/Lamivudina (DTG / 3TC) é um regime completo de 2 medicamentos (2DR) para o tratamento do HIV-1. A eficácia virológica não inferior foi comprovada ao longo de 3 anos em pessoas virgens de tratamento PARA HIV e 2 anos em um ambiente de troca estável. TANGO, um estudo randomizado, aberto e de não inferioridade, avalia a eficácia e a segurança da mudança para DTG/3TC em adultos virologicamente suprimidos (> 6 meses, sem falha virológica anterior, sem resistência maior a INI ou ITRN) vs permanecer em um regime baseado em tenofovir alafenamida (TBR) de 3 ou 4 medicamentos, estratificado pela 3ª classe de agente basal. As análises da semana 144 avaliaram a não inferioridade (margem de 4% para falha virológica e 8% para sucesso virológico; análise de snapshot, intenção de tratar na população exposta [ITT-E]). De 741 participantes randomizados/expostos (DTG/3TC, 369; TBR, 372), a maioria entrou no estudo com elvitegravir/cobicistate (66%). Na semana 144, a mudança para DTG/3TC foi não inferior à continuação da TBR (falha virológica snapshot, ITT-E): 0,3% vs 1,3%; diferença ajustada (IC 95%): -1,1% (-2,4%, 0,2%) e superior à TBR na análise por protocolo: 0% vs 1,1%; diferença ajustada: -1,1% (-2,3%, -0,0%); p = 0,044 (bilateral). O sucesso virológico por snapshot foi alto em ambos os braços, demonstrando não inferioridade (DTG/3TC, 85,9% vs TBR, 81,7%; diferença ajustada [IC de 95%]: 4,2% [-1,1%, 9,5%]). Nenhum participante no DTG/3TC e 3 (0,8%) no TBR preencheram os critérios de retirada por falha virológica confirmada sem resistência observada. Nenhum participante em DTG/3TC e 6 (1,6%) em TBR descontinuaram por falta de eficácia. As taxas gerais de eventos adversos foram semelhantes entre os braços (DTG/3TC, 91%; TBR, 90%). Colesterol total (CT), colesterol LDL e triglicerídeos melhoraram com DTG/3TC, colesterol HDL melhorou com TBR, sem diferença na razão TC/HDL entre os braços. As alterações nos biomarcadores renais foram semelhantes entre os braços. A alteração média ajustada da linha de base no peso foi de 2,2 kg com DTG/3TC e 1,7 kg com TBR, e a proporção de participantes com aumento de peso ≥10% foi semelhante (DTG / 3TC, 13%; TBR, 12%). Mudar para DTG/3TC de um TBR de 3 ou 4 medicamentos resultou em eficácia elevada e não inferior, sem falhas virológicas confirmadas e boa tolerabilidade ao longo de 3 anos de tratamento. DTG/3TC é uma opção robusta com eficácia durável, boa segurança e tolerabilidade e uma alta barreira à resistência.

Abstract Background DTG/3TC is a complete 2-drug regimen (2DR) for the treatment of HIV-1 infection. Non-inferior virologic efficacy has been proven over 3 years in treatment-naive people living with HIV (PLWH) and 2 years in a stable switch setting. Methods TANGO, a randomized, open-label, non-inferiority study, evaluates efficacy and safety of switching to DTG/3TC in PLWH who are virologically suppressed ( > 6 months, no prior virologic failure [VF], no major NRTI/INSTI resistance) vs remaining on a 3- or 4-drug TAF-based regimen (TBR), stratified by baseline 3rd agent class. Week 144 analyses assessed non-inferiority (NI) with a 4% NI margin for Snapshot virologic failure (VF) and 8% for virologic success (VS; FDA Snapshot algorithm, intention-to-treat–exposed [ITT-E] population). Results Of 741 randomized/exposed pts (DTG/3TC: 369; TBR: 372), most pts entered the study on EVG/c (66%). For Week 144 Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR in the ITT-E analysis: 0.3% vs 1.3%; adjusted difference (95% CI): −1.1% (−2.4%, 0.2%) and superior to TBR in the per-protocol analysis: 0% vs 1.1%; adjusted difference: −1.1% (−2.3, −0.0); P=0.044 (2-sided). Snapshot VS was high in both arms and demonstrated non-inferiority (Table). Zero pts on DTG/3TC and 3 (0.8%) on TBR met confirmed virologic withdrawal criteria with no resistance observed. Zero pts on DTG/3TC and 6 (1.6%) on TBR discontinued for lack of efficacy. Overall AE rates were similar between arms (Table). TC, LDL-C, and triglycerides improved with DTG/3TC, HDL-C improved with TBR, with no difference in TC/HDL-C ratio between arms. Changes in eGFR (cystatin C) and proximal tubular function marker were similar across arms. Adjusted mean change from BL in weight was 2.2 and 1.7 kg in the DTG/3TC and TBR arms, respectively, and proportion of pts with > 10% weight increase was similar across arms (13% and 12%, respectively). Table. Efficacy and Key Safety Results for the ITT-E and Safety Population Conclusion Switching to the 2-drug regimen of DTG/3TC from a TAF-based 3- or 4-drug regimen resulted in high, non-inferior efficacy with zero confirmed virologic withdrawals and good tolerability over 3 years of treatment. DTG/3TC 2DR is a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance. Disclosures Olayemi Osiyemi, M.D, Gilead (Advisor or Review Panel member, Speaker’s Bureau)Merck (Advisor or Review Panel member)ViiV Healthcare (Advisor or Review Panel member, Speaker’s Bureau) Fiona Bisshop, MBBBS, Gilead (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Stéphane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Joaquín Portilla, MD, AbbVie (Other Financial or Material Support)Gilead (Grant/Research Support, Other Financial or Material Support)Janssen (Grant/Research Support, Other Financial or Material Support)Merck Sharpe & Dohme (Other Financial or Material Support)ViiV Healthcare (Grant/Research Support, Other Financial or Material Support) Jean-Pierre Routy, MD, FRCPC, ViiV Healthcare (Grant/Research Support) Mounir Ait-Khaled, PhD, ViiV Healthcare (Employee) Keith Pappa, PharmD, Glaxo Smith Kline (Shareholder)ViiV Healthcare (Employee) Ruolan Wang, Master of Science, ViiV Healthcare (Employee) Peter Leone, MD, viiv healthcare (Employee) Jonathan Wright, MSc, GlaxoSmithKline (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Michael Aboud, MBChB, MRCP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kimberly Smith, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Infectious disease surveillance is often case-based, focused on people diagnosed and their contacts in a predefined time window, and treated as independent across infections. Network analysis of partners and contacts joining multiple investigations and infections can reveal social or temporal trends, providing opportunities for epidemic control within broader networks. We constructed a sociosexual network of all HIV and early syphilis cases and contacts investigated among residents of 11 contiguous counties in North Carolina over a two-year period (2012–2013). We anchored the analysis on new HIV diagnoses (“indexes”), but also included nodes and edges from syphilis investigations that were within the same network component as any new HIV index. After adding syphilis investigations and deduplicating people included in multiple investigations (entity resolution), the final network comprised 1470 people: 569 HIV indexes, 700 contacts to HIV indexes who were not also new cases themselves, and 201 people who were either indexes or contacts in eligible syphilis investigations. Among HIV indexes, nearly half (48%; n = 273) had no located contacts during single-investigation contact tracing, though 25 (9%) of these were identified by other network members and thus not isolated in the final multiple investigation network. Constructing a sociosexual network from cases and contacts across multiple investigations mitigated some effects of unobserved partnerships underlying the HIV epidemic and demonstrated the HIV and syphilis overlap in these networks.

Abstract Background The primary analysis of the STAT study demonstrated the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting through 24 weeks, with therapy adjustments for baseline resistance or hepatitis B virus (HBV) co-infection. Here we present secondary analyses through Week 48 of virologic outcomes in participants by baseline viral load (VL). Methods STAT is a single-arm study of treatment-naive adults with HIV-1 infection who initiated DTG/3TC ≤ 14 days after HIV-1 diagnosis without availability of screening/baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance < 30 mL/min/1.73 m2, then antiretroviral therapy (ART) was potentially adjusted and participants remained on study. Efficacy analyses included proportion of participants with HIV-1 RNA < 50 c/mL regardless of ART regimen at Week 48, among all participants (ITT-E missing = failure analysis) and among participants with available HIV-1 RNA data at Week 48 (observed analysis). Results Of 131 enrolled, DTG/3TC treatment was adjusted in 10 participants, and of those with available data (n=7), all (100%) achieved HIV-1 RNA < 50 c/mL at Week 48. At Week 48, 82% (107/131) of all participants (Figure 1) and 97% (107/110) of those with available data (Figure 2) achieved HIV-1 RNA < 50 c/mL. Of participants with baseline VL ≥ 500,000 c/mL, 89% (17/19) achieved HIV-1 RNA < 50 c/mL at Week 48; the remaining 2 withdrew from study. Of participants with baseline VL ≥ 1,000,000 c/mL, 90% (9/10) achieved HIV-1 RNA < 50 c/mL at Week 48 (Table); the remaining participant withdrew consent. Of the 17 participants with baseline VL ≥ 500,000 c/mL with available data through Week 48, 76% (13/17) achieved virologic suppression by Week 24. One participant with baseline VL ≥ 500,000 c/mL switched from DTG/3TC before the Week 48 assessment. Of the 9 participants with baseline VL ≥ 1,000,000 c/mL with available data through Week 48, most participants (8/9; 89%) were suppressed by Week 24. Figure 1. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: ITT-E missing = failure analysis. Figure 2. Virologic outcomes at Week 48, overall and by baseline VL and CD4+ cell count: observed analysis. Table. Viral Load by Study Visit Among Participants with Baseline HIV-1 RNA ≥1,000,000 c/mL Conclusion These data provide evidence for the efficacy and feasibility of using DTG/3TC as a first-line regimen in a test-and-treat setting, including among participants with very high baseline VL. Disclosures Charlotte-Paige M. Rolle, MD MPH, Gilead Sciences (Grant/Research Support, Scientific Research Study Investigator, Speaker’s Bureau)Janssen Infectious Disease (Scientific Research Study Investigator, Advisor or Review Panel member)ViiV Healthcare (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker's Bureau) Tulika Singh, MD MS AAHIVS, Gilead (Grant/Research Support, Advisor or Review Panel member)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker's Bureau) Moti Ramgopal, MD FIDSA, Abbvie (Scientific Research Study Investigator, Speaker's Bureau)Gilead (Consultant, Scientific Research Study Investigator, Speaker's Bureau)Janssen (Consultant, Scientific Research Study Investigator, Research Grant or Support, Speaker's Bureau)Merck (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator, Speaker's Bureau) Dushyantha Jayaweera, MD, mrcog(uk), face, Gilead (Research Grant or Support)Janssen (Research Grant or Support)viiv (Research Grant or Support) Peter Leone, MD, viiv healthcare (Employee) Jessica Matthews, BS, ViiV Healthcare (Employee) Michael Cupo, Ph.D., GlaxoSmithKline (Employee) Mark Underwood, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Kostas Angelis, PhD, GSK (Employee, Shareholder) Brian Wynne, MD, ViiV Healthcare (Employee, Shareholder, I have shares in GSK, the part owner of ViiV) Deanna Merrill, PharmD, MBA, AAHIVP, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Christopher T. Nguyen, MD, ViiV Healthcare (Employee) Jean A. van Wyk, MB,ChB, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Andrew Zolopa, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee)

Objectives: Dolutegravir/lamivudine (DTG/3TC) is indicated for treatment-naive and experienced people with HIV; however, questions remain about its utility in a test-and-treat setting because of potential transmitted resistance and baseline hepatitis B virus (HBV) co-infection. We present feasibility and efficacy of DTG/3TC in newly diagnosed individuals in a test-and-treat setting. Design: The single-arm STAT study evaluated DTG/3TC in a US test-and-treat setting. Methods: Eligible adults initiated DTG/3TC 14 days or less after HIV-1 diagnosis without availability of baseline laboratory results. If baseline testing indicated DTG or 3TC resistance, HBV co-infection, or creatinine clearance less than 30 ml/min per 1.73 m2, participants remained on study with treatment modification. Efficacy endpoints included proportions of participants with HIV-1 RNA less than 50 copies/ml at Week 24, regardless of antiretroviral regimen, among all participants (intention-to-treat exposed) and those with available HIV-1 RNA data (observed). Results: Of 131 participants enrolled, 8% were female and 50% were non-white. Through Week 24, treatment was modified in eight participants [five with HBV co-infection, one with baseline M184V, one for adverse event (rash), one participant decision]. At Week 24, 78% (102/131) of all participants and 92% (102/111) of those with available data achieved HIV-1 RNA less than 50 copies/ml. Incidence of drug-related adverse events was low (7%); no drug-related serious adverse events occurred. Conclusion: These data demonstrate the feasibility, efficacy, and safety of using DTG/3TC as a first-line regimen in a test-and-treat setting, with therapy adjustments for baseline resistance or HBV co-infection occurring safely via routine clinical care as needed [ClinicalTrials.gov, NCT03945981; see Supplemental Digital Content 1, video abstract (Video abstract summarizing the STAT study design and results), http://links.lww.com/QAD/C189].

Background Successful partner notification can improve community-level outcomes by increasing the proportion of persons living with human immunodeficiency virus (HIV) who are linked to HIV care and virally suppressed, but it is resource intensive. Understanding where HIV transmission pathways may be undetected by routine partner notification may help improve case finding strategies. Methods We combined partner notification interview and HIV sequence data for persons diagnosed with HIV in Wake County, NC in 2012 to 2013 to evaluate partner contact networks among persons with HIV pol gene sequences 2% or less pairwise genetic distance. We applied a set of multivariable generalized estimating equations to identify correlates of disparate membership in genetic versus partner contact networks. Results In the multivariable model, being in a male-male pair (adjusted odds ratio [AOR], 16.7; P = 0.01), chronic HIV infection status (AOR, 4.5; P < 0.01), and increasing percent genetic distance between each dyad member's HIV pol gene sequence (AOR, 8.3 per each 1% increase, P < 0.01) were all associated with persons with HIV clustering but not being identified in the partner notification network component. Having anonymous partners or other factors typically associated with risk behavior were not associated. Conclusions Based on genetic networks, partnerships which may be stigmatized, may have occurred farther back in time or may have an intervening partner were more likely to be unobserved in the partner contact network. The HIV genetic cluster information contributes to public health understanding of HIV transmission networks in these settings where partner identifying information is not available.

Background: Genital herpes simplex virus (HSV) type 2 is a common persistent infection that frequently reactivates to cause recurrent lesions and recurrent viral shedding which is incompletely controlled by antiviral therapy. GEN-003 is a candidate therapeutic vaccine containing 2 HSV-2 proteins, gD2 and ICP4, and Matrix-M2 adjuvant (M2). Methods: HSV-2 seropositive persons with genital herpes were randomized into three dose cohorts of Gen-003 (60 mu g antigen/50 mu g M2, 60 mu g/75 mu g M2 or Placebo). Three intramuscular doses 21 days apart of GEN-003 or placebo were administered. Participants obtained genital area swabs twice-daily for HSV-2 detection and monitored genital lesions for 12 months. The rates of virus shedding and lesion rates before vaccination were compared to 3 defined periods after vaccination; Days 43-71, Month 6 and Month 12. Results: GEN-003 at a dose of 60 mu g each antigen/50 mu g M2 reduced HSV shedding immediately after dosing with a rate ratio of 0.58, compared to 0.75 for the GEN-003 6014/75 mu g M2 and 1.06 for placebo. Lesion rates, recurrence rates, and duration of recurrences were also reduced. Reactogenicity was higher with the 75 mu g M2 dose than the 50 mu g M2 dose, specifically for pain, tenderness, malaise and fatigue. Antibody and cellular immune responses were stimulated by both doses and persisted to 12 months. Conclusions: GEN-003 vaccine manufactured with a scalable process gave results similar to those observed in prior clinical trials. GEN-003 had an acceptable safety profile and stimulated both humoral and cellular immune responses. The 60 mu g antigen/50 mu g M2 provided the maximal effect on virologic and clinical measures and warrants further development. (C) 2019 Published by Elsevier Ltd.

Background: Partner notification is an important component of public health test and treat interventions. To enhance this essential function, we assessed the potential for molecular methods to supplement routine partner notification and corroborate HIV networks. Methods: All persons diagnosed with HIV infection in Wake County, NC, during 2012–2013 and their disclosed sexual partners were included in a sexual network. A data set containing HIV-1 pol sequences collected in NC during 1997–2014 from 15,246 persons was matched to HIV-positive persons in the network and used to identify putative transmission clusters. Both networks were compared. Results: The partner notification network comprised 280 index cases and 383 sexual partners and high-risk social contacts (n = 131 HIV-positive). Of the 411 HIV-positive persons in the partner notification network, 181 (44%) did not match to a HIV sequence, 61 (15%) had sequences but were not identified in a transmission cluster, and 169 (41%) were identified in a transmission cluster. More than half (59%) of transmission clusters bridged sexual network partnerships that were not recognized in the partner notification; most of these clusters were dominated by men who have sex with men. Conclusions: Partner notification and HIV sequence analysis provide complementary representations of the existent partnerships underlying the HIV transmission network. The partner notification network components were bridged by transmission clusters, particularly among components dominated by men who have sex with men. Supplementing the partner notification network with phylogenetic data highlighted avenues for intervention.

BackgroundGEN-003 is a candidate therapeutic vaccine for genital herpes simplex virus type 2 (HSV-2). We compared virologic and clinical impact of varying GEN-003 doses.MethodsAdults with symptomatic HSV-2 received placebo or GEN-003 (30 or 60 µg antigen with 25, 50, or 75 µg adjuvant). Viral shedding and lesion rates before vaccination were compared with those measured immediately after vaccination, then at weeks 29-33 and 53-57 after last dose.ResultsCompared with baseline shedding rates, the rate ratios for viral shedding immediately after treatment were as follows: 0.82 (95% confidence interval [CI], 0.49-1.36), 30 µg antigen/25 µg adjuvant (30/25) dose; 0.64 (95% CI, 0.45-0.92), 30/50 dose; 0.63 (95% CI, 0.37-1.10), 30/75 dose; 0.56 (95% CI, 0.36-0.88), 60/25 dose; 0.58 (95% CI, 0.38-0.89), 60/50 dose; 0.45 (95% CI, 0.16-0.79), 60/75 dose; and 0.98 (95% CI, 0.76-1.26), placebo. Lesion rate reductions by GEN-003 ranged from 31% to 69%, but lesion rates also decreased among placebo recipients (62%). Reductions in shedding and lesion rate were durable for 12 months for the 60 µg antigen plus 50 or 75 µg adjuvant groups. No serious adverse events occurred with vaccination.ConclusionsThe most efficacious vaccine combinations for GEN-003 were the 60 µg/50 µg and 60 µg/75 µg doses.

Background The integration of traditional contact tracing with HIV sequence analyses offers opportunities to mitigate some of the barriers to effective network construction. We used combined analyses during an outbreak investigation of spatiotemporally clustered acute HIV infections to evaluate if the observed clustering was the product of a single outbreak. Methods We investigated acute and recent HIV index cases reported in North Carolina from 2013 to 2014 and their reported contacts. Contact tracing networks were constructed with surveillance data and compared with phylogenetic transmission clusters involving an index case using available HIV-1 pol sequences including 1672 references. Clusters were defined as clades of 2 or more sequences with a less than 1.5% genetic distance and a bootstrap of at least 98% on maximum-likelihood phylogenies. Results In total, 68 index cases and 210 contacts (71 HIV infected) were reported. The contact tracing network involved 58 components with low overall density (1.2% statewide); 33% of first-degree contacts could not be located. Among 38 (56%) of 68 index cases and 34 (48%) of 71 contacts with sequences, 13 phylogenetic clusters were identified (size 2–4 members). Four clusters connected network components that were not linked in contact tracing. The largest component (n = 28 cases) included 2 distinct phylogenetic clusters and spanned 2 regions. Conclusions We identified the concurrent expansion of multiple small transmission clusters rather than a single outbreak in a largely disconnected contact tracing network. Integration of phylogenetic analyses provided timely information on transmission networks during the investigation. Our findings highlight the potential of combined methods to better identify high-risk networks for intervention.

Abstract Background GEN-003 is an investigational genital herpes immunotherapy comprising gD2ΔTMR, an HSV-2 antigen that induces neutralizing antibody and T cell responses, ICP4.2, an HSV-2 T cell antigen selected through human T cell screens, and Matrix-M2™, a saponin-based adjuvant. This Phase 2b study was designed to evaluate efficacy and safety of GEN-003 vs. placebo. Methods Healthy persons, age 18–50 years, with 3–9 HSV-2 genital herpes outbreaks annually were randomized to 3 groups: placebo, or 60 µg of each antigen combined with 50 µg (60/50 group) or 75 µg (60/75 group) of adjuvant, administered 3 times 21 days apart. Study endpoints included safety, immunogenicity, HSV-2 shedding frequency, lesion rate and recurrence frequency. Viral shedding was measured from anogenital swabs by PCR. Swabs were collected for 28 days at baseline, and after the third dose, 6 months and 1 year. The presence of herpes lesions was recorded daily by electronic diary. Results One hundred and thirty-one participants enrolled and >90% received all 3 doses. In the 28-day post-treatment period, viral shedding was reduced by 40% and 27% in the 60/50 and 60/75 groups, respectively, compared with a 5% increase in the placebo group. At 6 months post-treatment, median lesion rates were significantly lower in the 60/50 and 60/75 groups (2.7% and 1.9%, respectively) vs. the placebo group (5.6%, p < 0.05), resulting in median reductions of 52% and 66%. In participants not receiving suppressive antivirals, the median recurrence frequency was 1.0/6 months in the 60/50 group vs. 2.0 in the placebo group (p = 0.08). The median recurrence duration in the 60/50 group was lower than in the placebo group (2.8 vs. 4.2 days; p < 0.05). The most commonly reported adverse events (AEs) following GEN-003 vaccination were injection site pain/tenderness (97%), fatigue (82%), headache (82%) and myalgia (80%). No vaccine-related serious AEs, autoimmune events or other AEs of special interest were reported. Conclusion In adults with recurrent genital herpes, GEN-003 reduced HSV-2 shedding frequency, genital herpes lesion rate, recurrence frequency and recurrence duration through 6 months after the last dose. Local and systemic symptoms were common in GEN-003 recipients, but treatment completion was high with few discontinuations due to AEs. Disclosures T. C. Heineman, GSK group of companies: Consultant and Shareholder, Consulting fee; D. Bernstein, Genocea Biosciences: Consultant and Investigator, Consulting fee and Research support; A. Wald, Genocea Biosciences: Investigator, Research grant and Support for travel to meetings for the study; N. Van Wagoner, Genocea Biosciences: Consultant, Research support and Travel support to present at scientific meetings; P. Leone, Genocea Biosciences: Grant Investigator and Scientific Advisor, Consulting fee, Research grant and Speaker honorarium; T. Oliphant, Genocea Biosciences: Consultant, Consulting fee; A. Natenshon, Genocea Biosciences: Employee, Salary; L. K. McNeil, Genocea Biosciences: Employee, Salary; J. B. Flechtner, Genocea Biosciences: Employee, Salary; S. Hetherington, Genocea Biosciences: Employee, Salary

Longitudinal opioid prescription use is unknown among HIV-infected patients. Group-based trajectory modeling followed by multinomial logistic regression was used to identify distinct trajectories and their association with baseline characteristics among 1239 HIV-infected UNC CFAR HIV Clinical Cohort participants, 2000-2014. Three trajectories were identified: (1) 72% never/sporadic opioid use (referent group), (2) 11% episodic use (associated with female sex, depression, drug-related diagnoses, antiretroviral therapy use, and undetectable HIV RNA), and (3) 16% chronic use (associated with older age, female sex, and mental health diagnoses). Overall, opioid prescription decreased substantially with longer time in HIV care among both episodic and chronic users.

Background Syphilis management is complex and demonstration of treatment response requires monitoring of nontreponemal antibody titers for a ≥ 4-fold decline and/or seroreversion to nonreactive titers. Methods We evaluated data from a multicenter clinical trial of syphilis treatment conducted from 2000 to 2009 involving human immunodeficiency virus (HIV)–negative patients 18 years or older with early syphilis. To assess the rate of titer decline and seroreversion after effective therapy, rapid plasma reagin (RPR) titers were analyzed at 1, 3, 6, 9, and 12 months among patients with an appropriate treatment response. We plotted the rate of RPR titer decline after treatment, estimated the frequency of seroreversion, and conducted multivariate analyses to assess characteristics associated with seroreversion. Results Among 369 (79.4%) of 465 HIV-negative patients with early syphilis who had an appropriate treatment response, 333 participants had complete RPR data over 12 months. Although the decline in RPR titers was ≥ 4-fold among 88.0% (293/333) of participants at 3 months and ≥ 8-fold among 77.8% at 6 months, only 9.6% achieved complete RPR seroreversion at 6 months and 17.1% at 12 months after therapy. Male sex (adjusted odds ratio, 4.3; 95% confidence interval, 1.8–10.5) and baseline RPR titers ≤ 1:32 (adjusted odds ratio, 14.5; 95% confidence interval, 6.8–31.2) were associated with higher odds of seroreversion compared with females and titers > 1:32, respectively. Conclusions Despite a ≥ 4-fold RPR titer decline after treatment, the majority of HIV-negative patients with early syphilis failed to have seroreversion at 12 months. Nontreponemal antibody titers often persist despite an appropriate treatment response.

BACKGROUND:Long-term HIV care and treatment engagement is required for maximal clinical and prevention benefits, but longitudinal care patterns are poorly understood. We used the last 10 years' worth of HIV surveillance data from North Carolina to describe longitudinal HIV care trajectories from diagnosis.METHODS:We conducted a retrospective, population-based cohort study of all persons newly diagnosed with HIV in North Carolina between March 31, 2006 and March 31, 2015 (N = 16,207). We defined HIV care attendance in each 3-month and 6-month interval after diagnosis as the presence of viral load and/or CD4 records (care visit proxies) in the interval. We used group-based trajectory modeling to identify common care trajectories and baseline predictors thereof.RESULTS:A predicted 26% of newly HIV-diagnosed persons showed consistently high care attendance over time; ∼16% exhibited steadily declining attendance; ∼26% showed consistently low attendance; ∼17% had initially weak attendance with an increase starting ∼1.5 year later; and ∼15% showed initially weak attendance with an increase starting ∼3 years later. Older age at diagnosis was protective against all suboptimal trajectories (with the "consistently high" pattern as referent), and being a man who has sex with men was protective against 3 of the 4 suboptimal patterns.CONCLUSIONS:As measured by surveillance-based laboratory proxies, most newly HIV-diagnosed persons exhibited suboptimal care trajectories, but there was wide variation in the particular pathways followed. The insights provided by this analytical approach can help to inform the design of epidemic models and tailored interventions, with the ultimate goal of improving HIV care engagement and transmission prevention.