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HIV UPDATE 2013

HIV UPDATE 2013. Ronald G Nahass , MD, FACP, FIDSA President ID CARE Medical Director AETC Clinical Professor RWJ Medical School. DISCLOSURES.

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HIV UPDATE 2013

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  1. HIV UPDATE 2013 Ronald G Nahass, MD, FACP, FIDSA President ID CARE Medical Director AETC Clinical Professor RWJ Medical School

  2. DISCLOSURES • I wish to acknowledge Clinical Care Options and the CDC two organizations that provide great slides for discussion. I have incorporated many of the slides from both organizations with some additions and deletions to focus our discussion

  3. Highlights of Atlanta 2013: ART as Treatment and PreventionCCO Independent Conference Coverageof the 2013 Conference on Retroviruses and Opportunistic Infections* March 3-6, 2013Atlanta, Georgia *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from

  4. Faculty Joel E. Gallant, MD, MPHProfessor of Medicine and EpidemiologyAssociate Director, Johns Hopkins AIDS ServiceDivision of Infectious DiseasesJohns Hopkins University School of MedicineBaltimore, Maryland Kathleen E. Squires, MD Professor of Medicine Director, Division of Infectious DiseasesJefferson Medical CollegeThomas Jefferson UniversityPhiladelphia, Pennsylvania Andrew R. Zolopa, MD Associate Professor of MedicineDirector, Stanford Positive Care ProgramPrincipal Investigator, Stanford AIDS Clinical Trials UnitStanford University School of MedicineStanford, California

  5. DHHS Guideline Update

  6. 2013 Update: DHHS Guidelines on ART for HIV-Infected Adults and Adolescents • ART is recommended for all HIV-infected, ART-naive pts to reduce risk of disease progression and transmission • Strength of recommendation varies by CD4+ cell count and risk group (perinatal, heterosexual, other) • Pts should be ready to commit to ART and understand benefits and risks of therapy and importance of adherence; individual pts may elect to defer ART • Regarding alternative regimens for ART-naive patients • RPV-based regimens recommended alternatives only for patients with baseline HIV-1 RNA ≤ 100,000 copies/mL • Fixed-dose EVG/COBI/TDF/FTC recommended for patients with CrCl > 70 mL/min • 3-NRTI regimens no longer recommended DHHS Guidelines. February 2013.

  7. 2013 Update: DHHS Guidelines on ART for HIV-Infected Adults and Adolescents • Pts failing INSTI-based regimens should undergo genotypic assay for INSTI resistance to determine future utility of class • Genotypic tropism assay now available as potential alternative test prior to initiating CCR5 antagonist regimens • Patients with early infection should be offered ART • “Early” HIV infection now refers to acute (after infection, prior to seroconversion) and recent (< 6 mos) infections • EFV may be continued in pregnant women with virologic suppression • New data on roles/mechanisms of RTV and COBI as pharmacokinetic enhancers DHHS Guidelines. February 2013.

  8. THE SEARCH FOR A CURE FOR HIV

  9. The Berlin Patient • Patient with HIV on long term therapy develops AML • Bone Marrow transplant performed with double Δ 32 • STI without rebound viral load for over 4 years now

  10. Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation Chemotherapy (x4) Total-body irradiation (x2) • off ART • no viral rebound CCR5– scBMT (X2) CCR5+ CCR5– • Donor • HIV-1+ • AML • HIV-1– ? Hütter. NEJM. 2009; Allers. Blood. 2010

  11. The Berlin Patient – What did we learn • Replication competent reservoirs can be eliminated • Long term viral control can be maintained despite waning immunity • Persistent low level viral DNA/RNA does not portend impending viral relapse

  12. Very Early Triple-Drug ART Elicits “Functional Cure” in HIV-Infected Child • Infant born to untreated HIV-infected mother at 35 wks’ gestation via spontaneous vaginal delivery[1] • Maternal HIV infection identified during labor • Infant HIV infection confirmed by HIV-1 RNA analysis of 2 separate samples at 30 and 31 hrs of age[2] – 19,812 c/ml • ZDV/3TC + NVP (at therapeutic dose) initiated at 31 hrs of age, continued for 7 days • ZDV/3TC + LPV/RTV continued from 7 days to 18 mos of age • HIV-1 RNA undetectable by Day 30 and remained so at Day 80 • Mother removed patient from care at 18 months of age 1. Persaud D, et al. CROI 2013. Abstract 48LB. 2. DHHS Pediatric Guidelines. 2012.

  13. “Functional Cure” Child: Standard HIV-1 Assays Undetectable to Age 26 Mos • Assessments at Months 24 and 26 • Western blot negative • No HIV-specific CD8+ or CD4+ T-cell responses • Standard HIV-1 RNA and HIV-1 DNA undetectable • By ultrasensitive assays • Mo 24: HIV-1 RNA 1 c/mL; HIV-1 DNA < 2.7 c/million PBMCs • Mo 26: HIV-1 DNA 4 c/million PBMCs • Clinical trials of exposed infants treated with ART recommended Persaud D, et al. CROI 2013. Abstract 48LB.

  14. Fiebig Stages Fiebig I: RNA+, p24̶ neg, 3rd-gen ELISA neg Would not be detected by 4th-gen ELISA Fiebig II: RNA+, p24+, 3rd-gen ELISA neg Fiebig III: 3rd-gen ELISA+, WB neg Early Treatment of Pts With Acute HIV Infection Restricts Seeding of Reservoirs • RV254/SEARCH 010: ongoing, prospective, open-label study of subjects seeking voluntary HIV testing (n = 75 with Fiebig stage I-III acute infection) • Before ART, HIV reservoir seeding limited • Integrated HIV-1 DNA undetectable in PBMCs (92%) and sigmoid colon (88%) of most Fiebig I pts • Lower infection frequencies of central memory CD4+ T cells vs other memory cells • After ART, decline in HIV reservoir size • Integrated HIV-1 DNA undetectable in PBMCs in 90% of pts at 1 yr • Reservoir primarily in transitionaland effector memory CD4+ T cells • Suggests very early ART may prevent seeding of reservoirs Ananworanich J, et al. CROI 2013. Abstract 47.

  15. Early Treatment with Treatment Interuption“The Visconti Cohort”

  16. Figure 1. Long-term control of viremia and stable CD4+ T cell counts in fourteen patients after interruption of antiretroviral treatment initiated in primary HIV-1 infection. • Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211 • http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211

  17. Figure 2. Patients to become post-treatment controllers have higher viral loads and lower CD4+ T cell counts than HIV controllers during primary HIV infection. • Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211 • http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211

  18. The Hope • 1995: David Ho and others suggest HIV eradication with early use of drug combinations, much like approach used to cure diseases like TB and leukemia • One and a half to three years of treatment necessary to kill off two HIV compartments: • Free HIV and actively infected CD4s • chronically infected cells (macrophages and dendritic cells)

  19. The Reality • 1997: Three teams discover third compartment • Resting, latently infected CD4 memory T-cells potentially lasting a lifetime 

  20. Residual viral replication <50 c/mL • Differential drug penetration in tissues • Greater HIV burden in tissues • No genetic evolution • (absence of DRM) • Cell-to-cell transmission • Stable RNA or DNA following cART intens • ART • intensification • Biological markers • Sensitivity • Interpretation RNA or DNA • www.neurosolutionsnow.net Hermankova, JAMA 2001; Persaud, J Virol 2004; Sedgahat, PLoSPathog 2007; Chun, J InfectDis 2008; Buzon. Nat Med 2010; Brennan, J Virol 2009; Dinoso, PNAS 2009; Yulk, J InfectDis 2010;Yulk, AIDS 2010; Sigal, Nature 2011; Llibre, AntivTher 2012; Fletcher. CROI’12; Joseffson. CROI’12

  21. How latency is established and maintained in T-cells • cART • Activated CD4+ T cell • Negative • regulators Resting CD4+ T cell • Survival • (long-half life) • Homeostatic proliferation • Eckstein, Immunity 2001; Swiggard, J Virol 2005; Saleh, Blood 2007; Marini, J Immunol 2008; Bosque, Blood 2009; Cameron, PNAS 2010; Lassen, PLoS One 2012

  22. HIV CURE – Two Models

  23. Strategies to Cure HIV Treatment optimization • & intensification Gene therapy (eliminate all replication) • Therapeutic • vaccination Reversal of HIV latency • (to enhance host-control) • (increase viral production) Immune-based therapies (reverse pro-latency signaling)

  24. Cytokines IL-71,2 IL-153 IFNa 2b Histonedeacetylase (HDAC) inhibitors4,5 Anti-alcohol agent Disulfiram6 Methylation inhibitors 5-aza-dC7 Immune modulation Anti PD1 NF-kB activators Prostratin, PMA, TNF4 Akt/HEXIM-1 modulators HMBA8 HistoneMethyltransferase inhibitors (HMTI)9 Chaetocin, BIX-01294 Other Quinolines10 Combination enhances potency4,9,11 Activating latent HIV: in vitro •  •  •  •  1Wang, J Clin Invest 2005; 2Saleh, Retrovirol 2011; 3Chomont, 6th IAS Rome 2011; 4Contreras, J BiolChem 2009; 5Wightman, Immunol Cell Biol 2012; 6Xing, J Virol 2011; 7Friedman, J Virol 2011; 8Contreras PLoSPathog 2007; 9Bouchat, AIDS 2012; 10Xing, J AntimicrobChemother 2012; 11Reuse, PLoS One 2009

  25. Purging the Reservoir D. D. Richman et al., Science 323, 1304 -1307 (2009)

  26. Interferon-alpha intensification in individuals on ART • week • –4 • 0 • 4 • 48 • IFNalpha approved to treat hepatitis C infection • Reduces the level of HIV in non-treated individuals • IFNa-2b Pre-IFN Post-IFN • n=4; NIAID/CCMD Clinic, Univof Pittsburgh • cART>1 year; HIV RNA<50 & >0.6; CD4>300 cells/µl • No effect on plasma viremia or total cell-associated HIV DNA • Reversible increase in immune activation (CD8+CD38+) cells NCT01295515

  27. HDACi turn HIV genes “on” • HDACi • TF • OFF nucleosomes • DNA Bolden, Nat Rev Drug Disc 2006; Prince. ClinCanc Res 2009; Contreras, J BiolChem 2009; Archin AIDS Res Hum Retrovir 2009; Reuse, PLoS One 2009; Burnett , J Virol 2010

  28. Vorinostat Activates HIV in Latently Infected CD4+ T Cells • Vorinostat investigated as possible strategy to eliminate latent HIV infection in pts on stable ART • Histone deacetylase inhibitor approved for cutaneous T-cell lymphoma • Single dose ↑ HIV-1 RNA expression in resting memory CD4+ cells of HIV-infected patients • Activation may result in elimination of latently infected T cells • Current study is a single-arm trial of vorinostat 400 mg QD for 14 days (N = 20) in pts on stable ART, CD4+ count > 500 cells/mm3 • 18/20 pts had significant increase in cell-associated unspliced HIV-1 RNA on ≥ 2 occasions while on drug • Mean 2.65-fold increase • All AEs mild (grade 1/2) • Most common: diarrhea, lethargy, thrombocytopenia, dysgeusia • No significant changes in HIV-1 DNA in PBMCs or rectal tissue • Suggests vorinostat alone not likely to eliminate latent infected cells Elliott EJ, et al. CROI 2013. Abstract 50LB.

  29. Disulfiram • FDA approved drug to treat alcoholism • Reactivates HIV gene expression in an in vitro model of latency • 0 • 3 • 7 • 14 • 84 • 10 • Day • cART • Disulfiram 500 mg/day • n=14; JHH & UCSF • cART>18 months; HIV RNA<40 c/ml; CD4>200 cells/µl • IUPM • IUPM • Transient increase of low-level viremia after the 1st dose • No decrease of the latent reservoir (IUPM) • Xing. JVirol 2011; NCT01286259; Spivak, 19th CROI, Seattle 2012, #369

  30. Therapeutic Vaccines • Training the immune system to better respond to HIV in the absence of ARV treatment • An effective preventive vaccine could potentially work as a therapeutic vaccine, and vice versa • Activate transcription of proviral DNA in the presence of ARV treatment

  31. Therapuetic Vaccines Older Approaches Newer Approaches Prime-boost (GeoVax) HIV DNA primer MVA (smallpox) booster Vacc-4x (Bionor Immuno) • Whole inactive virus • Remune • Virus-derived gp160 • Cell-derived gp160 • Canarypox-based • ALVAC 1452

  32. PrEP

  33. PrEP, PEP – What’s the Latest • PEP • Needlestick exposure regimen – new CDC guidelines • Tenofovir/Emtricidabine/Raltegravir • Testing post exposure ends at 12 weeks • PrEP • Non infected high risk individuals • Tenofovir daily is highly effective • Studies were in individuals exposed to persons with high viral loads whether there is incremental benefit for exposure to index patients with low viral load is unaswered

  34. PrEP Trials to Date *Underpowered to detect differences between sexes 1. Abdool Karim Q, et al. Science. 2010;329:1168-1174. 2. Grant RM, et al. N Engl J Med. 2010;363: 2587-2599. 3. Baeten JM, et al. N Engl J Med. 2012;367:399-410. 4. Thigpen MC, et al. N Engl J Med. 2012;367:423-434. 5. Van Damme L, et al. N Engl J Med. 2012;367:411-422.

  35. VOICE: Oral TDF, Oral TDF/FTC, Vaginal TFV Gel as PrEP in African Women • Phase IIB placebo-controlled trial of > 5000 women in South Africa, Uganda, and Zimbabwe of daily oral TDF, daily oral TDF/FTC, daily vaginal TFV 1% gel as PrEP • DSMB stopped daily oral TDF arm in September 2011 and daily vaginal gel arm in November 2011, both for lack of efficacy; daily oral TDF/FTC arm continued • 334 infections seen across 5 arms; 22 infected at enrollment *Censored when sites took women off TDF and TDF placebo. Total n = 1009. Marrazzo J, et al. CROI 2013. Abstract 26LB.

  36. VOICE: Lack of Detectable TFV in Plasma; High Rate of Infection in Younger Women • Despite high self-reported adherence, < 40% of women had detectable plasma TFV at first study visit • TFV detected in mean of ≤ 30% of samples in each arm • ≥ 50% of women in each arm had no TFV detected in any sample • TFV detection less likely if unmarried, younger than 25 yrs, partner younger than 28 yrs • Highest rates of HIV acquisition in unmarried, younger than 25 yrs Plasma TFV Detection in Random Cohort Sample 100 TDF/FTCTDFTFV 1% gel 80 60 Pts With Detectable TFV* (%) 40 20 0 1 2 3 4 5 6 Quarterly Visits Pts at Risk, n TDF/FTCTDF TFV 1% 135147166 123119156 11180107 1175682 952852 611630 *Level of TFV detection:≥ 0.3 ng/mL. Marrazzo J, et al. CROI 2013. Abstract 26LB. Graphic used with permission.

  37. Additional Data on PrEP • GSK1265744, dolutegravir analogue packaged in nanoparticles (GSK744LAP), permitting monthly or quarterly dosing in humans by IM injection • 8/8 macaques injected with GSK744LAP and rectally challenged with SHIV protected from infection; 8/8 controls became infected (P < .0001)[1] • Intravaginal rings containing TDF protected against SHIV infection in 6/6 macaques; 11/12 controls became infected (P < .0004)[2] • Among iPrEX participants stopping PrEP before entry into open-label extension (iPrEX OLE), incidence of HIV similar among participants originally on TDF/FTC PrEP and those originally on placebo (P = .43)[3] • Similarities indicate that although high-risk behaviors continued, there was lack of compensatory increase in high-risk behavior after PrEP discontinued • HIV incidence after stopping PrEP remained high 1. Andrews C, et al. CROI 2013. Abstract 24LB. 2. Smith J, et al. CROI 2013. Abstract 25LB. 3. Grant R, et al. CROI 2013. Abstract 27.

  38. Testing Update Newest – 4th Generation HIV tests offer single stage testing with high accuracy and early confirmation in acute infection

  39. Four FDA-approved Rapid HIV Tests

  40. Four FDA-approved Rapid HIV Tests

  41. Go Online for More CCO Coverage of CROI 2013! Capsule Summariesof key studies Additional downloadable slideset on Coinfection and Comorbidities Coming soon! CME-certified slidesets with expert faculty commentary on all key studies clinicaloptions.com/atlanta2013

  42. QUESTIONS? THANK YOU !

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