Highlights of IAS 2013.CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention
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Highlights of IAS 2013.CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention
- 1. June 30 - July 3, 2013 Kuala Lumpur, Malaysia Highlights of IAS 2013 CCO Official Conference Coverage of the 7th IAS Conference on HIV Pathogenesis, Treatment, and Prevention This program is supported by educational grants from Jointly sponsored by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC
- 2. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent. These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com). Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
- 3. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Faculty Andrew Carr, MBBS, MD, FRACP Professor of Medicine University of New South Wales Director, HIV, Immunology, and Infectious Diseases Unit St Vincent’s Hospital Sydney, Australia Joel E. Gallant, MD, MPH Associate Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland Anton L. Pozniak, MD, FRCP Consultant Physician Director of HIV Services Department of HIV and Genitourinary Medicine Chelsea and Westminster Hospital NHS Trust London, United Kingdom
- 4. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Disclosures Andrew Carr, MBBS, MD, FRACP, has disclosed that he has received funds for research support from Gilead Sciences and Merck Sharp & Dohme and has served as a consultant and on advisory boards for and received lecture and travel sponsorships from Gilead Sciences, Merck Sharp & Dohme, and ViiV. Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol Myers Squibb, Gilead Sciences, Janssen, and Merck‐ and funds for research support from Gilead Sciences. Anton L. Pozniak, MD, FRCP, has disclosed that he has received funds for research support and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, and ViiV and has participated in company-sponsored speaker bureaus for Gilead Sciences.
- 5. Please review the slide notes for analysis of each study by expert faculty Andrew Carr, MBBS, MD, FRACP; Joel E. Gallant, MD, MPH; and Anton L. Pozniak, MD, FRCP
- 6. Antiretroviral Therapy in Resource-Constrained Settings
- 7. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 WHO 2013: Updated Treatment Guidelines for Adults, Adolescents, and Children Expanded ART eligibility – Treatment initiation threshold: CD4+ ≤ 500 cells/mm3 – Prioritize severe or advanced HIV or CD4+ ≤ 350 cells/mm3 HIV-1 RNA testing preferred for monitoring ART Preferred initial regimen: fixed-dose TDF + 3TC (or FTC) + EFV – Discontinue use of d4T due to toxicity WHO Consolidated Treatment Guidelines. June 2013.
- 8. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Randomized, double-blind, placebo-controlled, noninferiority phase III trial – Part of ongoing effort to identify ARVs effective at lower doses (and cost) No significant difference in SAEs between treatment arms More pts with study drug–related AEs for EFV 600 mg vs EFV 400 mg (47.2% vs 36.8%; P = .008) More pts discontinued EFV 600 mg due to AE vs EFV 400 mg (1.9% vs 5.8%; P = .010) ENCORE1: 400-mg EFV Noninferior to 600-mg EFV With TDF/FTC for Initial ART Puls R, et al. IAS 2013. Abstract WELBB01. EFV* 400 mg + Placebo + TDF/FTC 300/200 mg (n = 324) EFV* 600 mg + TDF/FTC 300/200 mg (n = 312) ART-naive pts, CD4+ 50-500 cells/mm3 , HIV-1 RNA > 1000 c/mL (N = 636) Wk 48 Stratified by clinical site and HIV-1 RNA at screening (< 100,000 or ≥ 100,000 c/mL) *EFV administered as 200-mg tablets. HIV-1 RNA < 200 c/mL at Wk 48, % NC = F 90.0 85.8
- 9. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 EARNEST: Second-line LPV/RTV-Based ART After Initial NNRTI Failure Randomized, controlled, open-label, phase III trial Baseline demographics (medians): HIV-1 RNA 69,782 copies/mL; CD4+ 71 cells/mm3 ; time on ART 4 yrs Paton N, et al. IAS 2013. Abstract WELBB02. *Including clinical, CD4+ cell count (HIV-1 RNA confirmed), or virologic criteria. † Selected by physician according to local standard of care. HIV-infected adults and adolescents received first-line NNRTI-based ART > 12 mos, > 90% adherence in previous mo, treatment failure by WHO (2010) criteria* (N = 1277) LPV/RTV + 2-3 NRTIs† (n = 426) LPV/RTV + RAL (n = 433) LPV/RTV + RAL (n = 418) Wk 144Wk 12 LPV/RTV monotherapy (n = 418)
- 10. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 EARNEST: Clinical Outcomes at Wk 96 “Good disease control” at Wk 96 defined as pt alive, no new WHO 4 events from Wks 0-96, and CD4+ cell count > 250 cells/mm3 , and HIV-1 RNA < 10,000 copies/mL or > 10,000 copies/mL without PI resistance mutations Paton N, et al. IAS 2013. Abstract WELBB02. 100 80 60 40 20 0 Good Disease Control HIV-1 RNA < 400 copies/mL HIV-1 RNA < 50 copies/mL PI/NRTI PI/RAL PI Mono60 64 56 86 86 61 74 73 44 Patients,%
- 11. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 EARNEST: Other Outcomes LPV/RTV monotherapy arm discontinued due to inferior virologic suppression, higher frequency of LPV resistance No significant difference in 96-wk resistance rates between LPV/RTV + NRTIs and LPV/RTV + RAL Similar rates of grade 3/4 AEs across treatment arms (range: 22% to 24%) Paton N, et al. IAS 2013. Abstract WELBB02.
- 13. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Meta-analysis of Efficacy of Initial ART Regimens in Prospective Trials Meta-analysis of 216 treatment arms from prospective trials of initial ART, 1994-2010 (N = 40,124 pts) Mean rate of undetectable HIV-1 RNA: 60% overall – 66% at Wk 48, 60% at Wk 96, 52% at Wk 144 – 25% discontinued before end of study Better mean efficacy with more recent yr of initiation – 43% in 1994 vs 78% in 2010 Lee FJ, et al. IAS 2013. Abstract WEAB0104.
- 14. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Efficacy of Initial ART Associated With NRTI Backbone, Third Drug, Other Factors Mean efficacy 70% vs 62% with baseline HIV-1 DNA < vs ≥ 100,000 copies/mL Mean efficacy 75% vs 65% with DHHS “preferred” vs “alternative” ART Number of pills or doses per day did not predict overall efficacy Specific NRTI backbones, third drugs associated with efficacy Lee FJ, et al. IAS 2013. Abstract WEAB0104. Efficacy, % (SD) Coefficient (95% CI) P Value NRTI backbone TDF/FTC 73 (10) Ref ABC/3TC 63 (7) -7.6 (-12.7 to -2.6) .003 Third drug class NNRTI 61 (15) Ref INSTI 84 (5) 11.9 (4.6 to 19.2) .002 Boosted PI 67 (9) -0.9 (-4.7 to 3.0) .660 Adjusted for multivariable analysis including year of commencement, other drugs received, baseline patient characteristics, and duration of follow-up.
- 15. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Efficacy of EVG/COBI/TDF/FTC vs EFV/TDF/FTC When Adherence < 95% Preplanned adherence analysis at Wk 96 of Study GS-US-236-0102 ≥ 90% adherence in 93% with EVG/COBI/TDF/FTC, 89% with EFV/TDF/FTC Among pts with < 95% adherence, significantly greater improvement in CD4+ cell counts with EVG/COBI/TDF/FTC vs EFV/TDF/FTC (317 vs 245; P = .039) ART-naive pts, HIV-1 RNA ≥ 5000 copies/mL, no CD4+ restrictions, eGFR ≥ 70 mL/min (N = 700) EVG/COBI/TDF/FTC QD + EFV/TDF/FTC placebo (n = 348) EFV/TDF/FTC QHS + EVG/COBI/TDF/FTC placebo (n = 352) Wk 96 Stratified by HIV-1 RNA ≤ 100,000 or > 100,000 copies/mL Shalit P, et al. IAS 2013. Abstract TUPE293. ≥ 95% Adherence < 95% Adherence 88 74 89 63 HIV-1 DNA < 50 copies/mL at Wk 96
- 16. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Bangkok Study: Directly Observed PrEP With TDF Reduces HIV Acquisition in IDUs Phase III, randomized, double-blind, placebo-controlled trial – HIV-uninfected IDUs (N = 2413) received TDF or placebo – DOT at drug treatment clinics between 2005 and 2010 Significantly fewer new infections with TDF vs placebo (0.35/100 PY vs 0.68/100 PY; P = .01) – Overall efficacy: 49% – Detectable TDF at study end: 74% Higher adherence associated with greater efficacy Safety and tolerability similar to other TDF-containing PrEP trials Choopanya K, et al. IAS 2013. Abstract WELBC05.
- 17. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Bangkok TDF Study: Adherence to PrEP and Risk of HIV Acquisition Choopanya K, et al. IAS 2013. Abstract WELBC05. Graphic used with permission. 100 80 60 40 20 0 Efficacy(%) mITT > 67 > 75 > 90 > 95 > 97.5 Adherence (%) 49 54 58 68 72 84
- 18. New or Investigational Antiretroviral Agents
- 19. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 SAILING: Dolutegravir vs Raltegravir in ART-Exp’d, Integrase Inhibitor–Naive Pts Phase III randomized, double-blind, double-dummy, noninferiority study Treatment-experienced, integrase inhibitor–naive patients with HIV-1 RNA > 400 copies/mL and ≥ 2 class resistance (N = 715) Dolutegravir 50 mg QD + Raltegravir placebo + OBR (n = 354) Raltegravir 400 mg BID + Dolutegravir placebo + OBR (n = 361) Stratified by number of fully active background agents, use of DRV, screening HIV-1 RNA ≤ vs > 50,000 copies/mL Wk 48 Cahn P, et al. IAS 2013. Abstract WELBB03. Cahn P, et al. Lancet. 2013;382:700-708.
- 20. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 SAILING: Superior Rate of Virologic Suppression With DTG vs RAL at Wk 48 Lower incidence of resistance at VF with DTG vs RAL – Integrase resistance: 1% vs 5% – OBR resistance: 1% vs 3% Both regimens well tolerated with similar AE profiles – Grade 2-4: 8% vs 9% – Discontinuations: 3% vs 4% No difference in outcome between study arms when combined with fully active DRV/RTV Cahn P, et al. IAS 2013. Abstract WELBB03. Graphic used with permission. 100 80 60 40 20 0 Subjects(%) Virologic Success Virologic Nonresponse No Wk 48 Data DTG + OBR RAL + OBR 71 64 20 28 9 9 Δ 7.4 (95% CI: 0.7-14.2; P = .03)
- 21. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Long-Acting GSK1265744 and TMC278 Nanosuspensions: drug nanocrystals suspended in liquid – Increased drug dissolution rate – Nanocrystal design allows for low injection volume Potential use as long-acting injections for ART regimens, PrEP – GSK1265744 (DTG analogue) dosed monthly or quarterly – TMC278 nanosuspension of RPV dosed monthly Spreen W, et al. IAS 2013. Abstract WEAB0103.
- 22. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Randomized, open-label, repeated-dose phase I trial in healthy adults GSK744 200 mg IM GSK744 200 mg IM GSK744 400 mg IM GSK744 400 mg IM Monthly Oral Lead-in* Day 1 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24 Cohort 1 (n = 10) Cohort 2 (n = 10) Cohort 3 (n = 10) Quarterly Cohort 4 (n = 10) TMC278 (LD† ) 1200 mg IM TMC278 900 mg IM TMC278 (LD† ) 1200 mg IM TMC278 600 mg IM All cohorts followed for 52 wks after last injection (ongoing) Coadministration of Long-Acting GSK1265744 and TMC278 Spreen W, et al. IAS 2013. Abstract WEAB0103. *GSK744 30 mg/day for 14 days, then 7-day washout. † Loading dose given as split injection dose (2 x 2 mL). GSK744 800 mg IM (LD† ) GSK744 800 mg IM (LD† ) GSK744 800 mg IM (LD† ) GSK744 200 mg SC GSK744 200 mg SC GSK744 200 mg SC GSK744 200 mg IM GSK744 400 mg IM GSK744 800 mg IM (LD† ) GSK744 800 mg IM (LD† )
- 23. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 Favorable Drug Concentrations With GSK1265744 and TMC278 Injections PK results – GSK1265744 injected every 4 wks or every 12 wks achieved plasma levels > protein-adjusted IC90 – TMC278 dosed every 4 wks achieved plasma levels comparable to those achieved by oral RPV 25 mg/day in HIV-infected patients GSK1265744 safe, well tolerated alone and in combination with TMC278 Findings support phase II study of GSK1265744 + TMC278 as 2-drug ART regimen Spreen W, et al. IAS 2013. Abstract WEAB0103.
- 25. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 SECOND-LINE Subanalysis: BMD Loss With LPV/RTV + NRTIs vs LPV/RTV + RAL Subanalysis of randomized, open-label, multicenter, international trial Hoy J, et al. IAS 2013. Abstract WELBB05. LPV/RTV 400/100 mg BID + RAL 400 mg BID (n = 108) LPV/RTV 400/100 mg BID + 2-3 NRTIs QD or BID (n = 102) HIV-infected patients with virologic failure on first-line regimen of NNRTI + 2 NRTIs (N = 211 consented to BMD substudy) DXA scan at Wk 48 DXA scan at Wk 0
- 26. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 SECOND-LINE: Greater Mean BMD Loss With NRTI-Based Regimen at Wk 48 No significant difference in frequency of new osteopenia, osteoporosis Greater decline in lumbar spine BMD associated with lower BMI, no TDF before study, and TDF initiation on study Hoy J, et al. IAS 2013. Abstract WELBB05. Graphic used with permission. 0 -1 -3 -4 -6 Mean%Change(SE)inBMD FromBaselinetoWk48 -2 -5 Proximal Femur Lumbar Spine -5.2 -2.9 -4.2 -2 P = .0001 P = .0006 LPV/RTV + 2-3 NRTIs LPV/RTV + RAL
- 27. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 HIV Independently Associated With Increased Risk of Hip Fractures Population-based cohort study SIDIAPQ database, 2007-2009; Catalonia, Spain (N = 1,118,587 pts aged ≥ 40 yrs) – HIV-infected: 2489 (0.22%) – Identified incident major osteoporotic and hip fractures HIV infection associated with – 4.72-fold ↑ HR for hip fracture – 1.75-fold ↑ HR for all fractures – Independent of age, sex, BMI, smoking, alcohol use Knobel H, et al. IAS 2013. Abstract WEAB0205. Güerri-Fernandez R, et al. J Bone Miner Res. 2013;28:1259-1263. 5.0 4.5 3.5 2.5 1.5Age-SpecificHipFractureIncidences per1000Person-Yrs 4.0 2.0 1.0 0.5 0 3.0 Age (yrs) 40-45 45-50 50-55 55-60 60-65 65-70 70-75 75-80 HIV Infected HIV Uninfected
- 28. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 NVP Cutaneous Reactions Reduced by HLA-B*35:05 and CCHCR1 Screening CCHCR1 and HLA-B*35:05 associated with rash[1,2] – HLA-B*35:05 uncommon except Southeast Asian and South Americans Prospective, randomized, multicenter, controlled trial[3] – N = 1103 assigned to screening vs no screening – All started NVP-based therapy EXCEPT pts screened positive started EFV-based therapy Group Relative Risk P Value Overall, screened vs unscreened 0.68 .020 Sex Male Female 0.84 0.55 .491 .016 CD4+ count, cells/mm3 < 250 > 250 0.64 0.88 .027 .740 1. Chantarangsu S, et al. Pharmacogenet Genomics. 2009;19:139-146. 2. Chantarangsu S, et al. Clin Infect Dis. 2011;53:341-348. 3. Kiertiburanakul S, et al. IAS 2013. Abstract WELBB04. Table used with permission. Lower incidence of cutaneous AEs in screened group – 13.2% vs 18.0%
- 29. clinicaloptions.com/hiv HIV/AIDS Update From IAS 2013 High HCV Reinfection Rate Among HIV-Infected MSM Single-site, retrospective study (2004-2012) of HIV- infected MSM at London clinic – Cleared prior HCV infection spontaneously or after HCV treatment Reinfection rates similar in pts with prior spontaneous clearance vs SVR Martin T, et al. IAS 2013. Abstract TUAB0101. P = .15 HCVReinfectionIncidenceper100Person-Yrs 7.8 9.6 4.2 23.2 0 5 10 15 20 25 30 35 40 45 50 Overall Reinfection Rate Reinfection Posttreatment Reinfection After Spontaneous Clearance Second Reinfection Rate Following SVR or Clearance of First Reinfection
- 30. Go Online for More CCO Coverage of IAS 2013 Capsule Summaries of key studies selected by the faculty Expert Highlights audio podcasts by expert faculty clinicaloptions.com/ias2013
Editor's Notes
- This slide lists the faculty who were involved in the production of these slides.
- Please review the slide notes for a complete discussion of each study by expert faculty Andrew Carr, MBBS, MD, FRACP; Joel E. Gallant, MD, MPH; and Anton L. Pozniak, MD, FRCP.
- 3TC, lamivudine; ART, antiretroviral therapy; d4T, stavudine; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir; WHO, World Health Organization. Anton Pozniak, MD, FRCP: This slide presents a summary of significant updates found in the 2013 World Health Organization (WHO) treatment guidelines. An important change is that treatment initiation is now recommended for patients with CD4+ cell counts ≤ 500 cell/mm3, an increase from the previous threshold of 350 cells/mm3. This change represents a reprioritization that has significant implications for antiretroviral therapy (ART) utilization in resource-limited settings. The new guidelines further emphasize that HIV-1 RNA testing is the preferred method for monitoring patients receiving ART, and the single-tablet regimen of efavirenz/tenofovir DF/emtricitabine or lamivudine is the preferred initial regimen. Finally, WHO has strengthened its position on the nonuse of stavudine and now recommends that it be completely phased out from clinical use due to associated toxicities. This represents a change from previous recommendations that stavudine should be avoided if at all possible but allowed for its continued use in patients already on a stavudine-based regimen. Now, the enhanced recommendation is to discontinue the use of stavudine altogether and switch to a fixed-dose combination if at all possible. Reference World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. June 2013. Available at: http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf. Accessed September 10, 2013.
- AE, adverse events; ART, antiretroviral therapy; ARVs, antiretrovirals; EFV, efavirenz; FTC, emtricitabine; ITT, intent to treat; NC = F, noncompleters equals failure analysis; PP, per-protocol analysis; SAE, serious adverse event; TDF, tenofovir. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB01.aspx Joel E. Gallant, MD, MPH: ENCORE1 was a randomized, placebo-controlled, noninferiority phase III trial comparing a lower dose of efavirenz (400 mg) vs the standard efavirenz dose (600 mg), each combined with tenofovir/emtricitabine. The study found that the lower dose of efavirenz was noninferior to the higher dose at Week 48. Andrew Carr, MBBS, MD, FRACP: Equally importantly, although there was no difference in overall rates of toxicity, there were significantly fewer study drug-related adverse events with the 400-mg dose as well as fewer discontinuations. Anton L. Pozniak, MD, FRCP: ENCORE1 may be a game-changing study for the developing world, and perhaps even for the developed world, if the low-dose efavirenz is adopted because of the cost difference between the 2 efavirenz doses. This would be especially true if a generic version of the 400-mg tablet were to become available. Large national health services such as the United Kingdom’s would certainly use the lower dose if it came with a lower cost, especially if patients receiving the lower dose also experience fewer adverse events. The reduction in cost to individual patients may or may not be significant, but when the reduced price is spread across a national program, the savings could have an enormous impact.
- ART, antiretroviral therapy; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir; WHO, World Health Organization. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx Joel E. Gallant, MD, MPH: The EARNEST trial was a large randomized open-label trial that compared strategies for second-line therapy after failure of an initial NNRTI-based regimen in resource-limited settings. The study included 3 arms comparing the standard of care consisting of lopinavir/ritonavir plus NRTIs vs lopinavir/ritonavir plus raltegravir vs lopinavir/ritonavir monotherapy after an initial 12-week period with lopinavir/ritonavir and raltegravir. At baseline, the study populations were well matched for CD4+ cell count, HIV-1 RNA level, and the amount of time on ART.
- RAL, raltegravir; WHO, World Health Organization. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx Joel E. Gallant, MD, MPH: As shown in the graph, there was no significant difference between the PI plus NRTIs arm and the PI plus raltegravir arm at Week 96. However, the lopinavir/ritonavir monotherapy arm was associated with significantly poorer virologic outcomes.
- AE, adverse event; LPV, lopinavir; RAL, raltegravir; RTV, ritonavir. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB02.aspx Joel E. Gallant, MD, MPH: The lopinavir/ritonavir monotherapy arm was discontinued due to inferior virologic suppression. Although there was no significant difference in the 96-week resistance rates of the other treatment arms, patients in the monotherapy arm experienced a higher frequency of lopinavir resistance, which is not consistent with data from other trials.[1-4] Regimens were generally well tolerated with similar rates of grade 3/4 adverse events. This study has important implications for resource-limited setting, where second-line regimens are chosen empirically, without resistance testing, after failure of first-line NNRTI-based regimens. The findings are consistent with those of the previously presented SECOND-LINE study,[5-6] supporting the current practice of combining a ritonavir-boosted PI with 2 NRTIs. The poorer outcome with boosted PI monotherapy is somewhat surprising, since participants in this trial had no previous PI experience and were fully suppressed before the switch to monotherapy. Anton Pozniak, MD, FRCP: I do not think we know if they were fully suppressed at Week 12; we do not know if those who had an HIV-1 RNA done at Week 12 and were &lt; 50 copies/mL remained undetectable. There may have been a group still detectable at Week 12 switched to PI monotherapy who then failed. This study challenges the need for HIV-1 RNA or resistance testing in first-line failures in resource-limited settings and supports the current WHO strategy for second-line therapy. References Bartlett JA, Ribaudo HJ, Wallis CL, et al. Lopinavir/ritonavir monotherapy after virologic failure of first-line antiretroviral therapy in resource-limited settings. AIDS. 2012;26:1345-1354. Arribas JR, Delgado R, Arranz A, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and 2 nucleosides for maintenance therapy of HIV: 96-week analysis. J Acquir Immune Defic Syndr. 2009;51:147-152. Cameron DW, da Silva BA, Arribas JR, et al. A 96-week comparison of lopinavir-ritonavir combination therapy followed by lopinavir-ritonavir monotherapy versus efavirenz combination therapy. J Infect Dis. 2008;198:234-240. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J Acquir Immune Defic Syndr. 2005;40:280-287. Hoy J, Martin A, Moore C, et al. Changes in bone mineral density over 48 weeks among participants randomised to either lopinavir/ritonavir (LPV/r) + 2-3N(t)RTI or LPV/r + raltegravir as second-line therapy: a sub-study of the SECONDLINE trial. Program and abstracts of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30 - July 3, 2013; Kuala Lumpur, Malaysia. Abstract WELBB05. Humphries A, Boyd M; SECOND-LINE Study Team. SECOND-LINE: ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 180LB.
- ART, antiretroviral therapy. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0104.aspx Andrew Carr, MBBS, MD, FRACP: This slide summarizes a systematic review and meta-analysis of trials of combination ARTs initiated from 1994-2010. The study population consisted of 216 treatment groups that included more than 40,000 patients. The study’s primary outcome measure was efficacy defined as an undetectable HIV-1 RNA, which in almost all cases was defined as HIV-1 RNA &lt; 50 copies/mL, without change to assigned therapy. Overall, the mean efficacy was 60% with a mean follow-up of 82 weeks. The longest treatment duration assessed was 144 weeks because very few studies had longer follow-up. Overall, the rate of treatment discontinuation was 25%, with the most common reasons reported as loss to follow-up and adverse events, which were much more common than virologic failure. Finally, a trend indicated a substantial increase in treatment efficacy over time.
- ABC/3TC, abacavir/lamivudine; ART, antiretroviral therapy; DHHS, US Department of Health and Human Services; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; Ref, reference; SD, standard deviation; TDF, tenofovir. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0104.aspx Andrew Carr, MBBS, MD, FRACP: This study was undertaken to assess the improvement in treatments for HIV and to determine the magnitude of those improvements. It should be noted that the data are only based on 18 months of treatment, on average. Preferred regimens performed better than alternative regimens, and initiation of treatment at HIV-1 RNA levels &lt; 100,000 copies/mL was associated with better outcomes. The number of pills did not independently predict efficacy; there was a strong association, but after adjusting for the type of drug, it was no longer a predictor of efficacy. This suggests that the most important factor is probably not the number of pills taken but improvements in the drugs themselves. In addition, specific NRTI backbones and third drugs were associated with differing outcomes, as summarized in the table. The data suggest that guidelines should consider recommending initiation of ART if the HIV-1 RNA is increasing toward 100,000 copies/mL. Joel E. Gallant, MD, MPH: In addition, these data support current US treatment guidelines and demonstrate the steady improvement in effectiveness of antiretroviral regimens over time.
- COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; QHS, at bedtime; TDF, tenofovir. Joel E. Gallant, MD, MPH: Data from the phase III trial comparing the single-tablet regimen of elvitegravir/cobicistat/tenofovir DF/emtricitabine vs the single-tablet regimen efavirenz/tenofovir DF/emtricitabine have previously been published. In this preplanned Week 96 analysis, the investigators evaluated outcomes in patients with suboptimal adherence, defined as &lt; 95%. The results suggested that with adherence of &lt; 95%, elvitegravir/cobicistat/tenofovir DF/emtricitabine was associated with better HIV-1 RNA suppression and greater CD4+ cell count improvement. However, this study is limited by the fact that &lt; 95% adherence encompasses everything from 0% (or complete nonadherence) to 94% (which is still a very high level of adherence). Hypothetically, it is possible that patterns of nonadherence with efavirenz/tenofovir DF/emtricitabine could be different from patterns of nonadherence with elvitegravir/cobicistat/tenofovir DF/emtricitabine, perhaps because of the adverse events associated with efavirenz. Andrew Carr, MBBS, MD, FRACP: The investigators did also report that very few patients in each arm were &lt; 80% adherent. Overall, one can estimate that the large majority of patients with &lt; 95% adherence still managed to achieve at least 90% adherence. Nevertheless, that relatively small degree of nonadherence was associated with a 15% to 25% reduction in virologic response rates. These data underscore that patients really do need to take their pill every single day to secure good outcomes. Reference Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2013;381:2083-2090.
- DOT, directly observed therapy; IDU, injecting drug users; PrEP, pre-exposure prophylaxis; PY, person-years; TDF, tenofovir. Anton Pozniak, MD, FRCP: The Bangkok study was a randomized, placebo-controlled trial of tenofovir as pre-exposure prophylaxis (PrEP) conducted among injection drug users in Thailand. Participants received tenofovir or placebo daily as directly observed therapy at drug treatment clinics during a 5-year study period from 2005-2010. The results reinforce the findings of other studies with PrEP; namely, it is effective when patients are adherent to the regimen. In this study, the overall efficacy was 50%, and tenofovir levels were detectable in 74% of patients at study end. The safety and tolerability were also similar to other PrEP trials with tenofovir. One curious aspect of the study data is that the reduction in the rate of HIV acquisition was not observed during the first 3 years of follow-up; the rates diverged only in Years 4 and 5. One hypothetical explanation is that during the first 3 years, the risk-reduction education provided to all participants was effective in achieving a low rate of infection in both study arms, but that its effectiveness waned over time, resulting in more infections in those not receiving PrEP. Andrew Carr, MBBS, MD, FRACP: Another contentious issue about this study was the lack of needle exchange. In the studies of PrEP to prevent sexual HIV transmission, participants were given condoms, but by contrast, in this study, participants did not receive safe injecting gear and clean needles. As a consequence, it is not clear whether these results are applicable to settings where harm-reduction measures, such as needle exchange programs, are available.
- mITT, modified intent to treat; PrEP, pre-exposure prophylaxis; TDF, tenofovir. Anton Pozniak, MD, FRCP: The investigators also showed that increasing level of adherence to PrEP with tenofovir was associated with increasingly likelihood of remaining uninfected. To receive the maximum benefit from PrEP with tenofovir, which was an 84.0% reduction in risk, a patient needed to take as much as 97.5% of their scheduled doses. By contrast, taking only two thirds of the scheduled doses reduced the efficacy of PrEP in preventing HIV transmission to only 54%.
- ART, antiretroviral therapy; BID, twice daily; DRV, darunavir; OBR, optimized background regimen; QD, once daily. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB03.aspx Andrew Carr, MBBS, MD, FRACP: SAILING was a 48-week, double-blind, noninferiority phase III trial comparing the second-generation integrase inhibitor dolutegravir vs raltegravir, each combined with an optimized background regimen (OBR), in treatment-experienced but integrase inhibitor–naive patients with virologic failure and resistance to at least 2 drug classes. Patients were stratified by number of background drugs, darunavir/ritonavir use, and baseline HIV-1 RNA. In this instance, the stratification threshold was 50,000 copies/mL rather than the 100,000 copies/mL generally seen in trials of treatment-naive patients. Interim Week-24 results were previously presented at the 2013 Conference on Retroviruses and Opportunistic Infections.[1] Reference 1. Pozniak A, Mingrone H, Shuldyakov A, et al. Dolutegravir (DTG) versus raltegravir (RAL) in ART-experienced, integrase-naive subjects: 24-week interim results from SAILING (ING111762). Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 179LB.
- AE, adverse event; DRV, darunavir; DTG, dolutegravir; OBR, optimized background regimen; RAL, raltegravir; RTV, ritonavir; VF, virologic failure. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB03.aspx Andrew Carr, MBBS, MD, FRACP: The primary endpoint analysis demonstrated that dolutegravir was noninferior to raltegravir, with a numerically superior rate of virological success at Week 24, which was maintained out to Week 48. The differences between the 2 arms were due to a higher rate of virologic nonresponse with raltegravir, rather than differences in tolerability or in missing data. Anton Pozniak, MD, FRCP: Of note, SAILING is the first study in which treatment-emergent integrase resistance mutations have been observed at virologic failure with dolutegravir. Two patients who were integrase inhibitor–naive at study entry developed the R263K. In a planned subanalysis, there was no difference in outcomes between the raltegravir or dolutegravir arms in patients who were fully susceptible to darunavir and received darunavir/ritonavir as part of their OBR. At the other end of the spectrum, there was also no difference between the arms among patients whose OBR did not contain any other fully active agent to combine with the integrase inhibitor. Joel E. Gallant, MD, MPH: The reason for the superiority of dolutegravir is not clear, but the results suggest that its barrier to resistance may be higher than that of raltegravir. Patients with full darunavir susceptibility would be expected to respond equally well to a combination of darunavir/ritonavir and any integrase inhibitor, whereas those with partial resistance to darunavir might benefit from combining it with an integrase inhibitor with a higher barrier to resistance.
- ART, antiretroviral therapy; DTG, dolutegravir; PrEP, pre-exposure prophylaxis; RPV, rilpivirine. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx Joel E. Gallant, MD, MPH: A study by Spreen and colleagues evaluated the use of nanosuspensions of long-acting GSK1265744 and TMC278. Nanosuspension formulations are drug nanocrystals suspended in liquid providing a higher dissolution rate and allowing for a lower injection volume. These formulations have potential uses as long-acting injections both for ART regimens and PrEP. GSK1265744 is a dolutegravir analogue that would allow monthly or even quarterly dosing. TMC278-LA is a nanosuspension of rilpivirine that is dosed monthly.
- IM, intramuscular; LD, loading dose; SC, subcutaneous. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx Joel E. Gallant, MD, MPH: In this study, the authors evaluated the coadministration of GSK1265744 and TMC278. It was a randomized, open-label, phase I study in 40 healthy adults divided equally between 4 treatment cohorts. Cohorts 1-3 were scheduled to receive GSK744 dosing on a monthly basis, and Cohort 4 received GSK1265744 quarterly. Each cohort received a loading dose of GSK1265744 800 mg intramuscularly (IM) after an oral lead in period that consisted of GSK1265744 30 mg/day for 14 days followed by a 7-day washout period. Cohorts 1 and 2 then received a dose of GSK1265744 200 mg either subcutaneously (Cohort 1) or IM (Cohort 2). Cohort 3 was dosed with GSK1265744 400 mg IM. Each cohort then received a second dose at Week 8 with Cohorts 2 and 3 adding a 1200-mg loading dose of TMC278 IM to their regimen. Cohort 1 received a fourth and final dose of GSK1265744 200 mg subcutaneously at Week 12. Also in Week 12, Cohorts 2 and 3 received second doses of its Week 8 regimen, except with the TMC278 dose reduced in both cohorts (Cohort 2 = 900 mg; Cohort 3 = 600 mg). Also in Week 12, Cohort 4 received its second and final dose of GSK1265744 800 mg IM. Follow-up is ongoing and is scheduled to continue for 52 weeks after the last injection.
- ART, antiretroviral therapy; IC90, inhibitory concentration 90%; PK, pharmacokinetics; RPV, rilpivirine. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0103.aspx Joel E. Gallant, MD, MPH: Plasma levels for GSK1265744 were substantially greater than the protein-adjusted IC90 dosing with either monthly or quarterly dosing. Plasma levels of TMC278 administered every 4 weeks were comparable to those seen with oral rilpivirine dosed at 25 mg/day. GSK1265744 was safe and well tolerated both alone and in combination with TMC278. This study certainly supports moving to phase 2 studies of the combination regimen.
- BID, twice daily; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; LPV, lopinavir; QD, once daily; RAL, raltegravir; RTV, ritonavir. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB05.aspx Andrew Carr, MBBS, MD, FRACP: SECOND-LINE was a randomized noninferiority study, similar to the EARNEST study, evaluating lopinavir/ritonavir combined with either raltegravir or NRTIs in patients who had failed a first‑line regimen comprising an NNRTI plus NRTIs. The efficacy results were presented at the 2013 Conference on Retroviruses and Opportunistic Infections and demonstrated that the raltegravir-containing regimen was noninferior to the NRTI-containing regimen,[1] validating the current strategy of using second-line regimens comprising a boosted PI plus NRTIs. At IAS 2013, the investigators presented a subanalysis examining the rates of bone mineral density loss in the 211 consenting patients from the SECOND-LINE study. Almost all patients were from low- or intermediate-resource countries. Reference 1. Humphries A, Boyd M; SECOND-LINE Study Team. SECOND-LINE: ritonavir-boosted lopinavir with 2-3N(t)RTI or raltegravir in HIV+ subjects virologically failing 1st-line NNRTI/2N(t)RTI. Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections; March 3-6, 2013; Atlanta, Georgia. Abstract 180LB.
- BMD, bone mineral density; BMI, body mass index; LPV, lopinavir. TDF, tenofovir. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WELBB05.aspx Andrew Carr, MBBS, MD, FRACP: As the graph shows, there was a greater loss of bone mineral density (BMD) at the hip and at the lumbar spine in patients who received NRTIs with lopinavir/ritonavir, compared with those receiving raltegravir with lopinavir/ritonavir. In my estimation, the magnitude of loss is similar to that observed in treatment-naive patients starting first-line ART. There was no significant difference in the frequency of new osteopenia or osteoporosis, but the study was not powered to make a final determination. Lower body mass index, not being exposed to tenofovir prior to study enrollment, and initiating tenofovir while on-study were significant predictors of greater BMD loss at the lumbar spine. Joel E. Gallant, MD, MPH: These findings are somewhat surprising in that you might not expect that patients who continued using NRTIs and simply switched their third drug from an NNRTI to a boosted PI would have further loss in bone density. In treatment-naive patients, BMD typically declines when any first-line ART is initiated but then stabilizes and plateaus after a few months. However, in this study, most patients who switched to lopinavir/ritonavir plus NRTIs were switching from either a zidovudine‑ or stavudine‑based regimen to a regimen containing tenofovir, which is known to cause a greater decline in BMD than other NRTIs. This may explain the greater loss of bone density in patients switching to lopinavir/ritonavir plus NRTIs.
- BMI, body mass index. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/WEAB0205.aspx Anton Pozniak, MD, FRCP: This population-based cohort study compared the incidence of major osteoporotic and hip fractures in the HIV‑infected population with a general population cohort of &gt; 1.1 million persons in Catalonia, Spain. The HIV-infected population represented approximately 0.2% of the general population but accounted for a substantial number of the hip fractures reported during the study period from 2007-2009. This difference was independent of baseline factors such as age, sex, body mass index, smoking, and ethanol use. Unfortunately, the authors did not indicate if the fractures were traumatic or spontaneous. As the graph indicates, the incidence of age-specific hip fractures increased with increasing age and is particularly concerning among HIV-infected patients older than 65 years of age. Andrew Carr, MBBS, MD, FRACP: The age-specific rates for hip fracture are very intriguing. The rate of hip fracture in HIV-infected adults younger than 50 years of age appears similar to the rate in 65- to 70-year-old HIV-uninfected adults. This suggests that we may need to be more aggressive in managing low BMD in younger HIV-infected adults than in HIV-uninfected adults of the same age and not just confine intervention to older men and postmenopausal women, as is more typical in the general population. Anton Pozniak, MD, FRCP: Overall, the promotion of bone health should be encouraged, and studies are needed to look at the utility of screening HIV patients for osteopenia earlier than would be recommended for the general population. Reference Güerri-Fernandez R, Vestergaard P, Carbonell C, et al. HIV infection is strongly associated with hip fracture risk, independently of age, gender, and comorbidities: a population-based cohort study. J Bone Miner Res. 2013;28:1259-1263.
- AE, adverse event; EFV, efavirenz; NVP, nevirapine. Joel E. Gallant, MD, MPH: HLA-B*35:05 and CCHCR1 have been associated with the development of rash during nevirapine-based therapy—a relationship similar to that of HLA‑B*5701 with abacavir hypersensitivity. Both alleles have been associated with rash, although it is worth noting that HLA-B*35:05 is relatively uncommon outside of southeast Asia and South America. In this large (N = 1103), prospective, randomized, multicenter trial, patients were separated into cohorts who either were screened prior to beginning nevirapine-based therapy or were not screened. This is reminiscent of the design of the abacavir hypersensitivity study. All patients began nevirapine‑based therapy except those who screened positive, who instead started efavirenz. There was a lower incidence of rash in those patients who were screened for the HLA-B*35:05 and CCHCR1 variants than those who were not screened (13.2% vs 18.0%, respectively). Of note, a higher CD4+ cell count was associated with a higher rate of rash. Yet, among those patients at highest risk for developing rash—those with CD4+ cell counts &gt; 250 cells/mm3—there was no predictive value associated with testing. In fact, screening was only found to be protective in women and patients with low CD4+ cell counts. Nevirapine use is now discouraged in patients with higher CD4+ cell counts, and these results suggest that screening will not change that recommendation. In addition, screening for nevirapine hypersensitivity may not be as broadly applicable as HLA-B*5701 screening for abacavir hypersensitivity because of racial differences in the prevalence of these alleles.
- HCV, hepatitis C virus; MSM, men who have sex with men; SVR, sustained virologic response. For detailed information on this study, go to: http://clinicaloptions.com/HIV/Conference%20Coverage/IAS%202013/New%20Data/Capsules/TUAB0101.aspx Anton Pozniak, MD, FRCP: In this single-site study from my center in London, United Kingdom, my colleagues retrospectively evaluated HIV-infected men who have sex with men who either spontaneously cleared an acute hepatitis C virus (HCV) infection or who were successfully treated for chronic HCV infection during an 8-year period from 2004-2012. Nearly 8% of these patients were reinfected with HCV annually. Furthermore, 23.2% of these reinfected patients who again cleared their HCV infection either spontaneously or with treatment were infected with HCV for a third time (ie, a second reinfection). Some of the reinfections were with an HCV genotype different from the initial infection, indicating a different source for the reinfection. Of note, there was no significant difference in the reinfection rate when comparing individuals who spontaneously cleared their previous infection vs those who were cured following treatment, so these data do not provide evidence that the immune response associated with spontaneous clearance protects against subsequent reinfection.