HIV Alert- Novel Strategies and Agents for HIV Management.2016
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In this downloadable slideset, Daniel R. Kuritzkes, MD, and Paul E. Sax, MD, review potential future HIV treatment strategies—including long-acting ART, dual-therapy regimens, and investigational agents—and discuss where these strategies might fit into the current therapeutic landscape. Format: Microsoft PowerPoint (.ppt) File size: 926 KB Date posted: 6/21/2016
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HIV Alert- Novel Strategies and Agents for HIV Management.2016
- 1. HIV Alert: Novel Strategies and Agents for HIV Management This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.
- 2. Slide credit: clinicaloptions.com About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details
- 3. Faculty Daniel R. Kuritzkes, MD Chief, Division of Infectious Diseases Brigham and Women's Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Paul E. Sax, MD Clinical Director HIV Program and Division of Infectious Diseases Brigham and Women's Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts
- 4. Faculty Disclosure Information Daniel R. Kuritzkes, MD, has disclosed that he has received consulting fees from Bionor, Gilead Sciences, GlaxoSmithKline, InnaVirVax, Merck, ViiV. Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and ViiV.
- 5. Slide credit: clinicaloptions.com Program Overview Long-Acting Antiretroviral Therapy Dual-Therapy Regimens Emerging Investigational Agents
- 7. Slide credit: clinicaloptions.com Long-Acting Antiretroviral Therapy Regimens/agents – Cabotegravir + rilpivirine – MK-8591 (EFdA) – Broadly neutralizing antibodies (bNAbs) Key questions: – Can we move away from daily oral therapy for HIV? – Are long-acting therapies as effective as oral therapies? – What about toxicity? – What pts might be ideal candidates for long-acting therapy? – How can resistance be prevented if pts miss doses?
- 8. LATTE-2: Cabotegravir IM + Rilpivirine IM for Long-Acting Maintenance ART Multicenter, open-label phase IIb study – Cabotegravir: integrase inhibitor Margolis DA, et al. CROI 2016. Abstract 31LB. CAB 400 mg IM + RPV 600 mg IM Q4W† (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W‡ (n = 115) 6 pts discontinued for AEs or death in induction analysis. *Pts with HIV-1 RNA < 50 c/mL from Wk 16 to Wk 20 continued to maintenance phase. † Loading dose: Day 1, CAB 800 mg + RPV 600 mg. ‡ Loading dose: Day 1, CAB 800 mg + RPV 900 mg; Wk 4, CAB 600 mg. ART-naive HIV- infected pts with CD4+ cell count > 200 cells/mm3 (N = 309) CAB 30 mg PO + ABC/3TC PO QD (n = 56) CAB 30 mg PO QD + ABC/3TC Wk 32 primary analysis Wk 20 Induction Phase* Maintenance Phase Wk 1 Wk 96 Wk 16: RPV PO added Slide credit: clinicaloptions.com
- 9. LATTE-2: Wk 32 Efficacy and Safety No INSTI, NNRTI, or NRTI resistance mutations detected Most frequent ISRs were pain (67%), swelling (7%), and nodules (6%) – ISR events/injection: 0.53 – 99% of ISRs grade 1/2; none grade 4 – 1% of pts withdrew for ISRs Margolis DA, et al. CROI 2016. Abstract 31LB. 9594 91 4< 1 4 < 15 5 Virologic Success Virologic Non- response No Virologic Data HIV-1RNA<50c/mL(%) 100 80 60 40 20 0 IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) Oral CAB + ABC/3TC (n = 56) Treatment Differences (95% CI): Q4W IM vs Oral: 2.8 (-5.8 to 11.5) Q8W IM vs Oral: 3.7 (-4.8 to 12.2) AEs, % Pooled IM Arms (n = 230) Oral Arm (n = 56) Drug-related grade 3/4 AEs (excluding ISRs) 3 0 Serious AEs 6 5 AEs leading to withdrawal 3 2 Slide credit: clinicaloptions.com
- 10. LATTE-2: Wk 32 Pt Satisfaction With Maintenance Therapy vs Oral Induction Pts(%) How satisfied are you with your current treatment? (vs oral induction treatment) 100 80 60 40 20 0 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) More Neutral Less 100 80 60 40 20 0 Q8W (n = 106) Q4W (n = 100) Oral CAB (n = 49) More Neutral Less How satisfied would you be to continue with your present form of treatment? (vs oral induction treatment) 97 96 71 29 3 1 3 98 98 71 29 2 1 1 Margolis DA, et al. CROI 2016. Abstract 31LB. Slide credit: clinicaloptions.com
- 11. Slide credit: clinicaloptions.com Other Potential Long-Acting ARVs 1. Friedman EJ, et al. CROI 2016. Abstract 437LB. 2. Caskey M, et al. Nature. 2015;522:487-491. 3. Lynch RM, et al. Sci Transl Med. 2015;7:319ra206. Agent MoA Study results MK-8591 (EFdA) NRTI[1] Phase I study: treatment-naive pts, single 10-mg dose (N = 6) Mean t1/2: 108 hrs Mean VL reduction at 10 days postdose: 1.78 log10 3BNC117, VRC01 Broadly neutralizing antibodies (bNAbs) 3BNC117: single infusion reduced VL up to 2.5 log10 (n = 17); mean t1/2: 9 days[2] VRC01: single infusion reduced VL up to 1.8 log10 in treatment-naive pts (n = 8); 2 minimal responders exhibited resistant virus at BL[3]
- 12. Slide credit: clinicaloptions.com Long-Acting Antiretroviral Agents: Potential Use Potential challenges with long-acting CAB + RPV IM: – What dosing interval might be approved: Q4W or Q8W? – Oral induction phase – IM dose volume/ISRs – What if a dose is missed? What pts might be ideal candidates for long-acting therapy? – Pts with chaotic lifestyles? – Pts with good clinic attendance who dislike daily pills?
- 14. Slide credit: clinicaloptions.com Dual-Therapy Regimens Potential regimens/agents: – DTG + 3TC or RPV – Boosted PI + 3TC or RAL Key questions: – Can regimens that include 2 agents be as effective as regimens with 3+ agents for first-line, switch/maintenance, or salvage therapy? – If so, can the costs of HIV treatment be reduced by using dual therapy regimens? – Can the use of NRTIs be limited or eliminated with these regimens?
- 15. Boosted PI Dual Therapy: Phase III or IV Studies Study Treatment Setting N Regimen Results NEAT001[1] Initial 805 DRV/RTV + RAL Similar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high viral loads, low CD4+ cell counts GARDEL[2] Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs MODERN[3] Initial 797 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + 2 NRTIs OLE[4] Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART KITE[5] Switch 60 LPV/RTV + RAL Small study; encouraging efficacy SALT[6] Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs ATLAS-M[7] Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs Slide credit: clinicaloptions.comReferences in slidenotes.
- 16. PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts Figueroa MI, et al. EACS 2015. Abstract 1066. Open-label, single-arm phase IV exploratory trial Treatment-naive pts with HIV-1 RNA > 5000-100,000 copies/mL; CD4+ cell count ≥ 200 cells/mm3 ; HBsAg negative (N = 20) Second Cohort Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) Dolutegravir 50 mg QD + Lamivudine 300 mg QD (n = 10) First Cohort Second cohort to be enrolled following confirmation of first cohort success at Wk 8 Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL 20/20 pts achieved HIV-1 RNA < 50 copies/mL by Wk 8 Slide credit: clinicaloptions.com
- 17. Boosted PI Dual Therapy After Treatment Failure: Selected Studies Study Treatment Setting N Regimen Results EARNEST[1] Failure 1277 LPV/RTV + RAL Similar efficacy as LPV/RTV + 2/3 NRTIs; improved efficacy vs LPV/RTV monotherapy SECOND- LINE[2] Failure 541 LPV/RTV + RAL Similar efficacy as LPV/RTV + 2/3 NRTIs ACTG A5273[3] Failure 512 LPV/RTV + RAL Similar efficacy as LPV/RTV + best available NRTIs Slide credit: clinicaloptions.com 1. Paton NI, et al. N Engl J Med. 2014;371:234-247. 2. Amin J, et al. PLoS One. 2015;10:e0118228. 3. La Rosa AM, et al. CROI 2016. Abstract 30.
- 18. Slide credit: clinicaloptions.com Dual-Therapy Regimens: Potential Use Potential for use as first-line, switch, induction/maintenance, or salvage therapy in select pts Considerations for use: – Treatment regimens that include fewer agents might allow: – NRTI-sparing/limiting – Drug–drug interaction avoidance – Cost savings: – Modeling study suggested that, should DTG + 3TC demonstrate high virologic suppression rates in a larger trial, use of this regimen as first-line or induction/maintenance therapy could result in US savings of > $500 million[1] – Implications for developing countries (decreased lab monitoring vs NRTIs) – Regimens with 3TC as only NRTI should not be used in pts with HBV infection 1. Girouard MP, et al. Clin Infect Dis. 2016;62:784-791.
- 19. Slide credit: clinicaloptions.com Dual-Therapy Regimens: What is Coming? Study Description SWORD-1 and -2[1,2] Phase III, planned N = 510 per study DTG + RPV as maintenance therapy for virologically suppressed pts on 2 NRTIs + third drug ACTG A5353[3] Phase II, planned N = 120 DTG + 3TC for treatment-naive pts DUALIS[4] Phase III, planned N = 320 DRV/RTV + DTG as switch therapy for virologically suppressed pts on DRV/RTV + 2 NRTIs 1. ClinicalTrials.gov. NCT02429791. 2. ClinicalTrials.gov. NCT02422797. 3. ClinicalTrials.gov. NCT02582684. 4. ClinicalTrials.gov. NCT02486133.
- 21. Emerging Investigational Agents Agent Mechanism of Action Doravirine[1] NNRTI; activity against common NNRTI resistance mutations GS-9883 (bictegravir)[2] Unboosted INSTI Fostemsavir (BMS-663068)[3,4] Prodrug metabolized to attachment inhibitor; binds gp120 to prevent viral attachment and CD4+ cell entry BMS-955176[5] Maturation inhibitor; reversibly binds to HIV Gag protein Ibalizumab (TNX-355)[6] Entry inhibitor; antibody to CD4 Slide credit: clinicaloptions.com 1. Gatell JM, et al. CROI 2016. Abstract 470. 2. ClinicalTrials.gov. NCT02607956. 3. Feinberg J, et al. IDWeek 2015. Abstract 1075. 4. Thompson M, et al. CROI 2015. Abstract 545. 5. Hwang C, et al. IAS 2015. Abstract TUAB0106LB. 6. Jacobson JM, et al. Antimicrob Agents Chemother. 2009;53:450-457. Key question: – Where might emerging investigational agents fit into the current landscape for HIV treatment?
- 22. Slide credit: clinicaloptions.com Emerging Investigational Agents: Potential Use and Current Studies Agent Implications Ongoing Trials Doravirine NNRTI Notable: • New NNRTI • Phase II: similar efficacy with improved tolerability vs EFV for treatment-naive pts in combination with FTC/TDF[1] Phase III, tx naive: DOR vs DRV/RTV, both with FTC/TDF or ABC/3TC[2] Phase III, switch: DOR/3TC/TDF[3] Potential use: first-line, switch GS-9883 (bictegravir) INSTI Notable: • Unboosted INSTI coformulated with FTC/TAF • Phase II results yet to be presented[4] Phase III, tx naive: GS-9883/FTC/TAF vs DTG + FTC/TAF[5] or DTG/ABC/3TC[6] Phase III, switch: GS-9883/FTC/TAF from varied regimens (eg, EVG/COBI/FTC/TAF or DTG/ABC/3TC)[7-9] Potential use: first-line, switch 1. Gatell JM, et al. CROI 2016. Abstract 470. 2. ClinicalTrials.gov. NCT02275780. 3. ClinicalTrials.gov. NCT02397096. 4. ClinicalTrials.gov. NCT02397694. 5. ClinicalTrials.gov. NCT02607956. 6. ClinicalTrials.gov. NCT02607930. 7. ClinicalTrials.gov. NCT02603120. 8. ClinicalTrials.gov. NCT02603107. 9. ClinicalTrials.gov. NCT02652624.
- 23. Slide credit: clinicaloptions.com Emerging Investigational Agents: Potential Use and Current Studies 1. Thompson M, et al. CROI 2015. Abstract 545. 2. ClinicalTrials.gov. NCT02362503. 3. Hwang C, et al. IAS 2015. Abstract TUAB0106LB. 4. ClinicalTrials.gov. NCT02386098. Agent Implications Ongoing Trials Fostemsavir Attachment inhibitor Notable: • Novel ARV class • Phase IIb: generally similar responses vs ATV/RTV in tx- experienced pts when combined with RAL + TDF[1] Phase III: pts with ARV experience/resistance[2] Potential use: pts with multiple tx failures and drug-resistant virus BMS-955176 Maturation inhibitor Notable: • Novel ARV class • Phase IIa: dose-finding study; efficacy noted[3] Phase II: BMS-955176 + ATV ± RTV + DTG at varied doses in experienced pts[4] Potential use: under exploration
- 24. Slide credit: clinicaloptions.com 1. ClinicalTrials.gov. NCT00784147. 2. ClinicalTrials.gov. NCT02707861. 3. ClinicalTrials.gov. NCT02475629. Agent Implications Ongoing Trial(s) Ibalizumab (TNX-355) Entry inhibitor Notable: • Phase IIb: tx-experienced pts treated with OBR + IV Q2W or Q4W; Wk 24 viral suppression in 28% to 44% of pts[1] FDA breakthrough therapy and orphan drug designations; 2 current phase III trials assessing OBR + Q2W dose for pts with multidrug resistant HIV[2,3] Potential use: salvage therapy/tx- experienced pts Other Emerging Investigational Agents
- 25. Summary Strategy Regimens/Agents Potential Future Implications in HIV Treatment Long-acting ART Cabotegravir + RPV MK-8591 (EFdA) bNAbs Long-acting regimens could remove the need for daily pills May have role in maintenance therapy Dual therapy DTG + 3TC or RPV PI/RTV + 3TC or RAL Dual therapy regimens might be used in first-line, switch, induction/maintenance, or salvage settings Could allow treatment simplification, cost savings vs 3+ drug regimens, minimization of DDIs, AEs Investigational agents Doravirine GS-9883 (bictegravir) Novel agents with potential utility for treatment-naive or switch pts Fostemsavir BMS-955176 Ibalizumab Novel agents with potential utility for treatment-experienced pts Slide credit: clinicaloptions.com
- 26. Go Online for More CCO Coverage of HIV! Timely Webinars with expert faculty that address important developments in HIV care as they occur Downloadable Webinar slides and audio for self-study and use in your own presentations clinicaloptions.com/hiv
Hinweis der Redaktion
- These slides include notes based on commentary provided by Paul E. Sax, MD.
- 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.
- The topics discussed will include long-acting antiretroviral therapy, dual-therapy regimens, and emerging investigational agents. Please remember that this is a presentation on investigational approaches to therapy.
- One of the regimens that is currently in development, and perhaps the furthest along, is cabotegravir plus rilpivirine, so I will talk about the studies looking at that. I will mention briefly MK-8591, which used to be called EFdA, and also discuss broadly neutralizing antibodies, or bNAbs. The questions raised by long-acting therapy are: Can we move away from daily oral treatment? Are these as effective as oral therapies? What about the toxicity? What patients are the ideal candidates? How can resistance be prevented if patients miss doses?
- 3TC, lamivudine; ABC, abacavir; AE, adverse event; ART, antiretroviral therapy; CAB, cabotegravir; FDA, US Food and Drug Administration; IM, intramuscular; PO, orally; Q4W every 4 weeks; Q8W, every 8 weeks; QD, once daily; RPV, rilpivirine. The most important study that we have seen so far on long-acting therapy is the LATTE-2 study. Cabotegravir is an investigational integrase inhibitor that is available both orally and parenterally by injection. Rilpivirine is, of course, a nonnucleoside reverse transcriptase inhibitor that is already available orally; we use it as part of combination tablets or alone, and it has also been reformulated to be injectable in this particular study. Patients were treatment naive and had CD4+ cell counts &gt; 200. They underwent an induction phase where they received oral cabotegravir once daily plus abacavir/lamivudine, and then, at Week 16, oral rilpivirine was added for the remaining 4 weeks of induction. Thus, they were taking 3 or 4 drugs for 20 weeks. If virologically suppressed at Week 20 (and most were), patients were then randomized to 1 of 3 arms: injectable cabotegravir plus rilpivirine every 4 weeks, injectable cabotegravir plus rilpivirine every 8 weeks, or continuation of initial oral therapy. Notice the 2:2:1 randomization. So, oral induction for everyone and then, after virologic suppression, switching to the injectable options.
- 3TC, lamivudine; ABC, abacavir; AE, adverse event; CAB, cabotegravir; IM, intramuscular; INSTI, integrase strand transfer inhibitor; ISR, injection site reaction; NNRTI, non-nucleoside reverse-transcriptase inhibitor; NRTI, nucleoside reverse-transcriptase inhibitor; Q4W every 4 weeks; Q8W, every 8 weeks; QD, once daily; RPV, rilpivirine. This slide reviews efficacy and safety for this study. The 2 injectable arms, 4 and 8 weeks, demonstrated 94% and 95% virologic success, similar to the 91% in those who continued on oral therapy. Very few cases of virologic nonresponse occurred in any of the treatment arms, and only a few patients dropped out or had no virologic data. An important feature of this study to highlight is that there was no nucleoside, nonnucleoside, or integrase resistance detected. The most frequent adverse event, not surprisingly, was injection-site reaction. The patients had pain, swelling, and nodules. However, they were not very severe, with 99% of them occurring at the lowest grades, grade 1 or 2. None of them were grade 4, the severest, and only 1% of patients withdrew for injection-site reactions. These are very encouraging results for the LATTE-2 study at Week 32.
- CAB, cabotegravir; Q4W every 4 weeks; Q8W, every 8 weeks. Now, let’s examine patient satisfaction. Remember that all patients started with oral therapy. They were subsequently asked 2 questions after they had been randomized to and had received their injectable versus oral maintenance therapy: How satisfied are you with your current treatment compared to the oral induction? And then, how satisfied would you be to continue with your present form of treatment vs the oral induction? At the left side, you can see a higher proportion of the people in the injectable arms of the study were more satisfied with their treatment than they were with the oral induction. Similarly, at the right, a higher proportion wanted to continue if they were enrolled in injectable arms. This observed patient satisfaction is, of course, somewhat of a self-fulfilling prophecy. The patients who went in to this study clearly were interested in getting injectable therapy. These results do reinforce the idea that this particular injectable strategy for those who want an injectable strategy is actually preferable to oral therapy in a high proportion of people. It is noteworthy to reinforce that these patients were receiving 2 separate injections, 1 of cabotegravir and 1 of rilpivirine, and that these injections were intramuscular gluteal injections. This means that they needed to be administered by a healthcare provider; these were not self-injections. So, those are the results of LATTE-2 at Week 32. Again, as mentioned, these are the most important data on long-acting therapy that we have thus far.
- ARV, antiretroviral; BL, baseline; NRTI, nucleoside reverse-transcriptase inhibitor; OBR, optimized background regimen; VL, viral load. Next, we will discuss MK-8591. We saw a very interesting poster at CROI this year looking at a single 10-mg dose of this drug that demonstrated a half-life of 108 hours. That is extremely potent. The corresponding viral load reduction was nearly 2 logs at 10 days post-dose. MK-8591 is, therefore, a very long-acting drug. It will be fascinating to see how this is developed. Obviously, a drug like this with such a long half-life has to be paired with other active agents, and it is not clear exactly what those agents will be, but current data are very promising. In addition, there have been studies presented on various broadly neutralizing antibodies for treatment, or so-called bNAbs. These are less encouraging right now because some of the patients do not respond to these particular bNAbs at all. These 2 broadly neutralizing antibodies, 3BNC117 and VRC01, are probably not quite as potent or as broad as the optimal antibodies will be. Nonetheless, knowing about this novel strategy for treatment is important because these bNAbs might be used in the future as part of long-acting therapy.
- CAB, cabotegravir; IM, intramuscular; ISR, injection site reaction; Q4W every 4 weeks; Q8W, every 8 weeks; RPV, rilpivirine. Let&apos;s talk about potential uses and challenges. So, what is the right dosing interval for long-acting therapy? Is it going to be every 4 weeks or every 8 weeks? We don&apos;t know at this point. Clearly, for an injectable that has to be administered by a healthcare provider, every 8 weeks would be preferable to every 4. The oral induction phase is required mostly because it allows a clinician to identify any patient that might have an adverse event to long-acting therapy before beginning it. This ensures the safety of your patient. What about the volume of administration? What about injection-site reactions? And what happens if your patient misses a dose? Those are all issues that need to be addressed. So who are the ideal candidates? Patients who are somewhat adherence-challenged would arguably be both good and bad candidates. They are good candidates because they are tired of taking their pills; we could circumvent this by having a healthcare worker administer the injection when visiting them in their house or when they come into the clinic. They are bad candidates because they are the ones most likely to stop their therapy, which could select for resistance. Another possibility for an ideal candidate is the patient who is really good at coming to clinic but is sick of taking pills, though this may be a minority of people.
- Let’s switch now from long-acting therapy to dual-therapy regimens.
- 3TC, lamivudine; DTG, dolutegravir; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine. The dual-therapy options discussed in this presentation are the dolutegravir plus lamivudine or dolutegravir plus rilpivirine regimens, which are both under investigation, as well as boosted PIs plus either 3TC or raltegravir. The questions here are: Can regimens that include 2 agents be as effective as regimens with 3 or more agents as first-line, as switch or maintenance, or as salvage therapy? And, if so, if these 2 active agents work well, can we reduce the cost and potentially toxicity? Can we eliminate or limit the use of nucleoside reverse transcriptase inhibitors? This latter question was obviously much more of a concern in the past when we had toxic NRTIs such as stavudine, zidovudine, and didanosine. This is less of an issue today, although some toxicity is still seen with TDF and abacavir.
- 1. Raffi F, et al. Lancet. 2014;384:1942-1951. 2. Cahn P, et al. EACS 2015. Abstract 961. 3. Stellbrink HJ, et al. AIDS 2014. Abstract TUAB0101. 4. Arribas JR, et al. Lancet Infect Dis. 2015;15:785-792. 5. Ofotokun I, et al. AIDS Res Hum Retroviruses. 2012;28:1196-1206. 6. Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784. 7. Di Giambenedetto S, et al. EACS 2015. Abstract 867. 3TC, lamivudine; ATV, atazanavir; DTG, dolutegravir; DRV, darunavir; FTC, emtricitabine; LPV, lopinavir; MVC, maraviroc; NRTI, nucleoside reverse-transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir disoproxil fumarate. This table recaps some of the boosted PI dual therapy phase III and IV studies. Darunavir is an excellent protease inhibitor, and raltegravir is a very potent, very well-tolerated drug, but in the fully powered NEAT001 study, darunavir/ritonavir plus raltegravir was not as effective as darunavir/ritonavir plus FTC/TDF in patients who had high viral loads or low CD4 cell counts. Perhaps the most pivotal PI dual-therapy study was the GARDEL study, where lopinavir/ritonavir plus lamivudine was every bit as good as lopinavir/ritonavir plus 2 NRTIs. Viral efficacy was superb in patients with high viral loads. These results supported the idea that, with boosted PIs, you just need 1 other drug. The MODERN study had much less encouraging results. Darunavir/ritonavir plus maraviroc demonstrated inferior efficacy compared to darunavir/ritonavir plus 2 NRTIs. The rest of the studies listed here are switch studies. Patients who are already virologically suppressed with no history of failure are really good candidates for these studies because their viral suppression provides evidence of their positive medication adherence behavior.
- BL, baseline; HBsAg, hepatitis B virus surface antigen. Sometimes small studies give us something very novel to think about. The small, single-arm PADDLE study looked at dolutegravir—which is a known next-generation integrase inhibitor with a high barrier to resistance—plus lamivudine for treatment-naive patients. Now, importantly, only a small number of patients were enrolled: 10 per cohort for a total of 20. To get into the study, patients had to have a screening HIV RNA between 5000 and 100,000 and a CD4+ cell count &gt; 200, so this study did not look at patients with advanced disease. Viral load outcomes were presented at EACS 2015, and importantly, 20 of 20 patients achieved HIV RNA &lt; 50 copies by Week 8, and there were no virologic failures. This study included 4 patients who, though their screening viral loads were &lt; 100,000, had HIV RNA &gt; 100,000 at study entrance; these patients actually ended up virologically suppressed as well. This is good news for this regimen and has encouraged investigators to explore it in a larger capacity.
- LPV, lopinavir; NRTI, nucleoside reverse-transcriptase inhibitor; RAL, raltegravir; RTV, ritonavir. What about 2-drug therapy for patients who have experienced virologic failure? All of the data come from large, fully powered studies of second-line treatment in resource-limited settings where patients have failed their first-line, dual-nuc with non-nuc regimens. These studies typically occur in settings without viral load monitoring or genotype resistance testing. Patients were randomized to lopinavir/ritonavir plus either raltegravir, a dual therapy, or best available NRTIs, which are often recycled nucleosides. Interestingly, all of these studies show the same thing, essentially that the 2 strategies are equivalent in achieving virologic suppression. It is surprising that patients receiving lopinavir/ritonavir plus raltegravir did not demonstrate better efficacy because they were getting 2 new drugs. If patients were adherent, both of these strategies worked just fine, and this does underscore that nucleoside analogues continue to have significant antiviral effect even after people develop resistance mutations. This is not like loss of activity with, for example, efavirenz or rilpivirine. Once a patient develops a non-nuc mutation, there&apos;s really no activity, but that is not the case with nucleoside analogues; they&apos;re still quite active.
- 3TC, lamivudine; DTG, dolutegravir; NRTI, nucleoside reverse-transcriptase inhibitor. There is possible use for dual-therapy regimens as first-line, switch, induction/maintenance, or salvage therapy in select patients. When we want to limit nucleoside analogue exposure or drug–drug interactions, then appropriate dual-therapy options exist. A cost-effectiveness modeling study looked at the budgetary impact of dolutegravir plus lamivudine. If dolutegravir plus lamivudine proves as effective as triple therapy in larger clinical trials, this dual-therapy regimen would be extremely cost saving because lamivudine is already a generic drug. Two-drug regimens are also potentially useful in resource-limited settings because intensive renal monitoring would not be required. Now, the important caveat is that the data from the PADDLE study of dolutegravir plus lamivudine are very limited, from only 20 patients. I also want to emphasize that you cannot use lamivudine monotherapy in anyone who has hepatitis B coinfection, as it rapidly selects for hepatitis B resistance. Under these circumstances, tenofovir-based regimens are much, much better.
- 3TC, lamivudine; DTG, dolutegravir; DRV, darunavir; NRTI, nucleoside reverse-transcriptase inhibitor; RTV, ritonavir; RPV, rilpivirine. What dual-therapy regimen studies are planned? In addition to dolutegravir plus lamivudine, a dolutegravir plus rilpivirine pair of studies, both of them called SWORD, are currently ongoing. In these studies, patients who are virologically suppressed are randomized to either continue their treatment or to switch to dolutegravir plus rilpivirine. There&apos;s also ACTG A5353, a single-arm study of 120 patients getting dolutegravir/lamivudine as initial therapy; this study will include patients with HIV RNA levels greater than 100,000 to begin to answer the question of whether this regimen is potent enough in that subset. Finally, the DUALIS study of boosted darunavir plus dolutegravir will test whether this regimen could improve upon previous results from the NEAT001 study.
- INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse-transcriptase inhibitor. This table lists emerging investigational agents that are currently in various levels of development. The furthest along of these is doravirine, an NNRTI. There&apos;s also GS-9883 (or bictegravir), an unboosted integrase inhibitor. There&apos;s fostemsavir, which is an oral attachment inhibitor, and BMS-955176, a maturation inhibitor. Finally, there&apos;s ibalizumab (formerly TNX-355), which is an entry inhibitor that binds to CD4 receptor. Where are these going to fit in our treatment paradigms? It is hard to know right now. Let&apos;s talk about these drugs in a bit more detail.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DOR, doravirine; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse-transcriptase inhibitor; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. In a phase II study, doravirine demonstrated similar efficacy to efavirenz in treatment-naive patients and fewer drug-related adverse events. Doravirine is currently being studied in phase III trials: in comparison with darunavir/ritonavir for treatment-naive patients and in a switch study in which patients are switched to doravirine/3TC/TDF (a single, coformulated pill). These studies seek to address whether we can overcome some of the problems that we have with other NNRTIs. GS-9883 (or bictegravir) is an unboosted integrase inhibitor coformulated with TAF/FTC. This drug does not require the boosting with cobicistat, which will offer fewer drug–drug interactions. Data from a phase II trial have not yet been presented, and multiple phase III studies are ongoing. Two such phase III studies compare the coformulated GS-9883/FTC/TAF with dolutegravir plus FTC/TAF or dolutegravir/abacavir/lamivudine. This latter study is a single-pill design vs single-pill, blinded design.
- ARV, antiretroviral; ATV, atazanavir; DTG, dolutegravir; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir disoproxil fumarate. Fostemsavir is an attachment inhibitor with a novel mechanism of action. Interestingly, it&apos;s being developed as a salvage drug. A multicenter phase III trial is currently ongoing looking at patients with few or no treatment options. Data should come out from this trial soon, likely leading to a special category designation for this agent because so few drugs like this exist. Another possible drug in this area is the maturation inhibitor BMS-955176. As previously mentioned, the antiviral activity of this inhibitor does not appear to be reduced because of baseline-present polymorphisms. Development of this drug is still in early stages so its potential uses, such as initial or subsequent therapy, are currently under investigation.
- OBR, optimized background regimen; Q2W every 2 weeks; Q4W every 4 weeks. Ibalizumab is the last investigational agent to be discussed. It is an entry inhibitor that binds to CD4 and blocks viral entry into host cells. This drug has been around for some time and now has breakthrough therapy and orphan drug designations. There may not be a large need for this drug, but there may be utility for that small subset of patients who really do not have any other active agents, maybe in combination with another investigational drug. Ibalizumab is given as an infusion. Historically, we know that parenteral therapies such as enfuvirtide have not been very popular, but this is given as an IV infusion.
- 3TC, lamivudine; AE, adverse event; bNAbs, broadly neutralizing antibodies; DDI, drug-drug interaction; DTG, dolutegravir; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; RTV, ritonavir.