Our story

Three decades ago, there were little more than words of comfort for people diagnosed with HIV. Today, it is a manageable chronic health condition and HIV transmission can be stopped where the viral load is undetectable. The evolution of antiretroviral therapy has been underpinned by the pursuit of increasingly effective treatment regimens with lower pill burdens causing fewer side effects and less toxicity – all while minimising the development of resistance.

 

HIV management is at another significant crossroad with the emergence of two-drug therapy options. To discuss the implications of this new treatment approach for both patients and healthcare providers, ViiV Healthcare brought together Lance Feeney, Dr Benjamin Young and Professor Mark Boyd to share their insights.

Our speakers

  • Senior Global Medical Director, ViiV


    Ben is a Senior Global Medical Director at ViiV Healthcare, based in Colorado USA. He is the author of over 100 journal articles, reviews and book chapters relating to HIV disease, antiretroviral therapy, public health and human rights.
    The former chief medical officer of the International Association of Providers of AIDS Care, he served on the World Health Organization HIV Clinical Guideline Development Group and was Principle Investigator with the CDC's HIV Outpatient Study (HOPS), a massive ongoing cohort study of the health PLHIV throughout the US.
    Dr. Young is also a member of the HIV Medicine Association and the International AIDS Society. He is actively involved in educating healthcare professionals and community groups around the world.
     

  • Chair of Medicine, Lyell McEwin Hospital SA


    Mark is the founding Chair of Medicine at the Lyell McEwin Hospital in Adelaide, SA and Professor of Medicine and Professorial Fellow at the Kirby Institute, University of New South Wales.
    He is Co-editor-in-Chief of the open-access BioMed Central journal, AIDS Research and Therapy.
    In 2014 Professor Boyd was awarded the Frank Fenner Prize for Advanced Research in Infectious Diseases by the Australasian Society for Infectious Diseases for clinical research that has changed WHO guidelines for the use of first- and second-line antiretroviral therapy worldwide.
     

  • Consultant to NAPWHA


    Lance was diagnosed with HIV in 1984. Lance joined ACON in 2000 to reshape the Positive Living Centre and health promotion programs. In 2008 he moved to People Living with HIV New South Wales (now Positive Life NSW) where he advocated to state and federal governments for community pharmacy dispensing, for free access to HIV medicines, for improved anal cancer screening, for the service needs of older PLHIV and for those with HAND, HAD and complex care needs. He’s currently working on a national submission to the Royal Commission into Aged Care Quality and Safety and regularly collaborates with researchers at the Kirby, the Centre for Social Research and the Australian Research Centre in Sex Health and Society as a community investigator.
     

Positive Perspectives

A View from the Other Side

Navigating the healthcare system can be challenging, especially for PLHIV (people living with HIV) who are already dealing with multiple and complex issues. Healthcare providers are integral in facilitating patient-centred access to healthcare. Lance Feeney shares his observations and personal experience, stressing the importance of empathy and respect in interactions with PLHIV.

Polypharmacy and Comorbidities in People Living With HIV (PLHIV)

Ageing-related comorbidities are accompanied by polypharmacy. The potential for drug-drug interactions between HIV-related and non-HIV related medicines can also compound treatment complexities. Lance Feeney shares data from HIV Futures 8 and Positive Life NSW.

Clinicians speak out

The Evolution of HIV Treatment and a Short History of 2-Drug Regimens

Early innovations in antiretroviral therapy gave way to triple drug therapy; this formulaic regimen has continued for twenty years. Ben Young and Mark Boyd take the audience back in time, discussing the milestone discoveries leading to the two-drug combination of dolutegravir and lamivudine.

The Importance of PLHIV in Treatment

The Denver Principles are the first articulation of the idea of health as a human right, independent of one’s sexual orientation. The Denver Principles were penned by 20 gay men, 19 of whom would die shortly thereafter of AIDS. Fast forward to today, Ben Young talks about the continuing relevance of these principles insofar as improving the quality of life of PLHIV.

Could less offer more?

A new paradigm begs the question, does two equal three? In what is recognised as a robust clinical trials program the non-inferiority between DTG + 3TC and DTG + TDF/FTC was examined. Ben Young presents the data from the GEMINI 1&2 studies in treatment-naive PLHIV.

Your Questions Answered

  • The GEMINI studies recruited more than 1400 patients in total but did not specifically include patients with chaotic lives1. Additionally, participants within the GEMINI studies would have had a range of adherence levels, even in the context of a randomised controlled trial. Despite this, similar rates of confirmed virological withdrawals were observed in the 2-drug arm (n=6) and the 3-drug arm (n=4), and there was no evidence of antiretroviral resistance within these 10 subjects.

    Both Lamivudine (3TC) and Dolutegravir (DTG) have well-matched half-lives (DTG; 14h, 3TC; 15.5h)5,7. Based on PK modelling, it would take approximately 3.5 days from the last dose, before each drug would fall below the therapeutic range. This data suggests that the 2DR of DTG + 3TC would provide forgiveness in the setting of a missed dose2-6.

    References

    1. Cahn P et al. Lancet. 2019;393(10167):143-155
    2. Moore KH, et al. AIDS 1999;13:2239–50
    3. Yuen GJ, et al. Antimicrob Agents Chemother 2004;48:176–82
    4. Min S, et al. AIDS 2011;25:1737–45;
    5. Tivicay Australian Product Information June 2019
    6. Song I, et al. IAS 2009. Abstract WEPEB250
    7. 3TC Australian Product information April 2019
  • In general, if the patient’s viral load is declining, they may just need longer to reach viral suppression, especially if their baseline viral load >100,000 c/mL4. The GEMINI studies demonstrated that the magnitude and speed of viral load decline were similar in the DTG + 3TC and DTG + TDF/FTC arms, irrespective of baseline viral load1,2.

    It should be noted that 20% of participants overall in GEMINI 1 & 2 had baseline viral load >100,000 c/mL1.

    At Week 48, DTG + 3TC had comparable efficacy to DTG + FTC/TDF in patients with baseline viral loads <100,000 c/mL (91% vs. 94%), as well as with high baseline viral loads >100,000 c/mL (92% vs. 90%)1.

    In addition, viral suppression rates (to reach plasma HIV-1 RNA VL <50 copies/ml) were similar at Week 4 with 72% in the DTG + 3TC arm vs 70% in the DTG + TDF/FTC arm1,3. This correlated to a median time to viral suppression of 29 days for both arms2. In the high baseline viral load strata (>100,000 c/mL) the median time to viral suppression was longer; taking 57 days for both arms2. These data demonstrate that the antiviral potency of DTG + 3TC is similar to that of DTG + TDF/FTC1.

    References

    1.  Cahn P et al. Lancet. 2019;393(10167):143-155
    2.  Eron J, et al. HIV DART and Emerging Viruses 2018. Oral Presentation 7
    3.  Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
    4. Stephan C et al. HIV Medicine 2013; 14(5): 284-292.
  • The basis of U=U refers to the concept that an individual with an undetectable plasma HIV viral load (<50 c/mL) is incapable of transmitting HIV to sexual partners1. Importantly, the GEMINI studies demonstrated that the 2DR of DTG + 3TC achieved undetectability at the same speed and potency to that of the 3DR of DTG + TDF/FTC (72% in the DTG + 3TC arm vs 70% in the DTG + TDF/FTC were undetectable by Week 4)2,3. Additionally, the durability of viral suppression was maintained through to the primary endpoint at Week 48 (91% in the DTG + 3TC arm vs 93% in the DTG + TDF/FTC arm were undetectable (adjusted treatment difference −1·7%, 95% CI −4.4 to 1.1) as measured by the FDA Snapshot ITT-E analysis). This data clearly demonstrates the non-inferior virological efficacy of DTG + 3TC vs DTG + TDF/FTC2

    Some smaller studies have also compared rates of genital HIV-1 shedding in virologically suppressed subjects treated with 2DR or 3DR. Results from ASPIRE and ACTG 5353 demonstrated similar rates of genital HIV-1 shedding in DTG + 3TC treated males and females, (6%, 3/51) compared to subjects treated with 3DR (2-20%) in other studies5-8.    

    †The GEMINI 1 + 2 Studies were two identical, fully powered, randomised, double-blind, treatment-naïve, non-inferiority, phase III studies with more than 1400 patients in total2. GEMINI 1 and 2 aimed to evaluate the efficacy and safety of a two-drug regimen (DTG + 3TC) compared with a three-drug regimen (DTG + TDF/FTC) for the treatment of HIV-1 infection in ART-naive adults2

    References:

    1. Prevention Access Campaign Consensus Statement. Available from: https://www.preventionaccess.org/consensus (Accessed October 2018)
    2. Cahn P et al. Lancet. 2019;393(10167):143-155.
    3. Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB 
    4. Gianella S, et al. JAIDS. 2018;79(5):e112-e114
    5. Sheth PM,  et al. Mucosal Immunol. 2012;5:248–257.
    6. Politch JA et al. AIDS. 2012;26(12):1535-1543.
    7. Halfon P et al. PLoS One. 2010;5:e10569.
    8. Marcelin AG et al. AIDS. 2008;22:1677–1679.
  • We have submissions under consideration with the Therapeutic Goods Administration (TGA) and the Pharmaceutical Benefits Advisory Committee (PBAC) for the fixed-dose combination of Dolutegravir and Lamivudine (DTG + 3TC). The PBAC submission was evaluated at the July 2019 meeting and we expect an outcome later in 20191.

     

    References:

    1. Pharmaceutical Benefits Advisory Committee (PBAC) Meeting Agenda, July 2019 PBAC Meeting
  • 3TC (lamivudine) is a potent, selective inhibitor of HIV-1 and HIV-2 replication in vitro22. Lamivudine was first approved more than two decades ago as a component of antiviral regimens23.

    Though ‘potency’ is relatively subjective, in general, the log viral drop for all the nucleosides (including Lamivudine) is less than that observed for the integrase inhibitors (see figure). Lamivudine has a -1.19 log viral load drop in short-term monotherapy (300 mg BD) compared to dolutegravir (50 mg QD) which is the most potent antiretroviral available with a -2.46 log viral load drop15.

    The results of the GEMINI studies demonstrate the combination of DTG + 3TC had non-inferior efficacy, safety and tolerability to a traditional 3-drug regimen of DTG + TDF/FTC23.

    References:

    1. Gruzdev et al. AIDS 2003;17:2487–94.
    2. Goebel et al. AIDS 2006;20:1721–6.
    3. de Jong et al. J Infect Dis 1997;175:966–70.
    4. Murphy et al. AIDS 2001;15:F1–9. 
    5. Arastéh et al. AIDS 2005;19:943–7.
    6. BMS Clinical Study Report AI424007, August 2002.
    7. Eron et al. N Engl J Med 1995;333:1662–9.
    8. Ruane et al. Pharmacotherapy 2004;24:307–12.
    9. Staszewski et al. AIDS 1998;12:F197–202.
    10. Louie et al. AIDS 2003;17:1151–6.
    11. Ruane et al. J Acquir Immune Defic Syndr 2013;63:449–55.
    12. Friedman et al. CROI 2016; Abstract 437LB.
    13. Rousseau et al. J Infect Dis 2003;188:1652–8.
    14. Markowitz et al. J Acquir Immune Defic Syndr 2006;43:509–15.
    15. Min et al. AIDS 2011;25:1737–45.
    16. DeJesus et al. J Acquir Immune Defic Syndr 2006;43:1–5.
    17. Spreen et al. HIV Clin Trials 2013;14:192–203.
    18. Gallant et al. J Acquir Immune Defic Syndr 2017;75:61–6.
    19. Nettles et al. J Infect Dis 2012;206:1002–11.
    20. Fätkenheuer et al. Nat Med 2005;11:1170–2.
    21. Kilby et al. Nat Med 1998;4:1302–7.
    22. 3TC Australian Product Information
    23. Cahn P et al. Lancet. 2019;393(10167):143-155
    24. Quercia  R et al. J Acquir Immune Defic Syndr 2018;78:125-135.
  • The GEMINI studies evaluated the efficacy of a 2-drug regimen (DTG + 3TC) compared to a traditional 3-drug regimen (DTG + TDF/FTC) in naïve patients and yielded non-inferior results; pooled analysis, 655 (91%) of 716 participants in the two-drug regimen group and 669 (93%) of 717 in the three-drug regimen group had HIV-1 RNA of less than 50 copies per mL at week 48 (adjusted treatment difference −1·7%, 95% CI −4·4 to 1·1)1

    These results demonstrate the non-inferiority of a 2DR of DTG + 3TC compared to a 3DR of DTG + TDF/FTC in treatment naïve HIV-1 positive adult patients1. Achieving viral suppression in treatment naïve patients is generally accepted to represent a higher clinical hurdle compared to switching treatment in stable virologically suppressed patients2.

    ViiV Healthcare are currently generating data in switch populations via two fully powered phase III studies. The TANGO study is a phase III, randomised, open-label, multicentre, parallel group, non-inferiority, 200-week study. Virologically suppressed participants on TAF-based regimens were randomised to continue their 3 or 4-drug TAF-based regimen, or switch to DTG/3TC3. The objective of TANGO is to demonstrate the non-inferior antiviral activity of switching to DTG/3TC QD compared with continuation of TAF-based regimens over 48 weeks. The primary endpoint is subjects meeting snapshot virologic failure criteria at week 483. DTG/3TC was non-inferior to TAF-based regimens (TBR) at Week 48 for both the primary endpoint of virological failure (HIV-1 RNA ≥ 50 c/mL; 0.3% DTG/3TC vs 0.5% TBR, adjusted treatment difference -0.3%, 95% CI -1.2 to 0.7) and secondary endpoint of virological success (HIV-1 RNA < 50 c/mL; 93.2% DTG/3TC vs 93.0% TBR, adjusted treatment difference 0.2%, 95% CI -3.4 to 3.9) as per FDA Snapshot ITT-E analysis4.    

    A second switch study is planned.

    References:

    1. Cahn P et al. Lancet. 2019;393(10167):143-155
    2. US DHHS Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents 2019. http://aidsinfo.nih.gov/guidelines Accessed 31 July 2019
    3. TANGO. Available from: https://clinicaltrials.gov/ct2/show/NCT03446573. Accessed November 2018
    4. van Wyk et al. IAS 2019 Mexico City, Mexico WEAB0403LB
  • The efficacy of Dolutegravir (DTG) and Lamivudine (3TC) has not been studied in patients with neurological complications such as HIV-1-associated neurological disorder (HAND) and HIV-1-associated dementia (HAD). In addition, the correlation between antiretroviral drug penetration and viral efficacy outcomes in the central nervous system remains controversial5. However, DTG is known to have high CNS penetration, and 3TC has lower penetration2-4.

    In the GEMINI studies, patients receiving DTG + 3TC did not report higher rates of CNS related complications compared to those receiving DTG + TDF/FTC at week 481.

    Overall, the CNS safety profile of DTG + 3TC was consistent with the known safety profile of DTG-based regimens and no new CNS safety signals were observed. Neuropsychiatric AEs leading to withdrawal occurred in 10 (1%) and 5 (<1%) of patients on DTG + 3TC and DTG + FTC/TDF respectively, at Week 966.

     

    HAND, HIV-associated neurocognitive disorders; HAD, HIV-associated dementia

     

     

    References:

    1. Cahn P et al. Lancet. 2019;393(10167):143-155
    2. Letendre et al, CROI 2013 Abstract 178LB
    3. Lamuvidine (3TC) Australian Product Information v12.0 11 April 2019
    4. Tivicay Australian Product Information v9.0 11 June 2019
    5. Caniglia EC et al. Neurology. 2014;83(2):134-141
    6. Cahn P et al. IAS 2019 Mexico City, Mexico WEAB0404LB
  • The phase III GEMINI-1 & -2 (DTG + 3TC) and SWORD-1 & -2 (DTG + RPV) studies both demonstrated that treatment with a DTG-based 2DR resulted in low rates of confirmed virological withdrawals (CVW) that was similar to the 3DR comparison arm (summarised below). Within the CVW cases, no subjects developed DTG resistance mutations across SWORD-1, SWORD-2, GEMINI-1 or GEMINI-2. In the GEMINI studies, 2-year data demonstrated a low rate of CVWs; 11 (1.5%) in the DTG + 3TC arm vs 7 (1.0%) in the DTG + TDF/FTC arm, with no treatment emergent resistance mutations in any of the CVW cases. In the SWORD studies, 3-year data demonstrated a low rate of CVWs; 11 (1.1%) to Week 148, and only 6 (0.6%) of these developed NNRTI resistance mutations.

    These data suggest that there is no increased risk of resistance after virological failure on DTG-based 2DR compared to traditional three-drug regimens. DTG-based 2DR have demonstrated a high barrier to resistance over 2 to 3 years, which is consistent to that observed for DTG-based 3DR. 

    CVW defined as two consecutive plasma HIV-1 RNA values ≥200 c/mL on or after Week 24 or a decrease in plasma HIV-1 RNA of <1 log10 c/mL by Week 12. †† CVW defined as a confirmed plasma HIV-1 RNA ≥200 c/mL after a prior ≥ 50c/mL viral load. CAR, current antiretroviral regimen.

     

    References: 

    1. Cahn P et al. Lancet. 2019;393(10167):143-155
    2. Libre JM, et al. Lancet 2018;391:839–49
    3. Aboud M, et al. AIDS 2018; Amsterdam, the Netherlands. Poster THPEB047
    4. van Wyk et al. BHIVA 2019; Bournemouth, UK. Poster P008.

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Date of preparation: August 2019. PM-AU-HVU-WCNT-190008