HIV Drug Resistance (HIVDR) and Antimicrobial Resistance (AMR): Science and Action IAS 2017 Paris 24th July 2017 Modelling the cost and cost-effectiveness of responses to HIV drug resistance  Working Group on Modelling Potential Responses to High Levels of pre-ART Drug Resistance in Sub-Saharan Africa

No conflicts of interest to declare

Background The World Health Organization recommends drug resistance surveillance in people initiating antiretroviral therapy (ART). If high levels of pre-ART non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance are identified, options for ART program response must be considered. Potential policy options include: - transition from efavirenz to dolutegravir - introduction of individual level drug resistance testing pre-ART Modelling can inform the most cost effective choice

Objective To evaluate the effectiveness and cost-effectiveness of policy options in the presence of pre-ART NNRTI resistance, in the context of sub-Saharan Africa

Policy options considered – from 2018 No change in policy For all ART initiators / re-initiators: resistance test at treatment initiation – use dolutegravir if NNRTI resistance detected For all ART initiators / re-initiators: dolutegravir as 1st line regimen

Modelling approach - 1 Individual-based simulation model of HIV transmission, effect of ART, considering specific drugs and resistance mutations Model based around southern Africa with multiple potential setting-scenarios generated through simulation Parameters such as ART adherence profile ART interruption rate Switch rate after first line failure varied randomly within plausible bounds for settings in the region.

Characteristics of setting scenarios in 2017 Median; 90% range Examples of data from settings HIV prevalence (age 15-49) 11% (6% - 22%) HIV incidence age 15-49 (/100 person years) 0.72 (0.15 – 2.00) Proportion of HIV positive people diagnosed 79% (60% - 90%) Proportion of all HIV positive people on ART 63% (44% - 80%) Proportion of ART experienced people who 4% (0.5% - 13%) have started second line (boosted PI) ART Of people on ART, proportion with VL < 1000 83% (71% - 88%) Of ART initiators % with NNRTI resistance in majority virus 10% (1% - 34%) in minority or majority virus 12% (2% - 38%) % of ART initiators with prior ARV exposure 18% (8% - 35%) N=5000 setting scenarios. People age 15-64 unless stated. Zimbabwe DHS (2015) 14%, Tanzania (2011) 5%, Uganda (2011) 9%, Lesotho (2014 )25%. MPHIA (0.37%), ZAMPHIA (0.66%), ZIMPHIA (0.45%), Justman (2.4%), Huerga (0.39%) MPHIA (73%), ZAMPHIA (67%), ZIMPHIA (74%), Huerga (75%), Maman (77%) (see also Kim et al, which suggests undisclosed diagnosed HIV) ZAMPHIA (57%), MPHIA (64%), ZIMPHIA (64%), Maman (68%), Huerga (52%) MoH Malawi (1.5%), 16% by 10 years on ART, South Africa (Department of Health, SA) World Bank South Africa (60%-88% over districts), ZAMPHIA (89%), MPHIA (91%), ZIMPHIA (87%), Maman (91%), Huerga (90%), Brown (90%) WHO GAP resistance, Angola (14%), Botswana (8%), Cuba (8%), Mexico (10%), Papua New Guinea (16%) and South Africa (14%) (Afonso, Rowley, Pérez , Avila-Ríos, Lavu, National Institute for Communicable Diseases, SA)

Modelling approach - 2 For each setting scenario, we consider the situation with pre-ART NNRTI drug resistance in 2017 and compare outcomes of potential policy options over the next 20 years. Assumptions on effectiveness of dolutegravir vs efavirenz* - lower rate of resistance - greater potency - greater tolerability Cost effectiveness analysis: health systems perspective, 3% discount rate, cost effectiveness threshold $500. Absolute costs and DALYs relevant for a country of population size of approx 10 million adults in 2017 *e.g. Walmsley et al 2013 and 2015; van Lunzen et al 2012; Fettiplace et al 2017; Nicole et al 2016; de Boer et al 2016;

Mean percent with viral load < 1000 cps/mL 2018 – 2038 according to policy option Setting scenarios where > 10% of ART initiators have NNRTI resistance in 2017 Policy option No change Pre-ART resistance test Dolutegravir 1st line Percent Mean difference in percent compared with no change in policy (95% CI; 90% range): Pre-ART resistance test: +6.3 (+6.1 – +6.5; +1.7 – +13.0). Dolutegravir 1st line: +9.2 (+9.0 – +9.4; +2.7 – +16.8).

Mean death rate in people on ART 2018 – 2038 according to policy option Setting scenarios where > 10% of ART initiators have NNRTI resistance in 2017 Policy option No change Pre-ART resistance test Dolutegravir 1st line Rate / 100 person years Mean difference in percent compared with no change in policy (95% CI; 90% range). Pre-ART resistance test: -0.62 (-0.64 – -0.60; -1.43 - -0.18). Dolutegravir 1st line: -0.99 (-1.01 – -0.98; -2.00 - -0.28).

Mean annual cost over 2018-2038 according to policy option Setting scenarios where > 10% of ART initiators have NNRTI resistance in 2017 Policy Option No change Pre-ART resistance test Dolutegravir 1st line Milions of US $ (discounted at 3% per annum) Unit costs. Efavirenz $38 Dolutegravir $44 Atazanavir/r $213 Resistance test $100

Increment in cost and DALYs averted for each policy option, relative to no change in policy Setting scenarios where > 10% of ART initiators have NNRTI resistance in 2017 Increment in annual cost (mean 2018- 2038 ($m)* Pre-ART resistance test No change Dolutegravir 1st line *discounted at 3% per annum DALYs averted (per year)

Increment in cost and DALYs averted for each policy option, relative to no change in policy Setting scenarios where > 10% of ART initiators have NNRTI resistance in 2017 Increment in annual cost (mean 2018- 2038 ($m)* Policy option of choice due to lowest cost and highest DALYS averted Pre-ART resistance test No change Dolutegravir 1st line *discounted at 3% per annum DALYs averted (per year)

Difference in mortality rate for dolutegravir 1st line compared with no change, according to proportion of ART initiators with NNRTI resistance 27.5%- 25%- 22.5%- 20%- 17.5%- 15%- 12.5%- 10%- 7.5%- 5%- 2.5%- 0%- Proportion of all ART initiators with NNRTI resistance in 2017 95% confidence intervals have width narrower than +/- 1.0 Reduction in number of deaths per year per 1000 people on ART

MOAX0202LB  MOAX0202LB  Comments - 1 Sensitivity analyses suggest that cost effectiveness of transition to dolutegravir holds even in a worst case scenario for dolutegravir effectiveness High levels of pre-treatment drug resistance should prompt review of ART program quality. We focussed on low income settings in sub-Saharan Africa – elsewhere generic dolutegravir is unavailable. There are few data on safety of dolutegravir in pregnancy (although see Zash et al; Abstract MOAX0202LB).

MOAX0202LB  MOAX0202LB  Comments - 2 Dolutegravir dose may need to be increased with rifampicin. Generic fixed dose combination with dolutegravir not yet available These results were presented to the WHO Guidelines Development Group on the Public Health Response to Pre-treatment HIV Drug Resistance. In principle, the approach used here could be used to inform policy relating to antimicrobial resistance more broadly, albeit that the policy options often will not include use of new effective drugs.

Conclusions A future transition from efavirenz to dolutegravir is predicted to be effective and cost effective in low income settings in sub-Saharan Africa, regardless of the level of pre-ART NNRTI resistance. Timing and exact nature of the transition will depend on several factors, including the current level of pre-ART NNRTI resistance.

Acknowledgements Working Group on Modelling Potential Responses to High Levels of pre-ART Drug Resistance in Sub-Saharan Africa Andrew Phillips Valentina Cambiano Timothy Hallett Michael R. Jordan Meg Doherty Andrea De Luca Jens Lundgren Tsitsi Apollo John Mellors Fumiyo Nakagawa Brooke Nichols Urvi Parikh Elliot Raizes Paul Revill Deenan Pillay Tobias Rinke de Wit Kim Sigaloff Diane Havlir Dan Kuritzkes Anton Pozniak David van de Vijver Marco Vitoria Mark Wainberg Silvia Bertagnolio Funding support from WHO in finalising results for the Guidelines Development Group and Bill& Melinda Gates Foundation, including through the HIV Modelling Consortium