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Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study

Summary Background The integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains. Methods We used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted. Findings The greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving. Interpretation Using a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks. Funding Bill & Melinda Gates Foundation.


Introduction
Scaling up antiretroviral therapy (ART) in sub-Saharan Africa represents a major achievement, but there are ongoing challenges, including increasing transmitted drug resistance, 1 poor coverage of viral load monitoring, 2 and low numbers of people who have fulfilled the criteria for failure of first-line ART switching to second-line regimens. 3 Until recently, WHO recommended a sequence of first-line tenofovir, lamivudine (or emtricitabine), and efavirenz and second-line zidovudine, lamivudine, and a protease inhibitor in people with first-line failure. 4 However, WHO now recommends use of the integrase inhibitor dolutegravir with tenofovir and lamivudine in people initiating ART and, potentially, in those currently on first-line ART if they have a recent viral load measurement less than 1000 copies per mL. 5 In people with virological failure on tenofovir, lamivudine, and efavirenz, dolutegravir in the context of an optimised nucleoside reverse transcriptase inhibitor background is recommended as a second-line regimen, which most often will be zidovudine, lamivudine, and dolutegravir. Dolutegravir-based regimens are associated with less need to switch to other antiretroviral drugs and there is a lower risk of development of major drug resistance mutations compared with efavirenz-based regimens. 6,7 Dolutegravir therapy also has superior outcomes compared with a boosted protease inhibitor-based regimen in people starting second-line therapy with at least one active nucleoside reverse transcriptase inhibitor. 8 An alternative to this approach to dolutegravir use would be to transition all people on ART to tenofovir, lamivudine, and dolutegravir, unless or until there is sustained virological failure, at which point zidovudine, lamivudine, and a protease inhibitor would be used. Since access to viral load testing is difficult in many countries, this approach has the potential to bring greater public health benefits. However, these benefits should be balanced against concerns over a possible risk of increased resistance to dolutegravir and other drugs. Modelling can help policy makers think through the balance of these considerations in the context of a public health approach.
Furthermore, dolutegravir could be a cause of neural tube defects in the children of a small proportion of women taking dolutegravir at the time of conceptionin a 2018 report, 9 four incidences of neural tube defects occurred in 596 pregnancies, which is above the background expected for efavirenz-based therapy regimens. This finding has raised questions over the use of dolutegravir in women of child bearing age. However, restriction of dolutegravir use in women of child bearing age has a public health cost that policy makers should weigh against the possible neural tube defect risk.
In this study, we used an existing individual-based model of HIV transmission, progression, and the effect of ART to help inform policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains. We aimed to provide quantitative assessment of the risks and benefits of alternative policies for use of dolutegravir to inform ministries of health in their policy decision making in consultation with the communities they serve.

Model description
In this modelling study, we used the HIV Synthesis Model (for full details see appendix). 10 Briefly, this model (programmed in SAS version 9.4) generates a population who are individually tracked, with updates every 3 months, for risk of HIV acquisition. Those who acquire HIV are tracked in terms of their viral load, CD4 cell count, occurrence of WHO stage 3 and 4 conditions, use of specific drugs, presence of resistance mutations, adherence, and drug toxicities. The ongoing effects of a drug regimen (on viral load, drug resistance, and CD4 count, and hence risk of AIDS and death) are dependent on the sum of the activity of each drug in the regimen, accounting for presence of drug resistance mutations, drug potency, and level of adherence. This study was not submitted for ethics committee review as it does not involve research on human subjects.

Setting scenarios
The model is based on sub-Saharan Africa, with 1000 potential setting scenarios generated through simulation. We randomly varied parameters, including the rate of HIV testing, distribution of ART adherence across individuals, the rate of ART interruption, number of switches to a second-line regimen after failure of a first-line regimen (detected by confirmed viral load above 1000 copies per mL), and the ability to measure viral load as indicated, 11 within plausible bounds for settings in the region. For a complete list of parameters see the appendix (p 27).
For each setting scenario, we considered the situation in 2018 and compared outcomes of potential regimen policies over a 20 year time horizon (50 years in sensitivity analysis). The regimen policies considered are described in table 1. Our reference regimen policy was a continuation of the approach of use of tenofovir, lamivudine, and efavirenz in first-line regimens. We also considered four further policies, involving use of tenofovir, lamivudine, and dolutegravir. These policies consider tenofovir, lamivudine, and dolutegravir use with or without dependence on intention to have (more) children

Research in context
Evidence before this study The integrase inhibitor dolutegravir is expected to have a role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barriers to resistance, good tolerability, and low cost. However, which policy for use of dolutegravir will produce the greatest population health benefits is unclear because of considerations over the potential for virological failure and drug resistance spread if used with nucleoside reverse transcriptase inhibitors to which HIV is resistant, and a possible association between dolutegravir and an increased risk of neural tube defects in infants if used at conception in women. We searched Web of Knowledge using the terms "dolutegravir" and "model*" on Aug 14, 2018, with no date or language restrictions, and identified 74 papers. When we reviewed these papers we did not identify any that used modelling to quantify the risks and benefits of different policies for introduction of dolutegravir in sub-Saharan Africa.

Added value of this study
We used an existing individual-based model of HIV transmission and progression in adults to compare predicted outcomes of alternative regimen policies. The model takes into account the effects of drug resistance and potency in determining viral load and clinical treatment outcomes, and the effect of a potentially increased risk of neural tube defects in infants if dolutegravir is taken by women at conception. We considered policies of using a regimen containing tenofovir, lamivudine, and dolutegravir for all individuals on ART, or of making tenofovir, lamivudine, and dolutegravir dependent on viral load suppression (whether on first-line or second-line ART) or, for women, intention to have (more) children.

Implications of all the available evidence
Using a standard disability adjusted life-year framework for comparing health outcomes from a public health perspective, we found that the benefits of transition to a regimen of tenofovir, lamivudine, and dolutegravir for all people on ART, without dependence on viral suppression or intention to have (more) children, substantially outweighed the risks. Our evaluation provides quantitative assessment to guide policy formulation by ministries of health on the use of dolutegravir.
or current viral load suppression being docu mented. The rationale for restriction of use of tenofovir, lamivudine, and dolutegravir to those with viral sup pression is due to concern that resistance to tenofovir and lamivudine is likely to have developed in those with virological failure, making dolutegravir the only fully active drug and meaning the risk of resistance to dolutegravir is increased. The extent of any residual effects on viral replication due to continued exposure to lamivudine and tenofovir in these circumstances is uncertain. 12,13 Policies involving tenofovir, lamivudine, and dolutegravir depending on viral suppression also involve use of zidovudine rather than tenofovir in newly initiated second-line regimens. This approach is broadly consistent with current WHO interim guidance. 5 We refer throughout this Article to use of lamivudine in regimens, but emtricitabine might be used instead. Dependence on a woman's intention to have (more) children relates to concern over the risk of neural tube defects if dolutegravir is used at the time of conception. Policies with this dependence are envisaged to offer dolutegravir to women only upon reaching the point of intention to have no more children. We assume a rate of reaching a point of intention to have no more children to be 0·005 per 3 months from age 25 years. This rate results in 16% of women aged 15-55 years not intending to have (more) children, which is consistent with data from Demographic and Health Surveys. 14, 15 We assume that women who intend to have no more children are able to access and use contra ception, and that contraceptive efficacy is 80% (50% in sensitivity analysis). We refer to the policy for which tenofovir, lamivudine, and dolutegravir use is dependent on neither viral suppression nor intention to have more children as tenofovir, lamivudine, and dolutegravir for all.
Assumptions for resistance acquisition with dolutegravir-containing regimens are informed by data on the risk of resistance mutations existing at virological failure and studies of monotherapy, which were mainly done in people with existing viral suppression but include a small study of dolutegravir monotherapy in ART-naive people with viral loads less than 100 000 copies per mL. 6  resistance to dolutegravir than to efavirenz. Dolutegravir is generally associated with a lower risk of toxicity than are efavirenz and protease inhibitors, resulting in reduced discontinuation. 6,16,19,23 We assumed that the risk of neurological toxicity with dolutegravir was half that for efavirenz, and assumed that dolutegravir has 1·5 times higher potency than does efavirenz (lower than boosted protease inhibitors, which were assumed to have potency of 2), consistent with its effect as a monotherapy 17 (although insufficient for its clinical use as monotherapy). We assumed that the residual effects of tenofovir in the presence of the Lys65Arg mutation and lamivudine in the presence of the Met184Val mutation mean that they each have 0·25 times full drug activity in this situation. 12,13 We present our main results as the mean and mean difference compared with the policy of tenofovir, lamivudine, and efavirenz for all, with a 90% range reflecting variation across setting scenarios and 95% CI reflecting stochastic simulation variability.
Although these assumptions formed our base assumptions, we considered the possibility of different assumptions for dolutegravir in a proportion of our 1000 setting scenarios. These proportions for alternative assumptions were selected on the basis of the perceived probability that they hold. Thus, we considered that potency of dolutegravir could be 1 (20% of setting scenarios), 1·25 (20% of setting scenarios), or 2 times (5% of setting scenarios) that of efavirenz, instead of 1·5 times (55% of setting scenarios); that development of resistance to dolutegravir could be only 3 times lower than for efavirenz (20% of setting scenarios); that the risk of neurological toxicity using dolutegravir could be equal to that of efavirenz (20% of setting scenarios); and that the residual effects of tenofovir and lamivudine in the presence of the Lys65Arg and Met184Val mutations was 0·0 rather than the 0·25 of a fully active drug (20% of setting scenarios in each case). We also considered different degrees to which viral load monitoring was implemented (25% of setting scenarios each for probabilities of 0·0, 0·10, 0·25, and 0·85 of a viral load test being done, and the result delivered in accordance with the recommended monitoring strategy) and ART regimen was switched after viral failure was determined (probabilities of 0·05 in 30% of setting scenarios, 0·20 in 50% of setting scenarios, and 0·50 in 20% of setting scenarios per 3 months). We determined these alternative assumptions by random independent sampling for each setting scenario. Full details of the distribution of all sampled parameters used in deriving our 1000 setting scenarios are shown in the appendix (p 27). Excess risk of neural tube defects in babies of women on dolutegravir at the time of conception was assumed to be 0·58% (4 in 596=0·67% minus the 0·09% background rate in HIV-negative women); we did sensitivity analyses using values of 1% and 3%.
The range of HIV epidemic and programmatic characteristics in 2018 for our 1000 setting scenarios are shown in table 2 with comparable observed data.

Role of the funding source
The funder of the study had no role in study design, modelling approach, interpretation, or writing of the report. The corresponding author had full access to all model programs and outputs in the study and had final responsibility for the decision to submit for publication.

Results
Consequences of the various regimen policies for the use of each drug are shown in table 3. A mean of 98% of people receiving ART over 20 years would be expected to be on dolutegravir with the policy of tenofovir, lamivudine, and dolutegravir for all, compared with only 43% if its use was dependent on viral load suppression and being male or a woman not intending to have (more) children.
The predicted effect on viral load suppression is shown in people on ART over a mean of 1 year, 5 years, and 20 years (table 3). Restriction of tenofovir, lamivudine, and dolutegravir use in women who intend to have (more) children was predicted to lead to poorer overall viral suppression over 1 year, 5 year, and 20 year time periods. Dependence of use of tenofovir, lamivudine, and dolutegravir on viral load suppression was predicted to lead to reduced overall viral suppression over 1 year and 5 year time periods, although we found little difference in viral suppression over the 20 year time period. Restriction of analysis to the subgroup of people with viral loads greater than 1000 copies per mL and presence of drug mutations to tenofovir and lamivudine at baseline revealed a markedly higher predicted proportion of people with viral load suppression over the 1 year time period for the policy of tenofovir, lamivudine, and dolutegravir for all compared with the other policies, because with this policy a switch was made to tenofovir, lamivudine, and dolutegravir and with the dependence on viral suppression policies no switch was made. This difference persisted with longer follow-up durations but was less marked because of identification of virological failure and switching to zidovudine, lamivudine, and dolutegravir or zidovudine, lamivudine, and a protease inhibitor occurs with the policy of tenofovir, lamivudine, and dolutegravir dependent on viral suppression. Since this subgroup has a tendency for poorer adherence, and with our assumptions about resistance to dolutegravir and the residual activity of tenofovir and lamivudine, the percentage of patients with viral sup pression was predicted to remain at less than 60% with all policies, including tenofovir, lamivudine, and dolutegravir for all. Use of tenofovir, lamivudine, and dolutegravir was predicted to lead to more future dolutegravir resistance com pared with tenofovir, lamivudine, and dolutegravir dependent on viral sup pression (mean 6·7%, 90% range across setting scenarios 1·2-18·5 vs 4·4%, 0·7-12·9% in the context of no dependence on intention to have more children; table 3). In the final year of the 20 year time horizon, the corresponding figures were 9·4% (1·6-26·3) and 7·6% (1·4-21·3; data not shown).
The number of deaths due to AIDS in people on ART showed a similar pattern to overall viral suppression over the 1 year and 5 year time horizons, with AIDS deaths declining with increasing use of tenofovir, lamivudine, and dolutegravir, and at their lowest for the policy of tenofovir, lamivudine, and dolutegravir for all (table 3). Differences between policies in people on ART with viral load suppression translate into substantial differences in AIDS deaths because of the high death rate in those without viral suppression at any point in time. The lower death rate in those without viral suppression in the tenofovir, lamivudine, and dolutegravir for all policy is due to a lower CD4 count, even within the CD4 count less than 200 cells per µL range.  The predicted proportion of HIV-positive women for whom mother-to-child transmission occurs also followed this pattern. The reduction in risk of mother-tochild transmission with the tenofovir, lamivudine, and dolutegravir for all policy was greater in absolute terms than the increased risk of neural tube defects with the same policy (table 3).
There were substantially more DALYs averted with the tenofovir, lamivudine, and dolutegravir for all policy than for any of the policies in which tenofovir, lamivudine, and dolutegravir use was dependent on viral suppression or intention to have no (more) children. The lowest cost was for the tenofovir, lamivudine, and dolutegravir for all and tenofovir, lamivudine, and dolutegravir dependent on viral suppression only policies (figure). For net DALYs, the benefit of the tenofovir, lamivudine, and dolutegravir for all policy was greater still, reflecting the health gains elsewhere due to the lower costs, mainly because of reduced use of protease inhibitors, which are more than 7 times the cost of dolutegravir. The policy of tenofovir, lamivudine, and dolutegravir for all was the most costeffective in 83% of setting scenarios, with tenofovir, lamivudine, and dolutegravir dependent on viral suppression only the most cost-effective policy in 16% of setting scenarios. Tenofovir, lamivudine, and dolutegravir dependent on intention to have (more) children only was cost-effective in 1% of setting scenarios and tenofovir, lamivudine, and dolutegravir dependent on viral suppression and intention to have (more) children was costeffective in less than 1% of setting scenarios (table 4). Tenofovir, lamivudine, and efavirenz for all was not costeffective in any setting scenario.
Tenofovir, lamivudine, and dolutegravir for all remained the most effective and cost-effective policy in several sensitivity analyses (table 4).

DALYs averted
Net DALYs averted (% of setting scenarios in which policy is the most cost-effective*)

Discussion
Supporting earlier work, 31 we found that the benefits of a policy using tenofovir, lamivudine, and dolutegravir in people currently on first-line or second-line regimens, without any dependence on viral load or consideration of use of zidovudine rather than tenofovir, outweighed the risks. We also found that there were substantial net public health benefits of use of tenofovir, lamivudine, and dolutegravir, including in women of child bearing age, in terms of DALYs incurred in the whole population, and considering DALYs incurred as a result of birth of a child with a neural tube defect. The benefits of the policy of tenofovir, lamivudine, and dolutegravir for all compared with tenofovir, lamivudine, and dolutegravir dependent on viral suppression are due to proactive use of dolutegravir without requiring a viral load measure or a switch algorithm to have been fulfilled. Even in the subgroup of people with viral load greater than 1000 copies per mL and presence of drug mutations to tenofovir and lamivudine at baseline, switching to tenofovir, lamivudine, and dolutegravir was predicted to bring benefits compared with the policies of tenofovir, lamivudine, and dolutegravir dependent on viral suppression, as members of this subgroup must await fulfilment of the viral load failure criteria and subsequent switch to zidovudine, lamivudine, and dolutegravir. These benefits occur despite the fact that with the tenofovir, lamivudine, and dolutegravir for all policy, the proportion of people on ART with viral suppression over 1 year, 5 years, and 20 years is predicted to be low (55% on average over 5 years) because of the higher tendency for poor adherence in this subgroup and the potential for dolutegravir resistance to emerge. Overall, dolutegravir resistance (transmitted or acquired) is predicted to be present in 6·7% of people over a 20 year period under the policy of tenofovir, lamivudine, and dolutegravir for all compared with 4·4% under the policy of tenofovir, lamivudine, and dolutegravir dependent on viral sup pression only. Our findings were consistent in several sensitivity analyses, including one in which we assumed that lamivudine and tenofovir had no effect on viral replication in the presence of the Met184Val and Lys65Arg mutations, and one over a 50 year time horizon.
More children are predicted to be prevented from acquiring HIV through mother-to-child transmission than are born with neural tube defects with a tenofovir, lamivudine, and dolutegravir for all policy. When calculating DALYs in children born with HIV, we assumed availability of good HIV diagnosis and treatment services in infants meaning less poor consequences for an HIV infection in a child (0·1 DALYs per year) than for a child born with a neural tube defect (1 DALY per year). Without such good availability of diagnosis and treatment services, the DALY consequences of a child born with HIV would be worse and the benefits of a policy of tenofovir, lamivudine, and dolutegravir for all greater.
Our study has limitations. As for any cost-effectiveness analysis over a long time horizon, we relied on a model for predictions of the long-term effect of the alternative policies. We made assumptions about the benefits and harms associated with different ART regimens on the basis of available data, which included different levels of uncertainty. The reports 9 of neural tube defects in infants born to women using dolutegravir are the first indication of this risk and planned further follow-up of women who have been similarly exposed could reduce uncertainty over this risk. This situation emphasises that studies of novel drugs during the development phase and beyond-including in women before conception, during pregnancy, and postpartum-are crucial to support future decision making. Evidence of the anti retroviral effects of dolutegravir is more extensive, including recent data from a randomised trial in Cameroon. 32 Our results are robust to modifications in assumptions within plausible levels of uncertainty, which supports our main conclusions. We recognise that our assumption that women can access contraception from the time of intention to have no (more) children does not reflect reality in many settings, and partly accounted for this by considering both an 80% and 50% effectiveness of contraception. We did not consider a policy option in which women could move between efavirenz and dolutegravir between pregnancies because we considered that this would be unrealistic to implement.
Our results could be used to inform relevant constituencies about the risks and benefits of alternative dolutegravir-containing ART regi men policy options, and to help gain an informed representative view from people with HIV that can be considered during development of ministry of health policies. If ministries of health decide to give dolutegravir to women who might become pregnant without adequate consultation and it then becomes clear that there is a real risk of neural tube defects, this could undermine confidence in treatment and in the ministry of health, although the extent to which ART uptake could be affected is difficult to quantify. However, we recognise that there will be substantial challenges in achieving such effective consultation.
In conclusion, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed any risks when using a standard DALY framework to compare health outcomes from a public health perspective.

Contributors
All authors conceptualised the analysis, had substantial input into the modelling plan and advised on relevant data, interpreted the results, and made comments on the manuscript drafts. AP, VC, FN, and LB-M wrote and executed the modelling program. ANP was the overall study lead.

Declaration of interests
DK is a consultant to ViiV Healthcare, Gilead Sciences, and Merck, and reports research funding from all three companies, and Janssen and AbbVie. JM reports grant support from the Bill & Melinda Gates Foundation, USAID, Brigham Women's Hospital/AIDS Clinical Trials Group (ACTG) to the University of Pittsburgh Virology Support Laboratory, Janssen Pharmaceuticals, and Gilead Sciences, personal fees from University of Pittsburgh and Gilead Sciences, and share options in Co-Crystal Pharma, Inc. FV reports grants, personal fees and non-financial support from Viiv Healthcare and Gilead Sciences, personal fees and non-financial support from Mylan and Roche, personal fees from Adcock Ingram, Aspen Healthcare, J&J, and Merck, and grants from the Bill and Melinda Gates Foundation, Unitaid, USAID, and South African MRC, outside the submitted work. AP is a member of advisory boards for Gilead Sciences, ViiV Healthcare, Merck, and Jannsen, has spoken at non-commercial symposia funded by Gilead Sciences, ViiV Healthcare, Merck, and Jannsen, and is chair of the antiretrovirals section of the European AIDS Clinical Society guidelines. ADL reports research grants from ViiV Healthcare, Merck, and Gilead Sciences (Fellowship programme), and paid consultancies with ViiV Healthcare, Merck, Janssen, AbbVie, and Gilead Sciences. AW reports being on advisory boards for and grants from Janssen, Merck, Gilead Sciences, ViiV Healthcare, and CLJI. AC reports institutional unrestricted educational grants from ViiV Healthcare, AbbVie, BMS, MSD, and Gilead Sciences. All other authors declare no competing interests.

Data sharing
Model programs and simulations are accessible in Figshare.