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(dolutegravir Generic) Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa: a modeling study
 
 
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"The results of our modelling-based analysis predict that transition to use of dolutegravir instead of efavirenz in regimens for all ART initiators is likely to bring health benefits irrespective of the level of NNRTI pretreatment drug resistance because of its higher potency, lower risk of selection for resistance, and lower incidence of discontinuation because of toxicity..."
 
from Jules: at CROI several years ago 2015 WHO held a pre CROI meeting where EFV 400mg was being pushed for first line global use, and I was the only person pushing for DTG first line, it was an obvious call, the data & the future was clear; EFV 400 or full dose for that matter have so much baggage & risk. Now things are changed .......
 
Generic $75 Dolutegravir Fixed Dose - New single-day pill (dolutegravir) for HIV treatment promises more bang for less buck - (09/25/17)
 
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COMMENT - Resistance to first-line ART and a role for dolutegravir [Lancet HIV] - With large numbers of patients in sub-Saharan Africa needing effective ART, restricted budgets, and decreasing international funding, new strategies are urgently required to guide both cost-effective first-line and second-line ART to meet WHO's 90-90-90 targets in the region.....In a recent study4 of dolutegravir and two nucleoside reverse transcriptase inhibitors (NRTIs) compared with a WHO-recommended protease inhibitor ritonavir-boosted lopinavir and two NRTIs as second-line treatments, dolutegravir was superior to the protease inhibitor. This indicates that dolutegravir potentially has an important place as a second-line regimen in resource-limited settings where costs of protease inhibitors are prohibitive. The cost advantage of a cost-effective, first-line NNRTI-based regimen, followed by a cost-effective, dolutegravir-based second-line regimen could be substantial, and the potential savings on the diminished use of protease inhibitors could possibly offset the cost of pretreatment drug resistance testing to guide treatment choice in first line. we see several challenges. The authors do comment on some of these, namely that not enough evidence exists to guide dolutegravir use in pregnancy and tuberculosis and the possibility of increased risk of immune response inflammatory syndrome (IRIS), particularly in individuals with low CD4 cell counts,5 but they do not seem to consider these factors as caveats for use in first-line therapy. Pregnancy, tuberculosis, and IRIS are common in patients receiving ART in sub-Saharan Africa, and ongoing trials are testing dolutegravir in pregnant women and in patients with tuberculosis, but outcomes of these are not yet known.6, 7, 8
 
Pdf attached
 
Download the PDf here
 
Download the PDf here
 
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(Dolutegravir) Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa: a modeling study
 
"In conclusion, a transition from efavirenz-containing first-line regimens to generic dolutegravir-containing regimens is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa at any level of NNRTI pretreatment drug resistance. However, with high prevalence of NNRTI pretreatment drug resistance, the negative effect on the population health of postponing the transition to dolutegravir increases substantially and thus increases the urgency of this intervention."
 
"The results of our modelling-based analysis predict that transition to use of dolutegravir instead of efavirenz in regimens for all ART initiators is likely to bring health benefits irrespective of the level of NNRTI pretreatment drug resistance because of its higher potency, lower risk of selection for resistance, and lower incidence of discontinuation because of toxicity. However, the extent of benefits is predicted to be greatest in settings with high levels of NNRTI pretreatment drug resistance. Programmes in settings with even moderately increased NNRTI pretreatment drug resistance should plan to transition to use dolutegravir as a first-line drug; as well as being cost-effective, this is likely to also be cost saving. The appropriate timescale for such plans will depend on several factors, of which the actual current level of NNRTI pretreatment drug resistance is an important one. A generic, fixed-dose combination of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate is expected to be available in 2018. A recent announcement24 suggests that the cost of this regimen has become lower than that assumed in our modelling ($75 per year compared with $106), suggesting an even greater cost saving than that we projected. As a result of the WHO Guidelines Development Group process, at which these results were presented, a consensus statement was made that countries in which the prevalence of pretreatment HIV drug resistance to NNRTIs among people initiating first-line ART, irrespective of previous ARV drug exposure, is 10% or more should urgently consider an alternative first-line ART regimen that does not contain NNRTIs.9 The WHO alternative first-line drug to an NNRTI in the 2016 guidelines is dolutegravir."
 
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HIV Lancet Nov 2017- Andrew N Phillips, Valentina Cambiano, Fumiyo Nakagawa, Paul Revill, Michael R Jordan, Timothy B Hallett, Meg Doherty, Andrea De Luca, Jens D Lundgren, Mutsa Mhangara, Tsitsi Apollo, John Mellors, Brooke Nichols, Urvi Parikh, Deenan Pillay, Tobias Rinke de Wit, Kim Sigaloff, Diane Havlir, Daniel R Kuritzkes, Anton Pozniak, David van de Vijver, Marco Vitoria, Mark A Wainberg*, Elliot Raizes, Silvia Bertagnolio, Working Group on Modelling Potential Responses to High Levels of Pre-ART Drug Resistance in Sub-Saharan Africa
 
Summary
 
Background

 
There is concern over increasing prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance in people initiating antiretroviral therapy (ART) in low-income and middle-income countries. We assessed the effectiveness and cost-effectiveness of alternative public health responses in countries in sub-Saharan Africa where the prevalence of pretreatment drug resistance to NNRTIs is high.
 
Methods
 
The HIV Synthesis Model is an individual-based simulation model of sexual HIV transmission, progression, and the effect of ART in adults, which is based on extensive published data sources and considers specific drugs and resistance mutations. We used this model to generate multiple setting scenarios mimicking those in sub-Saharan Africa and considered the prevalence of pretreatment NNRTI drug resistance in 2017. We then compared effectiveness and cost-effectiveness of alternative policy options. We took a 20 year time horizon, used a cost effectiveness threshold of US$500 per DALY averted, and discounted DALYs and costs at 3% per year.
 
Findings
 
A transition to use of a dolutegravir as a first-line regimen in all new ART initiators is the option predicted to produce the most health benefits, resulting in a reduction of about 1 death per year per 100 people on ART over the next 20 years in a situation in which more than 10% of ART initiators have NNRTI resistance. The negative effect on population health of postponing the transition to dolutegravir increases substantially with higher prevalence of HIV drug resistance to NNRTI in ART initiators. Because of the reduced risk of resistance acquisition with dolutegravir-based regimens and reduced use of expensive second-line boosted protease inhibitor regimens, this policy option is also predicted to lead to a reduction of overall programme cost.
 
Interpretation
 
A future transition from first-line regimens containing efavirenz to regimens containing dolutegravir formulations in adult ART initiators is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa at any prevalence of pre-ART NNRTI resistance. The urgency of the transition will depend largely on the country-specific prevalence of NNRTI resistance.
 
Funding
 
Bill & Melinda Gates Foundation, World Health Organization.
 
Introduction

 
More than 18 million people in sub-Saharan Africa are now on antiretroviral therapy (ART). The standard WHO-recommended first-line regimen is the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz plus two nucleoside analogue reverse transcriptase inhibitors (usually lamivudine [3TC] or emtricitabine [FTC]) plus tenofovir disoproxil fumarate (TDF).1 Survey results and programme data suggest that more than 85% of people receiving treatment in several countries in southern Africa have viral loads of less than 1000 copies per mL.2, 3 However, HIV drug resistance, particularly to efavirenz, in people initiating ART has been increasing, with prevalence of more than 10% reported in several countries.4, 5, 6 Individuals with NNRTI-resistant HIV have two to three times greater risk of the ART regimen not achieving and maintaining virus suppression.7, 8, 9 In response to this concern, WHO recommends the routine implementation of pretreatment drug resistance surveys in ART initiators to guide ART programmatic responses in countries with increased prevalence of pretreatment drug resistance.10, 11, 12 ART initiators include those who have never been exposed to antiretroviral drugs and those with previous antiretroviral drug exposure, either because they have previously initiated ART but since interrupted or because they have previously been exposed to antiretroviral drugs for prevention of mother-to-child transmission of HIV. Pretreatment drug resistance is an operational definition and can result from transmitted resistance and acquired resistance developed during previous use of antiretroviral drugs.
 
Research in context
 
Evidence before this study

 
HIV drug resistance, particularly to efavirenz, in people initiating antiretroviral therapy (ART) is becoming more common, with a prevalence of more than 10% in several countries in sub-Saharan Africa. Individuals with HIV resistant to non-nucleoside reverse transcriptase inhibitor (NNRTI) are at 2-3-fold greater risk of the ART regimen not achieving and maintaining virus suppression. The appropriate public health response to the increased prevalence of NNRTI drug resistance in sub-Saharan Africa is unclear. We searched Web of Knowledge for reports in English and published until Aug 8, 2017, using the following search terms: hiv* AND resistan* AND (efavirenz OR non-nucleoside OR NNRTI) AND cost*. Few studies have addressed cost-effectiveness in the context of sub-Saharan Africa. We did not identify any cost-effectiveness study that included consideration of transition to a dolutegravir-containing first-line ART regimen as an option for responding to high prevalence of NNRTI pretreatment HIV drug resistance.
 
Added value of this study
 
A transition from efavirenz-based first-line regimens to regimens based on dolutegravir generic formulations in ART initiators is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa. Benefits are expected to be particularly substantial in populations with high prevalence of HIV drug resistance to NNRTI.
 
Implications of all the available evidence
 
Countries in sub-Saharan Africa with substantial prevalence of NNRTI drug resistance in ART initiators should begin to plan a managed transition from efavirenz to dolutegravir generic formulations in first-line ART regimens. The urgency of the transition depends on the country-specific prevalence of NNRTI pretreatment HIV drug resistance.
 
There are various possible policy options in response to increased NNRTI pretreatment drug resistance. One option is to test for HIV drug resistance at treatment initiation, with use of dolutegravir, the WHO-recommended alternative first-line regimen instead of efavirenz if NNRTI resistance is detected. A second option is to transition the standard first-line ART regimen to dolutegravir in all ART initiators, obviating the need for drug resistance testing in new initiators. Both policies could also be considered for implementation only among ART initiators with self-reported antiretroviral drug exposure, rather than in all ART initiators. Each option has different effects on viral suppression, future transmission of HIV drug resistance, and, ultimately, clinical disease, death, and disability-adjusted life-years (DALYs, a measure of overall disease burden that is expressed as the number of healthy years of life lost because of illness, disability, or early death) incurred in the entire adult population. However, responses need to be guided not only by what is predicted to be the most effective option for averting DALYs in the population but also by cost-effectiveness. If the cost per DALY averted is too high, then the resources could probably be used elsewhere in the health-care system to avert more DALYs.
 
Here we address the policy problem of how low-income countries in sub-Saharan Africa can respond to increasing prevalence of NNRTI pretreatment drug resistance. The findings of this analysis were considered by a WHO Guidelines Development Group tasked to develop guidelines for the public health response to pretreatment HIV drug resistance.
 
Discussion
 
The results of our modelling-based analysis predict that transition to use of dolutegravir instead of efavirenz in regimens for all ART initiators is likely to bring health benefits irrespective of the level of NNRTI pretreatment drug resistance because of its higher potency, lower risk of selection for resistance, and lower incidence of discontinuation because of toxicity. However, the extent of benefits is predicted to be greatest in settings with high levels of NNRTI pretreatment drug resistance. Programmes in settings with even moderately increased NNRTI pretreatment drug resistance should plan to transition to use dolutegravir as a first-line drug; as well as being cost-effective, this is likely to also be cost saving. The appropriate timescale for such plans will depend on several factors, of which the actual current level of NNRTI pretreatment drug resistance is an important one. A generic, fixed-dose combination of dolutegravir plus lamivudine plus tenofovir disoproxil fumarate is expected to be available in 2018. A recent announcement24 suggests that the cost of this regimen has become lower than that assumed in our modelling ($75 per year compared with $106), suggesting an even greater cost saving than that we projected. As a result of the WHO Guidelines Development Group process, at which these results were presented, a consensus statement was made that countries in which the prevalence of pretreatment HIV drug resistance to NNRTIs among people initiating first-line ART, irrespective of previous ARV drug exposure, is 10% or more should urgently consider an alternative first-line ART regimen that does not contain NNRTIs.9 The WHO alternative first-line drug to an NNRTI in the 2016 guidelines is dolutegravir.
 
Although recommended as part of first-line therapy in high income settings,25 some uncertainties remain over dolutegravir use. Data on safety in pregnancy are only just accumulating.26 There is also a concern that an interaction between dolutegravir and the tuberculosis drug rifampicin could reduce drug levels when used concomitantly, leading to excess risk of virological failure if the dose of dolutegravir is not increased.27 It remains unclear whether the extent of the reduction is such that that increasing the dolutegravir dose (from once to twice a day) is required when coadministered with rifampicin, given that dolutegravir is known to be efficacious at a dose one fifth of the standard dose (appendix, p 6). Lastly, some reports suggest that dolutegravir initiated in people with low CD4 cell count is associated with an increased risk of IRIS, which would result in increased health-care costs and a small excess mortality risk (appendix, p 8). We factored these risks into our worst plausible case for dolutegravir, but they did not change our conclusion. Venter and colleagues28 discussed prospects for transitioning to new regimens in sub-Saharan Africa, and transition has already started in Botswana and Brazil.
 
Although we considered a policy of using dolutegravir in all new ART initiators, we could also have considered a wider introduction of the drug for all people on first-line efavirenz-based ART. This policy is predicted to bring further health benefits,29 and ART programmes might find it easier to make a wholesale transition in all people on first-line ART, but we do not present results on this potential policy here. Likewise, here we have not considered the possibility of use of dolutegravir in second-line regimens, as considered elsewhere.30 We have focused on changes in policy to deal with the fact that, due to existence of NNRTI pretreatment drug resistance, the first-line ART regimen will not be fully effective in some people. However, the identification of high levels of pretreatment drug resistance should also prompt consideration of other programmatic improvements, such as strengthening of adherence, supporting retention, and increasing switching to second-line regimens in people with virological failure.
 
We are not aware of other studies of cost-effectiveness of transition to dolutegravir in sub-Saharan Africa. In a recent study of the cost-effectiveness of pretreatment drug resistance testing in Kenya,31 a low-cost point mutation assay ($30) before ART initiation was predicted to be very cost-effective. Such assays (adapted for integrase mutations) might eventually have a role in testing for resistance in people with increased viral load on first-line dolutegravir to identify if there is a need to switch regimen.
 
Modelling studies of projected mortality differences between available policy options become necessary when data on direct benefits of dolutegravir are only available for potential intermediate outcomes of viral load, resistance, and toxicity. The fact that differences in the ability of drug regimens to result in viral suppression does ultimately translate into differences in risk of AIDS and death is the basis of the reason why the FDA in 1997 moved from approving antiretroviral drugs on the basis of clinical endpoint data to approving them on the basis of viral load endpoint data.32
 
In our model, we capture the fact that some people discontinue ART and become disengaged from care and that this is more likely in people who are poorly adherent or for whom ART is failing, or both. These people are therefore likely to have NNRTI drug resistance.33, 34, 35 Nevertheless, model outputs for the proportion of ART initiators with NNRTI pretreatment drug resistance who have previous antiretroviral drug exposure were not substantially higher than for those who have no previous antiretroviral drug exposure, which is in contrast with survey findings of pretreatment drug resistance that show markedly higher levels. This implies an even greater tendency for interruption of ART to be more likely in those with poor adherence than was assumed, which might imply that the policies just targeted at those with previous antiretroviral drug exposure could be more effective than we have shown.
 
Our work has several limitations. As is inevitable for a cost-effectiveness analysis with an appropriately long-time horizon, which is required to consider the future consequences of current decisions, we rely on a model to give predictions of the long-term effect of the alternative policies. Our model is particularly detailed and relies on many assumptions, although these have generally been well informed by a wide array of observed data, albeit not always directly from the region itself. The benefits of dolutegravir compared with efavirenz are also well supported by data. We note that, since our model includes adults only, the potential beneficial effects of dolutegravir for people younger than 15 years have not been included, and we did not consider effects on transmission to children. Furthermore, our focus is on low-income settings in sub-Saharan Africa. Generic dolutegravir is unavailable elsewhere, and cost-effectiveness of the transition is likely to be country-specific and dependent on the cost of dolutegravir and to be affected by costs of other drugs and availability of HIV drug resistance testing capacity. Although drug prices can decrease over time, there is generally a floor price determined by the production cost, so generic drug prices might well not now decrease markedly over time in the future.
 
In conclusion, a transition from efavirenz-containing first-line regimens to generic dolutegravir-containing regimens is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa at any level of NNRTI pretreatment drug resistance. However, with high prevalence of NNRTI pretreatment drug resistance, the negative effect on the population health of postponing the transition to dolutegravir increases substantially and thus increases the urgency of this intervention.
 
Results
 
The range of HIV epidemic and programmatic characteristics of setting scenarios in 2017 generally reflected those observed in the region (table). We predicted outcomes for the next 20 years according to policy for setting scenarios in which more than 10% (median 19%) of all ART initiators have NNRTI pretreatment drug resistance in 2017 (figure 1). We calculated the mean percentage of ART initiators with viral load less than 1000 copies per mL 1 year from ART initiation over the 20 years and found a substantial predicted positive effect of using dolutegravir in all ART initiators and some positive effect of HIV drug resistance testing, with choice of dolutegravir in those with detected NNRTI pretreatment drug resistance (figure 1A). We also calculated the mean percentage of ART initiators with NNRTI pretreatment drug resistance and found that with no change in policy, the prevalence of NNRTI pretreatment drug resistance is predicted to be more than 30% on average over 2018-38, and only the policy of using dolutegravir in all ART initiators is predicted to substantially reduce NNRTI pretreatment drug resistance (figure 1B). We also found a predicted beneficial effect of dolutegravir for all ART initiators on the mean percentage of all people on ART with viral load of less than 1000 copies per mL and some benefit of pretreatment HIV drug resistance testing, with choice of dolutegravir in individuals with NNRTI resistance (figure 1C). Mortality in people on ART is predicted to follow a similar pattern, with use of dolutegravir in ART initiators leading to a reduction of 1 death per year per 100 people on ART and the use of pretreatment HIV drug resistance testing reducing mortality by 0 6 deaths per year per 100 people on ART (figure 1D). There is also a predicted reduction in HIV infection incidence of about 10% with adoption of the policy of using dolutegravir in all ART initiators (figure 1E).
 
We analysed the costs of each policy in the context of setting scenarios where more than 10% of ART initiators have NNRTI pretreatment drug resistance in 2017 (figure 2). Despite the slightly higher cost of dolutegravir assumed compared with efavirenz, the policy of using dolutegravir in ART initiators is the lowest-cost policy, primarily because less of the costly second-line boosted protease inhibitor regimen is used. The policy of HIV drug resistance testing with choice of dolutegravir in those with detected NNRTI pretreatment drug resistance also leads to no increase in costs compared with no change in policy, for the same reason. The policy of using dolutegravir in all ART initiators is predicted to avert the most DALYs and has the lowest cost. The association of this policy with the lowest incremental net DALYs suggests it is the policy of choice (figure 3).
 
So far, all results have focused on setting scenarios in which more than 10% of ART initiators have NNRTI pretreatment drug resistance in 2017. We also considered the cost-effectiveness of the policy alternatives according to the prevalence of NNRTI pretreatment drug resistance (appendix, p 10). The difference in net DALYs compared with no change in policy indicates that the policy of using dolutegravir in ART initiators is the most cost-effective at any prevalence of NNRTI pretreatment drug resistance. The higher the prevalence of NNRTI pretreatment drug resistance, the greater the extent of the benefit in cost-effectiveness by moving to a policy of using dolutegravir in ART initiators.
 
So far we have considered the overall proportion of all ART initiators with NNRTI pretreatment drug resistance. We also assessed the most cost-effective policy according to both the percentage of ART initiators with prior antiretroviral resistance with NNRTI pretreatment drug resistance and the percentage of ART initiators without prior antiretroviral drug exposure with NNRTI pretreatment drug resistance, each in 2017 (appendix, p 11). In each case, the policy of using dolutegravir in ART initiators is the most cost-effective.
 
We then considered the absolute difference in mortality (number of deaths per 1000 people on ART per year) and the percentage difference in cost for the policy of using dolutegravir instead of efavirenz in all ART initiators, according to the proportion of all ART initiators with NNRTI pretreatment drug resistance in 2017 (figure 4). We found a mortality benefit of the policy of using dolutegravir in all ART initiators even in the category with lowest NNRTI pretreatment drug resistance, reflecting the benefit of dolutegravir observed in randomised trials (appendix p 4) of people without prior ART resistance. However, the extent of benefit from transition to such a policy improves substantially with increasing NNRTI pretreatment drug resistance. For setting scenarios with a prevalence of NNRTI pretreatment drug resistance of 10-12 5% in 2017, no change and failure to adopt a policy of using dolutegravir in all ART initiators translates into a median of 5500 additional deaths per year (90% range 1050-16 750) on average in the next 20 years. For setting scenarios with a prevalence of NNRTI pretreatment drug resistance of 17 5-20%, 9000 additional deaths per year (2600-20 650) are expected in the next 20 years if there is no change in policy and a policy of using dolutegravir in all ART initiators is not adopted.
 
In the sensitivity analysis, we found that a worst plausible case scenario for the properties of generic dolutegravir (while maintaining an annual cost of dolutegravir of $44) has little effect on our overall conclusions, with the change in policy to use dolutegravir in all ART initiators predicted to be the most effective policy and to be cost-saving (appendix, p 11).

 
 
 
 
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