Should expectations about the rate of new antiretroviral drug development impact the timing of HIV treatment initiation and expectations about treatment benefits?

Amin Khademi,Mark S Roberts,Andrew J Schaefer,R Scott Braithwaite,Denis Saure,Kimberly Nucifora,Alan Winston

doi:10.1371/journal.pone.0098354

Abstract

BackgroundMany analyses of HIV treatment decisions assume a fixed formulary of HIV drugs. However, new drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, particularly when to initiate antiretroviral therapy (ART).ObjectivesTo determine the impact of considering the availability of new drugs on the optimal initiation criteria for ART and outcomes in patients with HIV/AIDS.MethodsWe enhanced a previously described simulation model of the optimal time to initiate ART to incorporate the rate of availability of new antiviral drugs. We assumed that the future rate of availability of new drugs would be similar to the past rate of availability of new drugs, and we estimated the past rate by fitting a statistical model to actual HIV drug approval data from 1982–2010. We then tested whether or not the future availability of new drugs affected the model-predicted optimal time to initiate ART based on clinical outcomes, considering treatment initiation thresholds of 200, 350, and 500 cells/mm3. We also quantified the impact of the future availability of new drugs on life expectancy (LE) and quality-adjusted life expectancy (QALE).ResultsIn base case analysis, considering the availability of new drugs raised the optimal starting CD4 threshold for most patients to 500 cells/mm3. The predicted gains in outcomes due to availability of pipeline drugs were generally small (less than 1%), but for young patients with a high viral load could add as much as a 4.9% (1.73 years) increase in LE and a 8% (2.43 QALY) increase in QALE, because these patients were particularly likely to exhaust currently available ART regimens before they died. In sensitivity analysis, increasing the rate of availability of new drugs did not substantially alter the results. Lowering the toxicity of future ART drugs had greater potential to increase benefit for many patient groups, increasing QALE by as much as 10%.ConclusionsThe future availability of new ART drugs without lower toxicity raises optimal treatment initiation for most patients, and improves clinical outcomes, especially for younger patients with higher viral loads. Reductions in toxicity of future ART drugs could impact optimal treatment initiation and improve clinical outcomes for all HIV patients.

Highlights

In June 2013, the World Health Organization (WHO) updated its recommendation regarding the time to initiate therapy, recommending an earlier initiation of antiretroviral therapy (ART) when the CD4 count falls below 500 cells/ml
[5] Because timing decisions are not amenable to randomized controlled trials, this problem has been widely modeled and discussed in published reports.[6,7,8,9,10,11]. These models generally seek to identify the clinical conditions under which a patient should initiate ART so as to maximize his/her quality-adjusted life expectancy, and consider many factors, such as the initial viral load and CD4 count, age, gender, CD4 threshold and viral load threshold for initiating drugs, adherence, resistance, and HIV mutations at baseline
While ART initiation on detection has been advocated on the grounds of reducing the epidemic impact, this suggestion may not be persuasive for individuals who maximally value their health and well-being over those of the population at large

Summary

Introduction

The timing of HIV therapy initiation has been controversial, and remains so in resource-limited settings.[1,2,3,4] In June 2013, the World Health Organization (WHO) updated its recommendation regarding the time to initiate therapy, recommending an earlier initiation of ART when the CD4 count falls below 500 cells/ml. [5] Because timing decisions are not amenable to randomized controlled trials, this problem has been widely modeled and discussed in published reports.[6,7,8,9,10,11] These models generally seek to identify the clinical conditions under which a patient should initiate ART so as to maximize his/her quality-adjusted life expectancy, and consider many factors, such as the initial viral load and CD4 count, age, gender, CD4 threshold and viral load threshold for initiating drugs, adherence, resistance, and HIV mutations at baseline. [5] Because timing decisions are not amenable to randomized controlled trials, this problem has been widely modeled and discussed in published reports.[6,7,8,9,10,11] These models generally seek to identify the clinical conditions under which a patient should initiate ART so as to maximize his/her quality-adjusted life expectancy, and consider many factors, such as the initial viral load and CD4 count, age, gender, CD4 threshold and viral load threshold for initiating drugs, adherence, resistance, and HIV mutations at baseline These models have not considered the rate of development of new antiretroviral drugs. New drugs are approved nearly twice a year, and the rate of availability of new drugs may affect treatment decisions, when to initiate antiretroviral therapy (ART)

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