title: Increasing the use of second-line therapy is a cost-effective approach to prevent the spread of drug-resistant HIV: a mathematical modelling study.
abstract: BACKGROUND
  Earlier antiretroviral therapy (ART) initiation reduces HIV-1 incidence. This benefit may be offset by increased transmitted drug resistance (TDR), which could limit future HIV treatment options. We analyze the epidemiological impact and cost-effectiveness of strategies to reduce TDR.
  
  
  METHODS
  We develop a deterministic mathematical model representing Kampala, Uganda, to predict the prevalence of TDR over a 10-year period. We then compare the impact on TDR and cost-effectiveness of: (1) introduction of pre-therapy genotyping; (2) doubling use of second-line treatment to 80% (50-90%) of patients with confirmed virological failure on first-line ART; and (3) increasing viral load monitoring from yearly to twice yearly. An intervention can be considered cost-effective if it costs less than three times the gross domestic product per capita per quality adjusted life year (QALY) gained, or less than $3420 in Uganda.
  
  
  RESULTS
  The prevalence of TDR is predicted to rise from 6.7% (interquartile range [IQR] 6.2-7.2%) in 2014, to 6.8% (IQR 6.1-7.6%), 10.0% (IQR 8.9-11.5%) and 11.1% (IQR 9.7-13.0%) in 2024 if treatment is initiated at a CD4 <350, <500, or immediately, respectively. The absolute number of TDR cases is predicted to decrease 4.4-8.1% when treating earlier compared to treating at CD4 <350 due to the preventative effects of earlier treatment. Most cases of TDR can be averted by increasing second-line treatment (additional 7.1-10.2% reduction), followed by increased viral load monitoring (<2.7%) and pre-therapy genotyping (<1.0%). Only increasing second-line treatment is cost-effective, ranging from $1612 to $2234 (IQR $450-dominated) per QALY gained.
  
  
  CONCLUSIONS
  While earlier treatment initiation will result in a predicted increase in the proportion of patients infected with drug-resistant HIV, the absolute numbers of patients infected with drug-resistant HIV is predicted to decrease. Increasing use of second-line treatment to all patients with confirmed failure on first-line therapy is a cost-effective approach to reduce TDR. Improving access to second-line ART is therefore a major priority.
authors.affiliation: Department of Viroscience, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands; b.nichols@erasmusmc.nl.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Nichols
authors.affiliation: Department of Global Health, Academic Medical Centre, Amsterdam Institute for Global Health and Development (AIGHD), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Kim C E
authors.initials: KC
authors.lastname: Sigaloff
authors.affiliation: Joint Clinical Research Centre (JCRC), Kampala, Uganda.
authors.forename: Cissy
authors.initials: C
authors.lastname: Kityo
authors.affiliation: Department of Global Health, Academic Medical Centre, Amsterdam Institute for Global Health and Development (AIGHD), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Raph L
authors.initials: RL
authors.lastname: Hamers
authors.affiliation: Department of Primary and Community Care, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Baltussen
authors.affiliation: HIV Department, World Health Organization, Geneva, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bertagnolio
authors.affiliation: Department of Geographic Medicine and Infectious Disease, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jordan
authors.affiliation: Department of Infectious Disease Epidemiology, Imperial College London, London, UK.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Hallett
authors.affiliation: Department of Viroscience, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Charles A B
authors.initials: CA
authors.lastname: Boucher
authors.affiliation: Department of Global Health, Academic Medical Centre, Amsterdam Institute for Global Health and Development (AIGHD), University of Amsterdam, Amsterdam, The Netherlands; PharmAccess Foundation, Amsterdam, The Netherlands.
authors.forename: Tobias F Rinke
authors.initials: TF
authors.lastname: de Wit
authors.affiliation: Department of Viroscience, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands.
authors.forename: David A M C
authors.initials: DA
authors.lastname: van de Vijver
mesh_terms: D019380:Anti-HIV Agents / Q000191:economics* / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000191:economics* / Q000379:methods*; D003362:Cost-Benefit Analysis; D016903:Drug Monitoring / Q000191:economics / Q000706:statistics & numerical data; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000635:transmission / Q000821:virology; D006801:Humans; D008962:Models, Theoretical; D014454:Uganda
chemical_list: D019380:Anti-HIV Agents
keywords: antiretroviral therapy; cost-effectiveness; drug resistance; pre-therapy genotyping; second-line treatment; viral load monitoring