The Impact of the 2013 WHO Antiretroviral Therapy Guidelines on the Feasibility of HIV Population Prevention Trials

Abstract Background: Several cluster-randomized HIV prevention trials aim to demonstrate the population-level preventive impact of antiretroviral therapy (ART). 2013 World Health Organization (WHO) guidelines raising the ART initiation threshold to CD4 <500/µL could attenuate these trials’ effect size by increasing ART usage in control clusters. Methods: We used a computational model to simulate strategies from a hypothetical cluster-randomized HIV prevention trial. The primary model outcome was the relative reduction in 24-month HIV incidence between control (ART offered with CD4 below threshold) and intervention (ART offered to all) strategies. We assessed this incidence reduction using the revised (CD4 <500/µL) and prior (CD4 <350/µL) control ART initiation thresholds. Additionally, we evaluated changes to trial characteristics that could bolster the incidence reduction. Results: With a control ART initiation threshold of CD4 <350/µL, 24-month HIV incidence under control and intervention strategies was 2.46/100 person-years (PY) and 1.96/100 PY, a 21% reduction. Raising the threshold to CD4 <500/µL decreased the incidence reduction by more than one-third, to 12%. Using this higher threshold, moving to a 36-month horizon (vs 24-month), yearly control-strategy HIV screening (vs bian-nual), and intervention-strategy screening every 2 months (vs biannual), resulted in a 31% incidence reduction that was similar to effect size projections for ongoing trials. Alternate assumptions regarding cross-cluster contamination had the greatest influence on the incidence reduction. Conclusions: Implementing the 2013 WHO HIV treatment threshold could substantially diminish the incidence reduction in HIV population prevention trials. Alternative HIV testing frequencies and trial horizons can bolster this incidence reduction, but they could be logistically and ethically challenging. The feasibility of HIV population prevention trials should be reassessed as the implementation of treatment guidelines evolves.

[1]  T. Bärnighausen,et al.  Use of antiretroviral therapy in households and risk of HIV acquisition in rural KwaZulu-Natal, South Africa, 2004–12: a prospective cohort study , 2014, The Lancet. Global health.

[2]  Deborah Watson-Jones,et al.  HPTN 071 (PopART): Rationale and design of a cluster-randomised trial of the population impact of an HIV combination prevention intervention including universal testing and treatment – a study protocol for a cluster randomised trial , 2014, Trials.

[3]  R. Walensky,et al.  The Survival Benefits of Antiretroviral Therapy in South Africa , 2013, The Journal of infectious diseases.

[4]  R. Walensky,et al.  Cost-effectiveness of HIV treatment as prevention in serodiscordant couples. , 2014, The New England journal of medicine.

[5]  M. Weinstein,et al.  Cost-effectiveness of HIV treatment as prevention in serodiscordant couples. , 2013, The New England journal of medicine.

[6]  E. Ross.  MODELING HIV TRANSMISSION DYNAMICS IN CONJUNCTION WITH A MICROSIMULATION OF DISEASE PROGRESSION , 2013 .

[7]  C. Rouzioux,et al.  Increasing Rate of TAMs and Etravirine Resistance in HIV-1–Infected Adults Between 12 and 24 Months of Treatment: The VOLTART Cohort Study in Côte d’Ivoire, West Africa , 2013, Journal of acquired immune deficiency syndromes.

[8]  T. Bärnighausen,et al.  Dramatic increase in HIV prevalence after scale-up of antiretroviral treatment , 2013, AIDS.

[9]  J. Baeten,et al.  High HIV Testing Uptake and Linkage to Care in a Novel Program of Home-Based HIV Counseling and Testing With Facilitated Referral in KwaZulu-Natal, South Africa , 2013, Journal of acquired immune deficiency syndromes.

[10]  N. Ford,et al.  Viral Load Monitoring as a Tool to Reinforce Adherence: A Systematic Review , 2013, Journal of acquired immune deficiency syndromes.

[11]  T. Bärnighausen,et al.  Evaluation of the impact of immediate versus WHO recommendations-guided antiretroviral therapy initiation on HIV incidence: the ANRS 12249 TasP (Treatment as Prevention) trial in Hlabisa sub-district, KwaZulu-Natal, South Africa: study protocol for a cluster randomised controlled trial , 2013, Trials.

[12]  T. Bärnighausen,et al.  Population-Based CD4 Counts in a Rural Area in South Africa with High HIV Prevalence and High Antiretroviral Treatment Coverage , 2013, PloS one.

[13]  J. Nachega,et al.  Emergence of HIV drug resistance during first- and second-line antiretroviral therapy in resource-limited settings. , 2013, The Journal of infectious diseases.

[14]  S. Faraoni,et al.  Evaluation of a rapid antigen and antibody combination test in acute HIV infection. , 2013, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[15]  J. Etard,et al.  Mortality, AIDS-Morbidity, and Loss to Follow-up by Current CD4 Cell Count Among HIV-1–Infected Adults Receiving Antiretroviral Therapy in Africa and Asia: Data From the ANRS 12222 Collaboration , 2013, Journal of acquired immune deficiency syndromes.

[16]  Paul J. Birrell,et al.  HIV incidence in men who have sex with men in England and Wales 2001–10: a nationwide population study , 2013, The Lancet. Infectious diseases.

[17]  A. Wensing,et al.  Sustained Virological Response on Second-Line Antiretroviral Therapy following Virological Failure in HIV-Infected Patients in Rural South Africa , 2013, PloS one.

[18]  Till Bärnighausen,et al.  Increases in Adult Life Expectancy in Rural South Africa: Valuing the Scale-Up of HIV Treatment , 2013, Science.

[19]  T. Bärnighausen,et al.  High Coverage of ART Associated with Decline in Risk of HIV Acquisition in Rural KwaZulu-Natal, South Africa , 2013, Science.

[20]  M. Hernán,et al.  Rates and Predictors of Failure of First-line Antiretroviral Therapy and Switch to Second-line ART in South Africa , 2012, Journal of acquired immune deficiency syndromes.

[21]  Frank Odhiambo,et al.  The adult population impact of HIV care and antiretroviral therapy in a resource poor setting, 2003–2008 , 2012, AIDS.

[22]  T. Bärnighausen,et al.  The effect of antiretroviral therapy provision on all-cause, AIDS and non-AIDS mortality at the population level – a comparative analysis of data from four settings in Southern and East Africa , 2012, Tropical medicine & international health : TM & IH.

[23]  Jeffrey W. Eaton,et al.  HIV Treatment as Prevention: Considerations in the Design, Conduct, and Analysis of Cluster Randomized Controlled Trials of Combination HIV Prevention , 2012, PLoS medicine.

[24]  D. Wilson.  HIV Treatment as Prevention: Natural Experiments Highlight Limits of Antiretroviral Treatment as HIV Prevention , 2012, PLoS medicine.

[25]  Michael Rayment,et al.  Prevention of HIV-1 infection with early antiretroviral therapy , 2012, Journal of Family Planning and Reproductive Health Care.

[26]  T. Bärnighausen,et al.  HIV Treatment as Prevention: Issues in Economic Evaluation , 2012, PLoS medicine.

[27]  W. Miller,et al.  HIV Treatment as Prevention: The Utility and Limitations of Ecological Observation , 2012, PLoS medicine.

[28]  K. Freedberg,et al.  Virologic Failure of Protease Inhibitor-Based Second-Line Antiretroviral Therapy without Resistance in a Large HIV Treatment Program in South Africa , 2012, PloS one.

[29]  J. Kahn,et al.  Expanding ART for Treatment and Prevention of HIV in South Africa: Estimated Cost and Cost-Effectiveness 2011-2050 , 2012, PloS one.

[30]  Anne M Johnson,et al.  Time from human immunodeficiency virus seroconversion to reaching CD4+ cell count thresholds <200, <350, and <500 Cells/mm³: assessment of need following changes in treatment guidelines. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[31]  S. Lawn,et al.  High Prevalence of Self-Reported Undiagnosed HIV despite High Coverage of HIV Testing: A Cross-Sectional Population Based Sero-Survey in South Africa , 2011, PloS one.

[32]  William C Miller,et al.  The role of acute and early HIV infection in the spread of HIV and implications for transmission prevention strategies in Lilongwe, Malawi: a modelling study , 2011, The Lancet.

[33]  K. Freedberg,et al.  Medication Possession Ratio: Predicting and Decreasing Loss to Follow-Up in Antiretroviral Treatment Programs in Côte d'Ivoire , 2011, Journal of acquired immune deficiency syndromes.

[34]  B. Haynes,et al.  Acute HIV-1 Infection. , 2011, The New England journal of medicine.

[35]  K. Freedberg,et al.  Association Between Medication Possession Ratio, Virologic Failure and Drug Resistance in HIV-1–Infected Adults on Antiretroviral Therapy in Côte d'Ivoire , 2011, Journal of acquired immune deficiency syndromes.

[36]  R. Baggaley,et al.  What do mathematical models tell us about the emergence and spread of drug-resistant HIV? , 2011, Current opinion in HIV and AIDS.

[37]  G. Cooke,et al.  Retention in HIV Care for Individuals Not Yet Eligible for Antiretroviral Therapy: Rural KwaZulu-Natal, South Africa , 2011, Journal of acquired immune deficiency syndromes.

[38]  M. Newell,et al.  COHORT PROFILE Cohort Profile : Hlabisa HIV Treatment and Care Programme , 2010 .

[39]  U. Unicef,et al.  Global HIV/AIDS response: epidemic update and health sector progress towards universal access: progress report 2011. , 2011 .

[40]  J. Sugarman,et al.  Ethics and the standards of prevention in HIV prevention trials. , 2010, AIDS.

[41]  M. Hughes,et al.  Assessing agreement in the timing of treatment initiation determined by repeated measurements of novel versus gold standard technologies with application to the monitoring of CD4 counts in HIV‐infected patients , 2010, Statistics in medicine.

[42]  Evan Wood,et al.  Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study , 2010, The Lancet.

[43]  T. Bärnighausen,et al.  Scale-up of a decentralized HIV treatment programme in rural KwaZulu-Natal, South Africa: does rapid expansion affect patient outcomes? , 2010, Bulletin of the World Health Organization.

[44]  Ian Sanne,et al.  The high cost of second-line antiretroviral therapy for HIV/AIDS in South Africa , 2010, AIDS.

[45]  Sandra I McCoy,et al.  Weighing the gold in the gold standard: challenges in HIV prevention research , 2010, AIDS.

[46]  R. Chaisson,et al.  Viremia, resuppression, and time to resistance in human immunodeficiency virus (HIV) subtype C during first-line antiretroviral therapy in South Africa. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[47]  R. Salamon,et al.  Medium-term probability of success of antiretroviral treatment after early warning signs of treatment failure in West African adults. , 2009, AIDS research and human retroviruses.

[48]  Matthias Egger,et al.  Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis , 2009, AIDS.

[49]  T. Bärnighausen,et al.  Lack of a decline in HIV incidence in a rural community with high HIV prevalence in South Africa, 2003-2007. , 2009, AIDS research and human retroviruses.

[50]  Christopher Dye,et al.  Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model , 2009, The Lancet.

[51]  Thomas Rehle,et al.  South African national HIV prevalence, incidence, behaviour and communication survey, 2008: a turning tide among teenagers? , 2009 .

[52]  T. Bärnighausen,et al.  HIV Incidence in Rural South Africa: Comparison of Estimates from Longitudinal Surveillance and Cross-Sectional cBED Assay Testing , 2008, PloS one.

[53]  Christophe Fraser,et al.  HIV-1 transmission, by stage of infection. , 2008, The Journal of infectious diseases.

[54]  M. Weinstein,et al.  Scaling up antiretroviral therapy in South Africa: the impact of speed on survival. , 2008, The Journal of infectious diseases.

[55]  E. Bateman,et al.  Effectiveness of antiretroviral treatment in a South African program: a cohort study. , 2008, Archives of internal medicine.

[56]  Till Bärnighausen,et al.  Cohort Profile: Africa Centre Demographic Information System (ACDIS) and population-based HIV survey , 2007, International journal of epidemiology.

[57]  S. Lawn,et al.  Conservation of First-Line Antiretroviral Treatment Regimen where Therapeutic Options are Limited , 2007, Antiviral therapy.

[58]  David R Bangsberg,et al.  Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection. , 2006, JAMA.

[59]  Milton C Weinstein,et al.  Cost-effectiveness of HIV treatment in resource-poor settings--the case of Côte d'Ivoire. , 2006, The New England journal of medicine.

[60]  K. Freedberg,et al.  CD4 Decline and Incidence of Opportunistic Infections in Cape Town, South Africa: Implications for Prophylaxis and Treatment , 2006, Journal of acquired immune deficiency syndromes.

[61]  James O Lloyd-Smith,et al.  The Potential Impact of Male Circumcision on HIV in Sub-Saharan Africa , 2006, PLoS medicine.

[62]  M. Weinstein,et al.  Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Côte d’Ivoire: a trial-based analysis , 2005, AIDS.

[63]  S. Vermund,et al.  Network-related mechanisms may help explain long-term HIV-1 seroprevalence levels that remain high but do not approach population-group saturation. , 2000, American journal of epidemiology.

[64]  M. Boily,et al.  Complementary hypothesis concerning the community sexually transmitted disease mass treatment puzzle in Rakai, Uganda , 2000, AIDS.

[65]  R. Salamon,et al.  Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial , 1999, The Lancet.

[66]  M. Iannelli,et al.  The HIV/AIDS epidemics among drug injectors: a study of contact structure through a mathematical model. , 1997, Mathematical biosciences.

[67]  Lisa Sattenspiel,et al.  Modeling and analyzing HIV transmission: the effect of contact patterns , 1988 .

[68]  E Windisch,et al.  [South Africa]. , 1976, Osterreichische Krankenpflegezeitschrift.