Genotype assays and third-line ART in resource-limited settings: a simulation and cost-effectiveness analysis of a planned clinical trial

Objectives:To project the clinical and economic outcomes of a genotype assay for selection of third-line antiretroviral therapy (ART) in resource-limited settings, as per the planned international A5288 trial (MULTI-OCTAVE). Methods:We used the Cost-effectiveness of Preventing AIDS Complications (CEPAC)-International Model to compare three strategies for patients who have failed second-line ART in South Africa: sustained second-line: no genotype assay, all patients remain on second-line ART; A5288: genotype to determine the resistance profile and assign an appropriate regimen; or population-based third-line: no genotype, all patients switch to a potent third-line regimen. Model inputs are from published data in South Africa. Resistance profiles, ART regimens, and efficacy data were those used for trial planning. Results:Projected life expectancy for sustained second-line, A5288, and population-based third-line are 61.1, 103.8, and 104.2 months. Compared to sustained second-line ($12 460), per person lifetime costs increase for the A5288 ($39 250) and population-based ($44 120) strategies. The incremental cost-effectiveness ratio of A5288, compared to sustained second-line, is $7500/year of life saved (YLS), and for population-based third-line, compared to A5288, is $154 500/YLS. In the A5288 strategy, very late presentation to care, coupled with lengthy delays to obtain the genotype, dramatically reduces 5-year survival, making the population-based third-line strategy more attractive. Conclusions:We project that, whereas the public health approach to third-line therapy is unaffordable, genotype assays and third-line ART in resource-limited settings will increase survival and be cost-effective compared to the population-based approach, supporting the value of an efficacy study.

[1]  Organización Mundial de la Salud,et al.  Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2009 , 2009 .

[2]  J. Robins,et al.  Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models. , 2003, American journal of epidemiology.

[3]  Elena Losina,et al.  HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme , 2009, Antiviral therapy.

[4]  T G Ganiats,et al.  Incremental cost-effectiveness analysis: the optimal strategy depends on the strategy set. , 1999, Journal of clinical epidemiology.

[5]  M. Johnson,et al.  Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures , 2005, AIDS.

[6]  H. Bang,et al.  Survival, plasma HIV-1 RNA concentrations and drug resistance in HIV-1-infected Haitian adolescents and young adults on antiretrovirals. , 2008, Bulletin of the World Health Organization.

[7]  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.

[8]  J. Eron,et al.  Triple-class antiretroviral drug resistance: risk and predictors among HIV-1-infected patients , 2007, AIDS.

[9]  L. Harrison,et al.  Predictors of Virologic Failure in HIV-1-Infected Patients Starting Highly Active Antiretroviral Therapy in Porto Alegre, Brazil , 2005, Journal of acquired immune deficiency syndromes.

[10]  D. Kuritzkes,et al.  Outcomes after virologic failure of first-line ART in South Africa , 2010, AIDS.

[11]  D. Owens,et al.  Cost-effectiveness of antiretroviral regimens in the World Health Organization's treatment guidelines: a South African analysis , 2011, AIDS.

[12]  N. Parkin,et al.  The public health approach to identify antiretroviral therapy failure: high-level nucleoside reverse transcriptase inhibitor resistance among Malawians failing first-line antiretroviral therapy , 2009, AIDS.

[13]  Tony Vangeneugden,et al.  Resistance profile of darunavir: combined 24-week results from the POWER trials. , 2008, AIDS research and human retroviruses.

[14]  C. Katlama,et al.  High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: results of the ANRS 139 TRIO trial. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  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.

[16]  K. Freedberg,et al.  Early Outcomes and the Virological Effect of Delayed Treatment Switching to Second-Line Therapy in An Antiretroviral Roll-Out Programme in South Africa , 2011, Antiviral therapy.

[17]  B. Walker,et al.  Prevalence of HIV-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in KwaZulu Natal, South Africa. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  R. Hammond,et al.  Efficacy of Antiretroviral Therapy in Africa: Effect on Immunological and Virological Outcome Measures – A Meta-Analysis a , 2008, International journal of STD & AIDS.

[19]  K. Hertogs,et al.  Long-term efficacy of routine access to antiretroviral-resistance testing in HIV type 1-infected patients: results of the clinical efficacy of resistance testing trial. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  Joel E Gallant,et al.  Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. , 2006, The New England journal of medicine.

[21]  K. Freedberg,et al.  The Independent Effect of Highly Active Antiretroviral Therapy on Severe Opportunistic Disease Incidence and Mortality in HIV-Infected Adults in Côte D'Ivoire , 2007, Antiviral therapy.

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

[23]  D. Mcintyre,et al.  Cost-effectiveness of antiretroviral treatment for HIV-positive adults in a South African township. , 2004 .

[24]  M. Egger,et al.  Public-Health and Individual Approaches to Antiretroviral Therapy: Township South Africa and Switzerland Compared , 2008, PLoS medicine.

[25]  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.

[26]  S. Lawn,et al.  Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort , 2005, AIDS.

[27]  Mark J van der Laan,et al.  Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification , 2008, AIDS.

[28]  R. Haubrich,et al.  Efficacy and safety of etravirine at week 96 in treatment-experienced HIV type-1-infected patients in the DUET-1 and DUET-2 trials , 2010, Antiviral therapy.

[29]  T. Quinn,et al.  Predictors of Long-Term Viral Failure Among Ugandan Children and Adults Treated With Antiretroviral Therapy , 2007, Journal of acquired immune deficiency syndromes.

[30]  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.

[31]  Richard D Moore,et al.  Trends in multidrug treatment failure and subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North America. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[32]  Ian Sanne,et al.  Varied Patterns of HIV-1 Drug Resistance on Failing First-Line Antiretroviral Therapy in South Africa , 2010, Journal of acquired immune deficiency syndromes.

[33]  D. Katzenstein,et al.  Expanding Antiretroviral Options in Resource-Limited Settings-A Cost-Effectiveness Analysis , 2009, Journal of acquired immune deficiency syndromes.

[34]  B. Stilwell,et al.  Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. 2006 revision. , 2006 .

[35]  R. Stone,et al.  Discordant Responses to Potent Antiretroviral Treatment in Previously Naive HIV-1-Infected Adults Initiating Treatment in Resource-Constrained Countries: The Antiretroviral Therapy in Low-Income Countries (ART-LINC) Collaboration , 2007, Journal of acquired immune deficiency syndromes.

[36]  D. Hazuda,et al.  Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. , 2008, The New England journal of medicine.

[37]  S. Lawn,et al.  Utility of CD4 cell counts for early prediction of virological failure during antiretroviral therapy in a resource-limited setting , 2008, BMC infectious diseases.

[38]  M. Hughes,et al.  First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial , 2011, AIDS.

[39]  P. Mee,et al.  Evaluation of the WHO criteria for antiretroviral treatment failure among adults in South Africa , 2008, AIDS.

[40]  D. Katzenstein,et al.  Viremia and drug resistance among HIV-1 patients on antiretroviral treatment: a cross-sectional study in Soweto, South Africa , 2010, AIDS (London).

[41]  A. Lazzarin,et al.  Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. , 2005, AIDS.

[42]  R. Grant,et al.  Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. , 2000, The Journal of infectious diseases.

[43]  J. Mellors,et al.  Protease Inhibitor Resistance Is Uncommon in HIV-1 Subtype C Infected Patients on Failing Second-Line Lopinavir/r-Containing Antiretroviral Therapy in South Africa , 2010, AIDS research and treatment.

[44]  L. Myer,et al.  Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa , 2007, AIDS.

[45]  P. F. Kauff.  Group , 2000, Elegant Design.

[46]  Roger Detels,et al.  Plasma Viral Load and CD4+ Lymphocytes as Prognostic Markers of HIV-1 Infection , 1997, Annals of Internal Medicine.

[47]  Milton C Weinstein,et al.  When to start antiretroviral therapy in resource-limited settings. , 2009, Annals of internal medicine.