Could Early Antiretroviral Therapy Entail More Risks than Benefits in Sub-Saharan African HIV-Infected Adults? A Model-Based Analysis

Abstract

Background

Initiation of antiretroviral therapy (ART) in all HIV-infected adults, regardless of CD4⁺ T-cell count, is a proposed strategy for reducing HIV transmission. We investigated the conditions under which starting ART early could entail more risks than benefits for patients with high CD4⁺ T-cell counts.

Methods

We used a simulation model to compare ART initiation upon entry to care (‘immediate ART') to initiation at CD4⁺ T-cell count ≤350 cells/μl (‘WHO 2010 ART') in African adults with CD4⁺ T-cell counts >500 cells/μl. We varied inputs to determine the combination of parameters (population characteristics, conditions of care, treatment outcomes) that would result in higher 15-year mortality with immediate ART.

Results

The 15-year mortality was 56.7% for WHO 2010 ART and 51.8% for immediate ART. In one-way sensitivity analysis, lower 15-year mortality was consistently achieved with immediate ART unless the rate of fatal ART toxicity was >1.0/100 person-years, the rate of withdrawal from care was >1.2-fold higher or the rate of ART failure due to poor adherence was >4.3-fold higher on immediate than on WHO 2010 ART. In multi-way sensitivity analysis, immediate ART led to higher mortality when moderate rates of fatal ART toxicity (0.25/100 person-years) were combined with rates of withdrawal from care >1.1-fold higher and rates of treatment failure >2.1-fold higher on immediate than on WHO 2010 ART.

Conclusions

In sub-Saharan Africa, ART initiation at entry into care would improve long-term survival of patients with high CD4⁺ T-cell counts, unless it is associated with increased withdrawal from care and decreased adherence. In early ART trials, a focus on retention and adherence will be crucial.

References

World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. (Updated 8 February 2011. Accessed 7 May 2012.) Available from http://www.who.int/hiv/pub/arv/adult2010/en/index.html.

Granich

R.M.

, Gilks

C.F.

, Dye

, De Cock

K.M.

, Williams

B.G.

Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet 2009; 373: 48–57.

Cohen

M.S.

, Chen

Y.Q.

, McCauley

Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365: 493–505.

Walensky

R.P.

, Paltiel

A.D.

, Losina

Test and treat DC: forecasting the impact of a comprehensive HIV strategy in Washington DC. Clin Infect Dis 2010; 51: 392–400.

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4⁺ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355: 2283–2296.

Kitahata

M.M.

, Gange

S.J.

, Abraham

A.G.

Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009; 360: 1815–1826.

When To Start Consortium. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet 2009; 373: 1352–1363.

Cain

L.E.

, Logan

, Robins

When to initiate combined antiretroviral therapy to reduce mortality and AIDS-defining illness in HIV-infected persons in developed countries: an observational study. Ann Intern Med 2011; 154: 509–515.

Danel

, Moh

, Minga

CD4-guided structured antiretroviral treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a randomised trial. Lancet 2006; 367: 1981–1989.

10.

Anglaret

, Minga

, Gabillard

AIDS and non-AIDS morbidity and mortality across the spectrum of CD4 cell counts in HIV-infected adults before starting antiretroviral therapy in Cote d'Ivoire. Clin Infect Dis 2012; 54: 714–723.

11.

Hargrove

J.W.

, Humphrey

J.H.

Mortality among HIV-positive postpartum women with high CD4 cell counts in Zimbabwe. AIDS 2010; 24: F11–F14.

12.

Williams

B.G.

, Hargrove

J.W.

, Humphrey

J.H.

The benefits of early treatment for HIV. AIDS 2010; 24: 1790–1791.

13.

Braithwaite

R.S.

, Roberts

M.S.

, Goetz

M.B.

Do benefits of earlier antiretroviral treatment initiation outweigh harms for individuals at risk for poor adherence?

Clin Infect Dis 2009; 48: 822–826.

14.

ANRS - French National Agency for Research on AIDS and Viral Hepatitits. Early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in HIV-infected adults (ANRS 12136 TEMPRANO). (Updated 19 October 2012. Accessed 10 January 2013.) Available from http://www.clinicaltrials.gov/ct2/show/NCT00495651.

15.

University of Minnesota CaTSI. Strategic Timing of Antiretroviral Treatment (START). (Updated 18 December 2012. Accessed 10 January 2013.) Available from http://www.clinicaltrials.gov/ct2/show/NCT00867048.

16.

Walensky

R.P.

, Wood

, Ciaranello

A.L.

Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis. PLoS Med 2010; 7: e1000382.

17.

Goldie

S.J.

, Yazdanpanah

, Losina

Cost-effectiveness of HIV treatment in resource-poor settings–the case of Cote d'Ivoire. N Engl J Med 2006; 355: 1141–1153.

18.

Yazdanpanah

, Losina

, Anglaret

Clinical impact and cost-effectiveness of co-trimoxazole prophylaxis in patients with HIV/AIDS in Côte d'Ivoire: a trial-based analysis. AIDS 2005; 19: 1299–1308.

19.

World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. (Updated 3 February 2009. Accessed 7 May 2012.) Available from: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf.

20.

Kimmel

A.D.

, Weinstein

M.C.

, Anglaret

Laboratory monitoring to guide switching antiretroviral therapy in resource-limited settings: clinical benefits and cost-effectiveness. J Acquir Immune Defic Syndr 2010; 54: 258–268.

21.

Yazdanpanah

, Wolf

L.L.

, Anglaret

CD4⁺ T-cell-guided structured treatment interruptions of antiretroviral therapy in HIV disease: projecting beyond clinical trials. Antivir Ther 2010; 15: 351–361.

22.

Minga

, Danel

, Abo

Progression to WHO criteria for antiretroviral therapy in a 7-year cohort of adult HIV-1 seroconverters in Abidjan, Cote d'Ivoire. Bull World Health Organ 2007; 85: 116–123.

23.

Minga

A.K.

, Lewden

, Gabillard

CD4 cell eligibility thresholds: an analysis of the time to antiretroviral treatment in HIV-1 seroconverters. AIDS 2011; 25: 819–823.

24.

Anglaret

, Chêne

, Attia

Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Côte d'Ivoire: a randomised trial. Lancet 1999; 353: 1463–1468.

25.

World Health Organization. World Mortality in 2000: life tables for 191 countries. Geneva: World Health Organization 2002.

26.

Toure

, Kouadio

, Seyler

Rapid scaling-up of antiretroviral therapy in 10,000 adults in Cote d'Ivoire: 2-year outcomes and determinants. AIDS 2008; 22: 873–882.

27.

Messou

, Chaix

M.L.

, Gabillard

Association between medication possession ratio, virologic failure and drug resistance in HIV-1-infected adults on antiretroviral therapy in Cote d'Ivoire. J Acquir Immune Defic Syndr 2011; 56: 356–364.

28.

Hunt

P.W.

, Deeks

S.G.

, Rodriguez

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 2003; 17: 1907–1915.

29.

Moore

R.D.

, Keruly

J.C.

CD4⁺ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis 2007; 44: 441–446.

30.

World Health Organization. WHO expert consultation on cotrimoxazole prophylaxis in HIV infection. WHO technical report series. Reference number WHO/HIV/2006.01. (Updated 18 April 2006. Accessed 7 May 2012.) Available from http://www.who.int/hiv/pub/meetingreports/ctxprophylaxismeeting.pdf.

31.

Mellors

J.W.

, Munoz

, Giorgi

J.V.

Plasma viral load and CD4⁺ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997; 126: 946–954.

32.

Losina

, Yazdanpanah

, Deuffic-Burban

The independent effect of highly active antiretroviral therapy on severe opportunistic disease incidence and mortality in HIV-infected adults in Cote d'Ivoire. Antivir Ther 2007; 12: 543–551.

33.

Seyler

, Messou

, Gabillard

, Inwoley

, Alioum

, Anglaret

Morbidity before and after HAART initiation in sub-Saharan African HIV-infected adults: a recurrent event analysis. AIDS Res Hum Retroviruses 2007; 23: 1338–1347.

34.

Cole

S.R.

, Hernan

M.A.

, Margolick

J.B.

, Cohen

M.H.

, Robins

J.M.

Marginal structural models for estimating the effect of highly active antiretroviral therapy initiation on CD4 cell count. Am J Epidemiol 2005; 162: 471–478.

35.

Danel

, Moh

, Chaix

M.L.

Two-months-off, four-months-on antiretroviral regimen increases the risk of resistance, compared with continuous therapy: a randomized trial involving West African adults. J Infect Dis 2009; 199: 66–76.

36.

Ekouevi

D.K.

, Rouet

, Becquet

Immune status and uptake of antiretroviral interventions to prevent mother-to-child transmission of HIV-1 in Africa. J Acquir Immune Defic Syndr 2004; 36: 755–757.

37.

Boyer

, Marcellin

, Ongolo-Zogo

Financial barriers to HIV treatment in Yaounde, Cameroon: first results of a national cross-sectional survey. Bull World Health Organ 2009; 87: 279–287.

38.

Young

, Cain

, Robins

, O'Reilly

, Hernán

Comparative effectiveness of dynamic treatment regimes: an application of the parametric g-formula. Statistics in Biosciences 2011; 3: 119–143.

39.

Mocroft

, Phillips

, Gatell

Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. Lancet 2007; 370: 407–413.

40.

Tarwater

P.M.

, Margolick

J.B.

, Jin

Increase and plateau of CD4 T-cell counts in the 3(1/2) years after initiation of potent antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 27: 168–175.

41.

Kaufmann

G.R.

, Furrer

, Ledergerber

Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microl in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 2005; 41: 361–372.

42.

Valdez

, Connick

, Smith

K.Y.

Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 2002; 16: 1859–1866.

43.

Seyler

, Adje-Toure

, Messou

Impact of genotypic drug resistance mutations on clinical and immunological outcomes in HIV-infected adults on HAART in West Africa. AIDS 2007; 21: 1157–1164.