The Independent Effect of Highly Active Antiretroviral Therapy on Severe Opportunistic Disease Incidence and Mortality in HIV-Infected Adults in Côte D'Ivoire

Abstract

Background

Studies in developed countries have shown highly active antiretroviral therapy (HAART) decreases incidence of severe opportunistic diseases (ODs) in HIV-infected patients beyond that which is expected from changes in CD4⁺T-cell count.

Objective

To estimate the independent impact of HAART on reducing ODs and mortality in Côte d'Ivoire.

Methods

Within two longitudinal studies of HIV-infected adults (1996–2003), we identified time on ‘cotrimoxazole alone’ and ‘HAART plus cotrimoxazole’. WHO stage 3–4 defining events and severe malaria were divided into those preventable and not preventable with cotrimoxazole. Incidence of ODs by CD4 count stratum was estimated using incidence density analysis. CD4⁺ T-cell count at time of OD was estimated using linear interpolation. Using Poisson regression, we estimated the effect of HAART on OD incidence and mortality by CD4 count stratum.

Results

Totals of 446 and 135 adults were followed during 6,216 and 3,412 person-months in the cotrimoxazole alone and HAART plus cotrimoxazole periods, respectively. There was a CD4⁺ T-cell-independent risk reduction for ODs and mortality during the HAART plus cotrimoxazole period compared with cotrimoxazole alone, which varied by time on HAART, CD4 count stratum and OD type. It was mainly seen after 6 months on HAART and for ODs not preventable by cotrimoxazole. The HAART effect differed significantly by CD4 count stratum (P=0.02), but was significant in all strata after 6 months on HAART.

Conclusions

In these sub-Saharan African adults, HAART initiation reduced ODs and mortality beyond that which was expected through the HAART-induced CD4⁺ T-cell increase. Further studies should examine practical implications of this independent ‘HAART effect’ on clinical outcomes in patients on HAART.

References

UNAIDS. Report on the Global AIDS Epidemic. Available at: http://www.unaids.org/en/HIV_data/2006GlobalReport/. Accessed 14 July 2006.

Corbett

E.L.

, Churchyard

G.J.

, Charalambos

Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.

Clin Infect Dis 2002; 34: 1251–1258.

Anglaret

, Chêne

, Attia

Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1-infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Cotrimo-CI Study Group.

Lancet 1999; 353: 1463–1468.

Anglaret

, Messou

, Ouassa

Pattern of bacterial diseases in a cohort of HIV-1 infected adults receiving cotrimoxazole prophylaxis in Abidjan, Cote d'Ivoire.

AIDS 2003; 17: 575–584.

Hammer

S.M.

, Squires

K.E.

, Hughes

M.D.

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team.

N Engl J Med 1997; 337: 725–733.

Palella

F.J.

Jr. , Delaney

K.M.

, Moorman

A.C.

Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators.

N Engl J Med 1998; 338: 853–860.

Hogg

R.S.

, Heath

K.V.

, Yip

Improved survival among HIV-infected individuals following initiation of antiretroviral therapy.

JAMA 1998; 279: 450–454.

Mocroft

, Ledergerber

, Katlama

Decline in the AIDS and death rates in the EuroSIDA study: an observational study.

Lancet 2003; 362: 22–29.

Girardi

, Palmieri

, Cingolani

Changing clinical presentation and survival in HIV-associated tuberculosis after highly active antiretroviral therapy.

J Acquir Immune Defic Syndr 2001; 26: 326–331.

10.

Miller

, Sabin

C.A.

, Phillips

A.N.

The impact of protease inhibitor-containing highly active antiretroviral therapy on progression of HIV disease and its relationship to CD4 and viral load.

AIDS 2000; 14: 2129–2136.

11.

Jones

J.L.

, Hanson

D.L.

, Dworkin

M.S.

, DeCock

K.M.

HIV-associated tuberculosis in the era of highly active antiretroviral therapy. The Adult/Adolescent Spectrum of HIV Disease Group.

Int J Tuberc Lung Dis 2000; 4: 1026–1031.

12.

Cole

S.R.

, Hernan

M.A.

, Robins

J.M.

Effect of highly active antiretroviral therapy on time to acquired immunodeficiency syndrome or death using marginal structural models.

Am J Epidemiol 2003; 158: 687–694.

13.

Barron

, Cole

S.R.

, Greenblatt

R.M.

Effect of discontinuing antiretroviral therapy on survival of women initiated on highly active antiretroviral therapy.

AIDS 2004; 18: 1579–1584.

14.

Gandhi

, Wei

, Amin

, Kazanjian

Effect of maintaining highly active antiretroviral therapy on AIDS events among patients with late-stage HIV infection and inadequate response to therapy.

Clin Infect Dis 2006; 42: 878–884.

15.

Kaplan

J.E.

, Hu

D.J.

, Holmes

K.K.

, Jaffe

H.W.

, Masur

, De Cock

K.M.

Preventing opportunistic infections in human immunodeficiency virus-infected persons: implications for the developing world.

Am J Trop Med Hyg 1996; 55: 1–11.

16.

Seyler

, Anglaret

, Dakoury-Dogbo

Medium-term survival, morbidity and immunovirological evolution in HIV-infected adults receiving antiretroviral therapy, Abidjan, Côte d'Ivoire.

Antivir Ther 2003; 8: 385–393.

17.

Holmes

C.B.

, Losina

, Walensky

R.P.

, Yazdanpanah

, Freedberg

K.A.

Review of human immunodeficiency virus type 1-related opportunistic infections in sub-Saharan Africa.

Clin Infect Dis 2003; 36: 652–662.

18.

Anglaret

, Toure

, Gourvellec

Impact of vital status investigation procedures on estimates of survival in cohorts of HIV-infected patients from Sub-Saharan Africa.

J Acquir Immune Defic Syndr 2004; 35: 320–323.

19.

Wiktor

S.Z.

, Sassan-Morokro

, Grant

A.D.

Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1-infected patients with tuberculosis in Abidjan, Côte d'Ivoire: a randomised controlled trial.

Lancet 1999; 353: 1469–1475.

20.

Currier

J.S.

, Williams

, Feinberg

Impact of prophylaxis for Mycobacterium avium complex on bacterial infections in patients with advanced human immunodeficiency virus disease.

Clin Infect Dis 2001; 32: 1615–1622.

21.

DiRienzo

A.G.

, van Der Horst

, Finkelstein

D.M.

, Frame

, Bozzette

S.A.

, Tashima

K.T.

Efficacy of trimethoprim-sulfamethoxazole for the prevention of bacterial infections in a randomized prophylaxis trial of patients with advanced HIV infection.

AIDS Res Hum Retroviruses 2002; 18: 89–94.

22.

Dworkin

M.S.

, Ward

J.W.

, Hanson

D.L.

, Jones

J.L.

, Kaplan

J.E.

Pneumococcal disease among human immunodeficiency virus-infected persons: incidence, risk factors, and impact of vaccination.

Clin Infect Dis 2001; 32: 794–800.

23.

WHO/Global Tuberculosis Program. Treatment of tuberculosis: guidelines for national programs. Available at: http://whqlibdoc.who.int/hq/2003/WHO_CDS_TB_2003.313_eng.pdf. Accessed 22 January 2007.

24.

Egger

, May

, Chêne

Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies.

Lancet 2002; 360: 119–129.

25.

World Health Organization. Antiretroviral Therapy for HIV Infection in Adults and Adolescents in Resource-limited Settings: Towards Universal Access; Recommendations for a public health approach. Available at http://www.who.int/hiv/pub/guidelines/arvguide-lines2006.pdf. Accessed 15 November 2006.

26.

Liang

K.Y.

, Zeger

S.L.

Longitudinal data analysis using generalized linear models.

Biometrika 1986; 73: 13–22.

27.

Zeger

S.L.

, Liang

K.Y.

Longitudinal data analysis for discrete and continuous outcomes.

Biometrics 1986; 42: 121–130.

28.

McNaghten

A.D.

, Hanson

D.L.

, Jones

J.L.

, Dworkin

M.S.

, Ward

J.W.

Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Adult/Adolescent Spectrum of Disease Group.

AIDS 1999; 13: 1687–1695.

29.

Murphy

E.L.

, Collier

A.C.

, Kalish

L.A.

Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease.

Ann Intern Med 2001; 135: 17–26.

30.

Ledergerber

, Egger

, Erard

AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study.

JAMA 1999; 282: 2220–2226.

31.

Sabine

AIDS events among individuals initiating HAART: do some patients experience a greater benefit from HAART than others?

AIDS 2005; 19: 1995–2000.

32.

d'Arminio Monforte

, Sabin

C.A.

, Phillips

The changing incidence of AIDS events in patients receiving highly active antiretroviral therapy.

Arch Intern Med 2005; 165: 416–423.

33.

Stringer

J.S.

, Zulu

, Levy

Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes.

JAMA 2006; 296: 782–793.

34.

Ferradini

, Jeannin

, Pinoges

Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment.

Lancet 2006; 367: 1335–1342.

35.

Etard

J.F.

, Ndiaye

, Thierry-Mieg

Mortality and causes of death in adults receiving highly active antiretroviral therapy in Senegal: a 7-year cohort study.

AIDS 2006; 20: 1181–1189.

36.

Zachariah

, Fitzgerald

, Massaquoi

Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi.

AIDS 2006; 20: 2355–2360.

37.

Gilks

C.F.

, Ojoo

S.A.

, Ojoo

J.C.

Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya.

Lancet 1996; 347: 718–723.

38.

Gilks

C.F.

, Godfrey-Faussett

, Batchelor

B.I.

Recent transmission of tuberculosis in a cohort of HIV-1-infected female sex workers in Nairobi, Kenya.

AIDS 1997; 11: 911–918.