Risk of Tuberculosis after Antiretroviral Treatment Initiation: A Comparison between Efavirenz and Nevirapine Using Inverse Probability Weighting

Abstract

Background

There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz (EFV) compared to nevirapine (NVP) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large, urban HIV clinic in Uganda.

Methods

Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multi-variable logistic regression model), stratifying by baseline CD4⁺ T-cell count. Adjustment for time-updated CD4⁺ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses.

Results

ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (sd 9) and a median baseline CD4⁺ T-cell count of 117 cells/mm³ (IQR 43–182). Overall, 60% (n=3,484) were initiated on NVP and 40% (n=2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4⁺ T-cell count <100 cells/mm³ (HR 2.05 [95% CI 1.29, 3.27]; P=0.003), but not at higher CD4⁺ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P=0.428). These estimates were robust to all sensitivity analyses.

Conclusions

There was a higher incidence of TB in patients with baseline CD4⁺ T-cell counts <100 cells/mm³ initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.

References

Corbett

E.L.

, Watt

C.J.

, Walker

The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009–1021.

Lawn

S.D.

, Wood

, De Cock

K.M.

, Kranzer

, Lewis

J.J.

, Churchyard

G.J.

Antiretrovirals and isoniazid preventive therapy in the prevention of HIV-associated tuberculosis in settings with limited health-care resources. Lancet Infect Dis 2010; 10: 489–498.

Lawn

S.D.

, Badri

, Wood

Tuberculosis among HIV-infected patients receiving HAART: long term incidence and risk factors in a South African cohort. AIDS 2005; 19: 2109–2116.

Manabe

Y.C.

, Breen

, Perti

, Girardi

, Sterling

T.R.

Unmasked tuberculosis and tuberculosis immune reconstitution inflammatory disease: a disease spectrum after initiation of antiretroviral therapy. J Infect Dis 2009; 199: 437–444.

Lawn

S.D.

, Myer

, Edwards

, Bekker

L.G.

, Wood

Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS 2009; 23: 1717–1725.

Fenner

, Forster

, Boulle

Tuberculosis in HIV programmes in lower-income countries: practices and risk factors. Int J Tuberc Lung Dis 2011; 15: 620–627.

Nicholas

, Sabapathy

, Ferreyra

, Varaine

, Pujades-Rodriguez

Incidence of tuberculosis in HIV-infected patients before and after starting combined antiretroviral therapy in 8 sub-Saharan African HIV programs. J Acquir Immune Defic Syndr 2011; 57: 311–318.

World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents. Recommendations for a public health approach. Geneva: World Health Organization 2010.

The Antiretroviral Therapy Cohort Collaboration. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005; 41: 1772–1782.

10.

The Antiretroviral Therapy in Low-Income Countries Collaboration of the International epidemiological Databases to Evaluate AIDS (IeDEA), The ART Cohort Collaboration. Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries. Clin Infect Dis 2007; 45: 1518–1521.

11.

Sterling

T.R.

, Lau

, Zhang

Risk factors for tuberculosis after highly active antiretroviral therapy initiation in the United States and Canada: implications for tuberculosis screening. J Infect Dis 2011; 204: 893–901.

12.

Uganda Ministry of Health. National antiretroviral treatment and care guidelines for adults, adolescents, and children. Kampala: Uganda Ministry of Health 2009.

13.

Uganda Ministry of Health. Manual of the National Tuberculosis and Leprosy Programme. Kampala: Uganda Ministry of Health 2010.

14.

Hermans

S.M.

, Kiragga

A.N.

, Schaefer

, Kambugu

, Hoepelman

A.I.M.

, Manabe

Y.C.

Incident tuberculosis during antiretroviral therapy contributes to suboptimal immune reconstitution in a large urban HIV clinic in sub-Saharan Africa. PLoS ONE 2010; 5: e10527.

15.

Hermans

S.M.

, Castelnuovo

, Katabira

Integration of HIV and TB services results in improved TB treatment outcomes and earlier, prioritized ART initiation in a large urban HIV clinic in Uganda. J Acquir Immune Defic Syndr 2012; 60: e29–e35.

16.

Hermans

S.M.

, Nasuuna

, Van Leth

Implementation and effect of intensified case finding on diagnosis of tuberculosis in a large urban HIV clinic in Uganda: a retrospective cohort study. BMC Public Health 2012; 12: 674.

17.

Uganda Ministry of Health. National antiretroviral treatment and care guidelines for adults, adolescents, and children. Kampala: Uganda Ministry of Health 2008.

18.

Kamya

M.R.

, Mayanja-Kizza

, Kambugu

Predictors of long-term viral failure among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr 2007; 46: 187–193.

19.

World Health Organization. Antiretroviral therapy for HIV Infection in adults and adolescents in resource-limited settings: towards universal access. Geneva: World Health Organization 2006.

20.

Muwanga

, Easterbrook

, Schaefer

Losses to follow-up in a large ART program in Uganda. Conference of Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 840.

21.

Hernán

M.A.

, Robins

J.M.

Estimating causal effects from epidemiological data. J Epidemiol Community Health 2006; 60: 578–586.

22.

Hermans

S.M.

, Sempa

, Castelnuovo

, Manabe

Y.C.

, van Leth

Comment on: Predictors of immune recovery and the association with late mortality while on antiretroviral treatment in Cambodia. Trans R Soc Trop Med Hyg 2012; 106: 328–329.

23.

Rosenbaum

P.R.

, Rubin

D.B.

Reducing bias in observational studies using subclassification on the propensity score. J Am Stat Assoc 1984; 79: 516–524.

24.

van Leth

, Phanuphak

, Ruxrungtham

Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004; 363: 1253–1263.

25.

Mbuagbaw

L.C.

, Irlam

J.H.

, Spaulding

, Rutherford

G.W.

, Siegfried

Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naive individuals. Cochrane Database Syst Rev 2010; 12: CD004246.

26.

Cozzi-Lepri

, Phillips

A.N.

, d'Arminio Monforte

Virologic and immunologic response to regimens containing nevirapine or efavirenz in combination with 2 nucleoside analogues in the Italian Cohort Naive Antiretrovirals (I.Co.N.A.) study. J Infect Dis 2002; 185: 1062–1069.

27.

Keiser

, Nassar

, White

, Koen

, Moreno

Comparison of nevirapine- and efavirenz-containing antiretroviral regimens in antiretroviral-naive patients: a cohort study. HIV Clin Trials 2002; 3: 296–303.

28.

Matthews

G.V.

, Sabin

C.A.

, Mandalia

Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 2002; 16: 53–61.

29.

Nachega

J.B.

, Hislop

, Dowdy

D.W.

Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008; 22: 2117–2125.

30.

Dao

C.N.

, Patel

, Overton

E.T.

Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis 2011; 52: 396–405.

31.

Nnoaham

K.E.

, Clarke

Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008; 37: 113–119.

32.

Martineau

A.R.

, Nhamoyebonde

, Oni

Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Proc Natl Acad Sci U S A 2011; 108: 19013–19017.

33.

Realegeno

, Modlin

R.L.

Shedding light on the vitamin D–tuberculosis–HIV connection. Proc Natl Acad Sci U S A 2011; 108: 18861–18862.

34.

Antunes

A.M.

, Godinho

A.L.

, Martins

I.L.

Protein adducts as prospective biomarkers of nevirapine toxicity. Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. Chem Res Toxicol 2010; 23: 1714–1725.

35.

Weiner

III , Parida

S.K.

, Maertzdorf

Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients. PLoS ONE 2012; 7: e40221.