Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa

Stefanie Kroeze; Pascale Ondoa; Cissy M Kityo; Margaret Siwale; Sulaimon Akanmu; Maureen Wellington; Marleen de Jager; Prudence Ive; Kishor Mandaliya; Wendy Stevens; T Sonia Boender; Marieke E de Pundert; Kim C E Sigaloff; Peter Reiss; Ferdinand W N M Wit; Tobias F Rinke de Wit; Raph L Hamers

doi:10.1097/QAD.0000000000001801

Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa

Stefanie Kroeze
, Pascale Ondoa
, Cissy M Kityo
, Margaret Siwale
, Sulaimon Akanmu
, Maureen Wellington
, Marleen de Jager
, Prudence Ive
, Kishor Mandaliya
, Wendy Stevens
, T Sonia Boender
, Marieke E de Pundert
, Kim C E Sigaloff
, Peter Reiss
, Ferdinand W N M Wit
, Tobias F Rinke de Wit
, Raph L Hamers

Health Sciences

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).

DESIGN: Multicountry prospective cohort.

METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata.

RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4+ cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200 cells/μl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery.

CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.

Original language	English
Pages (from-to)	1043-1051
Number of pages	9
Journal	AIDS
Volume	32
Issue number	8
DOIs	https://doi.org/10.1097/QAD.0000000000001801
Publication status	Published - 15 May 2018

Funding

aAmsterdam Institute for Global Health and Development, and Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands, bAfrican Society of Laboratory Medicine, Addis Ababa, Ethiopia, cJoint Clinical Research Centre, Kampala, Uganda, dLusaka Trust Hospital, Lusaka, Zambia, eDepartment of Haematology and Blood Transfusion, Lagos University Teaching Hospital, Lagos, Nigeria, fNewlands Clinics, Harare, Zimbabwe, gMuelmed Hospital, Pretoria, hClinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa, iCoast Province General Hospital, Mombasa, Kenya, jDepartment of Molecular Medicine and Haematology, University of the Witwatersrand, Johannesburg and the National Health Laboratory Service, Johannesburg, South Africa, kStichting HIV Monitoring, Amsterdam, and lDivision of Infectious Diseases, Department of Internal Medicine, Academic Medical Center of the University of Amsterdam, and Amsterdam Infection and Immunity Institute, Amsterdam, The Netherlands. Correspondence to Stefanie Kroeze, MSc, Amsterdam Institute for Global Health and Development, Amsterdam, The Netherlands. E-mail: [email protected] Received: 6 October 2017; revised: 13 November 2017; accepted: 16 November 2017. The authors thank the study participants, the staff at the collaborating clinical sites and reference laboratories. PASER was part of the Linking African and Asian Societies for an Enhanced Response to HIV/AIDS (LAASER) program, a partnership of Stichting Aids Fonds, the Foundation for AIDS Research (amfAR)-TREAT Asia, PharmAccess Foundation, and International Civil Society Support (ICSS). Funding: The PanAfrican Studies to Evaluate Resistance (PASER) is an initiative of the Amsterdam Institute for Global Health and Development, with major support provided by the Ministry of Foreign Affairs of The Netherlands through a partnership with Stichting Aids Fonds (grant no. 12454), and with additional support from De Grote Onderneming, The Embassy of the Kingdom of the Netherlands, Heineken Africa Foundation, Jura Foundation, and the Netherlands Organization for Scientific Research through the Netherlands-African Partnership for Capacity Development Clinical Interventions against Poverty-Related Diseases (NWO-WOTRO grant no. W07.10.101 and W07.10.106). RLH is supported by a grant from the Netherlands Organization for Scientific Research through the Innovational Research Incentives Scheme Veni (NWO grant no. 91615036). Siwale), Coptic Hospital (M. Labib), KARA Clinic and Laboratory (J. Menke), Lusaka, Zambia; Muelmed Hospital, Pretoria, South Africa (M.E. Botes†, M. de Jager); Themba Lethu Clinic, Clinical HIV Research Unit, (P. Ive, and I. Sanne) and Department of Molecular Medicine and Haematology (E. Letsoalo, W.S. Stevens, K. Steegen), University of the Witwatersrand, Johannesburg, South Africa; Acts Clinic, White River, South Africa (M. Hardman); Newlands Clinic, Harare, Zimbabwe (M. Wellington, R. Luthy); Coast Province General Hospital, International Centre for Reproductive Health Kenya, Mombasa, Kenya (K. Mandaliya); Mater Misericordiae Hospital, Nairobi, Kenya (M. Dolan); Joint Clinical Research Centre, Fort Portal, Mbale and Kampala, Uganda (C. Kityo, S. Balinda, W. Namala, H. Namata, F. Senono, R. Nakanjako, M. Mutebi, I. Nankya, P. Mugyenyi); Lagos University Teaching Hospital, Lagos, Nigeria (A. Osibogun, S. Akanmu, T. Adeyemo, T. Rodoye, H. Adelabu); Institute of Human Virology Nigeria, Abuja, Nigeria (N. Ndembi); Department of Virology, University Medical Center, Utrecht, The Netherlands (R. Schuurman); Amsterdam Institute for Global Health and Development, Kampala, Uganda (C. Nalubwama, H. Kakooza, M. Nakitto, M. O’Mello); Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam Institute for Global Health and Development, Amsterdam, the Netherlands (R.L. Hamers, K.C.E. Sigaloff, T.S. Boender, P. Ondoa, C. Manting-de Vries, N. Pakker, B. Prins, R. Meester, F.W. Wit, J.M. Lange†, T.F. Rinke de Wit).

Funders	Funder number
Asian Societies
Coast Province General Hospital
De Grote Onderneming, The Embassy of the Kingdom of the Netherlands
Department of Global Health
Department of Molecular Medicine and Haematology
Global Health and Development
Heineken Africa Foundation
Institute of Human Virology Nigeria
International Civil Society Support
Joint Clinical Research Centre
Lagos University Teaching Hospital
NWO-WOTRO
Netherlands Organization for Scientific Research
PharmAccess Foundation
University of Amsterdam
dLusaka Trust Hospital
amfAR, The Foundation for AIDS Research
Center for Global Health
University of the Witwatersrand, Johannesburg
Jurassic Foundation
Academisch Medisch Centrum
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	91615036
Ministry for Foreign Affairs
Addis Ababa University
Stichting Retina Fonds	12454
National Health Laboratory Service
iCoast Province General Hospital

Keywords

Adolescent
Adult
Africa South of the Sahara
Aged
Aged, 80 and over
Anti-Retroviral Agents/therapeutic use
CD4 Lymphocyte Count
Female
HIV Infections/complications
Humans
Immune Reconstitution
Male
Middle Aged
Prospective Studies
Survival Analysis
Sustained Virologic Response
Treatment Outcome
Tuberculosis, Pulmonary/epidemiology
Young Adult

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10.1097/QAD.0000000000001801

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Kroeze, S., Ondoa, P., Kityo, C. M., Siwale, M., Akanmu, S., Wellington, M., de Jager, M., Ive, P., Mandaliya, K., Stevens, W., Boender, T. S., de Pundert, M. E., Sigaloff, K. C. E., Reiss, P., Wit, F. W. N. M., Rinke de Wit, T. F., & Hamers, R. L. (2018). Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa. AIDS, 32(8), 1043-1051. https://doi.org/10.1097/QAD.0000000000001801

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abstract = "OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).DESIGN: Multicountry prospective cohort.METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata.RESULTS: One thousand, five hundred and ninety-two participants were included; 60\% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57\% of participants, respectively. Compared with participants with CD4+ cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200 cells/μl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery.CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.",

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author = "Stefanie Kroeze and Pascale Ondoa and Kityo, \{Cissy M\} and Margaret Siwale and Sulaimon Akanmu and Maureen Wellington and \{de Jager\}, Marleen and Prudence Ive and Kishor Mandaliya and Wendy Stevens and Boender, \{T Sonia\} and \{de Pundert\}, \{Marieke E\} and Sigaloff, \{Kim C E\} and Peter Reiss and Wit, \{Ferdinand W N M\} and \{Rinke de Wit\}, \{Tobias F\} and Hamers, \{Raph L\}",

year = "2018",

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doi = "10.1097/QAD.0000000000001801",

language = "English",

volume = "32",

pages = "1043--1051",

journal = "AIDS",

issn = "0269-9370",

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Kroeze, S, Ondoa, P, Kityo, CM, Siwale, M, Akanmu, S, Wellington, M, de Jager, M, Ive, P, Mandaliya, K, Stevens, W, Boender, TS, de Pundert, ME, Sigaloff, KCE, Reiss, P, Wit, FWNM, Rinke de Wit, TF & Hamers, RL 2018, 'Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa', AIDS, vol. 32, no. 8, pp. 1043-1051. https://doi.org/10.1097/QAD.0000000000001801

TY - JOUR

T1 - Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa

AU - Kroeze, Stefanie

AU - Ondoa, Pascale

AU - Kityo, Cissy M

AU - Siwale, Margaret

AU - Akanmu, Sulaimon

AU - Wellington, Maureen

AU - de Jager, Marleen

AU - Ive, Prudence

AU - Mandaliya, Kishor

AU - Stevens, Wendy

AU - Boender, T Sonia

AU - de Pundert, Marieke E

AU - Sigaloff, Kim C E

AU - Reiss, Peter

AU - Wit, Ferdinand W N M

AU - Rinke de Wit, Tobias F

AU - Hamers, Raph L

PY - 2018/5/15

Y1 - 2018/5/15

N2 - OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).DESIGN: Multicountry prospective cohort.METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata.RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4+ cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200 cells/μl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery.CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.

AB - OBJECTIVE: To assess incidence, determinants and clinical consequences of suboptimal immune recovery in HIV-1 infected adults in sub-Saharan Africa with sustained viral suppression on antiretroviral therapy (ART).DESIGN: Multicountry prospective cohort.METHODS: Suboptimal immune recovery was defined as proportions of participants who failed to attain clinically relevant CD4+ cell count thresholds (>200, >350 and >500 cells/μl) despite sustained viral suppression on continuous first-line ART. Participants were censored at the earliest of death, loss to follow-up, last viral load less than 50 copies/ml, or database closure. Determinants of immune recovery were assessed using multivariable Cox regression. We estimated incidence rates of AIDS, pulmonary tuberculosis and all-cause mortality for CD4+ strata.RESULTS: One thousand, five hundred and ninety-two participants were included; 60% were women, median age was 37 years (IQR 31-43) and median pre-ART CD4+ cell count was 147 cells/μl (IQR 76-215). After 6 years of ART, suboptimal immune recovery at CD4+ cell counts less than 200 cells/μl, less than 350 cells/μl, and less than 500 cells/μl occurred in 7, 27, and 57% of participants, respectively. Compared with participants with CD4+ cell count greater than 500 cells/μl, on-ART incidence rates were 12.5, 4.1, 0.9 times higher for AIDS and 16.9, 3.5, and 2.3 times higher for pulmonary tuberculosis in participants with CD4+ cell count less than 200, 200-349, and 350-499 cells/μl, respectively. All-cause mortality was highest in participants with CD4+ cell count less than 200 cells/μl, and comparable across the higher CD4+ strata. Older age, male sex, and lower pre-ART CD4+ cell count were strongly associated with suboptimal immune recovery.CONCLUSION: These findings warrant close clinical and laboratory monitoring until adequate immune reconstitution is achieved and support early ART initiation before decline of CD4+ cell count.

KW - Adolescent

KW - Adult

KW - Africa South of the Sahara

KW - Aged

KW - Aged, 80 and over

KW - Anti-Retroviral Agents/therapeutic use

KW - CD4 Lymphocyte Count

KW - Female

KW - HIV Infections/complications

KW - Humans

KW - Immune Reconstitution

KW - Male

KW - Middle Aged

KW - Prospective Studies

KW - Survival Analysis

KW - Sustained Virologic Response

KW - Treatment Outcome

KW - Tuberculosis, Pulmonary/epidemiology

KW - Young Adult

U2 - 10.1097/QAD.0000000000001801

DO - 10.1097/QAD.0000000000001801

M3 - Article

C2 - 29547445

SN - 0269-9370

VL - 32

SP - 1043

EP - 1051

JO - AIDS

JF - AIDS

IS - 8

ER -

Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub-Saharan Africa

Abstract

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Keywords

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