- Email: [email protected]
HIV and Heart Disease in Africa
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
VOL. 66, NO. 5, 2015 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.06.021
GUEST EDITOR’S PAGE
HIV and Heart Disease in Africa Pravin Manga, MBBCH, PHD
T
he global burden of human immunodefi-
HIV AND PERICARDIAL DISEASE
ciency virus (HIV) has largely been borne by Africa, particularly sub-Saharan Africa (1). In
Pericardial disease poses a significant health care
the sub-Saharan region, South Africa has the largest
problem in sub-Saharan Africa. Small pericardial ef-
population of HIV-infected individuals, with an esti-
fusions are common and largely asymptomatic in
mated 6 million living with HIV (1). HIV is no longer
HIV-infected individuals, but they do presage a worse
a fatal illness, which is largely the result of treatment
outcome compared with those without pericardial
with highly active antiretroviral treatment (HAART).
effusion (4). Because tuberculosis is endemic, the
As a result, the life expectancy of HIV-infected indi-
suspicion of infection with mycobacterium tubercu-
viduals has increased substantially compared with
losis is very high with larger effusions, and it has been
the pre-HAART era.
found to be the cause of pericardial disease in the vast
On the African subcontinent, the major subtype
majority (86% to 100%) of these individuals (5).
of HIV is the HIV-1, group M (major) subtype C,
Mortality from tuberculous pericarditis and HIV in
which accounts for 55% to 60% of all HIV-1 in-
sub-Saharan Africa, in spite of therapy, ranges be-
fections worldwide (2). To date, the majority of re-
tween 17% and 40% and is twice as high compared
search on cardiovascular disease in HIV-infected
with those without HIV (6). Some early studies sug-
patients has been performed in Caucasian patients
gested a benefit of adjunctive steroid therapy in pa-
infected with HIV-1 subtype B, which differs as
tients with HIV and tuberculous pericarditis with
much as 30% in its genome from HIV-1 subtype C
regard to improved mortality and decreased inci-
(2,3). However, in sub-Saharan Africa, there are
dence of constrictive pericarditis (7). To clarify this
scant data on the risk of cardiovascular disease in
important clinical issue, a large randomized study of
HIV-positive populations, and thus, the risk of car-
prednisolone and immunotherapy in constrictive
diovascular disease in HIV-infected African patients
pericarditis was performed in a number of clinical
is largely unknown. Also of importance is that some
sites all over Africa (8). The recently published results
countries, particularly South Africa, have managed
of that study demonstrated that, in HIV patients with
to introduce an active HAART program for a sig-
tuberculous pericardial effusion, not only did the
nificant number of individuals with HIV. However,
addition of steroid therapy fail to reduce the primary
many other developing nations in Africa, due to
endpoint of mortality, but importantly, the addition
limited resources, have far fewer individuals being
of steroids was associated with a significantly higher
treated with antiretroviral therapy. Thus, there
risk of cancer in these patients (8).
are 2 groups of HIV patients living in Africa, those not on HAART and those on HAART, leading to different challenges for managing cardiovascular disease in Africa.
HIV AND CORONARY ARTERY DISEASE Studies in developed countries report a 1.5- to 2-fold increase in cardiovascular events related to coronary artery disease in HIV-infected patients (the majority of whom are on HAART) compared with control
From the Division of Cardiology, Department of Internal Medicine,
populations (9). The underlying mechanism of early
Faculty of Health Sciences, University of Witwatersrand, Johannesburg,
atherosclerosis in HIV disease is not well under-
South Africa.
stood, and suggested mechanisms include vascular
Manga
JACC VOL. 66, NO. 5, 2015 AUGUST 4, 2015:586–8
Guest Editor’s Page
inflammation leading to endothelial dysfunction and
almost a 50% reduction in prevalence of HIV-
possibly the effect of antiretroviral treatment (10,11).
associated cardiomyopathy (18).
Because of the huge burden of HIV in sub-Saharan Africa, it was expected that there would be a significant increase in the prevalence of coronary artery disease. However, this has not materialized. The Heart of Soweto Study found that, in the cohort of cardiac patients admitted to the hospital and who were diagnosed with HIV—one-half of whom were on HAART—the overall prevalence of coronary artery disease was only 2.4% (12). The low prevalence may be related to a much younger population in this region and low use of protease inhibitors. The common findings in cohorts from both developed and developing countries is that the mean age at diagnosis of acute coronary syndrome is a decade younger and subjects are more likely to be male, be current smokers, have lower high-density lipoprotein levels, and have single-vessel disease on coronary angiography (12–14). Additionally, the South African cohort of HIV patients with acute coronary syndromes had less atherosclerotic burden angiographically but a significantly higher degree of thrombus burden in the infarct-related artery (14). The thrombotic burden in these patients is thought to be related to a prothrombotic state with lower protein C and higher factor VIII levels (15).
EFFECT OF HIV ON HEALTH CARE AND RESEARCH IN AFRICA The HIV epidemic infection has had a devastating effect on health care provision, resources, and life expectancy in Africa. The introduction of HAART, albeit in limited capacity in many parts of Africa, has dramatically improved life expectancy of many of these patients. However, many countries in subSaharan Africa are a long way from providing a comprehensive prevention program, as well as effective antiretroviral therapy for all infected with HIV. As antiretroviral therapy is associated with a significant reduction in HIV-related cardiovascular diseases, the strategies for prevention and treatment of HIV-related heart disease in developing countries has been to support the active campaigns to get universal access to HAART in the first place. Consequently, the major research focus in sub-Saharan Africa has largely been directed to prevention and treatment strategies of HIV infection itself. Very little research emphasis has been placed on specific targets such as the influence of HIV on heart disease. However, the expected improved survival related to progressively more patients being treated with HAART
HIV AND CARDIOMYOPATHY
will be an ideal platform for researchers in Africa to study the various aspects of cardiovascular disease in
HIV-related cardiomyopathy is a significant contrib-
HIV patients, both in those who are HAART naïve and
utor to morbidity and mortality in sub-Saharan Africa,
in those receiving HAART. Of note, the National
with prevalence ranging from 9% to 57% and in-
Institutes of Health recently identified various re-
hospital mortality of up to 15% (16). The pathogen-
search “gaps” in our knowledge of HIV and heart
esis of the cardiomyopathy in these HIV-infected
disease and has encouraged investigation in these
patients is unknown. Many hypotheses have been
areas (19).
proposed, including direct invasion of the myocardium by the HIV virus, autoimmunity and immune
ADDRESS CORRESPONDENCE TO: Dr. Pravin Manga,
dysregulation, endothelial dysfunction, and beta-
Division
adrenergic dysregulation (17). Initiation of antiretro-
Medicine, Faculty of Health Sciences, University of
viral therapy is important to decrease this burden as
Witwatersrand, Johannesburg, South Africa. E-mail:
the introduction of HAART has been associated with
[email protected].
of
Cardiology,
Department
of
Internal
REFERENCES 1. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Report 2013. Available at: http:// www.unaids.org/sites/default/files/media_asset/ UNAIDS_Global_Report_2013_en_1.pdf. Accessed June 16, 2015. 2. Peeters M. The genetic variability of HIV-1 and its implications. Transfus Clin Biol 2001; 8:222–5. 3. Gaschen B, Taylor J, Yusim K, et al. Diversity considerations in HIV-1 vaccine selection. Science 2002;296:2354–60.
4. Heidenreich PA, Eisenberg MJ, Kee LL, et al. Pericardial effusion in AIDS. Incidence and survival. Circulation 1995;92:3229–34. 5. Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis 2007;50:218–36. 6. Mayosi BM, Wiysonge CS, Ntsekhe M, et al. Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa. S Afr Med J 2008;98:36–40.
7. Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183–8. 8. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014;371: 1121–30. 9. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to
587
588
Manga
JACC VOL. 66, NO. 5, 2015 AUGUST 4, 2015:586–8
Guest Editor’s Page
decrease cardiovascular risk and increase quality of care for patients living with HIV/ AIDS: executive summary. Circulation 2008; 118:198–210. 10. de Gaetano Donati K, Rabagliati R, et al. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis 2004;4:213–22. 11. Mooser M. Atherosclerosis and HIV in the highly active antiretroviral therapy era: towards an epidemic of cardiovascular disease? AIDS 2003;17 Suppl 1:S65–9. 12. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in
Heart of Soweto Study cohort. Eur Heart J 2012;33: 866–74. 13. Hsue PY, Giri K, Erickson S, et al. Clinical features of acute coronary syndromes in patients with human immunodeficiency virus infection. Circulation 2004;109:316–9. 14. Becker AC, Sliwa K, Stewart S, et al. Acute coronary syndromes in treatment-naïve black South Africans with human immunodeficiency virus infection. J Interv Cardiol 2010; 23:70–7. 15. Becker AC, Jacobson B, Singh S, et al. The thrombotic profile of treatment-naïve HIVpositive black South Africans with acute coronary syndromes. Clin Appl Thromb Hemost 2011;17: 264–72.
16. Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in Africa. Circulation 2005;112:3602–7. 17. Syed FF, Sani UM. Recent advances in HIVassociated cardiovascular diseases in Africa. Heart 2013;99:1146–53. 18. Patel K, Van Dyke RB, Mittleman MA, et al. The impact of HAART on cardiomyopathy among children and adolescents perinatally infected with HIV-1. AIDS 2012;26:2027–37. 19. Shah MR, Cook N, Wong R, et al. Stimulating high impact HIV-related cardiovascular research: recommendations from a multidisciplinary NHLBI working group on HIV-related heart, lung and blood disease. J Am Coll Cardiol 2015;65: 738–44.
VOL. 66, NO. 5, 2015 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2015.06.021
GUEST EDITOR’S PAGE
HIV and Heart Disease in Africa Pravin Manga, MBBCH, PHD
T
he global burden of human immunodefi-
HIV AND PERICARDIAL DISEASE
ciency virus (HIV) has largely been borne by Africa, particularly sub-Saharan Africa (1). In
Pericardial disease poses a significant health care
the sub-Saharan region, South Africa has the largest
problem in sub-Saharan Africa. Small pericardial ef-
population of HIV-infected individuals, with an esti-
fusions are common and largely asymptomatic in
mated 6 million living with HIV (1). HIV is no longer
HIV-infected individuals, but they do presage a worse
a fatal illness, which is largely the result of treatment
outcome compared with those without pericardial
with highly active antiretroviral treatment (HAART).
effusion (4). Because tuberculosis is endemic, the
As a result, the life expectancy of HIV-infected indi-
suspicion of infection with mycobacterium tubercu-
viduals has increased substantially compared with
losis is very high with larger effusions, and it has been
the pre-HAART era.
found to be the cause of pericardial disease in the vast
On the African subcontinent, the major subtype
majority (86% to 100%) of these individuals (5).
of HIV is the HIV-1, group M (major) subtype C,
Mortality from tuberculous pericarditis and HIV in
which accounts for 55% to 60% of all HIV-1 in-
sub-Saharan Africa, in spite of therapy, ranges be-
fections worldwide (2). To date, the majority of re-
tween 17% and 40% and is twice as high compared
search on cardiovascular disease in HIV-infected
with those without HIV (6). Some early studies sug-
patients has been performed in Caucasian patients
gested a benefit of adjunctive steroid therapy in pa-
infected with HIV-1 subtype B, which differs as
tients with HIV and tuberculous pericarditis with
much as 30% in its genome from HIV-1 subtype C
regard to improved mortality and decreased inci-
(2,3). However, in sub-Saharan Africa, there are
dence of constrictive pericarditis (7). To clarify this
scant data on the risk of cardiovascular disease in
important clinical issue, a large randomized study of
HIV-positive populations, and thus, the risk of car-
prednisolone and immunotherapy in constrictive
diovascular disease in HIV-infected African patients
pericarditis was performed in a number of clinical
is largely unknown. Also of importance is that some
sites all over Africa (8). The recently published results
countries, particularly South Africa, have managed
of that study demonstrated that, in HIV patients with
to introduce an active HAART program for a sig-
tuberculous pericardial effusion, not only did the
nificant number of individuals with HIV. However,
addition of steroid therapy fail to reduce the primary
many other developing nations in Africa, due to
endpoint of mortality, but importantly, the addition
limited resources, have far fewer individuals being
of steroids was associated with a significantly higher
treated with antiretroviral therapy. Thus, there
risk of cancer in these patients (8).
are 2 groups of HIV patients living in Africa, those not on HAART and those on HAART, leading to different challenges for managing cardiovascular disease in Africa.
HIV AND CORONARY ARTERY DISEASE Studies in developed countries report a 1.5- to 2-fold increase in cardiovascular events related to coronary artery disease in HIV-infected patients (the majority of whom are on HAART) compared with control
From the Division of Cardiology, Department of Internal Medicine,
populations (9). The underlying mechanism of early
Faculty of Health Sciences, University of Witwatersrand, Johannesburg,
atherosclerosis in HIV disease is not well under-
South Africa.
stood, and suggested mechanisms include vascular
Manga
JACC VOL. 66, NO. 5, 2015 AUGUST 4, 2015:586–8
Guest Editor’s Page
inflammation leading to endothelial dysfunction and
almost a 50% reduction in prevalence of HIV-
possibly the effect of antiretroviral treatment (10,11).
associated cardiomyopathy (18).
Because of the huge burden of HIV in sub-Saharan Africa, it was expected that there would be a significant increase in the prevalence of coronary artery disease. However, this has not materialized. The Heart of Soweto Study found that, in the cohort of cardiac patients admitted to the hospital and who were diagnosed with HIV—one-half of whom were on HAART—the overall prevalence of coronary artery disease was only 2.4% (12). The low prevalence may be related to a much younger population in this region and low use of protease inhibitors. The common findings in cohorts from both developed and developing countries is that the mean age at diagnosis of acute coronary syndrome is a decade younger and subjects are more likely to be male, be current smokers, have lower high-density lipoprotein levels, and have single-vessel disease on coronary angiography (12–14). Additionally, the South African cohort of HIV patients with acute coronary syndromes had less atherosclerotic burden angiographically but a significantly higher degree of thrombus burden in the infarct-related artery (14). The thrombotic burden in these patients is thought to be related to a prothrombotic state with lower protein C and higher factor VIII levels (15).
EFFECT OF HIV ON HEALTH CARE AND RESEARCH IN AFRICA The HIV epidemic infection has had a devastating effect on health care provision, resources, and life expectancy in Africa. The introduction of HAART, albeit in limited capacity in many parts of Africa, has dramatically improved life expectancy of many of these patients. However, many countries in subSaharan Africa are a long way from providing a comprehensive prevention program, as well as effective antiretroviral therapy for all infected with HIV. As antiretroviral therapy is associated with a significant reduction in HIV-related cardiovascular diseases, the strategies for prevention and treatment of HIV-related heart disease in developing countries has been to support the active campaigns to get universal access to HAART in the first place. Consequently, the major research focus in sub-Saharan Africa has largely been directed to prevention and treatment strategies of HIV infection itself. Very little research emphasis has been placed on specific targets such as the influence of HIV on heart disease. However, the expected improved survival related to progressively more patients being treated with HAART
HIV AND CARDIOMYOPATHY
will be an ideal platform for researchers in Africa to study the various aspects of cardiovascular disease in
HIV-related cardiomyopathy is a significant contrib-
HIV patients, both in those who are HAART naïve and
utor to morbidity and mortality in sub-Saharan Africa,
in those receiving HAART. Of note, the National
with prevalence ranging from 9% to 57% and in-
Institutes of Health recently identified various re-
hospital mortality of up to 15% (16). The pathogen-
search “gaps” in our knowledge of HIV and heart
esis of the cardiomyopathy in these HIV-infected
disease and has encouraged investigation in these
patients is unknown. Many hypotheses have been
areas (19).
proposed, including direct invasion of the myocardium by the HIV virus, autoimmunity and immune
ADDRESS CORRESPONDENCE TO: Dr. Pravin Manga,
dysregulation, endothelial dysfunction, and beta-
Division
adrenergic dysregulation (17). Initiation of antiretro-
Medicine, Faculty of Health Sciences, University of
viral therapy is important to decrease this burden as
Witwatersrand, Johannesburg, South Africa. E-mail:
the introduction of HAART has been associated with
[email protected].
of
Cardiology,
Department
of
Internal
REFERENCES 1. Joint United Nations Programme on HIV/AIDS (UNAIDS). Global Report 2013. Available at: http:// www.unaids.org/sites/default/files/media_asset/ UNAIDS_Global_Report_2013_en_1.pdf. Accessed June 16, 2015. 2. Peeters M. The genetic variability of HIV-1 and its implications. Transfus Clin Biol 2001; 8:222–5. 3. Gaschen B, Taylor J, Yusim K, et al. Diversity considerations in HIV-1 vaccine selection. Science 2002;296:2354–60.
4. Heidenreich PA, Eisenberg MJ, Kee LL, et al. Pericardial effusion in AIDS. Incidence and survival. Circulation 1995;92:3229–34. 5. Syed FF, Mayosi BM. A modern approach to tuberculous pericarditis. Prog Cardiovasc Dis 2007;50:218–36. 6. Mayosi BM, Wiysonge CS, Ntsekhe M, et al. Mortality in patients treated for tuberculous pericarditis in sub-Saharan Africa. S Afr Med J 2008;98:36–40.
7. Hakim JG, Ternouth I, Mushangi E, et al. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart 2000;84:183–8. 8. Mayosi BM, Ntsekhe M, Bosch J, et al. Prednisolone and mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014;371: 1121–30. 9. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to
587
588
Manga
JACC VOL. 66, NO. 5, 2015 AUGUST 4, 2015:586–8
Guest Editor’s Page
decrease cardiovascular risk and increase quality of care for patients living with HIV/ AIDS: executive summary. Circulation 2008; 118:198–210. 10. de Gaetano Donati K, Rabagliati R, et al. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis 2004;4:213–22. 11. Mooser M. Atherosclerosis and HIV in the highly active antiretroviral therapy era: towards an epidemic of cardiovascular disease? AIDS 2003;17 Suppl 1:S65–9. 12. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in
Heart of Soweto Study cohort. Eur Heart J 2012;33: 866–74. 13. Hsue PY, Giri K, Erickson S, et al. Clinical features of acute coronary syndromes in patients with human immunodeficiency virus infection. Circulation 2004;109:316–9. 14. Becker AC, Sliwa K, Stewart S, et al. Acute coronary syndromes in treatment-naïve black South Africans with human immunodeficiency virus infection. J Interv Cardiol 2010; 23:70–7. 15. Becker AC, Jacobson B, Singh S, et al. The thrombotic profile of treatment-naïve HIVpositive black South Africans with acute coronary syndromes. Clin Appl Thromb Hemost 2011;17: 264–72.
16. Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in Africa. Circulation 2005;112:3602–7. 17. Syed FF, Sani UM. Recent advances in HIVassociated cardiovascular diseases in Africa. Heart 2013;99:1146–53. 18. Patel K, Van Dyke RB, Mittleman MA, et al. The impact of HAART on cardiomyopathy among children and adolescents perinatally infected with HIV-1. AIDS 2012;26:2027–37. 19. Shah MR, Cook N, Wong R, et al. Stimulating high impact HIV-related cardiovascular research: recommendations from a multidisciplinary NHLBI working group on HIV-related heart, lung and blood disease. J Am Coll Cardiol 2015;65: 738–44.