To the Editors:
The expansion of antiretroviral therapy (ART) in resource-limited settings (RLS) has dramatically changed the face of the AIDS epidemic in sub-Saharan Africa over the past decade.1 The progress in HIV/AIDS care is in large part due to successful bilateral and multilateral collaborations of governments and nongovernmental AIDS organizations. In Uganda, for example, with funding support from the National Institutes of Health and the President's Emergency Plan for AIDS Relief, the Case Western Reserve University (CWRU) and others have partnered with Ugandan institutions to develop a comprehensive HIV/AIDS infrastructure. Because of this concerted effort, the country has seen a fall in HIV prevalence from a peak of 25% to 30% in major urban areas to now <7% nationally, and nearly half of those who qualify for treatment are currently receiving it.2
These successes, however, bring new challenges. As HIV has now become a manageable chronic disease, the infected population has aged and the higher prevalence of comorbidities such as cardiovascular disease (CVD) is increasingly recognized. The specter of a dual epidemic of HIV/AIDS and noncommunicable disease threatens to place significant demands on these fragile health-care systems.3 In addition to the higher risk of ischemic heart disease observed in the developed and developing world, the burden of endemic CVD such as tuberculous pericarditis and rheumatic heart disease (RHD) among persons living with HIV in RLS is unknown. Recognizing this emerging need, Makerere University School of Medicine, Mulago Hospital, and the Uganda Heart Institute (UHI) have partnered with CWRU to extend collaboration beyond HIV/AIDS to CVD, neurology, and oncology. Funded in part by the National Institutes of Health/Fogarty International Medical Education Partnership Initiative, the cardiology collaboration aims to provide contextually appropriate training of cardiovascular specialists and conduct research on CVD risk factors, including the impact of HIV/AIDS.
As part of the Medical Education Partnership Initiative collaboration, a team of cardiologists from CWRU traveled to Kampala, Uganda, in August 2012 to perform procedures in the newly opened cardiac catheterization laboratory at the UHI, Mulago Hospital, including the country's first percutaneous mitral balloon valvuloplasties for rheumatic mitral stenosis (Figs. 1A, B). Although rarely seen in the developed world, RHD remains a leading cause of cardiovascular morbidity and mortality in RLS, affecting over 1 million children in sub-Saharan Africa alone.4 RHD is a chronic complication of rheumatic fever, an autoimmune reaction to antecedent group A streptococcus pharyngitis that causes varying degrees of carditis.5 Significant valvular regurgitation or stenosis may occur during the initial insult or after repeated damage to the valve from recurrent bouts of acute rheumatic fever.5 Congestive heart failure then develops insidiously and may lead to death in the second to fifth decades of life if the valve is not repaired. The current treatment of choice in developed countries for rheumatic mitral valve stenosis without significant regurgitation is percutaneous balloon valvuloplasty.6
The first patient to benefit from this minimally invasive procedure in Uganda was HIV infected. In a country with a high prevalence of HIV/AIDS, it may be a coincidence that this patient happened to be HIV infected. Nonetheless, several questions arise regarding the impact of HIV on RHD (and other endemic noncommunicable disease) in the country. Are perinatally HIV-infected children more or less likely than their uninfected peers to acquire acute rheumatic fever? What is the role of chronic inflammation and immune activation associated with HIV on outcomes among children with RHD? In patients with AIDS, does the CD4+ lymphopenia associated with acute rheumatic fever lead to further immunosuppression and increased susceptibility to opportunistic infections? Is someone with subclinical RHD acquired in childhood more or less likely to develop progressive disease if they become HIV infected as an adult? Among patients colonized with group A streptococci who are started on ART therapy, can subclinical rheumatic carditis develop within the spectrum of immune reconstitution inflammatory syndromes?
Although RHD is rare in the developed world, other rheumatic/immunologic complications of HIV/AIDS are not uncommon. The spectrum of disease has changed since the introduction of combination ART in the mid 1990s.7,8 Autoimmunity seems to be increased in chronic HIV infection, and molecular mimicry may be an important mechanism.9 For example, in a recent study from South Africa, anticyclic citrullinated peptide antibody titers were increased in advanced HIV infection compared with controls and decreased after initiation of ART.10 In this context, the anticyclic citrullinated peptide antibodies lacked the typically high specificity for rheumatoid arthritis. In some cases, inflammatory arthritis such as psoriatic arthritis11 or rheumatoid arthritis12 may be the initial presentation of HIV/AIDS. However, advanced immunosuppression may suppress the clinical manifestations of preexisting autoimmune conditions such as inflammatory bowel disease, systemic lupus erythematosis, and rheumatoid arthritis.13 Despite this literature, little is known about the interaction of HIV with rheumatic fever and RHD. Some studies have demonstrated an increased risk for group A streptococcal infection with underlying HIV infection14; however, to our knowledge, only 1 case of acute rheumatic fever in a patient with AIDS has been reported previously.15
The CWRU team continues to return quarterly to Uganda as part of a comprehensive skill transfer program that also includes training for Ugandan physicians in Cleveland, Ohio In addition, CWRU has partnered with the UHI and the Joint Clinical Research Centre (a center in existence in Uganda for care and research in HIV/AIDS) to focus specifically on RHD through an innovative foundation-funded project. This program will use an existing network of HIV/AIDS infrastructure to create community-based RHD treatment centers of excellence. If successful, this program may serve as a model for leveraging HIV/AIDS resources for the treatment of noncommunicable diseases among both HIV-infected and HIV-uninfected patients in RLS.
We are now at a crossroads. An opportunity exists to build upon the dramatic improvements in health care infrastructure that HIV/AIDS investment has brought over the past decade. To extend the benefits of the ART rollout to the treatment of non-AIDS comorbidities such as RHD will require a coordinated research effort and capital investment in health systems, particularly in human resources. Multilateral collaborations in medical specialties beyond infectious diseases that share the tripartite mission of research, education, and clinical care such as the one described in this report will be needed to move to the next level of HIV/AIDS treatment in sub-Saharan Africa and other RLS.
The authors acknowledge the Director of the Uganda Heart Institute, Dr John Omagino along with Dr Charles Mondo and the staff of the cardiac catheterization laboratory for their ongoing efforts to improve cardiovascular disease care in Uganda.
1. Hontelez JA, de Vlas SJ, Baltussen R, et al.. The impact of antiretroviral treatment on the age composition of the HIV epidemic in sub-Saharan Africa. AIDS. 2012;26(suppl 1):S19–S30.
2. WHO/UNAIDS/UNICEF. Global HIV/AIDS Response. 2011.
3. Negin J, Barnighausen T, Lundgren JD, et al.. Aging with HIV in Africa: the challenges of living longer. AIDS. 2012;26(suppl 1):S1–S5.
4. Essop MR, Nkomo VT. Rheumatic and nonrheumatic valvular heart disease: epidemiology, management, and prevention in Africa. Circulation. 2005;112:3584–3591.
5. Carapetis JR, McDonald M, Wilson NJ. Acute rheumatic fever. Lancet. 2005;366:155–168.
6. Bonow RO, Carabello BA, Chatterjee K, et al.. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2006;48:e1–e148.
7. Calabrese LH, Kirchner E, Shrestha R. Rheumatic complications of human immunodeficiency virus infection in the era of highly active antiretroviral therapy: emergence of a new syndrome of immune reconstitution and changing patterns of disease. Semin Arthritis Rheum. 2005;35:166–174.
8. Lawson E, Walker-Bone K. The changing spectrum of rheumatic disease in HIV infection. Br Med Bull. 2012;103:203–221.
9. Zandman-Goddard G, Shoenfeld Y. HIV and autoimmunity. Autoimmun Rev. 2002;1:329–337.
10. du Toit R, Whitelaw D, Taljaard JJ, et al.. Lack of specificity of anticyclic citrullinated peptide antibodies in advanced human immunodeficiency virus infection. J Rheumatol. 2011;38:1055–1060.
11. Njobvu P, McGill P. Psoriatic arthritis and human immunodeficiency virus infection in Zambia. J Rheumatol. 2000;27:1699–1702.
12. Jaffer AM. Seronegative rheumatoid arthritis associated with AIDS. Ann Rheum Dis. 1991;50:134.
13. Furie RA. Effects of human immunodeficiency virus infection on the expression of rheumatic illness. Rheum Dis Clin North Am. 1991;17:177–188.
14. Factor SH, Levine OS, Schwartz B, et al.. Invasive group A streptococcal disease: risk factors for adults. Emerg Infect Dis. 2003;9:970–977.
15. Radcliffe KW, McLean KA, Benbow AG. Acute rheumatic fever in human immunodeficiency virus infection. J Infect. 1991;22:187–189.