Highly active antiretroviral therapy (HAART) has led to dramatic reductions in HIV-related morbidity and mortality.1 HAART suppresses viral replication, allowing for partial restoration of the immune system and protection against opportunistic pathogens.2 Immune reconstitution, however, can result in an inflammatory response against infectious and non-infectious antigens and an apparent clinical deterioration of the patient. This phenomenon has been described under various descriptions such as "paradoxical reaction," "immune restoration disease," "HAART attacks," "immune reconstitution syndrome (IRS)," and "immune reconstitution inflammatory syndrome."3-5
Previous reports of IRS have primarily been published in the developed world.6 With declining costs in antiretroviral drugs, and production by generic manufacturers, tertiary care centers in the developing world are now able to afford and administer antiretroviral therapy to HIV-seropositive patients.7 With increased coprevalence of opportunistic infections and access to antiretroviral therapy in the developing world,8 we conducted this study to determine the incidence of immune reconstitution in resource-limited settings.
A retrospective cohort study was conducted at YRG Center for Research and Education, an HIV referral center in Chennai, India, to investigate incidence of IRS among HIV/tuberculosis (TB)-coinfected subjects within 6 months of initiating generic HAART. An individual was defined as having active TB in the study if they had symptoms of TB, had radiologic evidence suggestive of TB, and if they were, by microscopy or in culture from sputum or aspirates, positive for acid-fast bacilli. IRS is defined as new lymph node enlargement and localized tenderness or fever with no other cause identified after initiation of HAART after a systemic clinical and laboratory evaluation. Blood, urine, and sputum or pus cultures and blood smear for malarial parasite and microfilaria were done to rule out other causes of fever in the study subjects.
From May 1, 2000, until January 1, 2003, 333 patients (88% male, 95% acquired HIV heterosexually, median age 33 years) attending YRG CARE were on a generic HAART regimen for at least 3 months. Regimens included nevirapine with zidovudine/lamivudine, stavudine/lamivudine, or stavudine/didanosine. At initiation of HAART, 144 patients (44%) had active TB (107 pulmonary, 38 extrapulmonary) with a total follow-up of 72 person-years. Of these HIV/TB-coinfected patients, 91% were male, 93% had acquired HIV heterosexually, and median age was 34 years. The mean CD4 count at initiation of HAART was 122 cells/mm3, and the mean rise in CD4 counts after 6 months of therapy was 130 cells/mm3.
Eleven subjects (all men, median age 29 years, median CD4 at HAART initiation 123 cells/mm3, 6-month median CD4 rise 124 cells/mm3) were identified as having IRS. The characteristics of the study subjects are shown in Table 1. There was no statistical difference in CD4 at initiation of HAART or rise in CD4 after initiation of HAART between those who did and those who did not develop IRS (P = 0.8380). The median time to IRS was 42 days (range 10-89 days). The incidence of IRS in this cohort is 15.2 cases per 100 patient-years. The median duration between initiation of TB treatment and HAART initiation among the IRS group was 22 days and among persons without IRS it was 25 days (P = 0.8). Short-course steroids, aspiration, and counseling were selectively offered.
Following HAART, with the increase in CD4 T lymphocytes, there is shift toward a T-helper 1 (TH1) receptor profile, increasing production of inflammatory mediating cytokines such as interferon-γ and interleukin-2.9 In the case of TB, the predominant opportunistic infection in this case series, TH1 cytokines are critical to immunity. By augmenting the expression of TH1 cytokines, antiretroviral therapy improves the host response to TB.10,11 Unfortunately, the host's enhanced ability to mount an immune reaction and protect from the destruction of infectious agents may itself cause morbidity to the host.3,12,13 There have been cases published of clinical "progression" despite adequate anti-TB and antiretroviral therapy, including prolonged fever, increasing respiratory symptoms, increasing lymphadenopathy, ascites, and growth of intracranial tuberculomas.14,15
In this cohort from a resource-limited setting with a high background rate of TB, there is a high incidence of IRS. As the use of antiretroviral therapy increases in the developing world, initiation of therapy while patients have active opportunistic infections will lead to significant morbidity. An association between the duration of initiation of TB treatment and HAART initiation was seen in an earlier study for the occurrence of IRS.10 This association was not seen in our series. Appropriate therapy must be maintained in the face of apparently worsening clinical symptoms. The use of corticosteroids has anecdotally been successful in decreasing IRS without significantly compromising clinical care.16,17 In the case of TB-associated IRS, fine-needle aspiration cytology will usually show non-specific inflammatory reaction or beaded acid-fact bacilli consistent with previously treated TB.18,19 Therapeutic aspiration can be used to temporarily reduce lymph node bulk. However, there are no definitive guidelines for care of the patient with IRS. At this center, patients are counseled on the condition and are advised to continue with treatment. All patients are currently stable and tolerating therapy with no further adverse events.
With reports of IRS growing in frequency, and now detected significantly in a tertiary HIV center in the developing world, clinical trials in developing countries need to be conducted to help physicians better understand when to initiate antiretroviral therapy in the context of opportunistic infections. In addition, without adequate guidelines to identify and treat IRS, clinicians treating HIV-infected individuals in the developing world will face a new set of challenges to safe and effective therapy.
The authors thank the clinical staff of the YRG Centre for Research and Education, Chennai, India, and of the Immunology Center at Miriam Hospital, Providence, RI, for their generous facilitation of the study.
1. Palella FJ, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med.
2. Bower M, Fox P, Fife K, et al. Highly active antiretroviral therapy
(HAART) prolongs time to treatment failure in Kaposi's sarcoma. AIDS.
3. Chien J, Johnson H. Paradoxical reactions in HIV
and pulmonary TB. Chest.
4. Kunimoto DY, Chui L, Nobert E, et al. Immune mediated "HAART" attack during treatment for tuberculosis
. Int J Tuberc Lung Dis.
5. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC, et al. Immune reconstitution inflammatory syndrome
: emergence of a unique syndrome during highly active antiretroviral therapy
6. DeSimone JA, Pomerantz RJ, Bainchak TJ. Inflammatory reactions in HIV
-1 infected persons after initiation of highly active antiretroviral therapy
. Ann Intern Med.
7. Kumarasamy N, Solomon S, Peters E, et al. The use of antiretroviral drugs in the treatment of people living with HIV
: the experience in a South Indian tertiary referral centre. J Assoc Phys India.
8. Kumarasamy N, Solomon S, Flanigan TP, et al. Natural history of human immunodeficiency virus disease in southern India
. Clin Infect Dis.
9. Mitsuyasu R. HIV
protease inhibitors: immunological insights. AIDS.
10. Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis
following antiretroviral therapy in patients with AIDS
. Am J Respir Crit Care Med.
11. John M, French MAH. Exacerbation of the inflammatory response to Mycobacterium tuberculosis
after antiretroviral therapy. Med J Aust.
12. Fishman JE, Saraf-Lavi E, Narita M, et al. Pulmonary tuberculosis
patients: transient chest radiographic worsening after initiation of antiretroviral therapy. AJR AM J Roentgenol.
13. Furrer H, Malinverni R. Systemic inflammatory reaction after starting highly active antiretroviral therapy
patients treated for extra-pulmonary tuberculosis
. Am J Med.
14. McCormack JG, Bowler SD, Donnelly JE, et al. Miliary tuberculosis
with paradoxical expansion of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy
. Clin Infect Dis.
15. Orlovic D, Smego RA Jr. Paradoxical tuberculous reactions in HIV
infected patients. Int J Tuberc Lung Dis.
16. Cheng VCC, Yuen K, et al. Immunorestoration disease involving the innate and adaptive response. Clin Infect Dis.
17. Safdar A, Rubocki RJ, Horvath JA, et al. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis.
18. Jeena PM, Coovadia HM, Hadley LG, et al. Lymph node biopsies in HIV
-infected and non-infected children with persistent lung disease. Int J Tuberc Lung Dis.
19. Torlakovic E, Clayton F, Ames ED. Refractile mycobacteria in Romanowsky-stained bone marrow smears: a comparison of acid-fast stained tissue sections and Romanowsky-stained smears. Am J Clin Pathol.