Immune reconstitution and inflammatory syndrome due to disseminated tuberculosis in a case of human immunodeficiency virus 2 infection.

We present a case of human immunodeficiency virus 2 (HIV- 2) infection with acquired immune deficiency syndrome with immune reconstitution and inflammatory syndrome due to disseminated tuberculosis. We address here the drug interactions between antiretroviral therapy and antituberculous treatment (ATT), choice of ATT, and duration of ATT when rifampicin is omitted as in our case. Though this problem is encountered rarely, we felt that it is important to report the issue to counter drug resistance in tuberculosis and HIV.

Introduction

Although both human immunodeficiency virus 1 and 2 (HIV-1 and HIV-2) can cause acquired immune deficiency syndrome (AIDS), the clinical and biological characteristics of infection with these two viruses show substantial differences, as well as similarities.[1] Tuberculosis is a common opportunistic infection encountered in HIV-1 and also in HIV-2 infection. In this case report, we discussed the issues related to management of a patient of advanced HIV-2 and some of the important drug interactions which are likely to be encountered between antiretroviral therapy (ART) and standard antituberculous treatment (ATT). The objective of this case report is to discuss effective antituberculous therapy in HIV-2 patients while preventing the emergence of drug resistance to ART.

Case Report

A 45-year-old man, farmer by occupation, was referred to our institution for management of HIV infection complicated by untoward effects related to ART. He was diagnosed to have HIV infection six years ago at a district center and CD4 count at that time was 114 cells/μl. He was started on a combination of zidovudine, lamivudine, and nevirapine. A month later, he developed zidovudine-induced anemia. Hence, zidovudine was replaced with stavudine and lamivudine with nevirapine were continued. After few years, he developed severe painful peripheral neuropathy for which ART was stopped and the patient was referred to our institute for further management.

As part of work up at our institute, Western Blot test was done which confirmed infection with HIV-2. The CD4 count was found to be 110 cells/μl. He was started on abacavir, tenofovir, and lopinavir/ritonavir. After three months, patient developed fever with hepatosplenomegaly. CD4 improved to 350 cells/μl. Contrast-enhanced CT scan of abdomen showed hepatosplenomegaly, para-aortic lymphadenopathy, and minimally enhancing splenic lesions at the level of splenic hilum [Figure 1]. Ultrasound-guided fine needle aspiration cytology from the spleen showed granulomas [Figure 2]. Patient was continued on the same antiretroviral treatment consisting of abacavir, tenofovir, and ritonavir-boosted lopinavir, and Additionally, he was started on ATT consisting of isoniazid (INH), pyrazinamide (PZA), ethambutol, and streptomycin for the first two months. Rifampicin was not started. Subsequently, he was continued on INH, PZA, and ethambutol for 16 more months. Patient improved remarkably and continued on ART. Patient is presently on regular follow-up for last six years with good adherence to ART. The present CD4 count is 750 cells/μl.

Figure 1

Contrast-enhanced CT scan of abdomen showing hepatosplenomegaly, para-aortic lymphadenopathy, and minimally enhancing splenic lesion at the level of splenic hilum

Figure 2

Fine needle aspiration cytology from the spleen showing clusters of epithelioid cells surrounded by few lymphocytes (Giemsa stain × 40X) suggestive of granulomas

Discussion

HIV-2 infection is unique as it degrades the immune system more slowly than those who have HIV-1 infection. However, the ultimate effects of HIV-2 infection are the same as HIV-1 and lead to AIDS. HIV-2 infection is endemic in West Africa and has spread in the last decade to India and Europe. HIV2 was first reported in India from Mumbai.[2] Later on, it was reported from several other states in India. Kulkarni et al. from Vellore have reported that the frequency of HIV-2 was around 3% of the total HIV infections.[3] Majority of HIV-2 infections were identified from less-risk groups and blood donors.[3] It is important to realize that HIV-2 infections do prevail in India, though the incidence is much less than HIV-1.[2] Viral load testing in HIV-2 is not standardized in India and is unreliable. Also, the management of HIV-2 differs significantly from HIV-1. HIV-2 is sensitive to nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide analogues, such as tenofovir.[4] Furthermore, HIV-2 is resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) like efavirenz and nevirapine and the fusion inhibitor enfuvirtide.[4] Most protease inhibitors (PIs) also have activity against HIV-2.[4] Another important consideration particular to Indian patients is that the ART centers supply same class of antiretroviral drugs to all HIV patients, irrespective of their HIV-1 or HIV-2 status.[5] The ART regimen includes two nucleoside analogues and one non-nucleoside analogue. This regimen does not effectively cover the HIV-2 infection. If the HIV-2 patient takes only nucleoside and non-nucleoside analogue combination, there is a possibility of development of early resistance in this group.[5]

Tuberculosis is referred to as an AIDS-defining disease.[6] After 12 weeks of starting the appropriate ART, our patient developed fever with hepatosplenomegaly and caseating granulomas in spleen. Immune reconstitution inflammatory syndrome is characterized by a paradoxical deterioration of clinical condition, in whom ARV has recently been initiated.[4] It is associated with a decrease in viral load and at least a partial recovery of immune competence, usually associated with increases in CD4+ T cell counts. The improvement in CD4 counts along with fever and demonstration of caseating granulomas made us think of the possibility of immune reconstitution and inflammatory syndrome (IRIS) due to disseminated tuberculosis. Similar to the patient in our case report, IRIS due to tuberculosis usually manifests at around 1 to 3 months after starting ART.[7]

Treatment of tuberculosis in HIV is also complicated by drug interactions and overlapping toxicities of antiretroviral drugs and antituberculous drugs. Rifampin induces the activity of cytochrome P-450 CYP3A, which lowers the concentrations of HIV-PIs and non-nucleoside reverse-transcriptase inhibitors to subtherapeutic levels.[8] Low trough plasma levels of these antiretroviral drugs are associated with incomplete viral suppression and the emergence of drug resistance in HIV.[8]

The limited availability of antiretroviral drugs in India makes the treatment of HIV-2 infection even more difficult. The treatment becomes much more complex when the patient needs ATT concomitantly. For patients with HIV-2 infection with tuberculosis, who are not on PIs, standard ATT can be administered. In the present case, the patient was already on tenofovir, emtricitabine, and ritonavir-boosted lopinavir. He tolerated the antiretroviral regimen very well with increase in CD4 counts. So, we continued the same antiretroviral regimen. As rifabutin is a less potent inducer of CYP3A than rifampin, it can be administered in combination with the PI.[9] Another option in a resource-limited setting like ours is that an alternative ATT regimen (that does not include a rifamycin) should be started to avoid the risk of development of subtherapeutic levels of PIs.[9] It has been suggested that patients that have benefited from PIs before the development of tuberculosis should generally continue to receive them during ATT.[9] Though rifampicin is a very important part of ATT, we felt that an ATT regimen without rifampicin would allow the patient to continue the ART which is best suited for him. Treatment of drug-susceptible tuberculosis should include a 6-month regimen with an initial phase of INH, rifampicin, PZA, and ethambutol for two months, followed by INH and rifampicin for four additional months. Recommendations for anti-TB regimens in HIV-infected adults follow the same principles as for adults without HIV infection. Another issue is the duration of ATT in regimens without rifampicin. If rifampicin is not present in ATT regimens, an oral combination of INH, ethambutol, and PZA for 18 to 24 months is preferable in most patients.[10]

We feel that there is a need to tailor the ATT and ART regimen for individual patients with the help of guidelines and experience. Every effort should be made by the physician to offer the most effective ARV and ATT to curb drug resistance in patients with HIV and tuberculosis.