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Query: UMLS:C0019693 (HIV)
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HIV caregivers face many challenges following initiation of ART. The development of jaundice is uncommon but worrisome. In this case, two distinct and contrasting episodes of jaundice were observed. In the first instance, isolated elevation of the indirect bilirubin without elevation of the alkaline phosphatase was noted. The normal PT and serum aminotransferase levels indicate the absence of intrinsic liver dysfunction. Elevations in the indirect bilirubin may result from either impaired uptake/conjugation or excess production. The latter, usually from acquired hemolysis, may be a complication of an occult NHL. A work-up for this AIDS-related malignancy was not initiated since the caregivers recognized jaundice as a complication of IDV, which inhibits UDP-glucuronyl transferase and produces a Gilbert's-like syndrome. Physicians can expect to encounter this syndrome even more frequently with ATV. Experienced patients given RTV-boosted ATV have experienced elevations of unconjugated hyper-bilirubinemia in up to 45 percent of cases in clinical trials. However, such elevations do not reflect liver dysfunction and symptomatic jaundice requiring dosage reduction that occurred infrequently (7 to 8 percent of study patients). Counseling patients about this syndrome may promote adherence and prevent self-directed interruptions of ATV that compromise efficacy. The second case of jaundice provides a more formidable diagnostic challenge. The triad of LFT abnormalities (mild elevation of aminotransferases, normal PT, and marked cholestatic jaundice) implies an acute process that is mildly toxic to hepatocytes without affecting their synthetic function. The subacute nature of the patient's cholestatic jaundice suggests either intrahepatic infiltrative disease of the liver or extrahepatic obstruction of the biliary tree, most likely due to the patient's relatively modest level of pain and lack of fever. Despite LFT abnormalities occurring 17 months after a switch in his ART, cumulative drug-related toxicities must still be considered. Ritonavir can produce significant elevations in the AST/ALT, especially with pre-existing chronic liver disease as with hepatitis C virus coinfection. The NRTIs can produce hepatic steatosis, a result of mitochondrial toxicity and impaired fatty acid oxidation. However, jaundice and cholestasis are not typical of the latter syndrome. With a negative contrast CT that excludes parenchymal liver disease, investigation of the biliary tree to assess the presence of AIDS-related cholangitis was the next step. Performing a sphincterotomy or stent placement, and obtaining brushings or biopsy specimens to determine the extent of extrahepatic obstruction may help define a pathogen and be life-saving. The negative results of the ERCP justify the final diagnostic step, a liver biopsy to evaluate microscopic infiltrative disease that might not have been detected on contrast abdominal CT. Examples might include granulomatous disease (MAC), fungal etiologies (histoplasmosis), carcinomatosis (lymphoma, hepatoma, cholangiocarcinoma), and microvascular disease (bacillary angiomatosis). The failure to observe granulomatous inflammation in the liver does not exclude MAC infection, as MAC may involve other peri-aortic or mesenteric lymph nodes. This form of IRIS is unlikely given the abdominal CT findings, lack of systemic complaints, and extended persistence of liver aminotransferases. The nonspecific results of the liver biopsy are a common outcome in advanced AIDS patients with elevated alkaline phosphatase levels. Despite not having identified a pathogen, the biopsy establishes chronic liver disease and prompts re-evaluation and change of treatment to NFV. The subsequent normalization of the patient's aminotransferase levels suggests a prior adverse effect of LPV/r in the setting of unexplained, chronic liver disease. Most importantly, this case highlights the importance of HIV caregivers to review ART for safety when noting chronic liver dysfunction. Patients need to be counseled to minimize acetaminophen use, to consume alcohol in moderation, and to avoid behavior with risk for hepatitis C. Finally, all HIV patients should receive appropriate vaccination against hepatitis A and B if serology shows lack of protective immunity.
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PMID:Clinical vignette in antiretroviral therapy: jaundice. 1498 14

Highly active antiretroviral therapy (HAART) can improve immune system function through suppression of HIV-1 replication. In some cases, a vigorous paradoxical immune response may develop. Individuals treated effectively can, because of low immune reactivity, suffer from diseases which run subclinically until HAART is introduced. These symptoms are termed IRS (immune reconstitution syndrome/immune recovery syndrome), IRD (immune restoration disease), and IRIS (immune restoration inflammatory syndrome). There are some predisposing factors, such as long-lasting HIV-1 infection, severe immunodeficiency, rapid immune restoration, immune dysregulation during immune reconstitution, subclinical infection, and genetic susceptibility. A common feature of IRS is clinical symptoms different from those observed usually in HIV-1-infected patients. Sarcoidosis and some autoimmune diseases are less common. They are present for the first time or as an exacerbation of established diseases. Diagnosis is difficult. It is very often impossible to identify the pathogen. The clinical symptoms in patients receiving HAART should be differentiated into IRS, ineffective HAART leading to the development of opportunistic infection, and drug toxicity.
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PMID:[Immune reconstitution syndromes secondary to effective antiretroviral therapy]. 1592 1

Co-infection with HIV-1 and M. Leprae is a rare event in endemic areas for leprosy and HIV, such as India. Neither an increased HIV prevalence among leprosy cases, nor any rapid progression to AIDS was observed among dual HIV-leprosy infections. The current situation concerning continued new leprosy case-detection and gradual increase in HIV infection in India and a few other developing countries, such as Brazil, emphasizes the importance of monitoring the occurrence of co-infections. There is so far no change in the clinical spectrum of leprosy, PB/MB ratio, leprosy reactions and neuritis among co-infected patients. All types of leprosy occur in HIV patients [except in one study (Borgdorff et al, 1993) where more MB leprosy cases with HIV infection were seen]. Histopathological observations reveal a normal spectrum of appearance in biopsies of leprosy lesions from co-infected patients suggesting that cell-mediated immune response to M leprae is preserved at the site of the disease, despite evidence that these responses are abrogated systemically. All dual infection cases respond to regular treatment, except in three studies which noted more relapses. Therefore, a longer duration of surveillance is advisable after fixed duration therapy, for the detection of early relapse. Type 2 reaction can be managed with a higher dose of clofazimine. Type 1 reaction when developed as such, or as IRIS, needs oral steroids in adequate doses, particularly when associated with neuritis and motor loss, since lower doses may not be able to reverse the motor loss even of early onset. However, higher doses of corticosteroid when given need to be monitored closely. The impact of immune restoration in co-infected patients receiving ART is commonly observed in cases with borderline leprosy.
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PMID:Does concomitant hiv infection has any epidemiological, clinical, immunopathological and therapeutic relevance in leprosy? 1757 67

Cytomegalovirus (CMV) infection is a relatively late complication of AIDS. Like other viruses contributing to co-morbidity of HIV infection, cytomegalovirus has the propensity to cause multiorgan involvement. We report the case of a 34-year-old seropositive man who presented with bilateral lower limb weakness and symptomatic pallor. He was already on antiretroviral drugs for a month prior to presentation. Detailed clinical examination and laboratory investigations revealed cytomegalovirus polyradiculoneuropathy associated with bone marrow dysplasia. Dysplasia of haematopoeitic cell lines occurs in 30% to 70% of HIV infected patients, and is often indistinguishable from myelodysplastic syndrome. However, in our case, the bone marrow picture reverted back to normal with treatment of the CMV infection, pointing to a possible role of CMV as the causative agent of bone marrow dysplasia. Moreover, CMV has been incriminated as a pathogen producing the immune reconstitution inflammatory syndrome. The onset of the disease in our case one month after initiation of HAART strongly raises the possibility of this being a case of CMV related IRIS. This is the first reported case where IRIS has presented with CMV polyradiculoneuropathy and bone marrow dysplasia. We would like to highlight that in today's era of HIV care, clinicians should be aware of the possibility of multiorgan involvement by CMV, for appropriate management of this disease in the background of AIDS.
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PMID:Multiorgan involvement due to cytomegalovirus infection in AIDS. 1762 53

HIV-specific T-lymphocyte responses that underlie IRIS are incomplete and largely remain hypothetical. Of the several mechanisms presented by the host to control host immunological damage, Treg cells are believed to play a critical role. Using the available experimental evidence, it is proposed that enormous synthesis of conventional FoxP3- Th cells (responsive) often renders subjects inherently vulnerable to IRIS, whereas that of natural FoxP3+ Treg cell synthesis predominate among subjects that may not progress to IRIS. We also propose that IRIS non-developers generate precursor T-cells with a high avidity to generate CD4+CD25+FoxP3+ Tregs whereas IRIS developers generate T-cells of intermediate avidity yielding Th0 cells and effector T-cells to mediate the generation of proinflammatory cytokines in response to cell-signaling factors (IL-2, IL-6 etc.). Researchers have shown that IL-10 Tregs (along with TGF-beta, a known anti-inflammatory cytokine) limit immune responses against microbial antigens in addition to effectively controlling HIV replication, the prime objective of HAART. Although certain technical limitations are described herein, we advocate measures to test the role of Tregs in IRIS.
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PMID:Does CD4+CD25+foxp3+ cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease? 1828 73

Tremendous advances have occurred in the care of patients with HIV/AIDS resulting from the advent of highly active antiretroviral therapy (HAART). This has led to differences in the presentations of HIV-related pulmonary disease. Infections such as bacterial pneumonias, particularly Streptococcus pneumoniae, remain commonplace, while opportunistic agents such as Pneumocystis jirovecii remain a concern in patients without adequate access to optimal medical care. The tuberculosis epidemic, once thought to be slowing, has been re-energized by the spread of HIV, particularly in sub-Saharan Africa. Unusual inflammatory responses due to a phenomenon of immune reconstitution, are now recognized as a consequence of HAART, with a reported incidence of IRIS in this setting ranges from 7 to 45% in retrospective reviews. Noninfectious pulmonary conditions such as chronic obstructive lung disease and pulmonary malignancies are gaining prominence as patients are accessing antiretroviral care and enjoying significantly extended survival.
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PMID:Changing global epidemiology of pulmonary manifestations of HIV/AIDS. 1905 59

25 years old HIV-positive farmer on Anti-retroviral therapy from North Ethiopia with PKDL occurring as IRIS is reported. He developed popular and nodular lesions on the face, chest and arms (Grade II severe PKDL) one month after anti-retroviral therapy initiation, who had history of therapy for visceral leishmaniasis (VL) one year back. PKDL manifesting as IRIS after ART initiation in previously treated case for VL was among the few reported case in the world. The case is presented and discussed with the few available review literatures.
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PMID:Leishmaniasis (PKDL) as a case of immune reconstitution inflammatory syndrome (IRIS) in HIV-positive patient after initiation of anti-retroviral therapy (ART). 1974 85

This study analyzes immunologic markers to predict and diagnose tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV and TB coinfected adults who initiated antiretroviral therapy (ART) in Thailand. T helper 1 cytokines interleukin (IL)-2, IL-12, and interferon-gamma (IFN-gamma) levels in response to PPD and RD1 antigens were assessed prior to ART, at weeks 6, 12, and 24 of treatment, and at time of TB-IRIS. Of 126 subjects, 22 (17.5%) developed TB-IRIS; 14 (64%) subjects received steroid treatment and 3 (14%) received NSAIDs; none of the subjects died. Median interval between ART initiation and TB-IRIS development was 14 days. IFN-gamma, IL-2, and IL-12 responses did not differ between TB-IRIS and no TB-IRIS subjects (p > 0.05). More research into the immunopathogenesis of TB-IRIS and diagnostic potential of cytokine markers is warranted.
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PMID:Immunologic markers as predictors of tuberculosis-associated immune reconstitution inflammatory syndrome in HIV and tuberculosis coinfected persons in Thailand. 1988 38

The tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent early complication of antiretroviral therapy (ART), used to treat HIV-1 infection, especially in countries where TB is prevalent. TB-IRIS is characterized by an exaggerated inflammatory response toward the antigens of Mycobacterium tuberculosis that results in clinical deterioration in patients experiencing immune recovery during early ART. Two forms of TB-IRIS are recognized: paradoxical; and unmasking. Paradoxical TB-IRIS manifests with new or recurrent TB symptoms or signs in patients being treated for TB during early ART, and unmasking TB-IRIS is characterized by an exaggerated, unusually inflammatory initial presentation of TB during early ART. In this review the incidence, clinical features, risk factors, treatment, and prevention of TB-IRIS in adult and pediatric patients are discussed.
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PMID:Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. 1992 68

Fixed dose combination abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) among HIV-1 and tuberculosis (TB)-coinfected patients was evaluated and outcomes between early vs. delayed initiation were compared. In a randomized, pilot study conducted in the Kilimanjaro Region of Tanzania, HIV-infected inpatients with smear-positive TB and total lymphocyte count <1200/mm(3) were randomized to initiate ABC/3TC/ZDV either 2 (early) or 8 (delayed) weeks after commencing antituberculosis therapy and were followed for 104 weeks. Of 94 patients screened, 70 enrolled (41% female, median CD4 count 103 cells/mm(3)), and 33 in each group completed 104 weeks. Two deaths and 12 serious adverse events (SAEs) were observed in the early arm vs. one death, one clinical failure, and seven SAEs in the delayed arm (p = 0.6012 for time to first grade 3/4 event, SAE, or death). CD4 cell increases were +331 and +328 cells/mm(3), respectively. TB-immune reconstitution inflammatory syndromes (TB-IRIS) were not observed in any subject. Using intent-to-treat (ITT), missing = failure analyses, 74% (26/35) vs. 89% (31/35) randomized to early vs. delayed therapy had HIV RNA levels <400 copies/ml at 104 weeks (p = 0.2182) and 66% (23/35) vs. 74% (26/35), respectively, had HIV RNA levels <50 copies/ml (p = 0.6026). In an analysis in which switches from ABC/3TC/ZDV = failure, those receiving early therapy were less likely to be suppressed to <400 copies/ml [60% (21/35) vs. 86% (30/35), p = 0.030]. TB-IRIS was not observed among the 70 coinfected subjects beginning antiretroviral treatment. ABC/3TC/ZDV was well tolerated and resulted in steady immunologic improvement. Rates of virologic suppression were similar between early and delayed treatment strategies with triple nucleoside regimens when substitutions were allowed.
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PMID:Early versus delayed fixed dose combination abacavir/lamivudine/zidovudine in patients with HIV and tuberculosis in Tanzania. 2000 18


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