Background It is becoming increasingly clear that, during successful highly active antiretroviral therapy (HAART), a proportion of treated patients develop opportunistic infections (OIs), referred to in this setting as immune restoration disease (IRD). We examined the risk of developing IRD in HAART-treated HIV-infected patients. Methods A retrospective study of a cohort including all 389 patients treated with HAART between I January 1998 and 31 May 2004 in our HIV unit was performed to evaluate the occurrence of and risk factors for IRD during HAART. Baseline and follow-up values of CD4 T-cell counts and plasma viral loads (pVLs) were compared to assess the success of HAART. Results During successful HAART (significant increase in CD4 T-cell counts and decrease in pVL), at least one IRD episode occurred in 65 patients (16.7%). The median time to IRD was 4.6 months (range 212 months). IRDs included dermatomal herpes zoster (26 patients), pulmonary tuberculosis (four patients), tuberculous exudative pericarditis (two patients), tuberculous lymphadenitis (two patients), cerebral toxoplasmosis (one patient), progressive multifocal leucoencephalopathy (PML) (one patient), inflamed molluscum (one patient), inflamed Candida albicans angular cheilitis (three patients), genital herpes simplex (two patients), tinea corporis (two patients), cytomegalovirus (CMV) retinitis (two patients), CMV vitritis (one patient) and hepatitis B (three patients) or C (fifteen patients). A baseline CD4 T-cell count below 100 cells/mu L was shown to be the single predictor [odds ratio (OR) 2.5, 95% confidence interval (CI) 0.9-6.4] of IRD, while a CD4 T-cell count increase to  gt  400 cells/mu L, but not undetectable pVL, was a negative predictor of IRD (OR 0.3, 95% CI 0.1-0.8). Conclusions To avoid IRD in advanced patients, HAART should be initiated before the CD4 T-cell count falls below 100 cells/mu L

Aldeen T

Carcelain G

Chien JW

French MA

Gea-Banacloche JC

Jacobson MA

John M

Martinez E

Narita M

Shelburne SA III

HIV Medicine

English

Jevtović, Đorđe

Salemović, Dubravka

Ranin, Jovan

Pešić, I.

Zerjav, S

Đurković-Đaković, Olgica

RIMI

ORIGINAL ARTICLEThe prevalence and risk of immune restoration disease inHIV-infected patients treated with highly activeantiretroviral therapyDJ Jevtović,1 D Salemović,1 J Ranin,1 I Pešić,1 S %erjav1 and O Djurković-Djaković21Institute for Infectious & Tropical Diseases, Clinical Centre of Serbia, Belgrade, and2Institute for Medical Research,Belgrade, Serbia & MontenegroBackgroundIt is becoming increasingly clear that, during successful highly active antiretroviral therapy(HAART), a proportion of treated patients develop opportunistic infections (OIs), referred to inthis setting as immune restoration disease (IRD). We examined the risk of developing IRD inHAART-treated HIV-infected patients.MethodsA retrospective study of a cohort including all 389 patients treated with HAART between 1 January1998 and 31 May 2004 in our HIV unit was performed to evaluate the occurrence of and risk factorsfor IRD during HAART. Baseline and follow-up values of CD4 T-cell counts and plasma viral loads(pVLs) were compared to assess the success of HAART.ResultsDuring successful HAART (significant increase in CD4 T-cell counts and decrease in pVL), at leastone IRD episode occurred in 65 patients (16.7%). The median time to IRD was 4.6 months (range 2–12 months). IRDs included dermatomal herpes zoster (26 patients), pulmonary tuberculosis (fourpatients), tuberculous exudative pericarditis (two patients), tuberculous lymphadenitis (two patients),cerebral toxoplasmosis (one patient), progressive multifocal leucoencephalopathy (PML) (onepatient), inflamed molluscum (one patient), inflamed Candida albicans angular cheilitis (threepatients), genital herpes simplex (two patients), tinea corporis (two patients), cytomegalovirus(CMV) retinitis (two patients), CMV vitritis (one patient) and hepatitis B (three patients) or C (fifteenpatients). A baseline CD4 T-cell count below 100 cells/mL was shown to be the single predictor [oddsratio (OR) 2.5, 95% confidence interval (CI) 0.9–6.4] of IRD, while a CD4 T-cell count increase to4400 cells/mL, but not undetectable pVL, was a negative predictor of IRD (OR 0.3, 95% CI 0.1–0.8).ConclusionsTo avoid IRD in advanced patients, HAART should be initiated before the CD4 T-cell count fallsbelow 100 cells/mL.Keywords: HAART, HIV, immune restoration diseaseReceived: 16 July 2004, accepted 21 September 2004IntroductionThe major advance in HIV disease treatment coincided withthe introduction of highly active antiretroviral therapy(HAART) in 1996. HAART protocols comprised twonucleoside reverse transcriptase inhibitors (NRTIs) and anHIV protease inhibitor (PI), a rather complicated regimen,but potent enough for complete and prolonged cessation ofviral replication to allow reconstitution of the immunesystem. It has even been possible to achieve immunerecovery in terminally ill patients. An overall reduction inlate-stage complications of HIV infection, including death,dramatically decreased the number of hospital admissions,and an impressive improvement in the quality of lifebecame obvious.Correspondence: Dr Olgica Djurković-Djaković, Institute for MedicalResearch, Dr. Subotića 4, PO Box 102, 11000 Belgrade, Serbia andMontenegro. E-mail: olgicadj@imi.bg.ac.yuHIV Medicine (2005), 6, 140–143 r 2005 British HIV Association140However, although many patients continue to derivesubstantial benefit from HAART after 5–6 years oftreatment, we are now facing the other side of the medal.Cumulative long-term toxicity and the problem of thedevelopment of HIV resistance to all drug classes arethreatening to jeopardize the treatment benefits. Inaddition, over the past few years there have been growingnumbers of cases of opportunistic infections (OIs) inpatients on HAART. The common denominator in all thesecases was paradoxical symptomatic deterioration ofpresumably pre-existing subclinical infections that be-came symptomatic after the recovery of the immuneresponse and the consequent inflammatory response tocertain pathogens [1,2]. In this setting, numerous authorsdescribed conditions including dermatomal herpes zoster,tuberculous lymphadenitis, inflamed molluscum, in-flamed Candida albicans angular cheilitis, genital herpes,tinea corporis, hepatitis B or C virus (HBV or HCV)infection, and even Toxoplasma gondii encephalitis, aswell as cryptococcal meningitis and progressive multi-focal leucoencephalopathy (PML) [1–11], most commonlyreferred to as immune restoration disease (IRD). While thedistinction between immunodeficiency-related OIs andIRD is not clear, it is becoming accepted that theappearance of clinical OIs at a time of restored immunefunctions should be classified as IRD [12].The majority of HIV-infected patients in Serbia haveadvanced immunodeficiency on presentation. Even thesedeeply immunosuppressed patients may achieve a goodvirological and immunological response while on HAART,as well as clinically apparent restoration of the immunefunction. However, immune restoration may be associatedwith the development of OIs, some of which may beAIDS-defining and life-threatening [1–5]. These condi-tions are referred to as IRD. We examined the risks ofdeveloping OI/IRD in our patients during successfulHAART.MethodsPatientsA retrospective study of all 389 HIV-positive patientstreated with HAART at the HIV/AIDS Department of theInstitute of Infectious and Tropical Diseases in Belgradebetween 1 January 1998 and 31 May 2004 was conducted.The patient series consisted of 39.7% females and 60.3%males. The mean age was 41 10 years (range 16–78years). All patients were diagnosed according to the 1993revised CDC HIV classification system and expanded AIDSsurveillance definition for adolescents and adults.Over half (55.3%) of the patients were pretreated withmonotherapy or dual regimens. HAART regimens weredefined as combinations of two or three NRTIs, with one ortwo PIs (in 64% of all patients), or one nonnucleosidereverse transcriptase inhibitor (NNRTI). Dual Pneumoeystiscarinii pneumonia (PCP) and toxoplasmosis primaryprophylaxis was withdrawn after patients achieved asustained immune response (CD4 cell count4200 cells/mL).After commencing HAART, clinical evaluation wasperformed at least once every 2 months.Herpes zoster, inflamed molluscum, tinea corporis,genital herpes, and angulus infectiosus were all diagnosedby skin or mouth examination. For cerebral toxoplasmosisand PML, clinical and neuroradiological presentations werethe clue to the diagnosis. T. gondii serology was routinelyperformed. However, virological confirmation for PML,such as cerebrospinal fluid JC virus (JCV) immunoglobulinM (IgM) antibodies or PCR for JCV, was not available.Cryptococcal menigitis was diagnosed according to theclinical presentation and CSF findings, including Indianink stain and CSF culture. Tuberculosis was diagnosed onthe basis of clinical, radiographic and microbiologicalconfirmation. In patients who suffered coinfection of HIVwith HBV or HCV, the aggravation of hepatitis was definedas an increase in alanine aminotransferase (ALT) activity ofat least 5-fold above the upper limit of the reference range.Cytomegalovirus (CMV) retinitis relapse and vitritis werediagnosed according to typical symptoms and fundoscopyfindings.Laboratory methodsCD4 cell counts and viral loads were measured onperipheral blood samples drawn at baseline (immediatelybefore HAART initiation) and every 4–6 months duringfollow-up. CD4 T-cell counts were quantified by flowcytometry. Plasma HIV-1 RNA loads were measured by aquantitative reverse transcriptase PCR (Ultrasensitiveassay version 1.5, Roche Molecular Systems, Branchburg,NJ, USA), which has a lower limit of detection of 50 copies/mL (1.7 log10).StatisticsAll analyses were performed using an electronic databaseorganized with the SPSS (version 11.5) statistical package(SPSS Inc., Chicago, IL, USA). CD4 cell count and plasmaviral load means were compared by one-way analysis ofvariance (ANOVA). The level of significance was 0.05. Theassociation between IRD development and variables suchas basic and follow-up CD4 cell counts and plasma viralloads, as well as other possibly related variables, wasImmune restoration disease during HAART 141r 2005 British HIV Association HIV Medicine (2005) 6, 140–143assessed using univariate and step-wise multivariateregression models, and the Cox regression model. Resultsare presented as odds ratios (ORs) with 95% confidenceintervals (95% CIs).ResultsBaseline characteristicsOf the total of 389 patients, 87.3% had AIDS (CDC stagesA3–C3) before HAART was initiated. The baseline CD4 cellcount was below 100 cells/mL in 61.8% of patients, with amean of 108.2  92.8 cells/mL (range 0–450 cells/mL). Themedian plasma viral load was 4.6 log copies/mL beforetreatment.Treatment effectsAfter a mean duration of treatment of 34.7  24.4 months,the mean CD4 cell count in the whole patient series was375  240 cells/mL, while 37.2% of patients reached a valueof above 400 cells/mL. In 76.8% of patients, the viral loadfell below 50 copies/mL (1.7 log). However, the mostdesirable response to treatment, considered to be a rise in theCD4 cell count of 400 cells/mL, along with a plasma viralload of below 50 copies/mL, occurred in 44.6% of patients.Subgroup of OI/IRD patientsClinical findingsAt least one IRD episode occurred in 65 patients (16.7%).The median time on HAART to IRD was 4.6 months, with arange of 2–12 months. These included episodes ofdermatomal herpes zoster (26 patients), pulmonarytuberculosis (four patients), tuberculous exudative peri-carditis (two patients), tuberculous lymphadenitis (twopatients), cerebral toxoplasmosis (one patient), PML (onepatient), inflamed molluscum (one patient), inflamed C.albicans angular cheilitis (three patients), genital herpessimplex (two patients), tinea corporis (two patients), CMVretinitis (two patients), CMV vitritis (one patient) and HBV(three patients) or HCV (fifteen patients) infection. In thepatients with tuberculosis, cerebral toxoplasmosis andcryptococcosis as manifestations of IRD, symptoms andsigns occurred after early initiation of HAART, beforewithdrawal of antimicrobial therapy. In the case ofinflamed molluscum, aggravation of skin lesions alsooccurred soon after HAART initiation. Genital herpes,angular cheilitis, and herpes zoster and warts occurred denovo. Aggravation of hepatitis was associated withclinical disease in only two cases, both of HCV infection,of which one female patient with HCV-induced cirrhosisdied of liver failure. In a patient who experienced immunerecovery vitritis, the sight-threatening vitreomaculartraction syndrome and detachment of the retina occurred,which did not resolve during 2 years of successful HAART.Response to HAART: laboratory findingsIn the subgroup of IRD patients, the mean CD4 cell countduring HAART rose from 106  104 to 337  219 cells/mL.The median plasma viral load simultaneously decreased by41 log copies/mL (from the initial 4.6 to 2.1  0.8 log10copies/mL), with 80% of patients reaching undetectableviraemia. However, the median CD4 count increase and themedian plasma viral load decrease were similar to those inthe non-IRD patients (P5 0.6 and P5 0.7, respectively).IRD risk assessmentMultivariate logistic regression analysis showed that, of allthe examined factors, including age over 40 years, gender,AIDS-related OIs prior to HAART, pretreatment with monoand/or dual antiretroviral regimens, and baseline CD4count below 100 cells/mL, the latter was the only predictorof IRD (OR 2.5, 95% CI 0.9–6.4). However, the Coxregression model showed that achievement of a rise inthe CD4 cell count to above 400 cells/mL, but notundetectable viraemia, was a negative predictor of IRD(OR 0.3, 95% CI 0.1–0.8).IRD managementAnti-infective therapy was used to treat IRD when needed,to which all patients responded well, with the exception ofone fatal case of HCV infection, as described above. Duringsuch treatment, HAART was temporarily withdrawn,mostly because of potential unfavourable drug–druginteractions. Corticosteroids or other anti-inflammatorydrugs were not used to treat IRD. After IRD resolution,patients continued HAART successfully.DiscussionNumerous studies have shown that HAART corrects manyof the immune defects caused by HIV infection [12–14].Restored pathogen-specific immune responses may resultin regression or prevention of OIs [13–16]. However, therestoration of pathogen-specific immune responses mayalso cause inflammation of tissues infected by thepathogen, known as IRD [1–12]. Thus, the major questionin the setting of HAART-treated HIV disease is whether aclinical OI is immunodeficiency-related or an IRD,because the appearance of OIs among HIV-infectedpatients on HAART always raises the concern of possibleHAART failure. Attempts at solving this problem resultedin the first proposal of criteria for the diagnosis of IRD142 DJ Jevtović et al.r 2005 British HIV Association HIV Medicine (2005) 6, 140–143[12], which include, in addition to precise clinicalfindings, success of HAART, where virological successis considered a major criterion and an increased bloodCD4 cell count a minor criterion.In our patient series, all 65 OI episodes fulfilled theabove criteria for the clinical OI to be defined as IRD, assignificant immunological and virological improvementwas documented. Hence, the incidence of IRD in our serieswas 16.7%. This is in sharp contrast with the study ofMichelet et al. [6], who reported that 68% of patientsexhibited one or more disease episodes after successfulHAART. One reason for the lower incidence in our studymay be that our series included patients observed over arather long period of over 6 years; at the beginning of thisperiod (1998), the IRD syndrome was not well known,so some OIs as IRDs may have been overlooked becausesymptoms had not been searched for, while someinfections of possible IRD origin had been consideredHIV-related OIs. However, our results are not in disagree-ment with those of French et al. [3], who reported that 25%of HAART-treated patients developed IRD episodes aftercommencing HAART, all related to pre-existingsubclinical infections with opportunistic pathogens. TheIRD episodes were more common in patients with abaseline CD4 count of less than 50 cells/mL [3]. We alsoshowed that a low baseline CD4 count represents a riskfactor for IRD. These data indicate the need for earlierHAART initiation.In conclusion, with the wide use of HAART in AIDSpatients, the frequency of IRD may be expected to increase.IRD should particularly be considered during the first 12months following HAART initiation. We showed that thelikelihood of developing IRD was elevated in those whocommenced HAART at an advanced stage of HIV diseaseand, conversely, extremely low in patients who achievedCD4 cell count rises to above 400 cells/mL. Thus, any effortto decrease the incidence of IRD should include HAARTinitiation before the disease has reached an advanced stage,i.e. before the CD4 cell counts have fallen below 100 cells/mL. In patients with OIs as a consequence of HIV-inducedimmunodeficiency, it seems wise to complete antimicrobialtherapy before commencing HAART.AcknowledgementsThe work was supported by grant M1474 from the Ministryof Science, Technologies and Development of the Republicof Serbia.References1 Jacobson MA, French MA. Altered natural history of AIDS-related opportunistic infections in the era of potentcombination anti-retroviral therapy. AIDS 1998; 12 (Suppl. A):S157–S163.2 French MA, Price P. Immune restoration disease in HIVpatients: aberrant immune responses after antiretroviraltherapy. J HIV Ther 2002; 7: 46–51.3 French MA, Lenzo N, John M et al. Immune restoration diseaseafter the treatment of immunodeficient HIV-infected patientswith highly active antiretroviral therapy. HIV Med 2000; 1:107–115.4 John M, French MA. Exacerbation of inflammatory response toMycobacterium tuberculosis after antiretroviral therapy. Med JAust 1998; 169: 473–474.5 Narita M, Ashkin D, Hollender ES, Pitchenik AE. Paradoxicalworsening of tuberculosis following antiretroviral therapy inpatients with AIDS. Am J Respir Crit Care Med 1998; 158:157–161.6 Michelet C, Arvieux C, Francois C et al. Opportunisticinfections occurring during highly active antiretroviraltreatment. AIDS 1998; 12: 1815–1822.7 Aldeen T, Hay P, Davidson F, Lau R. Herpes zoster infectionin HIV-seropositive patients associated with highly activeanti-retroviral therapy. AIDS 1998; 12: 1719–1720.8 Martinez E, Gatell J, Moran Y et al. High incidence of herpeszoster in patients with AIDS soon after therapy with proteaseinhibitors. Clin Infect Dis 1998; 27: 1510–1513.9 Dunić I, Djurković-Djaković O, Vesić S et al. Herpes zoster asan immune restoration disease in AIDS patients duringtherapy incuding protease inhibitors. Int J STD AIDSin press.10 Chien JW, Johnson JL. Paradoxical reactions in HIV andpulmonary TB. Chest 1998; 114: 933–936.11 Cinque P, Pierotti C, Vigano MG et al. The good and evil ofHAART in HIV-related progressive multifocalleucoencephalopathy. J Neurovirol 2001; 7: 358–363.12 French MA, Price P, Stone SF. Immune restoration disease afterantiretroviral therapy. AIDS 2004; 18: 1615–1627.13 Carcelain G, Li TS, Autran B. Immune reconstitution underhighly active antiretroviral therapy (HAART). AIDS Rev 1999;1: 51–56.14 Gea-Banacloche JC, Lane CH. Immune reconstitution in HIVinfection. AIDS 1999; 13 (Suppl. A): S25–S38.15 Shelburne SA III, Hamill RJ. The immune reconstitutioninflammatory syndrome. AIDS Rev 2003; 5: 67–79.16 Dunić I, Vesić S, Jevtović DJ. Oral candidiasis and seborrheicdermatitis in HIV-infected patients on highly activeantiretroviral therapy. HIV Med 2004; 5: 50–54.Immune restoration disease during HAART 143r 2005 British HIV Association HIV Medicine (2005) 6, 140–143

The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

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The prevalence and risk of immune restoration disease in HIV-infected patients treated with highly active antiretroviral therapy

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