AIDS-defining illnesses: A comparison between before and after commencement of highly active antiretroviral therapy (HAAART)

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1 University of Malaya From the SelectedWorks of Yvonne Lim Ai Lian September, 007 AIDS-defining illnesses: A comparison between before and after commencement of highly active antiretroviral therapy (HAAART) Yvonne Lim Ai Lian, University of Malaya Available at:

2 8 Current HIV Research, 007, 5, 8-89 AIDS-Defining Illnesses: A Comparison Between Before and After Commencement of Highly Active Antiretroviral Therapy (HAART) Yvonne Lim Ai Lian *,1, Benedict Sim Lim Heng, Veeranoot Nissapatorn 1 and Christopher Lee 1 Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Infectious Diseases Unit, Department of Medicine, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia Abstract: Attempts to address the significant impact of HAART on medical variables on the Malaysian HIV/AIDS population have yet to be evaluated. This study aims to analyze the proportions of AIDS-defining illnesses (ADIs) before and after HAART. A retrospective study was carried out on 18 new cases of HIV infected patients who first commenced HAART in 00 at the national HIV reference center. Before commencement of HAART, 76 clinical episodes of ADIs were recorded in 5 patients. Most common being pulmonary Mycobacterium tuberculosis (8.9%), PCP (7.6%) and disseminated and extrapulmonary Mycobacterium tuberculosis (11.8%). During HAART, 8 clinical episodes of ADIs were documented in 7 patients with a median time of onset of 10 weeks after initiation of HAART (range, -36 weeks). The median CD count at the time of the commencement of HAART for these patients was 11 cells/mm 3. ADIs reported include PCP ( episodes), disseminated and extrapulmonary Mycobacterium tuberculosis ( episodes), extrapulmonary cryptococcosis (1 episode), esophageal candidiasis (1 episode), recurrent pneumonia (1 episode) and disseminated or extrapulmonary histoplasmosis (1 episode). Three (37.5%) of these occurred despite a reduction of viral load by at least log 10 and an increased in the CD cell count. In conclusion, ADIs can still present after the initiation of successful HAART especially in those with CD counts below 100 cells/mm 3. In Malaysia, ADIs are the major causes of HIV/AIDS associated morbidity and mortality, thus increased awareness on the management of these illnesses is warranted especially in the months following HAART. Keywords: AIDS-defining illnesses, HAART, immune restoration diseases, Malaysia. INTRODUCTION Acquired Immunodeficiency Syndrome (AIDS) is one of the most destructive epidemics in modern time. In Malaysia, a total of 8,10 (10.6%) HIV/AIDS patients have succumbed to HIV/AIDS since its first case in Until June 005, 77,55 (approximately 0.3% of Malaysian present population) HIV/AIDS cases have been identified with an average of 17 new cases per day or 1 in every 85 minutes 1. Globally, in 005, 1 new case emerges every 7 seconds [5]. AIDS-defining illnesses (ADIs) have been and still are the major cause of HIV/AIDS associated morbidity and mortality in Malaysia [16]. The prognosis of HIV infected patients has dramatically improved since the advent of highly active antiretroviral therapy (HAART) in the mid 90s [18,19]. Nevertheless, ADIs still remain as one of the biggest stumbling block for physicians, mainly due to the late presentation of patients which put them at significant risk of developing life threatening ADIs both prior and after commencement of HAART. Introduction of HAART also present new clinical issue such as the occurrence of diseases that are a consequence of restoration of the immune response. These diseases, called *Address correspondence to this author at the Department of Parasitology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; Tel: ; Fax: ; s: limailian@um.edu.my, yvonne@ummc.edu.my 1 Ministry of Health, Malaysia (005). Summary of HIV and AIDS cases reported by year. Malaysia: 1986 until June 005. Section of AIDS/STD, Ministry of Health, Malaysia, X/07 $ immune restoration diseases (IRDs), usually occur within a few weeks to months after the start of HAART. The majority of patients present with unusual manifestations of opportunistic infections, most often while the number of CD lymphocytes is increasing and the HIV viral load is decreasing [3,5,7,10]. Although in most cases the symptoms of IRDs resolve after a few weeks, the syndrome can be severe, and does result in significant morbidity and occasional mortality. Attempts to address the significant impact of HAART on medical variables on the Malaysian HIV/AIDS population have yet to be evaluated. This study focused on the analyses of the proportions of ADIs before and after commencement of HAART. The information collated could serve as a platform for further systematic studies into the assessment of the effectiveness of HAART in significantly improving the outcome of HIV patients with ADIs. MATERIALS AND METHODS This retrospective study, conducted at the Infectious Diseases Unit, Hospital Kuala Lumpur, Malaysia, included a cohort of 18 HIV infected patients who first commenced HAART in 00. Inclusion criteria were: (i) age 18 years or older (ii) new HIV infected out-patient cases in 00; and (iii) first commenced HAART in 00. Hospital Kuala Lumpur is the largest tertiary hospital under the Ministry of Health of Malaysia with a capacity of 81 wards and 50 beds. The Infectious Diseases Unit, Hospital Kuala Lumpur is the national reference centre for adult patients with HIV and AIDS in Malaysia. The use of HAART in Malaysia started towards the late 1990s. Currently, there are a total of 10 readily available antiretroviral agents of differing classes of NRTI, NNRTI and PI. 007 Bentham Science Publishers Ltd.

3 AIDS-Defining Illnesses: Before and After Commencement of HAART Current HIV Research, 007, Vol. 5, No Patients were evaluated for the development of AIDSdefining illnesses (ADIs) which were established based on the 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults []. Clinical evaluation, plasma HIV-1 RNA quantification, CD cell count were recorded at baseline (e.g. first visit and before initiation of HAART) and at the onset of event. Median CD counts were calculated based on the sample taken nearest to the time of diagnosis of the ADIs. Each new or recurrent ADIs is counted as one episode (i.e. a patient with two diagnoses would contribute two episodes). Data were entered into a computer database and checked for errors and inconsistencies. Statistical analyses were performed using SPSS version 9.05 software (SPSS Inc, Chicago, USA). Differences in number of patients who had ADIs before and after the initiation of HAART were evaluated using the Wilcoxon signed-ranks test. Comparisons of proportions of ADIs due to two most common infections (Pneumocyctis carinii pneumonia and Mycobacterium tuberculosis) between before and after HAART were made using chi-square test. RESULTS A total of 37 new HIV cases were reported at the Infectious Diseases Unit, Hospital Kuala Lumpur, Malaysia for the year 00. Out of this total, only 18 (3.%) started on HAART within the mentioned period. Table 1 summarises the demographic profile of those who are undergoing HAART. Preponderant age group identified as 1-0 years (59.%) followed by 1-60 years (35.9%), 61 years and above (3.1%) and 0 years and below (1.6%). The majority consists of male (77.3%). Racial composition is made up of 53.1% Chinese, 3.8% Malay and bumiputra (i.e. East Malaysians), 8.6% Indian and 5.5% foreigner. More than 50% of them were married or divorced (57%) and were non professionals (5.7%). Reported risk factors for HIV infection were heterosexual contact (60.%), intravenous drug use (18%), homosexual contact (10.1%), blood transfusion (1.%) and unknown (10.1%). 80.5% of the patients were exposed to single risk factor, however, 8.6% were exposed to two risk factors, most common being a combination of being heterosexual and an intravenous drug user. Of those 18 who commenced HAART, 5 (0.6%) and 7 (5.5%) patients had AIDS-defining illnesses (ADIs) before and after initiation of HAART respectively (Wilcoxon test, p<0.05). The median value of CD on first visit was 70 cells/mm 3 with a lowest count of 0 and a highest count of 59 cells/mm 3 respectively. As for the CD count at the start of HAART, the median value of CD was 66 cells/mm 3 with a lowest count of 0 and a highest count of 651 cells/mm 3 (Table ). A significant decrease in episodes of Pneumocyctis carinii pneumonia and Mycobacterium tuberculosis which are the two most common infections between before and after HAART were also noted (p<0.05). Before commencement of HAART, 76 clinical episodes of ADIs (1 types) were recorded in 5 patients (1.% of patients had two concurrent illnesses whilst 11.5% of patients had three to four concurrent illnesses). The ADIs were mainly infections of bacteria, fungus, virus and parasites. Table 1 Demographic Profile of HIV-Infected Patients who Started on HAART in the Year 00 at Infectious Diseases Unit, Hospital Kuala Lumpur, Malaysia Age group (Age range: years) 0 years and below 1-0 years 1-60 years 61 years and above Gender Male Female Ethnic group Chinese Malay + Bumiputra Indian Others Marital status Married + Divorced Single No record Last reported occupation Non professional Professional Jobless No record Risk factor Heterosexual IDU Homosexual Blood transfusion Not known Single risk factor Double risk factors Frequency Percentage (%) Pulmonary Mycobacterium tuberculosis (8.9%) represented the most commonly diagnosed illness, followed by Pneumocyctis carinii pneumonia (PCP) (7.6%) and disseminated and extrapulmonary Mycobacterium tuberculosis (11.8%). Each of the remaining illnesses accounted for less than 6% of reported illnesses ranging from 5.3% for extrapulmonary cryptococcosis, esophageal candidiasis and herpes simplex, 3.9% for brain toxoplasmosis,.6% for disseminated or extrapulmonary Mycobacterium avium complex, cytomegalovirus disease, recurrent pneumonia and disseminated or extrapulmonary histoplasmosis to 1.3% for candidiasis of bronchi, trachea or lungs (Table 3). The median CD counts for these ADIs ranges from 0 to 83 cells/mm 3. The ADIs were noted more frequently in males, above 0 years, of Chinese origin and with heterosexual risk behaviour. During HAART, 8 clinical episodes of ADIs were documented in 7 patients (1.3% of patients had two concurrent diseases) with a median time of onset of 10 weeks after initiation of HAART (range, -36 weeks), of which episodes

4 86 Current HIV Research, 007, Vol. 5, No. 5 Lian et al. Table First Available CD Count and CD Count at Commencement of HAART CD count (cells/mm 3 ) Median Lowest value Highest value Mean + sd* First available on presentation At commencement of HAART *Standard deviation. Table 3 Distribution of AIDS-Defining Illnesses According to Gender, Age, Ethnic Group and Risk Factors Before Commencement of HAART AIDS defining illnesses Frequency Median CD (cells/mm 3 ) Male Female (n=99) (n=9) Gender (%) Age (%) Ethnic group (%) Risk factor (%) 18-0 years (n=78) > 1 Chinese years (n=68) (n=50) Malay + Bumiputra (n=) Indian (n=11) Others (n=7) Heterosexual (n=8) IDU (n=5) Homo/ Bisexual (n=1) Other (n=16) Pneumocystis jiroveci pneumonia (PCP) 1 (7.6%) Fungal infection Cryptococcosis: extrapulmonary Candidiasis: esophageal Histoplasmosis: disseminated or extrapulmonary Candidiasis of bronchi, trachea or lungs Mycobacterium tuberculosis: pulmonary Mycobacterium tuberculosis: disseminated and extrapulmonary Mycobacterium avium complex: disseminated or extrapulmonary Pneumonia: recurrent (5.3%) (5.3%) (.6%) 1 (1.3%) (8.9%) 9 (11.8%) (.6%) (.6%) Herpes simplex (5.3%) Cytomegalovirus disease (other than liver, spleen or nodes) (.6%) Bacterial infection Viral infection Toxoplasmosis of brain 3 (3.9%) Total

5 AIDS-Defining Illnesses: Before and After Commencement of HAART Current HIV Research, 007, Vol. 5, No (50%) were observed during the first months of HAART. The median CD count at the time of the commencement of HAART for these patients was 11 cells/mm 3. The ADIs reported include PCP ( episodes), disseminated and extrapulmonary Mycobacterium tuberculosis ( episodes), extrapulmonary cryptococcosis (1 episode), esophageal candidiasis (1 episode), recurrent pneumonia (1 episode) and disseminated or extrapulmonary histoplasmosis (1 episode) (Table ). Three (37.5%) of these occurred despite a reduction of viral load by at least log 10 and an increased in the CD cell count, in other words despite successful HAART regimens. The 7 patients noted with ADIs while on HAART did not suffer from any ADIs before commencement of HAART except for oral candidiasis. All except one had CD counts below 100 cells/mm 3 at the commencement of HAART. DISCUSSION In this single-centre retrospective study, the issue of late presentation is very evident as shown by the median value of CD cell counts on first visit and at the commencement of HAART which were both below 100 cells/mm 3. Although HAART has been widely accessible and affordable in the recent years in Malaysia, these data clearly indicate that a majority of patients still present to the HIV treatment centres at an advanced stage of the disease. While mortality rates among HIV-infected individuals have fallen since the HAART era, the deaths that do occur now are more diverse and are the result of a number of factors which includes late presentation [0]. In Malaysia, patients who present with very low CD counts are more likely to have significant or life-threatening opportunistic infections which may interfere with the efficacy, tolerability and compliance to HAART. More importantly, they pose a risk of transmissibility that is higher due to the longer temporal period and the higher viral load levels before being diagnosed. A comparison of the AIDS-defining illnesses (ADIs) before and after HAART in this present study showed a significant decrease in the episodes of ADIs (Tables 3 and ). Many have reported that the introduction of antiretroviral therapy has indeed dramatically altered the incidence of AIDS-defining illnesses. In the EuroSIDA study, it has been proven that there were substantial falls in the incidence and total number of AIDS-defining episodes between 199 and 1998 [15]. During this period the proportions of reported AIDS-defining illnesses due to cytomegalovirus retinitis and Mycobacterium avium have decreased from 9% to % and 8% to 3% respectively [15]. Substantial decreases in the incidence of disease caused by cytomegalovirus, Pneumocystis carinii, Mycobacterium avium and other opportunistic infections have also been observed in the United States [11,18]. However, little has been reported regarding the pattern of HIV-related conditions following the introduction of antiretroviral therapy in Asia [1]. A retrospective study carried out in Malaysia from 199 to 001 indicated that the four main AIDS-defining illnesses include tuberculosis (8%), Pneumocystis carinii pneumonia (PCP) (13%), Toxoplasma encephalitis (11%) and cryptococcal meningitis (7%) [16]. Other studies conducted in Malaysia among the general public and specifically among drug addicts with HIV infection also reported similar findings [,17,7]. In Singapore, a study of all adult patients seen at the national HIV referral center between 1985 and 001 reported PCP (35.7%) and Mycobacterium tuberculosis (.7%) as the two most common ADIs [1]. Over in Bangkok, extrapulmonary tuberculosis (.8%), PCP (7.0%) and cryptococcal meningitis (10.9%) were the most frequent AIDS-defining diagnoses between 1987 and 1993 [1]. A study in the rural Central Thailand revealed cryptococcal meningitis (15%), bacterial pneumonia (1%), extrapulmonary tuberculosis (1%), PCP (7%), cerebral toxoplasmosis (%) and pulmonary tuberculosis (3%) as the commonest HIV-related conditions. However, septicemia and tuberculosis was postulated to be under-diagnosed in this study, highlighting the need for improved diagnostic laboratory facilities [1]. In Hong Kong where two-thirds majority are ethnic Chinese, PCP (50%), extrapulmonary tuberculosis (10%) and cytomegalovirus (CMV) disease (8%) were again the primary AIDS defining illnesses [6]. Generally the profiles of ADIs are similar around the Asia region. The studies mentioned thus far did not distinguish whether the patients were undergoing HAART or that the Table Details of the 7 Patients with AIDS-Defining Illnesses After Commencement of HAART Patient AIDS defining illnesses CD count at commencement of HAART CD count at presentation of AIDS defining illness Presentation of AIDS-defining illness after commencement of HAART (weeks after HAART) 1 Pneumocystis jiroveci pneumonia (PCP) 1 15 weeks Histoplasmosis: disseminated or extrapulmonary weeks Cryptococcosis: extrapulmonary 7 7 weeks 3 Pneumonia: recurrent 8 weeks Mycobacterium tuberculosis: disseminated and extrapulmonary weeks 5 Pneumocystis jiroveci pneumonia (PCP) weeks 6 Candidiasis: esophageal 5 NA* 1 weeks 7 *NA = Not available. Mycobacterium tuberculosis: disseminated and extrapulmonary weeks

6 88 Current HIV Research, 007, Vol. 5, No. 5 Lian et al. illnesses happened before or after HAART. The present study attempts to differentiate the frequencies and types of ADIs before and after the initiation of HAART. It was noted that the two most common ADIs before the commencement of HAART were Mycobacterium tuberculosis and Pneumocystis carinii pneumonia. Other illnesses detected were extrapulmonary cryptococcosis, esophageal and tracheobronchial candidiasis, herpes simplex, brain toxoplasmosis, disseminated or extrapulmonary Mycobacterium avium complex, cytomegalovirus disease, recurrent pneumonia and disseminated or extrapulmonary histoplasmosis. These findings are very similar to the findings of studies mentioned in the previous paragraph [1,,1,1,17,6,7]. Fewer episodes of ADIs were documented during HAART. A total of 8 episodes were reported in 5.5% (7) of patients who initiated HAART. The ADIs reported were PCP, disseminated and extrapulmonary Mycobacterium tuberculosis, extrapulmonary cryptococcosis, esophageal candidiasis, recurrent pneumonia and disseminated or extrapulmonary histoplasmosis. The median time of onset was 10 weeks after initiation of HAART and the median CD count at the time of the commencement of HAART for these patients was 11 cells/mm 3. The CD counts of five out of these seven patients with ADIs post HAART remained unchanged giving strong hints of non-compliancy. However 37.5% of the episodes occurred despite successful HAART regimens. In a prospective multicentre study conducted in Thailand, similar findings were noted whereby 0 episodes of opportunistic infection occurred in 3% of advanced AIDS patients with very low CD cell counts (ranges 0 and 17 cells/μl) after commencement of HAART []. These clinical episodes occurred between and 3 (median 16) weeks after commencing HAART and were associated with increased CD T cell counts. The diseases reported included tuberculosis, M. avium complex infection, relapsed cryptococcal meningitis, herpes zoster, toxoplasmosis and herpes genitalis. In recent years, it has been increasingly evident that during successful HAART (indicated by a significant increase in CD cell counts and decrease in viral load), a proportion of treated patients develop opportunistic infections (OIs), referred to as immune restoration diseases (IRDs) [8,9]. A retrospective study by Jevtovi et al. observed that at least one IRD episode occurred in 16.7% of patients with a median time of.6 months to IRD [13]. These immune restoration conditions only seem to affect a minority of people and usually occur within the first few weeks of starting antiretroviral therapy. People who have CD cell counts below 100 cells/mm 3 before starting an effective antiretroviral regimen are most at risk of IRDs [13,17]. Although IRDs have previously been reported and reviewed as early as 1999 [3,5,6,1-3], there continues to be an uncertainty about the pathogenic mechanisms and their management. French et al. reported that the most common pathogens associated with infectious IRD are infections by mycobacteria, cryptococci, herpesviruses, hepatitis B and C virus, and JC virus [7]. Early IRD (presenting during the first 3 months of therapy) is said to reflect an immune response against an active (often quiescent) infection by opportunistic pathogens however the late IRD is probably the result from an immune response against the antigens of nonviable pathogens. Nonetheless, data on the immunopathogenesis of IRD is rather limited [7]. As the use of HAART increases in Malaysia, physicians managing patients with HIV infection will encounter escalating numbers of patients with IRDs in the near future. Therefore, awareness of IRDs is important because management of these conditions can often be problematic. It is crucial to understand the immunopathogenesis of IRDs because differentiation has to be made against other opportunistic infections or drug toxicity. Investigation of strategies to prevent IRD is a priority, particularly in a developing country like Malaysia, and requires the development of risk assessment methods and diagnostic criteria. It is also imperative to note that HAART should be initiated before CD cell counts falls below 100 cells/mm 3 in order to avoid the possible occurrence of immune restoration diseases (IRDs) as indicated by the occurrence of ADIs despite successful HAART (in this study). This study has shown that ADIs can still present after the initiation of successful HAART therapy especially in those with CD counts below 100. In Malaysia, ADIs are the major causes of HIV/AIDS associated morbidity and mortality, thus increased awareness on the management of these illnesses is warranted especially in the months following HAART. As data on IRDs are extremely limited in Malaysia, it is of utmost importance then that patients who have been on HAART since 1990s to the present day be included in a large scale systematic study for the assessment of the development of ADIs in the months following HAART initiation and thus improve the outcome of HIV patients as a whole. ACKNOWLEDGEMENTS We are grateful to Ahmad Arif bin Che Ismail, Hadita bt. Sapari, Lott Pooi Wah, Ng Kean Tee, Poh Mau Ern and Zuliana bt. Jamli for their meticulous extraction of information from the patients' records. We also gratefully acknowledge the excellent administrative and technical support provided by the staff at the Infectious Diseases Unit, Hospital Kuala Lumpur. ABBREVIATIONS ADIs = AIDS-defining illnesses HAART = Highly active antiretroviral therapy IRDs = Immune restoration diseases REFERENCES [1] Bellamy R, Sangeetha S, Paton NI. (00). 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