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Incidence of common opportunistic infections in HIV-infected individuals in Pune, India: analysis by stages of immunosuppression represented by CD4 counts

Open ArchivePublished:July 04, 2008DOI:https://doi.org/10.1016/j.ijid.2008.03.029

      Summary

      Background

      Opportunistic infections (OIs) influence the morbidity and mortality due to HIV infections. Data from India on the incidence of OIs among HIV-infected individuals by stages of immunodeficiency are scarce.

      Methods

      Between September 2002 and November 2004, HIV-infected individuals were enrolled in a prospective study in Pune. They were clinically and immunologically evaluated quarterly. Incidence rates of specific OIs were calculated.

      Results

      Median CD4 counts in HIV-infected male and female patients at baseline were 197/mm3 and 413/mm3, respectively. Tuberculosis was the most common OI with an incidence of 15.4 (95% CI 12.2–19.2) per 100 person-years, followed by oral candidiasis 11.3 (95% CI 8.6–14.5), herpes zoster 10.1 (95% CI 7.6–13.1), and cryptococcal meningitis 1.7 (95% CI 0.8–3.1) per 100 person-years. Patients with baseline CD4 counts of <200/mm3 were six times more likely to develop OIs compared to those with CD4 counts of >350/mm3 (p < 0.001).

      Conclusions

      The high incidence of commonly reported OIs in Indian HIV-infected individuals highlights the need for early screening and also the need to increase awareness in healthcare providers, in order to improve decisions regarding prophylaxis for prevention and appropriate therapeutic intervention. Emphasis needs to be given to the early diagnosis and management of tuberculosis in HIV-infected individuals.

      Keywords

      Introduction

      It has recently been estimated that 2.5 million individuals are living with HIV infection in India.

      Joint United Nations Programme on HIV/AIDS (UNAIDS). 2.5 Million people in India living with HIV, according to new estimates. Press release. Available at: http://data.unaids.org/pub/PressRelease/2007/070706_indiapressrelease_en.pdf (accessed May 2008).

      With an HIV epidemic history in the country of more than two decades duration,
      • Solomon S.
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      • Ganapathy M.
      • Jagadeeswari
      Sentinel surveillance of HIV-1 infection in Tamilnadu, India.
      an increase in the number of persons at the advanced stage of disease presenting with medical complications is expected, and this is likely to pose a challenge to the healthcare delivery system. Opportunistic infections (OIs), leading to significant morbidity and mortality might grossly affect the health and quality of life of people infected with HIV.
      • Singh A.
      • Bairy I.
      • Shivananda P.G.
      Spectrum of opportunistic infections in AIDS cases.
      There is global evidence that the overall incidence of opportunistic diseases increases with the degree of immunosuppression resulting from HIV disease progression.
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      Spectrum and prognostic significance of opportunistic diseases in HIV/AIDS patients in Ilorin, Nigeria.
      • Yazdanpanah Y.
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      • et al.
      Incidence of primary opportunistic infections in two human immunodeficiency virus-infected French clinical cohorts.
      The primary medical care for HIV/AIDS in India mainly consists of symptomatic supportive treatment, chemoprophylaxis, and management of OIs. The Government of India initiated a free antiretroviral therapy (ART) roll-out program in 2004, and around 39 000 patients had been placed on ART by the end of March 2006.

      Gupta I, Trivedi M, Kandamuthan S. Costing of the free ART programme of the Government of India. Delhi: Health Policy Research Unit, Institute of Economic Growth. Available at: http://iegindia.org/dis_111_2006.pdf (accessed May 2008).

      Even if initiation of ART results in the suppression of OIs,
      • Corey D.M.
      • Kim H.W.
      • Salazar R.
      • Illescas R.
      • Villena J.
      • Gutierrez L.
      • et al.
      Effectiveness of combination antiretroviral therapy on survival and opportunistic infections in a developing world setting: an observational cohort study.
      issues of non-adherence, ART drug resistance, and treatment failure might not be able to totally prevent or avert OIs among the HIV-infected. Also, in a resource-limited setting like India, every individual who is eligible to receive ART cannot be covered in the Government-sponsored ART program, and those who are not covered will not necessarily be able to afford to buy the drugs on their own.
      Many studies on HIV prevalent cohorts have reported and described the spectrum of OIs worldwide, including in India.
      • Vajpayee M.
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      • Wig N.
      Spectrum of opportunistic infections and profile of CD4 counts among AIDS patients in North India.
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      CD4+ cell counts and opportunistic protozoa in Indian HIV-infected patients.
      • Kumarasamy N.
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      • Flanigan T.P.
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      • Solomon S.
      Clinical profile of HIV in India.
      Tuberculosis is the most commonly reported OI among HIV-infected individuals in India.
      • Singh A.
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      • Shivananda P.G.
      Spectrum of opportunistic infections in AIDS cases.
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      • Agrawal N.R.
      • Singh S.P.
      • et al.
      Study on clinico-epidemiological profile of HIV patients in eastern India.
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      A 16-year study of HIV seroprevalence and HIV-related diseases in a teaching tertiary care hospital in India.
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      • Bhatia V.P.
      • Dupont H.L.
      The natural history of human immunodeficiency virus infection among adults in Mumbai.
      Other commonly reported OIs include oral candidiasis, herpes zoster, cryptococcal meningitis, cerebral toxoplasmosis, and cytomegalovirus retinitis.
      • Singh A.
      • Bairy I.
      • Shivananda P.G.
      Spectrum of opportunistic infections in AIDS cases.
      • Vajpayee M.
      • Kanswal S.
      • Seth P.
      • Wig N.
      Spectrum of opportunistic infections and profile of CD4 counts among AIDS patients in North India.
      • Kothari K.
      • Goyal S.
      Clinical profile of AIDS.
      • Sharma S.K.
      • Kadhiravan T.
      • Banga A.
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      • Saha P.K.
      Spectrum of clinical disease in a series of 135 hospitalized HIV-infected patients from north India.
      • Wadia R.S.
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      • Kulkarni S.
      • Bhagat S.
      • et al.
      Neurological manifestations of HIV disease.
      Although, data on the ‘prevalence’ of various OIs from HIV-infected individuals are available, data on the ‘incidence’ of OIs in India are scarce. A natural history study from Mumbai among HIV-infected individuals documented the annual incidence of active clinical tuberculosis as 5.7/100 person-years, and emphasized strategies to prevent the occurrence of tuberculosis among HIV-infected patients.
      • Hira S.K.
      • Shroff J.J.
      • Lanjewar D.N.
      • Dholkia Y.N.
      • Bhatia V.P.
      • Dupont H.L.
      The natural history of human immunodeficiency virus infection among adults in Mumbai.
      A retrospective analysis from southern India reported the prevalence and survival patterns in different OIs.
      • Kumarasamy N.
      • Solomon S.
      • Flanigan T.P.
      • Hemalatha R.
      • Thyagarajan S.P.
      • Mayer K.H.
      Natural history of human immunodeficiency virus disease in southern India.
      However, incidence rates of OIs from a prospective study of HIV-infected individuals at various levels of immunosuppression have not been reported from India. Such estimates would be useful to guide healthcare workers in the institution of appropriate intervention strategies for the prevention of specific OIs, and also in the decision to initiate ART. In a prospective cohort study in Pune, India, we estimated the incidence of commonly occurring OIs, including tuberculosis, among HIV-infected individuals at various levels of immunosuppression.

      Materials and methods

      In collaboration with the Johns Hopkins University, Baltimore, USA, the National AIDS Research Institute, Pune conducted a prospective cohort study entitled “HIV incidence and participant retention” as part of the HIV Prevention Trial Network (HPTN) funded by the National Institutes of Health (NIH), USA. The study was carried out in Pune, a city located in the high HIV prevalence state of Maharashtra in India. The study was initiated in September 2002, enrolling HIV serodiscordant couples, with the objectives of determining the incidence of HIV infection in the uninfected spouses of HIV-infected persons and the retention of the enrolled couples in the cohort at the end of one year. Enrollment into the study was continued until November 2004. Although originally designed as a one-year follow-up study, the follow-up was extended until August 2005 to accumulate more person-years of follow-up for the determination of HIV incidence. In this paper, we present the findings from the HIV-infected partners who were enrolled and followed as a part of the HIV discordant couples cohort.

      Patients and clinic-based procedures

      The study was approved by the Scientific Advisory Committee and Ethics Committee of the National AIDS Research Institute. Demographic and clinical data were captured at each follow-up visit; HIV-infected individuals were called for 3-monthly follow-up visits. The clinical procedures in the study consisted of pre-test and post-test counseling, informed consents, and collection of demographic and clinical information on structured proformas. HIV-infected participants were monitored for their CD4 count and viral load estimations every 3 and 6 months, respectively. Participants were advised to report to the study physicians for any illnesses. They were clinically evaluated by study physicians during all follow-up visits and also during unscheduled interim visits whenever required. The study participants requiring in-patient care were admitted to two pre-identified local hospitals and were jointly managed by the study and hospital physicians.

      Clinical management

      Patients were categorized into stages I, II, III, and IV based on World Health Organization (WHO) clinical staging criteria after their study enrollment.

      World Health Organization. WHO Clinical charts and tables. Available at: http://www.womenchildrenhiv.org (accessed May 2008).

      The following case definitions were used for common OIs based on clinical presentation and/or reports of laboratory investigations as part of the locally available standard of care: (1) tuberculosis: clinical presentation suggestive of pulmonary or extrapulmonary tuberculosis along with supportive evidence (chest X-ray, Mantoux test, sputum examination for acid-fast bacilli, fine needle aspiration cytology and/or biopsy for tubercular lymphadenitis, ultrasonography of the abdomen for evidence of lymph nodes, or cerebrospinal fluid (CSF) examination for tubercular meningitis); (2) oral candidiasis: clinical evidence supported by clinical response to appropriate therapy; (3) herpes zoster: clinical evidence of prototypic skin eruptions with pain along with typical dermatological distribution; (4) cryptococcal meningitis: clinical evidence of meningitis with demonstration of cryptococci in the CSF detected by India ink preparation.
      All patients were provided with the appropriate locally available standard clinical care for their illnesses. Trimethoprim–sulfamethoxazole prophylaxis (once daily, orally) was initiated for the prevention of Pneumocystis jiroveci pneumonia when CD4 counts fell below 200/mm3. Patients were advised to commence ART as per national guidelines,

      Antiretroviral therapy guidelines for HIV-infected adults and adolescents including post-exposure. National AIDS Control Organisation, Ministry of Health and Family Welfare, Government of India. Available at: http://www.nacoonline.org/About_NACO/Policy__Guidelines/ (accessed May 2008).

      and this was initiated in patients who were willing and could afford it, following adherence counseling. OIs were diagnosed on the basis of clinical evaluation supported by appropriate laboratory investigations.

      Statistical analysis

      Baseline characteristics of HIV-infected individuals were compared by gender employing appropriate statistical tests.
      Patients who did not present with any specific OI at study enrollment were considered at risk of developing an OI from their date of entry into the study until their last date of visit, or the date of development of such an event. Patients who presented to the clinic with pre-existing conditions were excluded from the incidence estimation.
      We initially calculated incidence rates for any OI (tuberculosis, herpes zoster, oral candidiasis, cryptococcal meningitis, cytomegalovirus retinitis, toxoplasmosis, cryptosporidium diarrhea, etc.) experienced by the participants during the follow-up visits, but commonly reported OIs from our population (n = 10 or more) were considered for subsequent in-depth analysis. Only the first OI was considered for this analysis, even if the patient had more than one OI subsequently. The Cox proportional hazards model
      • Cox D.R.
      • Oakes D.
      Analysis of survival data.
      was used to assess the relationship between baseline characteristics and progression to any OI, adjusted for the CD4 count. The relative risk (RR) estimates reflect the relative hazard estimates from the model.
      We also carried out a detailed analysis for four of the commonly diagnosed conditions: tuberculosis (pulmonary and extrapulmonary), oral candidiasis, herpes zoster, and cryptococcal meningitis. In this analysis, we used the time from study entry to development of that specific OI for calculation of person-years for incidence estimation and did not consider any other OI that might have occurred during this interval. Incidence rates were estimated by age, gender, CD4 counts, and antiretroviral status at baseline, and 95% confidence intervals were calculated.
      Kaplan–Meier survival analysis was performed to determine survival or disease-free time from common OIs among the study participants by different categories of CD4 counts. Log rank statistics were used to test the equality of survival distributions. Results were considered statistically significant with a two-sided p value of <0.05. Data analysis was carried out using SPSS (version 14.0, SPSS Inc., USA).

      Results

      As a part of the prospective cohort study, 457 consenting HIV-infected individuals and their spouses were enrolled and followed. The median duration of follow-up was 15 months, with the accumulation of 625 person-years of follow-up. The male:female ratio in the enrolled study participants was 6:1.
      The median age of the 393 HIV-infected males was significantly higher than that of the 64 HIV-infected females (34 years vs. 28 years; p < 0.001). The median CD4 count in HIV-infected male patients was significantly lower than in female patients: 197/mm3 (IQR 96–338) vs. 413/mm3 (IQR 249–496), respectively (p < 0.001). Males were nearly three times more likely to be at an advanced stage of immunosuppression (characterized by CD4 counts of <200/mm3) as compared to females (51% and 19%, respectively). The median viral load in males was 109 622 RNA copies/ml (IQR 25 106–261 416) and was significantly higher than that in females (20 614 RNA copies/ml (IQR 2222–118 384); p < 0.001). At the time of study entry, 53%, 8%, 21%, and 18% of individuals were at WHO stages I, II, III, and IV of the disease, respectively. Males were more likely to be at stages II and III of HIV disease (p < 0.001). A history of tuberculosis, oral candidiasis, and herpes zoster in the past was found in 22.5%, 8%, and 27.1% individuals, respectively (data not shown). Nine percent of male patients and 5% of female patients were already on ART at the study initiation (p = 0.48).
      Sixty-seven HIV-infected individuals (65 males and two females) had at least one OI at the study entry visit and were not considered for the subsequent incidence analysis. Table 1 summarizes the incidence rate and relative risk of developing any OI by baseline characteristics for the remaining 390 study participants. The overall incidence of OIs was 35.7 per 100 person-years of follow-up (95% CI 30.1–41.9), with a total of 147 OI events reported by the respondents. The incidence of OIs was higher in the older age groups, in males, and among patients with low CD4 counts and not on antiretroviral treatment. Although males had a significantly higher risk of developing OIs than females (RR of 1.0 vs. 0.5 (95% CI 0.3–0.8; p = 0.008)), the difference was not statistically significant after adjusting for CD4 counts (p = 0.51). Patients with a baseline CD4 count <200/mm3 were almost six times more likely to develop OIs compared to those with CD4 counts of >350/mm3 (95% CI 3.6–9.9; p < 0.001). These findings remained unchanged even after adjusting for age, gender, and ART at baseline. The incidence of any OI was lower in patients exposed to highly active antiretroviral therapy (HAART) (23.9, 95% CI 12.3–41.7) as compared to the HAART-naïve population (37.3, 95% CI 31.3–44.2). However, this difference was not statistically significant.
      Table 1Incidence and relative risk of any opportunistic infections (OIs) by baseline CD4 counts, demographic characteristics, and antiretroviral treatment status
      CharacteristicNo.OI
      Opportunistic infection (OI): any incident opportunistic infection diagnosed in the HIV-infected individual during follow-up.
      Rate /100 person-years (95% CI)Relative risk
      UnadjustedpAdjusted
      Adjusted relative risk for baseline CD4 count.
      p
      All39014735.7 (30.1–41.9)
      Age
       ≥45301242.3 (21.9–73.9)2.8 (0.8–10.0)0.171.3 (0.4–4.7)0.71
       35–451395943.1 (32.8–55.5)3.0 (0.9–9.5)0.071.3 (0.4–4.3)0.62
       25–352027332.2 (25.2–40.4)2.2 (0.7–7.1)0.101.2 (0.4–4.0)0.68
       <2519314.7 (2.9–42.8)11
       Total390147
      Gender
       Female621317.9 (9.5–30.7)0.5 (0.3–0.8)0.0080.8 (0.5–1.5)0.51
       Male32813439.4 (33.0–46.7)11
       Total390147
      CD4 count/mm3
       <2001649169.6 (56.1–85.4)6.0 (3.6–9.9)<0.001
       200–3501043732.5 (22.9–44.8)2.9 (1.6–5.1)<0.001
       ≥3501211810.7 (6.4–17.0)1
       Total389
      Missing data: data were missing for one individual.
      146
      Antiretroviral treatment
       No35313537.3 (31.3–44.2)1.5 (0.8–2.7)0.191.2 (0.7–2.2)0.49
       Yes371223.9 (12.3–41.7)11
       Total390147
      a Opportunistic infection (OI): any incident opportunistic infection diagnosed in the HIV-infected individual during follow-up.
      b Adjusted relative risk for baseline CD4 count.
      c Missing data: data were missing for one individual.
      Incidence rates of four commonly reported OIs among HIV-infected individuals by gender are summarized in Table 2. The overall incidence of tuberculosis was 15.4 per 100 person-years of follow-up (95% CI 12.2–19.2). The incidence of extrapulmonary tuberculosis was higher (7.9 per 100 person-years) than pulmonary tuberculosis (6.9 per 100 person-years), resulting in the reporting of 45 and 39 cases of extrapulmonary and pulmonary tuberculosis, respectively, among the study participants during the follow-up. Four patients developed pulmonary as well as extrapulmonary tuberculosis during the follow-up period.
      Table 2Incidence of common and specific opportunistic infections (OIs) by gender in HIV-infected individuals in Pune, India
      Opportunistic infectionAllMaleFemale
      No. of respondents
      Number of respondents excludes HIV-infected individuals having the specified OIs at baseline.
      Incident casesIncidence/100 person-years (95% CI)No. of respondentsIncident casesIncidence /100 person-years (95% CI)No. of respondentsIncident casesIncidence/100 person-years (95% CI)
      Tuberculosis
      Tuberculosis includes cases with pulmonary TB and/or extrapulmonary TB.
      4248015.4 (12.2–19.2)3607517.2 (13.5–21.6)6456.0 (2.0–14.1)
      Pulmonary TB436396.9 (5.0–9.5)372388.0 (5.7–11.0)6411.2 (0.02–6.5)
      Extrapulmonary TB445457.9 (5.7–10.5)381418.4 (6.0–11.4)6444.8 (1.3–12.2)
      Oral candidiasis4236011.3 (8.6–14.5)3615311.7 (8.7–15.3)6278.8 (3.5–18.2)
      Herpes zoster4505610.1 (7.6–13.1)3865010.5 (7.8–13.9)6467.6 (2.8–16.4)
      Cryptococcal meningitis457101.7 (0.8–3.1)39391.7 (0.8–3.3)6411.2 (0.02–6.5)
      Other OIs
      Other OI includes cytomegalovirus retinitis, Pneumocystis jiroveci pneumonia, toxoplasmosis, and Cryptosporidium diarrhea.
      450193.2 (1.9–5.0)386193.7 (2.2–5.8)6400
      TB, tuberculosis.
      a Number of respondents excludes HIV-infected individuals having the specified OIs at baseline.
      b Tuberculosis includes cases with pulmonary TB and/or extrapulmonary TB.
      c Other OI includes cytomegalovirus retinitis, Pneumocystis jiroveci pneumonia, toxoplasmosis, and Cryptosporidium diarrhea.
      The incidence rates of herpes zoster and oral candidiasis were above 10% per year in all the patients and also in males (10.5% for herpes zoster and 11.7% for oral candidiasis, per year). In females, the incidence rates of herpes zoster and oral candidiasis were 7.6 and 8.8 per 100 person-years, respectively. The incidence of cryptococcal meningitis and other conditions was comparatively low (range 1.2 to 3.7 per 100 person-years in men and women). The incidence rates were lower in females as compared to males for all of the commonly observed OIs.
      Median CD4 counts around the time of developing tuberculosis, herpes zoster, oral candidiasis, and cryptococcal meningitis were 114.0/mm3 (IQR 58.0–195.0), 207/mm3 (IQR 146–293), 113/mm3 (IQR 39–203), and 71/mm3 (IQR 39–118), respectively. The median CD4 count among patients who developed pulmonary tuberculosis was 142/mm3 (IQR 44–244) and the median CD4 count among those who developed extrapulmonary tuberculosis was 94/mm3 (IQR 70–143). This difference was not statistically significant.
      Figure 1 shows the incidence of various OIs among study participants stratified by CD4 counts. It was observed that the patients at an advanced stage of immunosuppression had a very high chance of developing an OI. A classical stepladder pattern was observed, indicating increasing incidence rates of OIs with falls in CD4 counts. The incidence of pulmonary tuberculosis, extrapulmonary tuberculosis, oral candidiasis, herpes zoster, and cryptococcal meningitis increased many-fold with falling CD4 counts. The risk of developing tuberculosis and oral candidiasis was more than 10 times greater at CD4 counts of <200/mm3 compared to at CD4 counts of >350/mm3. Even among patients who had a CD4 count range of 200–350/mm3 at baseline, the incidence rates of tuberculosis and herpes zoster were above 11 per 100 person-years.
      Figure thumbnail gr1
      Figure 1Incidence of opportunistic infections (OIs) by baseline CD4 counts in HIV-infected individuals in Pune, India.
      Kaplan–Meier analysis for common OIs in different categories of CD4 counts showed that there was an increased risk of developing OIs almost immediately after the CD4 count started falling below 200/mm3 (Figure 2). The period of acquisition of common OIs was longer at higher CD4 counts except for herpes zoster, where the risk of getting the disease was high even at higher CD4 counts.
      Figure thumbnail gr2
      Figure 2Kaplan–Meier survival curves for common opportunistic infections (OIs) stratified by baseline CD4 counts in HIV-infected individuals in Pune, India.

      Discussion

      Many research studies have described the types and rates of OIs in HIV-infected individuals globally.
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      It has also been reported that the incidence of OIs has decreased in developed countries due to the availability of ART.
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      However, in India in the present phase of transition of the epidemic from HIV infection to AIDS, a rise in the burden of OIs is anticipated.
      The HIV epidemic in India is geographically diverse and there are regional differences, not only in the incidence and prevalence of HIV infection, but also in the burden of background communicable diseases. Facilities and access to healthcare in rural areas are limited. While preparing appropriate strategies for the effective management of AIDS patients, significant effort and investment will have to be made to build infrastructure, diagnostic facilities, and clinical expertise to manage OIs. If the public health managers are provided with accurate estimates of the existing burden and the rate of occurrence of OIs among HIV-infected individuals, they will be able to plan and implement appropriate management strategies and interventions. The highlight of our data is that we are reporting the incidence rates of four commonly observed OIs at various levels of immunosuppression in HIV-infected patients enrolled in a prospective study in Pune.
      The strengths of this study include the recruitment of a cross-section of HIV-infected individuals and an excellent retention up to one year. We observed that the male:female ratio of HIV-infected index cases in the HIV discordant couple setting was 6:1. This is higher than that reported elsewhere in India
      • Kumarasamy N.
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      and probably reflects the selective intake of couples in our study. The HIV epidemic in Indian women is younger than that in men, and this is why men are more likely to enter the study at an advanced stage of the disease than women. Higher viral loads and lower CD4 counts among male study participants indicate that they are at a more advanced stage of HIV disease. This also explains why the incidence of OIs was lower in women as compared to men.
      The overall incidence of OIs in our study population was 35.7/100 person-years of follow-up. The chances of developing OIs increased with decreasing CD4 counts, and incidence rates of OIs were six times higher in patients with CD4 counts below 200/mm3 as compared to others. These findings are consistent with observations from other developed and developing countries.
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      A study from Brazil reported an incidence of 51% OIs per year in patients with CD4 counts below 100/mm3 who were either on monotherapy or dual therapy antiretroviral regimens.
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      In a study in southern India, the incidence of OIs before initiation of ART was up to 10 per 100 person-years of follow-up.
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      This is low compared to our study, and may be due to the difference in the profile of the study population, study design, and differential follow-up rates.
      The high incidence of OIs in our study was expected, as nearly half of the study participants entered the study at an advanced stage of immunosuppression and the majority were ART-naïve. The patients who were on ART prior to study entry had a lower chance of developing OIs. This finding is similar to reports from other developed and developing countries, which have shown declines in the incidence of OIs as well as mortality in HIV-infected patients after the initiation of ART.
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      However, the observation that the incidence of OIs in those on HAART and in the HAART-naïve in our study was not statistically different could be attributed to the small sample size of patients on HAART at baseline and a lack of information on drug compliance and adherence at the intermediate point of study participant evaluation. With the availability of free antiretroviral drugs provided by the Government of India, the incidence of OIs is likely to reduce, but the sustainability of ART, the emergence of antiretroviral resistance, the management of treatment failures, and the lack of compliance to ART are likely to be challenges that will have to be dealt with in the future.
      The overall incidence of tuberculosis in our study population was much higher than that reported in Western countries.
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      It was also higher than that reported from South Africa in AIDS patients not at an advanced clinical stage of disease.
      • Wood R.
      • Maartens G.
      • Lombard C.J.
      Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis.
      Though tuberculosis is the most commonly reported HIV-related OI in India,
      • Steinbrook R.
      Tuberculosis and HIV in India.
      our study is the first prospective study to demonstrate a marked increase in tuberculosis incidence with advanced degree of immunosuppression.
      A natural history study from western India (Mumbai) reported the incidence of pulmonary tuberculosis to be 5.7 per 100 person-years of follow-up.
      • Hira S.K.
      • Shroff J.J.
      • Lanjewar D.N.
      • Dholkia Y.N.
      • Bhatia V.P.
      • Dupont H.L.
      The natural history of human immunodeficiency virus infection among adults in Mumbai.
      Managing the dual HIV–tuberculosis epidemic is a major public health challenge. In our study, the median CD4 count at the development of pulmonary tuberculosis was 142/mm3, which is higher than that reported in a natural history study in southern India (111/mm3).
      • Kumarasamy N.
      • Solomon S.
      • Flanigan T.P.
      • Hemalatha R.
      • Thyagarajan S.P.
      • Mayer K.H.
      Natural history of human immunodeficiency virus disease in southern India.
      We have also reported a high incidence of extrapulmonary tuberculosis. A study in northern India stated that both pulmonary and extrapulmonary tuberculosis had low positive predictive values (PPV; 51% and 42%, respectively) for CD4 levels of <200/mm3 as compared to disseminated tuberculosis including extrapulmonary tuberculosis (75%) in AIDS patients.
      • Attili V.S.
      • Singh V.P.
      • Rai M.
      • Varma D.V.
      • Sundar S.
      Evaluation of the status of tuberculosis as part of the clinical case definition of AIDS in India.
      A study in Nigeria reported the prevalence of extrapulmonary tuberculosis to be 13.7%, higher than in our population, with a mean CD4 count of 107/mm3, which was similar to our finding.
      • Salami A.K.
      • Olatunji P.O.
      • Oluboyo P.O.
      Spectrum and prognostic significance of opportunistic diseases in HIV/AIDS patients in Ilorin, Nigeria.
      A study from the Netherlands reported a rise in prevalence of extrapulmonary tuberculosis from 24.5% in 1993 to 51.8% in 2000 among HIV-infected individuals, but this rise was mainly attributed to the increase in AIDS patients of foreign descent.
      • Hesselink D.A.
      • Yoo S.M.
      • Verhoeven G.T.
      • Brouwers J.W.
      • Smit F.J.
      • van Saase J.L.
      A high prevalence of culture-positive extrapulmonary tuberculosis in a large Dutch teaching hospital.
      The diagnosis and management of tuberculosis, especially, extrapulmonary tuberculosis, is likely to pose unique challenges for medical practitioners from the diagnostic viewpoint, particularly in resource-limited settings. Although early diagnosis of extrapulmonary tuberculosis can be a challenge, if accomplished it can significantly reduce associated morbidity and mortality. The issue of prophylaxis against tuberculosis in HIV-infected individuals, especially using a potent drug like isoniazid, is debatable. However, it is certainly important that studies be undertaken to evaluate various drugs that can be used as prophylactic agents against tuberculosis in HIV-infected persons in settings like India, where there is a high disease burden of tuberculosis. Early prediction, correct diagnosis, and appropriate intervention for tuberculosis are likely to result in significant public health benefits. Another study from the city of Pune has also stressed the important role of private medical practitioners in treating HIV and tuberculosis co-infected patients.
      • Sheikh K.
      • Porter J.
      • Keilmann K.
      • Rangan S.
      Public-private partnership for equity of access to care for tuberculosis and HIV/AIDS: lessons from Pune, India.
      Oral candidiasis is a commonly described OI globally
      • Ranganathan K.
      • Hemalatha R.
      Oral lesions in HIV infection in developing countries: an overview.
      and has been reported as a marker of immunosuppression.
      • Sharma G.
      • Pai K.M.
      • Suhas S.
      • Ramapuram J.T.
      • Doshi D.
      • Anup N.
      Oral manifestations in HIV/AIDS infected patients from India.
      • Shiboski C.H.
      HIV-related oral disease epidemiology among women: year 2000 update.
      The high incidence of oral candidiasis, especially at low CD4 counts, necessitates the introduction of appropriate intervention for the same.
      • Singh A.
      • Bairy I.
      • Shivananda P.G.
      Spectrum of opportunistic infections in AIDS cases.
      • Vajpayee M.
      • Kanswal S.
      • Seth P.
      • Wig N.
      Spectrum of opportunistic infections and profile of CD4 counts among AIDS patients in North India.
      • Sharma G.
      • Pai K.M.
      • Suhas S.
      • Ramapuram J.T.
      • Doshi D.
      • Anup N.
      Oral manifestations in HIV/AIDS infected patients from India.
      • Shiboski C.H.
      HIV-related oral disease epidemiology among women: year 2000 update.
      The median CD4 counts at the time of diagnosis of oral candidiasis in our study were lower than those determined elsewhere,
      • Mbuagbaw J.
      • Eyong I.
      • Alemnji G.
      • Mpoudi N.
      • Same-Ekobo A.
      Patterns of skin manifestations and their relationships with CD4 counts among HIV/AIDS patients in Cameroon.
      but in India this condition is shown to have an association with low CD4 counts.
      • Sharma G.
      • Pai K.M.
      • Suhas S.
      • Ramapuram J.T.
      • Doshi D.
      • Anup N.
      Oral manifestations in HIV/AIDS infected patients from India.
      • Ghate M.V.
      • Mehendale S.M.
      • Mahajan B.A.
      • Yadav R.
      • Brahme R.G.
      • Divekar A.D.
      • et al.
      Relationship between clinical conditions and CD4 counts in HIV-infected persons in Pune, Maharashtra, India.
      Oral candidiasis is one of the clinical markers of immunosuppression, and antiretroviral therapy should be initiated in patients with persistent oral candidiasis if facilities for performing CD4 counts are not available. A study has shown that ART is highly effective in decreasing oral candidiasis in association with a rise in CD4 counts.
      • Yang Y.L.
      • Lo H.J.
      • Hung C.C.
      • Li Y.
      Effect of prolonged HAART on oral colonization with Candida and candidiasis.
      Herpes zoster, a commonly reported skin condition,
      • Vajpayee M.
      • Kanswal S.
      • Seth P.
      • Wig N.
      Spectrum of opportunistic infections and profile of CD4 counts among AIDS patients in North India.
      • Morgan D.
      • Mahe C.
      • Malamba S.
      • Okongo M.
      • Mayanja B.
      • Whitworth J.
      Herpes zoster and HIV-1 infection in a rural Ugandan cohort.
      was found in our study population, even at higher CD4 counts compared to the other common OIs, and the median CD4 count at the time of diagnosis was observed to be 207/mm3. A higher incidence of herpes zoster (17.21 per 100 person-years) was reported in Taiwan in the pre-HAART era.
      • Sun H.Y.
      • Chen M.Y.
      • Hsieh S.M.
      • Sheng W.H.
      • Chang S.Y.
      • Hsiao C.F.
      • et al.
      Changes in the clinical spectrum of opportunistic illnesses in persons with HIV infection in Taiwan in the era of highly active antiretroviral therapy.
      The incidence of herpes zoster was lower than that reported in developed countries,
      • Engels E.A.
      • Rosenberg P.S.
      • Biggar R.J.
      Zoster incidence in human immunodeficiency virus infected hemophiliacs and homosexual men, 1984–1997. District of Columbia Gay Cohort Study. Multicenter Hemophilia Cohort Study.
      but similar to that reported in another Indian study (11.8%).
      • Das A.L.
      • Sayal S.K.
      • Gupta C.M.
      • Chatterjee M.
      Herpes zoster in patients with HIV infection.
      The sequelae and chronic complications of this condition need to be studied, and the role of herpes vaccine in HIV-infected individuals needs to be evaluated in India.
      Among the different infections affecting the central nervous system, cryptococcal meningitis is the most common HIV-associated complication both in developed and developing countries,
      • Hakim J.G.
      • Gangaidzo I.T.
      • Heyderman R.S.
      • Mielke J.
      • Mushangi E.
      • Taziwa A.
      • et al.
      Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients.
      • Bicanic T.
      • Harrison T.S.
      Cryptococcal meningitis.
      contributing significantly to increased morbidity and mortality. This is the most common type of meningitis reported in important neurological studies in India.
      • Wadia R.S.
      • Pujari S.N.
      • Kothari S.
      • Udhar M.
      • Kulkarni S.
      • Bhagat S.
      • et al.
      Neurological manifestations of HIV disease.
      • Satishchandra P.
      • Nalini A.
      • Gourie-Devi M.
      • Khanna N.
      • Santosh V.
      • Ravi V.
      • et al.
      Profile of neurologic disorders associated with HIV/AIDS from Bangalore, South India (1989–96).
      Cryptococcal meningitis, an AIDS-defining illness, usually appears when CD4 counts are below 100/mm3 and is associated with an increased risk of death. Clinicians should carefully investigate those patients with very low CD4 counts presenting with symptoms suggestive of meningitis. Early diagnosis and effective treatment may considerably reduce the morbidity and mortality associated with this condition.
      There are certain limitations to our study: (1) the sample size was small, especially for women, and this did not allow elaborate gender-specific analysis; (2) the follow-up was short-term; (3) we were not able to capture the details of ART drug regimens and adherence, and it is possible that patients were taking treatment irregularly; (4) the diagnoses of herpes zoster and oral candidiasis were mainly based on clinical examination and response to therapy; (5) all the pulmonary tuberculosis cases were not confirmed by sputum culture; and (6) data on Pneumocystis jiroveci pneumonia were not included as we could not perform specialized diagnostic techniques of confirmation for this clinical condition. However, we feel that for the resource-limited setting, we have used the best available diagnostic algorithms for OIs, as would reflect the ‘real life situation’.
      This study provides important information about the risks of commonly reported OIs at lower CD4 counts. These results highlight the need for early screening and also the need to increase awareness in healthcare providers in order to improve decisions regarding prophylaxis for prevention and appropriate therapeutic interventions. This will reduce the morbidity and improve the quality of life of HIV-infected individuals. As the free ART roll-out program is extended to many states in India, many long-term studies will have to be undertaken to assess the effects of this program on the incidence of various OIs. Our study will also help program managers to plan appropriate strategies for the investigation and treatment of common OIs as a part of the management package for HIV-infected populations.

      Acknowledgements

      The National AIDS Research Institute, Indian Council of Medical Research (ICMR) provided the infrastructural, operational, and logistical support for this study. The ICMR and the Health Ministry Screening Committee, Government of India approved the study. Funding support was provided by the Fogarty International Center, U.S. National Institutes of Health, Program of International Training Grants in Epidemiology Related to AIDS, D43 TW00010-AITRP, as well as a contract from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) through Family Health International (FHI) (AI 47968) under the HIV Prevention Trials Network (HPTN) project. The manuscript review committee (MRC) of the HPTN approved the manuscript being submitted. The views expressed do not necessarily reflect the views of the ICMR, the Johns Hopkins University, FHI, or the NIH.
      Ethical approval: The study was approved by the Ethics Committee of the National AIDS Research Institute.
      Conflict of interest: No conflict of interest to declare.

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