phase III initiative by the Indian government the free ArT roll ... medical center in south India who were initiated on ART (generic, fixed-dose combinations) as per ...
© JAPI • december 2012 • VOL. 60
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Original Article
Risk Factors for Mortality in a South Indian Population on Generic Antiretroviral Therapy Priscilla Rupali1, Sam Mannam1, Annie Bella1, Lydia John1, S Rajkumar1, Peace Clarence1, Susanne A Pulimood2, Prasanna Samuel3, Rajiv Karthik1, Ooriapadickal Cherian Abraham1, Dilip Mathai4 Abstract Background : Antiretroviral treatment (ART) programs from low-income countries utilizing standardized ART regimens, simplified approaches to clinical decision making and basic lab monitoring have reported high mortality rates. We determined the risk factors for mortality among HIV-infected adults following the initiation of ART from a single center in south India. Methods : ART-naive HIV-infected south Indian adults attending the Infectious Diseases clinic in a 2000-bed academic medical center in south India who were initiated on ART (generic, fixed-dose combinations) as per the national guidelines were followed up. Cases (32 patients who died) were compared with age and sex matched controls. Results : Eight-hundred and twenty-two patients were started on ART from January 1, 2000 to December 31, 2008. The cumulative mortality was 6.8% (56/822).Among the cases mean age was 44 years, 18% were women and mean CD4 counts was 107 cells/µl. Among the controls mean age was 41 years, 18% were women and mean CD4 counts were 113 cells/ µl. Stavudine based ART was predominant 62.5% in the cases vs 37.5% in the controls, followed by zidovudine based therapy in 31.2% of cases and 43.7% in the controls. Tenofovir based therapy was used in 6.2% of cases vs 18.7% in the controls. The commonest causes of death were drug toxicity 19%, advanced Acquired Immunodeficiency Syndrome (AIDS) in 37%, Immune Reconstitution Inflammatory Syndrome (IRIS) in 16%, non AIDS related deaths in 22% and malignancies 6%. In a univariate analysis, absolute lymphocyte count 16 11 (42%) 8 (34%) Hb < 10 g% 12 (40%) 7 (22%) 2.38 (0.69 – 8.56) 0.12 > 10 g% 18 25 Leukocyte count (TC 9 5 2.31 (0.58 – 0.05) 0.176 < 4000/ cu.mm) ALC (< 1200/cu.mm) 18 (60%) 10 (32%) 3.15 (0.98-10.28) 0.03 Abnormal LFT 16(62%) 15(48%) 1.7 (0.52- 5.63) 0.321 Stavudine based ART 20(63%) 12(37%) 5 (0.71 – 56) 0.04 IRIS 13(41%) 0 0.000 Median CD4 (cells/ 80 97 0.57 µL) Median CD4 gain 73 252 0.001 at 1 yr Weight gain at 1 year 2 6 0.172 (kg)
A univariate analysis of factors contributing to mortality was compared among cases and controls (Table 3). Among them lymphopenia i.e., absolute lymphocyte count (ALC) < 1200/ cu.mm, stavudine based NRTI backbone, development of IRIS and median CD4 gain < 75 cells at 1 year were significantly found to be associated with mortality (Table 3).
Discussion Since the introduction of fixed dose combinations (FDC) of generic antiretroviral drugs, there have been many studies documenting their efficacy/effectiveness,10,11 however issues of concern have been safety and tolerability. NACO has now been able to scale up to provide ART to 2,7,781 patients (data till March 2009).12 As of March 2010, there are 269 ART centers providing antiretroviral therapy. As access to care and treatment improves it is appropriate for us to now evaluate whether this endeavour has indeed improved survival and prolonged life. Survival analysis of HIV-infected patients started on ART attending an urban clinic in Northern India indicated that 90% of the patients were alive at 6 months, 87% at 12 months and 84% at the end of 36 months.12 The authors have indicated that their figures of mortality and loss to follow up indeed seem to be higher than that reported from other developing countries. The cumulative mortality of 6.8% in our cohort was comparable to that seen in the Antiretroviral Therapy in lower income countries (ART-
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© JAPI • december 2012 • VOL. 60
LINC) collaboration at the end of a year.13 We think that this low mortality seen in our cohort of patients is due to active follow-up, early detection of complications and treatment failure along with intensive and repetitive adherence counseling. We found that two-thirds of the deaths in our cohort occurred in the first 6 months similar to the ART-LINC collaboration and a report from Haiti14 and Southern India.15 But while AIDS defining illnesses contributed to almost all the deaths in the Haitian cohort, in our cohort drug toxicity, IRIS and AIDS defining illnesses contributed to the deaths occurring early (< 24 weeks). In most series, IRIS is not believed to contribute to any significant morbidity and mortality 16, however the difference in our cohort was remarkable in that, none of the controls developed IRIS. It is possible that in resource poor settings, the effect of IRIS on mortality is underestimated. Sparse data is available with regard to mortality directly attributable to severe drug toxicity and most estimates are available only from developed countries,17 where data suggests that the contribution of drug toxicity to mortality is insignificant. The late causes of death (> 24 weeks) in our series included late drug toxicity due to lactic acidosis, advanced AIDS due to treatment failure or non adherence, vascular events like acute coronary syndrome and pulmonary embolism and intercurrent infections. Risk factors identified in an Indian study include persistent diarrhea and presence of tuberculosis 5 with a possible contribution of a low CD4 count.15 In our study, an ALC < 1200/ cu.mm, stavudine based ART, development of IRIS and a CD4 change < 75 cells/cu.mm at the end of 1 year seemed to have a trend towards increased mortality; however the confidence intervals were very wide due to the small numbers.
2.
Towards universal access: scaling up priority HIV/AIDS interventions in the health sector. Progress report 2010 (WHO, UNICEF, UNAIDS),p 53 accessed online http://www.who.int/hiv/ topics/treatment/data/en/index2.html
3. Department of AIDS Control, Ministry of Health and Family Welfare, Government of India: Annual report 2008-2009 accessed from http://nacoonline.org/upload/Publication/Annual_Report_ NACO_2008-09.pdf on 3rd May 2009. 4. Bishai D, Colchero A, Durack DT. The cost effectiveness of antiretroviral treatment strategies in resource limited settings. AIDS 2007;21:1333-40. 5.
Rajagopalan N, Suchitra JB, Shet A et al. Mortality among HIVinfected patients in resource limited settings: a case controlled analysis of inpatients at a community care center. Am J Infect Dis 2009;5:219-224.
6.
Teja VD, Sudha T, Lakshmi V. Causes and pattern of mortality in HIV-infected, hospitalized patients in a tertiary care hospital: a fourteen year study. Indian J Med Sci 2007;61:555-61.
7.
Lewden C, Salmon D, Morlat P et al. Causes of death among human immunodeficiency (HIV)-infected adults in the era of potent antiretroviral therapy: emerging role of hepatitis and cancers, persistent role of AIDS. Int J Epidemiol 2005;34:121-30.
8.
Palella FJ Jr, Baker RK, Moorman AC et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006;43:27-34.
9.
Sivadasan A, Abraham OC, Rupali P et al. High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first line antiretroviral treatment. J Assoc Physicians India 2009;57:384-8.
10. Calmy A, Pinoges L, Szumilin E et al. Generic fixed-dose combination antiretroviral treatment in resource-poor settings: multicentre observational cohort. AIDS 2006;20:1163-9.
The limitations from this study are we were unable to do get details on a majority of the cases who died at home and hence only 32 of 56 could be included in the analysis. Second is that, as the study spans a longitudinal follow-up period of 10 years - prior to the NACO ART rollout to the period where free ART became available in our centre i.e., 2008 to the ready availability of cheap tenofovir based regimens our study population is heterogenous. However we believe that the conclusions from this study are robust as this is a closely followed up fairly large cohort of patients.
11. Pujari SN, Patel AK, Naik E et al. Effectiveness of generic fixed-dose combinations of highly active antiretroviral therapy for treatment of HIV infection in India. J Acquir Immune Defic Syndr 2004;37:1566-69.
In conclusion, mortality in India in a closely monitored cohort seems to be comparable to ART programmes anywhere in the developing world amounting to 6.8%. Active case detection with earlier initiation of a safe ART regimen has the potential to reduce mortality significantly. The mortality in the tenofovir based regimen was 6% vs 62% in the stavudine based ART regimen. The cost effectiveness of tenofovir based first line regime vs the NACO recommended has been studied17 and has been proven efficacious and cost-effective. The incidence of IRIS is likely to reduce with earlier case detection and initiation of ART but the switching to safer regimens with emphasis on adherence is likely to significantly impact the mortality in India.
14. Severe P, Leger P, Charles M et al. Antiretroviral therapy in a thousand patients with AIDS in Haiti. N Engl J Med 2005;353:232534.
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12. Sharma SK, Dhooria S, Prasad KT et al. Outcomes of antiretroviral therapy in a northern Indian urban clinic. Bull WHO 2010;88:222226.doi:10.2471/BLT.09.068759. 13. The Antiretroviral Therapy in Low Income Countries [ARTLINC] collaboration and the Antiretroviral Therapy Cohort Collaboration [ART-CC]. Mortality of HIV-1 patients in the first year of antiretroviral therapy: comparison between low- income and high-income countries. Lancet 2006;367:817-24.
15. Kumarasamy N, Venkatesh KK, Devaleenol B et al. Factors associated with mortality among HIV-infected patients in the era of highly active antiretroviral therapy in Southern India. Int J Infect Dis 2010;14:e127-131. Epub 2009 July 25. 16. Castelnuovo B, Manabe YC, Kiragga A et al. Cause specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first three years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 2009;49:965-72. 17. Keiser O, Fellay J, Opravil M et al. Adverse events to antiretrovirals in the Swiss HIV Cohort Study: effect on mortality and treatment modification. Antivir Ther 2007;12:1157-64. 18. Bender MA, Kumarasamy N, Mayer KH et al. Cost-effectiveness of tenofovir as first line antiretroviral therapy in India. Clin Infect Dis 2010;50:416-25.
