Evaluation of Direct Cost of Adverse Drug Reactions to Highly Active Antiretroviral Therapy in Indian Human Immunodeficiency Virus Positive Patients

Human immunodeficiency virus (HIV) infected patients requires a combination of three to four antiretroviral, termed highly active antiretroviral therapy(HAART). HIV infected patients with HAART have a higher risk of developing adverse drug reactions (ADRs) than the general population and have a significant impact on patient’s current and future care options.¹ ADRs to HAART is recognized as the key factor that increases the overall healthcare costs in both admission to hospital and prolongation of length of hospital stay.² ADRs to HAART are one of the leading causes that affects the quality of life in HIV/Acquired immunodeficiency syndrome(AIDS) and results in increase in direct and indirect cost of HIV management with economic burden to the HIV infected patients as well as to the society.³ In India, the National AIDS Control organization (NACO) initiated free HAART for HIV and related opportunistic infections⁴.Currently, over 320,000 people living with HIV receiving HAART at more than 260 public government hospitals across the country. According to NACO treatment, HIV infected patients receive a fixed dose HAART regimen, consisting of either zidovudine or stavudine with lamivudine in combination with either efavirenz or nevirapine.⁵ In India, 25% of HIV patients discontinue their initial HAART regimen within the first eight months of therapy because of ADRs which leads to noncompliance.⁶ Studies^{7, 8, 9, 10}have assessed the direct cost of ADRs at different hospitals using length of stay as a parameter for evaluation.. Recent study¹¹ suggest that indirect cost such as disability, work productivity losses related to absenteeism and other financial cost was also associated in the management of HIV/AIDS. The evaluation of indirect cost associated from ADRs is rare and is found in only very few studies¹².The cost analysis of ADRs in HIV infected patients depends upon different HAART regimen based on the patient’s viral load as well as individual level of HIV/AIDS care.^{13, 14, 15, 16} In an Australian study 5.7% of all admissions were drug related, out of which 4.9% were due to ADRs, resulted in a calculated cost of > € 2 million, or €3077 per patient.¹⁷Study Conducted in Germany estimated direct cost associated with ADRs ranged from 0.4 billion dollars annually.¹⁸In United States study¹⁹ revealed that the cost of ADRs per patient was in the range of US$2000 to US$4000. Wasserfallen et al ²⁰ showed that a mean length of stay of nine days in a hospital attributes to ADRs resulting in a cost of €3122 per ADR. Moore et al ²¹showed that the average cost of ADRs was estimated to be €2900 and Lagnaoui et al²²showed that the mean cost of ADRs € 2700 per patient in a department of internal medicine. In India, Ramesh et al^{23, 24}estimated cost associated in treating all reported ADRs was US$ 1595, with average US$ 15 per ADR. Thiyagu et al² study from India showed that total cost incurred due to ADRs in a tertiary care teaching hospital was found to be US$ 36451 with average US$ 115 per patient hospitalized with ADRs. The aim of this work was to evaluate the direct cost incurred in the management of ADRs to HAART in Indian HIV positive patients.

A prospective observational study was conducted from March 2010 to February 2011 among HIV-infected hospitalized in-patients by a clinical pharmacist at the medicine department in a teaching hospital where ADR reporting system exists. The study was approved by the institutional ethics committee. HIV-infected hospitalized in-patients of either sex who were on fixed dose drug combinations of HAART were included in the study and HIV positive patients with Systemic Lupus Erythmatosus (SLE), cancer, pregnant women and patients with traditional medicines were excluded from the study. Patients were divided into two groups. The first group with presence of ADRs to HAART regimen (Cases) and second group with absence of ADRs to HAART regimen (Controls). Based on the study criteria, the study procedure was explained and written informed consent was obtained from these patients. For the study purposes World health organization (WHO) definition of an ADR was adopted^{.25, 26}

During the study period, hospitalized in-patients was intensively monitored for short term and long term ADRs to HAART by active follow-up after treatment and ADRs was detected by asking patients directly and by screening patients medical case records. The occurrence of ADRs to HAART was documented with details of suspected HAART involved for ADRs; treatment given for ADRs was documented using ADR documentation forms. Documented ADRs was reviewed and assessed by senior clinical pharmacist and was reported to the treating clinicians and affected HIV patients. WHO probability scalewas used for the causality assessment of ADRs.²⁷ The severity of suspected ADRs was assessed using the modified Hart wig and Siegel scale.²⁸

Evaluation of actual direct cost with ADRs and without ADRs to HAART was based on the cost of treatment, cost of hospitalization stay, and cost of laboratory investigations in comparison to a “normal” length of stay without ADR.²⁹ In cases of ADR causing a hospital admission, all hospital costs to the ADR was calculated, as the patient would not have been hospitalized without the ADR i.e. length of stay multiplied by costs per in-patient per day. Assessment of ADR that leads to increase in the length of stay was performed after physician’s judgement. Billing details was collected from computerized Hospital In-Patients Billing System (HIPBS). The cost of treatment that includes, all costs of medications, surgical supply such as syringes, professional charges, nursing care charges, administrative charges. The cost of laboratory investigations that includes all costs of clinical laboratory investigation charges and any other invasive or noninvasive additional procedures performed. The cost of hospitalization charges includes cost of ward charges, bed charges and hospital stay charges. The data observed was analyzed in order to study the total mean direct cost versus mean direct cost per ADRs.

Patients who presented with ADRs to HAART (Cases) and those who had not experienced with ADR to HAART (Controls) were compared with Chi-square test for gender, age and CD4 Count. Frequencies with percentage were used to represent gender, age, CD4 count, HAART regimen implicated, occurrence of ADRs and severity of ADRs to HAART. The association between direct cost incurred due to ADRs in HIV positive patients receiving HAART were determined at a P value <0.05 by investigating mean cost of treatment, mean cost of laboratory investigations and mean cost of hospitalization stay charges. (Minimum, maximum), Median and Chi-square test was used to evaluate the direct cost incurred to ADRs to HAART. All statistical calculations were performed using Statistical Package for Social Science (SPSS), version 17.0. A P-value of <0.05 was considered as statistically significant.

A total of 110 HIV positive patients (84 males and 26 females) with HAART were admitted to the hospital during the study period. Out of which 56 patients (42 males and 14 females) experienced ADRs to HAART i.e. (Cases) and 54 patients was not experienced with ADRs to HAART i.e. (Control). A total of 57.2% of HIV positive hospitalized in-patients experienced ADRs to HAART and 41.1% of ADRs to HAART were related to hospital admissions. ADRs were highest with zidovudine + lamivudine+ nevirapine (35.5%) and lamivudine + stavudine + nevirapine (17.9%) combinations. CD4 cell count in patients with ADRs to HAART was ≤ 200 cells/ µl. Pearson chi-square test showed statistical significant difference of mean direct cost incurred among age group between cases and control (p=0.021 i.e. p<0.05). The total cost incurred in managing ADRs to HAART among age group 18-40 years INR 5391.2 (US$ 117.2) and 41-60 years INR 2714 (US$ 59). Demographic Characteristic of the patients is shown in Table 1.

The direct cost incurred between cases (with ADR) and control (without ADR) was based on mean cost of treatment, mean cost of laboratory investigations and mean cost of hospitalization stay. It was identified that mean cost of treatment significantly contributed to the overall direct cost incurred between cases, INR 8556 (US$ 186) and control, INR 2645 (US$ 57.5). The mean cost of laboratory investigations with an ADR to HAART per patient was INR 1913.6(US$ 41.6). The mean cost of hospitalization stay with an ADR to HAART per patient was INR 3261.4(US$ 70.9).The median length of hospital stay with patients with ADRs to HAART was 10 days (range of 10 to 25 days) where as median length of hospital stay with HIV patients without ADRs to HAART was 4 days (range of 4 to 6 days). The association of direct cost incurred between cases (with ADR) and control (without ADR) in HIV positive patients receiving HAART was determined using Pearson chi-square test by investigating the mean cost of treatment (p=0.004 i.e. p<0.05), the mean cost of laboratory investigations (p=0.001 i.e. p<0.05) and mean cost of hospitalization stay (p=0.003 i.e. p<0.05). Results are summarized in Table 2.

The total direct cost of treating ADRs to HAART was highest with tenofovir + emtricitabine + lopinavir + ritonavir combination, INR 21822.4 (US$ 474.4) and lamivudine + stavudine + tenofovir combination, INR 17521.4 (US$ 380.9). Mean direct cost incurred in treating per ADR in hospitalized patients with HAART ranges from INR 524.4 (US$ 11.4) to INR 17521.4 (US$ 380.9), as presented in Table 3.

The cost of ADRs was studied based on the reported adverse reaction to HAART. In our study stavudine induced pancreatitis that led to highest cost of management INR 26105 (US$ 567.5) followed by efavirenz induced depression INR 19807.6 (US$ 430.6) followed by nevirapine induced Steven Johnson Syndrome (SJS) INR19182 (US$ 417), tenofovir induced renal failure INR 11113.6 (US$ 241.6) and zidovudine induced anemia INR 10695 (US$ 232.5). The ADRs that led to the lowest cost for management was reported with zidovudine induced fever INR 3362.6 (US$ 73.1) followed by stavudine induced peripheral neuropathy INR 4057.2 (US$ 88.2). The total direct costs of some of the important ADRs to HAART are summarized in Table 4.

In our study the direct cost incurred in managing ADRs to HAART reported was INR 72428(US$ 1574.51). The cost incurred in treating each ‘mild’, ‘moderate’ and ‘severe’ ADRs to HAART was INR 3549 (US$ 77.15), INR 39926 (US$ 867.95) and INR 28953 (US$ 629.41) respectively. The cost of management of ADRs to HAART based on the severity was summarized in Table 5. In our study, the overall incidence of ADRs to HAART was found to be 50.9%. In the majority of ADRs to HAART, causality assessment was ‘probable’ and ‘possible’ by WHO probability scale. Out of 56 ADRs to HAART, level of severity as per modified Hart wig and Siegel scale²⁸ accounted for ‘mild 6(10.7%)’, ‘moderate 42(75%)’ and ‘severe 8(14.3%). Results are shown in Figure 1.

Figure 1.Level of severity adverse drug reaction to highly active antiretroviral therapy

This is the first study conducted on Indian HIV-infected patients that explores the direct cost incurred in the management of ADRs to HAART. Use of HAART results in a wide range of adverse effects which are expensive to manage leading to morbidity and mortality. In a United States study³⁰, it has been shown that ADRs rank from the fourth to sixth leading cause of death. Various studies^{31, 32}concluded that in industrialized countries, ADRs accounts for 5 to 10% of hospital costs. In the present study, we estimated only the direct cost incurred in the management of ADRs to HAART, as indirect cost includes social cost, loss of productivity that are difficult to analyze. Various studies ^{33, 34} have also analyzed direct cost of ADRs.

Our study revealed male predominance over female. This may be due to the fact that in our study female HIV infected patients refuse for HIV treatment due to social stigma and illiteracy. These observations are in agreement with the previously published study elsewhere³⁵. However, in our study mean direct cost incurred in treating ADRs to HAART in female patient was higher compared to males. This may be due to the fact that in our study two female HIV-infected patients presented with nevirapine induced Steven–Johnson Syndrome resulted in increased length of hospital stay of 20 days. This is in accordance with published studies.^{36, 37}

The total mean direct cost seems very less in developing country like India, compared to developed countries like United States where the direct cost incurred in treating ADRs to HAART ranges to several thousand dollars.^{19, 20} But when compared to economic status of expenditure on health care cost in India, this cost associated with ADRs is significantly high. This is because most of our HIV infected patients were below the poverty line, even unable to afford their daily food and inability to pay for their HAART. This is in accordance with published studies.³⁸

In our study, the patient presented with severe renal dysfunction with increased risk of grades 3 to 4 nephrotoxicity due to tenofovir usage, necessitating them to receive multiple dialysis. Thus overall costs leads to higher expenditure from the patients in terms of laboratory investigations to investigate tenofovir induced renal failure; the length of stay in the hospital was prolonged and resulted in escalating the cost of treatment. This finding is in agreement with published studies^{19, 20, 39}where the laboratory investigations, length of hospital stay and treatment costs are responsible components for the overall direct cost of management of ADRs.

In the management of stavudine induced pancreatitis costs incurred was due to laboratory investigations such as lipase measurement, serum amylase and imaging studies. Three patients in our study with stavudine induced pancreatitis also developed sepsis with systemic inflammatory response syndrome and multiple organ failure. The offending drug stavudine was withdrawn and patient was on supportive measures of intravenous fluid administration, complete bed rest in the hospital for 10 days. which leads to higher expenditure of direct cost. A finding consistent with the study carried out by Moore et al.⁴⁰

Efavirenz induced severe depression developed psychiatric symptoms with aggressive behavior with nonfatal suicide attempts, insomnia, irritability, suicidal ideation, impaired concentration, vivid dreams, and paranoid reactions and manic reactions. The patient’s length of stay in the hospital was prolonged for more than 20 days which resulted in higher cost burden associated with ADRs to HAART. These observations are in agreement with published study.⁴¹

In our study the cost of management of nevirapine induced Steven–Johnson Syndrome (SJS) includes supportive measures with antimicrobial therapy, extra skin care, intravenous fluid administration, electrolyte maintenance cost and increased in the length of hospital stay in intensive medical care resulted in greater expenditure to the patient. One case of SJS with Level 7 severity which led to the death of the patient. This finding reflects the cost burden of ADRs to HAART. This is in accordance with published studies.^{42, 43, 44}

The overall direct cost associated in treating ADRs to HAART was found to be higher and significantly represents that ADRs to HAART increases the overall health care cost in the management of HIV/AIDS as well as reflects high economic burden to HIV/AIDS patients. I Clinicians and pharmacist must focus to prevent early ADRs to HAART thereby decreasing ADR related costs.

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