|Year : 2009 | Volume
| Issue : 5 | Page : 224-226
A prospective, observational cohort study to elicit adverse effects of antiretroviral agents in a remote resource-restricted tribal population of Chhattisgarh
Harminder Singh1, Navin Dulhani1, Pawan Tiwari1, Prabhakar Singh2, Tiku Sinha1
1 Department of Pharmacology, Medicine, Anatomy and PSM, Government Medical College, Jagdalpur, Chhattisgarh - 494001, India
2 Department of Pharmacology, SS Medical College, Rewa, MP, India
|Date of Submission||05-Feb-2009|
|Date of Decision||23-Apr-2009|
|Date of Acceptance||24-Oct-2008|
|Date of Web Publication||24-Dec-2009|
Department of Pharmacology, Medicine, Anatomy and PSM, Government Medical College, Jagdalpur, Chhattisgarh - 494001
Objective : To assess the adverse effects of antiretroviral therapy (HAART) and its adherence in HIV-infected patients, in remote and tribal area with restricted resources.
Materials and Methods : This was a prospective, observational study carried out at Department of Medicine, Government Medical College, Jagdalpur. A set of questions were asked and adverse drug reactions (ADRs) were recorded for every patient.
Results : 79 HIV positive patients were analyzed. Among them, 68 (86%) had at least one ADR. The mean ADR per patient was 1.64 (±1.09). The most common ADR in our study was peripheral neuropathy (20.83%), followed by skin rashes (15.83%). Twenty-one patients (26.58%) had severe (grade-3 and grade-4) ADRs. Female patients had more ADRs (45.71%) than males (11.36%); severe ADRs had a statistically significant positive correlation with sex and CD4 cell count of the patients.
Conclusion : In spite of high ADRs, HAART is the only answer to HIV/AIDS; thus, management requires a highly precise balance between benefits of durable HIV suppression and the risks of drug toxicity to achieve the therapeutic goals, with conventional drugs or with newer less toxic agents.
Keywords: Highly affective antiretroviral therapy, antiretroviral therapy, adverse drug reaction, antitubercular treatment
|How to cite this article:|
Singh H, Dulhani N, Tiwari P, Singh P, Sinha T. A prospective, observational cohort study to elicit adverse effects of antiretroviral agents in a remote resource-restricted tribal population of Chhattisgarh. Indian J Pharmacol 2009;41:224-6
|How to cite this URL:|
Singh H, Dulhani N, Tiwari P, Singh P, Sinha T. A prospective, observational cohort study to elicit adverse effects of antiretroviral agents in a remote resource-restricted tribal population of Chhattisgarh. Indian J Pharmacol [serial online] 2009 [cited 2014 Dec 19];41:224-6. Available from: http://www.ijp-online.com/text.asp?2009/41/5/224/58512
| » Introduction|| |
Universal access to antiretroviral therapy (ART) is the aim of World Health Organization and UNAIDS.  In June 1996, the World AIDS Conference in Vancouver reported new AIDS cocktails and thus 'highly active antiretroviral therapy' (HAART) became popular. The potent antiretroviral therapy resulted in marked reduction in the rates of illness and death in the developed world and has led to the effective management of HIV-1 infection.  A successful ART regimen involves a combination of at least three drugs. Reduction in morbidity and mortality have been confirmed in all settings in which it has been used, including developing countries.  The choice of regimen depends on their side-effect, potential drug interactions, co-morbidities (e.g. tuberculosis, hepatitis), and alternative options in the setting of treatment failure and drug availability and cost.  The major individual toxicities include bone marrow suppression (zidovudine), pancreatitis (didanosine), hypersensitivity (abacavir), hepatic necrosis (nevirapine), neuropsychiatric complaints (efavirenz), and nephrolithiasis (indinavir). Hyperlipidemia has emerged as an important concern with HAART, due to the potential for premature atherosclerosis and coronary artery disease.  Patients who report significant side effects are more often non-adherent to therapy, 25% of them stop therapy within the first year on HAART and the same number stop because of their concern regarding side effects. ,, There are several factors predisposing to antiretroviral-associated adverse events, e.g. female sex, concomitant medications with overlapping and additive toxicities, co-infection with hepatitis B or C, drug-drug interactions, and alcoholism.  The present work was carried out to assess the ADR profile of HAART in a remote, tribal area with restricted resources.
| » Materials and Methods|| |
This was a prospective, observational study conducted at the Department of Medicine of Government Medical College and associated Maharani Hospital, Jagdalpur Chhattisgarh, with an assistance from the Department of Pharmacology after approval from Institutional Human Research Ethics committee and written consent of patients. The study was conducted from December 2006 to November 2008, in a cohort of 79 patients. All adult HIV patients on HAART therapy of either sex were included. Patients taking antitubercular treatment (ATT) and other drugs with a potential for hepatic or renal toxicity or interactions with HAART drugs and those with a history of alcohol abuse and noncompliance were excluded from the study.
A baseline interview was taken before initiating the therapy followed by further interrogation at first, fourth, and seventh month for the development of ADRs. Information on adverse reactions and data related to health care utilization variables were collected from the medical charts as well as through self-reporting by patients. An adverse reaction to ART was defined as any undesirable effect or symptom registered in the medical charts by the treating physician, that occurred up to 1 year of the first ART prescription.
Baseline laboratory investigations such as hemoglobin (Hb), total and differential leukocyte counts, erythrocyte sedimentation rate, urine analysis, serum venereal disease research laboratory (VDRL) test, serum hepatitis B surface antigen (HBsAg), Mantoux test (MT), and fine needle aspiration cytology (FNAC) of lymph nodes were carried out in each patient to rule out any opportunistic infection or specific contraindications to any drug. The chest X-ray and ultrasonography of the abdomen were done to determine the focus of tuberculosis. Patients were also subjected to liver function tests (LFTs); renal function tests (RFTs), lipid profile, and blood sugar analysis. Clinical examination along with appropriate lab investigations, histopathology, and radiodiagnosis were documented in the adverse reactions reported by the treating physician.
Three types of HAART regimens were used: A: Stavudine, lamivudine, and nevirapine (63%); B: Lamivudine, zidovudine, and nevirapine (30.37%) and C: Stavudine, lamivudine, and efavirenz (6.32%). Allotment of HAART regimens was based on physician's judgment. Data were analyzed using the chi-square test for establishing correlation between severe ADR and different variables. A P value < 0.05 was considered to be statistically significant.
| » Results|| |
A total of 137 HIV patients were enrolled. Among them, 15 expired, 16 patients stopped the therapy midway, 9 were lost to follow up, and 18 patients were on antitubercular treatment (ATT) simultaneously and so were excluded from the study. Of the 79 patients included in the study, 44 were males and 35 were females. The study group had a mean age of 31.16 ± 8.39 years.
At least one ADR was seen in 68 (86%) patients. The mean ADR per patient was 1.64 (±1.09). The most common ADR observed was peripheral neuropathy (20.83%) and second most common was skin rash (15.83%) [Table 1]. A total of 120 ADRs were noted in 68 patients. Among these 68 patients, 21 had severe (grade-3 and grade-4) ADRs, whereas 47 patients had mild to moderate ADR (Grade-1 and Grade-2). A highly significant correlation between sex and severe ADR was found.
The incidence of severe adverse reactions was 32.55% in patients less than 35 years of age, as compared to only 19.44% in those more than that. This was statistically insignificantly [Table 2].
Among 79 patients, 33 had a CD4 count < 200 cells/mm 3 . Sixteen of these patients (48.48%) had severe side effects and in 46 patients who had CD4 count of > 200 cells/mm 3 , only 5 (10.86%) had severe side effects which is statistically highly significant. The co-relation between different regimens and severity of ADRs reported were also as statistically insignificant.
| » Discussion|| |
In the present study, 79 patients on HAART regimens were observed over a period of 2 years. Adverse effects were seen in 86% of cases. Sharma et al. (2008) reported ADRs in 71.1% of cases, and the most common ADR reported was cutaneous manifestation.  In our study, the most common ADR reported was peripheral neuropathy (31.64%), mainly with stavudine (d4t) containing regimens. Another study by Kumarasamy et al. (2002) has also shown peripheral neuropathy, anemia, and nail hyperpigmentation as the most common side effects. In our study, lipodystrophy was observed in 20.04% of cases, while in other studies it was seen in 14.5% of the cases. , Saint-Marc et al. (2002) reported the incidence of lipodystrophy to be 46.5%. 
A study by Malangu et al. (2008) reported ADRs in 94% of cases, the most common being a sexual disorder (40%),  but in our study, peripheral neuropathy was the most common ADR. In addition, we found that abdominal disorders (11.67%) were the ADRs that affected patient compliance and adherence to prescribed drug regimens.
The correlation between female sex and severe ADR was found to be statistically highly significant. It is not clearly known why sex difference exists in adverse reactions to antiretroviral drugs. Factors cited include differences in weight and body mass index, hormonal changes unique to females, and the effect of these changes on drug metabolism.  Other possible factors include differences in fat composition (thereby affecting drug distribution) and genomic differences influencing the level of enzymes involved in drug metabolism. 
ADR to ART may depend on the baseline CD4+ cell count at initiation of therapy. A study by Center for Disease Control and Prevention on HIV outpatients suggested that some complications were more frequent and severe when therapy is started at lower CD4+ cell counts. Thus, patients may actually experience fewer side effects over a 10-20 year period of drug exposure if they start therapy 18-24 months earlier than if they delay therapy until the CD4+ cell count decreases to less than 0.200 x 10 9 cells/L. 
The measurement of viral loads and CD4 cell counts and the standard of care for assessing efficacy and response to HAART are not possible everywhere, particularly in resource-restricted places. Also, as eradication of the disease is currently not possible, significant problems related to compliance and long-term toxicity can be anticipated with decade-long therapies. Patient compliance can be improved with proper education and counseling regarding the disease process and inherent but innocuous side effects of HAART. More research is needed to develop low-cost investigations and algorithms for prediction of adverse effects of existing regimen, along with generation of more efficacious and less toxic drugs.
| » References|| |
|1.||WHO and HIV/AIDS. Available from: http://www.who.int/hiv/en/. (last accessed on 2006 Sep 29). |
|2.||Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338:853-60. |
|3.||Scaling up antiretroviral therapy in resource limited settings guidelines for a public health approach. Available from: http://www.who.int/hiv/pub/prev_care/en/ScalingUp_E.pdf. World Health Organization 2002. |
|4.||Charlesr F. Antiretroviral agents and treatment of hiv infection. In: Laurence LB, John SL, Keith L. Parker editors. Goodman Gilman′s the pharmacological basis of therapeutics. 11 th ed. McGraw-Hill: Medical Publishing Division; 2006. p. 1284-308. |
|5.||d′Arminio Monforte A, Lepri AC, Rezza G, Pezzotti P, Antinori A, Phillips AN, et al. Insights into the reasons for discontinuation of the first highly active antretroviral therapy (HAART) regimen in a cohort of antiretroviral naοve patients: Italian cohort of antiretroviral Naοve patients. AIDS 2000;14:499-507. |
|6.||Chesney MA, Ickovics JR, Chambers DB, Gifford AL, Neidig J, Zwickl B, et al. Self-reported adherence to antiretroviral medications among participants in HIV clinical trials: The AACTG adherence instruments. Patient Care Committee and Adherence Working Group of the Outcomes Committee of the Adult AIDS Clinical Trials Group (AACTG). AIDS Care 2000;12:255-66. |
|7.||Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De Longis P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic SynDr. 2001;28:445-9. |
|8.||Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. November 3,2008; 1-139. Available from: http://www.aidsinfo.nih.gov. |
|9.||Sharma A, Vora R, Modi M, Sharma A, Marfatia Y. Adverse effects of antiretroviral treatment. Indian J Dermatol Venereol Leprol 2008;74:234-7. [PUBMED] |
|10.||Balakrishnan K. Safety, tolerability and effectiveness of locally produced generic antiretroviral drugs in persons with HIV disease in Southern India. Int Cong Drug Ther HIV 2002;6:298. |
|11.||Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, et al. A syndrome of peripheral fat wasting (Lipodystrophy) in patients receiving long term nucleoside analogue therapy. AIDS1999;13:1659-67. |
|12.||Malangu NG. Self-Reported Adverse Effects as Barriers to Adherence to Antiretroviral Therapy in HIV-Infected Patients in Pretoria. SA FAM pract 2008;50:49. |
|13.||Tran C, Knowles SR, Liu BA, Shear NH. Gender differences in adverse drug reactions. J Clin Pharmacol 1998;38:1003-9. |
|14.||Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50:222-39. |
|15.||Lichtenstein KA, Delaney KM, Armon C, Ward DJ, Moorman AC, Wood KC, et al. Incidence of and risk factors for lipoatrophy (abnormal fat loss) in ambulatory HIV-1-infected patients. J Acquir Immune Defic SynDr. 2003;32:48-56. |
[Table 1], [Table 2]
|This article has been cited by|
|| A prospective analysis of adverse effects of antiretroviral agents: Additional points to consider
| ||Shah, M. |
| ||Indian Journal of Pharmacology. 2010; 42(2): 116 |
|| Authorsę reply
| ||Singh, H., Dulhani, N., Nel, K.B. |
| ||Indian Journal of Pharmacology. 2010; 42(2): 116 |