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Year : 2014  |  Volume : 3  |  Issue : 2  |  Page : 107-117

Evaluating the effects of combination antiretroviral therapy regimens and the development of adverse drug reactions in Indian human immunodeficiency virus positive patients

1 Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal, India
2 Department of Medicine, Kasturba Medical College, Manipal University, Manipal, India
3 Department of Statistics, Manipal University, Manipal, Karnataka, India

Date of Web Publication20-Jun-2014

Correspondence Address:
Radhakrishnan Rajesh
Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences and Kasturba Medical College Hospital, Manipal University, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-0521.134865

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Background: In India, adverse drug reactions (ADRs) occur frequently with combination antiretroviral therapy (cART) leading to switching or discontinuing cART intentionally. Objective: The study was conducted to characterize the effects of cART regimen and the development of ADRs in human immunodeficiency virus positive patients (HIV) in a tertiary care teaching hospital. Materials and Methods: A prospective observational study was conducted from August 2009 to May 2012 to characterize the pattern of ADRs to cART at Kasturba Hospital, Manipal in South India. Collection of the data was done by a clinical pharmacist during daily ward rounds to identify the suspected ADRs associated with the use of cART for various parameters which included patient demographics, cART with its adverse reaction characteristics. Assessment was also done for preventability, predictability and seriousness of ADRs, system organ classes affected and causality of the suspected ADRs using the World Health Organization (WHO) Probability Scale. Results: Among 450 patients enrolled, 230 suspected ADRs to cART were reported. By Pearson Chi-square test, higher occurrence of ADRs (P < 0.001) was noted in females, age 41-60 years, CD4 + T-cell counts 350-500 cells/μl, 5 years use of cART. ADRs were highest with zidovudine + lamivudine + nevirapine (42.3%) and tenofovir + emtricitabine + efavirenz (14.2%). On bivariate analysis, (P < 0.001) were identified in 1) Anemia with zidovudine use, 2) Pancytopenia with zidovudine, lamivudine use 3) Hepatotoxicity with nevirapine, efavirenz use, 4) Peripheral neuropathy with stavudine use, 5) Renal failure with tenofovir use and 6) Maculopapular rash with emtricitabine, tenofovir, efavirenz use. The system organ class most affected with ADRs to cART was red blood cell disorders (30.9%) followed by skin and appendages disorders (16.5%). Conclusion: With increasing reports of ADRs in India, clinicians need to select a safe cART regimen with underlying illness, medicines and drug intolerances.

Keywords: Adverse drug reactions, antiretroviral therapy, human immunodeficiency virus

How to cite this article:
Rajesh R, Vidyasagar S, Varma DM, Guddattu V, Patel NR, Varghese M, Pulagam P. Evaluating the effects of combination antiretroviral therapy regimens and the development of adverse drug reactions in Indian human immunodeficiency virus positive patients. Saudi J Health Sci 2014;3:107-17

How to cite this URL:
Rajesh R, Vidyasagar S, Varma DM, Guddattu V, Patel NR, Varghese M, Pulagam P. Evaluating the effects of combination antiretroviral therapy regimens and the development of adverse drug reactions in Indian human immunodeficiency virus positive patients. Saudi J Health Sci [serial online] 2014 [cited 2022 Sep 28];3:107-17. Available from: https://www.saudijhealthsci.org/text.asp?2014/3/2/107/134865

  Introduction Top

Worldwide the overall number of people living with human immunodeficiency virus (HIV) has significantly increased due to new infections [1] and beneficial effects of combination antiretroviral therapy (cART) has brought about a dramatic increase in life expectancy and decreased mortality among people with HIV infection. [2] Concern about adverse drug reactions (ADRs) with use of all cART are among the most common reasons for switching or discontinuing therapy as well as for intentional medication nonadherence. [3],[4] An estimated 33 million people are infected with HIV, with 2.5 million new infections worldwide. [5] India being at the third position in having the highest burden of HIV/Acquired Immunodeficiency Syndrome [6] (AIDS), at the present time more than 12, 53,500 people have been registered in HIV/AIDS care and more than 404,882 patients were on cART. [7] HIV infected patients are destined to undergo treatment with cART for life time [8] and use of cART have been known to cause short term and long term ADRs. [9] The line of management of ADRs to cART with suspected drug discontinuation, dose adjustment or switching to the other cART and supportive treatments are frequent methods that increase the tolerability of cART. [10] Most often under reporting of ADRs among clinicians was observed as a major obstacle in the characterization of the pattern of ADRs in HIV infected patients with cART. Prospective intensive monitoring of ADRs in HIV infected patients with cART in a tertiary care teaching hospital helps in characterizing the pattern of ADRs and thereby help clinicians to select a cART regimen that is not only effective in achieving, maintaining viral suppression, and improving immune function but also safe in overall HIV management. The study was aimed to characterize the pattern of ADRs to older and newer cART in a tertiary care teaching hospital in Indian HIV-positive patients with regard to the demographics of patients affected, causality, outcome, preventability, predictability, seriousness of ADRs and suspected antiretroviral (ARV) medications with adverse reactions characteristics to system organ classes and codes.

  Materials and methods Top

Prospective, intensive monitoring of pattern of ADRs to older and newer cART was conducted in HIV-infected patients from August 2009 to May 2012 in medical wards of a tertiary care teaching hospital (Kasturba Hospital, Manipal) in South India.

Ethical approval

The study protocol was approved by the University Ethics Committee (UEC) of Manipal University.

Collection of data

Patients admitted to the study wards with suspected cases of HIV infection were initially routed through integrated counseling and testing center (ICTC) of the study hospital, where pre-test and post-test counseling for HIV testing were done. HIV infected positive patients were then counseled by counselor from ICTC, on information on mode of transmission and prevention of HIV/AIDS for promoting behavioral change and to reduce vulnerability as per the essential requirements of National Accreditation Board for Hospitals and Healthcare Providers [11] (NABH) as well as National AIDS Control Organization (NACO) guidelines. [7] The World Health Organization (WHO) definition [12] of ADRs was adopted to detect and classify causality of ADRs.

Inclusion and exclusion criteria

HIV-infected patients of either sex who were receiving cART regimens were included and HIV-infected patients treated with "traditional medicines" practiced in India like ayurveda, yoga, naturopathy, unani, siddha and homeopathy were excluded. Study procedure was explained and informed consent was obtained.

Patient characteristics

The study patients were intensively monitored by a clinical pharmacist in collaboration with the clinicians during daily ward rounds and data were collected from in-patient cases notes, treatment charts and laboratory reports to identify the suspected ADRs associated with the use of cART.

Analysis of ADRs

Each suspected ADRs to cART was assessed for its causality by using WHO Probability Scale. [13] ADRs was also assessed for its predictability if literature incidence of any reported ADRs ≥1/100 was considered 'predictable', preventability of ADRs was assessed by Schumock and Thornton criteria, [14] outcome of management, treatment outcome of the reactions, seriousness, number of ADRs reported with cART and duration to onset of ADRs to cART was classified and assessed as per WHO recommendations on the pharmacovigilance of antiretroviral medicines. [15] Suspected ADRs to cART was documented by a senior academic clinical pharmacist from the Department of Pharmacy Practice of the study hospital, where the national pharmacovigilance programs for reporting of ADRs exist.

Data with ADRs to cART (Cases) was compared without ADRs to cART (Control) to understand the pattern of occurrence of ADRs with respect to patient demographics such as gender, age, CD4 + T-cell counts (cells/μl), characteristics of the cART involved, type of treatment, habits, educational status, employment status, duration of use of cART and overall incidence of ADRs to cART was calculated. ADRs to ARV medications were further classified according to system organ classes and codes using WHO adverse reaction terminologies [WHO-ART]. [16] WHO/AIDS Clinical Trail Group (ACTG) criteria of severity were used to grade Anemia. [17],[18]

Statistical analysis

Pearson Chi-square test was used to compare between Cases (with ADRs to cART) and Controls (without ADRs to cART) to find an association between occurrence of ADRs in HIV positive patients receiving cART determined at P < 0.05 by investigating the effects of gender, age, CD4 + T-cell counts (cells/μl), cART treatment regimen, type of treatment, habits, education level, employment and duration of use of cART. Bivariate analysis was used to determine predictors associated with individual ADRs to cART at P < 0.05. All statistical calculation was performed using Statistical Package for Social Sciences (SPSS), version 17.0. A P < 0.05 was considered as statistically significant.

  Results Top

A total of 450 HIV positive patients with cART [329 (73.1%) males and 121 (26.9%) females] were admitted to the hospital during this study period. Out of which {149 (68.7%) males and 68 (31.3%) females} were reported with ADRs to cART (cases). A total of 230 suspected ADRs to antiretroviral medications were reported from 217 patients (cases) during the study period.

Pearson Chi-square test showed a statistically significant association (P < 0.001) of occurrence of ADRs with females, age 41-60 years, CD4 + T-cell counts 350-500 cells/μl;(5/10 × 100 = 50%), compared to ≤350 cells/μl; (209/426 × 100 = 49.06%), Illiterate patients and one to five years of use of cART. ADRs to cART were highest with zidovudine 300 mg + lamivudine 150 mg + nevirapine 200 mg (42.3%; P < 0.001) zidovudine 300 mg + lamivudine 150 mg + efavirenz 600 mg (15.7%; P < 0.001) and tenofovir + emtricitabine + efavirenz (14.2%; P < 0.001). The overall incidence rate of ADRs to cART was 48.2%. Patients' demographic characteristics are shown in [Table 1].

Out of 230 suspected ADRs, WHO causality assessment was Probable in 132 (57.4%) of ADRs. In 181 (78.7%) of the reports, the suspected drug was predictable. In 71 (30.9%) of the reports the reaction was probably preventable and 93 (40.4%) of the reactions were not preventable. The suspected drug was withdrawn for the management of the ADRs in 165 (71.7%) of the reports and symptomatic treatment was instituted in 88 (38.3%) of the ADRs to cART.

In 197 (85.7%) of the ADR reports to cART prolonged the length of hospital stay. Three fatal ADRs were reported. In 30 (13%) of the ADRs was considered to be life-threatening. Among the outcome of ADRs reports, 111 (48.3%) were found to be resolving as at the recorded date. In 65 (28.3%) of the reports, affected patient got resolved from the reactions at the time of evaluation of the ADR report. Patient discharged from study hospital against medical advice of clinicians resulted in 18 (7.8%) of unknown ADRs.
Table 1: Demographic characteristic of patients

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In 63.5% of the reports after "dechallenge" of the suspected antiretroviral medication, definite improvement was documented. In 94% of the reports "No rechallenge" was instituted. After "rechallenge of the suspected antiretroviral medication" recurrence of symptoms positive was observed in 1.3% of the reports and no occurrence of symptoms negative with "rechallenge of the suspected antiretroviral medication" was seen in 1.7%. In majority (95.7%) of the reports, one ADR was suspected from cART at the time of experiencing an ADR. A maximum of three suspected ADRs to cART were reported in a single patient.

In the current study, 91.7% of the reports showed duration to onset of ADRs with cART in ≤365 days. The characteristic details of the ADRs to cART are shown in [Table 2].
Table 2: Characteristic details of the adverse drug reactions to combination ART

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Bivariate analysis revealed that the occurrence of ADRs to antiretroviral medications was significantly associated and predicted with the percentage of occurrence as summarized in [Table 3]: for the following 1) Anemia with zidovudine use (18.3%; P < 0.001), 2) Pancytopenia with zidovudine, lamivudine use (10%; P < 0.001), 3) Hepatotoxicity with nevirapine, efavirenz use (8.2%; P < 0.001), 4) Peripheral neuropathy with stavudine use (6.5%; P < 0.001), 5) Renal failure with tenofovir use (3.7%; P < 0.001) and 6) Maculopapular rash with emtricitabine, tenofovir, efavirenz use (3.4%; P < 0.001). Red blood cell disorders {1210};(30.9%) was found to be most affected system organ class.

The system organ class and [WHO-ART code] most affected was found to be red blood cell disorders {1210}; (30.9%) followed by skin and appendages disorders {0100}; (16.5%). Of the 42 ADRs to zidovudine induced anemia, grade II and grade IV anemia accounted for 27 (64.2%) and 8 (19%) respectively as shown in [Table 3].
Table 3: Adverse drug reactions characteristics of combination antiretroviral therapy to system organ classes and codes [WHO-ART code]

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  Discussion Top

The pharmacovigilance reports of various studies on ADRs to ART cited a predominance of the females over males. This study revealed that males were found to be more susceptible to ADRs to cART. On studying statistics of incidence of ADRs to cART in our study, it was found that females (56.1%, P = 0.040) experienced higher percentage of incidence of ADRs to cART compared to males (45.2%). This result confirms known sex difference in patterns of ADRs to cART, similar to Ighovwerha et al.[19] This may be due to the fact that in our study, female patients who were admitted to the study hospital with CD4 + T-cell counts of 350-500 cells/μl (P < 0.001) had experienced  Stevens-Johnson syndrome More Details and skin rashes due to adverse effects of nevirapine compared with males. This finding is consistent with reports of other studies [20],[21],[22],[23] from other countries with sex difference in ADRs to cART.

In this study, age distribution of 41-60 years in patients with reported ADRs to cART (48.3%, P = 0.001) was similar to studies [24],[25] conducted with similar frequencies in age distribution of patients with ADRs to cART. This may be due to higher number of similar age group patients (52.7%) admitted for HIV treatment during the study period. However, other studies [26],[27],[28] that were carried out reported higher percentage of ADRs to cART in children's and older patients.

The pattern of use of cART regimen observed in the study reflects a private tertiary care teaching hospital perspective. In the present study (3.4%; P = 0.001) of patients experienced maculopapular rash with emtricitabine + tenofovir + efavirenz cART regimen. Maculopapular rash was presented with severe hyperpigmentation and resolved after three weeks of discontinuation of emtricitabine + tenofovir + efavirenz cART regimen similar to findings of studies. [29],[30] where hyperpigmentation with maculopapular rash was confirmed with emtricitabine + tenofovir + efavirenz group.

During this study, change of cART regimen was done in 45.7% due to ADRs. In the study hospital, although physicians prescribe zidovudine based cART regimen to HIV infected positive patients only when hemoglobin levels (Hb) greater than 8g/dl at baseline to avoid the occurrence of zidovudine induced anemia. However, red blood cell disorders (30.9%) are due to zidovudine induced anaemia which accounted for higher incidence (18.3%, P = 0.001). However, after discontinuation of zidovudine therapy to stavudine based cART showed improvement in hemoglobin levels.

Grade II anemia (Hb level 8.0-9.4g/dl) and grade IV anemia (Hb level ≤6.5g/dl) was observed with zidovudine use four weeks after initiation similar to other studies. [31],[32] ADRs to zidovudine-induced anemia (18.3%) were easily predictable with follow-up of Hb levels and complete blood count (CBC) as they were common (incidence ≥1/100 and <1/10) or very common (incidence ≥1/10) similar to study carried by Mehta et al.[25] In most preventable cases of zidovudine-induced anemia, preventive measures for blood transfusion, administration of recombinant human erythropoietin and change to non zidovudine based cART regimen were instituted. Various studies have reported higher incidence of zidovudine-induced anemia in India. [24],[33],[34],[35] However, other studies [36],[37],[38],[39] that carried out in other countries reported low incidence of anemia exclusively in patients on zidovudine based cART regimen.

Exofoliative dermatitis was observed in one patient receiving efavirenz cART and associated with blistering, fever, desquamation and resolved within one month after discontinuation of efavirenz therapy similar to the very recent findings by Zhang et al. [40] The occurrence of hematological ADRs was associated with zidovudine + lamivudine cART regimen with cases of pancytopenia (10%; P = 0.001), hyperbilirubinemia (1.8%), marrow depression, eosinophilia, leucopenia (3.4%; P = 0.001) and neutropenia (1.3) in patients with advanced HIV disease which is similar to other studies [41],[42],[43],[44] that reported with higher incidence of hematological ADRs with zidovudine + lamivudine + nevirapine (68.4%) and zidovudine + lamivudine + efavirez (31.5%) cART regimen.

Renal failure was observed in patients who were on tenofovir based cART regimen. The occurrence of acute renal failure was significantly associated with tenofovir 300 mg + emtricitabine 200 mg + efavirenz 600 mg and tenofovir 300 mg + lamivudine 300 mg + efavirenz 600 mg (3.7%, P = 0.001) cART regimen. In all nine cases of suspected tenofovir induced renal failure, an elevated renal function tests from that of baseline value after four weeks of follow-up was observed and suspected drug "tenofovir" was then discontinued. This is in accordance with published studies. [45],[46],[47],[48],[49] where uses of tenofovir show a variety of pre-renal, renal, and obstructive causes of acute renal failure.

Diarrhea (1.7%) with abdominal pain and bloating was observed in four patients who were on lopinavir/ritonavir based regimen during early treatment. It was observed that due to shorter duration of diarrhea associated with these cART regimens, patients intentionally discontinued taking their ART which leads to medication non-adherence and affected quality of life. During their follow-up visit to hospital, these patients were recommended for the management of diarrhea such as to drink plenty of liquids or Oral dehydration solutions (ORS), dietary modifications like avoiding coffee, spicy food and fatty food while taking cART. Studies [50],[51] reported GI adverse effects like diarrhea, vomiting and nausea are common with all most all protease inhibitors (PIs). This finding are in agreement with Jodie et al.,[52] demonstrating that rates of diarrhea in patients with HIV receiving lopinavir-ritonavir based regimen has less severe, shorter duration of diarrhea compared to other PIs.

Three patients experienced pancreatitis (1.3%) due to ADRs to cART. In one of these three cases, patient was on fixed dose of tenofovir + emtricitabine + lopinavir + ritonavir cART regimen for more than 10 months, developed severe abdominal pain followed by symptoms of nausea and severe vomiting. No medical history of pancreatitis was linked to the use of alcohol, renal illness, gall stones, use of stavudine and no concomitant use of trimethoprim + sulfamethoxazole. An elevated level of serum amylase 185U/L (normal reference range 28-100U/L), serum lipase levels 192U/L (normal reference range 5-80 U/L) and hypertriglyceridemia 392 mg/dl (normal reference range 40-140 mg/dl) was reported. Cause of pancreatitis was suspected with lopinavir 200 mg + ritonavir 50 mg cART regimen. [53] Recent study by Boyle et al., reported that lopinavir and saquinavir had a significant Higher Observed Toxicity Switch Rate (OTSR) than other PIs as does zidovudine compared with other Nucleoside Reverse Transcriptase Inhibitor (NRTIs). [54] This finding supports for de-challenge of lopinavir + ritonavir and switch to other cART. After de-challenge of lopinavir + ritonavir and switch to tenofovir + emtricitabine + efavirenz cART regimen, decreased in the levels of serum amylase and serum lipase levels within few weeks was observed that confirmed lopinavir + ritonavir induced pancreatitis. In this case re-challenge of lopinavir + ritonavir was not attempted to find exact relationship between the lopinavir + ritonavir and the event of pancreatitis. However, a previous study by Anand et al., has reported stavudine-induced pancreatitis followed by lopinavir-ritonavir-induced pancreatitis where they reported pancreatitis can recur with lopinavir-ritonavir in patients with a history of stavudine-induced pancreatitis. [55]

During this study, hepatotoxicity was observed in patients who were on nevirapine or efavirenz cART regimen. A total of (8.2%, P = 0.001) of patients developed severe hepatotoxicity with elevated liver enzyme levels to five times the upper limit of normal, and after discontinuation of nevirapine or efavirenz liver enzyme levels were normal, this findings are similar to a Hossein et al., study [56] where reported similar rates of hepatotoxicity associated with nevirapine and efavirenz use and alcohol intake in patients with cART. Various studies [57],[58],[59],[60] also reported severe hepatotoxicity with nevirapine use, coinfected with Hepatitis C virus (HCV), hepatitis B virus (HBV) and co-administered with PIs.

Nephrolithiasis (0.9%) was observed in two patients who were on Indinavir 400mg for more than six months presented with flank pain associated with haematuria. Additionally these patients also experienced hyperlipidemia induced by Indinavir use. There were no other predisposing factors or contributing factors for the nephrolithiasis other than the use of Indinavir have been identified in the present study. These patients were also advised to take plenty of fluids for 2 to 5 days to increase the clearance of indinavir at the time of discontinuation of Indinavir therapy. On discontinuation of Indinavir therapy patients recovered from the symptoms of flank pain and/or hematuria similar to the findings reported by Lori et al., as described for temporary cessation of Indinavir use, when patients have symptoms consistent with nephrolithiasis, indinavir stones should be suspected with radiographic imaging to reveal obstruction. [61] However, other studies [62],[63],[64] reported Indinavir-associated asymptomatic nephrolithiasis and renal cortex atrophy in pediatric population.

In the present study, Fifteen cases of stavudine induced peripheral neuropathy accounted for (6.5%, P = 0.001). In most of the cases stavudine therapy (40mg) was discontinued. This finding is concurrent with the incidence of stavudine induced peripheral neuropathy in a study carried out by Browne et al.,[65] similar to other studies, [24],[56] peripheral neuropathy were reported in most patients during the first 6 months of stavudine therapy. The patients who experienced vomiting due to zidovudine therapy 13 (5.7) showed that intolerance/toxicity to these adverse effects was the main reason for discontinuation of ART within 4 to 8 weeks of initiation. These findings are in agreement with other studies. [66],[67],[68]

Immune reconstitution inflammatory syndrome (IRIS) was reported with tenofovir + emtricitabine + efavirenz cART regimen and developed opportunistic infections (OIs) of mycobacterium tubercular meningitis with exacerbation of eosinophillic folliculitis due to IRIS. These observations are in agreement with the previously published studies [69],[70],[71] that showed greatest risk for the development of IRIS in a patient infected with HIV after initiation of cART. However, Cabral et al., reported occurrence of IRIS and cerebral toxoplasmosis after the initiation of cART with increased CD4 + T-cell counts and decreased HIV-1 viral loads. [72] In a low income country like India, HIV-1viral load monitoring is not routinely practiced for assessment of onset of systemic inflammatory clinical signs and symptoms of IRIS.

Drug Hypersensitivity Syndrome (DHS) was observed with abacavir + lamivudine + atazanavir + ritonavir cART regimen in about 0.9% of patients on abacavir during six weeks of treatment. In Abacavir induced DHS patients were presented with urticarial rash, abdominal pain dyspnea, hypotension and mouth ulceration. Complete recovery from these adverse effects was seen after four weeks of discontinuation of abacavir. Similar results have been reported from studies [73],[74] on the risk of abacavir induced DHS. Death due to fatal ADRs was reported in three cases of navirapine induced Steven Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN) This is in accordance with published studies where nevirapine induced SJS/TEN has resulted in life threatening fatal ADRs. [75],[76]

Usages of emtricitabine + tenofovir + efavirenz cART regimen in the study hospital were indicated only for HIV infected adult patients who had virological failure for greater than three months with other cART regimen. As per NACO guidelines, [7] tenofovir + lamivudine + efavirenz based cART regimen were used as a second-line ART in patients who developed treatment failure to zidovudine or stavudine based regimen. Emtricitabine is not recommended under the NACO regimen, however private teaching hospitals which are not directly under NACO; practice to use tenofovir + emtricitabine + efavirenz based ART regimen. [77]

As per newer WHO consolidated guidelines 2013 on the use of antiretroviral drugs for treating and preventing HIV infection strongly recommend the use of Tenofovir + lamivudine (or emtricitabine) + efavirenz as a fixed-dose combination with the least adverse effects. [78] However, before initiation of Tenofovir + lamivudine (or emtricitabine) + efavirenz cART regimen risk factors such as underlying renal disease, older age, Body mass index (BMI) <18.5 (or body weight <50kg), untreated diabetes mellitus and hypertension, concomitant use of nephrotoxic drugs or a boosted PIs, history of osteomalacia and osteoporosis should be assessed.

  Conclusion Top

The finding of this study showed that in India, zidovidine based cART regimen predominantly resulted in hematological toxicity while nevirapine/efavirenz based cART regimen resulted in skin and appendages disorders. The finding collectively indicate with increasing reports of ADRs to cART regimens in India, pharmacist and physicians must focus for regular clinical and laboratory monitoring of signals for ADRs.

  Acknowledgments Top

The authors thank the staff of Department of Medicine, Kasturba Hospital, Manipal University Manipal College of pharmaceutical sciences, Manipal University for their assistance and cooperation during the study period.

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  [Table 1], [Table 2], [Table 3]


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