Recognition of possible risk factors for clinically significant drug-drug interactions among Indian people living with HIV receiving highly active antiretroviral therapy and concomitant medications

Abstract

BACKGROUND:

Greatest challenges for clinician is to recognize risk factors for clinically significant drug interactions (CSDIs). There is a lack of awareness about CSDIs among healthcare professionals in India.

OBJECTIVE:

To recognize all possible risk factors for drug-drug interactions (DDIs) and to identify clinically significant drug interactions (CSDIs), the prevalence, pattern of occurrence of DDIs in People Living with HIV (PLW-HIV) receiving highly active antiretroviral therapy (HAART) and concomitant medications.

METHODS:

A retrospective medical record review was carried out by clinical pharmacist with ethics committee approval. Case files of HIV patients receiving HAART with concomitant medications were analyzed for CSDIs using University of Liverpool drug interaction database and CSDIs were classified based on red flag indication (RFI) or contraindicated drug-drug interaction (XDDIs) and orange flag indication (OFI) or DDIs that needs close monitoring. Patients with DDIs (cases) and patients without DDIs (controls) were compared with Chi-square tests. P value <0.05 was considered as statistically significant.

RESULTS:

A total of 240 HIV patients’ cases were screened. Out of which 267 DDIs were reported in 107 patients. Prevalence of DDIs was higher in male 71 (66.4%) compared to female 36 (33.6%). On zero-inflated poisson regression analysis, factors of polypharmacy, opportunistic infections, comorbid condition like Ischemic heart disease, respiratory tract infections, and psychiatric disorder were found to be predictors of high risk factors for DDIs to HAART. Fourteen XDDIs with RFI and two hundred fifty three DDIs with OFI were reported. XDDIs were atazanavir with fluconazole 4 (28.6%), ritonavir with fluconazole 4 (28.6%), nevirapine with rifampicin 2 (14.4%), ritonavir with quetiapine, atazanavir with pantoprazole. Pharmacokinetic DDIs were highest 238 (89.1%). Sixteen DDIs were reported in a single patient. The majority 97 (90.6%) patients had developed ≤5 DDIs, 8 (7.5%) developed six to eleven DDIs. The highest DDIs were reported with efavirenz 49 (18.4%) and zidovudine 44 (16.5%) based HAART regimen.

CONCLUSION:

In India, with the increasing access to HAART usage, Clinician must focus to pay attention to recognize possible risk factors for CSDIs associated with HAART regimen and strictly to avoid “Red Flag Indication combinations” while prescribing so as to prevent CSDIs.

Keywords

Human immunodeficiency virus highly active antiretroviral therapy clinically significant drug interactions risk factors for drug-drug interactions

1 Introduction

Worldwide, Drug-Drug Interactions (DDIs) is the major health concern associated with drug use in elderly patients, longer hospitalization stay and increased number of poly pharmacy (PP) [1]. DDIs are classified into pharmacokinetic and pharmacodynamics interactions. Some of these DDIs are very minor in severity, while some are potentially serious leading to treatment failure and severe in toxicity [2]. Use of Highly Active Antiretroviral Therapy (HAART) in People Living with HIV (PLW-HIV) has dramatically increased the quality of life expectancy. However, in HIV- Seropositive positive patients (HIV-SP), there is an increase in Opportunistic Infections (OIs), comorbid diseases, non-Acquired Immunodeficiency Syndrome (AIDS) related malignancies. Due to these comorbid diseases, a wide range of poly pharmacy are used along with HAART which leads to adverse drug reactions (ADRs) and DDIs [3–5].

In United States of America (USA), [6] 30 to 42% of HIV-SP patients with HAART are associated for clinically significant DDIs, 20–30% in The Netherlands [7] and incidence rate of DDIs was 65.2% in India [8]. Studies have reported association of increased risk for clinically significant drug interactions (CSDIs) in HIV-SP patients were due to increased age and poly pharmacy [9]. Most of the DDIs with HAART were mediated by inhibition or by induction of hepatic drug metabolism. However, several studies [10, 11] on DDIs were focused with HAART and ignoring other concomitant medications, despite the fact that such medications are responsible for possible DDIs with HAART there by results for non-adherence, treatment failure and development of drug resistance. The management of possible DDIs must be taken into consideration during the selection of HAART regimen, along with concomitant medications so as to minimize undesirable DDIs. This study was intended to recognize the possible DDIs, prevalence, and pattern of occurrence, and to identify possible risk factors for DDIs in PLW-HIV receiving HAART and concomitant medications.

2 Methods

A retrospective medical record review was conducted from Kasturba Hospital (South Indian teaching hospital), Manipal, India. The study was approved by the Institutional Ethics Committee. Data were collected from January to December 2014 from In-patients medical records of HIV-SP patients receiving HAART with concomitant medications and were selected, analyzed for DDIs.

HIV-SP patients above 18 years of age were included in the study; and HIV-SP patients who were not on HAART, with chronic renal disease, traditional alternative medicines, pregnant women and out-patients were excluded from the study. In-patients case records was reviewed by a pharm D graduate clinical pharmacist for possible DDIs with HAART with concomitant medications prescribed. The complete drug treatment of these patients was screened from medical records from the day of admission, till day of discharge and follow-ups. All the relevant data were collected from patients’ case records, treatment chart, including the implication of HAART, OIs, comorbid conditions, risk factors, laboratory reports, number of drug prescribed, including demographic details of the patients, viral load and follow-up CD4 T-cell counts. In a suitably designed ‘Individual case record form’ (ICRF) data related to concomitant drugs with dosage and patients’ allergic reactions to food and drugs were noted and documented. University of Liverpool drug interaction database (ULPDIDB) [12] and Micromedex database (MDB) [13] were used for evaluation of DDIs. Additionally, the severity level of the CSDIs were assessed using Stockley’s drug Interactions [14]. As per criteria of ULPDIDB, DDIs were classified based on three indications. 1. If the DDIs is contraindicated [Red Flag Indication (RFI)] or contraindicated drug-drug interactions (XDDIs). 2. If the DDIs needs close monitoring [Orange Flag Indication (OFI)]. 3. If the DDIs has no significant interactions [Green Flag Indication (GFI)] [12]. World Health Organization (WHO) clinical staging of HIV disease in adults, adolescents and children was used to assess the stage of HIV disease [15]. Definition of CSDIs were defined as those drug interactions that needed a dosage adjustment or drug combination that is contraindicated due to its greater potential for adverse clinical effects [9].

2.1 Statistical analysis

The risk factor for the occurrence and prevalence of DDIs were assessed based on two groups. Patients with DDIs (cases) and patients without DDIs (controls) were compared with Chi-square tests. The association between risk factors for DDIs in HIV-SP patients receiving HAART were determined at a P value <0.05 by investigating the age, stages of HIV, Body mass index (BMI), CD4 T-cell counts, comorbid conditions, OIs. Zero-inflated poisson regression was used to assess the influence of these risk factors for development of significant DDIs. All statistical calculations were performed using Statistical Package for Social Sciences (SPSS) version 20. P value <0.05 was considered as statistically significant.

3 Results

During the study, a total of 240 HIV-SP patients with HAART [(males 152 (63.3%), females 88 (36.7%)] were screened from medical case records. Out of which 131 (54.6%) were in the age group of 41 to 59 years and 23 (9.6%) of patients were elderly ≥ 60 years of age. The average age of the HIV-SP patients was found to be 44.72±10.5 years. The majority 139 (57.9%) of patients were presented with BMI of 18.5 to 24.9. Social habits of smoking and alcoholic were 57 (23.8%) and 56 (23.3%) respectively. The CD4 T-cell count in the majority of patients 183 (76.2) was ≤ 200 cell/μl. Stage III HIV diseases was found to be 184 (76.7%). Number of poly pharmacy per prescription excluding HAART regimen ranges from nine to eleven drugs 57 (23.75%). Most of the patients 105 (43.75%) has one comorbid disease. Patient characteristics are shown in Table 1.

Table 1
Demographic details of the patients

Characteristics Number of patients (%)

(n = 240)

Gender

Male 152 (63.3)

Female 88 (36.7)

Age (years)

18 to 40 86 (35.8)

41 to 59 131 (54.6)

≥60 23 (9.6)

BMI (Kg/m²)

<18.5 82 (34.2)

18.5 to 24.9 139 (57.9)

>24.9 19 (7.9)

Smoking

Yes 57 (23.8)

No 183 (76.2)

Alcoholic

Yes 56 (23.3)

No 184 (76.7)

CD4 T-cell count (cells/μl)

≤200 183 (76.2)

>200 57 (23.8)

Stages of HIV

Stage 1 10 (4.1)

Stage 2 46 (19.2)

Stage 3 184 (76.7)

Poly Pharmacy per prescription without HAART regimen

≤8 drugs 138(57.5)

9 to 11 drugs 57(23.8)

≥12 drugs 45(18.7)

Number of Comorbid disease

No comorbidity 57(23.8)

One comorbidity 105(43.7)

>1 comorbidity 78(32.5)

Characteristics	Number of patients (%)
Gender
Male	152 (63.3)
Female	88 (36.7)
Age (years)
18 to 40	86 (35.8)
41 to 59	131 (54.6)
≥60	23 (9.6)
BMI (Kg/m²)
<18.5	82 (34.2)
18.5 to 24.9	139 (57.9)
>24.9	19 (7.9)
Smoking
Yes	57 (23.8)
No	183 (76.2)
Alcoholic
Yes	56 (23.3)
No	184 (76.7)
CD4 T-cell count (cells/μl)
≤200	183 (76.2)
>200	57 (23.8)
Stages of HIV
Stage 1	10 (4.1)
Stage 2	46 (19.2)
Stage 3	184 (76.7)
Poly Pharmacy per prescription without HAART regimen
≤8 drugs	138(57.5)
9 to 11 drugs	57(23.8)
≥12 drugs	45(18.7)
Number of Comorbid disease
No comorbidity	57(23.8)
One comorbidity	105(43.7)
>1 comorbidity	78(32.5)

The comorbid diseases in the majority of HIV-SP patients was respiratory tract infections; 41 (17.1%), followed by anemia; 34 (14.2%), hypertension; 28 (11.7%) and gastritis; 27 (11.2%). Majority of OIs was tuberculosis; 76 (31.7%) followed by candidiasis; 41 (17.1) and 98 (40.8%) of patients experienced at least one OIs during their previous stay in hospital. Pattern of comorbid diseases and occurrence of opportunistic infections are shown in Table 2.

Table 2

Pattern of comorbid diseases and occurrence of opportunistic infections

Comorbid Conditions	Number of patients (%)
	(n = 240)
Respiratory tract infections
Yes	41 (17.1)
No	199 (82.9)
Anaemia
Yes	34 (14.2)
No	206 (85.8)
Hypertension
Yes	28 (11.7)
No	212 (88.3)
Gastritis
Yes	27 (11.2)
No	213 (88.8)
Diabetes Mellitus
Yes	23 (9.6)
No	217 (90.4)
Renal Failure
Yes	18 (7.5)
No	222 (92.5)
Significant bacterial infections
Yes	17 (7.1)
No	223 (92.9)
Hepatitis
Yes	13 (5.4)
No	227 (94.6)
Seizures
Yes	11 (4.6)
No	229 (95.4)
Thyroid disorders
Yes	8 (3.3)
No	232 (96.7)
Psychiatric disorders
Yes	8 (3.3)
No	232 (96.7)
Cardiovascular disease
Yes	7 (2.9)
No	233 (97.1)
Alcoholic Liver Disease
Yes	6 (2.5)
No	234 (97.5)
Ischemic heart disease
Yes	4 (1.7)
No	236 (98.3)
Deep vein thrombosis
Yes	2 (0.8)
No	238 (99.2)
Pancreatitis
Yes	1 (0.4)
No	239 (99.6)
Opportunistic Infections (OIs)
Number of OIs
No OIs	112 (46.7)
One OIs	98 (40.8)
Two OIs	25(10.4)
Three OIs	5 (2.1)
Tuberculosis
Yes	76 (31.7)
No	164 (68.3)
Candidiasis
Yes	41 (17.1)
No	199 (82.9)
Herpes zoster infection
Yes	15 (6.2)
No	225 (93.8)
Pneumocystis Carinii pneumonia (PCP)
Yes	11 (4.6)
No	229 (95.4)
Tubercular meningitis
Yes	5 (2.1)
No	235 (97.9)
Cytomegaloviral disease
Yes	3 (1.2)
No	237 (98.8)
Cryptococcal meningitis
Yes	3 (1.2)
No	237 (98.8)
Cryptococcalsporidiosis
Yes	2 (0.8)
No	238 (99.2)

During the study, 267 DDIs to HAART were reported in 107 patients. Prevalence of DDIs was higher in male population 71 (66.4%) compared to female 36 (33.6%). The majority 60 (56.1) of DDIs were observed in 41 to 59 years of age followed by 18 to 40 years; 36 (33.6%) and 60 years of age and above patients were also included. The DDIs in smoker 34 (31.8%) and alcoholic were 33 (30.8%). The baseline CD4 T-cell count in the majority of patients with DDIs 84 (78.5) was ≤ 200 cell/μl. DDIs were higher in stage III 85 (79.4%), followed by stage II 18 (16.8%) and stage I, 4 (3.8) of HIV diseases. Most 28 (26.2%) of patients who developed DDIs were presented with nine to eleven drugs in their prescription excluding standard HAART regimen and reported with at least one comorbid disease 35 (32.7). DDIs associated with comorbid diseases was respiratory tract infections; 26 (24.3%), followed by hypertension; 18 (16.8%), diabetes mellitus; 15 (14%); and anemia 13 (12.1%). Patients with DDIs were much associated with OIs of tuberculosis; 35 (32.7%) followed by candidiasis; 20 (18.7). In our study, 46 (42.9%) of patients developed one DDIs and 25 (23.3%) developed two DDIs. In a single patient maximum of 16 DDIs were reported. The majority 97 (90.6%) patients had developed ≤5 DDIs, 8 (7.5) developed six to eleven DDIs and 2 (1.86%) patients developed ≥12 DDIs. Characteristics of patients with DDIs are shown in Table 3.

Table 3

Characteristic of patients with Drug-Drug Interactions

Characteristics	Number of patients
	with DDIs (%) (n = 107)
Gender
Male	71 (66.4)
Female	36 (33.6)
Age (years)
18 to 40	36 (33.6)
41 to 59	60 (56.1)
≥60	11 (10.3)
BMI (Kg/m²)
<18.5	39 (36.5)
18.5–24.9	56 (52.3)
>24.9	12 (11.2)
Smoking
Yes	34 (31.8)
No	73 (68.2)
Alcoholic
Yes	33 (30.8)
No	74 (69.2)
CD4 T- cell count (cells/μl)
≤200	84 (78.5)
>200	23 (21.5)
Stages of HIV
Stage 1	4 (3.8)
Stage 2	18 (16.8)
Stage 3	85 (79.4)
Poly Pharmacy per prescription without HAART regimen
≤8 drugs	53 (49.5)
9 to 11 drugs	28 (26.2)
≥12 drugs	26 (24.3)
Number of Comorbid disease
No comorbidity	22 (20.6)
1 comorbidity	35 (32.7)
≥2 comorbidity	50 (46.7)
Comorbid Conditions
Respiratory tract infections
Yes	26 (24.3)
No	81 (75.7)
Hypertension
Yes	18 (16.8)
No	89 (83.2)
Diabetes Mellitus
Yes	15 (14.0)
No	92 (86.0)
Anemia
Yes	13 (12.1)
No	94 (87.9)
Bacterial infections
Yes	11 (10.3)
No	96 (89.7)
Renal Failure
Yes	11 (10.3)
No	96 (89.7)
Gastritis
Yes	10 (9.3)
No	97 (90.7)
Seizures
Yes	9 (8.4)
No	98 (91.6)
Psychiatric disorder
Yes	8 (7.5)
No	99 (92.5)
Cardiovascular disease
Yes	7 (6.5)
No	100 (93.5)
Thyroid disorders
Yes	6 (5.6)
No	101 (94.4)
Hepatitis
Yes	6 (5.6)
No	101 (94.4)
Ischemic heart disease
Yes	4 (3.7)
No	103 (96.3)
Alcoholic liver disease
Yes	3 (2.8)
No	104 (97.2)
Deep vein thrombosis
Yes	2 (1.9)
No	105 (98.1)
Opportunistic Infections (OIs)
Tuberculosis
Yes	35 (32.7)
No	72 (67.3)
Candidiasis
Yes	20 (18.7)
No	87 (81.3)
Pneumocystis Carinii pneumonia
Yes	10 (9.3)
No	97 (90.7)
Herpes zoster infection
Yes	7 (6.5)
No	100 (93.5)
Toxoplasmosis
Yes	5 (4.7)
No	102 (95.3)
Tubercular meningitis
Yes	3 (2.8)
No	104 (97.2)
Cytomegaloviral disease
Yes	2 (1.9)
No	105 (98.1)
Cryptococcalsporidiosis
Yes	2 (1.9)
No	105(98.1)
Cryptococcal meningitis
Yes	1 (0.9)
No	106 (99.1)
Maximum number of DDIs
≤5 DDIs	97 (90.6)
6 to 11 DDIs	8 (7.5)
≥12 DDIs	2 (1.9)

During the study, 267 DDIs to HAART and concomitant medications were observed in 107 patients using Liverpool data and majority of DDIs were of OFI 253 (94.8%) and RFI 14 (5.2%). The prevalence of pharmacokinetic DDIs was 238 (89.1%) and pharmacodynamics DDIs was 29 (10.9%). The prevalence of DDIs was higher in male 178 (66.7%) compared to female 89 (33.3%). The majority of DDIs were reported between 41 to 59 years of age. Most (49.4%) of number of DDIs reported were receiving greater than eight other medications excluding standard HAART regimen. Prevalence of DDIs was higher with HAART regimen of lamivudine+zidovudine+nevirapine (29.2%) and lowest with tenofovir+emtricitabine+nevirapine (0.4%). Assessment of drug-drug interactions as per Liver pool are summarized in Table 4.

Table 4

Assessment of drug-drug interactions (Liverpool)

Characteristics	Number of DDIs (%)
	(n = 267)
Liverpool database
Orange Flag Indication	253 (94.8)
Red Flag Indication	14 (5.2)
Types of DDIs
Pharmacokinetic DDIs	238 (89.1)
Pharmacodynamic DDIs	29 (10.9)
Gender
Male	178 (66.7)
Female	89 (33.3)
Age (years)
18 to 40	81 (30.34)
41 to 59	152 (56.93)
≥60	34 (12.73)
Poly Pharmacy per prescription without HAART regimen
≤8 drugs	132 (49.41)
9 to 11 drugs	75 (28.09)
≥12 drugs	60 (22.5)
CD4 T- cell count (cells/μl)
≤200	215 (80.5)
>200	52 (19.5)
Number of Comorbid disease
No comorbidity	50 (18.8)
1 comorbidity	78 (29.2)
≥2 comorbidity	139 (52)
HAART Regimens
Lamivudine + Zidovudine + Nevirapine	78 (29.2)
Tenofovir + Emtricitabine + Efavirenz	63 (23.6)
Tenofovir + Emtricitabine + Atazanavir + Ritonavir	31 (11.6)
Lamivudine + Tenofovir + Efavirenz	20 (7.5)
Lamivudine + Stavudine + Nevirapine	19 (7.2%)
Lamivudine + Zidovudine + Efavirenz	16 (6.0%)
Tenofovir + Lamivudine + Nevirapine	8 (3.0%)
Lamivudine + Tenofovir + Lopinavir + Ritonavir	8 (3.0%)
Darunavir + Ritonavir + Lamivudine + Zidovudine	7 (2.6%)
Lamivudine + Zidovudine + Lopinavir + Ritonavir	5 (1.9%)
Atazanavir + Ritonavir + Abacavir	4 (1.5%)
Lamivudine + Stavudine + Efavirenz	3 (1.1%)
Atazanavir + Ritonavir + Lamivudine + Zidovudine	2 (0.7%)
Atazanavir + Ritonavir + Tenofovir + Lamivudine	2 (0.7%)
Tenofovir + Emtricitabine + Nevirapine	1 (0.4%)

Of 267 DDIs to HAART 136 DDIs were able to be analyzed according to MDB. Of the remaining 131 DDIs were excluded because of lack of information’s for DDIs in MDB. Most of the time of onset of DDIs was delayed in nature 87 (64%), followed by not specified 40 (29.4) and very few are rapid in action 9 (6.6%). Severity of DDIs were minor (44.9%), major 39 (28.6%) and moderate in 36 (26.5%). In most of the DDIs, documentation was ‘probable’ (78.7%) followed ‘established’ by 28 (20.6%). Significance rating of possible DDIs was Level-3, 61 (44.9%), followed by Level-1, 42 (30.9%) and Level-2, 32 (23.5%). Assessment of drug-drug interactions (as per MDB) are shown in Table 5.

Table 5

Assessment of drug-drug interactions (Micromedex)

Characteristics			Number of DDI (%) (n = 136)
Time of Onset
Rapid			9 (6.6)
Delayed			87 (64)
Not specified			40 (29.4)
Severity
Major			39 (28.6)
Moderate			36 (26.5)
Minor			61 (44.9)
Documentation
Established			28 (20.6)
Probable			107 (78.7)
Unlikely			1 (0.7)
Significance rating
Level-1	Major	Suspected or greater	42 (30.9)
Level-2	Moderate	Suspected or greater	32 (23.5)
Level-3	Minor	Suspected or greater	61 (44.9)
Level-5	Minor/any	Possible/Unlikely	1 (0.7)

Influential risk factors for development of DDIs was seen with Ischemic heart disease (p = 0.025), Diabetes mellitus (p = 0.036), cardiovascular attacks (p = 0.003), hypertension (p = 0.026), respiratory tract infections (p = 0.008) and psychiatric disorder (p = 0.001) and pneumocystis carini pneumonia (p = 0.002). A couple of factors such as gender (p = 0.723), age (p = 0.805), thyroid disorder (p = 0.078) were not significantly associated with DDIs. Possible risk factors for DDIs are shown in Table 6.

Table 6

Risk factors for drug-drug interactions in HIV positive patients receiving HAART

Risk Factors	Number of patients (%)		p-value
	Patients with DDIs	Patients without DDIs
	(n = 107)	(n = 133)
Gender
Male	71 (66.4)	81 (61)	0.723
Female	36 (33.6)	52 (39)
Age (years)
18 to 40	36 (33.6)	50 (37.6)	0.805
41 to 59	60 (56.1)	71 (53.4)
≥60	11 (10.3)	12 (9)
BMI (Kg/m²)
<18.5	39 (36.5)	43 (32.3)	0.136
18.5 to 24.9	56 (52.3)	83 (62.4)
>24.9	12 (11.2)	7 (5.3)
CD4 T- cell count (cells/μl)
≤200	84 (78.5)	99 (74.4)	0.462
>200	23 (21.5)	34 (25.6)
Stages of HIV
Stage 1	4 (3.8)	6 (4.5)	0.660
Stage 2	18 (16.8)	28 (21.1)
Stage 3	85 (79.4)	99 (74.4)
Comorbid Diseases
Respiratory tract infections
Yes	26 (24.3)	15 (11.3)	0.008
No	81 (75.7)	118 (18.7)
Hypertension
Yes	18 (16.8)	10 (7.5)	0.026
No	89 (83.2)	123 (92.5)
Diabetes Mellitus
Yes	15 (14.0)	8 (6.0)	0.036
No	92 (86.0)	125 (94.0)
Anemia
Yes	13 (12.1)	21 (15.8)	0.422
No	94 (87.9)	112 (84.2)
Significant bacterial infection
Yes	11 (10.3)	6 (4.5)	0.083
No	96 (89.7)	127 (95.5)
Renal failure
Yes	11 (10.3)	7 (5.3)	0.142
No	96 (89.7)	126 (94.7)
Psychiatric disorder
Yes	8 (7.5)	0 (0)	0.001
No	99 (92.5)	133 (100)
Cardiovascular diseases
Yes	7 (6.5)	0 (0.0)	0.003
No	100 (93.5)	133 (100)
Thyroid disorder
Yes	6 (5.6)	2 (1.5)	0.078
No	101 (94.4)	131 (98.5)
Hepatitis
Yes	6 (5.6)	7 (5.3)	0.907
No	101 (94.4)	126 (94.7)
Ischemic heart disease
Yes	4 (3.7)	0 (0.0)	0.025
No	103 (96.3)	133 (100)
Deep vein thrombosis
Yes	2 (1.9)	0 (0.0)	0.113
No	105 (98.1)	133 (100)
Opportunistic Infections (OIs)
Tuberculosis (TB)
Yes	35 (32.7)	41 (30.8)	0.477
No	72 (67.3)	92 (69.2)
Candidiasis
Yes	20 (18.7)	21 (15.8)	0.553
No	87 (81.3)	112 (84.2)
Pneumocystis Carinii pneumonia
Yes	10 (9.3)	1 (0.8)	0.002
No	97 (90.7)	132 (99.2)
Herpes zoster infection
Yes	7 (6.5)	8 (6)	0.867
No	100 (93.5)	125 (94)
Toxoplasmosis
Yes	5 (4.7)	2 (1.5)	0.147
No	102 (95.3)	131 (98.5)
TB meningitis
Yes	3 (2.8)	2 (1.5)	0.483
No	104 (97.2)	131 (98.5)
Cryptococcalsporidiasis
Yes	2 (1.9)	0 (0)	0.357
No	105 (98.1)	133(100)
Cryptococcal viral infection
Yes	2 (1.9)	1 (0.8)	0.439
No	105 (98.1)	132 (99.2)
Cryptococcal meningitis
Yes	1 (0.9)	2 (1.5)	0.693
No	106 (99.1)	131 (98.5)

The highest number of DDIs were reported with efavirenz based HAART combinations 49 (18.4%) followed by zidovudine based HAART 44 (16.5%) (Table 7). CSDIs with PIs and concomitant medications were reported in (n = 44) number of DDIs. HAART regimen much associated for CSDIs with PIs were tenofovir+emtricitabibe+atazanavir+ritonavir. CSDIs with PIs based interactions includes atazanavir +fluconazole 4 (8.85%), ritonavir+ fluconazole 4 (8.85%), ritonavir + quetiapine, lopinavir+ quetiapine, atazanavir + lithium. The drug interactions with PIs are shown in Table 8. Out of 267 DDIs, 14 XDDIs were reported with RFI and 253 DDIs were reported with OFI which needs close monitoring. Medication classes significantly associated for XDDIs were atazanavir with fluconazole 4 (29%), ritonavir with fluconazole 4 (29%), nevirapine with rifampicin 2 (14.3%), atazanavir with pantoprazole 1 (7.1%) and ritonavir with quetiapine 1 (7.1%) (Table 9). General management of DDIs are shown in Table 10. Among 267 DDIs, antiretroviral drug class associated were Nucleoside reverse transcriptase inhibitors (NRTIs), n = 135, (50.6%), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) n = 88, (32.9%), and Protease Inhibitors (PIs) n = 44, (16.5%) (Fig. 1).

Fig.1

Antiretroviral associated with drug-drug interactions. NRTIs: Nucleoside Reverse Transcriptase Inhibitors; NNRTIs: Non-Nucleoside Reverse Transcriptase Inhibitors; PIs: Protease Inhibitors.

Table 7

Drug interactions to anti-retroviral combinations

Highly active antiretroviral therapy combinations	Interacting drug	Number of Interactions (%)
		(n = 267)
Lamivudine + Zidovudine + Efavirenz	Efavirenz	49 (18.3)
Tenofovir + Emtricitabine + Efavirenz
Lamivudine + Tenofovir + Efavirenz
Lamivudine + Stavudine + Efavirenz
Lamivudine + Zidovudine + Efavirenz	Zidovudine	44 (16.5)
Lamivudine + Zidovudine + Nevirapine
Lamivudine + Zidovudine + Lopinavir + Ritonavir
Atazanavir + Ritonavir + Lamivudine + Zidovudine
Darunavir + Ritonavir + Lamivudine + Zidovudine
Lamivudine + Zidovudine + Nevirapine	Lamivudine	42 (15.7)
Lamivudine + Zidovudine + Efavirenz
Lamivudine + Tenofovir + Efavirenz
Lamivudine + Stavudine + Nevirapine
Lamivudine + Tenofovir + Lopinavir + Ritonavir
Tenofovir + Lamivudine + Nevirapine
Atazanavir + Ritonavir + Lamivudine + Zidovudine
Darunavir + Ritonavir + Lamivudine + Zidovudine
Lamivudine + Zidovudine + Nevirapine	Nevirapine	39 (14.6)
Lamivudine + Stavudine + Nevirapine
Tenofovir + Lamivudine + Nevirapine
Tenofovir + Emtricitabine + Efavirenz	Emtricitabine	31 (11.6)
Tenofovir + Emtricitabine + Atazanavir + Ritonavir
Tenofovir + Emtricitabine + Nevirapine
Tenofovir + Emtricitabine + Atazanavir + Ritonavir	Ritonavir	20 (7.5)
Lamivudine + Tenofovir + Lopinavir + Ritonavir
Atazanavir + Ritonavir + Tenofovir + Lamivudine
Atazanavir + Ritonavir + Abacavir
Lamivudine + Zidovudine + Lopinavir + Ritonavir
Darunavir + Ritonavir + Lamivudine + Zidovudine
Tenofovir + Emtricitabine + Atazanavir + Ritonavir	Atazanavir	17 (6.4)
Atazanavir + Ritonavir + Tenofovir + Lamivudine
Atazanavir + Ritonavir + Abacavir
Tenofovir + Emtricitabine + Efavirenz	Tenofovir	11 (4.1)
Tenofovir + Emtricitabine + Atazanavir + Ritonavir
Tenofovir + Lamivudine + Nevirapine
Lamivudine + Stavudine + Efavirenz	Stavudine	7 (2.6)
Lamivudine + Stavudine + Nevirapine
Lamivudine + Tenofovir + Lopinavir + Ritonavir	Lopinavir	5 (1.9)
Lamivudine + Zidovudine + Lopinavir + Ritonavir
Darunavir + Ritonavir + Lamivudine + Zidovudine	Darunavir	2 (0.8)

Table 8

Drug interactions with Protease Inhibitors

HAART Regimen	Frequency of	Protease	Interacting	Number of DDIs (%)	Liverpool Flag
	HAART Regimen	Inhibitors	Drug	(n = 44)	Indication
	associated with
	DDIs
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	4	Atazanavir	Fluconazole	4 (8.85)	Red Indication
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	4	Ritonavir	Fluconazole	4 (8.85)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Atazanavir	Lithium	2 (4.5)	Orange Indication
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Atazanavir	Olanzapine	2 (4.5)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Amitriptyline	2 (4.5)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Amitriptyline
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Ritonavir	Olanzapine	2 (4.5)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Tamsulosin	2 (4.5)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Ritonavir	Tamsulosin
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Ritonavir	Quetiapine	1 (2.3)	Red Indication
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Lopinavir	Quetiapine	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Pantoprazole	1 (2.3)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Zolpidem	1 (2.3)	Orange Indication
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Phenytoin	1 (2.3)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Mirtazapine	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Methyl Prednisolone	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Amlodipine	1 (2.3)
Atazanavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Chlordiazepoxide	1 (2.3)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Clonazepam	1 (2.3)
Atazanavir+Ritonavir+Abacavir	1	Ritonavir	Dutasteride	1 (2.3)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Escitalopram	1 (2.3)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Amitriptyline	1 (2.3)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Clonazepam	1 (2.3)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Escitalopram	1 (2.3)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Lopinavir	Tamsulosin	1 (2.3)	Orange Indication
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Darunavir	Mirtazapine	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Ranitidine	1 (2.3)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Darunavir	Zolpidem	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Amlodipine	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Amitryptyline	1 (2.3)
Atazanavir+Ritonavir+Tenofovir+Lamivudine	1	Atazanavir	Chlordiazepoxide	1 (2.3)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Dutasteride	1 (2.3)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Methyl Prednisolone	1 (2.3)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Tamsulosin	1 (2.3)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Phenytoin	1 (2.3)

Table 9

Antiretroviral most commonly associated with drug to drug interactions

Highly active antiretroviral therapy	Frequency of	Index	Interacting	Number of	Liverpool Flag
combinations	HAART Regimen	Drug	Drug	DDIs (%)	Indication
	associated with DDIs			Red flag (n = 14),
				Orange flag (n = 253)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	4	Atazanavir	Fluconazole	4 (28.6)	Red Indication
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	4	Ritonavir	Fluconazole	4 (28.6)
Lamivudine+Zidovudine+Nevirapine	2	Nevirapine	Rifampicin	2 (14.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Dexamethasone	1 (7.1)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Ritonavir	Quetiapine	1 (7.1)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Lopinavir	Quetiapine	1 (7.1)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Pantoprazole	1 (7.1)
Lamivudine+Zidovudine+Nevirapine	20	Lamivudine	Cotrimoxazole	37 (14.6)	Orange Indication
Lamivudine+Tenofovir+Efavirenz	6	Lamivudine	Cotrimoxazole
Lamivudine+Stavudine+Nevirapine	3	Lamivudine	Cotrimoxazole
Tenofovir+Lamivudine+Nevirapine	3	Lamivudine	Cotrimoxazole
Lamivudine+Zidovudine+Efavirenz	1	Lamivudine	Cotrimoxazole
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lamivudine	Cotrimoxazole
Atazanavir+Ritonavir+Lamivudine+Zidovudine	1	Lamivudine	Cotrimoxazole
Darunavir+Ritonavir+Lamivudine+Zidovudine	2	Lamivudine	Cotrimoxazole
Tenofovir+Emtricitabine+Efavirenz	25	Emtricitabine	Cotrimoxazole	29 (11.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	3	Emtricitabine	Cotrimoxazole
Tenofovir+Emtricitabine+Nevirapine	1	Emtricitabine	Cotrimoxazole
Lamivudine+Zidovudine+Nevirapine	19	Zidovudine	Cotrimoxazole	22 (8.7)
Lamivudine+Zidovudine+Efavirenz	1	Zidovudine	Cotrimoxazole
Atazanavir+Ritonavir+Lamivudine+Zidovudine	1	Zidovudine	Cotrimoxazole
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Zidovudine	Cotrimoxazole
Tenofovir+Emtricitabine+Efavirenz	3	Efavirenz	Albendazole	8 (3.2)
Lamivudine+Tenofovir+Efavirenz	5	Efavirenz	Albendazole
Lamivudine+Zidovudine+Nevirapine	6	Zidovudine	Fluconazole	6 (2.3)
Lamivudine+Zidovudine+Nevirapine	5	Nevirapine	Fluconazole	6 (2.3)	Orange Indication
Tenofovir+Lamivudine+Nevirapine	1	Nevirapine	Fluconazole
Lamivudine+Zidovudine+Efavirenz	4	Zidovudine	Rifampicin	5 (1.9)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Rifampicin
Tenofovir+Lamivudine+Nevirapine	1	Nevirapine	Methyl Prednisolone	5 (1.9)
Lamivudine+Stavudine+Nevirapine	1	Nevirapine	Methyl Prednisolone
Lamivudine+Zidovudine+Nevirapine	3	Nevirapine	Methyl Prednisolone
Lamivudine+Stavudine+Nevirapine	5	Stavudine	Cotrimoxazole	5 (1.9)
Tenofovir+Emtricitabine+Efavirenz	4	Efavirenz	Glimiperide	4 (1.6)
Tenofovir+Emtricitabine+Efavirenz	4	Efavirenz	Phenytoin	4 (1.6)
Lamivudine+Zidovudine+Efavirenz	2	Zidovudine	Acetaminophen	3 (1.2)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Acetaminophen
Lamivudine+Zidovudine+Nevirapine	3	Nevirapine	Atorvastatin	3 (1.2)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Clonazepam	3 (1.2)
Lamivudine+Stavudine+Nevirapine	2	Nevirapine	Clonazepam
Lamivudine+Stavudine+Nevirapine	3	Nevirapine	Sildenafil	3 (1.2)
Tenofovir+Emtricitabine+Efavirenz	3	Tenofovir	Valaciclovir	3 (1.2)
Lamivudine+Tenofovir+Efavirenz	2	Lamivudine	Ofloxacin	3 (1.2)
Lamivudine+Zidovudine+Nevirapine	1	Lamivudine	Ofloxacin
Tenofovir+Emtricitabine+Efavirenz	3	Efavirenz	Venlafaxine	3 (1.2)
Lamivudine+Zidovudine+Efavirenz	2	Efavirenz	Amlodipine	3 (1.2)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Amlodipine
Tenofovir+Emtricitabine+Efavirenz	3	Efavirenz	Clonazepam	3 (1.2)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Escitalopram	3 (1.2)
Tenofovir+Emtricitabine+Efavirenz	2	Efavirenz	Escitalopram
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Atazanavir	Lithium	2 (0.8)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Atazanavir	Olanzapine	2 (0.8)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Emtricitabine	Lithium	2 (0.8)
Lamivudine+Stavudine+Efavirenz	2	Stavudine	Dapsone	2 (0.8)
Tenofovir+Emtricitabine+Efavirenz	2	Efavirenz	Alprazolam	2 (0.8)
Tenofovir+Emtricitabine+Efavirenz	2	Efavirenz	Atorvastatin	2 (0.8)
Tenofovir +Emtricitabine+Efavirenz	1	Efavirenz	Methyl Prednisolone	2 (0.8)
Lamivudine+Zidovudine+Efavirenz	1	Efavirenz	Methyl Prednisolone	Orange Indication
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Prazosin	2 (0.8)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Prazosin
Lamivudine+Zidovudine+Efavirenz	1	Efavirenz	Rifampicin	2 (0.8)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Rifampicin
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Warfarin	2 (0.8)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Warfarin
Tenofovir+Lamivudine+Nevirapine	1	Lamivudine	Levofloxacin	2 (0.8)
Lamivudine+Zidovudine+Efavirenz	1	Lamivudine	Levofloxacin
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Amitriptyline	2 (0.8)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Amitriptyline
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Ritonavir	Olanzapine	2 (0.8)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Tamsulosin	2 (0.8)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Ritonavir	Tamsulosin
Tenofovir+Emtricitabine+Efavirenz	2	Tenofovir	Aspirin	2 (0.8)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	2	Tenofovir	Lithium	2 (0.8)
Lamivudine+Stavudine+Nevirapine	1	Nevirapine	Alprazolam	2 (0.8)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Alprazolam
Lamivudine+Stavudine+Nevirapine	2	Nevirapine	Escitalopram	2 (0.8)
Tenofovir+Lamivudine+Nevirapine	1	Nevirapine	Mirtazapine	2 (0.8)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Mirtazapine
Lamivudine+Zidovudine+Nevirapine	2	Nevirapine	Zolpidem	2 (0.8)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Pyrazinamide	2 (0.8)
Lamivudine+Zidovudine+Efavirenz	1	Zidovudine	Pyrazinamide
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Valproic acid	1 (0.4)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Zidovudine	Quitiapine	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Phenytoin	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Ganciclovir	1 (0.4)
Lamivudine+Zidovudine+Efavirenz	1	Zidovudine	Dapsone	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Zidovudine	Clarithromycin	1 (0.4)
Lamivudine+Stavudine+Nevirapine	1	Nevirapine	Amlodipine	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Domperidone	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Clopidogrel	1 (0.4)	Orange Indication
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Levofloxacin	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Phenytoin	1 (0.4)
Lamivudine+Stavudine+Nevirapine	1	Nevirapine	Prazosin	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Venlafaxine	1 (0.4)
Lamivudine+Zidovudine+Nevirapine	1	Nevirapine	Clarithromycin	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Tenofovir	Acyclovir	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Tenofovir	Ganciclovir	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Tenofovir	Diclofenac	1 (0.4)
Tenofovir+Lamivudine+Nevirapine	1	Tenofovir	Furosemide	1 (0.4)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Zolpidem	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Phenytoin	1 (0.4)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Mirtazapine	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Methyl Prednisolone	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Ritonavir	Amlodipine	1 (0.4)
Atazanavir+Ritonavir+Lamivudine+Zidovudine	1	Ritonavir	Chlordiazepoxide	1 (0.4)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Clonazepam	1 (0.4)
Atazanavir+Ritonavir+Abacavir	1	Ritonavir	Dutasteride	1 (0.4)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Ritonavir	Escitalopram	1 (0.4)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Amitriptyline	1 (0.4)
Lamivudine +Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Clonazepam	1 (0.4)
Lamivudine+Tenofovir+Lopinavir+Ritonavir	1	Lopinavir	Escitalopram	1 (0.4)
Lamivudine+Zidovudine+Lopinavir+Ritonavir	1	Lopinavir	Tamsulosin	1 (0.4)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Darunavir	Mirtazapine	1 (0.4)
Darunavir+Ritonavir+Lamivudine+Zidovudine	1	Darunavir	Zolpidem	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Acenocoumarol	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Diclofenac	1 (0.4)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Domperidone	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Glipizide	1 (0.4)
Tenofovir+Stavudine+Efavirenz	1	Efavirenz	Ibuprofen	1 (0.4)
Lamivudine+Zidovudine+Efavirenz	1	Efavirenz	Primaquine	1 (0.4)
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Rifabutin	1 (0.4)	Orange Indication
Tenofovir+Emtricitabine+Efavirenz	1	Efavirenz	Sildenafil	1 (0.4)
Lamivudine+Tenofovir+Efavirenz	1	Efavirenz	Zolpidem	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Amlodipine	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Amitryptyline	1 (0.4)
Atazanavir+Ritonavir+Tenofovir+Lamivudine	1	Atazanavir	Chlordiazepoxide	1 (0.4)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Dutasteride	1 (0.4)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Methyl Prednisolone	1 (0.4)
Atazanavir+Ritonavir+Abacavir	1	Atazanavir	Tamsulosin	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Phenytoin	1 (0.4)
Tenofovir+Emtricitabine+Atazanavir+Ritonavir	1	Atazanavir	Ranitidine	1 (0.4)

Table 10

Management of drug interactions

Index drug	Interacting drug	Effect	Mechanism	Management
Efavirenz	Acenocoumarol	Plasma concentrations and effects of acenocoumarol are potentially increased or decreased by efavirenz.	Effect the metabolism of acenocoumarol.	Dose adjustment of acenocoumarol may be required
Zidovudine	Acetaminophen	Neutropenia, acetaminophen toxicity	Unknown	Alternate therapy with aspirin, ibuprofen
				Monitor LFT, WBC
Tenofovir	Acyclovir	Increased serum concentration of tenofovir and/or acyclovir	Competition for active tubular secretion leading to decreased renal clearance	Monitor for toxicity of both the drugs like dizziness, diarrhoea etc.
Efavirenz	Alprazolam	Decreased alprazolam exposure	Induction of alprazolam metabolism	Monitor clinical effect and withdrawal symptoms
Nevirapine	Alprazolam	Decreased alprazolam exposure	Induction of alprazolam metabolism	Monitor clinical effect and withdrawal symptoms
Lopinavir	Amitriptylline	Increased amitriptyline concentration	Decreased amitriptyline metabolism	Monitor for amitryptilline toxicity like sedation, arrhythmias etc.
Ritonavir	Amitriptylline	Increased amitriptylline concentration	Decreased amitriptyline metabolism	Monitor for amitryptilline toxicity like sedation, arrhythmias etc.
Atazanavir	Amitriptylline	Increased amitriptylline concentration	Decreased amitriptyline metabolism	Monitor for amitryptilline toxicity like sedation, arrhythmias etc.
Atazanavir	Amlodipine	Increased risk of cardiotoxicity (Prolonged PR interval)	Inhibition of metabolism of amlodipine &PR interval prolongation	Monitor ECG abnormalities
Efavirenz	Amlodipine	Decreased amlodipine concentration	Induction of amlodipine metabolism	Monitor clinical effect and increase the dose if needed
Nevirapine	Amlodipine	Decreased amlodipine concentration	Induction of amlodipine metabolism	Monitor clinical effect and increase the dose if needed
Ritonavir	Amlodipine	Increased amlodipine concentration	Inhibition of amlodipine metabolism	Monitor for adverse effects like dizziness, abnormal heart rhythm, loss of consciousness
Tenofovir	Aspirin	Increased risk of nephrotoxicity	Competition for renal excretion	Monitor renal function adequately
Efavirenz	Atorvastatin	Decreased serum concentration of atorvastatin	Induction of atorvastatin metabolism	Cholesterol levels to be monitored. Dosage adjustments to be needed
Nevirapine	Atorvastatin	Decreased atorvastatin concentration	Induction of atorvastatin metabolism	Cholesterol levels to be monitored. Dosage adjustments to be needed
Atazanavir	Chlordiazepoxide	Increased activity of chlordiazepoxide	Inhibition of cytochrome P450	Monitor for increased effects of chlordiazepoxide
Ritonavir	Chlordiazepoxide	Increased activity of chlordiazepoxide	Inhibition of cytochrome P450	Monitor for increased effects of chlordiazepoxide
Nevirapine	Clarithromycin	Decreased serum concentration of clarithromycin	Induction of clarithromycin metabolism	Use Alternative such as azithromycin, monitor for hepatic abnormalities
Zidovudine	Clarithromycin	Decreased serum concentration of zidovudine	Clarithromycin decreases absorption of zidovudine.	Co-administration should be separated atleast by 2 hours
Efavirenz	Clonazepam	Decreased clonazepam concentrations	Induction of clonazepam metabolism	Perform therapeutic monitoring for clonazepam
Lopinavir	Clonazepam	Decreased clonazepam concentrations	Induction of clonazepam metabolism	Perform therapeutic monitoring for clonazepam
				Use with caution
Nevirapine	Clonazepam	Decreased clonazepam concentrations	Induction of clonazepam metabolism	Dose adjustment may be required
Ritonavir	Clonazepam	Increased clonazepam concentrations	Inhibition of clonazepam metabolism	Use with caution
				Decrease in dose may be required
Nevirapine	Clopidogrel	Increased nevirapine concentration	Inhibition of nevirapine metabolism	Use with caution
				Monitor for side effects
Emtricitabine	Cotrimoxazole	Increased emtricitabine concentration	Competitive inhibition of renal excretion of emtricitabine	Co-administration with higher doses of cotrimoxazole should be avoided
Stavudine	Cotrimoxazole	Increased stavudine concentration	Competition for active renal secretion	Monitor for adverse effects like GI disturbances, headache, fatigue etc.
Lamivudine	Cotrimoxazole	Increased risk of lamivudine adverse effects	Competition for renal excretion	Monitor for adverse effects like GI disturbances, headache, fatigue etc.
Zidovudine	Cotrimoxazole	Increased serum concentration of zidovudine	Competitive inhibition of renal excretion of zidovudine	Monitor for adverse effects like GI disturbances, headache, fatigue etc.
Stavudine	Dapsone	Increased risk of peripheral neuropathy	Causes additive toxicity	Dosage adjustment required
Zidovudine	Dapsone	Increased risk of adverse reactions to zidovudine	Decreased renal clearance of zidovudine	Monitor renal function and haematological parameters and consider dose reduction if required
Nevirapine	Dexamethasone	Decreased dexamethasone and/or nevirapine concentration	Unknown	Monitor nevirapine concentration and steroid effect
Efavirenz	Diclofenac	Hydroxylation of diclofenac	Unknown	Use the lowest recommended dose of diclofenac
Tenofovir	Diclofenac	Increased risk of nephrotoxicity	Competitive inhibition of renal excretion of tenofovir	Alternative therapy is to be considered
				Monitor renal function
Efavirenz	Domperidone	Decreased exposure of domperidone	Induction of domperidone metabolism	Dose adjustment may be needed
Nevirapine	Domperidone	Decreased exposure of domperidone	Induction of domperidone metabolism	Dose adjustment may be needed
Atazanavir	Dutasteride	Increased dutasteride concentrations	Dutasteride mainly metabolised by CYP3A4	Due to dutasteride’s wide margin of safety, no prior dosage adjustment is recommended
Ritonavir	Dutasteride	Increased dutasteride concentrations	Dutasteride mainly metabolised by CYP3A4	Due to dutasteride’s wide margin of safety, no prior dosage adjustment is recommended
Efavirenz	Escitalopram	Decreased escitalopram concentrations	Induction of escitalopram metabolism	No prior dosage adjustment is recommended but monitor clinical effect
Nevirapine	Escitalopram	Decreased escitalopram concentrations	Induction of escitalopram metabolism	No prior dosage adjustment is recommended but monitor clinical effect
Lopinavir	Escitalopram	Increased escitalopram concentrations	Inhibition of escitalopram metabolism	Use with caution due to increased risk of QT interval prolongation
Ritonavir	Escitalopram	Increased escitalopram concentrations	Inhibition of escitalopram metabolism	Use with caution due to increased risk of QT interval prolongation
Atazanavir	Fluconazole	Increased risk of QT interval prolongation	Inhibition of atazanavir metabolism	Co-administration is avoided
Nevirapine	Fluconazole	Increase in nevirapine exposure	Unknown	Co-administration not recommended
				Monitor closely for nevirapine associated adverse effects
Ritonavir	Fluconazole	Increased ritonavir concentrations	Decreased ritonavir metabolism	No dosage adjustment required
Zidovudine	Fluconazole	Increased zidovudine concentrations	Decreased zidovudine metabolism	Monitor for increased adverse effects of zidovudine
Tenofovir	Furosemide	Decreased renal elimination of tenofovir	Competitive inhibition for renal clearance	Monitor renal function
Tenofovir	Ganciclovir	Increased concentrations of tenofovir	Competition for active tubular secretion	Monitor renal function
Zidovudine	Ganciclovir	Increased serum concentration and hematologic toxicity of zidovudine	Inhibition of zidovudine metabolism	Monitor renal function and haematological parameters and consider dose reduction if required
Efavirenz	Glimepiride	Increased glimepiride concentrations	Inhibition of glimepiride metabolism	Monitor clinical effect and decrease glimepiride dosage if needed
Efavirenz	Glipizide	Increased glipizide concentrations	Inhibition of glipizide metabolism	Monitor clinical effect and decrease glipizide dosage if needed
Efavirenz	Ibuprofen	Increased risk of gastrointestinal complications	Inhibition of ibuprofen metabolism	Use the lowest recommended dose of ibuprofen
Lamivudine	Levofloxacin	Increased lamivudine concentrations	Competitive inhibition of renal elimination	Adjustment of dosage is required
Nevirapine	Levofloxacin	Unknown	Metabolism of levofloxacin is affected.	Monitoring is required
Atazanavir	Lithium	Increased QT interval prolongation	Inhibition of lithium metabolism	Monitor lithium concentration
Emtricitabine	Lithium	Increased risk of nephrotoxicity	Competitive inhibition for renal elimination	Monitor renal function
Tenofovir	Lithium	Increased risk of nephrotoxicity	Competitive inhibition for renal elimination	Monitor renal function
Atazanavir	Methylprednisolone	Increased risk of steroid related side effects	Increased methylprednisolone concentrations	Use the lowest possible dose of corticosteroid
Efavirenz	Methylprednisolone	Decreased methylprednisolone concentrations	Induction of methylprednisolone metabolism	Monitor therapeutic effect and adjust methylprednisolone dosage
Nevirapine	Methylprednisolone	Decreased methylprednisolone concentrations	Induction of methylprednisolone metabolism	Monitor therapeutic effect and adjust methylprednisolone dosage
Ritonavir	Methylprednisolone	Increased risk of steroid related side effects	Increased methylprednisolone concentrations	Use the lowest possible dose of corticosteroid
Darunavir	Mirtazapine	Increased mirtazapine concentrations	Inhibition of mirtazapine metabolism	Caution is required
Nevirapine	Mirtazapine	Decreased mirtazapine concentrations	Increased clearance of mirtazapine	Caution is required
Ritonavir	Mirtazapine	Increased mirtazapine concentrations	Inhibition of mirtazapine metabolism	Caution is required
Lamivudine	Ofloxacin	Increased lamivudine concentration	Competitive inhibition of renal elimination	Monitor for side effects
Atazanavir	Olanzapine	Decreased olanzapine exposure	Induction of olanzapine metabolism	Monitor the clinical effect and increase dosage if needed
Ritonavir	Olanzapine	Decreased olanzapine concentration	Induction of olanzapine metabolism	Monitor for adverse effects
Atazanavir	Pantoprazole	Decreased atazanavir exposure and risk of reduced efficacy and development of resistance.	Reduced absorption due to decreased intra-gastric acidity	Co-administration should be avoided
Atazanavir	Phenytoin	Decreased atazanavir concentration	Induction of atazanavir metabolism	Dosage adjustment of phenytoin may be required
Efavirenz	Phenytoin	Decreased efavirenz and/or phenytoin concentration	Induction of the metabolism of phenytoin and efavirenz	Monitor for phenytoin and efavirenz efficacy
Nevirapine	Phenytoin	Decreased nevirapine concentrations	Induction of nevirapine metabolism	Perform therapeutic drug monitoring for nevirapine
Ritonavir	Phenytoin	Decrease in serum concentration of phenytoin	Induction of phenytoin metabolism	Monitor for signs of decreased phenytoin efficacy
Zidovudine	Phenytoin	Alters phenytoin concentration	Alters phenytoin metabolism	Monitor phenytoin levels
Efavirenz	Prazosin	Decreased prazosin concentration	Induction of prazosin metabolism	Dosage of prazosin should be titrated until required therapeutic effect is reached
Nevirapine	Prazosin	Decreased prazosin concentration	Induction of prazosin metabolism	Dosage of prazosin should be titrated until required therapeutic effect is reached
Efavirenz	Primaquine	Increased haemolytic effects of primaquine	Increased amount of hemotoxic metabolites	Caution is required
Zidovudine	Pyrazinamide	Decreased efficacy of pyrazinamide	Unknown	Monitor the levels of pyrazinamide
				Alternate TB therapy may need to be considered
Lopinavir	Quetiapine	Increased quetiapine concentration	Inhibition of quetiapine metabolism	Do not co-administer
				ECG monitoring is required
Ritonavir	Quetiapine	Increased quetiapine concentration	Inhibition of quetiapine metabolism	Do not co-administer
Zidovudine	Quetiapine	Increased haematological toxicity	Effects the metabolism	Monitor haematological parameters
Atazanavir	Ranitidine	Decreased atazanavir concentrations	unknown	Dosage adjustment is required
Efavirenz	Rifabutin	Decreased rifabutin concentrations	Induction of rifabutin metabolism	Dosage adjustment of rifabutin is required
Efavirenz	Rifampicin	Decreased serum efavirenz concentration	Induction of efavirenz metabolism by rifampicin	Monitor for efavirenz efficacy
				Efavirenz dose can be increased to 800 mg/day for patients >60 Kg
Nevirapine	Rifampicin	Decreased nevirapine concentration and possible loss of nevirapine efficacy	Induction of CYP 3A4 mediated metabolism by rifampicin	Co-administration not recommended
				Rifabutin can be considered
Zidovudine	Rifampicin	Decreased zidovudine concentrations	Increased zidovudine metabolism	Monitor efficacy of zidovudine and make necessary dose adjustments
Efavirenz	Sildenafil	Decreased sildenafil concentrations	Induction of sildenafil metabolism	Monitoring of sildenafil efficacy and dosage adjustments to be required
Nevirapine	Sildenafil	Decreased sildenafil concentrations	Induction of sildenafil metabolism	Monitoring of sildenafil efficacy and dosage adjustments to be required
Atazanavir	Tamsulosin	Increased tamsulosin exposure	Inhibition of tamsulosin metabolism	Caution is required
Lopinavir	Tamsulosin	Increased tamsulosin exposure	Inhibition of tamsulosin metabolism	Caution is required
Ritonavir	Tamsulosin	Increased tamsulosin exposure	Inhibition of tamsulosin metabolism	Caution is required
Tenofovir	Valaciclovir	Increased tenofovir concentrations	Competitive inhibition for renal elimination	Monitor renal function
Zidovudine	Valproic acid	Increased zidovudine concentration	Decreased clearance of zidovudine	Monitor for zidovudine toxicity
Efavirenz	Venlafaxine	Decreased venlafaxine concentration	Induction of venlafaxine metabolism	No prior dosage adjustment required
Nevirapine	Venlafaxine	Decreased venlafaxine concentration	Induction of venlafaxine metabolism	No prior dosage adjustment required
Efavirenz	Warfarin	Plasma concentrations and effects of warfarin are potentially increased or decreased by efavirenz.	Induction or inhibition of warfarin metabolism	Dose adjustment of warfarin may be required
				Monitor INR
Darunavir	Zolpidem	Increased sedation	Increased exposure of zolpidem	Dosage reduction is required
Efavirenz	Zolpidem	Decreased zolpidem exposure	Induction of zolpidem metabolism	Monitor clinical effect and withdrawal symptoms
Nevirapine	Zolpidem	Decreased zolpidem exposure	Induction of zolpidem metabolism	Monitor clinical effect and withdrawal symptoms
Ritonavir	Zolpidem	Increased sedation	Increased exposure of zolpidem	Dosage reduction is required

LFT: Liver function tests, WBC: White blood cell, ECG: Electrocardiogram, TB: Tuberculosis, INR: International Normalized Ratio. PR Interval: PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization). QT Interval: QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle.

4 Discussion

CSDIs with HAART and concomitant medications are common. In India, no study has previously reported risk factors for all possible DDIs with HAART and concomitant medications and also no study reports for prescriber awareness on CSDIs of HAART and concomitant medications in HIV patients. There is lack of data for all possible DDIs associated with HAART and concomitant medications in Indian setup on safety of practice of medicine. Hence, our study evaluating medical record review for recognizing allpossible DDIs to HAART, prevalence, nature of occurrence, and associated risk factors of DDIs to HAART and concomitant medications in PLW-HIV in India is important. The study observed significant pharmacokinetic (89.1%) and pharmacodynamics DDIs associated with use of poly pharmacy (concomitant use of greater than eight drugs), with use of NRTIs, NNRTIs and PIs based HAART regimen, which was similar to that observed in other studies [16, 17]. The prevalence of DDIs in our study was (44.9%) and there exist difference in prevalence of DDIs from various other studies conducted elsewhere [7, 9, 18]. However, Recognition of all possible DDIs from this study will focus to help the treating clinician in India to promote awareness for all possible DDIs associated with HAART and concomitant medications, which will also promote prescriber for preventing CSDIs while prescribing concomitant medications along with HAART regimen.

In our study, risk factors associated for major DDIs was observed with comorbid conditions of cardiovascular disease. Greater risk for DDIs with HAART were observed among patients when treated for hypertension, ischemic heart disease followed by myocardial infraction (p < 0.001). Most of the DDIs were observed among patients who were on HAART with antithrombotic therapy, antiplatelet drugs like clopidogrel, aspirin that are used to control cardiovascular disease risk. Greater risk for DDIs were reported in cases of efavirenz with warfarin, tenofovir with aspirin, nevirapine with amlodipine, nivirapine with clopidogrel and efavirenz with acenocoumarol. These findings of our results will help clinical cardiologists to familiarize with all possible DDIs between HAART and concomitant cardiovascular drugs, so as to prevent DDIs. However, our findings supports the review study of Raposeiras-Roubin et al. in which ischemic heart disease is an associated risk factor in HIV patients treated with HAART and cardiovascular risk [19].

In our study, male gender (p < 0.001) were identified as risk factors for the development of DDIs. This may be due to the fact that most of the male patients were first hospitalized and treated for OIs of tuberculosis, candidiasis, and pneumocystis carnie pneumonia who experienced DDIs at much higher rate whereas, female patients were admitted to hospital at the late or end stage of HIV disease due to social stigma. Other risk factors for DDIs in our study were due to respiratory tract infections followed by psychiatric disorder (p < 0.001). In our study use of antibiotics, drugs for treating OIs, drugs for the treatment of psychiatric disorders such as lithium, Olanzapine, escitalopram, zolpidem, valproic acid, Quitiapine, alprazolam, escitalopram, clonazepam are highly implicated DDIs with HAART regimen. Whereas, Piscitelli et al. study observed a highly significant association of DDIs between the use of drugs for only treating OIs [2].

In our study, majority of DDIs were pharmacokinetic (89.1%) compared to pharmacodynamics (10.9%). This is mainly because most of HAART regimen are extensively metabolized by the cytochrome (CYP) isoenzyme, CYP3A415, CYP450 and CYP3A4. However, other studies have reported higher incidence of pharmacodynamics DDIs in clinical practice [20, 21]. The overall risk of XDDIs was significantly associated with use of PIs compared to NNRTI with lowest risk. XDDIs was observed in patients who were on fluconazole + atazanavir (28.6%), fluconazole + ritonavir (28.6%), nevirapine + rifampicin (14.4%), nevirapine + dexamethasone, ritonavir + quetiapine, lopinavir+ quetiapine and atazanavir + pantoprozole. The risk of XDDIs was highest with HAART regimen with PIs which is similar to other studies [22, 23]. However, differs with various studies [10, 24, 25] in which they found a higher risk for XDDIs was much associated with NNRTI based HAART regimen. In addition, risk of XDDIs (i.e., RFI) was highest in combination of tenofovir+emtricitabine+atazanavir+ritonavir regimen. This may be due to interactions of atazanavir with tenofovir resulting in reduced plasma concentration of the PIs. However this is in contrast to previous reports [26, 27] that when ritonavir is used as a booster, interactions of atazanavir with tenofovir is not clinically relevant.

HIV-SP patients being treated with HAART experienced DDIs with warfarin at a much higher rate when used with PIs or NNRIs [28]. Depending on the type of antiretroviral agent, either inhibition or induction of warfarin metabolism do occur [29]. We observed occurrence of DDIs with warfarin and efavirenz in two cases. DDIs with warfarin and efavirenz is due to alteration in CYP2C9 metabolism. However, we could not directly correlate with anticoagulation effects with increase in international normalization ratio (INR). DDIs with cotrimoxazole was observed in patients who were on lamivudine (14.6%), emtricitabine (11.4%), zidovudine (8.7%) and stavudine (1.9%) containing regimen. In ninety three cases, cotrimoxazole DDIs with HAART regimen suggesting a likely association of risk for DDIs. Our study findings are similar to a study [30] wherein use of cotrimoxazole manifested for higher DDIs in HIV patients.

DDIs with statins are attributed to CYP3A4 inhibitors [31]. In this study, we found five cases of CSDIs with hypolipidemic agents such as atorvastatin and HAART regimens containing nevirapine and efavirenz. This may be due to the fact that in our hospital setup, atorvastatin were the most commonly used class of hypolipidemic drugs prescribed in clinical practice. These findings of CSDIs of atorvastatin with nevirapine or efavirenz containing HAART regimen will help practitioners to recognize and prevent risk for CSDIs associated with the concomitance use of statins along with HAART regimen containing nevirapine and efavirenz. In our hospital setup, extensive use of proton pump inhibitors (PPIs) are common in clinical practice. In our study, one case of XDDIs with the use of PPIs (i.e. Pantoprazole) with atazanavir was reported. These finding are consistent with the study carried out by Lewis et al. [32]. On the other hand, study that was carried by Saberi et al. [33] reported to minimize or to avoid use of PPIs while taking PIs based HAART regimen. However concomitant use of PPIs with PIs are acceptable for less than 30 days of indications [33].

5 Conclusion

HIV patients who are on HAART and treated for opportunistic infections, respiratory tract infections, psychiatric disorder, cardiovascular disease and who are on antiplatelet drugs, antithrombotic therapy need intensive monitoring for DDIs. Recognition of all possible risk factors for clinically significant drug interaction will help clinicians to prevent DDIs. Furthermore, clinicians strictly need to pay attention to avoid “Red Flag Indication combinations” while prescribing concomitant medications along with HAART regimen.

Conflict of interest

The authors declare no conflicts of interest.

Footnotes

Acknowledgments

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

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