Incidence of Adverse Drug Reactions in Patients on ... · Incidence of Adverse Drug Reactions in Patients on Antiretroviral Therapy: A study of Pharmaceutical Care in HIV Interventions

Incidence of Adverse Drug Reactions in Patients on Antiretroviral Therapy: A study of Pharmaceutical Care in HIV Interventions in Nigeria

1 1 1 1 1Kenneth A. Agu , Muhammadu A. Isah , Dorothy Oqua , Mohammed A. Habeeb , Peter O. Agada , Samuel I.

1 1 1 3 2 2 2,4Ohiaeri , Pollock N. Ali , Paul G. Iyaji , Rosalyn C. King , Bolatito Aiyenigba , Kwasi Torpey , Otto N. Chabikuli , 3Anthony K Wutoh

1 2 3 Howard University Pharmacist And Continuing Education (PACE) Center, Nigeria; FHI360, Nigeria; Howard

4University College of Pharmacy, PACE Center, Washington DC, United States of America (USA); Honorary Lecturer, Department of Family Medicine, Medical University of Southern Africa, Pretoria, South Africa

Corresponding author: Kenneth A. Aguemail: [email protected]; [email protected] no: +234-09-4615626. +2348033031467.

ABSTRACTBackground: Over 415,000 HIV-infected patients are receiving antiretroviral therapy (ART) in Nigeria but studies documenting their adverse reactions are limited.

Objectives: This study determined the incidence and type of ADRs of severity grades II to IV in ART patients following pharmaceutical care directed active ADR surveillance program in Nigeria.

Methods: This was a longitudinal study. A study-specific pharmaceutical care daily worksheet and national ADR reporting form were used for ADR screening and reporting respectively. Study population included 73,589 ART patients who were screened for ADR from April 2009 to December 2010 in 69 HIV treatment centres. All individual case safety reports (ICSRs) of severity grades II to IV in these patients were collated and analyzed. Chi-square was used to test the association between groups of variables at 95% Confidence Interval.

Results: A total of 4600 ICSRs of severity grades II to IV reported were analyzed. Mean age of patients was 35.5 (95%CI, 35.2-35.9) years; 68.1% were females; and 7002 ADRs were reported, an average of 1.5 ADR per patient. ADR incidences were 18.2% for d4T/3TC/EFV, 13.9% for d4T/3TC/NVP, and 4.4% for AZT/3TC/NVP regimens; however overall incidence was 6.3%. Major reported ADRs included skin rash (16.5%); peripheral neuropathy (12.7%); and headache (9.4%). ADR occurrence was associated with specific ART regimens, concomitant medicines and age groups (p<0.05), unlike gender. Lipodystrophy was associated with d4T/3TC/NVP [OR=3.9 (95%CI: 2.2-6.7), p=0.0000] and d4T/3TC/EFV [OR=2.9 (95%CI: 1.1-7.2), p=0.0095] regimens compared with other regimens.

Conclusion: There was low incidence of ADRs of severity grades II to IV which was higher in patients who received d4T-based regimen compared to other regimens.

Key words: HIV, ART, ADR Active Surveillance, Pharmaceutical Care, Nigeria

30 West African Journal of Pharmacy (2013) 24 (1)

West African Journal of Pharmacy (2013) 24 (1) 30-42


INTRODUCTIONAdverse drug reactions (ADRs) can affect adherence to medication and consequently the outcomes of

1, 2antiretroviral terapy (ART). ADRs are a serious problem in health care delivery, not only limited to ART but extends to other diseases like TB, Malaria, hypertensions and diabetes etc especially where drug combinations are used on chronic basis and can be life threatening. A meta-analysis of studies in hospitals suggested that ADRs due to various

th thmedicines were the 4 –6 leading cause of death in

3the USA. The overall incidence of serious ADRs was 36.7% and life threatening ADRs accounted for 0.32%.

There are evidences that ADRs prevalence and incidence in ART programs are much higher and has a wide ranging in manifestation. Studies in India

4reported ADR incidence of 43.8% and ADR prevalence 5of 39.7% in intensively monitored ART patients.

Anaemia, hepatotoxicity and vomiting were the most 4, 5commonly observed ADRs. In another study in India,

the most common ADR observed was peripheral 6neuropathy (20.83%) and skin rash (15.83%). There

was a significant correlation between sex and the 6

occurrence of severe ADR. Conversely, the incidence of severe adverse reactions was 32.55% in patients <35 years of age compared to 19.44% in those >35 years of age, though the difference was not

6statistically significant.Subbaraman et al (2007) estimated that 10% to 20% of persons exposed to stavudine developed peripheral

7neuropathy in developing countries. The prevalence of stavudine-associated lipodystrophy was as high as

8-1063%. In Southeast Asia, about 17% of patients on stavudine developed lipodystrophy, compared with

7 24.8% in Rwanda and 46.1% in Indian. In Uganda, ADRs incidence rate was 4.47/100 person-months; and common ADRs were peripheral neuropathy

11 (36%), rash (6%), and hypersensitivity reaction (2%).In Nigeria, there are limited studies on adverse reaction of antiretroviral drugs. However, Olowookere et al, reported the occurrence of the following ADRs as determinants of medication non-adherence; nausea/vomiting (19.5%), skin rash (15.7%), diarrhea (23.9%), dizziness (13.8%), paraesthesia (11.9%) and

12bad dreams (14.5%) in patients on ART. Eluwa et al (2012) reported ADR incidence rate of 4.6/100 person-years; and commonest ADRs were pain (30%)

22and skin rash (18%).

ADR monitoring is core to pharmaceutical care, which can be defined as the responsible provision of medication-related care designed to achieve definite

13, 14 outcomes that improve a patient's quality of life. .Pharmaceutical care aims to eliminate or reduce drug

15therapy related problems including ADRs. Active ADRs surveillance and reporting is one of the most

16, 17effective methods of pharmacovigilance.

16-18. Analysis of the national database showed that from 2004 to April 2009, only a total of 879 individual case safety reports was received and of which just 78 (8.9%) were reported to be attributable

16to ART. Although this figure increased to 17.0% in

19September (2009) , it represents a case of severe under-reporting. There are over 415,000 ptients currently on ART in the country; however, information regarding the incidence of ADRs is limited due to dearth of active ADR surveillance in clinical practice.

implemented by four c o n s o r t i u m p a r t n e r s . G H A I N s u p p o r t e d comprehensive HIV treatment and care services in 125 tertiary and secondary health facilities; and implemented SRS of the national system but severe under-reporting was the major barrier. Between September 2004 and June 2011, a total of 172,967 were initiated on ART in all the supported health facilities. However, data on ADRs related to ART were still scanty. Consequently, active pharmacovigilance was piloted and scaled up in the program through pharmaceutical care in HIV interventions under the technical leadership of Howard University Pharmacists and Continuing Education Center (HU PACE), a core consortium partner. This study therefore, aimed to determine the incidence and type of ADRs of severity grades II to IV reported among HIV/AIDS patients on ART following the implementation of pharmaceutical care directed active ADR surveillance program in Nigeria.

METHODS Study Design This was a longitudinal study that evaluated individual case safety reports (ICSRs) of severity grades II to IV among HIV/AIDS patients on ART following pharmaceutical care led active ADR surveillance program between April 2009 and December 2010 at the supported hospital pharmacies in Nigeria.

In Nigeria, spontaneous reporting system (SRS) is widely used but has evidence of significant and widespread under-reporting of ADRs

Global HIV/AIDS Initiative Nigeria (GHAIN) was funded by the President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S Agency for International Development (USAID)

Adverse Drug Reactions in Patients on Antiretroviral Therapy

Setting and Study population The study was conducted in 69 GHAIN supported hospitals providing comprehensive package of HIV prevention, treatment, care and support. There are no user fees for HIV services. In a typical comprehensive site, clients pass through several service delivery points namely HIV testing and counselling unit (the entry point in the ART program), prevention of mother to child transmission (PMTCT), ART clinics, laboratory and pharmacy. The type of service provided was recorded at each point on nationally approved data collection tools. Patients on ART refill their antiretroviral medications on bimonthly basis and that opportunity was used for the routine ADR screening. This screening was done at the ART clinic and the pharmacy. However, screening at the pharmacy was monitored intensively for purpose of this study. All ART patients were screened for new signs and/or symptoms indicating possible ADRs at each medication refill encounter in the pharmacy irrespective of any previous screening at the ART clinic. After inspection, responses were recorded on the pharmaceutial care daily worksheet (PCDW) and other observations not listed were specified in the blank spaces provided. However, pharmacists also record the suspected ADR cases on the national ICSR form (the yellow form), categorized as moderate (grade II), severe (grade III), or life threatening ADRs (grade IV) using the WHO severity grading scale for

16ADRs. Mild ADR (grade I) cases are not reported in the yellow form in accordance with the SOP in use at these hospitals. The 69 GHAIN-supported sites that had (i) pharmaceutical care directed active ADR screening program and (ii) a completed individual case safety reports were selected for inclusion in the study. The study population included 73,589 patients enrolled on the ART register and screened for ADRs between April 2009 and December 2010 in the selected sites. Of these patients, all ART patients who had at least one individual case safety reports of severity grades II to IV during study period were assessed. Patients who did not meet these criteria were not included.

InterventionsThe interventions included a centralized didactic pharmaceut ica l care in HIV and c l in ica l pharmacovigilance for antiretroviral drugs trainings followed by an onsite hands-on pharmacy best practices training. The training curricula were developed by Howard University PACE Center for the GHAIN project. PCDW designed for active screening of

HIV-infected ART patients for drug therapy problems was deployed to the sites for use in screening patients for drug therapy problems including ADR. The yellow form designed for national SRS was deployed to supported sites without modification for reporting of suspected ADRs of severity grades II to IV. A focal person was appointed and a multidisciplinary team constituted to provide technical leadership. Standard operating procedure (SOP) for pharmacovigilance was developed and disseminated. Bimonthly feedback and ADR cases review meetings, monthly monitoring and mentoring on active surveillance program were instituted. No monetary incentive was provided to the health workers involved in the program.

Outcome variablesThe occurrence of ADRs segregated by ART regimens during the study period was the main outcome variable. This variable was measured as clinical signs and/or symptoms that may indicate possible ADRs. Secondary outcomes were description of the type of ADRs report and factors related to the ADR in patients that reported ADRs.

Data collection All ADR cases identified irrespective of the severity grades were documented in the PCDW. The tool included sections on patients' demographics, ART regimens, and list of signs/symptoms that may indicate possible ADRs in an organ-system classification, interventions and outcomes. However, only ADR cases of severity grade II to IV were recorded in the yellow form. This form included sections on the patients' demographics, ADR description, intervention and outcome of reaction, suspected drug details, and the concomitant medicines. All new ADR case reports in ART patients documented in the yellow form during the study period (April 2009 to December 2010) were collated for analysis by the trained research assistants. The case reports were filtered in manner to ensure that only new ADR cases of grade II to IV were collated for analysis. Mild ADR (grade I) cases were excluded in the analysis. The data on the number of patients exposed to different ART regimens during the study period were obtained from ART register in the study sites. ART register is a longitudinal tool designed to keep record of all patients on ART over long period of time (years). The treatment status of the ART patients (transferred out, stopped treatment, loss to follow up or died etc) are captured in this register.


Agu et al

Data managementEnd users and their supervisors were trained on the data collection tools prior to data collection. About one-fifth of ADR data extracted from the yellow forms were randomly verified from source document (PCDW) and validated before data entry and analysis. The research assistants used patient identifiers to sort and filter out duplicate case reports and assigned a code to each of the patient's case safety reports before data entry.

Data analysisPASW statistics® version 18 was used for data analysis. Descriptive statistics was conducted and included frequency distribution of key items. The ADR incidence was calculated as “the number of ART patients reporting new ADR cases of severity grades II to IV between April 2009 and December 2010 / Total number of patients exposed to ART between April 2009 and December 2010.

Patients noted in the ART register as having transferred out, died, stopped treatment or loss to follow up contributed to the analysis if they had reported ADRs of severity grades II to IV before been declared no longer a patient of the facility because there were yellow form filled for them. Bivariate analysis was conducted to describe the relationship between reported ADRs and the following variables: age, gender and ART regimens. Chi-square statistic was used to test the association between reported ADRs and patients' age, gender, and ART regimens. The association between reported ADRs and specific variables was assessed by an odds ratio (OR). All reported P values were 2 - sided and P< 0.05 used to determine statistical significance. However,

A new recurrence of ADR in a patient was excluded in this computation.

Bonferroni method was used to determine statistical significance after correcting for multiple comparisons.

Ethical considerationsEthical approval was obtained from FHI 360's PHSC, USA and the National Health Research Ethics committee (NHREC), Abuja, Nigeria. Confidentiality was assured by excluding the patients' identifiers during the analysis.

RESULTSFrom 73,589 HIV/AIDS patients who commenced ART and were screened for ADRs within the study period (between April 2009 and December 2010), a total of 4,600 ICSRs of severity grades II to IV in these patients were analyzed. The mean age of the patients was 35.5 (95%CI, 35.2–35.9) years. There were 68.0% females, 31.0% males and there were no indication of gender in 1.0% of the ICSRs. There were a total of 7,002 ADRs reported in these patients; an average of 1.5 ADR per patient. Of all patients who reported ADRs, 39.9% were on AZT/3TC/NVP regimen, while 34.3% were on d4T/3TC/NVP regimen (Table 1). The incidence of ADRs was 18.2% in patients that received d4T/3TC/EFV, 13.9% for d4T/3TC/NVP, and 4.4% for AZT/3TC/NVP; though the overall incidence of grades II to IV ADRs in these patients was 6.3% (Table 1).

"A new recurrence of ADR in a patient was excluded in this computation”



Table 1: Proportion of ART patients who reported grade II to IV ADRs (suspected) segregated by the specific antiretroviral drug regimens

Antiretroviral Drugs (ARVs) Regimens

Number of patients

receiving ARVs regimens (%)

N = 73,589

Number of patients who reported

ADRs (%)

N = 4600

Proportion of patients who

reported

ADRs

(%)

Zidovudine/Lamivudine/Nevirapine (AZT/3TC/NVP)

41784 (56.8)

1836 (39.9)

4.4

Stavudine/Lamivudine/Nevirapine (d4T/3TC/NVP)

11357 (15.4)

1576 (34.3)

13.9

Zidovudine/Lamivudine/ Efavirenz (AZT/3TC/EFV)

6355 (8.6)

254 (5.5)

4.0

Tenofov ir/Emtricitabine/Nevirapin (TDF/FTC/NVP)

5655 (7.7)

235 (5.1)

4.2

Tenofovir/Emtricitabine/Efavirenz (TDF/FTC/EFV)

2678 (3.6)

84 (1.8)

3.1

Tenofovir/Lamivudine/Nevirapine (TDF/3TC/NVP)

1275 (1.7)

76 (1.7)

6.0

Stavudine/Lamivudine/Efavirenz (d4T/3TC/EFV)

1036 (1.4)

189 (4.1)

18.2

Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV)

616 (0.8)

17 (0.4)

2.8

Zidovudine/Lamivudine/Abacavir (AZT/3TC/ABC)

43 (0.1)

1 (0.0)

2.3

enofovir/Emtricitabine/Lopinair/ Ritonavir (TDF/FTC/LPVr)

251 (0.3)

10 (0.2)

4.0

Tenofovir/Stavudine/Nevirapine (TDF/d4T/NVP)

4 (0.0)

2 (0.0)

50.0

Tenofovir/Zidovudine/Efavirenz (TDF/AZT/EFV)

2 (0.0)

1 (0.0)

50.0

Tenofovir/Emtricitabine/Nelfinavir/Ritonavir (TDF/FTC/NFVr)

4 (0.0)

3 (0.1)

75.0

Not indicated

2529 (3.4)§

316 (6.9)*

12.5

Overall

73589 (100.0)

4600 (100.0)

6.3

* Number of patients without indication of specific ART regimens received;

§Number of patients who received other antiretroviral drug regimens among the general population that is not listed on the table.

The reported ADRs included (16.5%) skin rash, (12.7%) peripheral neuropathy (which was reported as tingling, numbness, and pain in the extremities) and (9.4%) headache (Table 2). The occurrence of ADRs had significant association with the following parameters: the ART regimens received by the patients (p=0.0000), the concomitant medicines (including all medicines taken in the last 3 months) and self medications (p=0.0000), and the patients' age (p=0.0000). Gender was found not to have any significant association with the occurrence of ADR (p=0.0834). Tables 2, 4 and 6 showed the distribution and association of specific ADRs with antiretroviral drugs regimens, age and concomitant medicines respectively. However, the reported ADRs that had

significant association were linked to specific antiretroviral drug regimens, age groups and concomitant medicines. For example, the occurrence of lipodystrophy was associated with d4T/3TC/NVP [OR=3.9 (95%CI: 2.2, 6.7), p=0.0000] and d4T/3TC/EFV [OR=2.9 (95%CI: 1.1, 7.2), p=0.0095] regimens compared to other regimens (Table 3). The occurrence of headache was significantly more common in age group 25–34 [OR=1.4 (95%CI: 1.2, 1.6), p=0.0002] years compared to other age groups (Table 5) and patients who received NSAIDs as concomitant medicines [OR=2.0 (95%CI: 1.1, 3.6), p=0.0134], Table 7.


Agu et al

Table 2: Frequency distribution of suspected ADRs segregated by ART regimens; percentages are in parenthesis§, n = 7002.

ADR descriptions Antiretroviral Drugs Regimen Total

P-valueD4T/3TC/NVP

d4T/3TC/EFV

AZT/3TC/NVP

AZT/3TC/EFV

TDF/3TC/NVP

TDF/FTC/NVP

TDF/FTC/EFV

Others* Not indicated

Headache 172 (26.1) 24 (3.6) 321 (48.8) 41 (6.2) 15 (2.3) 28 (4.3) 9 (1.4) 1 (0.2) 47 (7.1) 658 (9.4) 0.0016

Oedema

38 (33.6)

5 (4.4)

34 (30.1)

7 (6.2)

0 (0.0)

12 (10.6)

1 (0.9) 1 (0.9) 15 (13.3) 113 (1.6) 0.0573

Amenorrhea

25 (47.2)

1 (1.9)

17 (32.1)

0 (0.0)

0 (0.0)

4 (7.5)

1 (1.9) 0 (0.0) 5 (9.4) 53 (0.8) 0.3084

Insomnia

42 (30.4)

13 (9.4)

40 (29.0)

19 (13.8)

1 (0.7)

4 (2.9)

9 (6.5) 0 (0.0) 10 (7.2) 138 (2.0) 0.0000

Anaemia

23 (15.2)

0 (0.0)

87 (57.6)

19 (12.6)

1 (0.7)

6 (4.0)

1 (0.7) 3 (2.0) 11 (7.3) 151 (2.2) 0.0000

Fatigue

129 (29.3)

20 (4.5)

200 (45.4)

23 (5.2)

6 (1.4)

20 (4.5)

10 (2.3) 6 (1.4) 27 (6.1) 441 (6.3) 0.4754

Abdominal

Pain 113 (31.7)

4 (1.1)

165 (46.2)

16 (4.5)

10 (2.8)

19 (5.3)

5 (1.4) 6 (1.7) 19 (5.3) 357 (5.1) 0.0203

Lipodystrophy

36 (64.3)

6 (10.7)

8 (14.3)

1 (1.8)

0 (0.0)

2 (3.6)

1 (1.8) 0 (0.0) 2 (3.6) 56 (0.8) 0.0000

Skin rash

366 (31.6)

27 (2.3)

491 (42.4)

51

(4.4)

21 (1.8)

65 (5.6)

17 (1.5) 5 (0.4) 114 (9.9) 1157 (16.5) 0.0020

Nausea /Vomiting

67 (17.1)

11 (2.8)

228 (58.2)

17 (4.3)

10 (2.6)

29 (7.4)

6 (1.5) 3 (0.8) 21 (5.4) 392 (5.6) 0.0000

Dizziness

44 (13.7)

33 (10.2)

106 (32.9)

60 (18.6)

3 (0.9)

20 (6.2)

31 (9.6) 5 (1.6) 20 (6.2) 322 (4.6) 0.0000

Tingling, Numbness, Pain in the extremities

505 (56.9)

62 (7.0)

196 (22.1)

31 (3.5)

22 (2.5)

31 (3.5)

10 (1.1) 7 (0.8) 24 (2.7)

888 (12.7)0.0000

Flatulence

10 (38.5)

1 (3.8)

5 (19.2)

0 (0.0)

2 (7.7)

3 (11.5)

3 (11.5) 0 (0.0) 2 (7.7) 26 (0.4) 0.0083

Diarrhea

52 (30.2)

5 (2.9)

48 (27.9)

5 (2.9)

5 (2.9)

31 (18.0)

3 (1.7) 4 (2.3) 19 (11.0) 172 (2.5) 0.0000

Anorexia

66 (31.7)

2 (1.0)

105 (50.5)

7 (3.4)

2 (1.0)

13 (6.3)

5 (2.4) 2 (1.0) 6 (2.9) 208 (3.0) 0.0210

Hyperpigmentation

16 (22.5)

1 (1.4)

42 (59.2)

6 (8.5)

0 (0.0)

1 (1.4)

0 (0.0) 0 (0.0) 5 (7.0) 71 (1.0%) 0.0721

Pruritus

142 (30.4)

10 (2.)

216 (46.3)

20 (4.3)

7 (1.5)

25 (5.4)

8 (1.7) 2 (0.4) 37 (7.9) 467 (6.7) 0.2126

Nightmares

3 (5.4)

9 (16.1)

6 (10.7)

27 (48.2)

0 (0.0)

2 (3.6)

4 (7.1) 0 (0.0) 5 (8.9) 56 (0.8) 0.0000

SJS

9 (23.7)

0 (0.0)

17 (44.7)

1 (2.,6)

1 (2.6)

0 (0.0)

0 (0.0) 0 (0.0) 10 (26.3) 38 (0.5) 0.0039

Hallucination

1 (11.1)

0 (0.0)

0 (0.0)

5 (55.6)

0 (0.0)

0 (0.0)

2 (22.2) 0 (0.0) 1 (11.1) 9 (0.1) 0.0000

Somnolence

1 (11.1)

2 (22.2)

1 (11.1)

1 (11.1)

1 (11.1)

2 (22.2)

0 (0.0) 0 (0.0) 1 (11.1) 9 (0.1) 0.0167

Depression

1 (10.0)

3 (30.0)

2 (20.0)

3 (30.0)

0 (0.0)

0 (0.0)

1 (10.0) 0 (0.0) 0 (0.0) 10 (0.1) 0.0001

Epigastric pain

6 (14.6)

0 (0.0)

18 (43.9)

2 (4.9)

3 (7.3)

1 (2.4)

2 (4.9) 1 (2.4) 8 (19.5) 41 (0.6) 0.0054

Erectile dysfunction

0 (0.0)

1 (50.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0) 0 (0.0) 1 (50.0) 2 (0.0) 0.0453

Gynaecomastia 1 (25.0) 2 (50.0) 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (0.1) 0.0019

Loss of concentration 1 (33.3) 0 (0.0) 0 (0.0) 2 (66.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (0.0) 0.0138

Total 2238 (32.0) 278 (4.0) 2826 (40.4) 411 (5.9) 132 (1.9) 383 (5.5) 149 (2.1) 57 (0.8) 528 (7.5) 7002 (100.0)

–

*TDF/3TC/EFV, AZT/3TC/ABC, TDF/FTC/LPVr, TDF/d4T/NVP, TDF/AZT/EFV and TDF/FTC/NFVr; SJS, Steven Johnson's Syndrome. §Some insignificant ADRs are omitted in this table.



Table 3: Association of significant ADRs reported in patients on ART with the specific ART regimens; Values are Odds ratio at 95% Confidence Interval (CI)*. n = 7002

ADR descriptions ART Regimens associated with the ADR

Odds Ratios (95% CI) Total, N P-value

Lipodystrophy D4T/3TC/ NVP 3.9 (2.2, 6.7) 56 0.0000 D4T/3TC/EFV 2.9 (1.1, 7.2) 0.0095


D4T/3TC/ NVP 3.3 (2.9, 3.9) 888 0.0000 D4T/3TC/EFV 2.1 (1.5, 2.8) 0.0000

Gynaecomastia D4T/3TC/EFV 24.4 (2.5, 241.9) 4 0.0000 Headache AZT/3TC/NVP 1.5 (1.2, 1.7) 658 0.0000 Abdominal pain AZT/3TC/NVP 1.3 (1.0 , 1.6) 357 0.0206 Nausea / Vomiting AZT/3TC/NVP 2.2 (1.7 , 2.7) 392 0.0000 Anorexia AZT/3TC/NVP 1.5 (1.2, 2.0) 151 0.0025 Dizziness D4T/3TC/EFV 3.0 (2.0, 4.5) 322 0.0000

AZT/3TC/EFV 4.1 (3.0, 5.6) 0.0000 TDF/FTC/EFV 5.9 (3.9, 9.0) 0.0000

Insomnia D4T/3TC/EFV 2.6 (1.4, 4.8) 138 0.0009 AZT/3TC/EFV 2.6 (1.6, 4.4) 0.0000 TDF/FTC/EFV 3.4 (1.6, 7.0) 0.0003

Nightmares D4T/3TC/EFV 4.8 (2.2, 10.2) 56 0.0000 AZT/3TC/EFV 15.9 (9.0, 28.0) 0.0000 TDF/FTC/EFV 3.6 (1.1, 10.6) 0.0090

Hallucination AZT/3TC/EFV 20.3 (4.7, 90.0) 9 0.0000 TDF/FTC/EFV 13.3 (2.7 , 64.6) 0.0000

Depression D4T/3TC/EFV 10.5 (2.7 , 40.7) 10 0.0000 AZT/3TC/EFV 6.9 (1.4, 29.7) 0.0012

Somnolence D4T/3TC/EFV 7.0 (1.4, 33.6) 9 0.0050 Loss of concentration AZT/3TC/EFV 32.2 (2.3, 898.5) 3 0.0000 Anaemia AZT/3TC/NVP 2.0 (1.5, 2.9) 151 0.0000

AZT/3TC/EFV 2.4 (1.4, 4.0) 0.0004 Flatulence TDF/3TC/NVP 4.4 (1.0, 18.8) 26 0.0292

TDF/FTC/EFV 6.1 (1.4, 21.7) 0.0006 Erectile dysfunction D4T/3TC/EFV 24.3 (0.0, 888.3) 2 0.0009

Not Indicated 12.3 (0.8, 196.7) 0.0229 Diarrhoea TDF/FTC/NVP 4.0 (2.7, 6.2) 172 0.0000 Skin rash Not Indicated 1.4 (1.2, 1.8) 1157 0.0011 Epigastric pain Not Indicated 3.0 (1.3, 6.8) 41 0.0036

TDF/3TC/NVP 4.2 (1.0, 14.3) 0.0103

* was p < Statistical significance after correcting for multiple comparisons using the Bonferroni method0.041; ** TDF/3TC/EFV, AZT/3TC/ABC, TDF/FTC/LPVr, TDF/d4TNVP, TDF/AZT/EFV and TDF/FTC/NFVr


Agu et al

Table 4: Frequency distribution of the suspected ADRs reported in patients on ART segregated by age; percentages are in parenthesis§, n = 7002.

ADR descriptions

Age group (Years)

P-value

<15

15 –

24

25 –

34

35 –

44

45 –

54

55 – 64 >64 Not

indicated

Headache

10 (1.5)

68 (10.3)

270 (41.0)

164 (24.9)

85 (12.9)

14 (2.1) 9 (1.4) 38 (5.8) 0.0036Oedema

2 (1.8)

6 (5.3)

35 (31.0)

36 (31.9)

16 (14.2)

2 (1.8) 1 (0.9) 15 (13.3) 0.0869Amenorrhea

1 (1.9)

1 (1.9)

26 (49.1)

15 (28.3)

4 (7.5)

1 (1.9) 0 (0.0) 5 (9.4) 0.2554Insomnia

2 (1.4)

9 (6.5)

37 (26.8)

48 (34.8)

22 (15.9)

8 (5.8) 5 (3.6) 7 (5.1) 0.0685Anaemia

7 (4.6)

8 (5.3)

65 (43.0)

39 (25.8)

16 (10.6)

6 (4.0) 0 (0.0) 10 (6.6) 0.1645Fatigue

2 (0.5)

24 (5.4)

169 (38.3)

114 (25.9)

82 (18.6)

13 (2.9) 8 (1.8) 29 (6.6) 0.0027Abdominal Pain

9 (2.5)

46 (12.9)

145 (40.6)

90 (25.2)

41 (11.5)

5 (1.4) 3 (0.8) 18 (5.0) 0.0060Lipodystrophy

1 (1.8)

2 (3.6)

21 (37.5)

21 (37.5)

5 (8.9)

2 (3.6) 2 (3.6) 2 (3.6) 0.4236Skin rash

41 (3.5)

111 (9.6)

416 (36.0)

310 (26.8)

141 (12.2)

52 (4.5) 9 (0.8) 77 (6.7) 0.0426Nausea / Vomiting

14 (3.6)

59 (15.1)

162 (41.3)

92 (23.5)

37 (9.4)

6 (1.5) 3 (0.8) 19 (4.8) 0.0000Syncope

0 (0.0)

0 (0.0)

4 (40.0)

1 (10.0)

1 (10.0)

0 (0.0) 0 (0.0) 4 (40.0) 0.0044Dizziness

2 (0.6)

36 (11.2)

89 (27.6)

105 (32.6)

56 (17.4)

10 (3.1) 4 (1.2) 20 (6.2) 0.0525Tingling, Numbness, Pain in the extremities

2 (0.2)

26 (2.9)

245 (27.6)

282 (31.8)

199 (22.4)

54 (6.1) 18 (2.0) 62 (7.0) 0.0000Arthralgia

0 (0.0)

6 (7.7)

16 (20.5)

31 (39.7)

14 (17.9)

7 (9.0) 2 (2.6) 2 (2.6) 0.0168Cough

23(14.6)

14 (8.9)

38 (24.2)

45 (28.7)

21 (13.4)

8 (5.1) 1 (0.6) 7 (4.5) 0.0000Anorexia 8 (3.8) 26 (12.5) 81 (38.9) 55 (26.4) 24 (11.5) 6 (2.9) 2 (1.0) 6 (2.9) 0.1627Hyperpigmentation 1 (1.4) 7 (9.9) 25 (35.2) 21 (29.6) 13 (18.3) 2 (2.8) 0 (0.0) 2 (2.8) 0.9074Pruritus 5 (1.1) 53 (11.3) 147 (31.5) 156 (33.4) 63 (13.5) 19 (4.1) 4 (0.9) 20 (4.3) 0.0438Nightmares 1 (1.8) 5 (8.9) 17 (30.4) 17 (30.4) 9 (16.1) 3 (5.4) 1 (1.8) 3 (5.4) 0.9974SJS 1 (2.6) 2 (5.3) 15 (39.5) 7 (18.4) 7 (18.4) 1 (2.6) 0 (0.0) 5 (13.2) 0.6068Fever 13 (6.9) 21 (11.1) 66 (34.9) 51 (27.0) 20 (10.6) 6 (3.2) 2 (1.1) 10 (5.3) 0.0214Depression 0 (0.0) 0 (0.0) 2 (20.0) 4 (40.0) 2 (20.0) 2 (20.0) 0 (0.0) 0 (0.0) 0.2728Epigastric pain 1 (2.4) 6 (14.6) 12 (29.3) 12 (29.3) 6 (14.6) 1 (2.4) 0 (0.0) 3 (7.3) 0.9454

Table 5: Association of significant ADRs reported in patients on ART with age; Values are Odds ratio at 95% Confidence interval*.

AD descriptions

Age group associated with the suspected ADR (years)

Odds Ratios (95% CI)

Total, N

P-value

Headache

25 –

34

1.4 (1.2, 1.6)

658

0.0002

Fatigue

45 –

54

1.4 (1.1, 1.8)

441

0.0144

Hearing difficulty

< 15

5.3 (1.3, 18.8)

25

0.0026

Abdominal pain

15 –

24

1.6 (1.2, 2.2)

357

0.0037

25 –

34

1.3 (1.1, 1.7)

0.0126

Skin rash

< 15

1.5 (1.1,

2.2)

1157

0.0178

Nausea / Vomiting

15 –

24

2.0 (1.5, 2.6)

392

0.0000

25 –

34

1.4 (1.1, 1.7)

0.0035


35 –

44

1.2 (1.0, 1.4)

888

0.0291

45 –

54

1.9 (1.6, 2.2)

0.0000

55 –

64

1.9 (1.3, 2.4)

0.0002

> 64

2.0 (1.1, 3.5)

0.0095

Arthralgia

35 –

44

1.7 (1.0, 2.7)

78

0.0295

55 –

64

2.5 (1.1, 5.7)

0.0177

Cough

< 15

7.4 (4.3, 12.1)

157

0.0000

Pruritus

15 –

24

1.4 (1.0, 1.9)

467

0.0331

35 –

44

1.3 (1.0, 1.6)

0.0190

Feer

< 15

3.0 (1.6, 5.5)

189

0.0001

Dystonia

< 15

77.5 (7.0, 859.1)

3

0.0000

Restlessness

< 15

25.8 (3.0, 190.5)

5

0.0000

Dysuria

> 64

86.5 (5.4, 1395.1)

2

0.0000

Syncope

Not Indicated

10.5 (2.5, 42.1)

10

0.0000

* p < 0.042.

Statistical significance after correcting for multiple comparisons using the Bonferroni method was



Table 6: Frequency distribution of significant suspected ADRs segregated by concomitant medicines received by patients on ART who reported the ADRs; Percentages are in parenthesis§, n = 5564 ADR descriptions Concomitant Medicines

P-valueCotrimoxazole Haematinics Antimalarial Fluconazole NSAID Metronidazole Others* Not indicated

Headache 297 (61.4) 80 (16.5) 8 (1.7) 0 (0.0) 15 (3.1) 0 (0.0) 4 (0.8) 80 (16.5) 0.0001Anaemia

98 (69.0)

11 (7.7)

5 (3.5)

1 (0.7)

0 (0.0)

0 (0.0) 6 (4.2) 21 (14.8) 0.0321

Abdominal Pain

208 (69.1)

39 (13.0)

4 (1.3)

2 (0.7)

1 (0.3)

8 (2.7) 15 (5.0) 24 (8.0) 0.0001Lipodystrophy

37 (67.3)

4 (7.3)

0 (0.0)

0 (0.0)

4 (7.3)

2 (3.6) 7 (12.7) 1 (1.8) 0.0000

Skin rash

806 (70.1)

141 (12.3)

10 (0.9)

19 (1.7)

17 (1.5)

3 (0.3) 23 (2.0) 131 (11.4) 0.0080Syncope

2 (40.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0) 3 (60.0) 0 (0.0) 0.0000

Dizziness

145 (59.2)

19 (7.8)

6 (2.4)

1 (0.4)

6 (2.4)

1 (0.4) 15 (6.1) 52 (21.2) 0.0000Tingling, Numbness, Pain in the extremities

616 (69.8)

144 (16.3)

9 (1.0)

6 (0.7)

26 (2.9)

1 (0.1) 20 (2.3) 60 (6.8)

0.0000

Flatulence

7 (38.9)

7 (38.9)

0 (0.0)

0 (0.0)

0 (0.0)

0 (0.0) 3 (16.7) 1 (5.6) 0.0050Myalgia

35 (43.8)

10 (12.5)

0 (0.0)

1 (1.3)

4 (5.0)

0 (0.0) 2 (2.5) 28 (35.0) 0.0000Diarrhoea

71 (49.3)

22 (15.3)

0 (0.0)

3 (2.1)

1 (0.7)

7 (4.9) 13 (9.0) 27 (18.8) 0.0000Pruritus

151 (57.6)

30 (11.5)

0 (0.0)

3 (1.1)

7 (2.7)

0 (0.0) 5 (1.9) 66 (25.2) 0.0000Polyuria

20 (55.6)

8 (22.2)

2 (5.6)

0 (0.0)

0 (0.0)

2 (5.6) 2 (5.6) 2 (5.6) 0.0014Depression 3 (60.) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0) 1 (20.0) 0.0001Dysphagia 2 (22.2) 0 (0.0) 0 (0.0) 6 (66.7) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0.0000Malaise 4 (33.3) 2 (16.7) 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) 0 (0.0) 5 (41.7) 0.0210Confusion 2 (33.3) 1 (16.7) 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) 1 (16.7) 0.0228Seizures 0 (0.0) 2 (66.7) 0 (0.0) 1 (33.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0.0000Increased perspiration 2 (40.0) 1 (20.0) 1 (20.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (20.0) 0 (0.0)

0.0051Hearing difficulty 10 (41.7) 3 (12.5) 0 (0.0) 0 (0.0) 3 (12.5) 0 (0.0) 5 (20.8) 3 (12.5) 0.0000Total 3664 (65.9) 809 (14.5) 63 (1.1) 54 (1.0) 95 (1.7) 35 (0.6) 167 (3.0) 677 (12.2) –

Others* include Antihistamines, Ciprofloxacin, Amoxicillin, Anti-tuberculosis drugs, Antacids, Erythromycin, Loperamide, Albendazole, Nifedipine, Acyclovir, Metoclopramide, Cefuroxime, Lincomycin, Prednisolone, Amitriptyline, Hyoscine Butyl bromide, Verapamil, Omeprazole, Lisinopril,Gentamicin, Atenolol, Tetracycline, Salbutamol, Clarithromycin, Diazepam and

§Bromocriptine. Some insignificant ADRs are omitted in this table.


Agu et al

Table 7: Association of significant ADRs reported in patients on ART with concomitant medicines; Values are Odds ratio at 95% Confidence interval*.

ADR descriptions Concomitant Medicines associated with the suspected ADR

Odds Ratios (95% CI) Total, N P-value

Headache NSAIDs 2.0 (1.1, 3.6) 658 0.0134

Anaemia Antimalarial drugs 3.4 (1.2, 8.9) 151 0.0064

Increased perspiration Antimalarial drugs 22.1 (2.4, 201.2) 5 0.0000

Others**

8.1 (0.9, 3.1)

0.0258

Hearing Difficulty

NSAIDs

8.5 (2.0, 30.6)

24 0.0000

Others**

8.7 (2.8, 25.2)

0.0000

Skin rash

Cotrimoxazole

1.3 (1.1, 1.5)

1150 0.0007

Fluconazole

2.1 (1.2, 3.8)

0.0081

Abdominal pain

Metronidazole

5.3 (2.2, 12.3)

301 0.0000

Others**

1.8 (1.0, 3.1)

0.0383

Lipodystrophy

NSAIDs

4.7 (1.4, 13.8)

55 0.0014

Metronidazole

6.3 (1.5, 26.8)

0.0046

Others**

4.9 (2.0, 11.4)

0.0000

Syncope

Others**

49.3 (6.7, 43.0)

5

0.0000

Dizziness

Others**

2.2 (1.2, 3.9)

245 0.0034ingling, Numbness, Pain in the extremities

Cotrimoxazole

1.2 (1.1, 1.5)

882 0.0065NSAIDs

2.0 (1.3, 3.3)

0.0019Flatulence

Haematinics

3.8 (1.3, 10.5)

18 0.0033Others**

6.6 (1.5, 24.4)

0.0007Myalgia

Not Indicated§

4.0 (2.5, 6.5)

80 0.0000Diarrhoea

Metronidazole

9.8 (3.8, 24.1)

144 0.0000Others**

3.4 (1.8, 6.3)

0.0000Not Indicated§ 1.7 (1.1, 2.6) 0.0144

Pruritus Not Indicated§ 2.6 (1.9, 3.5) 262 0.0000Ysphagia Fluconazole 229.5 (49.2, 1197.7) 9 0.0000Polyuria Antimalarial drugs 5.3 (1.2, 22.4) 36 0.0119

Metronidazole 9.8 (2.3, 42.5) 0.0002Depression Metronidazole 40.6 (4.4, 373.0) 5 0.0000Malaise Not Indicated§ 5.2 (1.4, 18.2) 12 0.0018Confusion Antimalarial drugs 17.7 (2.0, 154.0) 6 0.0003

* was p < 0.042. NSAID §means Non-Steroidal Anti-inflammatory Drugs; Not indicated means that the name or class of the concomitant medicines were

not indicated; Others** include Antihistamines, Ciprofloxacin, Amoxicillin, Anti-tuberculosis drugs, Antacids, Erythromycin, Loperamide, Albendazole, Nifedipine, Acyclovir, Metoclopramide, Cefuroxime, Lincomycin, Prednisolone, Amitriptyline, Hyoscine Butyl bromide, Verapamil, Omeprazole, Lisinopril, Gentamicin, Atenolol, Tetracycline, Salbutamol, Clarithromycin, Diazepam and Bromocriptine

Statistical significance after correcting for multiple comparisons using the Bonferroni method

ADR TreatmentThe actions taken to manage the reported ADRs were not indicated in 3521(76.5%) of cases. The actions taken (where indicated) included: 329 (7.2%) substitution of the suspected drug with another; 550(12.0%) new drugs taken to treat ADR; 128(2.8%) patients' counselling on the management of the ADRs; 24(0.5%) blood transfusion due to ADR; 3(0.1%) treatment interruptions due to ADRs; 42(0.9%), patient hospitalization; 1(0.0%) referral to specialized clinic for ADR management; and 2(0.0%) reduction of

the dose of the suspected drug.

ADR outcomes Of these reported ADR cases, 1,074(23.3%) recovered fully, 196(4.3%) showed improvement though still recovering, 11(0.2%) recovered with disability, 6(0.1%) death due to reported ADR, 3(0.1%) congenital abnormality, and 42(0.9%) of the suspected ADRs were reported as life threatening. However, the outcome of 3,268(71.0%) suspected ADR cases was not indicated. The nature of the disability and congenital abnormality



were also not indicated.

DISCUSSIONThis study reported incidence and nature of ADRs in patients on ART in Nigeria. The overall incidence of grade II to IV ADRs reported in this study was 6.3%. This incidence was very low compared to 43.8% reported in intensively monitored ART patients in

4India , but slightly higher than previous reports in 11, 22

Uganda and Nigeria. The exclusion of mild ADRs in this study may be contributory to the low ADR incidence reported. The proportion of patients on ART who reported ADRs was higher among those who received d4T-based regimen (32.1%) compared to AZT-based regimen (10.7%). This f inding supports the WHO recommendation to discontinue the use of d4T-based regimens in adolescents and adults patients due to

20associated adverse effects. Currently, all patients who received d4T-based regimens are gradually being switched to AZT-based, TDF-based or other regimens while ART-naïve patients are no longer commenced d4T-based regimens. Lipodystrophy was highest among those that received d4T-based regimens. Skin rash constituted the highest ADR reported among the ART patients followed by tingling, numbness, and pain in the extremities (known symptoms of peripheral neuropathy) and headache. This study corroborated previous research findings that skin rash and peripheral neuropathy were common ADRs in

6, 12, 13ART patients. The study findings showed very low occurrence of nausea/vomiting, diarrhoea, dizziness, and bad dreams/nightmares compared to previous

12study findings by Olowookere et al. However, the occurrence of skin rash was higher in this study. Of cases of skin rash, majority of the patients received NVP-based regimens. The common adverse effect of

21NVP is skin rash. However; there was no significant association between skin rash and NVP-based regimens; significant association was found between skin rash and Cotrimoxazole, a concomitant medicine used by these patients. The occurrence of ADRs was found to be associated with specific ART regimens, concomitant medicines and age. This is consistent

6with previous research findings. Lipodystrophy was associated with d4T-based regimens. This is

8-10consistent with previous study findings but the proportion of patients who reported lipodystrophy in this study was very low (0.8%) compared to previous

8-11 reports (17% to 63%).The study showed no significant association between sex and occurrence of ADR, contrary to a previous

6study finding. This lack of association between sex and ADR occurrence may be due to large proportion of female participants that were neither pregnant nor breastfeeding or there may be no association.

20Pregnancy is a known risk factor for ADRs occurrence.The occurrence of “tingling, numbness, and pain in the extremities” was highest in patients who received a d4T/3TC/NVP regimen. Headache and anaemia were highest in patients who received AZT/3TC/NVP regimen. Nightmares, hallucination, drowsiness, and depression were highest in patients that received an EFV-based regimen. This is consistent with known CNS adverse effects of EFV-based regimens. The incidence of moderate, severe or life-threatening ADRs was 45.7% in patients less than 35 years of age compared to 48.3% in patients greater than 35 years of age. This difference was not statistically significant comparable

6to previous study findings. Causality assessment is required to determine the extent of relationship

16between a drug and a suspected adverse reaction. The majority of the actions taken to treat ADRs were not indicated. In cases where ADR treatments were indicated, the majority involved initiation of other drugs to treat the ADR and the substitution of the suspected drug with another. A large preponderance of the ADR outcomes was also not indicated and this suggests the need to more closely follow up and complete documentation of all services provided to patients.Following GHAIN interventions, ADRs reporting rates increased significantly by over 58-folds from April 2009 to December 2010 compared to previous report of scanty ICSRs related to ARVs in NAFDAC database from

15 2004 to April 2009.The study provided the second data on the incidence of suspected ADRs in patients on ART in Nigeria. It also shows that active surveillance for ADRs in HIV-positive patients on ART is feasible in resource-constrained health facilities using pharmaceutical care in HIV interventions. However, the study excluded ADRs caused by other drug related problems such as overdose, drug abuse, misuse, poisoning, medication errors and therapeutic failures. Inadequate pharmacy personnel and high patient load were the major barriers to achieving active surveillance for ADRs, thus some ADRs cases in patients may have been missed. Only moderate, severe or life-threatening ADRs cases were analyzed in this study. Though, grade II to IV ADRs cases were reported, the specific severity grades of the ICSRs were not indicated in the case reports. This limited the stratification of the case reports by ADR severity grades. The reported ADR was defined in this study as clinical signs and/or symptoms suggestive


Agu et al

ADRs. No confirmatory clinical investigations were conducted at the time of the ADR reporting. This has the potential to over-estimate the incidence of ADRs of severity grades II to IV, if HIV or opportunistic infections related signs and/or symptoms were reported as ADRs. Other potential limitations of this study included the use of self-reported data, lack of inclusion of all sites due to lack of ADR screening programs uniformly, potential for patients to not report symptoms out of fear or other concerns, etc.

CONCLUSION There was low incidence of ADRs of severity grades II to IV which was higher in patients that received d4T-based regimen compared to other regimens. The occurrence of ADRs had significant association with ART regimens, the concomitant medicines and patients' age unlike gender. The tingling, numbness, and pain in the extremities (symptoms of peripheral neuropathy) and skin rash were major ADRs reported.Provision of adequate qualified personnel is warranted to sustain routine active ADR surveillance in a resource-constrained setting.

CONFLICT OF INTERESTWe declare no conflict of interest

ACKNOWLEDGMENTSSupport for this paper was provided by Global HIV/AIDS Initiative in Nigeria (GHAIN) with funds from the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through U.S. Agency for International Development (USAID) Cooperative Agreement No. 620-A-00-04-00122-00. We acknowledge Dr. Henry Fomundam for his technical assistance. We also acknowledge Dr Grace Jennings and all staff of HU PACE in Nigeria and USA who supported the successful conduct of the GHAIN pharmacovigilance program. The views expressed in this publication are that of the authors and do not necessarily reflect those of FHI360 and Howard University Pharmacists and Continuing Education (HU PACE) Center.

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