Introduction Methods Materials Result and discussion

POSTGRADUATE PROGRAM DIRECTORATE

November 8, 2022

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Introduction Methods Materials Result and discussion

INCIDENCE AND PREDICTORS OF SEVERE ADVERSE DRUG

REACTIONS AMONG PATIENTS ON ANTIRETROVIRAL DRUGS
IN HARARI REGIONAL STATE, EASTERN ETHIOPIA

MPH Thesis Open Defence

By: Obsa A.

Advisors: Tariku Dingeta (Ph.D) And Bahelu (MPH, Assis. Prof.)

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Introduction Methods Materials Result and discussion

Presentation Outlines

1. Introduction

2. Methods and Materials

3. Result and Discussion

4. Conclusion and Recommendation

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Introduction Methods Materials Result and discussion

Background
The introduction of Combination ART Played a great role
in treatment of HIV infection, reduction of morbidity and
mortality, improved survival and clinical outcome (Gonzalo
et al., 2009, Punyawudho et al., 2016, Korten et al., 2021)

-However alongside all its advantage, challenges related

to its associated ADRs are threatening the progress still
which is the major reason for defaulting, nonadherence that
leads to poor treatment outcome (WHO, 2009, WHO, 2010,
Eluwa et al., 2012b, Hagos et al., 2019, Kibret et al.,
2019, Tetteh et al., 2016, Hadaye et al., 2020) 4 / 43
Introduction Methods Materials Result and discussion

Statement of the Problem

▶ Severe ADRs is one of the major public health con-
cerns for the reason that majority of the patients on
ART experiences ADRs (Oumar et al., 2017).

▶ Due to potential prolonged exposure to ARV PLWH ex-

perience ARV associated toxicity which is one of the
common reasons for; poor/non adherence, RX discon-
tinuation, and drug substitution esp. in the 1st 3-6Month,
premature RX cessation, affect their life and finally leads
to early death (Abdissa et al., 2012, FMOH, 2017, Mendes et al.,

2018, Ejigu et al., 2018, Assemie et al., 2019, Carr et al., 2019)
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Introduction Methods Materials Result and discussion

...Cont’d
To overcome these ADRs associated with ART different
interventions were undertaken
Some drugs like stavudine (d4T) were phased out (WHO,
2010, Castelnuovo et al., 2011)
Different kinds of literature reported different predictors
of severe ADRs (Anwikar et al., 2011, Coffie et al., 2010,
Gebremeskel et al., 2021,..)
Several previous studies reported that advanced HIV disease (WHO clinical
stage 3 and 4) as independent predictors (Abah et al., 2015a, Kindie et al.,
2017, and Kibret et al., 2019 )

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Introduction Methods Materials Result and discussion

...Cont’d
In controversy to this other studies reported that ad-
vanced WHO clinical stage was not an independent predic-
tor (Mengistu, 2007, Lartey et al., 2014b, Bezabhe et al.,
2015,. . . ).
Several previous studies on the adverse reaction of ART
were focused on the incidence and predictors of all forms
of ADRs and few were assessed the severe forms of the
ADRs of ART drugs in Ethiopia particularly in the current
study area

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Introduction Methods Materials Result and discussion

Objectives
General Objective
To assess the incidence and predictors of the severe ADRs
among PLWH on antiretroviral therapy from February 25 to
March 25, 2022 GC.

Specific Objective
▶ To assess the incidence of the Severe ADRs among
PLWH on antiretroviral therapy.

▶ To identify Predictors of the severe ADRs among PLWH

on antiretroviral therapy in Harari, Eastern Ethiopia.

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Introduction Methods Materials Result and discussion

Study Area and Period

▶ Study was conducted in Harari Regional State, located
in the Eastern part of the Country and 526km away
from the capital
▶ The region has a total population of 276,424.
▶ Randomly selected Public health hospitals were study
setup.
▶ Data extraction was conducted from February 25 to
March 25, 2022 GC.

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Introduction Methods Materials Result and discussion

...Cont’d
Study Design: A hospital-based retrospective cohort
study design was used
Population
▶ Source Population: PLWH attending ART clinic in
Harari Region Public hospitals
▶ Study Population
1. Exposed Group: Randomly selected PLWH attending ART clinic
and whose baseline WHO clinical stage III and IV (with advanced
disease at baseline)
2. Unexposed Group: Randomly selected PLWH attending ART clinic
and whose baseline WHO clinical stage I and II
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Introduction Methods Materials Result and discussion

Sample Size determination

Was determined for the survival data, Cox regression
model by using Epi info version 7 by taking the percent of
the exposed and unexposed group who experienced se-
vere ADRs 19% and 9% respectively from previous studies
(Kibret et al., 2019), with considerations of the following
assumptions :
Variables Assumption (per-

cent)
Exposed group who experienced severe 19%
ADRs
Unexposed group who experienced se- 9%
vere ADRs
Confidence level 5%
Power 80%
Margin of error 5% 11 / 43
Introduction Methods Materials Result and discussion

...Cont’d
Sampling Technique
▶ PPS was employed to select the study setup

▶ All eligible participants on ART follow-up were obtained

from facilities ART clinics and used as Sampling frame

▶ Computer-generated simple random sampling using a

unique ART ID was employed to select the study unit

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Introduction Methods Materials Result and discussion

Sampling Procedure

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Introduction Methods Materials Result and discussion

Data Collection Method

Data Collection Tool
Structured questionnaire/data extraction form was used

Study variables
Dependent/outcome Variable
Severe ADRs
Independent/Exposure variables
Sociodemographic: Age, Sex, Place of residence, Occupational status,
educational status, Marital status, religion, and enrollment month/year
Behavioral Variables: disclosure status and nutritional status
Clinical and immunological: BMI, CD4 count, WHO Clinical Stage, the
experience of TB infection, etc. . .

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Introduction Methods Materials Result and discussion

Data Quality Control

▶ Any missed data was checked before the next day col-
lection starts

▶ Double entry was conducted by HIT to check the data

consistency

▶ 95% CI of hazard ratio was calculated and variable

with p-value 0.05 in the Cox The proportional hazards
model was considered and declared as significant

▶ The Schoenfeld residuals test was used to check the

goodness of model fitness
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Introduction Methods Materials Result and discussion

Sociodemographic Chxs of the Cohort

▶ In this study total of 449 (150 exposed and 299 unex-
posed) participants’ data was retrieved and included in
the analysis
▶ 55.5% of the participants were females and nearly half
of the patients’ age ranged from 35-44 years at the time
of the ART initiation with a mean of 38 years (+8.44 SD)
▶ Nearly half of the patients’ one-third of the patients were
self employed and 58.8% were married

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Introduction Methods Materials Result and discussion
...Result
Characteristic (n=449) Exposed (n=150) Unexposed (n=299)
HFSUH 92 (61.3%) 232 (77.6%)
Hospitals Jugol Hospital 58 (39.7%) 67 (22.4/%)
Male 59 (39.3%) 141 (47.2%)
Gender Female 91 (40.7%) 158 (52.8%)
8 (5.3%) 10 (3.3%)
15-24
25-34 40 (27%) 98 (32.8%)
35-44 68 (46%) 135 (45.2%)
Age in years 45 34 (21.7%) 56 (18.7%)
Single 16 (10.7%) 24 (8%)
Married 75 (50%) 189 (63.2%)
Separated/Divorced 39 (26%) 64 (21.4%)
Marital status Widowed/Widower 20 (13.3%) 22 (7.4%)
Employed 33 (22%) 46 (15.4%)
Daily Laborer 20 (13.3%) 39 (13%)
Driver 11 (7.3%) 31 (10.4%)
Private 44 (29.3%) 96 (32.1%)
Occupation No Job 42 (28%) 87 (29.1%)
No Formal education 34 (23%) 85 (28.4%)
Primary (1-8) 57 (38%) 111 (37.1%)
Secondary (9-12) 37 (25%) 61 (20.4%)
Education College and above 22 (14%) 42 (14.1%)
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Introduction Methods Materials Result and discussion

...Cont’d
Within Catchment 49 (33%) 99 (33.1%)
Residence Out of Catchment 101 (67%) 200 (66.9%)
Orthodox 89 (59.3%) 172 (57.5%)
Muslim 53 (35.3%) 109 (36.5%)
Religion Protestant 8 (5.4%) 18 (6%)

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Introduction Methods Materials Result and discussion

Behavioral and nutritional chxs of the Cohort

▶ More than one-third of the patients have disclosed their
serostatus to either their family or sexual partners and
also have normal nutritional status at the time of ART
initiation
Characteristics (n=449) Exposed (n=150) Unexposed (n=299)
Disclosed 95 (63.3%) 207 (69.2%)
Disclosure Status Not Disclosed 55 (36.7%) 92 (30.8%)
Undernutrition 227 (75.9%)
Normal 58 (19.4%)
Nutritional Status Overnutrition 14 (4.6%)

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Introduction Methods Materials Result and discussion

Clinical chxs of the Cohort

▶ More than 80% of the cohort had a CD4 count of
200cells/mm3
▶ More than one-third of the patients had normal BMI
15% of the patients at ART initiation time experienced
HIV/TB infections
▶ Most of the HIV-positive patients at their ART initiation
were on WHO Clinical stage I (39.2%)
▶ More than one-third of the patients were on
1e (TDF+EFV+3TC) regimen at baseline

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Introduction Methods Materials Result and discussion

Characteristics (n=449) Exposed (n=150) Unexposed (n=299)

<200 63(42%) 24 (8%)
CD4 Count (cells/mm3) * ≥ 200 87 (58%) 275 (92%)
Underweight 62 (41.3%) 59 ((19.7%)
Normal 84 (56%) 226 (75.6%)
BMI Overweight and obese 4 (2.7%) 14 (4.7%)
Stage I
176 (58.8%)
Stage II
123(41.2%)
Stage III 128 (85.3%)
WHO Clinical stage Stage IV 22 (14.7%)
Yes 56 (37.3%) 12 (4%)
Experience of TB infection No 94 (62.7%) 287 (96%)
Experience of Yes 73 (48.7%) 176 (58.8%)
regimen change No 77 (51.3%) 123 (41.2%)
Experience of other Yes 92 (61.3%) 84 (28.1%)
OIs other than TB No 58 (38.7%) 215 (71.9%)
15 (10%) 257 (86%)
Working
106 (70.6%) 42 (14%)
Functional Status Ambulatory
29 (19.4%) 0
during ART initiation Bedridden
1c/1e 109 (72.6%) 215 (71.9%)
1J 33 (22%) 72 (24%)
Baseline Regimen Others 8 (5.4%) 12 (4.1%)
..continues
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Introduction Methods Materials Result and discussion

Characteristics (n=449) Exposed (n=150) Unexposed (n=299)

Experience of taking Yes 150 (100%) 217 (72.6%)
of other medication¥ No 0 82 (21.4%))
Yes 82 (54.6%) 148 (49.5%)
Ever took CPT No 68 (46.4%) 151 (50.1%)
Yes 49 (32.6%) 158 (52.8%)
Ever took anti-TB prophylaxis No 101 (73.4%) 141 (47.2%)
Adherence status Good 111 (76.6%) 246 (82.6%)

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Introduction Methods Materials Result and discussion

Survival Probability
▶ Due to smaller events in the cohort the median survival
time was not computable
▶ About 40 (81.63%) events occurred in the first year of
ART enrollment of which 59.1% occurred in the first six
months.
▶ The cumulative survival probability of developing severe
ADRs among PLWH on ART at 6, 12, 24, and 36 were
0.82, 0.57, 0.23, and 0.036, respectively

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Introduction Methods Materials Result and discussion

Overall Kaplan-Meir Survival estimate curve among PLWHA on ART in

Harari, Eastern Ethiopia

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Introduction Methods Materials Result and discussion

Kaplan-Meir Survival estimate Curve for the time to develop severe ADRs
among PLWHA on ART by their Exposure status in Harari, Eastern Ethiopia

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Introduction Methods Materials Result and discussion

Life table for Severe Adverse drug reactions among HIV-positive patients on

ART in Harari, Eastern Ethiopia, February 25 to March 25, 2022 GC

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Introduction Methods Materials Result and discussion

Incidence of severe ADRs

▶ From total study participants 49 (10.91%) of them de-
veloped Severe ADRs in 6782 person-months of obser-
vations
▶ Incidence rate was 1.8 (95% CI: 0.013, 0.025), and
1.1 (95% CI: 0.78, 1.5) per 100 person month among
exposed, and females patients respectively

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Introduction Methods Materials Result and discussion

Incidence of severe ADRs

▶ The overall incidence was 0.722 (95% CI: 0.55 - 0.96)
per 100 person-month observations which are con-
sistent with studies conducted in RCT study in Haiti
11% (Severe et al., 2010), Observational study in
Kenya, 13% (Wangai et al., 2011), Arbaminch, South-
ern Ethiopia, 0.53 per 100 person month (Sherfa et
al., 2021), Seven teaching hospital in Ethiopia, 9.5%
(Gudina et al., 2017), Observational study in Black loin
Hospital,7.7% (Abdissa et al., 2012)
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Introduction Methods Materials Result and discussion

...Cont’d
▶ On the other hand the finding in the current study was
lower than the findings in:
▶ India 23.1% (Nagpal et al., 2010), Nigeria, 16.8% (Obiako et al.,

2012b), Ethiopia, Felege Hiwot/Gondar University, 3.2/100 person

month (Bezabhe et al., 2015) and 22.9Nigist Elleni memorial hospital
(Tamirat et al., 2020)
This difference is attributed to differences in; follow up period
▶ 6 Mo in India, 12 mo in Felege Hiwot, Gondar university
▶ FMOH, WHO, and other studies stated that ADRs among PLWH

on ART in the first year is high/common (WHO, 2020, FMOH, 2017,

Mendes et al., 2018, Carr et al., 2019, Gudina et al., 2017)

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Introduction Methods Materials Result and discussion

...Cont’d
Data collection/study design may influence the incidence
Definitions of ADRs across the study were different.
Another possible reason is the difference in sample size
On the other hand, the current finding is relatively higher
than the study conducted in Tigray regional state reports
3.6 per 100 person-year (Gebremeskel et al., 2021), and
Debramarkos which reports 3 per 100 person-years (Kibret
et al., 2019);
This is supported by that the current study follow-up was shorter than the
two studies. ADRs are more likely to occur in the first years (WHO, 2020). 30 / 43
Introduction Methods Materials Result and discussion

Predictors of the Severe ADRs

After hazard assumptions were checked for each covari-
ate, all covariates with P-value 0.25 in bivariate analysis
were considered as a candidate for multivariate CPH re-
gression analysis
Those covariates were health facility, sex, CD4 count
at baseline, baseline BMI, WHO clinical stage, HIV/TB
confection, experiencing other OIs than TB, and taking
of other medication at baseline.
In the final model only 3 covariates; WHO clinical stage, Gender, and HIV/TB
infection were significantly associated with the severe 31 / 43
Introduction Methods Materials Result and discussion

Multivariate CPH

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Introduction Methods Materials Result and discussion

...Cont’d
▶ Exposed group, those who presented with the advanced
clinical disease at ART initiation, (AHR=3.29; 95% CI:
1.47, 7.39) were more likely to experience severe ADRs
compared to unexposed
▶ This finding is supported by an observational study
in Nigeria (Abah et al., 2015b), Debramarkos, North-
ern Ethiopia, Arbaminch, Southern Ethiopia, and Kaffa
Zone, south West Ethiopia (Kibret et al., 2019, Sherfa
et al., 2021, Mitkie et al., 2021).
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Introduction Methods Materials Result and discussion

...Cont’d
▶ Patients with advanced disease were more likely to
experience d/t comorbidities which may lead to taking
multiple drugs at one time and place them to experience
severe ADRs (Alomar, 2014b);
▶ Those patients with multiple medications are more likely
to experience severe ADRs (Alomar, 2014b)
▶ Patients with advanced disease may have altered pharmacodynamics
and pharmacokinetics mechanisms due to drug reactions that predispose
them to experience ADRs (Alomar, 2014a, Mudigubba et al., 2018)

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Introduction Methods Materials Result and discussion

...Cont’d
▶ Patients who experienced HIV/TB coinfection at ART
initiation were two times more likely to experience se-
vere ADRs compared to those who didn’t
▶ The finding is similar to study findings in seven teaching
hospitals and Southern Ethiopia (Tamirat et al., 2020,
Gudina et al., 2017); this may be explained by:

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Introduction Methods Materials Result and discussion

...Cont’d
▶ Overlapping toxicities of anti-TB and ART drugs that
were well documented and even some kinds of literature
defer ART drugs during the intensive phase of TB Rx
▶ There is also well-documented drug-to-drug interactions
between anti-TB and ART drugs (Regazzi et al., 2014,
Cerrone et al., 2020, Breen et al., 2006)

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Introduction Methods Materials Result and discussion

...Cont’d
▶ Female patients were three times (AHR=3.06; 95% CI:
1.54, 6.06) at higher risk of experiencing severe ADRs
compared to males; which is consistent with the study
in:

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Introduction Methods Materials Result and discussion

...Cont’d
A possible explanation may be attributed to:
▶ Physiological differences i.e. female has lower lean
body mass than male
▶ Reduction of hepatic clearance in females
▶ Differences in activity of cytochrome P450 (CYP) en-
zymes and metabolization at different rates compared
with men (Rademaker, 2001)

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Introduction Methods Materials Result and discussion

...Cont’d
▶ Additionally, females are known to use contraceptives,
and hormonal supplements during reproductive age
adding to increase the number of drugs that may make
them more likely to experience ADRs (Mudigubba et al.,
2018)

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Introduction Methods Materials Result and discussion

Conclusion and Recommendations

Conclusion
▶ In this study incidence of the severe ADRs was consis-
tent with other studies with considerable burden

▶ HIV-positive Patients with advanced WHO clinical dis-

ease, HIV/TB co-infection, and female patients at the
ART initiation should get special attention and close
follow-up to minimize the risk of severe ADRs

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Introduction Methods Materials Result and discussion

Conclusion and Recommendations

Recommendations
▶ HIV-positive patients with advanced clinical disease (ex-
posed) at the time of ART initiation should get attention
and be identified before ART initiation and followed
closely for severe ADRs; Early diagnosis and ART initi-
ation without delay is highly recommended to minimize
the risk of severe ADRs among HIV-positive patients

▶ Female patients and patients with HIV/TB coinfection

should be closely followed for all possible severe ADRs
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Introduction Methods Materials Result and discussion

Conclusion and Recommendations

Recommendations
▶ A prospective study should be done for precise mea-
surement of the incidence and its predictors of severe
ADRs among HIV-positive patients on ART

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Introduction Methods Materials Result and discussion

Thank You!

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