World Journal of AIDS, 2013, 3, 327-334
Published Online December 2013 (http://www.scirp.org/journal/wja)
http://dx.doi.org/10.4236/wja.2013.34042
Open Access WJA
327
Pattern of HIV-1 Drug Resistance among Adults on ART
in Nigeria*
Georgina N. Odaibo1, Prosper Okonkwo2, Isaac F. Adewole3, David O. Olaleye1#
1Department of Virology, College of Medicine, University of Ibadan, Ibadan, Nigeria; 2AIDS Prevention Initiative Nigeria, Arab
Contractor Building, Abuja, Nigeria; 3Department of Obstetrics and Gynecology, College of Medicine, University of Ibadan, Ibadan,
Nigeria.
Received July 1st, 2013; revised July 20th, 2013; accepted July 25th, 2013
Copyright © 2013 Georgina N. Odaibo et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Background: The development of anitiretroviral drug resistance may limit the benefit of antiretrov iral therapy. There-
fore the need to closely monitor these mutations, especially the use of ART is increasing. This study was therefore de-
signed to determine the ARV drug resistance pattern among ART naïve and expose individuals attending a PEPFAR
supported by antiretroviral clinic in Nigeria. Methodology: The study participants included patients attending the
PEPFAR supported by Univ ersity College Hospital (UCH), Ibadan ART clinic who have been on HIV treatment for at
least one year with consecutive viral load of over 2000 copies/ml as well some ART Naïve individuals with high
(>50,000 copies/ml) baseline viral level attending the hospital for pre-ART assessment. Blood sample was collected
from each individual for CD4 enumeration, viral load level determination and DNA sequencing for genotypic typing.
Antiretroviral drug resistance mutations (DRM) were determined by using the Viroseq software and drug mutations
generated by using a combination of Viroseq and Stanford algorithm. DRM were classified as major or minor mutations
based on the June 2013 Stanford DR database. Results: The most common major NRTI, NNRTI and PI mutation were
D67N (33.3%), Y181C (16.7%) and M46L/I (55.6%) respectively. Lamivudine (3TC) and emtricitabine (FTC); nevi-
rapine (NVP) and nelfinavir (NFV) were the most common NRTI, NNRTI, and PI drugs to which the virus in the in-
fected individuals developed resistance. Isolates from 4 patients were resistant to triple drug class, including at least one
NRTI, NNRTI and a PI. Only one (4.8%) of the isolates from drug Naïve individuals had major DRM that conferred
resistance to any drug. Conclusion: Demonstration of high rates of antiretroviral DRM among patients on 1st and 2nd
line ART and the presence of DRM in drug Naïve ind ividuals in this study show the importance of surveillan ce for re-
sistance to ARV in line with the magnitude of scaling up of treatment program in the country.
Keywords: Antiretroviral Therapy; Drug Resistance Mutation; ART Naïve; 1st and 2nd Line ART
1. Introduction
HIV/AIDS continues to be a global health problem since
its discovery in 1981 [1] with over 33 million people
living with the viru s at the end of 2011 [2 ]. The first case
of AIDS was reported in Nigeria in 1986 and the rate of
HIV infection in the country increased steadily from
0.6% in 1987 to a peak of 5.8% in 2003. The last HIV
national sentinel su rvey in the co untry sh ows th at the rate
of infection has declined to 3.4% [3], though the pre-
valence varies by locations from a relatively low rate of
2.1% in the north central and 2.9% in south western
zones respectively to a high rate of 7.5% in the north
central zone of the country.
According to UNAIDS, the number of new infections
globally reduced to 2.5 million in 2011 from 3.2 million
in 2001 [2]. Part of the reasons for this success may not
be unrelated to the wide spread use of antiretroviral the-
rapy (ART). There are evidences that ART contributes
greatly to the reduction of transmission, morbidity and
mortality caused by HIV infection [4-6]. This dramatic
improvement that is most prominent in the North Amer-
ica, Western Europe and recently Brazil, has led to the
advocacy for increased access to antiretroviral drugs in
*Funding: the study was carried out with funding from Center for Dis-
ease Control and Prevention through AIDS Prevention Initiative Nige-
ria (APIN).
#Corresponding author.

Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 328
resource limited settings [1,7-10]. Many African coun-
tries have responded positively and increased access to
ART, though with support from international agencies
[11-15].
In Nigeria, wide use of ART started in 2002 when the
Federal Government launched the pilot HIV treatment
program [9,10]. Additional funding for antiretroviral
treatment became available in the country through the US
government funded by President’s Emergency Plan for
AIDS Relief (PEPFAR) program and the Global Funds
and thus they increased access to ART greatly. To date,
over 500,000 patients are on ART i n Ni geria, alt hough this
number is a far cry to the almost 1.5 million HIV positive
individuals who require treatment in the country [16].
The introduction of antiretroviral therapy has substan-
tially changed the natural history of HIV and AIDS. Un-
like the 80s and early 90s, peop le living with HIV/ AIDS
[PLWAs] now live better and longer, thus they are able
to contribute meaningfully to the economy of their coun-
try. However, development of drug resistance may limit
the benefit of antiretroviral therapy. Various r eports have
documented the increase of ARV drug resistance in dif-
ferent countries and regions of the world [17-21]. Al-
though the result of a recent WHO DRM survey which
reported that “rate of tran smitted DR continues to remain
limited in low-and-middle-income countries” [22] is as-
suring because of the initial skepticism [23,24] by the
international community, th ere is still the need to closely
monitor these mutations in each country, especially as
the use of ART increases. This study was therefore de-
signed to determine the ARV drug resistance pattern
among ART naïve and expose individuals attending the
PEPFAR supported by antiretrov iral clinic at the Univer-
sity College Hospital, Ibadan, the premier tertiary hospi-
tal in Nigeria.
2. Methodology
2.1. Study Site
This study was carried out among patients attending the
antiretroviral treatment clinic of the University College
Hospital (UCH), Ibadan, Nigeria. The UCH is the fore-
most teaching hospital located in the southwestern region
of Nigeria. The hospital runs 55 weekly specialty clinics
with patients’ referrals from many states in the south-
western region and from other parts of the country. Anti-
retroviral treatment started in the hospital in 2002 when
the Federal Government of Nigeria introduced ARV
program in the country. The treatment program was
scaled up in 2004 with support from the US government
President Emergency Fund for AIDS Relief (PEPFAR)
program throug h funding provided to th e Harvard Sch ool
of Public Health, Boston, USA. There are over 10,000
HIV infected individuals currently receiving care and
treatment in the hospital.
2.2. Study Population
The study participants included patients attending the
PEPFAR supported UCH ART clinic who have been on
HIV treatment for at least one year with consecutive viral
load of over 2000 copies/ml as well some ART Naïve
patients attending the hospital for pre-ART assessment.
Individuals who commenced therapy before 2005 were
excluded from this study because there were reported
drug stock-outs during the government of Nigeria pilot
treatment program that lasted un til late 2004 and so me of
the patients on that program were reported to have de-
veloped drug resistance mutations [20].
2.3. HIV Viral Load Determination (RNA
Quantification)
Viral load measurement was carried using the Roche
Amplicor version 1.5 with lower and upper detection li-
mits of 400 copies/m l and 750,000 copi es/m l respectivel y.
2.4. HIV Drug Resistance Genotyping
HIV RNA was extracted from 500 ul of plasma using the
QIAamp Viral RNA Extraction Mini Spin Kit (Qiagen,
Germany). HIV RNA was reverse transcribed to cDNA,
amplified and subsequently sequenced using the Viroseq
HIV-1 genotyping assay, version 2.0 as previously de-
scribed by Chaplin et al. [25]. Sequences were generated
using a 3130 XL genetic analyzer (Applied Biosystems)
and the generated sequences were edited and compared
with an HXB2 subtype B reference using the Viroseq
software and list of mutations generated. The mutations
were classified as minor or major base on the June 22,
2013 updated HIV drug resistance data base (http:/hivdb.
standard.edu). Resistance to each drug was determined
using a combination of the Viroseq and Stanford drug
resistance algorithms and resistance to each drug as-
signed as susceptible, intermediate or resistant.
3. Results
A total of 46 samples were analyzed in this study. The
characteristics of the patients whose samples were ana-
lyzed are shown in Table 1. The mean age of the par-
ticipants was 43 years (range, 29 - 70) and 58.7% of
them were female. However more male patients seem to
be failing 2nd line treatment while more female failed 1st
line drugs. The average time on ART was 3.2 (range, 0.5
- 5.5) years and 2.8 (range, 1 - 4) years for those failing
the 1st line and the 2nd line drugs respectively. There was
a gender bias in the time between ART commencement
and virologic failure for patients on 1st line regimen. The
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Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria
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329
average time was 4 years and 1.5 years for female and
male patients respectively. Only on e of the 21 patients on
ART had a major resistance mutation while 71.4% of
them had no resistance mutation (Table 2). Fifty percent
of the patients failing 1st line and 100% of those failing
2nd line had major resistance mutations. About 30% of
those failing 1st line drugs did not have any resistance
mutation while 19.8% of them had only minor mutations.
Table 3 shows the characteristics of individuals with
major resistance mutations. The mean CD4 and median
viral load of those with major resistance mutations were
lower than those of the study population (Table 1). The
only ART Naïve individual with a major mutation was a
female with CD4 of 23 cells/ul and viral load of 78,792
copies/ml.
The most common major NRTI mutation was D67N
followed by T215Y and M41L while the most frequent
major NNRTI mutations were Y181C and K103N. A mo ng
the PI mutations, the most frequent was M46L/I followed
by V82F/S/I and then I47V (Table 4). Other mutations
detected include: M184V/I (13) M41L (6), E44D (1)
T69N (2), L10I/V (16), V11I (3), A98G (7), P225H (1)
AND P236L (L). Table 5 shows the drugs by class to
which virus developed resistance. Lamivudine (3TC) and
emtricitabine (FTC); nevirapin (NVP) and nelfinavir
(NFV) were the most common NRTI, NNRTI, and PI
drugs respectively to which the virus in the infected indi-
viduals developed resistance. Virus from 4 of the patients
were resistant to more than six antiretroviral drugs (Ta-
ble 5) including 3TC, FTC, AZT, d4T, ABC, APV, FOS,
IDV, LPV, NFV, TPV. Isolates from the 4 patient sam-
ples were resistant to triple drug class, including at least
one NRTI, NNRTI and a PI. Interestingly the virus from
one of the patients who failed 2nd line treatment was re-
sistant to all the eleven drugs listed abo ve (Table 6). Vi-
rus from the only ART Naïve individual with major drug
resistance mutation was resistant to the PI nelvinavir
(NFV).
Table 1. Showing character i stic s of study the participants in the study.
ART status N Mean age (yrs.) Average time on ART (yrs.)Gender CD4 (cells/ul) Viral load (copies/ml)
MaleFemaleMean Range Median Range
Naïve 21 43.6 NA 9 12 219 14 - 723 102,755 8655 - 2,623,338
1st line failure 16 40.7 2.9 4 12 367 35 - 1165 168,008 3785 - 1,201,535
2nd line failure 9 45.8 2.1 6 3 199 32 - 769 95,261 3899 - 43,926
Total (overall) 46 43.0 NA 19 27 267 14 - 1165 100,417 3785 - 2,623,338
NA: Not Applicable.
Table 2. Resistance mutation types among patients enrolled in the study.
ART status No tested No.(%) mutations Minor mutations Major mutations
No. % No. % No. %
Naïve 21 15 71.4 5 23.8 1 4.8
1st line failure 16 5 31.2 3 19.8 8 50.0
2nd line failure 9 0 0.0 0 0.0 9 100
Total (overall) 46 20 43.5 8 17.4 18 39.1
Table 3. Showing some demogr aphic and laboratory parameters of various categories of patients wi th major drug resistance
mutations in the study.
ART status No with MRM Gender CD4 (cells/ul) Viral load (copies/ml)
Male Female Mean Range Median Range
Naïve 1 0 1 23 NA 78,792 NA
1st line failure 8 3 5 199 35 - 538 79,132 3785 - 608,333
2nd line failure 9 6 3 199 32 - 769 95,261 3899 - 43,926
Total (overall) 18 9 9 197 23 - 769 79,132 3785 - 60,8333
MRM = Major Resistance Mutation; NA = Not Applicable.

Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 330
Table 4. Showing frequency of major resistance mutations among the study participants.
Class of drugs NRTI NNRTI PI
Mutation Frequency Mutation Frequency Mutation Frequency
M41L 5 (27.8%) V179E 1 (5.6%) L24I 1 (5.6%)
D67N 6 (33.3%) G190A 1 (5.6%) M46L/I 10 (55.6%)
K70R 1 (5.6%) K101E 1 (5.6%) I47V 3 (16.7%)
L210W 3 (16.7%) K103N 2 (11.1) G48V 1 (5.6%)
T215Y 4 (22.2%) Y181C 3(16.7%) I54V 1 (5.6%)
- - Y188L 1 (5.6%) L76V 2 (11.1%)
- - F227L 1 (5.6%) V82F/S/I 4 (22.2%)
Mutations
- - - - I84V 1 (5.6%)
Table 5. Showing patterns of drug resistance among the
study participants.
Class of drug Drug No of sample(s) with
resistance to each drug
3TC 10 (55.6%)
FTC 10 (55.6%)
AZT 3 (16.7%)
STAVUDINE 3 (16.7%)
ABC 3 (16.7%)
NRTIs
TDF 4 (22.2%)
DLV 6 (33.3%)
EFV 6 (33.3%)
NVP 7 (38.9%)
NNRTIs
ETR 1 (5.6%)
APV 3 (16.7%)
FOS 3 (16.7%)
IDV 4 (22.2%)
SQV 1 (5.6%)
LPV 2 (11.1%)
NFV 7 (38.9%)
PIs
TPV 1 (5.6%)
4. Discussion
This study describes the prevalence and pattern of muta-
tions associated with ARV drug among patients on 1st
and 2nd line therapy as well as ART naïve patients in Ni-
geria. Our results show that more female failed 1st line
drugs and a higher average time on ART before failure
among female than male patients who failed 1st line. Th is
finding is in accord with an earlier finding by Chaplin et
Table 6. Showing number of patients whose virus had the
various drug resistance combination indicated.
Sample of number(s)Drug resistance
1 NFV
2 DLV, NVP
1 SQV, NFV
2 3TC, FTC, EFV
2 3TC, FTC, ETR
1 DLV, EFV, NVP, TDF
1 3TC, FTC, EFV, NVP
1 3TC, FTC, DLV, NPV, NFV, IDV
1 3TC, FTC, DLV, EFV, NVP, TDF
1 3TC, FTC, DLV, EFV, NVP, NFV, TDF
2 3TC, FTC, DLV, EFV, NVP, NFV, TDF
1 3TC, FTC, AZT, d4T, ABC,
APV, FOS, IDV, NFV
1 3TC, FTC, AZT, d4T, ABC,
APV, FOS, IDV, LPV, ATV
1 3TC, FTC, AZT, d4T, ABC,
APV, FOS, IDV, LPV, NFV, TPV
al. [26] who observed a potential difference in time to
failure based on gender. These earlier workers recom-
mended better drug adherence in women in the first 12
months and gender response to therapy as possible rea-
son for rapid resistance mutations in men. It is therefore
reasonable to suggest that problem of poor adherence
may also explain why more men seem to be failing 2nd
line therapy as observed in this study. The low mean
CD4+ cells and high viral load found ART among the
naïve individuals is similar to previous reports from Ni-
geria [25,26] and some other low-and-middle-income
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Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 331
countries [21,27-29]. This may be due to the poor health
seeking behavior in Africa where most patients seek
medical attention only when their health condition has
deteriorated significantly.
Only one [4.8%] of the ART naïve individuals had any
major drug resistance mutations with possible resistance
to nelvinavir. Although this rate is lower than reports
from Europe and some other African counties [28,30-34],
it is still a cause for concern because the major source of
DR in ART naïve is through transmission of resistance
strains. This finding underscores the need for drug resis-
tance surveillance among newly infected individual in
order to detect DR transmitted viru ses for early interven-
tion. The 4.8% rate of major drug resistance mutations
among drug naïve individuals obtained in this study is
similar to the rates reported in other low and middle-
income countries. A survey conducted by WHO in 20
countries showed an overall transmitted drug resistance
virus rate of 3.7% [30]. Globally, the rates of transmis-
sion of DR viruses is increasing [20,22,32,35] and there-
fore the need for pre-ART resistance testing cannot be
over emphasized. However, the cost of this testing is
enormous and may be difficult to implement in resource
limited settings [7].
Although antiretroviral therapy is effective in sup-
pressing HIV-1 replication and prolonging live of in-
fected individuals, some patients are experiencing de-
tectable viral replication even under highly active anti-
retroviral therapy [36-38]. Several factors such as resis-
tance to current drugs, poor adherence, co-infection with
tuberculosis have been associated with this phenomenon
[22,39-41]. In this study, 31.2% [5/21] and 19.8% [3/21]
of the 1st ART failures had no DR mutation and minor
mutations/polymorphisms respectively. The therapeutic
failure of these individuals may be due to other factors
than DR mutation. The medical records of the patients
showed that 50% of th ese ind ividu als had dru g adher en ce
problem, 25% had co-infection with TB and no obvious
reason could be attributed to the failure in the remaining
25%. A similar finding was reported by Abar et al.
among patients failing 1st line therapy in Djibouti [32].
The finding that 50% and 100% of those on 1st line
and 2nd line drugs respectively had major drug resistance
mutations compared to 4.8% of ART naïve indicates that
these mutations developed as a result of ART use rather
than transmission of resistant strains. Drug pressure as
well as poor drug adherence and drug absorption rate that
lead to circulation of sub-op timal blood lev el of drug are
known factors th at contribute to the development of drug
resistance mutations [22,40,42,43].
The M184V/I mutation was the most common minor
mutation found in 72 .2% of the samples which is similar
to findings of other studies [27,30,44] and known glob-
ally as the most common NRTI-resistance mutation [22,
45]. Although the mutations are known to cause high-
level in-vitro resistance to 3TC/FTC, they are not con-
traindication to 3TC/FTC due to reduction of viral repli-
cation fitness and increase susceptibility to TDF, AZT,
and d4T [45]. The most common NRTI, NNRTI and PI
associated major resistance mutation detected were D67N
[33.3%], Y181C [16.7%] and M46L/I respectively. All
the NRTI mutations identified [M41C, D67N, L201W,
T215Y, K70R] were TAMS that are known to increase
resistance to AZT, tenofovir, d4T, abacavir, and DDI
[33,45]. No NRTI conferring multidrug resistance [MDR]
was detected. The NNRTI mutation at position 181,
Y181C is known to result in high-level ETR and RPV
resistance [46-48] while the PI mutation, M46LI is
known to have high-level reduced susceptibility or in-
crease resistance to FPV/r and IDV/r [45,49].
The drugs to which each of the virus isolates was re-
sistant to were determined using a combination of the
Viroseq and Stanford algorithm. Over 50% of the pa-
tients had viruses that were resistant to 3TC or FTC.
Only 16.7% of them had viruses that are resistant to AZT
while no resistance to d4T was detected. These two drugs
are NNRTI backbones for some of the 1st line drugs used
in the Nigeria and the results therefore indicate that Ni-
gerian patients are responding well to these drugs and
hence can continue to serve as good backbone for 1st line
antiretroviral therapy in the country. The high rate of
multidrug class resistance found in this study, especially
among individuals on 2nd line therapy is of great concern
and suggests the need for careful selection of second line
drugs based on drug resistance testing. Genotypic testin g
has been shown to be beneficial in guiding appropriate
ART selection [30], hence the significance of this study.
5. Conclusions
We have shown that the high rate of some resistance mi-
nor and major mutations occurs in HIV-1 among patients
failing first and second line antiretroviral drugs in Nige-
ria. The study also showed occurrence of resistance mu-
tations in HIV-1 in ARV Naïve patients in our study po-
pulation. The work therefore emphasizes the importance
of surveillance for resistance to ARV in line with the
magnitude of scaling up of treatment program in the
country.
WHAT IS ALREADY KNOWN ON THIS SUB-
JECT
Previous studies have shown that development of drug
resistance is a major problem associated with wide
spread use of antiretroviral drugs for treatment of HIV
infected patients. However there is dearth of information
on the drug resistance pattern in settings with predomi-
nance of non-subtype B of HIV-1 like Nigeria.
WHAT THIS STUDY ADDS TO LITERATURE
The results of this study show the rate and pattern of
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Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 332
antiretroviral drug resistance among HIV-1 infected pa-
tients failing first and second line regimens in Nigeria
where non-B subtypes of the virus circulate. The high
rate of multidrug resistance reported in this study, espe-
cially among patients on second line regimen is signifi-
cant and will be helpful in the choice of drugs for treat-
ment.
6. Acknowledgement
The ART program at the University College Hospital is
supported by USG PEPFAR program through a Coop-
erative Agreement (No: 1U2GPS001058) from the Cen-
ters for Disease Control and Prevention to the AIDS
Prevention Initiative Nigeria. The content of the manu-
script are solely the responsibility of the authors and do
not necessarily represent the official views of the Centers
for Disease Control and Prevention. We are grateful to
all the staff of the ART clinic and Virology laboratory
for patient enrolment and laboratory analysis. We also
appreciate our patients who participated in the study.
7. Authors’ Contribution
GNO and DOO conceived the idea of the study, GNO,
PO, IFA and DOO were involved in collection and
analysis of data, PO and IFA supervised recruitment and
enrolment the patients, GNO and DOO supervised the
laboratory investigations. GNO wrote the draft manu-
script while all authors reviewed the manuscript and ap-
proved the final version. DOO is the guarantor of the
paper.
8. Ethical Considerations
Approval for the study was obtained from the University
of Ibadan/University College hospital ethical review
board. Informed consent was obtained from all partici-
pants in the study.
9. Competing Interest
We declare that we have no conflicting interest in the
conduct of the study.
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