![](paperimages\40443_1.jpg) 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. Email: #davidoolaleye@gmail.com 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.
![](paperimages\40443_2.jpg) 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 Open Access WJA
![](paperimages\40443_3.jpg) Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria Open Access WJA 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.
![](paperimages\40443_4.jpg) 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 Open Access WJA
![](paperimages\40443_5.jpg) 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 Open Access WJA
![](paperimages\40443_6.jpg) 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. 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