World Journal of AIDS, 2013, 3, 327-334 327 Published Online December 2013 (http://www.scirp.org/journal/wja) http://dx.doi.org/10.4236/wja.2013.34042 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 antiretroviral 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 University 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 individuals in this study show the importance of surveillance 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 valence varies by locations from a relatively low rate of HIV/AIDS continues to be a global health problem since 2.1% in the north central and 2.9% in south western its discovery in 1981 [1] with over 33 million people zones respectively to a high rate of 7.5% in the north central zone of the country. living with the virus at the end of 2011 [2]. The first case According to UNAIDS, the number of new infections of AIDS was reported in Nigeria in 1986 and the rate of globally reduced to 2.5 million in 2011 from 3.2 million HIV infection in the country increased steadily from in 2001 [2]. Part of the reasons for this success may not 0.6% in 1987 to a peak of 5.8% in 2003. The last HIV be unrelated to the wide spread use of antiretroviral the- national sentinel survey in the country shows that the rate rapy (ART). There are evidences that ART contributes of infection has declined to 3.4% [3], though the pre- greatly to the reduction of transmission, morbidity and mortality caused by HIV infection [4-6]. This dramatic *Funding: the study was carried out with funding from Center for Dis- ease Control and Prevention through AIDS Prevention Initiative Nige- improvement that is most prominent in the North Amer- ria (APIN). ica, Western Europe and recently Brazil, has led to the #Corresponding author. advocacy for increased access to antiretroviral drugs in Open Access WJA UNIVERSITY OF IBADAN LIBRARY 328 Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria resource limited settings [1,7-10]. Many African coun- HIV infected individuals currently receiving care and tries have responded positively and increased access to treatment in the hospital. ART, though with support from international agencies [11-15]. 2.2. Study Population In Nigeria, wide use of ART started in 2002 when the Federal Government launched the pilot HIV treatment The study participants included patients attending the program [9,10]. Additional funding for antiretroviral PEPFAR supported UCH ART clinic who have been on treatment became available in the country through the US HIV treatment for at least one year with consecutive viral government funded by President’s Emergency Plan for load of over 2000 copies/ml as well some ART Naïve AIDS Relief (PEPFAR) program and the Global Funds patients attending the hospital for pre-ART assessment. and thus they increased access to ART greatly. To date, Individuals who commenced therapy before 2005 were over 500,000 patients are on ART in Nigeria, although this excluded from this study because there were reported number is a far cry to the almost 1.5 million HIV positive drug stock-outs during the government of Nigeria pilot treatment program that lasted until late 2004 and some of individuals who require treatment in the country [16]. the patients on that program were reported to have de- The introduction of antiretroviral therapy has substan- veloped drug resistance mutations [20]. tially changed the natural history of HIV and AIDS. Un- like the 80s and early 90s, people living with HIV/ AIDS 2.3. HIV Viral Load Determination (RNA [PLWAs] now live better and longer, thus they are able Quantification) to contribute meaningfully to the economy of their coun- try. However, development of drug resistance may limit Viral load measurement was carried using the Roche the benefit of antiretroviral therapy. Various reports have Amplicor version 1.5 with lower and upper detection li- documented the increase of ARV drug resistance in dif- mits of 400 copies/ml and 750,000 copies/ml respectively. ferent countries and regions of the world [17-21]. Al- though the result of a recent WHO DRM survey which 2.4. HIV Drug Resistance Genotyping reported that “rate of transmitted DR continues to remain HIV RNA was extracted from 500 ul of plasma using the limited in low-and-middle-income countries” [22] is as- QIAamp Viral RNA Extraction Mini Spin Kit (Qiagen, suring because of the initial skepticism [23,24] by the Germany). HIV RNA was reverse transcribed to cDNA, international community, there is still the need to closely amplified and subsequently sequenced using the Viroseq monitor these mutations in each country, especially as HIV-1 genotyping assay, version 2.0 as previously de- the use of ART increases. This study was therefore de- scribed by Chaplin et al. [25]. Sequences were generated signed to determine the ARV drug resistance pattern using a 3130 XL genetic analyzer (Applied Biosystems) among ART naïve and expose individuals attending the and the generated sequences were edited and compared PEPFAR supported by antiretroviral clinic at the Univer- with an HXB2 subtype B reference using the Viroseq sity College Hospital, Ibadan, the premier tertiary hospi- software and list of mutations generated. The mutations tal in Nigeria. were classified as minor or major base on the June 22, 2013 updated HIV drug resistance data base (http:/hivdb. 2. Methodology standard.edu). Resistance to each drug was determined using a combination of the Viroseq and Stanford drug 2.1. Study Site resistance algorithms and resistance to each drug as- This study was carried out among patients attending the signed as susceptible, intermediate or resistant. antiretroviral treatment clinic of the University College Hospital (UCH), Ibadan, Nigeria. The UCH is the fore- 3. Results most teaching hospital located in the southwestern region A total of 46 samples were analyzed in this study. The of Nigeria. The hospital runs 55 weekly specialty clinics characteristics of the patients whose samples were ana- with patients’ referrals from many states in the south- lyzed are shown in Table 1. The mean age of the par- western region and from other parts of the country. Anti- ticipants was 43 years (range, 29 - 70) and 58.7% of retroviral treatment started in the hospital in 2002 when them were female. However more male patients seem to the Federal Government of Nigeria introduced ARV be failing 2nd line treatment while more female failed 1st program in the country. The treatment program was line drugs. The average time on ART was 3.2 (range, 0.5 scaled up in 2004 with support from the US government - 5.5) years and 2.8 (range, 1 - 4) years for those failing President Emergency Fund for AIDS Relief (PEPFAR) the 1st line and the 2nd line drugs respectively. There was program through funding provided to the Harvard School a gender bias in the time between ART commencement of Public Health, Boston, USA. There are over 10,000 and virologic failure for patients on 1st line regimen. The Open Access WJA UNIVERSITY OF IBADAN LIBRARY Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 329 average time was 4 years and 1.5 years for female and by V82F/S/I and then I47V (Table 4). Other mutations male patients respectively. Only one of the 21 patients on detected include: M184V/I (13) M41L (6), E44D (1) ART had a major resistance mutation while 71.4% of T69N (2), L10I/V (16), V11I (3), A98G (7), P225H (1) them had no resistance mutation (Table 2). Fifty percent AND P236L (L). Table 5 shows the drugs by class to of the patients failing 1st line and 100% of those failing which virus developed resistance. Lamivudine (3TC) and 2nd line had major resistance mutations. About 30% of emtricitabine (FTC); nevirapin (NVP) and nelfinavir those failing 1st line drugs did not have any resistance (NFV) were the most common NRTI, NNRTI, and PI mutation while 19.8% of them had only minor mutations. drugs respectively to which the virus in the infected indi- Table 3 shows the characteristics of individuals with viduals developed resistance. Virus from 4 of the patients major resistance mutations. The mean CD4 and median were resistant to more than six antiretroviral drugs (Ta- viral load of those with major resistance mutations were ble 5) including 3TC, FTC, AZT, d4T, ABC, APV, FOS, lower than those of the study population (Table 1). The IDV, LPV, NFV, TPV. Isolates from the 4 patient sam- only ART Naïve individual with a major mutation was a ples were resistant to triple drug class, including at least female with CD4 of 23 cells/ul and viral load of 78,792 one NRTI, NNRTI and a PI. Interestingly the virus from copies/ml. one of the patients who failed 2nd line treatment was re- The most common major NRTI mutation was D67N sistant to all the eleven drugs listed above (Table 6). Vi- followed by T215Y and M41L while the most frequent rus from the only ART Naïve individual with major drug major NNRTI mutations were Y181C and K103N. Among resistance mutation was resistant to the PI nelvinavir the PI mutations, the most frequent was M46L/I followed (NFV). Table 1. Showing characteristics 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) Male Female Mean 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 demographic and laboratory parameters of various categories of patients with 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. Open Access WJA UNIVERSITY OF IBADAN LIBRARY 330 Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 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%) Mutations 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%) - - - - I84V 1 (5.6%) Table 5. Showing patterns of drug resistance among the Table 6. Showing number of patients whose virus had the study participants. various drug resistance combination indicated. Class of drug Drug No of sample(s) with Sample of number(s) Drug resistance resistance to each drug 3TC 10 (55.6%) 1 NFV FTC 10 (55.6%) 2 DLV, NVP AZT 3 (16.7%) 1 SQV, NFV NRTIs STAVUDINE 3 (16.7%) 2 3TC, FTC, EFV ABC 3 (16.7%) 2 3TC, FTC, ETR TDF 4 (22.2%) 1 DLV, EFV, NVP, TDF DLV 6 (33.3%) 1 3TC, FTC, EFV, NVP EFV 6 (33.3%) 1 3TC, FTC, DLV, NPV, NFV, IDV NNRTIs NVP 7 (38.9%) 1 3TC, FTC, DLV, EFV, NVP, TDF ETR 1 (5.6%) 1 3TC, FTC, DLV, EFV, NVP, NFV, TDF APV 3 (16.7%) 2 3TC, FTC, DLV, EFV, NVP, NFV, TDF FOS 3 (16.7%) 1 3TC, FTC, AZT, d4T, ABC, APV, FOS, IDV, NFV IDV 4 (22.2%) 1 3TC, FTC, AZT, d4T, ABC, PIs SQV 1 (5.6%) APV, FOS, IDV, LPV, ATV LPV 2 (11.1%) 1 3TC, FTC, AZT, d4T, ABC, APV, FOS, IDV, LPV, NFV, TPV NFV 7 (38.9%) TPV 1 (5.6%) al. [26] who observed a potential difference in time to failure based on gender. These earlier workers recom- 4. Discussion mended better drug adherence in women in the first 12 months and gender response to therapy as possible rea- This study describes the prevalence and pattern of muta- son for rapid resistance mutations in men. It is therefore tions associated with ARV drug among patients on 1st reasonable to suggest that problem of poor adherence and 2nd line therapy as well as ART naïve patients in Ni- may also explain why more men seem to be failing 2nd geria. Our results show that more female failed 1st line line therapy as observed in this study. The low mean drugs and a higher average time on ART before failure CD4+ cells and high viral load found ART among the among female than male patients who failed 1st line. This naïve individuals is similar to previous reports from Ni- finding is in accord with an earlier finding by Chaplin et geria [25,26] and some other low-and-middle-income Open Access WJA UNIVERSITY OF IBADAN LIBRARY 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 45]. Although the mutations are known to cause high- seeking behavior in Africa where most patients seek level in-vitro resistance to 3TC/FTC, they are not con- medical attention only when their health condition has traindication to 3TC/FTC due to reduction of viral repli- deteriorated significantly. cation fitness and increase susceptibility to TDF, AZT, Only one [4.8%] of the ART naïve individuals had any and d4T [45]. The most common NRTI, NNRTI and PI major drug resistance mutations with possible resistance associated major resistance mutation detected were D67N to nelvinavir. Although this rate is lower than reports [33.3%], Y181C [16.7%] and M46L/I respectively. All from Europe and some other African counties [28,30-34], the NRTI mutations identified [M41C, D67N, L201W, it is still a cause for concern because the major source of T215Y, K70R] were TAMS that are known to increase DR in ART naïve is through transmission of resistance resistance to AZT, tenofovir, d4T, abacavir, and DDI strains. This finding underscores the need for drug resis- [33,45]. No NRTI conferring multidrug resistance [MDR] tance surveillance among newly infected individual in was detected. The NNRTI mutation at position 181, order to detect DR transmitted viruses for early interven- Y181C is known to result in high-level ETR and RPV tion. The 4.8% rate of major drug resistance mutations resistance [46-48] while the PI mutation, M46LI is among drug naïve individuals obtained in this study is known to have high-level reduced susceptibility or in- similar to the rates reported in other low and middle- crease resistance to FPV/r and IDV/r [45,49]. income countries. A survey conducted by WHO in 20 The drugs to which each of the virus isolates was re- countries showed an overall transmitted drug resistance sistant to were determined using a combination of the virus rate of 3.7% [30]. Globally, the rates of transmis- Viroseq and Stanford algorithm. Over 50% of the pa- sion of DR viruses is increasing [20,22,32,35] and there- tients had viruses that were resistant to 3TC or FTC. fore the need for pre-ART resistance testing cannot be Only 16.7% of them had viruses that are resistant to AZT over emphasized. However, the cost of this testing is while no resistance to d4T was detected. These two drugs enormous and may be difficult to implement in resource are NNRTI backbones for some of the 1 st line drugs used limited settings [7]. in the Nigeria and the results therefore indicate that Ni- Although antiretroviral therapy is effective in sup- gerian patients are responding well to these drugs and st pressing HIV-1 replication and prolonging live of in- hence can continue to serve as good backbone for 1 line fected individuals, some patients are experiencing de- antiretroviral therapy in the country. The high rate of tectable viral replication even under highly active anti- multidrug class resistance found in this study, especially nd retroviral therapy [36-38]. Several factors such as resis- among individuals on 2 line therapy is of great concern tance to current drugs, poor adherence, co-infection with and suggests the need for careful selection of second line tuberculosis have been associated with this phenomenon drugs based on drug resistance testing. Genotypic testing [22,39-41]. In this study, 31.2% [5/21] and 19.8% [3/21] has been shown to be beneficial in guiding appropriate of the 1st ART failures had no DR mutation and minor ART selection [30], hence the significance of this study. mutations/polymorphisms respectively. The therapeutic failure of these individuals may be due to other factors 5. Conclusions than DR mutation. The medical records of the patients We have shown that the high rate of some resistance mi- showed that 50% of these individuals had drug adherence nor and major mutations occurs in HIV-1 among patients problem, 25% had co-infection with TB and no obvious failing first and second line antiretroviral drugs in Nige- reason could be attributed to the failure in the remaining ria. The study also showed occurrence of resistance mu- 25%. A similar finding was reported by Abar et al. tations in HIV-1 in ARV Naïve patients in our study po- among patients failing 1st line therapy in Djibouti [32]. pulation. The work therefore emphasizes the importance The finding that 50% and 100% of those on 1st line of surveillance for resistance to ARV in line with the and 2nd line drugs respectively had major drug resistance magnitude of scaling up of treatment program in the mutations compared to 4.8% of ART naïve indicates that country. these mutations developed as a result of ART use rather WHAT IS ALREADY KNOWN ON THIS SUB- than transmission of resistant strains. Drug pressure as JECT well as poor drug adherence and drug absorption rate that Previous studies have shown that development of drug lead to circulation of sub-optimal blood level of drug are resistance is a major problem associated with wide known factors that contribute to the development of drug spread use of antiretroviral drugs for treatment of HIV resistance mutations [22,40,42,43]. infected patients. However there is dearth of information The M184V/I mutation was the most common minor on the drug resistance pattern in settings with predomi- mutation found in 72.2% of the samples which is similar nance of non-subtype B of HIV-1 like Nigeria. to findings of other studies [27,30,44] and known glob- WHAT THIS STUDY ADDS TO LITERATURE ally as the most common NRTI-resistance mutation [22, The results of this study show the rate and pattern of Open Access WJA UNIVERSITY OF IBADAN LIBRARY 332 Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria antiretroviral drug resistance among HIV-1 infected pa- Global_Report_2012_with_annexes_en.pdf tients failing first and second line regimens in Nigeria [3] FMOH, “National HIV Sero-Prevalence Sentinel Survey where non-B subtypes of the virus circulate. The high among Pregnant Women Attending Antenatal Clinics in rate of multidrug resistance reported in this study, espe- Nigeriam,” Technical Report, 2010, pp. 1-96. cially among patients on second line regimen is signifi- [4] S. M. Hammer, J. J. Eron Jr., P. Reiss, et al., “Antiretro- cant and will be helpful in the choice of drugs for treat- viral Treatment of Adult HIV Infection: 2008 Recom- ment. mendations of the International AIDS Society-USA Panel,” JAMA, Vol. 300, No. 5, 2008, pp. 555-570. 6. Acknowledgement http://dx.doi.org/10.1001/jama.300.5.555 [5] World Health Organization, UNAIDS and UNICEF, “To- The ART program at the University College Hospital is wards Universal Assess: Scaling up Priority HIV/AIDS supported by USG PEPFAR program through a Coop- Interventions in the Health Sector,” 2010. erative Agreement (No: 1U2GPS001058) from the Cen- [6] G. Panos, G. Samonis, V. G. Alexiou, G. A. Kavarnou, G. ters for Disease Control and Prevention to the AIDS Charatsis and M. E. Falagas, “Mortality and Mobidity of Prevention Initiative Nigeria. The content of the manu- HIV-Infected Patients Receiving H ART: A Cohort Study,” script are solely the responsibility of the authors and do Current HIV Research, Vol. 6, No. 3, 2008, pp. 257-260. http://dx.doi.org/10.2174/157016208784324976 not necessarily represent the official views of the Centers for Disease Control and Prevention. We are grateful to [7] P. Severe, P. Leger, M. Charles, et al., “Antiretroviral all the staff of the ART clinic and Virology laboratory Therapy in a Thousand Patients with AIDS in Haiti,” New England Journal of Medicine, Vol. 353, No. 32, 2005, pp. for patient enrolment and laboratory analysis. We also 2325-2334. http://dx.doi.org/10.1056/NEJMoa051908 appreciate our patients who participated in the study. [8] P. E. Sax, R. Islam, R. P. Walensky, et al., “Should Re- sistance Testing Be Performed for Treatment-Naïve HIV- 7. Authors’ Contribution Infected Patients? A Cost-Effectiveness Analysis,” Clini- GNO and DOO conceived the idea of the study, GNO, cal Infectious Diseases, Vol. 41, No. 9, 2005, pp. 1316- 1323. http://dx.doi.org/10.1086/496984 PO, IFA and DOO were involved in collection and analysis of data, PO and IFA supervised recruitment and [9] A. Mocroft, S. Vella, T. Benifield, et al., “Charging Pat-terns of Mortality Across Europe in Patients Infected with enrolment the patients, GNO and DOO supervised the HIV-1,” Lancet, Vol. 352, No. 9142, 1998, pp. 1725- laboratory investigations. GNO wrote the draft manu- 1730. http://dx.doi.org/10.1016/S0140-6736(98)03201-2 script while all authors reviewed the manuscript and ap- [10] J. Marins, L. Jamal, S. Chen, et al., “Dramatic Improve- proved the final version. DOO is the guarantor of the ment in Survival among Adult Brazilian AIDS Patients,” paper. AIDS, Vol. 17, No. 11, 2003, pp. 1675-1682. http://dx.doi.org/10.1097/00002030-200307250-00012 8. Ethical Considerations [11] J. Peterson and O. Obileye, “Access to Drugs for HIV/ Approval for the study was obtained from the University AIDS and Related Opportunistic Infections in Nigeria,” POLICY Project, Nigeria, 2002. of Ibadan/University College hospital ethical review board. Informed consent was obtained from all partici- [12] O. Odutolu, B. A. Ahonsi, M. Gboun and O. M. Jolayemi, pants in the study. “The National Response to HIV/AIDS,” In: O. Adeyi, P. H. Kanki, O. Odutolu and J. A. Idoko, Eds., AIDS in Ni- geria: “A Nation on a Threshold”, Harvard University 9. Competing Interest Press, Cambridge, 2006, pp. 241-279. We declare that we have no conflicting interest in the [13] C. Wallis, M. Papthanasopoulos, M. Fox, et al., “Lows conduct of the study. Rate of Nucleoside Reverse Transcriptase Inhibitor (NRTI) Resistant Detected in a Well Monitored Cohort in South Africa Accessing Antiretroviral Therapy,” Antiviral Ther- REFERENCES apy, Vol. 17, No. 2, 2012, pp. 313-320. http://dx.doi.org/10.3851/IMP1985 [1] S. Robert, S. M. Gottlieb, M. H. Schanker, D. Joel, D. O. Weisman, F. P. Thim, A. R. Wolf and S. Andrew, “Pnue- [14] V. C. Marconi, H. Sunpath, Z. G. Lu, M. Gordon, K. mocystiscarinii Pnuemoniaand Mucosal Candidiasis in Koranteng-Apeagyei, J. Hampton, S. Carpentar, et al., Previously Healthy Homosexual Men—Evidence of a “Prevalence of HIV-1 Drug Resistance After Failure of a new Acquire Cellular Immunodeficiency,” New England First Highly Active Antiretroviral Therapy Regimen in Journal of Medicine, Vol. 305, 1981, pp. 1425-1431. KwaZulu Natal, South Africa,” Clinical Infectious Dis- http://dx.doi.org/10.1056/NEJM198112103052401 eases, Vol. 46, No. 10, 2008, pp. 1589-1597. [2] UNAIDS, “State of the Epidemic,” Report of the Global http://dx.doi.org/10.1086/587109 AIDS Epidemic, 2012, pp. 1-103. [15] H. Hatano, P. Hunt, J. Weidler, et al., “Rate of Vira Evo- http://www.unaids.org/en/media/unaids/contentassets/doc lution and Risk of Losing Future Drug Options in Heavily uments/epidemiology/2012/gr2012/20121120_UNAIDS_ Pretreated, HIV-Infected Patients Who Continue to Re- Open Access WJA UNIVERSITY OF IBADAN LIBRARY Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria 333 ceive a Stable, Partially Suppressive Treatment Regimen,” al., “Prevalence of Drug-Resistance HIV-1 Variants in Clinical Infectious Diseases, Vol. 43, No. 10, 2006, pp. Untreated Individuals in Europe: Implications for Clinical 1329-1336. http://dx.doi.org/10.1086/508655 Management,” Journal of Infectious Diseases, Vol. 192, [16] Nigeria’s HIV/AIDS Information Website, “Current HIV/ No. 6, 2005, pp. 958-966. AIDS Statistics in Nigeria.” www.nigeriahivinfo.com http://dx.doi.org/10.1086/432916 [17] R. E. Nettles, T. L. Kieffer, R. P. Simmons, et al, “Geno- [28] D. Paraskevis, E. Magiokinis, A. Katsoulidou, et al., “Pre- typic Resistant in HIV-1-infcted Patients with Persistently valence of Resistance-Associated Mutations in Newly Di- Detectable Low Level Viremia While Receiving Highly agnosed HIV-1 Patients in Greece,” Virus Research, Vol. Active Antiretroviral Therapy,” Clinical Infectious Dis- 112, No. 1, 2005, pp. 115-122. eases, Vol. 39, No. 7, 2004, pp. 1030-1037. http://dx.doi.org/10.1016/j.virusres.2005.03.004 http://dx.doi.org/10.1086/423388 [29] S. J. Litle, S. Holte, J. P. Routy, et al., “Antiretrovi- [18] S. Palmer, M. Kearney, F. Maldarelli, et al., “Multiple, ral-Drug Resistance among Patients Recently Infected Linked Human Immunodeficiency Virus Type Drug Re- with HIV,” New England Journal of Medicine, Vol. 347, sistance Mutations in Treatment-Experienced Patients Are 2002, pp. 385-394. Missed by Standard Genotype Analysis,” Journal of Clinical http://dx.doi.org/10.1056/NEJMoa013552 Microbiology, Vol. 43, No. 1, 2005, pp. 406-413. [30] R. L. Hamers, K. C. Sigaloff, A. M. Wensing, L. C. Wal- http://dx.doi.org/10.1128/JCM.43.1.406-413.2005 lis, C. KItyo, M. Siwale, K. Mandaliya, et al., “Patterns of [19] F. Doualla-Bell, T. Gaolathe, A. Avalos, et al., “Five Years HIV-1 Drug Resistance after First-Line Antiretroviral Follow Up of Genotypic Resistance Patterns in HIV-1 Therapy (ART) Failure in 6 Sub-Saharan African Coun- Subtype C Infected Patients in Botswana after Failure of tries: Implications for Second-Line ART Strategies,” Clini- Thymidine Analogue-Based Regimens,” Journal of the cal Infectious Diseases, Vol. 54, No. 11, 2012, pp. 1660- International AIDS Society, Vol. 12, 2009, p. 25. 1669. http://dx.doi.org/10.1186/1758-2652-12-25 [31] S. Jallow, A. Alabi, R. Sarge-Njie, K. Peterson, H. Whit- [20] E. O. Idigbe, T. A. Adewole, G. Eisie, et al., “Manage- tle, et al., “Virological Response to Highly Active Anti- ment of HIV-1 Infection with a Combination of Nevirap- retroviral Therapy in Patients Infected with Human Im- ine, Stavudine, and Lamivudine: A Preliminary Report on munodeficiency Virus Type 2 (HIV-2) and in Patients Nigerian Antiretroviral Program,” Journal of Acquired Dually Infected with HIV-1 and HIV-2 in the Gambia and Immune Deficiency Syndromes, Vol. 40, No. 1, 2005, pp. Emergence of Drug Resistant Variants,” Journal of Clini- 65-69. cal Microbiology, Vol. 47, No. 7, 2009, pp. 2200-2208. http://dx.doi.org/10.1097/01.qai.0000159516.39982.1b http://dx.doi.org/10.1128/JCM.01654-08 [21] J. E. Gallant, A. E. Rodriguez, W. G. Weinberg, et al., [32] E. A. Abar, A. Jlizi, Y. H. Darar, et al., “HIV-1 Drug “Early Virologic Nonresponse to Tenofovir, Abacavir, and Resistance Genotyping from Antiretroviral Therapy (ART) Lamivudine in HIV-Infected Antiretroviral-Naïve Sub- Naïve and First-Line Treatment Failures in Djiboutian jects,” Journal of Infectious Diseases, Vol. 192, No. 11, Patients,” Diagnostic Pathology, Vol. 7, 2012, p. 138. 2005, pp. 921-930. http://dx.doi.org/10.1086/498069 http://dx.doi.org/10.1186/1746-1596-7-138 [22] World Health Organization, “HIV Drug Resistance Re- [33] V. Novitsky, C. W. Wester, V. DeGruttola, et al., “The port,” 2012, pp. 3-78. Reverse Transcriptate 67N 70R 215Y Genptype Is the [23] D. R. Kuritzkes, “Extending Antiretroviral Therapy to Re- Predominant TAM; Athway Associated with Virologic source-Poor Settings: Implications for Drug Resistance,” Failure among HIV Type 1C-Infected Adults Treated AIDS, Vol. 18, Suppl. 3, 2004, pp. S45-S48. with ZDV/ddl-Containing HAART in Southern Africa,” http://dx.doi.org/10.1097/00002030-200406003-00009 AIDS Research and Human Retroviruses, Vol. 23, 2007, pp. 868-878. http://dx.doi.org/10.1089/aid.2006.0298 [24] J. M. Lang, J. Perriens, D. Kuritzkes and D. Zewdie, “What Policymakers Should Know about Drug Resis- [34] J. Liu, J. Yue, S. Wu and Y. Yan, “Polymorphisms and tance and Adherence in the Context of Scaling-Up Treat- Drug Resistance Analysis of HIV-1 CRF01_AE Strains ment of HIV Infection,” AIDS, Vol. 18, Suppl. 13, 2004, Circuiting in Fujian Province, China,” Archives of Virol- pp. 569-574. ogy, Vol. 152, No. 10, 2007, pp. 1799-1805. [25] B. Chaplin, G. Eisen, J. Idoko, D. Onwujekwe, E. Idigbe, http://dx.doi.org/10.1007/s00705-007-1019-9 I. Adewole, W. Gashau, S. Meloni, A. D. Sarr, J. L. [35] UK Group on Transmitted HIV Drug Resistance, “Time Sankalé, E. Ekong, R. L. Murphy and P. Kanki, “Impact Trends in Primary Resistance HIV Drugs in the United of HIV Type 1 Subtype on Drug Resistance Mutations in Kingdom: Multicenter Observational Study,” British Me- Nigerian Patients Failing First-Line Therapy,” AIDS Re- dical Journal, Vol. 331, No. 7529, 2005, pp. 1368-1373. search and Human Retroviruses, Vol. 27, No. 1, 2011, pp. http://dx.doi.org/10.1136/bmj.38665.534595.55 71-80. http://dx.doi.org/10.1089/aid.2010.0050 [36] N. A. Ingole, S. M. Kukreja and P.-R. Mehata, “Role of [26] G. N. Odaibo, S. O. Ola, M. Landerz, U. Dietrich and D. HIV-1 Viral Load in Initiating Antiviral Therapy,” World O. Olaleye, “HIV-1 Drug Resistant Mutations in Chroni- Journal of AIDS, Vol. 1, No. 4, 2011, pp. 149-154. cally Infected Treatment Naive Individuals in the Pre- http://dx.doi.org/10.4236/wja.2011.14022 ARV Era in Nigeria,” African Journal of Medicine & [37] WHO, “Clinical and Laboratory Monitoring of Antiretro- Medical Sciences, Vol. 41, 2012, pp. 61-63. viral therapy in Resource-Limited and Unlimited Set- [27] A. M. J. Wensing, D. A. van de Vijver, G. Angarano, et tings,” HIV/AIDS Antiretroviral Newsletter, No. 4, 2000, Open Access WJA UNIVERSITY OF IBADAN LIBRARY 334 Pattern of HIV-1 Drug Resistance among Adults on ART in Nigeria pp. 1-4. [44] M. Vidya, S. Saravana, S. Uma, N. Kumarasamy, et al., [38] S. P. Eholie, C. C. T. N’Dour, M. Cisse, E. Bissagnene “Genotypic HIV Type 1 Drug Resistance among Patients and P. M. Girad, “Observance of Antiretroviral Treat- with Immunological Failure to First Line Antiretroviral ments African Specificities,” Médecine et Maladies Infec- Therapy on South India,” Antiviral Therapy, Vol. 14, No. tieuses, Vol. 36, 2006, pp. 443-448. 7, 2009, pp. 1005-1009. http://dx.doi.org/10.3851/IMP1411 [39] B. Shah, L. Walshe, D. G. Saple, et al., “Adherence to Antiretroviral Therapy and Virologic Suppression among [45] “Stanford HIV Drug Resistance Database,” 2013. HIV-Infected Persons Receiving Care in Private Clinics http//hivdb.stanford.edu/pages/drugSummaries.html in Mumbai, India,” Clinical Infectious Diseases, Vol. 44, [46] A. M. Geretti, “Clinical Implication of HIV Drug Resis- No. 9, 2007, pp. 1235-1244. tance to Nucleoside Reverse Transcriptase Inhibitors,” http://dx.doi.org/10.1086/513429 AIDS Reviews, Vol. 8, No. 4, 2006, pp. 210-220. [40] A. M. Geretti, C. Smith, A. Haberl, et al., “Determinants [47] V. A. Johnson, C. Vincent, H. F. Gunthard, P. Roger, P. of Virological Failure after Successful Viral Load Sup- Deenan, S. Robert, A. M. Wensing and D. D. Richman, pression in First-Line Highly Active Antiretroviral Ther- “2011 Update of the Drug Resistance Mutation in HIV- apy,” Antiviral Therapy, Vol. 13, No 7, 2008, pp. 927- 1,” Topics in Antiviral Medicine, Vol. 19, No. 4, 2011, pp. 936. 156-164. [41] M. A. Chesney, J. Ickovics, F. M. Hecht, et al., “Adher- [48] E. P. Coakley, J. M. Gills and S. M. Hammer, “Pheno- ence: A Necessity of Successful HIV Combination Ther- typic and Gonotypicrersistance Pattern of HIV-1 Isolate apy,” AIDS, Vol. 13, Suppl. A, 1999, pp. S271-S278. Derived from Individuals Treated with Diagnosing and [42] A. J. Leigh Brown, S. D. Frost, W. C. Matthews, et al., Stavudine,” AIDS, Vol. 14, 2002, pp. F9-F15. “Transmission Fitness of Drug-Resistant Human Immu- http://dx.doi.org/10.1097/00002030-200001280-00002 nodeficiency Virus and the Prevalence of Resistance in [49] R. K. Gupta, A. Hill, A. W. Sawyer, et al., “Virological the Antiretroviral-Treated Population,” Journal of Infec- Monitoring and Resistant to First-Line Highly Active tious Diseases, Vol. 187, No. 4, 2003, pp. 683-686. Antiretroviral Therapy in Adults Infected with HIV-1 http://dx.doi.org/10.1086/367989 Treated under WHO Guidelines: A Systematic Review [43] A. Fibrian, R. Wisaksana, A. Indrati, Y. Hartantri, et al., and Mental Analysis,” Lancet Infectious Diseases, Vol. 9, “Virology Failure and Drug Resistance during First Line 2009, pp. 409-417. Antiretroviral Treatment in Indolnesia,” Journal of Medi- http://dx.doi.org/10.1016/S1473-3099(09)70136-7 cal Virology, Vol. 85, No. 8, 2013, pp. 1394-1401. http://dx.doi.org/10.1002/jmv.23606 Open Access WJA UNIVERSITY OF IBADAN LIBRARY