Open Forum Infectious Diseases BRIEF REPORT follow-up VL level is >1000 copies/mL, the patient is considered Human Immunodeficiency Virus-1 to have second-line VF and is referred to the Central Clinical Drug Resistance Patterns Among Adult Committee for HIVDR testing to determine the antiretroviral Patients Failing Second-Line Protease (ARV) combination needed for a third-line regimen based on observed mutations. Inhibitor-Containing Regimens in Namibia, 2010–2015 METHODS 1 2 1 Souleymane Sawadogo, Andreas Shiningavamwe, Clay Roscoe, A retrospective data review of laboratory genotyping results 1 1 1 Andrew L. Baughman, Taffa Negussie, Gram Mutandi, 3 4 1 was conducted for adult patients (>15 years) treated with a sec- Chunfu Yang, Ndapewa Hamunime, and Simon Agolory 1 2 ond-line ART regimen containing lopinavir/ritonavir (LPV/r) Division of Global HIV and Tuberculosis, Windhoek, Namibia; Namibia Institute of Pathology, 3 4 Windhoek; Division of Global HIV and Tuberculosis, Atlanta, Georgia; Ministry of Health and and 3 nucleoside reverse-transcriptase inhibitors (NRTIs) with Social Services, Windhoek, Namibia VF who had HIVDR tests performed between 2010 and 2015. During the study period, Namibia’s first-line ART was lami- Three hundred sixty-six adult patients in Namibia with sec- vudine (3TC), tenofovir (TDF), and nevirapine (NVP) until ond-line virologic failures were evaluated for human immuno- 2014, then changing to emtricitabine (FTC), TDF, and efavirenz deficiency virus drug-resistant (HIVDR) mutations. Less than (EFV). Second-line ART consisted of zidovudine (ZDV), 3TC, half (41.5%) harbored ≥1 HIVDR mutations to standardized TDF, and LPVr. Third-line ART is determined on a case-by- second-line antiretroviral therapy (ART) regimen. Optimizing adherence, viral load monitoring, and genotyping are critical to case basis by the HIVDR Clinical Review Committee using prevent emergence of resistance, as well as unnecessary switch- clinical history and genotype results . Between 2010 and ing to costly third-line ART regimens. 2015, a total of 898 adult and pediatric patients suspected of Keywords: ART; drug resistance; Namibia; second line. failing second-line ART had genotyping requested, and this investigation evaluated the prevalence and patterns of HIVDR In 2016, globally, 54% of people living with human immuno- mutations in adults with suspected second-line VL failure with deficiency virus (HIV) were estimated to be on antiretro- genotype results. viral therapy (ART), and, between 2005 and 2016, acquired We identified 366 adult patients with HIVDR results avail- immune deficiency syndrome (AIDS)-related deaths able. The HIVDR mutations causing low-, intermediate-, or decreased by 48% . The 2016 World Health Organization high-level of resistance, using the Stanford HIVdb algorithm, guidelines for ART in low- and middle-income countries were identified. Resistance patterns were analyzed for any asso- recommends implementing routine viral load (VL) testing ciation with gender and age. to detect virologic failure (VF) and to monitor treatment RESULTS response to ART. However, limited availability of VL mon- itoring and delayed switching to second-line ART in some A total of 366 adult patients with genotype results were included, settings could contribute to the accumulation of HIV drug 51.1% were female, and the median age was 40 (interquartile resistance (HIVDR) in populations living with HIV/AIDS in range, 33–47). Human immunodeficiency virus-1 subtype C sub-Saharan Africa (SSA). represented 90% of cases, followed by recombinants B/C (5%), e N Th amibian National ART guidelines recommends VL and 08_BC/C, and CRF02_AG (3% each). testing 6 months aer sw ft itching to second-line ART. If the Overall, 58.5% (214 of 366) of the patients demonstrated VL level is >1000 copies/mL, intensive adherence counseling no HIVDR mutations, and 41.5% harbored 1 or more HIVDR is performed and VL testing is repeated aer 3 ft months. If the mutations. The prevalence of the most common mutations observed for NRTIs were as follows: any 138 (37.7%); M184V 114 (31.1%); T215Y/F 46 (12.6%); D67N 36 (9.8%); M41L 32 (8.7%); K219Q/E 31 (8.5%); K70R 26 (7.1%); and L210W 15 Received 19 October 2017; editorial decision 2 January 2018; accepted 10 January 2018. (4.1%). For protease inhibitors (PIs), the most common muta- Correspondence: S. Sawadogo, MSc, Florence Nightingale Street, Windhoek, Namibia (firstname.lastname@example.org). tions observed were as follows: any 37 (10.1%); V82A 25 (6.8%); Open Forum Infectious Diseases M46I/L 24 (6.6%); L76V 12 (3.3%); I54V 10 (2.7%); L90M 7 Published by Oxford University Press on behalf of Infectious Diseases Society of America 2018. (1.9%); and I84V 6 (1.6%). Of all patients with resistance to PIs This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/ofid/ofy014 (n = 37), 20 (54.1%) also had thymidine analogue mutations BRIEF REPORT • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy014/4802190 by Ed 'DeepDyve' Gillespie user on 16 March 2018 (TAMs). Of those with both PI HIVDR and TAMs, 8 (40%) testing for patients clearly suspected of failing second-line ART. had 2 TAMs and 11 (55%) had ≥3. Of the 20 total cases with PI This approach can help prevent unnecessary switching to costly HIVDR and TAMs, 6 patients (30%) had both type 1 and type third-line drugs, which should be preserved for patients with 2 TAMs, with the remainder having only type 1 (n = 8, 40%) or confirmed second-line ART failure [5, 6]. Inappropriate switch- only type 2 (n = 6, 30%). ing to second- and third-line ART drains limited resources, A total of 152 (41.5%) patients had HIVDR mutations to with recent pricing data estimating the cost of first-line ART the standardized second-line ARV drugs (SLDs), including 45 at US dollars (USD)$106, compared with second-line ART at (12.3%) with resistance to 1 drug, 30 (8.2%) with resistance to USD$286 and third-line ART at USD$1859 . 2 drugs, 61 (16.7%) with resistance to 3 drugs, and 18 (4.9%) Second, any resistance to the NRTI backbone used in sec- with resistance to all 4 SLDs (Figure 1). The number of patients ond-line ART regimens was observed in 138 (37.7%), of which with resistance to NRTIs used in standardized second-line ART 32 (23.2%), 31 (22.5%), and 75 (54.3%) patients were resistant was variable: 3TC 126 (34.4%), azidothymidine 89 (24.3%), to 1, 2 or 3 drugs, respectively. The NRTI resistance observed and TDF 104 (28.4%). The number of patients with resistance could partially or completely render the NRTI backbone inef- to LPV/r was 37 (10.1 %), and the resistance rate to LPVr did fective in patients being evaluated for third-line ART. However, not differ per year (8.0%–12.0%, P = .98). No association was the low PI resistance rate (10.1%) to LPV/r observed in this observed between HIVDR and age (>25 versus 16–24 years) study is reassuring, considering that genotypic resistance test- (relative risk [RR] = 0.87; 95% confidence interval [CI], 0.52– ing may not accurately predict NRTI activity when prescribing 1.43; P = .46) or sex (female versus male) (RR = 1.05; 95% CI, protease inhibitor-based ART to patients failing second-line 0.76–1.44; P = .70). ART. The PI-based regimens have demonstrated full virologic suppression in this setting, even with no predicted NRTI ac- DISCUSSION tivity, suggesting a role for NRTI resistance mutations in reduc- ing viral fitness . This study has several important findings. First, 58.5% of the Third, the 10.1% of patients who had resistance to LPVr were patients with second-line failure did not harbor any HIVDR to considered to have true second-line VF, and this finding high- SLDs, suggesting that most VFs were not due to HIVDR. This lights the need for HIVDR testing for second-line ART patients observations suggests that intensified adherence counseling and with true VF (not VF secondary to poor adherence) to ensure management of side effects may be the best first approach to these patients are prescribed effective third-line ART regimens. managing a detectable VL aer s ft tarting second-line ART . Finally, the prevalence rates for overall, class- and drug-spe- As reported in other countries in SSA , the high rates of no cific HIVDR in this study were comparable to HIVDR preva- HIVDR detected in patients suspected of failing second-line lence studies that have been performed in other countries in ART highlights the importance of routine HIV VL monitoring SSA [9–11]. for early detection of ART nonadherence, followed by genotype CONCLUSIONS This study demonstrated extensive NRTI resistance mutations 140 40% and emerging PI resistance in patients failing second-line ART in Namibia, supporting the importance of optimizing ART ad- 35% herence, routine VL monitoring to detect early emergence of 30% VF, and genotypic analysis before initiating third-line ART . 25% These findings also underscore the need for increased access 20% to salvage ARVs (eg, durable PIs and integrase strand transfer 15% inhibitors) to ensure that patients failing second-line ART are 10% able to switch to efficacious, third-line ART regimens to prevent 5% the further accumulation of HIVDR. er Th e are 2 limitations to this study. First, there was no 0 0% access to individual patient ART regimen history, duration on ART, adherence data, or other clinical information that would have been useful for further interpreting findings. Second, the sample size was relatively small, limiting the power to detect Figure 1. Pattern and prevalence of human immunodeficiency virus (HIV) drug associations and assess confounding factors. The findings of resistance in the 366 patients with confirmed virological failures and treated this study provides important information that can be used with the standard Namibia LPV/r-containing second-line antiretroviral regimen programmatically for the management of patients with VF on from 2010 to 2015. No. of patients with drug-resistant mutations (DRM) ( ); second-line PI-containing regimens in Namibia. percentage of patients with DRM ( ). 2 • OFID • BRIEF REPORT Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy014/4802190 by Ed 'DeepDyve' Gillespie user on 16 March 2018 3TC AZT TDF 3TC+AZT 3TC+TDF AZT+TDF AZT+TDF+3TC LPV/R PI+1NRTI PI+2NRTI PI+3NRTI # patients with DRM # patients with DRM 5. Collier D, Iwuji C, Derache A, et al. Virological outcomes of second-line pro- Acknowledgments tease inhibitor-based treatment for human immunodeficiency virus type 1 in Disclaimer. e fin Th dings and conclusions in this report are those of the a high-prevalence rural South African setting: a competing-risks prospective authors and do not necessarily represent the official position of the funding cohort analysis. Clin Infect Dis 2017; 64:1006–16. agencies. 6. Boyd MA, Kumarasamy N, Moore CI, et al. Ritonavir-boosted lopinavir plus Financial support. This project has been funded in part by the President’s nucleoside or nucleotide reverse transcriptase inhibitors versus ritonavir-boosted Emergency Plan for AIDS Relief through the Centers for Disease Control lopinavir plus raltegravir for treatment of HIV-1 infection in adults with virologi- and Prevention under cooperative agreement number U2GPS002058. cal failure of a standard first-line ART regimen (SECOND-LINE): a randomised, open-label, non-inferiority study. Lancet 2013; 381:2091–99. Potential conifl cts of interest. All authors: No reported conflicts of 7. Médecins Sans Frontières. 2016. Untangling the Web of Antiretroviralprice interest. All authors have submitted the ICMJE Form for Disclosure of Reductions, 18th Edition—July 2016. Available at: https://www.msfaccess.org/sites/ Potential Conflicts of Interest. default/files/ HIV_report_Untangling-the-web-18thed_ENG_2016.pdf. Accessed 18 December 2017. References 8. Paton NI, Kityo C, Thompson J, et al. Nucleoside reverse-transcriptase inhibitor 1. UNAIDS. Fact sheet - Latest statistics on the status of the AIDS epidemic. cross-resistance and outcomes from second-line antiretroviral therapy in the pub- 2016. Available at: http://www.unaids.org/en/resources/fact-sheet. Accessed lic health approach: an observational analysis within the randomised, open-label, 15 May 2017. EARNEST trial. Lancet HIV 2017; 4:e341–8. 2. National Guidelines for Antiretroviral Therapy, Third Edition, July 2010. 9. Namakoola I, Kasama I, Mayanja BJ, et al. From antiretroviral therapy access Available at: http://www.who.int/hiv/pub/guidelines/namibia_art.pdf. Accessed to provision of third line regimens: evidence of HIV drug resistance mutations 15 May 2017. to first and second line regimens among Uganda adults. BMC Res Notes 2016; 3. Boyd MA, Moore CL, Molina JM, et al. Baseline HIV-1 resistance, virological 9:515–25. outcomes, and emergent resistance in the SECOND-LINE trial: an exploratory 10. Meintjes G, Dunn L, Coetsee M, et al. Third-line antiretroviral therapy in Africa: analysis. Lancet HIV 2015; 2:e42–51. effectiveness in a Southern African retrospective cohort study. AIDS Res Ther 4. Johnston V, Cohen K, Wiesner L, et al. Viral suppression following switch to sec- 2015; 12:39. ond-line antiretroviral therapy: associations with nucleoside reverse transcriptase 11. Rawizza HE, Chaplin B, Meloni ST, et al. Accumulation of protease mutations inhibitor resistance and subtherapeutic drug concentrations prior to switch. among patients failing second-line antiretroviral therapy and response to salvage J Infect Dis 2014; 209:711–20. therapy in Nigeria. PLoS One 2013; 8:e73582. BRIEF REPORT • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofy014/4802190 by Ed 'DeepDyve' Gillespie user on 16 March 2018
Open Forum Infectious Diseases – Oxford University Press
Published: Feb 1, 2018
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