HIV-1 Transmitted Drug Resistance in Latin America and the Caribbean: What Do We Know?

Transcription

1 AIDS Rev. Andrea-Clemencia 2012;14: Pineda-Peña: (Supplementary Transmitted Methods) Resistance in Latin America (Supplementary Methods) HIV-1 Transmitted Drug Resistance in Latin America and the Caribbean: What Do We Know? Andrea-Clemencia Pineda-Peña 1,2, Diana-Carolina Bello 1, Otto Sussmann 1, Anne-Mieke Vandamme 2,3, Jurgen Vercauteren 2, Kristel Van Laethem 2,4, Arley Gomez-Lopez 1 1 Clinical and Molecular Infectious Disease Group, Faculty of Sciences and Mathematics, Universidad del Rosario, Bogotá, Colombia; 2 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium; 3 Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal; 4 AIDS Reference Laboratory, Universitaire Ziekenhuizen Leuven, Leuven, Belgium Systematic searching A systematic strategy (Fig. 3) was used to search for Spanish, Portuguese and English literature published in the period June 1999 to May 2011 and available within the following databases: MEDLINE via PubMed, SciELO, BIREME, IBECS, Cochrane, and LILACS. Additionally, abstracts from Conference on Retroviruses and Opportunistic Infections (CROI), International AIDS Conference, IAS Conference on HIV Pathogenesis and Treatment, Meetings of the Infectious Diseases Society of America, European AIDS Clinical Society, International Congress on Drug Therapy in HIV Infection, and the International Drug Resistance Workshop were identified. The combinations of the following MeSH (Medline descriptor) or DeCS (Lilacs descriptor) terms were used: HIV or HIV-1 and Drug Resistance or Anti-HIV Agents or Anti-Retroviral Agents and Latin America, Caribbean, Central America, South America, or each individual LAC country (Fig. 1). For the respective international conferences, HIV and Resistance and the name of the LAC country were used as search items. The data were independently extracted and reviewed by two researchers (Pineda AC, Bello DC). Only studies in which naive patients were clearly defined as having no exposure to any ARV were included. Duplicates or preliminary versions of studies with similar data were excluded. Resistance surveys in pregnant women and in children and studies investigating mother-to-child transmission (MTCT) were also excluded due to the high probability of including treated patients. Studies based upon point mutation assays (e.g. Line Probe Assay LiPA) were not included as the data collection was restricted to specific mutations and sensitivity and specificity characteristics of these assays substantially differ from sequencing technology. The following data were extracted from the articles: region, sample size, data collection period, type of infection, mode of transmission, gender, age, CDC classification, CD4 count, subtype, TDR, technique and algorithm to determine drug resistance. Analysis of resistance Transmitted drug resistance was reanalyzed according to the SDRM list The sequences from the publications that were found through the systematic search were downloaded from Los Alamos database ( accessed in July 2011) and Stanford database ( accessed in August 2011). The RegaDB sequence alignment tool (available was used to determine amino acid mutations. If sequences were not available, TDR was recalculated based upon the mutations reported in the original figures and tables and excluding mutations that were not part of the SDRM list Both databases were also searched for additional HIV-1 sequences from Latin America and the Caribbean. The inclusion criteria were therapy naive patients (according to database and article referenced) and availability of RT and protease (PR) sequences for each patient. The exclusion criteria were duplicated sequences, clones, unknown treatment history, evidence of hypermutation, and short sequences (minimum requirements: RT positions 41 to 219 positions and PR positions 30 to 90). Dubious data were not extracted.the viral subtypes were evaluated by REGA HIV-1 subtyping tool 50. The analysis of the data was done with the statistical software R version Prevalence values were calculated with a 95% Wilson score confidence interval on the basis of a binomial distribution. Categorical data were compared with the chi-square test. Logistic regression analysis was used to examine TDR time trends in LAC, Brazil and Argentina, likewise the trends of NRTI, NNRTI and PI resistance and of 41L and 103N mutations. 3

2 AIDS Reviews. 2012;14 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Caribbean Caribbean Antigua, Dominica, Grenada, Guyana, Montserrat, St. Lucia, St. Vincent, Suriname, Trinidad and Tobago Transmission risk factor n (%) Barbados Barbados 24 Het 20 (56), Bi 8 (22), MSM 5 (14), U 3 (8)* Male gender n (%) Age (range)* CD4 (range) or clinical state* Subtype n (%) Technology Ref. [55] B 36 (100) [52] [54] [53] B 42 (100) [60] [59] [27] [58] [44] (57.5) 22 (2-65) B 67(94), C 1(1), B/D 3 (4) 22 (61) m (2-888) (21-77) AIDS 23 (64) Cuba 27 MSM 60 (58.3), Het 42 (40.8), MTC 1 (0.97) B 81(79), A 19(18), C 3 (3) PBMC Mexico 352 B 109 (44), C 10 (4), G 7 La Habana 250 MSM 318 (75); Het 107 (25) (82.8) (3), H 3 (1), CRF18_cpx 21 (8), CRF19_cpx 44 (17), CRF02_AG 2 (1), URF 54 (22) Mexico Northeast 39 Het 16 (41), MSM 6 (15.4), IVDU 5 (12.5), Bi 3 (7.7), U 9 (23) Central America Honduras 35 (89.7) 33 (20-58) m (0-712) Western (90) 214 (4-1,360) Trugene Tijuana and Ciudad Juarez San Pedro Sula, Tegucigalpa San Pedro Sula, Tegucigalpa 11 IVDU 8 (73), FSW 3 (27) B 11 (100) 336 m 109 B 333 (99), F and A/D 2 (1) 200 Het 172 (86), MSM 28 (14) 105 (53) 31 (15-64) B 198 (99), URF 2 (1) 4

3 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Central America Panama South America Panama, San Miguelito, Arraiján Districts. Colón, La Chorrera, Capira and 6 samples from other provinces Transmission risk factor n (%) Andrea-Clemencia Pineda-Peña: Transmitted Resistance in Latin America (Supplementary Methods) Male gender n (%) Age (range)* CD4 (range) or clinical state* Subtype n (%) Technology Ref. 53 Het 73 (54), U 42 (31), MSM 17 (13), Bi 3 (2) 109 (80.7) B 53(100) Argentina Buenos Aires 107 Sexual 72 (67) IVDU 9 (8), U 26 (24) 74 (69.2) m 33 m 338 PBMC and plasma Trugene and in-house Buenos Aires, Mendoza, Córdoba, Salta, La Plata 16 FSW 16 (100) 0 (0) B 3 (19), C 2 (12), CRF12_BF 3 (19), B/F 8 (50) Buenos Aires 284 Het 140 (49), MSM 132 (47), IVDU 6 (2), U 6 (2) Buenos Aires City and province, Rosario, Neuquén, Rio Negro Buenos Aires, Santiago del Estero, Rosario, Paraná, Cordoba, La Plata, Mendoza 52 Het 27 (52), MSM 18 (35), Bi 5 (10), transfusion 1 (2), IVDU 1 (2) 214 MSM 135 (63), MDU 13 (6), FDU 3 (1), Het 11 (5), FSW 16 (7), TSW 30 (14), PW 6 (3) 213 (75) years: 190 (66) > 250: 176 B 128 (45), B/F 147 (52), (64.2) other 9 (3) 39 (75) 36 (11) 427 m ( ) B 21 (40), B/F 31 (60) (45% of cases could be CFR12_BF ) 159 (74.3) m 470 B 124 (58), C 5 (0.5), F 1 (0.5), B/F 84 (39) Brazil Rio de Janeiro 65 IVDU (100) B 45 (70), F 10 (15), B/F 10 (15) Rio de Janeiro and Rio Grande do Sul 32 Blood donors B 23 (72), C 2 (6), D 1 (3), CRF01_AE 4 (12), B/F 2 (6) Rio de Janeiro 44 B 39 (89), C 1 (2), B/F 1 (2), U/B or U/F 3 (7) PBMC In house [56] [76] [25] [31] [41] [33] [26] [23] [66] 5

4 AIDS Reviews. 2012;14 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Transmission risk factor n (%) Male gender n (%) Age (range)* CD4 (range) or clinical state* Brazil São Paulo City 341 Blood donors B 277 (81), C 13(4), F1 25 (7), B/F1 23 (7), other 3 (1) Santos City 90 B 48 (54), C 1(1), B/F 40 (45) Rio de Janeiro (66.2) (19-62) B 60 (84), C 2 (3), F 7 (10), B/D and D/F 2 (3) 45 (80) B 39 (70), C 1 (2), F1 3 Rio de Janeiro 56 Het 38 (68), Bi 4 (7), MSM 1 (1.8) A 36 (64) (5), CRF02_AG 1 (2) URF 12 (21) São Paulo City (72) 37 ± ± 243 B 101 (82), C 7 (6), F 8 (6), B/F 5 (4), B/C 2 (2) Amazon basin, Bahia, Pernambuco, Rio de Janeiro, Minas Gerais and São Paulo states Rio Grande do Sul, Paraná, São Paulo, Rio de Janeiro, Mato Grosso do Sul, Pará, Bahía and Ceará 74 Blood donors B 62 (84), F 2 (3), B/F 8 (11), URF 2 (2) 356 Het 172 (62), MSM 55 (20) Bi 20 (7), IVDU 14 (5), other 18 (6) ± 9.1 B 212 (62), C 100 (29), F (59.2) 27 (8) in RT. B/C, B/F, C/F 42 (14.5) in PR + RT Subtype n (%) Technology Ref. PBMC Miracema (44) 30 (22-57) C 11 (40.7) B 27 (100) PBMC Pernambuco 80 Het 49 (61), MSM 31 (39) 51 (63.8) B 61 (73), C 1 (1), F 19 (23), B/F 3 (3) Rio Grande do Sul (44) ± B 6 (43), C 6 (43), NR 2 (14) Rio Grande 25 Het 50 (59), MSM/Bi 15 (18), IVDU 15 (18), transfusion 2 (2), U 3 (3) 45 (53) 35.2 ± ± 260 SD B 6 (24), C 19 (76) ViroSeq [22] [34] [35] [73] [72] [24] [67] [70] [71] [69] [91] 6

5 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Transmission risk factor n (%) Andrea-Clemencia Pineda-Peña: Transmitted Resistance in Latin America (Supplementary Methods) Male gender n (%) Age (range)* CD4 (range) or clinical state* Brazil Recife 84 Het 49 (58), MSM 35 (42) 54 (64.3) (68) Symptomatic (90.5) Subtype n (%) Technology Ref. B 61 (73), C 1 (1), F 19 (23), B/F 3 (3) Porto Alegre 108 MSM (15) 65 (60) B 35 (32), C 63 (58), F1 3 (3), URF (7) Saquarema, Santo Antonio de Padua Porto Alegre, Santa Catarina 50 B 77 (81), D 1 (1),F 8 (8), CRF02_AG 2 (2), B/F 7 (7) 209 B 59 (28), C 87 (42), F 18 (9), CRF31_BC 30 (14), B/C 10 (5), other 5 (2) Curitiba 57 B 32 (56), C 17 (30), F 1 (2), B/C 5 (9), C/D 1 (2), C/F 1(2) Santos City (54) 35 B 22 (67), C 2 (6), F 4 (12), B/F 5 (15) Ribeirão Preto, Santo André, Santos, Nova Iguaçu, Rio de Janeiro, Belo Horizonte, Curitiba, Florianópolis, Salvador, Brasília, Campinas, Porto Alegre, and São Paulo City 387 Het 217 (54), MSM (66.3) (43), IVDU 10 (2) Central West 97 Het 47 (48), MSM 25 (26) IVDU 2 (2), MTC 1 (1), U 20 (21) São Paulo City, Rio de Janeiro, Salvador, Porto Alegre, Brasilia, Belen 210 Het (56), MSM (24), Bi (11), other/multiple (10) 66 (68) m 32 (15-71) 35 (15-66) m 375 B 264 (66), C 51 (13), non-b non-c 68 (17), U 17 (4) m (4-1,184) B 80 (83), C 3(3), F 6 (6), B/F1 7 (7) B/C/F1 1 (1) 36 ± B 153 (72), C 31 (15), F 14 (7), URF 11 (6) ViroSeq PBMC PBMC ViroSeq Trugene, ViroSeq [92] [74] [93] [30] [36] [94] [75] [47] [39] 7

6 AIDS Reviews. 2012;14 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Transmission risk factor n (%) Brazil Palmas 52 Het 38 (73), MSM 9 (17), IVDU 1 (2), others 4 (8) Chile Colombia Peru Ceará State, Northeast 74 Het 23 (32), MSM 41 (55), MTC 10 (13) Central, North and South Regions Santiago 60 Het 16 (26), MSM-Bi 41 (68), IVDU 1 (1), U 3 (5) Male gender n (%) Age (range)* CD4 (range) or clinical state* 31 (59.6) 30 (14-65) m 380 (25-1,082) B 41 (79), C 3 (6), F 1 (2), B/F1 or C/F1 7 (13) 30 m 418 (15-932) asymptomatic 54 (73) Subtype n (%) Technology Ref. B 63 (85), C 4 (5), F 6 (8), CRF28_BF 1 (1) Trugene 79 Het 49 (36), MSM 48 (35), MTC 39 (29), 72 (74.2), B 115 (85), B/F 20 (15), Santiago 25 MSM 15 (60), Het 6 (24), Bi 3 (12), MSM+IVDU 1 (4) 74 MSM-Bi 57 (77), Het 17 (23) Bogotá, Valle del Cauca, Antioquia, Atlántico, Bolívar, Santander, Caldas Lima, Sullana, Piura, Arequipa, Iquitos, Pucallpa 54 (90) 37 (23-60) 200 (52-520) C 34 (56.7) Trugene 25 (100) 35 (25-45) Trugene 66 (88) 32 (18-58) 510 (211-1,450) A 74 (100) 103 MSM 56 (55), Het 46 (45) 85 (82.5) 34 (18-59) m 240 (7-837) C 26 (25.2) Trugene ViroSeq 359 MSM 359 (100) 359 (100) B 359 (100) ViroSeq [48] [29] [79] [83] [37] [38] [64] [32] 8

7 Table 1. Characteristics of published studies on transmitted drug resistance in Latin America and the Caribbean (continued) Country Region Sample* (n) Transmission risk factor n (%) Venezuela 31 MSM 50 (50), Het 30 (30), Bi 13 (13), U 4 (4), IVDU 3 (3) Andrea-Clemencia Pineda-Peña: Transmitted Resistance in Latin America (Supplementary Methods) Male gender n (%) Age (range)* CD4 (range) or clinical state* Subtype n (%) Technology Ref. 86 (86) B 99 (99), B/F1 (1) PBMC Caracas 63 B 63 (100) Trugene Caracas (85) 772 ± 388 B (100) PBMC Caracas (78.46) 33 (18-58) 551 B 57 (91), CRF01_AE 1 (2), CRF06_cpx 2 (3), B/ F1 2 (3) *The sample was defined as the number of patients with amplified sequences, the average or median (m) of age and CD4 as reported in reference. When available, clinical status, CDC classification or WHO clinical staging were specified. Percentage or number based upon the patients who were included in the study or who completed the questionnaire, not according to number of amplified samples. The study included epidemiological data from a survey in naive and treated patients. Reported values described the combined patient population. Data according to the age group or if CD4 are > 250 cells/µl; Study that followed the eligibility criteria of WHO surveys. Ref: references; ( ): not reported or dubious data; MSM: men having sex with men; Het: heterosexual; Bi: bisexual; IVDU: intravenous drug users; FSW: female sex worker; MDU: male drug user; FDU: female drug user; TSW: trans sex worker; PW: pregnant women; MTC: mother-to-child transmission; CDC: Centers for Disease Control; WHO: World Health Organization; PBMC: peripheral blood mononuclear cell; DBS: dried blot spot; CRF: circulating recombinant form; URF: unique recombinant form; U: unknown or unassigned; m: median; PR: protease; RT: reverse transcriptase; SD: standard deviation. DBS [62] [95] [61] [46] 9

8 AIDS Reviews. 2012;14 Table 2. Levels of transmitted drug resistance in Latin America and the Caribbean (articles) (continued) Country Type of infection Years Sample n TDR n (%)* Observations Ref. Caribbean Any (CI) NRTI NNRTI Major PI > 1 Class Algorithm Caribbean Naive HIVdb [55] SDRM 2009 Barbados Naive (4.2) 1 (4.2) [52] 2 (8.3) 1 (4.2) 0 1 (4.2) 0 SDRM 2009 Cuba Naive (7.4) 2 (7.4) IAS 2001 Not possible to recalculate TDR. [54] Mexico Naive May-Sep (5.2) 13 (5.2) HIVdb TDR recalculated from tables. [53] 9 (3.6) 9 (3.6) SDRM 2009 Mexico Chronic Feb 2001-Sep RT 1 (2.8) 1 (2.8) IAS 2005 TDR recalculated based upon 30 available sequences. [60] Central America Chronic Mar 2002-Mar (16) (8-23) 33 PR 1 (2.8) SDRM 2009 ^ 6 (6) 3 (3) 4 (4.2) HIVdb IAS 2004 Not possible to recalculate TDR. [59] Naive Feb-Apr (18) 1 (9) 0 0 [27] SDRM 2009 Honduras Naive Jul 2002-Jun (9.2) 26 (7.7) 24 (7.1) 9 (2.7) Total sample (7) ( ) Recent 24 (12) Apr 2004-Apr (21) Chronic 176 (88) (5) (7.5) 15 (6.3) 12 (5) 4(1.7) 6 (3) 10 (5) 0 3 (1.5) SDRM 2007 SDRM 2009 Not possible to recalculate TDR. 336 patients presented to MOH of Honduras to initiate therapy, but naive status was only confirmed by retrospective chart review in 239 patients. [44] Panama Naive HIVdb Not possible to recalculate TDR. [56] South America Argentina Chronic Jan 1997-Jun (2.4) 1 (1.2) 0 1 (1.2) 0 IAS-USA Primary infection was defined by symptoms or laboratory criteria. TDR recalculated from tables. Primary infection 13 2 (15.4) 1 (7.7) 0 1 (7.7) (4) 2 (2) 0 2 (2) 0 SDRM 2009 Naive Mar 2000-Mar (18.8) 3 (18.8) 1 (6.2) 0 1 (6.2) HIVdb IAS 2005 TDR recalculated based upon 8 available sequences. [25] Chronic 256 (90) Recent 28 (10) 2 (12.5) 2 (12.5) 1 (6.2) 0 1 (6.2) SDRM 2009 Mar 2003-Oct (4.2) 4 (1.4) 6 (2.1) 4 (1.4) 3 (1) IAS 2005 TDR recalculated based upon 283 available sequences. [31] Recent infection Jun 2004-Oct (7.7) ( ) Chronic 205 (78) Recent 57 (22) 11 (3.9) 5 (1.8) 4 (1.4) 4 (1.4) 2 (0.7) SDRM (1.9) 3 (5.7) 0 0 IAS 2005 Recent infection was defined with IWB or PNS < 9 months. [41] 4 (7.7) 1 (1.9) 3 (5.7) 0 0 SDRM 2009 Oct 2006-Sep (8.4) 9 (4.2) 12 (5.6) 7 (3.3) 7 (3.3) SDRM 2009 STARHS was performed on a subset. Only 214 were amplified. [33] [58] [76] 10

9 Andrea-Clemencia Pineda-Peña: Transmitted Resistance in Latin America (Supplementary Methods) Table 2. Levels of transmitted drug resistance in Latin America and the Caribbean (articles) (continued) Country Type of infection Years Sample n TDR n (%)* Observations Ref. Any (CI) NRTI NNRTI Major PI > 1 Class Algorithm Brazil Naive (18.5) 6 (22.2) HIVdb IAS 2005 For the first period it was not possible to recalculate TDR. [26] (13.2) 5 (13.2) 0 3 (7.9) 2 (5.3) TDR recalculated from tables for the second period. 3 (7.9) 2 (5.3) 0 3 (7.9) 2 (5.3) SDRM 2009 Naive Jan-Dec RT 3 (9.8) 3 (9.8) 0 TDR recalculated based upon 18 available sequences. [23] 3 (9.8) 3 (9.8) 0 SDRM 2009 Naive RT + PR IAS 2000 [66] Total sample Jul 1998-Mar (6.1) ( ) Chronic 280 (83.6) (5) ( ) Recent 55 (16.4) 55 7 (12.7) ( ) 4 (9) 4 (9) SDRM (3.5) 3 (0.8) 4 (1.2) 1 (0.2) IAS 2005 STARHS was performed on a subset. TDR recalculated from tables. [22] 19 (5.6) 12 (3.5) 3 (0.8) 5 (1.5) 1 (0.2) SDRM 2009 Chronic Jan 1999-Dec (21) 14 (21) 2 (3) 1 (1.5) 1 (1.5) HIVdb TDR recalculated based upon 69 RT and 70 PR available sequences. [34] Recent 25^ 8 (36.8) 5 (22.7) 0 3 (13.6) 0 14 (20.3) 14 (20.3) 2 (3) 1 (1.5) 1 (1.5) SDRM 2009 Chronic (1.4) 1 (1.4) HIVdb IAS 2006 Recent infection was defined < 1 year of seroconversion. TDR recalculated from Recent 20 1 (1.4) 1 (1.4) SDRM 2009 tables. Chronic Mar 2000-Nov RT 7 (14) 7 (14) [73] 49 PR 6 (12) 5 (10) 0 1 (2) 0 SDRM 2009 Chronic Jan 2000-Dec (6.5) 2 (1.6) 2 (1.6) 1 (0.8) 3 (2.4) SDRM 2007 TDR recalculated from tables. [72] 7 (5.7) 4 (3.2) 3 (2.4) 3 (2.4) 3 (2.4) SDRM 2009 Chronic 53 (71.6) (1.3) 1 (1.3) HIVdb IAS STARHS was performed on a subset. TDR recalculated from tables. [24] Recent 16 (21.6) 1 (1.3) 1 (1.3) SDRM 2009 Chronic 3 months RT 8 (2.3) 7 (2) 8 (2.3) 0 IAS 2000 TDR reanalysis was performed on a subset. [67] 356 PR 8 (2.3) 1 (0.3) 8 (2.3) SDRM 2009 Naive Dec 2001-Mar HIVdb version 4.1 [70] SDRM 2009 Naive IAS 2002 TDR recalculated from tables. [71] 6 (7.5) 6 (7.5) SDRM 2009 Naive Jul-Sep HIVdb IAS 2002 Not possible to recalculate TDR. [69] Naive Sep-Dec (8) (4) 0 HIVdb IAS 2003 TDR recalculated from tables. [91] 1 (4) (4) 0 SDRM 2009 Chronic Feb 2002-Jan (3.6) 3 (3.6) HIVdb TDR recalculated from tables. [92] 3 (3.6) 3 (3.6) SDRM 2009 [35] 11

10 AIDS Reviews. 2012;14 Table 2. Levels of transmitted drug resistance in Latin America and the Caribbean (articles) (continued) Country Type of infection Years Sample n TDR n (%)* Observations Ref. Brazil Naive RT+PR 21 RT 11 PR Any (CI) NRTI NNRTI Major PI > 1 Class Algorithm 3 (3) 1 (1) 2 (2) 0 0 HIVdb [74] 5 (5) 2 (2) 3 (3) 0 0 SDRM 2009 Naive (2) 1 (2) SDRM 2007 [93] Chronic 59 of 76 Recent 17 of 76 Chronic 24 of 32 Recent 8 of 32 Jul Mar (8.3) (5-13) Jan Feb (8.8) (3-18) 1 (2) 1 (2) SDRM (3.7) 14 (6.8) 1 (0.6) 4 (2.1) SDRM 2007 STARHS was performed on a subset. Not possible to recalculate TDR. [30] 1 (1.8) 4 (7) 0 0 SDRM 2007 STARHS was performed on a subset. TDR recalculated from tables. [36] 4 (7) 1 (1.8) 3 (5.2) 0 0 SDRM 2009 Naive (18.2) 2 (6) 4 (12) 0 0 HIVdb TDR recalculated based upon 31 available sequences. [94] Chronic Mar-Sep (4.9) ( ) Chronic (10.3) ( ) 8 (25) 3 (9.6) 5 (16) 1 (3.2) 1 (3.2) SDRM (1.8) 12 (3.1) 3 (0.8) 4 (1) SDRM 2007 TDR recalculated from tables. [75] 20 (5.2) 7 (1.8) 14 (3.6) 4 (1) 4 (1) SDRM (6) 4 (4) 2 (2) 3 (3) IAS and SDRM 2008 There was one minor PI mutation. [47] 10 (10.3) 6 (6) 4 (4) 2 (2) 3 (3) SDRM 2009 Recent (8.1) 5 (2.4) 9 (4.3) 4 (2) 1 (0.5) SDRM 2009 Recent infection was defined < 6 month of diagnosis. Not possible to recalculate TDR. Naive (11.5) ( ) Chronic 69 (93.2) Recent 5 (6.8) 2 (3.8) 3 (5.8) 1 (1.9) 0 SDRM 2009 [48] May 2008-May (9.5) 3 (4.1) 2 (2.7) 3 (4.1) 1 (1.4) SDRM 2009 [29] Chile Naive Jun Dec (2.5) 2 (2.5) HIVdb The author reported high or intermediate resistance. [79] Chronic Nov Dec (85) any mutation Recent (40) any mutation Recent Jul Dec (99) any mutation Colombia Naive (5.8) ( ) Peru Chronic 326 (90.8) Recent 33 (9.2) Oct Mar (6.2) 4 (5) 0 1 (1.3) 0 SDRM (3) 3 (5) 0 0 TDR recalculated from tables. [83] 1 (1.6) 1 (1.6) SDRM (4) Trugene GuideLines8 Recent infection was defined PNS < 12 months. TDR recalculated from tables [37] 3 (12) 2 (8) 2 (8) 0 1 (4) SDRM (8) 3 (4) 0 0 HIVdb IAS 2007 Recent infection was defined PNS < 18 months or symptoms of primary infection. TDR recalculated from tables. 3 (4) 2 (2.7) 1 (1.3) 0 0 SDRM (3.3) 7 (2) 1 (3) 3 (2.9) 5 (4.8) 1 (1) 3 (2.9) HIVdb Not possible to recalculate TDR. [64] 2 (0.6) 1 (3) 6 (1.8) 1 (3) 4 (1.2) 2 (6) IAS 2003 Not possible to recalculate TDR. [32] [39] [38] 12

11 Andrea-Clemencia Pineda-Peña: Transmitted Resistance in Latin America (Supplementary Methods) Table 2. Levels of transmitted drug resistance in Latin America and the Caribbean (articles) (continued) Country Type of infection Years Sample n TDR n (%)* Observations Ref. Any (CI) NRTI NNRTI Major PI > 1 Class Algorithm Venezuela Naive (3) 1 (3) IAS 2000 TDR recalculated based upon 30 available sequences. [62] SDRM 2009 Naive (11) SDRM Not possible to recalculate TDR. [95] Chronic (10) 2 (10) HIVdb TDR recalculated based upon 16 available sequences.. [61] 1 (5) 1 (5) SDRM 2009 Chronic (7) 1 (1.7) 2 (3.5) 1 (1.7) 0 ANRS [46] 8 (12.9) 1 (1.7) 2 (3.5) 5 (8) 0 SDRM 2009 *TDR is reported according to the reference (first row) and/or according to the SDRM list 2009 using sequences available in Los Alamos or Stanford database or numbers reported in tables and figures of original manuscript (second row) with exclusion of mutations that were not part of the SDRM list Defined as the number of amplified samples. Study that followed the eligibility criteria of WHO surveys. (^) ambiguous data. ( ): Not reported; TDR: transmitted drug resistance; n: number; CI: confidence interval; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; Ref: references; PR: protease; RT: reverse transcriptase; STARHS: serologic testing algorithm for recent HIV seroconversion; SDRM: Surveillance Drug Resistance Mutation list; IAS: International AIDS Society list; ANRS: National Agency for AIDS Research list; MOH: Ministry of Health; PNS: previous negative serology; IWB: indeterminate western blot; HIVdb: genotypic resistance interpretation algorithm from Stanford University. 13

12 AIDS Reviews. 2012;14 Table 3. Levels of transmitted drug resistance in Latin America and the Caribbean (abstracts) (continued) Reported TDR n (%) Countries Years Sample n * Any (%) (CI) NRTI NNRTI PI > 1 Class Algorithm Observations and mutations: n (%) Ref. Mexico Central America (13) 5 (11) 0 1 (2) Region: Central Mexico. Five samples had 41L (11%), one 210W, one 82I. [96] (5.9) HIVdb Region: 7 Mexican states [97] (1.8) Region: 8 National Medical Centers. For RT positions: 103: 3 (5.3), 215: 2 (3.5), 181: 1 (1.8) and 70: 1 (1.6); for PI position 30 1 (1.8). Mar 2003-Mar Region: Guadalajara. [99] Feb 2004-May (7.44) 25 (6.2) 9 (2.2) 5 (1.2)^ HIVdb Region: 9 cities in Central Mexico. Recent infection. For NRTI: 41L 8 (2), 70R 5 (1.2), 210W, 215Y/F, 219Q/E in 4 (1), and 67N 3 (0.7); for NNRTI: 103N 4 (1), 100I 3 (0.7), 106M/A and 181C/I with 1 (0.3); for PI: inclusion of polymorphism. Feb 2004-Jan (4.7) [ ] 4 (2) 5 (2.5) 4 (2) 3 (1.5) Region: Mexico City and two other states NR. For NRTI: 41L (1), 67N (1) and 215S, 115F, 151M, 219E, 219Q (0.5); for NNRTI: 103N (1.5), and 100I, 103R, 108I (0.5); for PI: 54V(1.5), 46I, 82A (1) , (6.8) 69 (4.2) 31 (1.9) 29 (1.8) NR SDRM 2009 Region: 12 states of Mexico. For NRTI: 215 revertants 36 (2.2), 41L 19 (1.1), for NNRTI, for PI: 90M 14 (0.8), 46IL 12 (0.7). At the national level, a decreasing trend was observed for NNRTI TDR (p = ), and an increasing trend for PI TDR (p = ). Panama (11.6) 5 (11.6) 3 (7) 0 NR HIVdb Recent infection. For NRTI: 77F/L, 210W, 62V, 215L, 41L, 219E, for NNRTI: 103N, 181C, 225H. [57] South America Argentina (5.6) 1 (1.1) 1 (1.1) 3 (3.3) 0 IAS patients with chronic and 7 with acute infection. For NRTI: 41L and 215 (1/5), for NNRTI: 103N (1/5) and for PI: 46I/L (2/5) and 82A (1/5) (3.2) 16 (8) Jun 2004-Dec (8.4) ( ) (3.5) 1 (1.2) 2 (2.3) 0 0 HIVdb IAS (1.4) 5 (2.5) NR 8 (4) 4 (1.4) NR For the two periods 184V (1/9) versus (5/16), 103N (3/9) versus (7/16), and 41L (3/9) versus (4/16) in Buenos Aires. [77] 2 (1.2) 8 (4.8) 1 (0.6) 3 (1.8) SDRM 2009 Region: Buenos Aires. Recent infection was defined based upon PNS, IWB or ARS. Mutations were 103N/S (9/14), 90M and 41L (3/14). TDR changes between 2004 and 2009 were not significant. Region: Buenos Aires, Cordoba and Rosario. For NRTI: 41L and 210W, NNRTI: 103K/N and 108I. Major PI mutations were not detected. Nov 2006-Dec (6.1) 1 (1.5) HIVdb Region: La Plata. One patient had 103N, 181C, 67G, 70R, 215L, 219E. [104] (6.4) 0 2 (4.3) 1 (2.1) SDRM 2009 Region: Buenos Aires Province. For NNRTI: 103N and 181C (2/3) and for PI: 85V (1/3). [42] Brazil 71 1 (1.3) 1 (1.3) NR NR 0 HIVdb 184V was detected. [105] 58 9 (16) 4 (7.1) 2 (3.6) HIVdb Region: Rio de Janeiro State. Recent infection 58 (33.7), chronic infection 114 (66.3) as determined using STARSH. [106] Oct 1994-Sept (5.3) 10 (8.8) 3 (2.7) 25 RT 72 PR 9/25 6/72 ^ ^ 6 (8.3) 2 (^) Region: Belo Horizonte. 19 patients had documented primary infection 6-12 months before. For RT: 41L, 179D/E/I, 184V, 188L, 210W (4/9) + 215Y (3/9), 188L, 210W (1/9), 181C (1/9). For PI 32I (1/72), 90M (3/72), 50V+ I93L (2/72) ^ ^ 1 (3) HIVdb Recent infection 19 (41). For RT positions: 41 2 (5), (3), 106 2(5), (3) and at (3) and for PI 82 1 (3). [108] (8.63) SDRM 2009 Region: Rio de Janeiro State. Chronic infection. No TDR detected between 1996 and 2000, (6.98) CI [ ] for 2002, (10.64) CI [ ] for NNRTI resistance was the most frequent. Mutations 41L, 103N, 215 revertants, 77L, 46I, 82A, 90M were the most prevalent mutations (41.5) 9 (21.9) 12 (29.2) 2 (4.9) ^ HIVdb High prevalence of BF recombinants and resistance in Santos. [110] (15) 7 (4) 19 (11) 7 (4) 3 (1.7) Region: Sao Paulo. Recent infection. 103N 12 (7) and 184V 5 (3) were the most prevalent. Polymorphisms were excluded (3.2) 24 (5.4) 0 6 (1.4) SDRM Region: South Brazil. The most prevalent mutation was 103N 19 (4.3). [112] RT + PR 43 PR 2 (6.8) NR 4 (5.5) Rio de Janeiro City [113] (18.7) 2 (6.3) 4 (12.5) 0 0 Region: Santos. 5 samples displayed a single mutation: 184V, 184I, 103N, 181V and 230L. One sample displayed 103N + 230L. Oct 2006-Aug (7.2) 2 (13.3) ^ ^ Region: Rio Grande. Recent infection 15 (13.8), chronic infection 94 (86.2). [115] Jul 2008-Dec (12.3) 21 (7.6) 11 (4.4) 10 (4) 9 (3.6) SDRM 2009 Region: Manaus, Salvador, Brasilia, Rio de Janeiro, Santos, Porto Alegre, Itajai. The most frequent mutations were for NRTI: 41L and 215 revertants, for NNRTI: 103N, for PI: 46IL and 30N. Peru and Ecuador (4.3) 1 (0.9) 3 (2.6) 1 (0.9) Region: Guayaquil (Ecuador) and Lima, Arequipa, Ica and Sullana (Peru). [65] TDR is reported according to the reference. For some studies, TDR has been recalculated using SDRM 2009 list and values available in tables from the referenced poster or abstract. *Defined as the number of amplified samples. Study that followed the eligibility criteria of WHO surveys. (^) ambiguous data. TDR: transmitted drug resistance; n: number; CI: confidence interval; NRTI: nucleoside reverse transcriptase inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitor; PI: protease inhibitor; Ref: references, ( ): not reported; STARHS: Serologic Testing Algorithm for Recent HIV Seroconversion; SDRM: Surveillance Drug Resistance Mutation list; IAS: International AIDS Society list; ANRS: National Agency for AIDS Research list; PNS: previous negative serology; IWB: indeterminate western blot; ARS: acute retroviral syndrome. [98] [100] [101] [45] [102] [78] [103] [107] [109] [111] [114] [43] 14