PI-Resistance Mutations and Response to New PI-Containing Regimens
Three fundamental types of correlations form the basis of drug resistance knowledge: (i) Correlations between genotypic data with the treatments of persons from whom sequenced HIV-1 isolates have been obtained (genotype-treatment); (ii) Correlations between genotype and in vitro drug susceptibility (genotype-phenotype); and (iii) Correlations between genotype and the clinical response to a new treatment regimen (genotype-outcome). The following table summarizes the results of published studies linking genotype and the clinical response to a new PI-containing regimen.
Nearly all publications on genotype and clinical outcome have described only the results of their analyses. None have published their underlying data, in part, because until now there had been no resource for making such data publicly available. As this database has now been modified to represent such data we have written to the authors of those studies that are most relevant today to request such data.
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Harrigan (1999) | PI-naïve (30); >=1 PI (37) | SQV/r
(400-600 mg of each BID) | NA | 67 | 24 | M46I/L, G48V, I54V, A71V/T, V82A/T, I84V, and L90M were weakly associated with a poor virological response |
| Tebas (1999) | NFV | SQV/r
(400 mg of each BID) | NRTIs | 24 | 24 | At baseline, 13 had D30N and 5 had L90M. 17/24 had RNA <500 and 10/24 had RNA <50 at W24. Insufficient data to establish association with baseline genotype. |
| Zolopa (1999) | >=1 PI | SQV/r
(400-600 mg SQV; 300-400 mg RTV BID) | NRTIs | 54 | 26 | RNA decrease of >=0.5 occurred in patients with <= 3 of mutations at positions 46, 48, 54, 82, 84, and 90. D30N did not affect response to SQV/r. |
| Marcelin (2004) | >=1 PI | SQV/r
(800 mg SQV and 100 mg RTV BID) | NRTIs | 72 | 16 | L10F/I/R/V, L24I, M46I/L, G48V, I54V, I62V, A71V/T, V82A/T/F/S, I84V, and L90M were univariate predictors. L24I, I62V, V82A/T/F/S, I84V, and L90M were the best predictors in multivariate analyses: Patients with 0, 1, and >=2 of these 5 mutations had a median 2.2, 1.2, and 0.3 log RNA decrease. |
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Para (2000) | SQV (>=12M) | IDV
(800 mg TID) | NRTIs | 51 | 8 | Mutations at positions 10, 20, 48, 82, 84, and 90 predicted a decreased virologic response at W8. 0 mutations: 1.7 log decrease, 1 mutation: -1.1 log decrease, 2-5 mutations: 0.3 log decrease. |
| Saah (2003) | NFV | IDV
(1000 mg TID) | EFV | 29 | 48 | D30N occurred in 17 and L90M in 11. RNA <500 occurred in 9/17 with D30N vs 2/11 with L90M. |
| Shulman (2002) | IDV ± PIs other than RTV | IDV/r
(400 mg of IDV and RTV BID) | NRTIs | 31 | 48 | 10/14 vs 3/14 subjects with >=3 mutations at the following positions responded to RTV boosting: 10, 20, 30, 32, 33, 36, 46, 47, 48, 50, 54, 71, 73, 77, 82, 84, 88, 90 |
| Campo (2003) | >= 1 PI(26/28 IDV, 15/28 RTV) | IDV/r
(IDV 800 mg and RTV 200 mg BID) | NRTIs ± NNRTIs | 28 | 24 | Virologic response correlated better with adherence than the pattern of drug-resistance mutations. |
Nelfinavir (NFV, NFV/SQV)
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Lawrence (1999) | SQV | NFV
(750 mg TID) | NRTI | 16 | 24 | No sustained responses were observed. L90M was associated with more rapid virologic failure. |
| Walmsley (2001) | >=1 PI(SQV, IDV, RTV) | NFV
(750 mg TID) | NRTIs ± NNRTIs | 63 | 24 -48 | 41% and 22% had RNA declines >=0.5 logs at 24 and 48 weeks respectively. Mutations at position 48, 82, 84, and/or 90 were present in 69% and were correlated with a poor virological response. |
| Casado (2001) | IDV ± RTV | NFV/SQV
(NFV 750-1250 mg; SQV 600-1000 mg BID-TID) | d4T/NVP | 31 | 26 -52 | 35% and 56% of patients had RNA <50 after 6 and 12 months. L90M (0% vs 43%) but not V82A (38% vs 36%) decreased the rate of response. |
Fosamprenavir (FPV, FPV/r)
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Duval (2002) | >=1 PI | APV (1,200 mg BID)vs APV/r (450-900 mg / 100 mg BID) | NRTIs + EFV | 22 | 24 | Most pts had >= 1 DRM at position 46, 54, 82, or 90. 13/14 receiving APV/r vs 2/8 receiving APV had HIV-1 RNA <200 at W24. |
| Marcelin (2003) | >=1 PI | APV/r (600 mg / 100 mg BID) | NRTIs | 49 | 12 | 70% of 49 pts achieved RNA <400. Lack of response was associated with >5 of the following DRM: L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S, and I84V. |
| Clevenbergh (2004) | >=1 PI | APV/r(APV 600 mg BID, RTV 100 mg BID) | Highly variable | 39 | 16 | No. DRM in the 2002 French ANRS algorithm (L10I, V32I, M46I/L, I47V, I50V, I54L/M/V, G73S, V82A/F/I/T/S, I84V, L90M) correlated with RNA changes. Median RNA decrease was 1.4 logs in 25 pts with <=3 DRM and 0.3 logs in 14 patients with >=4 DRM. |
| Lastere (2004) | >=1 PI | APV (1,200 mg BID) | Highly variable | 84 | 12 | In univariate and multivariate analyses DRMs at positions 10, 20, 36, 73, 82, and 90, and gag p6 PTAPP insertions were associated with poorer virological response. |
| Pellegrin I (2007) | Median of 3 (range 1:5); 26% had received APV | FPV/r (700/100 BID) | OB | 121 | 12 | 10IFRV, 33F, 36I, 46IL, 54LMTV, 62V, 63P, 71ILVT, 73ACST, 82AFST, 84V, and 90M were associated with decreased virological response. The presence of <4 mutations was associated with a median 2.3 log decrease whereas the presence of >=4 was associated with a 0.1 log decrease. |
| Masquelier (2008) | >=1 PI | FPV/r (700 mg / 100 mg) BID | OB | 63 | 12 | L10F/I/V, L33F, M46I/L, I47V, I54L/M/V/A/T/S, A71V, G73C/S/A/T, V82A/F/C/G, and L90M were associated with a decreased virologic response; V77I and N88S were associated with an increased virological response. |
| Marcelin AG (2007) CONTEXT and TRIAD studies | >=1 PI | FPV/r (700/100 BID) | Usually 2 NRTIs | 113 | 12 | The mutations I15V + M46IL + I54LMV + D60E + L63PT +I84V. Persons with 0 or 1 mutation had a mean 2 log decrease, those with 2 mutations had a median 1.5 log decrease, and those with >=3 mutations had <=0.6 log decreases. Mutations at positions 10, 33, 73, and 90 were negatively associated with response in univariate analyses. In this APV/FPV-naive population, no patient had V32I, I47V, or I50V. |
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Kempf (2002) | >=1 PI | LPV/r | NRTIs + EFV | 50 | 72 | DRMs at 11 positions were associated with decreased virologic response: 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90. 21/23 with 0-5, 15/21 with 6-7 mutations, and 2/6 with 8-10 of these DRM had RNA <400 at W72. |
| Masquelier (2002) | >=2 PIs | LPV/r | Highly variable | 68 | 12 | 34% of pts had RNA <400. Lack of response was associated with the baseline DRMs M46I, I54V, and V82A and with >=5 of the Kempf DRMs. |
| Bongiovanni (2003) | >=1 PI | LPV/r | NRTIs ± NNRTIs | 134 | 12 | 71/112 pts with <5 and 5/22 pts with >=6 Kempf DRM had RNA <50 at W12. |
| Loutfy (2004) | >=1 PI | LPV/r | Highly variable | 456 | 4-12 | In univariate analyses, the DRMs most predictive of virologic failure were M46I, Q58E, V82A/F/T, and L90M. The most predictive 3-mutation combination was L10F/I/R/V, M46I, and V82A/T/F. |
| Delaugerre (2004) | PI-naïve (21); >=1 PI (48) | LPV/r | NRTIs (PI-naïve) + NNRTI | 69 | 24-72 | Among the PI-experienced pts, L10I/F, M46I, I54V/L, A71V/I, V82A/F/S/T, and L90M were associated with virologic failure. |
| King (2007) |
3.1 previous PIs (excluding ATV, TPV, DRV) | LPV/r | OB | 792 | 9-23 | Mutations at positions 10, 20, 24, 33, 36, 47, 48, 54, 82, and 84 were associated with decreased likelihood of 1.0 log10 RNA decrease or RNA <400. Mutations at positions 46, 53, 63, 71, 90 from the original score were not significantly associated with response in a multivariate analysis. |
| Marcelin AG (2005) |
Median of 3 (range 1-5) | LPV/r | OB | 116 | 24 | The Genotypic Inhibitory Quotient (GIQ) defined as the median LPV Cmin concentration divided by the number of mutations at the following positions (10, 20, 24, 33, 36, 47, 48, 54, 82, 84). In a multivariate analysis, the GIQ but not the number of mutations was significantly associated with virological response. |
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Johnson (2005) | >=1 PI | ATV/r (ATV 300 mg; RTV 100 mg QD) | 2-NRTI including TDF | 120 | 48 | At baseline, 15%, 41%, 19%, and 25% of pts had a median of 0, 1-2, 3-4, or ³4 DRMs at the following positions: 10, 20, 24, 33, 36, 46, 48, 54, 63, 71, 73, 82, 84, and 90 [Colonno, 2003 #2420]. Overall, 38% achieved RNA <50 copies/ml including 44% with <4 DRM and 25% with >=4 DRMs |
| Vora (2006) | >=1 PI | ATV/r(ATV 300 mg; RTV 100 mg QD) | OB | 62 | 12 | 13 PI mutations at baseline were associated with a reduced virologic response: 10F/I/V, 16E, 33F/I/V, 46I/L, 60E, 84V, 85V, and 90M. RNA decrease >1 log occurred in 100% with <2 mutations, 80% with 2 mutations, 43% with 3 mutations, and 0% with 4-5 mutations. In a follow-up study of 53 patients (Marcelin 2006), only four mutations (L10F/I/V, L33F/I, I84V, and L90M were predictive of reduced response, although the original score remained predictive. |
| Pellegrin (2006) | >=1 PI; median 5 PIs, 6 NRTIs, 1 NNRTI | ATV/r (300 mg / 100 mg) QD | 2NRTIs (75%), 1 additional PI (17%); T20 (4%) | 71 | 12 | L10F/I/V. K20M/R, L24I, M46I/L, Q58E, L63P, G73S/A, V77I, V82A/F/S/T, I84A/V, L90M were associated with failure to reach RNA <50 copies/ml (p<=0.1) in a univariate analysis. A score that also included I54L/M/T/V, A71I/L/V/T was significantly associated with response in that 63% of persons with <5 total mutations vs 11% with >=5 total mutations had RNA <50 copies/ml. G16E and D60E occurred at baseline in 5 and 9 persons, respectively, but were not associated with virological response. |
| Bertoli (2006) Drug Resistance Workshop, Sitges Spain, 2006 | >=1 PI | ATV/r (300 mg / 100 mg) QD; ATV 400 mg QD | OB | 74 ATV/r; 85 ATV | 12 - 24 | For ATV/r, L10C/I/V, V32I, E34Q, M46I/L, F53L, I54A/M/V, V82A/F/I/T, and I84V reduced probability of RNA < 50 (92%, 83%, 75%, and 0% when 0, 1, 2, or >=3 mutations were present respectively). For ATV, G16E, K20I/M/R/T/V, V32I, L33F/I/V, F53L/Y, I64L/M/V, A71I/T/V, I85V, and I93L/M reduced probability of RNA < 50 (83%, 67%, 6%, and 0% for 0, 1-2, 3, or >=4 mutations, respectively). |
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| De Meyer (2008) | >=1 PI (and >=1 of 30N, 46IL, 48V,50LV, 82AFST, 84V,90M); median 5 PIs, 6 NRTIs, 1 NNRTI | DRV/r (600 mg / 100 mg) BID | OB +/- T20 | 377 (DRV/r) | 24 | V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V at baseline were associated with a decreased virologic response to DRV/r. About 60% with 0, 45% with 1-2, and <=20% with >=3 DRMs had RNA <50 copies/ml at wk 24. In phenotypic studies, I50V, I54M, L76V, and I84V reduced susceptibility to the greatest extent. V32I emerged in 30% of failures according to prescribing information. |
| Reference | Previous PI | Follow-up PI | Other Rx | No.Pts | Wk | Effect of Baseline Mutations on Response |
|---|
| Baxter (2006) RESIST-1 (1182,12; NCT00054717) and -2 (1182.48; NCT00144170) + 3 phase II studies (1182.2, 1182.4, 1182,51, 1182.52) | >=2 PIs (and >=1 of 30N, 46IL, 48V,50LV, 82AFLST, 84V, 90M but <3 mutations at codons 33, 82, 84, or 90); median 4 PIs, 6 NRTIs, 1 NNRTI | TPV/r (500 mg / 200 mg) BID | OB +/- T20 | 688 (TPV/r) | 24 | 21 mutations at 16 positions were found to correlate with a decreased virologic response to TPV/r salvage therapy: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. Each additional mutation was associated with a 0.04 log decreased 2-week and 0.16 log decreased 24 week response. The 24 week response dropped from 1.3 logs when 3 mutations were present to 0.64 logs when 4 mutations were present and was completely lost when 8 mutations were present. Note: The vast majority of isolates used to derive the list belonged to subtype B which is relevant because I13V, K20 mutations, M36I, and H69K are highly common in several non-B subtypes. |
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