Protease Inhibitors (PIs) There are seven FDA-approved PIs: amprenavir, indinavir, lopinavir (manufactured in combination with ritonavir), nelfinavir, ritonavir, saquinavir, and the recently approved compound atazanavir. The dynamic susceptibility range for each of the PIs is about 100-fold in most drug susceptibility assays (Hertogs et al., 1998; Hertogs et al., 2000; Petropoulos et al., 2000; Kempf et al., 2001; Parkin et al., 2003). The spectrum of mutations developing during therapy with indinavir, nelfinavir, saquinavir, ritonavir, and amprenavir have been well characterized (Condra et al., 1996; Molla et al., 1996; Schapiro et al., 1996; Boden & Markowitz, 1998; Craig et al., 1998; Patick et al., 1998; Shafer et al., 1999; Atkinson et al., 2000; Maguire et al., 2002) but fewer data are available for lopinavir (Masquelier et al., 2002; Romano et al., 2002) and atazanavir (Colonno et al., 2002). Pharmacologic factors influence the clinical efficacy of PIs more than that of the other two classes of HIV drugs (Schapiro et al., 1996; Stein et al., 1996; Burger et al., 1998; Hoetelmans et al., 1998; Acosta et al., 1999; Murphy et al., 1999; Durant et al., 2000; Hoetelmans, 2001; van Heeswijk et al., 2001). Virologic response is highly correlated with the inhibitory quotient (IQ) defined as the trough concentration divided by the inhibitory concentration of the drug (e.g. the IC50 in a standardized assay) (Hoetelmans, 2001; Shulman et al., 2002; Marcelin et al., 2003b). Drug levels achieved during PI monotherapy can vary greatly among individuals, often resulting in low IQs (van Heeswijk et al., 2001). This has led to the practice of administering sub-therapeutic doses of ritonavir (a cytochrome P450 enzyme inhibitor) in combination with other PIs to increase, or “boost” their drug levels (van Heeswijk et al., 2001). Lopinavir is formulated in a fixed combination with ritonavir (Hurst & Faulds, 2000); and saquinavir, indinavir, and amprenavir are now usually administered with low-dose ritonavir (van Heeswijk et al., 2001). Boosted PIs require higher levels of resistance than PIs given as monotherapy before significant loss of antiviral activity and virologic rebound occur (Condra et al., 2000a; Kempf et al., 2000; Shulman et al., 2002; Marcelin et al., 2003b). Protease substrate cleft mutations (Figure 3) V82A/T/F/S occur predominantly in HIV-1 isolates from patients receiving treatment with indinavir or ritonavir (Condra et al., 1996; Molla et al., 1996). V82A also occurs in isolates from patients receiving prolonged therapy with saquinavir following the development of the mutation G48V (Winters et al., 1998; Sevin et al., 2000). By themselves, mutations at codon 82 confer reduced susceptibility in vitro to indinavir, ritonavir, and lopinavir (Condra et al., 1996; Molla et al., 1996; Sham et al., 1998; Kempf et al., 2001) but not to nelfinavir, saquinavir, or amprenavir. However, when present with other PI mutations, V82A/T/F/S contributes phenotypic and clinical resistance to each of the PIs (Shafer et al., 1998; Sham et al., 1998; Winters et al., 1998; Kempf et al., 2001; Colonno et al., 2003; Marcelin et al., 2003b). V82A is the most common mutation at this position; V82S, the least common. The phenotypic and clinical significance of the differences between each of these mutations has not been studied. V82I occurs in about 1% of untreated individuals with subtype B HIV-1 and in 5-10% of untreated individuals with non-B isolates (Gonzales et al., 2001). Although V82I occasionally emerges during PI therapy (Maguire et al., 2002), preliminary data suggest that V82I confers minimal or no resistance to the available PIs (King et al., 1995; Descamps et al., 1998; Brown et al., 2001; Rhee et al., 2003). I84V has been reported in patients receiving indinavir, ritonavir, saquinavir, and amprenavir as their sole PI (Condra et al., 1996; Molla et al., 1996; Craig et al., 1998; Hertogs et al., 2000; Sevin et al., 2000; Maguire et al., 2002) and causes phenotypic (Partaledis et al., 1995; Tisdale et al., 1995; Condra et al., 1996; Patick et al., 1996; Carrillo et al., 1998; Palmer et al., 1999; Kempf et al., 2001; Prado et al., 2002; Colonno et al., 2003) and/or clinical (Zolopa et al., 1999b; Para et al., 2000; Kempf et al., 2002; Marcelin et al., 2003b) resistance to each of the PIs. I84V is rarely the first major PI-resistance mutation to develop, usually developing in isolates that already have the mutation L90M (Kantor et al., 2002; Wu et al., 2003). I84A and I84C are extremely rare mutations that are also associated with resistance to multiple PIs when present in combination with other PI-resistance mutations (Mo et al., 2003b). G48V occurs primarily in patients receiving saquinavir and rarely in patients receiving indinavir. This mutation causes 10-fold resistance to saquinavir and about 3-fold resistance to indinavir, ritonavir, and nelfinavir (Jacobsen et al., 1995; Patick et al., 1996; Hertogs et al., 1998; Winters et al., 1998). G48V has been reported to cause low-level biochemical resistance to APV when present in site-directed mutants, but to interfere with APV resistance when present together with more typical APV-resistance mutations such as M46I, I47V, and I50V (Markland et al., 2000). Its affect on lopinavir and atazanavir is not known. G48V usually occurs with mutations at positions 54 and 82 (Shafer et al., 1998; Palmer et al., 1999; Schiffer et al., 2001; Wu et al., 2003). D30N occurs solely in patients receiving nelfinavir and confers no in vitro or clinical cross-resistance to the other PIs (Patick et al., 1996; Markowitz et al., 1998; Winters et al., 1998; Zolopa et al., 1999a). D30N confers reduces nelfinavir susceptibility by 5-20 fold. D30N is often followed by the development of N88D and the combination reduces nelfinavir susceptibility by about 50-fold (Rhee et al., 2003). D30N usually does not develop in isolates containing other primary PI-resistance mutations (Kantor et al., 2002; Sugiura et al., 2002; Wu et al., 2003). I50V has been reported only in patients receiving amprenavir as their first PI (Maguire et al., 2002). In addition to causing reduced amprenavir susceptibility, it causes reduced susceptibility to ritonavir and lopinavir (Partaledis et al., 1995; Tisdale et al., 1995; Molla et al., 2001; Prado et al., 2002; Mo et al., 2003a; Parkin et al., 2003). The development of I50V usually requires a specific compensatory cleavage site mutation (Maguire et al., 2002; Prado et al., 2002). I50L occurs in patients receiving atazanavir as their first PI (Colonno et al., 2002). It reduces atazanavir susceptibility by 5-10 fold and causes hypersusceptibility to each of the remaining PIs (Colonno et al., 2002). V32I occurs in patients receiving indinavir, ritonavir, or amprenavir. It usually occurs in association with other PI resistance mutations in the substrate cleft or flap and by itself appears to cause minimal resistance to any one drug. However, in combination with other mutations such as M46I/L, I47V, V82A, and I84V, high levels of resistance to multiple PIs, including lopinavir, have been repoted (Parkin et al., 2003). R8K and R8Q are substrate cleft mutations that cause high-level resistance to one of the precursors of ritonavir (A-77003) (Ho et al., 1994; Gulnik et al., 1995) but they have not been reported with the current PIs. Protease flap mutations (Figure 3) The protease flaps (residues 33-62) extends over the substrate-binding cleft and must be flexible to allow entry and exit of the polypeptide substrates and products (Shao et al., 1997; Scott & Schiffer, 2000). The flap tips (residues 46-54) are particularly mobile and are the site of many drug-resistance mutations. In addition to mutations at positions 48 and 50, which extend into the substrate cleft, mutations at positions 46, 47, 53, and 54 make important contributions to drug resistance. Mutations at position 54 (generally I54V, less commonly I54T/L/M/S) contribute resistance to each of the approved PIs (Condra et al., 1996; Molla et al., 1996; Kempf et al., 2001; Maguire et al., 2002; Colonno et al., 2003) and have been frequently reported during primary therapy with indinavir, ritonavir, amprenavir, and saquinavir, (Condra et al., 1996; Molla et al., 1996; Schapiro et al., 1996; Patick et al., 1998; Maguire et al., 2002) and salvage therapy with lopinavir (Masquelier et al., 2002; Romano et al., 2002; King et al., 2003). I54L and I54M are particularly common in persons receiving amprenavir and have a greater effect on amprenavir than does I54V (Maguire et al., 2002). Mutations at position 46 (usually M46I/L, rarely M46V) contribute to resistance to each of the PIs except possibly saquinavir (Condra et al., 1996; Molla et al., 1996; Kempf et al., 2001; Maguire et al., 2002; Colonno et al., 2003) and have been frequently reported during primary therapy with indinavir, ritonavir, amprenavir, and nelfinavir (Molla et al., 1996; Schapiro et al., 1996; Patick et al., 1998; Condra et al., 2000b; Maguire et al., 2002) and during salvage therapy with lopinavir (Masquelier et al., 2002; Romano et al., 2002). I47V has been reported in patients receiving amprenavir, indinavir, and ritonavir, and often occurs in conjunction with the nearby substrate cleft mutation, V32I (Parkin et al., 2003). I47A is an uncommon mutation that is associated with high-level resistance to lopinavir and intermediate resistance to amprenavir (Kagan et al., 2003). F53L has been reported rarely in patients receiving PI monotherapy, but it occurs in more than 10% of patients treated with multiple PIs (Wu et al., 2003). In a multivariate analysis it has been associated with phenotypic resistance to lopinavir (Kempf et al., 2001). F53Y is a less commonly occurring substitution at this position which occurs only in treated persons and probably has a similar role as F53L (Wu et al., 2003). Protease mutations at other conserved residues (Figure 3) L90M has been reported in isolates from patients treated with saquinavir, nelfinavir, indinavir, and ritonavir. L90M either contributes to or directly confers in vitro resistance to each of the seven approved PIs (Condra et al., 1996; Patick et al., 1998; Lawrence et al., 1999; Hertogs et al., 2000; Para et al., 2000; Dronda et al., 2001; Kempf et al., 2001; Kempf et al., 2002; Colonno et al., 2003; Marcelin et al., 2003a). Crystal structures with and without the mutant have shown that the Leu90 side chain lies next to Leu24 and Thr26 on either side of the catalytic Asp25 (Mahalingam et al., 1999; Olsen et al., 1999; Mahalingam et al., 2001) but the mechanism by which L90M causes PI resistance is not known. Mutations at codon 73, including G73C/S/T, have been reported in 10% of patients receiving indinavir and saquinavir as their only PI and less commonly in patients receiving nelfinavir as their only PI (Shafer et al., 1999; Wu et al., 2003). However, this mutation occurs most commonly in patients failing multiple PIs, usually in conjunction with L90M (Kantor et al., 2002; Wu et al., 2003). Mutations at position 88 (N88D and N88S) commonly occur in patients receiving nelfinavir and occasionally in patients receiving indinavir. By itself, a mutation at this position causes low-level resistance to nelfinavir and indinavir. However, mutations at this position causes high-level nelfinavir resistance in the presence of D30N or M46I (Colonno et al., 2000; Petropoulos et al., 2000; Ziermann et al., 2000). N88S (but not N88D) has been shown to hypersensitize isolates to amprenavir (Ziermann et al., 2000). L24I has been reported primarily in HIV-1 isolates from patients receiving indinavir (Condra et al., 2000b) and has not been shown to confer cross-resistance to other PIs, except possibly lopinavir (Kempf et al., 2001). L33F has been reported primarily in persons treated with ritonavir or amprenavir (Molla et al., 1996; Maguire et al., 2002). Its effect on PI susceptibility levels has not been studied. However, it has gained attention recently because of its association with lack of response to the experimental PI, tipranavir (McCallister et al., 2003). In contrast, L33I/V are polymorphisms in untreated persons and their effect, if any, on drug resistance is not known. Polymorphic sites contributing to resistance (Figure 3) Amino acid variants at several polymorphic positions also make frequent contributions to drug resistance but only in combination with drug-resistance mutations at non-polymorphic positions. Mutations at positions 10, 20, 36, and 71 each occur in up to 5 to 10% of untreated persons infected with subtype B viruses. However, in heavily treated patients harboring isolates with multiple other PI-resistance mutations, the prevalence of mutations at these positions increases dramatically. Mutations at positions10 and 71 increase to 60 to 80%, whereas mutations at positions 20 and 36 increase to 30 to 40% (Hertogs et al., 2000; Wu et al., 2003). Position 63 is the most polymorphic protease position. In untreated persons about 45% of isolates have 63L (considered the subtype B consensus), about 45% have 63P, and about 10% have other residues at this position. However, the prevalence of amino acids other than L increases to 90% in heavily treated patients (Yahi et al., 1999; Wu et al., 2003). Mutations at positions 77 and 93 increase in prevalence from about 25% in untreated persons to about 40% in heavily treated persons (Wu et al., 2003). I93L is statistically associated with multiple PIs; whereas V77I is statistically associated only with nelfinavir. In some HIV-1 subtypes, mutations at codons 20, 36, and 93 occur at higher rates than they do in subtype B isolates (Cornelissen et al., 1997; Pieniazek et al., 2000; Gonzales et al., 2001). In contrast, mutations at positions 63 and 77 usually occur more commonly in subtype B than in non-B isolates. It has been hypothesized that individuals harboring isolates containing multiple accessory mutations may be at a greater risk of virologic failure during PI therapy (Perez et al., 2001; Perno et al., 2001). However, most studies have not supported this hypothesis (Bossi et al., 1999; Harrigan et al., 1999; Kuritzkes et al., 2000; Alexander et al., 2001; Frater et al., 2001; Perez et al., 2001; Perno et al., 2001; Servais et al., 2001). Additional treatment-associated mutations In a recent analysis of 2,244 protease isolates from 1,919 persons, 45 protease positions were more likely to be mutant in isolates from treated compared with untreated persons, 17 positions exhibited polymorphisms that were unrelated to treatment, and 37 positions rarely, if ever varied (Wu et al., 2003). The 45 treatment-associated positions included 23 positions previously associated with drug resistance that are described above and 22 positions that had not previously been associated with drug resistance. Thirteen of the 22 newly described treatement- associated positions (positions 11, 22, 23, 45, 58, 66, 74, 75, 76, 79, 83, 85, 85) were highly conserved in untreated persons. Nine of the newly described treatment-associated positions (positions 13, 34, 35, 43, 45, 55, 62, 72, 89) were polymorphic in untreated persons. Several of these mutations have also been described in other recent publications containing analyses of large databases (Parkin et al., 2003; Wang et al., 2003). The phenotypic and clinical impact of these mutations is not yet known because they rarely occur in the absence of other known drug- resistance mutations and have not been studied in vitro (Wu et al., 2003). PI cross-resistance patterns and salvage therapy In a study of over 6000 HIV-1 isolates tested for susceptibility to indinavir, nelfinavir, ritonavir, and saquinavir, 59% to 80% of isolates with a 10-fold decrease in susceptibility to one PI also had a 10-fold decrease in susceptibility to at least one other PI (Hertogs et al., 2000). In a study of 3000 HIV-1 isolates, resistance to indinavir, ritonavir, and lopinavir were highly correlated (Parkin et al., 2001). Isolates that were resistant to these drugs were generally also resistant to nelfinavir; however, isolates resistant to nelfinavir due to D30N were not resistant to other drugs. Susceptibilities to saquinavir and amprenavir are less well correlated with one another and with susceptibilities to the other PIs (Race et al., 1999; Schmidt et al., 2000a; Kemper et al., 2001; Parkin et al., 2001), although isolates that are highly resistant to amprenavir are often cross- resistant to lopinavir (Parkin et al., 2003). Atazanavir selects for a unique protease mutation in previously untreated persons, I50L, but most of the mutations that confer resistance to other PIs, appear to also confer atazanavir resistance (Colonno et al., 2003). Patients in whom nelfinavir-resistant isolates arise after nelfinavir treatment often respond to a regimen containing a different PI because D30N and N88D/S confer little cross- resistance to other PIs (Zolopa et al., 1999b; Kemper et al., 2001). But because as many as 15% of nelfinavir failures may be associated with mutations at positions 46 and/or 90, virologic failure during nelfinavir does not guarantee susceptibility to other PIs (Patick et al., 1998; Atkinson et al., 2000; Saah et al., 2003). Nelfinavir is usually unsuccessful as salvage therapy because most of the mutations that confer resistance to other PIs confer cross-resistance to nelfinavir (Lawrence et al., 1999; Hertogs et al., 2000; Schmidt et al., 2000b; Walmsley et al., 2001). In a study of ritonavir/saquinavir salvage therapy using the hard gel capsule formulation of saquinavir (400-600 mg twice daily), the number of mutations at positions 46, 48, 54, 82, 84, and 90 predicted the virologic response at 4, 12, and 24 weeks. Patients with three or more of these mutations had no virologic response to salvage therapy (Zolopa et al., 1999b). Decreased phenotypic susceptibility also predicted a reduced virologic response in this cohort (Zolopa et al., 1999b). However, nine patients with isolates having mutations at positions 82 and 90 and at either or both positions 46 and 54 had no virologic response to ritonavir/saquinavir salvage despite the fact that their isolates were found to be phenotypically susceptible to saquinavir or to have only low-level reductions of saquinavir susceptibility (Zolopa et al., 1999b; Zolopa et al., 2001). There are few data on the genotypic predictors of response to indinavir/ritonavir salvage therapy. In two small published studies, adherence, indinavir levels, and the number of PI- resistance mutations at positions 46, 48, 54, 82, 84, 90 were predictive of virologic response (Shulman et al., 2002; Campo et al., 2003). In vitro susceptibility studies suggest that patients failing other PIs often have isolates that retain susceptibility to amprenavir (Race et al., 1999; Schmidt et al., 2000a). Data on the utility of amprenavir for salvage therapy, however, are limited (Falloon et al., 2000; Klein et al., 2000; Descamps et al., 2001; Duval et al., 2002). In the NARVAL ANRS 088 trial, the presence of fewer than four of the following mutations -- L10I, V32I, M46IL, I47V, I54V, G73S, V82A/T/F/S, I84V, L90M -- was associated with a 1.6 log10 RNA reduction 12 weeks after the administration of an amprenavir-containing regimen (Descamps et al., 2001). The presence of exactly four mutations was associated with a 0.6 log10 RNA reduction. In another study, suppression of plasma HIV-1 RNA levels to <400 copies/ml during treatment with amprenavir/ritonavir was associated with having fewer than 6 of the following mutations (L10FIV, K20MR, E35D, R41K, I54V, L63P, V82AFTS, I84V) (Marcelin et al., 2003b). Of note, the mutations at positions 35 and 41 are common polymorphisms and have not been associated with PI resistance in any previous analyses. In a study of salvage therapy with a regimen containing lopinavir and efavirenz, the number of mutations at positions 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, and 90 predicted the level of phenotypic resistance and the virologic response after 24 weeks of therapy (Kempf et al., 2000; Kempf et al., 2001). A decreased response to therapy was observed only in those patients that had six or more of the listed mutations. Subsequent analyses have suggested that mutations at positions 10, 20, 46, 54, and 82 may be more predictive than the other mutations listed (Calvez et al., 2001; Molla et al., 2001) and that other mutations, including V32I, I47V/A, I50V, and G73S may contribute to resistance in patient cohorts with different antiretroviral treatment experience (Harrigan et al., 2001; Prado et al., 2002; Bongiovanni et al., 2003; Parkin et al., 2003). Lopinavir has also proven highly effective as salvage therapy when combined with nevirapine in NNRTI- naive patients failing their first PI regimen (Benson et al., 2002). During in vitro passage experiments atazanavir-resistant isolates develop mutations at positions 32, 50, 84, and/or 88, a pattern of mutations that differs from but overlaps with the mutations developing in patients treated with other PIs (Gong et al., 2000). In patients receiving atazanavir as their first PI, the most common drug resistance mutation to develop, I50L, causes resistance to atazanavir alone, while hypersensitizing to other PIs. However, two of eight atazanavir failures had mutations at positions 46 and/or 82 in addition to I50L (Colonno et al., 2002) suggesting that susceptibility to other PIs may not be guaranteed. The usefulness of atazanavir for salvage therapy is currently being studied in phase III clinical trials (Badaro et al., 2003). These studies suggest that because of the high cross-resistance between the approved PIs, the choice of a PI for salvage therapy depends primarily on the drug levels that are likely to be achieved. The presence of mutations known to preferentially affect one drug (e.g. G48V and saquinavir, I50V and amprenavir), will occasionally also influence the choice of salvage therapy. However, many combinations of mutations produce only subtle differences in susceptibility between available drugs. Clinical studies are needed to determine the usefulness of the protease genotype or phenotype at pointing to a preferred boosted PI for salvage. Investigational PIs Tipranavir is the investigational PI at the most advanced state of clinical development. The potency of tipranavir in vitro (i.e. IC50 of wildtype isolates in a standard susceptibility assay) and in vivo (reduction in plasma HIV-1 RNA levels in previously untreated individuals) has not been well described (Plosker & Figgitt, 2003). However, tipranavir has a remarkably high genetic barrier to resistance. After prolonged in vitro passage, mutations at positions 32, 33, 45, 82, and 84 have been selected leading to a virus with 14-fold reduced susceptibility (Doyon et al., 2002). However, most PI-resistant clinical isolates, even those with >10-fold resistance to the original four PIs (saquinavir, indinanvir, ritonavir, and nelfinavir) rarely have more than 2-fold resistance to tipranavir (Larder et al., 2000). Reduced susceptibility of clinical isolates obtained from persons with other PIs appears to require three of the following four mutations: L33F/I/V, V82A/F/L/T, I84V, L90M (Cooper et al., 2003). Phase II salvage therapy studies have shown that the optimal response to tipranavir occurs when 500 mg of tipranavir is administered with 200 mg of ritonavir twice daily (Yeni et al., 2003). In heavily treated persons harboring viruses resistant to most other PIs, 14 days of boosted tipranavir reduced plasma HIV-1 RNA levels by 1.2 logs provided baseline tipranavir susceptibility was reduced by <2-fold (Yeni et al., 2003). No virologic suppression was observed with viruses having >2-fold reduction in susceptibility. Figure 1. Structural Model of HIV-1 Protease Homodimer Labeled with Protease Inhibitor Resistance Mutations The polypeptide backbone of both protease subunits (positions 1-99) is shown. The active site, made up of positions 25-27 from both subunits, is displayed in ball and stick mode. The protease inhibitor resistance mutations are shown for the subunit on the left but not for the mirror-image subunit on the right. The protease was co-crystallized with indinavir which is displayed in space-fill mode. This drawing is based on a structure published by Chen et al. Figure 1 References Chen Z, Li Y, Chen E, Hall DL, Darke PL, Culberson C, Shafer JA, Kuo LC. Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. J Biol Chem 1994;269(42):26344-8. Figure 2. Schematic Representation of How the Protease Recognizes Nine Cleavage Sites to Create the Structural Proteins from the gag Gene and Enzymes from the pol Gene The inset shows the peptides recognized by the HIV-1 protease. Compensatory changes at these cleavage sites occur commonly in viruses containing certain protease mutations. References Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. 1999. Indinavir concentrations and antiviral effect. Pharmacother 19:708-712. Alexander CS, Dong W, Chan K, Jahnke N, O'Shaughnessy MV, Mo T, Piaseczny MA, Montaner JS, Harrigan PR. 2001. HIV protease and reverse transcriptase variation and therapy outcome in antiretroviral-naive individuals from a large North American cohort. AIDS 15:601-607. Atkinson B, Isaacson J, Knowles M, Mazabel E, Patick AK. 2000. Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J Infect Dis 182:420-427. Badaro R, DeJesus E, Lazzarin A, Jemsek J, Clotet B, Rightmire A, Thiry A, Wilber R. 2003. Efficacy and safety of atazanavir (ATV) with ritonavir (RTV) or saquinavir (SQV) versus lopinavir/ritonavir (LPV/RTV) in combination with tenofovir (TFV) and one NRTI in patients who have experienced virologic failure to multiple HAART regimens. 2nd IAS Conference on HIV Pathogenesis and Treatment. Paris, France. Benson CA, Deeks SG, Brun SC, Gulick RM, Eron JJ, Kessler HA, Murphy RL, Hicks C, King M, Wheeler D, Feinberg J, Stryker R, Sax PE, Riddler S, Thompson M, Real K, Hsu A, Kempf D, Japour AJ, Sun E. 2002. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in human immunodeficiency virus type 1-infected protease inhibitor-experienced patients. J Infect Dis 185:599-607. Boden D, Markowitz M. 1998. Resistance to human immunodeficiency virus type 1 protease inhibitors. Antimicrob Agents Chemother 42:2775-2783. Bongiovanni M, Bini T, Adorni F, Meraviglia P, Capetti A, Tordato F, Cicconi P, Chiesa E, Cordier L, Cargnel A, Landonio S, Rusconi S, d'Arminio Monforte A. 2003. Virological success of lopinavir/ritonavir salvage regimen is affected by an increasing number of lopinavir/ritonavir- related mutations. Antivir Ther 8:209-214. Bossi P, Mouroux M, Yvon A, Bricaire F, Agut H, Huraux JM, Katlama C, Calvez V. 1999. Polymorphism of the human immunodeficiency virus type 1 (HIV-1) protease gene and response of HIV-1- infected patients to a protease inhibitor. J Clin Microbiol 37:2910-2912. Brown AJ, Precious HM, Whitcomb J, Simon V, Daar ES, D'Aquila R, Keiser P, Connick E, Hellmann N, Petropoulos C, Markowitz M, Richman D, Little SJ. 2001. Reduced susceptibility of HIV-1 to protease inhibitors from patients with primary HIV infection by three distinct routes [abstract 424]. 8th Conference on Retroviruses and Opportunistic Infections. Chicago, Il. Burger DM, Hoetelmans RM, Hugen PW, Mulder JW, Meenhorst PL, Koopmans PP, Brinkman K, Keuter M, Dolmans W, Hekster YA. 1998. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther 3:215-220. Calvez V, Cohen-Codar I, Marcelin AG, Descamps D, Tamalet C, Ritter J, Segondy M, Peigue-Lafeuille H, Brun-Vezinet F, Guillevic E, Isaacson J, Rode R, Bernstein B, Sun E, Kempf D, Chauvin JP. 2001. Identification of individual mutations in HIV protease associated with virological response to lopinavir/ritonavir therapy. Antivir Ther 6:64. Campo RE, Moreno JN, Suarez G, Miller N, Kolber MA, Holder DJ, Shivaprakash M, DeAngelis DM, Wright JL, Schleif WA, Emini EA, Condra JH. 2003. Efficacy of indinavir-ritonavir-based regimens in HIV-1-infected patients with prior protease inhibitor failures. AIDS 17:1933-1939. Carrillo A, Stewart KD, Sham HL, Norbeck DW, Kohlbrenner WE, Leonard JM, Kempf DJ, Molla A. 1998. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol 72:7532-7541. Colonno RJ, Friborg J, Rose RE, Lam E, Parkin N. 2002. Identification of amino acid substitutions correlated with reduced atazanavir susceptibility in patients treated with atazanavir containing regimens. Antivir Ther 7(Supplement 4):S6. Colonno RJ, Hertogs K, Larder B, Limoli K, Heilek-Snyder G, Parkin N. 2000. BMS-232632 sensitivity of a panel of HIV-1 clinical isolates resistant to one or more approved protease inhibitors [abstract 8]. Antivir Ther 5(Supplement 3):7. Colonno RJ, Thiry A, Limoli K, Parkin N. 2003. Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors. Antimicrob Agents Chemother 47:1324-1333. Condra J, Holder D, Schleif WA, Bakshi KK, Danovich RM, Graham D, Shivaprakash M, Holmes K, Saah A, Leavitt R, Chodakewitz J, Emini E. 2000a. Genetic correlates of virological response to an indinavir-containing salvage regimen in patients with nelfinavir failure. Antivir Ther 4, Supplement 1:44. Condra JH, Holder DJ, Schleif WA, Blahy OM, Danovich RM, Gabryelski LJ, Graham DJ, Laird D, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, Yang T, Chodakewitz JA, Deutsch PJ, Leavitt RY, Massari FE, Mellors JW, Squires KE, Steigbigel RT, Teppler H, Emini EA. 1996. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J Virol 70:8270-8276. Condra JH, Petropoulos CJ, Ziermann R, Schleif WA, Shivaprakash M, Emini EA. 2000b. Drug resistance and predicted virologic responses to human immunodeficiency virus type 1 protease inhibitor therapy. J Infect Dis 182:758-765. Cooper D, Hall D, Jayaweera D, Moreno S, Katlama C, Schneider S, Minoli L, Yeni P, Steigbigel R, McCallister S, Kohlbrenner V, Cuaresma E, Sabo J, Mayers DL. 2003. Baseline phenotypic susceptibility to tipranavir/ritonavir (TPV/r) is retained in isolates from patients with multiple protease inhibitor experience (BI 1182.52) [abstract 596]. 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA. Cornelissen M, van dB, Zorgdrager F, Lukashov V, Goudsmit J. 1997. pol gene diversity of five human immunodeficiency virus type 1 subtypes: evidence for naturally occurring mutations that contribute to drug resistance, limited recombination patterns, and common ancestry for subtypes B and D. J Virol 71:6348-6358. Craig C, Race E, Sheldon J, Whittaker L, Gilbert S, Moffatt A, Rose J, Dissanayeke S, Chirn GW, Duncan IB, Cammack N. 1998. HIV protease genotype and viral sensitivity to HIV protease inhibitors following saquinavir therapy. AIDS 12:1611-1618. Descamps D, Apetrei C, Collin G, Damond F, Simon F, Brun-Vezinet F. 1998. Naturally occurring decreased susceptibility of HIV-1 subtype G to protease inhibitors [letter]. AIDS 12:1109-1111. Descamps D, Masquelier B, Mamet JP, Calvez C, Ruffault A, Telles F, Goetschel A, Girard PM, Brun- Vezinet F, Costagliola D. 2001. A genotypic sensitivity score for amprenavir based genotype at baseline and virological response. Antivir Ther 6:103. Doyon L, Tremblay C, Cartier M, Cordingley M. 2002. In vitro susceptibility of HIV-1 to tipranavir. Antivir Ther 7(Supplement 1):S12. Dronda F, Casado JL, Moreno S, Hertogs K, Garcia-Arata I, Antela A, Perez-Elias MJ, Ruiz L, Larder B. 2001. Phenotypic cross-resistance to nelfinavir: the role of prior antiretroviral therapy and the number of mutations in the protease gene. AIDS Res Hum Retrovirus 17:211-215. Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, Del Giudice P, Montagne N, Schapiro JM, Dellamonica P. 2000. Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study. AIDS 14:1333-1339. Duval X, Lamotte C, Race E, Descamps D, Damond F, Clavel F, Leport C, Peytavin G, Vilde JL. 2002. Amprenavir inhibitory quotient and virological response in human immunodeficiency virus- infected patients on an amprenavir-containing salvage regimen without or with ritonavir. Antimicrob Agents Chemother 46:570-574. Falloon J, Piscitelli S, Vogel S, Sadler B, Mitsuya H, Kavlick MF, Yoshimura K, Rogers M, LaFon S, Manion DJ, Lane HC, Masur H. 2000. Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease- inhibitor regimen: pharmacokinetic drug interactions and antiviral activity. Clin InfectDis 30:313-318. Frater AJ, Beardall A, Ariyoshi K, Churchill D, Galpin S, Clarke JR, Weber JN, McClure MO. 2001. Impact of baseline polymorphisms in RT and protease on outcome of highly active antiretroviral therapy in HIV-1-infected African patients. AIDS 15:1493-1502. Gong YF, Robinson BS, Rose RE, Deminie C, Spicer TP, Stock D, Colonno RJ, Lin PF. 2000. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother 44:2319-2326. Gonzales MJ, Machekano RN, Shafer RW. 2001. Human immunodeficiency virus type 1 reverse- transcriptase and protease subtypes: classification, amino acid mutation patterns, and prevalence in a northern california clinic-based population. J Infect Dis 184:998-1006. Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson B, Mitsuya H, Erickson JW. 1995. Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry 34:9282-9287. Harrigan PR, Alexander C, Dong W, Jahnke N, O'Shaughnessy MV, Montaner JS. 1999. Prevalence of resistance-associated mutations in patients starting antivirals: virologic response after approximately one year of therapy [abstract 124]. Antivir Ther 4(Suppl 1):88. Harrigan PR, Van Den Eynde C, Larder BA. 2001. Quantitation of lopinavir resistance and cross-resistance and phenotypic contribution of mutations shared with other protease inhibitors. Antivir Ther 6:40. Hertogs K, Bloor S, Kemp SD, Van den Eynde C, Alcorn TM, Pauwels R, Van Houtte M, Staszewski S, Miller V, Larder BA. 2000. Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples. AIDS 14:1203-1210. Hertogs K, de Bethune MP, Miller V, Ivens T, Schel P, Van Cauwenberge A, Van Den Eynde C, Van Gerwen V, Azijn H, Van Houtte M, Peeters F, Staszewski S, Conant M, Bloor S, Kemp S, Larder B, Pauwels R. 1998. A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs. Antimicrob Agents Chemother 42:269-276. Ho DD, Toyoshima T, Mo H, Kempf DJ, Norbeck D, Chen CM, Wideburg NE, Burt SK, Erickson JW, Singh MK. 1994. Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J Virol 68:2016-2020. Hoetelmans R. 2001. Pharmacological exposure and the development of drug resistance in HIV. Antivir Ther 6:37-47. Hoetelmans RM, Reijers MH, Weverling GJ, ten KR, Wit FW, Mulder JW, Weigel HM, Frissen PH, Roos M, Jurriaans S, Schuitemaker H, de WF, Beijnen JH, Lange JM. 1998. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS 12:F111-F115. Hurst M, Faulds D. 2000. Lopinavir. Drugs 60:1371-1379; discussion 1380-1371. Jacobsen H, Yasargil K, Winslow DL, Craig JC, Krohn A, Duncan IB, Mous J. 1995. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology 206:527-534. Kagan R, Shenderovich M, Ramnarayan K, Heseltine P, Perrin V, Mammano F. 2003. Emergence of a novel lopinavir resistance mutation at codon 47 correlates with ARV utilization Parameters driving the selection of nelfinavir-resistant HIV-1 variants Antivir Ther Volume 8:S54 S55. Kantor R, Fessel WJ, Zolopa AR, Israelski D, Shulman N, Montoya JG, Harbour M, Schapiro JM, Shafer RW. 2002. Evolution of primary protease inhibitor resistance mutations during protease inhibitor salvage therapy. Antimicrob Agents Chemother 46:1086-1092. Kemper CA, Witt MD, Keiser PH, Dube MP, Forthal DN, Leibowitz M, Smith DS, Rigby A, Hellmann NS, Lie YS, Leedom J, Richman D, McCutchan JA, Haubrich R. 2001. Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors. AIDS 15:609-615. Kempf D, Brun S, Rode R, Isaacson J, King M, Xu Y, Real K, Hsu A, Granneman R, Lie Y, Hellmann N, Bernstein B, Sun E. 2000. Identification of clinically relevant phenotypic and genotypic breakpoints for ABT-378/r in multiple PI-experienced, NNRTI-naive patients [abstract 89]. Antivir Ther 5(Supplement 3):70-71. Kempf DJ, Isaacson JD, King MS, Brun SC, Sylte J, Richards B, Bernstein B, Rode R, Sun E. 2002. Analysis of the virological response with respect to baseline viral phenotype and genotype in protease inhibitor-experienced HIV-1-infected patients receiving lopinavir/ritonavir therapy. Antivir Ther 7:165-174. Kempf DJ, Isaacson JD, King MS, Brun SC, Xu Y, Real K, Bernstein BM, Japour AJ, Sun E, Rode RA. 2001. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J Virol 75:7462-7469. King MS, Mo H, Molla A, Brun S, Kempf D. 2003. Evolution of lopinavir (LPV) resistance in protease inhibitor-experienced patients treated with LPV/r [abstract H-912]. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL: American Society for Microbiology. pp 323. King RW, Winslow DL, Garber S, Scarnati HT, Bachelor L, Stack S, Otto MJ. 1995. Identification of a clinical isolate of HIV-1 with an isoleucine at position 82 of the protease which retains susceptibility to protease inhibitors. Antivir Res 28:13-24. Klein A, Maguire M, Paterson D, Nacci P, Mustafa N, Yeo J, Snowden W, Kleim JP. 2000. Virological response to amprenavir combination therapy in PI-experienced paediatric patients: association with distinct baseline HIV-1 protease variants - study PROAB3004 [abstract 3]. Antivir Ther 5 Supplement 2:4. Kuritzkes DR, Sevin A, Young B, Bakhtiari M, Wu H, St Clair M, Connick E, Landay A, Spritzler J, Kessler H, Lederman MM. 2000. Effect of zidovudine resistance mutations on virologic response to treatment with zidovudine-lamivudine-ritonavir: genotypic analysis of human immunodeficiency virus type 1 isolates from AIDS clinical trials group protocol 315.ACTG Protocol 315 Team. J Infect Dis 181:491-497. Larder BA, Hertogs K, Bloor S, van den Eynde CH, DeCian W, Wang Y, Freimuth WW, Tarpley G. 2000. Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples. AIDS 14:1943- 1948. Lawrence J, Schapiro J, Winters M, Montoya J, Zolopa A, Pesano R, Efron B, Winslow D, Merigan TC. 1999. Clinical resistance patterns and responses to two sequential protease inhibitor regimens in saquinavir and reverse transcriptase inhibitor- experienced persons. J Infect Dis 179:1356-1364. Maguire M, Shortino D, Klein A, Harris W, Manohitharajah V, Tisdale M, Elston R, Yeo J, Randall S, Xu F, Parker H, May J, Snowden W. 2002. Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors. Antimicrob Agents Chemother 46:731-738. Mahalingam B, Louis JM, Hung J, Harrison RW, Weber IT. 2001. Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes. Proteins 43:455-464. Mahalingam B, Louis JM, Reed CC, Adomat JM, Krouse J, Wang YF, Harrison RW, Weber IT. 1999. Structural and kinetic analysis of drug resistant mutants of HIV-1 protease. Eur J Biochem 263:238-245. Marcelin A, Dalban C, Peytavin G, Delaugerre C, Agher R, Katlama C, Costagliola D, Calvez V. 2003a. Clinically relevant interpretation of genotype for resistance to ritonavir (100 mg twice daily) plus saquinavir (800 mg twice daily) in HIV-1-infected protease inhibitor-experienced patients. Antivir Ther Volume 8:S117. Marcelin AG, Lamotte C, Delaugerre C, Ktorza N, Ait Mohand H, Cacace R, Bonmarchand M, Wirden M, Simon A, Bossi P, Bricaire F, Costagliola D, Katlama C, Peytavin G, Calvez V. 2003b. Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients. Antimicrob Agents Chemother 47:594-600. Markland W, Rao BG, Parsons JD, Black J, Zuchowski L, Tisdale M, Tung R. 2000. Structural and kinetic analyses of the protease from an amprenavir-resistant human immunodeficiency virus type 1 mutant rendered resistant to saquinavir and resensitized to amprenavir. J Virol 74:7636-7641. Markowitz M, Conant M, Hurley A, Schluger R, Duran M, Peterkin J, Chapman S, Patick A, Hendricks A, Yuen GJ, Hoskins W, Clendeninn N, Ho DD. 1998. A preliminary evaluation of nelfinavir mesylate, an inhibitor of human immunodeficiency virus (HIV)-1 protease, to treat HIV infection. J Infect Dis 177:1533-1540. Masquelier B, Breilh D, Neau D, Lawson-Ayayi S, Lavignolle V, Ragnaud JM, Dupon M, Morlat P, Dabis F, Fleury H. 2002. Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients. Antimicrob Agents Chemother 46:2926-2932. McCallister S, Kohlbrenner V, Squires K, Lazzarin A, Kumar P, DeJesus E, Nadler J, Gallant J, Walmsley S, Yeni P, Leith J, Dohnanyi C, Hall D, Sabo J, MacGregor T, Verbiest W, McKenna P, Mayers D. 2003. Characterization of the impact of genotype, phenotype, and inhibitory quotient on antiviral activity of tipranavir in highly treatment-experienced patients Antivir Ther Volume 8:S15. Mo H, Lu L, Dekhtyar T, Stewart KD, Sun E, Kempf DJ, Molla A. 2003a. Characterization of resistant HIV variants generated by in vitro passage with lopinavir/ritonavir. Antivir Res 59:173-180. Mo H, Parkin N, Stewart K, Lu L, Dekhtyar T, Kempf D, Molla A. 2003b. I84A and I84C mutations in protease confer high-level resistance to protease inhibitors and impair replication capacity Antivir Ther Volume 8:S56. Molla A, Brun S, Garren K, Mo H, Richards B, Marsh T, Sylte J, King M, Han L, Sun E, Kempf D. 2001. Patterns of resistance to lopinavir in protease inhibitor-experienced patients following viral rebound during lopinavir/ritonavir therapy. Antivir Ther 6:49. Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper PJ, Mo HM, Markowitz M, Chernyavskiy T, Niu P, Lyons N, Hsu A, Granneman GR, Ho DD, Boucher CA, Leonard JM, Norbeck DW, Kempf DJ. 1996. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med 2:760-766. Murphy RL, Sommadossi JP, Lamson M, Hall DB, Myers M, Dusek A. 1999. Antiviral effect and pharmacokinetic interaction between nevirapine and indinavir in persons infected with human immunodeficiency virus type 1. J Infect Dis 179:1116-1123. Olsen DB, Stahlhut MW, Rutkowski CA, Schock HB, vanOlden AL, Kuo LC. 1999. Non-active site changes elicit broad-based cross-resistance of the HIV- 1 protease to inhibitors. J Biol Chem 274:23699-23701. Palmer S, Shafer RW, Merigan TC. 1999. Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS 13:661-667. Para MF, Glidden DV, Coombs R, Collier A, Condra J, Craig C, Bassett R, Leavitt R, Snyder S, McAuliffe VJ, Boucher C. 2000. Baseline human immunodeficiency virus type I phenotype, genotype, and RNA response after switching from long-term hard-capsule saquinavir to indinavir or soft-gel- capsule saquinavir in AIDS clinical trials group protocol 333. J Infect Dis 182:733-743. Parkin NT, Chappey C, Maranta M, Whitehurst N, Petropoulos C. 2001. Genotypic and phenotypic analysis of a large database of patient samples reveals distinct patterns of cross-resistance. Antivir Ther 6:49. Parkin NT, Chappey C, Petropoulos CJ. 2003. Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance. AIDS 17:955-961. Partaledis JA, Yamaguchi K, Tisdale M, Blair EE, Falcione C, Maschera B, Myers RE, Pazhanisamy S, Futer O, Cullinan AB, et al. 1995. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J Virol 69:5228-5235. Patick AK, Duran M, Cao Y, Shugarts D, Keller MR, Mazabel E, Knowles M, Chapman S, Kuritzkes DR, Markowitz M. 1998. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob Agents Chemother 42:2637-2644. Patick AK, Mo H, Markowitz M, Appelt K, Wu B, Musick L, Kalish V, Kaldor S, Reich S, Ho D, Webber S. 1996. Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob Agents Chemother 40:292-297. Perez EE, Rose SL, Peyser B, Lamers SL, Burkhardt B, Dunn BM, Hutson AD, Sleasman JW, Goodenow MM. 2001. Human immunodeficiency virus type 1 protease genotype predicts immune and viral responses to combination therapy with protease inhibitors (PIs) in PI-naive patients. J Infect Dis 183:579-588. Perno CF, Cozzi-Lepri A, Balotta C, Forbici F, Violin M, Bertoli A, Facchi G, Pezzotti P, Cadeo G, Tositti G, Pasquinucci S, Pauluzzi S, Scalzini A, Salassa B, Vincenti A, Phillips AN, Dianzani F, Appice A, Angarano G, Monno L, Ippolito G, Moroni M, Monforte A. 2001. Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy. J Infect Dis 184:983-991. Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ, Whitcomb JM. 2000. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 44:920-928. Pieniazek D, Rayfield M, Hu DJ, Nkengasong J, Wiktor SZ, Downing R, Biryahwaho B, Mastro T, Tanuri A, Soriano V, Lal R, Dondero T. 2000. Protease sequences from HIV-1 group M subtypes A-H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide. HIV Variant Working Group. AIDS 14:1489-1495. Plosker GL, Figgitt DP. 2003. Tipranavir. Drugs 63:1611-1618. Prado JG, Wrin T, Beauchaine J, Ruiz L, Petropoulos CJ, Frost SD, Clotet B, D'Aquila RT, Martinez- Picado J. 2002. Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity. AIDS 16:1009-1017. Race E, Dam E, Obry V, Paulous S, Clavel F. 1999. Analysis of HIV cross-resistance to protease inhibitors using a rapid single-cycle recombinant virus assay for patients failing on combination therapies. AIDS 13:2061-2068. Rhee SY, Gonzales MJ, Kantor R, Betts BJ, Ravela J, Shafer RW. 2003. Human immunodeficiency virus reverse transcriptase and protease sequence database. Nucleic Acids Res 31:298-303. Romano L, Peduzzi C, Venturi G, Di Pietro M, Carli T, Corsi P, Gonnelli A, Valensin PE, Zazzi M. 2002. Treatment with lopinavir/ritonavir in heavily pretreated subjects failing multiple antiretroviral regimens in clinical practice. J Acquir Immune Defic Syndr 30:533-535. Saah AJ, Haas DW, DiNubile MJ, Chen J, Holder DJ, Rhodes RR, Shivaprakash M, Bakshi KK, Danovich RM, Graham DJ, Condra JH. 2003. Treatment with indinavir, efavirenz, and adefovir after failure of nelfinavir therapy. J Infect Dis 187:1157-1162. Schapiro JM, Winters MA, Stewart F, Efron B, Norris J, Kozal MJ, Merigan TC. 1996. The effect of high- dose saquinavir on viral load and CD4+ T-cell counts in HIV-infected patients. Ann Intern Med 124:1039-1050. Schiffer CA, Scott WRP, Stewart F, King M, Kempf D. 2001. The uncommon HIV-1 protease mutation I54T is highly associated with G48V and may affect cleavage dynamcis by stabilizing the structure of the flaps. Antivir Ther 6:52. Schmidt B, Korn K, Moschik B, Paatz C, Uberla K, Walter H. 2000a. Low level of cross-resistance to amprenavir (141W94) in samples from patients pretreated with other protease inhibitors. Antimicrob Agents Chemother 44:3213-3216. Schmidt B, Walter H, Moschik B, Paatz C, van Vaerenbergh K, Vandamme AM, Schmitt M, Harrer T, Uberla K, Korn K. 2000b. Simple algorithm derived from a geno-/phenotypic database to predict HIV-1 protease inhibitor resistance. AIDS 14:1731-1738. Scott WR, Schiffer CA. 2000. Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure Fold Des 8:1259-1265. Servais J, Lambert C, Fontaine E, Plesseria JM, Robert I, Arendt V, Staub T, Schneider F, Hemmer R, Burtonboy G, Schmit JC. 2001. Variant human immunodeficiency virus type 1 proteases and response to combination therapy including a protease inhibitor. Antimicrob Agents Chemother 45:893-900. Sevin AD, DeGruttola V, Nijhuis M, Schapiro JM, Foulkes AS, Para MF, Boucher CA. 2000. Methods for investigation of the relationship between drug- susceptibility phenotype and human immunodeficiency virus type 1 genotype with applications to AIDS clinical trials group 333. J Infect Dis 182:59-67. Shafer RW, Hsu P, Patick AK, Craig C, Brendel V. 1999. Identification of biased amino acid substitution patterns in human immunodeficiency virus type 1 isolates from patients treated with protease inhibitors. J Virol 73:6197-6202. Shafer RW, Winters MA, Palmer S, Merigan TC. 1998. Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients. Ann Intern Med 128:906-911. Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM. 1998. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 42:3218-3224. Shao W, Everitt L, Manchester M, Loeb DD, Hutchison CA, Swanstrom R. 1997. Sequence requirements of the HIV-1 protease flap region determined by saturation mutagenesis and kinetic analysis of flap mutants. Proc Natl Acad Sci USA 94:2243-2248. Shulman N, Zolopa A, Havlir D, Hsu A, Renz C, Boller S, Jiang P, Rode R, Gallant J, Race E, Kempf DJ, Sun E. 2002. Virtual inhibitory quotient predicts response to ritonavir boosting of indinavir-based therapy in human immunodeficiency virus-infected patients with ongoing viremia. Antimicrob Agents Chemother 46:3907-3916. Stein DS, Fish DG, Bilello JA, Preston SL, Martineau GL, Drusano GL. 1996. A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 10:485-492. Sugiura W, Matsuda Z, Yokomaku Y, Hertogs K, Larder B, Oishi T, Okano A, Shiino T, Tatsumi M, Matsuda M, Abumi H, Takata N, Shirahata S, Yamada K, Yoshikura H, Nagai Y. 2002. Interference between D30N and L90M in selection and development of protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 46:708-715. Tisdale M, Myers RE, Maschera B, Parry NR, Oliver NM, Blair ED. 1995. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother 39:1704-1710. van Heeswijk RP, Veldkamp A, Mulder JW, Meenhorst PL, Lange JM, Beijnen JH, Hoetelmans RM. 2001. Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther 6:201-229. Walmsley SL, Becker MI, Zhang M, Humar A, Harrigan PR. 2001. Predictors of virological response in HIV-infected patients to salvage antiretroviral therapy that includes nelfinavir. Antivir Ther 6:47- 54. Wang D, Larder B, Revell A, Harrigan R, Montaner J. 2003. A neural network model using clinical cohort data accurately predicts virological response and identifies regimens with increased probability of success in treatment failures Antivir Ther Volume 8:S112. Winters MA, Schapiro JM, Lawrence J, Merigan TC. 1998. Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment. J Virol 72:5303- 5306. Wu TD, Schiffer CA, Gonzales MJ, Taylor J, Kantor R, Chou S, Israelski D, Zolopa AR, Fessel WJ, Shafer RW. 2003. Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments. J Virol 77:4836-4847. Yahi N, Tamalet C, Tourres C, Tivoli N, Ariasi F, Volot F, Gastaut JA, Gallais H, Moreau J, Fantini J. 1999. Mutation patterns of the reverse transcriptase and protease genes in human immunodeficiency virus type 1-infected patients undergoing combination therapy: survey of 787 sequences. J Clin Microbiol 37:4099-4106. Yeni P, MacGregor T, Gathe J, Arasteh K, Jayaweera D, Jemsek J, Hawkins T, Cameron W, Bodsworth N, McCallister S, Kohlbrenner V, Quinson AM, Leith J, Sabo J, Mayers D. 2003. Correlation of viral load reduction and plasma levels in multiple protease inhibitor (PI)-experienced patients taking tipranavir / ritonavir (TPV/r) in a phase IIB trial: BI 1182.52 [abstract 528]. 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA. Ziermann R, Limoli K, Das K, Arnold E, Petropoulos CJ, Parkin NT. 2000. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J Virol 74:4414-4419. Zolopa AR, Gonzales MJ, Rice H, Hertogs K, Shafer RW. 2001. Protease inhibitor-experienced patients with protease mutatios 82A and 90M: saquinavir phenotype, response to saquinavir/ritonavir and genotypic and phenotypic evolution. Antivir Ther 6:97. Zolopa AR, Hertogs K, Shafer R, Dehertogh P, De Vroey V, Efron B, Bloor S, Larder B. 1999a. A comparison of phenotypic, genotypic, and clinical / treatment history predictors of virologic response to saquinavir / ritonavir salvage therapy in a clinic-based cohort [abstract 68]. Antivir Ther 4(Supplement 1):47-48. Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B. 1999b. HIV-1 genotypic resistance patterns predict response to saquinavir- ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 131:813-821.
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