Although there was no earthshaking news at the 9th Conference on Retroviruses and Opportunistic Infections regarding resistance to protease inhibitors (PI), interesting new information building on our current knowledge was presented. Following is a review of data presented on the investigational drugs atazanavir and tipranavir, the relatively new lopinavir/ritonavir (lopinavir/r), and the veteran PI, saquinavir, indinavir, ritonavir, nelfinavir and amprenavir.

Atazanavir
Studies looking at the efficacy, safety and pharmacology of atazanavir were presented, but very little regarding resistance. Although atazanavir may have an attractive dosing schedule, pill load and toxicity profile, nothing has been shown to suggest the drug will be of benefit in heavily PI pre-treated patients. On the contrary, reports from previous years and pediatric data from this meeting suggest that cross resistance will be significant in patients who have accumulated mutations as a result of previous therapy with the currently approved PI [1-4]. The degree to which atazanavir will still be of clinical benefit in patients with limited PI experience and few PI resistance-associated mutations remains to be determined.

Tipranavir
Pharmacological considerations have slowed the development of tipranavir as researchers have struggled with the challenge of getting sufficient amounts of drug to the virus. Initial reports at previous meetings have suggested a very favorable resistance pattern with low levels of cross-resistance to currently approved PI. Data presented at CROI continued to support this cross-resistance profile, but only preliminary clinical trial data have been reported so far [5]. Since clinical cross-resistance is a function of both the intrinsic cross-resistance profile of the PI (which may be characterized in vitro) and the degree of viral exposure to the drug (which is dependent upon pharmacologic factors), sound clinical data will be needed before we can determine to what degree tipranavir will be useful in heavily PI-experienced patients.

Lopinavir/r
A number of studies provided further insight into the resistance pattern of lopinavir/r. In addition to the original mutations described by its manufacturer, other mutations associated with resistance to lopinavir/r were presented [6-9]. As with the other approved PI, the list of mutations impacting lopinavir/r susceptibility is extensive, although the relative importance of each mutation remains to be accurately determined. This indeed is now the challenge we face with lopinavir/r: learning the relative importance of the different mutations in conferring clinical resistance to the drug.

While it is known that the accumulation of many out of a large variety of mutations will reduce efficacy, it is also now clear that in some instances as few as 3 or 4 key mutations will have a similar effect (see Table) [8].

Table. Odds Ratios for Mutations Associated With Lopinavir/r Resistance (adapted from J Isaacson et al, 9th CROI, poster 559 [8]).

Mutation	Odds Ratio	95% CI	P-value
10	0.48	(0.34, 0.67)	<0.0001
20	0.56	(0.37, 0.83)	0.0045
24	0.48	(0.21, 1.02)	0.0680
46	0.92	(0.69, 1.24)	0.5880
53	1.80	(0.84, 3.88)	0.1310
54	0.68	(0.49, 0.94)	0.0176
63	1.07	(0.77, 1.49)	0.6890
71	1.29	(0.93, 1.80)	0.1270
82	0.63	(0.46, 0.85)	0.0028
84	0.80	(0.56, 1.14)	0.2110
90	1.14	(0.85, 1.55)	0.3840

We are just now beginning to properly weigh the impact of the different mutations' effect upon lopinavir/r susceptibility. This will ultimately allow us to fine tune our understanding of resistance to this drug. What is becoming clear from the data presented is that similar to the other approved PI, the majority of mutations impacting lopinavir/r susceptibility are associated with resistance to other drugs and only a small number of mutations are unique to lopinavir/r. This suggests that the ability of lopinavir/r to inhibit PI-resistant virus does not primarily come from a unique mutational pattern of the drug, but from the very high plasma concentrations that are obtained [6,7]. Here again the importance of considering drug pharmacology and resistance together is highlighted. Along these lines, a number of abstracts once again looked at the Inhibitory Quotient (IQ) - a measure that incorporates both the resistance pattern of the virus and the blood level of the drug - and found it to be a predictor of virological success [6,7, 9-11].

Veteran PI
Numerous investigators presented data concerning pharmacologic issues relating to the approved PI. New once- and twice-daily dosing schedules, PI combinations, drug interactions and formulations were investigated (see mainly Oral Session 28 and Poster Sessions 62 and 75). Since the pharmacologic effects of these new applications vary significantly, their impact on resistance remains to be delineated. However, as in the case of lopinavir/r, data looking at dual PI and/or PI-boosting regimens demonstrated a correlation between IQ and virological success [12,13]. Since there are numerous ways of calculating the IQ, it is still unclear how useful a clinical tool it will be. Finally, a growing body of data related to PI resistance in different HIV subtypes (or clades) now exists. Although a number of studies once again showed equally good responses or probability of responses to antiretroviral therapy in B and non-B subtypes [14-17], data were presented suggesting that in specific instances subtype may have an effect on resistance. Specifically, non-subtype B HIV-infected patients receiving nelfinavir were found by Gomes et al to often develop resistance using pathways other than the D30N mutation [18]. If confirmed, this might have important clinical implications

References

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Squires K et al. 48-week safety and efficacy results from a phase II study of a once-daily HIV-1 protease inhibitor (PI), BMS-232632. 8th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 15.
R. Schwartz , P. Kazanjian, L. Slater, B. Hathaway, M. Markowitz, D. Wheeler, M. Goldman , M. Drulak, S. McCallister, D. Mayers. Resistance to Tipranavir is Uncommon in a Randomized Trial of Tipranavir/Ritonavir (TPV/RTV) in Multiple PI-Failure Patients (BI 1182.2). 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 562.
A. Hsu, D. Kempf, G. R. Granneman, E. Sun. Exploring Theoretical Mechanisms for Lack of Resistance to Lopinavir/Ritonavir (LPV/r) in Antiretroviral (ARV)-Naïve Subjects. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 436.
M. Boffito, I. Arnaudo, S. Bonora, A. Sinicco, R. Raiteri, P. Hoggard, D. Back, G. Di Perri. Pharmacokinetics and Genotyping in Lopinavir Recipients with Prior PI Failure. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 453.
J. Isaacson, D. Kempf, V. Calvez, I. Cohen-Codar, D. Descamps, E. Guillevic, B. Bernstein, E. Sun, J. P. Chauvin, R. Rode. Quantitative Estimate of the Effect of Individual Baseline Mutations in HIV Protease on the Virologic Response to Lopinavir/Ritonavir Therapy in Heavily Antiretroviral-Experienced Patients. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 559.
A. Castagna, A. Danise, H. Hasson, E. Boeri, A. Lazzarin, M. Peeters, S. Piscitelli, R. Hoetelmans. The Normalized Inhibitory Quotient (NIQ) of Lopinavir Is Predictive of Viral Load Response over 48 Weeks in a Cohort of Highly Experienced HIV-1-Infected Individuals. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 128.
F. Baldini, M. G. Rizzo, R. Hoetelmans, R. Murri, S. Di Giambenedetto, A. Cingolani, R. Cauda, A. De Luca. A Prospective Study of Deep Salvage Therapy with Lopinavir/r, Amprenavir, and NRTIs: Final 24-Week Data, Pharmacokinetics, and Association of Drug Levels/Drug Susceptibility with Virologic Response. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 423.
D. Back, S. Khoo, S. Gibbons. The Role of Therapeutic Drug Monitoring (TDM) in Clinical Practice. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract S20.
The Inhibitory Quotient (IQ) for Saquinavir (SQV) Predicts Virologic Response to Salvage Therapy C. V. Fletcher, H. Cheng, S. A. Fiscus, R. Swanstrom, N. S. Hellmann, R. Haubrich, D. Katzenstein, and R. Gulick for the ACTG 359 Team. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 129.
E. Phillips, A. Tseng , S. Walker , M. Loutfy, S. Walmsley , S. Tailor, P. R. Harrigan. The Use of Virtual Inhibitory Quotient (VIQ) in Antiretroviral (ART)-Experienced Patients Taking Amprenavir/Lopinavir Combinations. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 130.
Z. Grossman, S. Maayan, D. Auerbuch, E. Sahar, I. Levi, M. Lorber, G. Gottesman, K. Rizenfeld, M. Chowers, Z. Kra-Oz, E. Mendelson, Z. Bentwich, M. Elkan, D. Engelhard, S. Polak, I. Yust, J. M. Schapiro for Israel Multi-Ctr. AIDS Study Group. Longitudinal Analysis of RT and Protease Mutations among Israeli Patients Infected with HIV Subtype C. 9th Conference on Retroviruses and Opportunistic Infections. 24-28 Feb 2002, Seattle, WA. Abstract 565.
S. M. Agwale, C. Zeh, E. Paxinos, L. Odama, D. Pienazek, C. Wambebe, M. L. Kalish, R. Ziermann. Genotypic and Phenotypic Analyses of Drug Susceptibility in HIV-1 Isolates from Drug-Naïve Patients in Nigeria. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 461.
P. Hermans, J-C. Schmit, K. Kabeya, E. O'Doherty, S. De Wit, B. Sommereijns, N. Clumeck. Virological Response to Salvage Therapy at 6 Months in Patients with B or Non-B Subtypes. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 427.
H. Fleury, A. Caumont, M. Faure, J. C. Plantier, P. Roques, E. Couturier, F. Simon. HIV-1 Diversity in France, 1999-2001: Molecular Characterization of non-B HIV-1 Subtypes and Potential Impact on ARV Susceptibility. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 758.
P. Gomes, I. Diogo, M. F. Gonçalves, P. Carvalho, J. Cabanas, M. C. Lobo, R. Camacho. Different Pathways to Nelfinavir Genotypic Resistance in HIV-1 Subtypes B and G. 9th Conference on Retroviruses and Opportunistic Infections. 24-28-4 Feb 2002, Seattle, WA. Abstract 46.