Presentations

Clinical optimisation of protease inhibitor sequencing

Abstract

The choice of initial antiretroviral regimen is critical to attaining the goal of successful management of HIV in the long term. The first-line regimen must not only provide potent and durable suppression of HIV replication (HIV RNA <50 copies/ml), but also be easy to take and well tolerated. However, perhaps the most important strategic requirement for the initial antiretroviral regimen is that it must also leave open subsequent therapy options to regain control of HIV replication in the event of viral load rebound.

Given the overlap in resistance profiles of many PIs, it is not surprising that many clinicians might be sceptical of the potential benefit of using subsequent PIs when patients fail on their first PI. However, there is now a growing body of evidence suggesting that if we evaluate the data and act strategically we can use PIs in a sequential fashion, to prolong the clinical benefits offered by this potent class of drugs.

Nelfinavir has demonstrated a number of characteristics that warrant consideration as the PI of choice in an initial antiretroviral regimen, as it has been shown clearly that this drug allows the subsequent use of intra-class drug sequencing:

1. Virus with the nelfinavir-selected D30N primary resistance mutation does not replicate as well as (is less fit than) wild-type or other PI-selected mutants

2. Nelfinavir has a unique resistance profile with infrequent cross resistance to other PIs

3. Nelfinavir is highly potent in combination with NRTIs in antiretroviral-na�ve individuals and is well tolerated in a convenient bid regimen.

I will address each of these points in order.

Viral fitness
It has been shown that most primary drug-resistance mutations impair viral fitness to some degree. With nelfinavir, the most commonly occurring mutant, D30N, is associated with a significant decrease in viral replication rates compared with L90M mutants or wild-type strains, possibly requiring more compensatory mutations than initial mutants selected by other PIs [1,2] (see figure 1).

Figure 1

If the D30N mutant is less fit than wild-type strains, this may allow for a response to a second protease inhibitor-based regimen. A less fit virus with a lower rate of replication may produce a lower level of viremia and decrease the rate at which new drug resistance mutations arise. Both of these features could in turn, result in a better response to subsequent PI-based regimens.

On the basis of the current data relating to viral fitness, we should question whether there is a role for fitness phenotype testing to complement existing genotype and phenotype drug susceptibility testing.

Unique resistance profile of nelfinavir
The D30N mutation is unique to nelfinavir and data have shown that patients entering a trial with D30N at baseline have virologic response rates similar to those entering with no primary resistance mutations � 100% and 82% achieving HIV RNA levels <500 copies/ml respectively [3] (see figure 2).

Figure 2

This observation is complemented and extended by data from the GART study showing that patients with the D30N mutation had better virological response rates than those with other primary PI mutations [4] (see figure 3).

Figure 3

The observed lack of genotypic cross-resistance between nelfinavir and other PIs [5] is supported by phenotypic evidence of a lack of cross resistance in study CCTG 575 [6] , where patients with high-level nelfinavir resistance had significantly lower cross-resistance to other PIs (see figure 4).

Figure 4

This lack of cross-resistance seen with nelfinavir-resistant strains, has also been observed in the VIRA 3001 study where patients entering the trial with nelfinavir resistance, had relatively low levels of resistance to other PIs [7] . In contrast, patients with IDV resistant strains had higher levels of resistance to nelfinavir, amprenavir and saquinavir. In addition, clinical data from one study of ritonavir-boosted saquinavir after failure of nelfinavir-containing antiretroviral therapy showed impressive virological response, with nearly 60% of patients (OT data) maintaining viral levels below 500 copies/ml at 48 weeks [8] (see figure 5).

Figure 5

Nelfinavir is effective and well tolerated
As a final point in consideration of selecting and sequencing PIs in combination therapy, it should be noted that nelfinavir is also a highly potent PI that provides durable viral suppression in antiretroviral-na�ve patients [9]. Treatment with nelfinavir (1250 mg twice-daily) in combination with stavudine (d4T) and lamivudine (3TC) sustained HIV RNA levels below 50 copies/ml up to 96 weeks in approximately 65% of patients using an on-treatment analysis (approximately 45% by intention-to-treat) in prelimi-nary results from a subset of patients [10].

It is of significant relevance that, in contrast to PIs, NNRTIs have significant overlap of primary resistance mutations, suggesting that sequencing of these would be almost impossible. This has been borne out in clinical trials [11,12].

In conclusion, strategic use of antiretroviral therapy will require consideration of resistance and cross-resistance patterns from day 1 of therapy. Use of resistance testing should help in making best use of antiretrovirals over time. The D30N mutation appears to be unique to nelfinavir, with little or no
cross-resistance to other PIs. There is growing evidence that dual PI therapy can provide a good response in patients who have failed nelfinavir-based regimens.

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References

1. Martinez-Picado J, Savara AV, Sutton L and D'Aquila RT. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. Journal of Virology 1999; 73:3744-3752

2. Gamarnik A, Wrin T, Ziermann R et al. Drug resistance is associated with impaired protease and reverse transcriptase function and reduced replication capacity: characterization of recombinant viruses derived from 200 HIV-1-infected patients. Antiviral Therapy 2000; 5 (Suppl. 3): 92-93

3. Zolopa AR, Shafer RW, Warford A et al. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Annals of Internal Medicine 1999; 131:813-821

4. Mayers DL, Baxter JD, Wentworth DN et al. The impact of drug resistance mutations in plasma virus of patients failing protease inhibitor-containing HAART regimens on subsequent virological response to the next HAART regimen: results of CPCRA 046 (GART). Antiviral Therapy 1999; 4 (Suppl. 1):51

5. Hirsch MS, Brun-Vezinet F, D'Aquila RT et al. Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel. Journal of the American Medical Association 2000; 283:2417-2426

6. Haubrich R, Kemper C, Witt M et al. Differences in protease inhibitor (PI) phenotypic susceptibility after failure of the first PI-containing regimen. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, 26-29 September 1999. Abstract 1167

7. Cohen C, Kessler H, Hunt S et al. Phenotypic resistance testing significantly improves response to therapy: final analysis of a randomized trial (VIRA3001). Antiviral Therapy 2000; 5 (Suppl. 3):67

8. Tebas P, Patick AK, Kane EM et al. Virologic responses to a ritonavir/saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999; 13:F23-F28

9. Gathe J, Chu A, Kass C et al. Three year experience with nelfinavir combination therapy. The XIII International AIDS Conference, Durban, South Africa, 9-14 July 2000. Abstract TuPeB3236

10. Petersen A, Antunes F, Arasteh KN et al. A comparison of the long-term antiviral efficacy of bid and tid dosing of nelfinavir in combination with stavudine (d4T) and lamivudine (3TC) beyond 48 weeks. Seventh European Conference on Clinical Aspects and Treatment of HIV-infection, Lisbon, Portugal, 23-27 October 1999. Abstract 205

11. MacArthur RD, Kosmyna JM, Crane LR et al. Sequencing of non-nucleoside reverse transcriptase inhibitors based on specific mutational patterns fails to lower plasma HIV-RNA levels in persons extensively pre-treated with antiretrovirals who are failing virologically on nevirapine-containing antiretroviral regimens. Seventh European Conference on Clinical Aspects and Treatment of HIV-infection, Lisbon, Portugal, 23-27 October 1999. Abstract 208

12. Shulman N, Zolopa A, Murlidharan U et al. Efavirenz (EFV) and adefovir (ADV)-based salvage in antiretroviral experienced HIV+ patients. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, USA, 26-29 September 1999. Abstract 2201

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Biography

Andrew Zolopa is Assistant Professor of Medicine at Stanford University School of Medicine where he directs the Stanford Positive Care Program and is Chief of AIDS Medicine Division at Santa Clara Valley Medical Center. The program consists of the Stanford Positive Care Clinic and the Positive PACE clinic at SCVMC. Dr Zolopa serves on the Institute of Medicine�s Committee on HIV Prevention Strategies.

Dr Zolopa is the Principal Investigator for Stanford AIDS Clinical Trials Group subunit at Santa Clara County and is actively involved in HIV clinical trials research including evaluation of the role of HIV resistance testing in clinical practice. He is the PI for the Clinic-Based Investigator's Group (CBIG) and he maintains an active collaboration with researchers at San Francisco General Hospital Division of Epidemiology, evaluating effectiveness and resistance to HIV treatments in San Francisco�s homeless population.

Dr Zolopa has published extensively in the field of HIV.

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