Written by Mark A. Wainberg, Ph.D.
Published on HIVresistanceWeb: September 5, 2001
Introduction
Considerable new information on HIV drug resistance was presented at the 1st IAS Conference on HIV Pathogenesis and Treatment, which took place on 8-11 July 2001 in Buenos Aires, Argentina. The conference included an overview of work presented at the recent Workshop on HIV Drug Resistance and Treatment Strategies. That session was coordinated by Professor Joep Lange of the Academic Medical Center in Amsterdam and included the following presenters: Dr. Charles Boucher of Utrecht University, Dr. John Mellors of the University of Pittsburgh and Dr. Douglas Richman of the University of California at San Diego. Included among the topics discussed were:
- Availability of new antiretroviral agents
- Host immunology, pathogenesis and dynamics
- Mechanisms of HIV drug resistance
- Drug resistance, exposure to drugs and treatment response
- Relationship between genotype and phenotype
- Modeling and algorithms in regard to interpretation of drug resistance data.
Persistence of NNRTI mutations
The conference also featured a number of specialized presentations concerning HIV drug resistance. In one of these, V. Joly, et al evaluated the evolution of NNRTI resistance mutations after patients had ceased to take all NNRTI's (abstract 123) [1]. The results showed that most NNRTI mutations could still be detected, even in the aftermath of withdrawal of this class of drugs. At 6 months after discontinuation, 82% of patients had maintained some level of NNRTI mutational presence. This figure dropped to 70% after 12 months following NNRTI withdrawal. These findings indicate the relative stability of NNRTI-related mutations and introduce a note of caution with respect to the future use of NNRTI's in patients who have previously failed drugs belonging to this class.
Resistance test-guided treatment decisions
D. Meynard, et al presented findings concerning the impact of treatment when guided by phenotypic or genotypic resistance test results (abstract 126) [2]. This presentation represented the final analysis of the NARVAL trial (ANRS 088) and confirmed the previously released, preliminary conclusion of this study: that neither phenotyping nor genotyping were able to significantly improve responsiveness to future treatment regimens in patients failing a PI-containing regimen. It must be pointed out that the physicians who made treatment decisions in the NARVAL study were, in general, highly sophisticated and may have been able to make exceptionally accurate second-line treatment decisions without relying resistance test data; physicians in other settings might therefore still benefit from information yielded by phenotypic and genotypic testing. This caveat may help to explain differences between the findings of the NARVAL study and other evaluations of this type - e.g., VIRADAPT, GART - which determined HIV drug resistance testing to be useful in selecting effective antiretroviral therapies for patients failing a previous regimen.
In this context, a presentation by D. Mayers (abstract 124) sought to determine the short-term biological impact of drug-level monitoring and baseline HIV drug resistance as a part of the GART study [3]. The author observed that both the number of active drugs and drug levels for each drug in new regimens were important considerations in determining short-term antiviral responses in patients undergoing salvage therapy. Hence, these results reaffirm the importance of genotyping and drug-level monitoring in the achievement of short-term success following a change in antiviral regimen.
R. Haubrich presented a randomized prospective study of phenotype-guided decision making vs. standard of care in patients failing antiretroviral regimens (abstract 127) [4]. The Phenosense assay (ViroLogic) was used to phenotype viral samples. Samples from 256 patients who had received ART for at least 6 months were either phenotyped or not. The authors concluded that equivalent levels of HIV suppression following a change in therapy were observed in both arms. However, it was felt that this may reflect the need for more precise cutoff values for certain of the drugs commonly used (e.g., d4T, ddI). In addition, an improved ability to salvage patients who had failed a single PI-containing regimen may have led to equivalent responses in the standard of care arm. In all instances, baseline phenotype was a strong predictor of outcome.
Primary resistance
V. Simon presented data from a study that dealt with evolving patterns of resistance-conferring mutations in newly infected individuals during 1999-2000 (abstract 122) [5]. In comparison with the period 1995-2000, it was observed that increased numbers of newly infected individuals possessed resistance-associated mutations, but maintained wild-type phenotypes. Strikingly, an absence of the 184V mutation, associated with resistance to 3TC, was observed in the group studied during 1999-2000. It was felt that this may reflect a discontinuation of 3TC by patients who had transmitted virus to newly infected individuals. This evaluation will continue over the next several years with regard to changing patterns in transmission of drug-resistant viruses in North America.
Kaletra resistance after 48 weeks
D. Kempf presented data on the emergence of resistance associated mutations over 48 weeks of therapy with Kaletra or nelfinavir together with d4T/3TC (abstract 129) [6]. At week 48, there was an absence of mutations associated with Kaletra resistance in the Kaletra arm, but 33% of individuals in the nelfinavir group had mutations associated with resistance to nelfinavir. Resistance to 3TC (184V mutation) was noted in 41% of the Kaletra-treated subjects after this time and in 82% of individuals who had been treated with nelfinavir. No significant differences in viral RNA levels were reported. These results suggest that Kaletra may pose a higher genetic barrier to resistance than nelfinavir in the context of triple therapy with d4T/3TC. However, it should be recognized that Kaletra involves a combination of two drugs (ABT-378 + ritonavir), whereas nelfinavir is a unique compound; this issue is certainly relevant when interpreting these results.
Tenofovir
In abstract 128, Miller et al presented data on plasma viremia in patients who received 96 weeks of treatment with tenofovir [7]. In general, the addition of tenofovir (300 mL dose) to existing antiretroviral therapy in treatment-experienced individuals yielded durable patterns of HIV RNA reductions throughout a 96 week period of treatment. In some instances, the development of the K65R mutation was detected, and it is possible that this mutation may have conferred a small degree of resistance to tenofovir in such individuals.
Detecting resistance in non-subtype B HIV
E. Paxinos et al of ViroLogic reported on the utility of a new Phenosense assay to detect drug resistance among viruses derived from non-B subtypes (abstract 560) [8]. This evaluation included viruses of subtypes A, C, D, F, and G. In addition, this new assay, developed by ViroLogic, was capable of detecting resistance with enhanced sensitivity compared to previously used methods.
Line probe assay
Abstract 559 presented results on the use of the line probe assay (LiPA) as a means of detecting HIV drug resistance by hybridization-based procedures (G. Kijak et al) [9]. Although the LiPA method proved useful for a large number of samples, it was noted that no reaction at codon 74 was observed in 35% of samples that tested positive for this mutation by sequencing. Sequencing results further showed that a silent mutation at codon 72 was present in virtually all of the non-reactive samples. It was further shown by phylogenetic analysis that lack of reactivity at codon 74 and the presence of the polymorphism at codon 72 were associated with an F1/B subtype viral recombinant. It was concluded that the genetic diversity of HIV-1, as illustrated by this example of a silent mutation at codon 72, remains a major obstacle for hybridization based assays in regard to HIV genotyping.
References
Full conference abstracts can be viewed at www.ias.se
- Joly V, Descamps D, Zeng F, Ttouati F, Mentre F, Yeni P, Brun-Vezinet F. Evolution of HIV-1 Resistance Mutations to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Following Withdrawal. Program & Abstracts of The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001.
Abstract 123.
- Meynard J, Vray M, Morand-Joubert L, Peytavin G, Brun-Vezinet F, Clavel F, Girard P. Impact of treatment guided by phenotypic or genotypic resistance tests on the response to antiretroviral therapy (ART): Final analysis of the NARVAL trial (ANRS 088). Program & Abstracts of The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 126.
- Mayers D. Both antiretroviral drug levels and drug resistance are associated with short-term virologic responses to subsequent drug regimens in CPCRA 046 (GART study). The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 124.
- Haubrich R, Keiser P, Kemper C, Witt M, Leedom J, Forthold D, Hellmann N.
CCTG 575: A randomized, prospective study of phenotype testing (Pheno) verus standard of care (SOC) for patients failing antiretroviral therapy. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 127.
- Simon V, Vanderhoeven J, Hurley A, Louie M, Parkin N, Boden D, Markowitz M, Ramtatnam B, Dawson K. Evolving patterns of of HIV-1 resistance to antiretroviral agents in newly infected individuals. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 122.
- Kempf D, Bernstein B, King M, Mosely J, Gu K, Cernohous P, Sun E. Comparison of the emergence of genotypic resistance over 48 of therapy with ABT-378/R (Kaletra) or nelfinavir plus d4T/3TC. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 129.
- Miller M, Johnson A, Isaacson E, Margot N. Genotypic analyses and HIV RNA responses in patients after 96 weeks of tenofovir DF(TDF) therapy. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 128.
- Paxinos E, Werhane H, Whitcomb J, Petropoulos C. Enhanced phenotypic drug susceptibility assay for HIV-1 subtypes: A, B, C, D, F, AND G. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 560.
- Kijak G, Carobene M, Rubio A, Salomon H. HIV-1 genetic diversity is a major obstacle for antiretroviral drug resistance hybridization-based assays. The 1st. IAS Conference on HIV Pathogenesis and Treatment, Buenos Aires, Argentina, 8-11 July 2001. Abstract 559.
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