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The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 138: Reverse Transcriptase Genotype after Multiple, Sequential Nucleoside Analog Drugs and Their Response to HAART and ACTG 364

February 1, 1999

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

The objective of this study was to determine the mutations and extent of genotypic nucleoside resistance after a history of nucleoside combinations. Drug resistance in mutations in the reverse transcriptase genome were defined a priori and assessed from sequences (genotypes) on 146 subjects with greater than 2,000 copies of HIV RNA at the study entry. To determine whether reverse transcriptase mutations contributed to virologic failure by comparing the RT sequences of the subjects who developed virologic failure compared to the subjects with sustained suppression under 500 copies on the assigned HAART regimen over 48 weeks. Virologic failure was based on the confirmed detection of greater than 2,000 copies of HIV RNA in plasma, 16 weeks on the new therapy. The authors of this study reiterate the observation that nucleoside analog reverse transcriptase inhibitors (NRTI) remain an essential element of current HAART. HIV infected individuals treated with combination nucleosides with continuing viral replication may develop mutations and reverse transcriptase associated drug resistance, reducing the potency to this or subsequent nucleoside analog therapies. Currently a combination of nucleoside regimens may be determined by a history of antiretroviral drug treatment, and genotyping and, less commonly, phenotyping. Of note, there is little information on the prevalence and incidence of resistance among subjects with well-documented prolonged multi-nucleoside analog treatment.

The ACTG protocol 364 is an ongoing study of 236 patients with a well-documented history of treatment with nucleoside analogs from 1992 to 1996. The subjects considered here are adherent subjects who had tolerated therapy with reverse transcriptase inhibitors (RTI) for more than four years, and had not reached a clinical, age defining end point, or developed a serious nucleoside toxicity. The subjects were provided with at least one (38%), and in most cases two (70%) nucleoside analogs, based upon their documented drug histories and randomized to received Nelfinavir and Efavirenz, or both drugs in a new HAART regimen. Looking at the results with a logistic regression model, the authors observe a high baseline viral load is consistently a very strong predictor of subsequent virologic failure. Considering baseline viral load and RT mutations, we see that the number of RT mutations are significant and each additional RT mutation is associated with an additional odds ratio of 1.3 for having virologic failure. However, the number of RT mutations is no longer significant when prior 3TC exposure is in the model. Interestingly, having no RT mutations at baseline is a marginally significant risk factor for subsequent virologic failure. After adjusting for baseline viral load, prior exposure to multiple nucleoside analogs is associated with an odds ratio of 4.4 for having subsequent virologic failure on an AZT-containing arm of this study. More simply, the more NRTI's the patient was exposed to over the years, the more likely there would be genotypic resistance. Of the ten subjects who had received NRTI drugs for greater than five years without genotypic evidence for resistance, five out of the ten failed HAART therapy. In highly nucleoside experienced patients, multi-variant models demonstrate that baseline virus load and a number of nucleoside RT drug resistant mutations are independent predictors of virologic failure on HAART.

Notwithstanding the results of this paper, we are often confronted with the situation of a patient that is highly drug experienced. Many clinicians have noted that salvage therapy often consists of recycling drugs. This study clearly demonstrates the extent and significance of multiple drug resistance mutations. It will become increasingly important to know how many mutations, and at what codons patients have accumulated these mutations in order to design optimum salvage regimens.

This paper also demonstrates that even by designing a regimen with several new agents, the accumulation of mutations will limit the effectiveness and durability of the regimen. The other implication is that we have to decide when therapy is good enough, and by this I mean that even with evidence of a mildly elevated, or rising, viral load, in patients who are highly drug experienced, we may be doing the patient a disservice to make a rapid change in the regimen. It may be wiser in a patient who is stable at a level of 20,000 or 15,000 copies of HIV RNA in the serum, to remain on their current regimen until enough novel agents are available that have a significant impact on the patient's clinical and virologic course.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Abstract: Reverse Transcriptase Genotype after Multiple, Sequential Nucleoside Analog Drugs and Their Response to HAART and ACTG 364
Authored by: D. Katzenstein, R. Bosch, R. Shafer, M. Albrecht, M. Winters, S. Hammer

See Also
The Body's Guide to HIV Drug Resistance
HIV Mutations
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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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