The Body Covers: The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
Science and ART: Optimizing the Use of NRTIs/NtRTIs in HIV Therapy
September 29, 2002
Dr. Eron began the meeting with a review of HIV therapies. He highlighted the weighty issues of when and with what to start HIV therapy and he reviewed the new IAS-USA guidelines (published in the Journal of the American Medical Association). In a sobering summary, he pointed out that despite the successes of therapy, many people currently taking HIV therapies in the U.S. have detectable virus, while others are experiencing significant side effects or toxicity from their therapies.
Our current patterns of HIV therapy selection reflect the order in which our medications were discovered. Hence, most regimens in use today are comprised of two NRTIs with either a protease inhibitor or non-nucleoside RT inhibitor (non-nuke). Very recent clinical data (for example, studies ACTG 384 and Gilead 903) have begun to change our views of nucleoside therapies. A favorable view of the commonly used combination of AZT (ZDV, zidovudine, Retrovir) and 3TC (lamivudine, Epivir) has been reinforced; the emergence of new NRTI or NtRTI pairs, like tenofovir (TDF, Viread) and 3TC or abacavir (ABC, Ziagen) and 3TC may offer improved dosing and side effect profiles. Dr. Eron reviewed information from studies where people were switched from d4T (stavudine, Zerit) to AZT or to abacavir, which highlighted the role that d4T plays in causing lipoatrophy (fat wasting).
Dr. Eron concluded his lecture with a summary of the strategic use of this class of medications, pointing out that increasing NRTI/NtRTI treatment options may permit once-daily dosing with low pill count and low toxicity.
He also mentioned that we now have two HIV medications (3TC and tenofovir) with activity against hepatitis B, offering new hope for those with HIV/HBV coinfection. The optimal sequence of the medications in the NRTI/NtRTI class to use remains to be fully answered, but an appreciation for the resistance patterns and clinical results of treatment will be essential.
Dr. Lange summarized the characteristics of our currently-approved NRTI and NtRTI medications and pointed out that the efficacy of optimal HIV therapies depends on three things -- antiviral potency, low toxicity and patient adherence. Newer RT inhibitors, like abacavir and tenofovir have shown increased antiviral activity. As we know, toxicity to therapies remains an important reason for treatment discontinuation. In fact, in the ICONA study from Italy, toxicity was responsible for nearly 60 percent of all discontinuation from HIV treatment (D'Arminio, AIDS 2000). Dr. Lange next spoke about the critical role that patient adherence plays in the performance of HIV therapy, but pointed out that real-life adherence can be challenging. The reasons for suboptimal adherence to a treatment regimen vary from regimen to regimen, however, the possible reasons need to be acknowledged by care provider and patient alike and dealt with.
Lastly, Dr. Lange reviewed the status of pill burden and dosing frequency improvements. Many of the older drugs had a nearly impossible number of pills and had to be taken three times a day. Things have changed, there are currently three medications -- ddI QD (didanosine, Videx EC), tenofovir and 3TC -- approved for once-daily dosing. Three other drugs (d4T, abacavir and AZT) are now being studied as possible once-daily drugs. Preserving the activity of the NRTI/NtRTI class is important, since these drugs remain the "backbone" of current therapies. Selection of which drugs any patient uses depends on an understanding of all the factors that affect clinical outcomes -- potency, toxicities, adherence issues, coinfection (with HBV) as well as the preservation of future treatment options.
Dr. Richman, one of the first researchers to describe HIV drug resistance, next summarized the complex issues of NRTI/NtRTI drug resistance. A new understanding of the ways in which HIV becomes resistant to these drugs was reviewed. Two major mechanisms are thought to account for most resistance and treatment failures. The first -- reduced binding of the drug to the RT enzyme -- is responsible for resistance to a variety of drugs (3TC, ddI and tenofovir, for example). The best characterized example of this mechanism is 3TC resistance -- a mechanism where the M184V mutational substitution results in a situation where the 3TC molecule is unable to bind into the active site (the business end, so to speak) of the RT. Other important binding mutations result in multi-drug resistance -- substitutions Q151M and 69 insertions cause broad resistance within the class of drugs (though virus with Q151M retains susceptibility to tenofovir).
The other major mechanism of RT resistance is characterized by mutations that result in the so-called nucleoside analogue mutations (Names; substitutions at RT positions 41, 67, 70, 210, 215 and 219). Previously thought to only affect the thymidine drugs (AZT and d4T), recent data shows an effect of these RT substitutions on the potency of ddI, abacavir and tenofovir. Viruses that harbor RT with multiple Names, in conjunction with the M184V substitution, have reduced susceptibility to abacavir; particular patterns (but not all) of Names result in resistance to tenofovir. Names have the interesting property of enabling the virus to more efficiently remove the NRTI or NtRTI from the replicating viral chromosome, thereby overcoming the inhibitory effect of the drug. This effect is not particularly specific for any one drug, so that these mutations can affect the potency of multiple drugs, even if only one drug (for example, d4T) was the reason that the mutation was selected.
The effects of individual RT substitutions were reviewed. Particular interest has been focused on the effects of the K65R substitution. This is the substitution that is selected by tenofovir in the test tube -- data about the role that the mutation plays in people receiving tenofovir therapy (at least those who are treatment naive when starting) remains to be presented. The mutation is found only infrequently in the current viral population, occurring in less than 3 percent of persons. Viruses with the K65R substitution have reduced susceptibility to tenofovir and ddI, but retain susceptibility to AZT, d4T and abacavir. A key, and largely unanswered question, is whether abacavir therapies may select for the K65R substitution. GlaxoSmithKline virologists have suggested that when HIV is exposed to abacavir -- without AZT -- a higher proportion of virus may harbor the K65R substitution.
Dr. Richman discussed the now well-established cross resistance between the two thymidine drugs, AZT and d4T. He also pointed out that an increasing understanding of the best use of drugs -- that the use of one thymidine analog after the virologic failure of the other, for example -- should minimize the accumulation of high-level resistance and the loss of future treatment options. Dr. Richman also discussed novel, thymidine drug-sparing regimens or regimens that avoided the selection of the M184V substitution.
The final speaker of the evening, Dr. Gallant, reviewed information about the side effect and toxicity profiles of NRTI/NtRTI medications. These parameters can be an important factor in the choice of medications in HAART.
Recognizing the wealth of information about thymidine analog-based therapies, he reviewed recent information from the ACTG 384 trial that showed the superiority of the AZT/3TC combination (compared with d4T/ddI) when combined with the popular medication, efavirenz (EFV, Sustiva).
A key consideration in choosing between the available thymidine analogues has been side effect profile. The availability of newer NRTIs and NtRTIs will certainly fuel discussion about new options for therapy. Dr. Gallant reviewed the accumulating information about the previously unsuspected side effects of d4T, including lactic acidosis, elevations in lipids (cholesterol and triglycerides) and lipoatrophy (fat wasting). At this meeting, data from the Gilead 903 trial confirmed previous observations from Kumar that demonstrated that d4T caused elevations in both cholesterol and triglycerides -- factors that can raise the risk of cardiovascular disease. Other studies that were reviewed showed that persons with lipoatrophy had small, but reproducible benefit in switching from d4T to other medications (either abacavir or AZT).
This meeting was an extremely timely and interesting review of the state of the art in NTRI and NtRTI therapies. Treatments have improved dramatically in recent years -- with simpler and less side effect prone drugs now available. A lot of new information about optimal dosing and side effects has emerged; hopefully, permitting medical caregivers to make improved decisions about treatment options. The field of HIV medicine continues to evolve at a dizzying pace. New information about previous medications and altogether new medications should result in improved quantity and quality of life for those affected by HIV infection.
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