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The Latest Advances Against ART Drug Resistance: An Expert Interview With Dr. Jonathan Schapiro


Editor's note:
Antiretroviral drug resistance continues to be one of the most significant challenges confronting both clinicians and patients. Knowledge of the drug resistance profiles of existing antiretroviral agents and how to use tests for drug resistance can help to guide the selection of initial and subsequent antiretroviral regimens. Furthermore, along with improvement in toxicity and pharmacokinetic profiles, development of new agents that have activity against drug-resistant HIV is one of the most important factors in antiretroviral drug discovery. Following the 14th International HIV Drug Resistance Workshop in Quebec City, Quebec, Canada, Scott Williams, Editor and Program Director of Medscape HIV/AIDS, interviewed Jonathan Schapiro, MD, Adjunct Clinical Professor, Stanford University School of Medicine, Stanford, California, about recent advances in this key area of AIDS research, including data on the new class of antiretroviral agents, CCR5 inhibitors, as well as transmitted drug resistance, strategies to reduce resistance in preventing mother-to-child HIV transmission, and more.

Medscape: Many clinicians have been interested in how ritonavir-boosted atazanavir (Reyataz boosted by low-dose Norvir) compares against ritonavir-boosted lopinavir (Kaletra), especially among treatment-experienced or salvage patients. Certainly, the individual resistance profiles of these 2 agents play a significant role in predicting which agent might show superior activity in these patient groups. Were there any new data at the Workshop on this topic?

Dr. Schapiro: That issue has a lot of relevance to clinicians, and it directly affects decisions about patient management. There were much data presented, specifically on atazanavir/ritonavir. Much of the original resistance work on atazanavir was actually done on unboosted atazanavir, but in the clinic most physicians are boosting this drug with low-dose ritonavir. .

For patients who cannot tolerate 100 mg/day of ritonavir, unboosted atazanavir could be an option in PI-naive patients. For patients who can tolerate ritonavir 100 mg/day, the way to go is boosted atazanavir, whether the patient is treatment-naive or -experienced.

Regarding the resistance profile of boosted atazanavir, there is really an issue of comparing it with boosted lopinavir. A number of studies examined protease-experienced patients who have received atazanavir/ritonavir-containing regimens, and investigators tried to correlate patterns of baseline mutations with subsequent virologic outcome to see what characteristics were associated with a good or bad response. The investigators developed a score to help predict which resistance patterns predicted success or failure. A previous study gave us some indication, and now we have a larger follow-up.. We are seeing that patients who have 3 or fewer protease mutations seem to do well on atazanavir/ritonavir. In one study, patients receiving atazanavir/ritonavir or lopinavir/ritonavir seem to equally do well if the virus harbored a very small number of protease mutations. With more than 5 mutations, the response to atazanavir/ritonavir was poor compared with boosted lopinavir.

It's very hard to conceive every possible combination of mutations, and further research will help identify specific patterns, but it seems to be that in general if you have 1 key resistance mutation and maybe 1 or 2 accessory mutations, those patients can probably still get good activity from atazanavir/ritonavir. In those patients who have multiple mutations, 2-3 key mutations and maybe another 2-3 accessory mutations, this boosted PI is not the drug for them.

If you cannot give any other PI because there are toxicity issues, consult an expert to see if that specific mutational pattern may be okay. For instance, consider the patient who had received nelfinavir, had a D30N or L90M mutation, and who was caught early in virologic failure. Here you probably are okay giving boosted atazanavir. For other more evolved resistance patterns, other treatment options may often be preferred.

Medscape: And this interim option might be preferable, as it has a better lipid profile compared with other boosted PIs?

Dr. Schapiro: Absolutely. If we can give a patient a once-daily, potent PI with a better lipid profile, we would like to. As another example, you may have a patient who failed saquinavir way back in the 1990s, and then went on to a really successful NNRTI-based regimen, but now that regimen failing.

You often don't have the resistance data because it was so many years ago, but you know the patient received only a single, unboosted PI such as saquinavir or nelfinavir. Here, based on these data, there may still be a good chance that atazanavir-ritonavir will work.

[Editor's note: For more information on this topic, Dr. Shapiro suggested abstracts 6-8, 28, 29. At press time, complete references were unavailable at the conference Web site.]

Medscape: What do the latest data tell us about which treatment-experienced patients are likely to benefit from tipranavir (Aptivus), and how should it optimally be used?

Dr. Schapiro: The FDA just approved tipranavir, and therefore clinicians definitely need help on how to use this drug. There were not much new data on ritonavir-boosted tipranavir at the Workshop. However, at recent meetings we have begun to get a handle on tipranavir/ritonavir and how it compares with other commonly used boosted PIs. Currently we really only know about this drug in experienced patients, because we don't have resistance data from patients who were naive and received tipranavir. However, in patients who had received at least 2 protease inhibitors and have evidence of at least 1 PI mutation, tipranavir/ritonavir clearly outperformed all the other approved PIs, including lopinavir/ ritonavir. This gives us confidence that in patients who have multiple PI failures and resistance mutations, this agent is better. Investigators presented data on a "tipranavir score," which actually would allow clinicians to predict full, partial, or no response according to baseline mutations. Some of the mutations we already know, and some of them are somewhat new. However, tipranavir is still affected by many of the common PI mutations, although you need a greater number of mutations to observe a negative impact on activity compared with other PIs.

Medscape: In a salvage setting, what is the likelihood of benefit of boosted tipranavir compared with other boosted PIs?

Dr. Schapiro: There are 2 very large studies[1,2] that clearly show that the virologic efficacy of tipranavir in this patient population is superior to that of other approved PIs. Since tipranavir is clearly more potent when there is a lot of resistance, and even in patients with many mutations, the clinical question concerns the toxicity of tipranavir. Although tipranavir was clearly more effective overall, there was more toxicity in the tipranavir arm compared with the comparator PI arm.. There were more elevations in liver function tests, especially among patients coinfected with hepatitis B virus or hepatitis C virus, and greater increases in lipids: cholesterol, and triglyceride levels.

Most of these patients handled it well, but here is the trade-off for clinicians: You have a drug that clearly will work better if multiple mutations are present; on the other hand, it does appear to have more toxicity. So if you have a patient who still has good activity from the currently approved PIs, you need not go to tipranavir as it will likely have unnecessary added toxicity. Therefore, the key often is determining the predicted activity of the older boosted PIs before deciding whether you need to use tipranavir.

On the other hand, once you have viruses that are showing reduced activity to currently approved PIs, here the trade-off is different. Accepting increased toxicity for an agent that is clearly better is worthwhile. As of now, the most potent PI for highly drug-experienced patients is tipranavir/ritonavir. In any event, we need to monitor both the liver and the lipids when we change to tipranavir/ritonavir and follow them closely to watch for toxicity.

One additional comment: It was very clear that the best results were seen when tipranavir was combined with enfuvirtide (Fuzeon). We have also seen this in another study with TMC-114. If the patient has not received enfuvirtide and has multidrug-resistant virus, then tipranavir coadministered with enfuvirtide greatly improves the chance of achieving undetectable viral load.

Medscape: This really gives a second wind to this drug.

Dr. Schapiro: Yes. And in this situation it doesn't necessarily mean life-long treatment with this particular combination, because we have other good drugs coming in a year or two that have less toxicity and that can be given orally.

[Editor's note: For more information on this topic, Dr. Shapiro suggested abstracts 27, and 63. At press time, complete references were unavailable at the conference Web site.]

Medscape: Along these lines, were there data at the Workshop on other investigational agents on the near-term horizon that have activity against drug-resistant HIV?

Dr. Schapiro: All clinicians who go to this meeting always want to go back and tell our patients that there are good, exciting drugs on the horizon. The new entry inhibitors, NNRTIs, and PIs seem to hold great promise. Unfortunately, we continue to be somewhat disappointed in new NRTIs. There are few new agents on the horizon and we didn't see any really convincing virologic or pharmacologic data at this workshop on any of them.

NRTIs that are moving forward include Reverset and dioxolane thymidine (DOT). Many experts are reserving judgment if, indeed, these drugs are really going to be a leap forward for the NRTI class. For instance, there are still no convincing resistance data that show us that these will actually be significantly better than drugs like tenofovir (Viread), didanosine (Videx), or abacavir (Ziagen) for experienced patients.. Furthermore, seeing positive in-vitro data translate to superior clinical efficacy is a very large step. One must also keep in mind that the successful development of these agents will also largely depend on their pharmacology.

For the NNRTIs, there are 2 very interesting Tibotec compounds that we're also following: TMC-125 (etravirine) and the newer drug TMC-278. Both of these previously were shown to have favorable resistance profiles. What that really means is that despite having 1 or maybe even 2 NNRTI mutations, they still retain potency against NNRTI-resistant virus, which is key to an effective salvage regimen. We saw no new data on either of these drugs in terms of resistance profiles. Although I remain optimistic, there's nothing from this meeting.

In terms of new PIs, we have already discussed tipranavir, which has just moved from the "experimental" to the "approved" category. The other PI is, of course, TMC-114, which is being developed by Tibotec and moving into phase 3 trials. The results from the TMC-114 studies[3] that were sent to CROI were extremely exciting. Here patients with many mutations seem to do really well at least in the medium term, and again, when it was combined with enfuvirtide, these patients had actually good percentages of undetectability, something we never dreamed of 2 or 3 years ago. We had thought the company would divulge some of the mutational scores for this drug, specific mutational patterns predicting response; regrettably, we didn't see any of that at the meeting. Hopefully we will see this in the future. Since not all patients responded to TMC-114, obviously resistance patterns will need to be determined for this drug as well.

Of course there was a lot of "buzz" about the CCR5 inhibitors and resistance to this new class of entry inhibitors. As we know, HIV can use either CCR5 [R5] or CXCR4 [X4] as a coreceptor for entry, so switching to X4 from R5 would be one mechanism of resistance. The other, of course, would be a more standard mechanism whereby there would be some change in the viral envelope, which would then allow the virus to evade the drug.

We saw some preliminary data that suggested that changes in the envelope (which cause resistance to one of the CCR5 inhibitors) did not reduce susceptibility to other inhibitors, but other studies actually did show that changes to one affected resistance to the others. What I would stress is that none of this really gives us any significant insight into: (1) mechanism of resistance: how the virus will evade R5 inhibitors, by switching tropism to X4 or by mutations that change the interaction of HIV with R5; and (2) what is the cost to HIV of the resistance. What I would be excited about is the fact that everyone is studying this and developing tools to look at this, because a standard resistance assay cannot be used for determining CCR5 inhibitor resistance

[Editor's note: For more information on this topic, Dr. Shapiro suggested abstracts 58-62, 64-66, 71, 73, 75, 77. At press time, complete references were unavailable at the conference Web site.]

Medscape: There has been some hypothesis and preliminary data showing that tenofovir and zidovudine (Retrovir) may be a beneficial combination due to characteristics of the resistance profiles. Can you explain a little more about this topic, and let us know whether there were any new data on this issue at the workshop?

Dr. Schapiro: As you know, a favorable interaction between the RT mutation K65R and zidovudine has indeed been found and clinicians have shown a lot of interest in the fact that K65R may actually make zidovudine, work better. Since K65R is associated with tenofovir use, there is interest in the idea of sort of "trapping" the virus by using tenofovir and zidovudine together, especially with a drug like 3TC (lamivudine; Epivir) or FTC (emtricitabine; Emtriva), which adds one more mutation [M184V] that also resensitizes AZT. All of this is very intriguing and it has pushed us to look at possible clinical applications. Indeed there were 2 small studies that do speak right to that issue, and they really ask, "Is there something special about putting these drugs together?" Of course what we care about is whether it really has clinical relevance.

One study was simply a small case series using tenofovir/lamivudine/zidovudine as an initial regimen There was about a 66% response, which is not that bad, and it raises the question of whether this can be an alternative for very select patients needing therapy where standard regimens are not possible.

A second interesting series of case reports used this as salvage in patients with virus that selected K65R (their initial regimen did not have AZT in it). When these patients began to have an increase in viral load, instead of switching them, they simply added AZT to the mix, thinking this virus now had been pushed to a pathway that would make AZT work especially well. These few case reports showed excellent response. The patients went undetectable again. These data suggest that AZT now was able to work very well, and in order to get resistance to AZT, the virus would have the difficult task of selecting TAMs in a background of K65R (or else use other rare pathways).

I would stress that we did not see anything here to say that AZT/3TC/tenofovir is as good as the other antiretroviral combinations we have. That has to be a very clear message. This is not a new option and there are no data to say that, but if you have a patient for whom you do not have other choices, this may be a favorable regimen to consider. Although you will still be experimenting, I think at least you have something, some little ledge to stand on if you want to try that strategy.

Medscape: Do you think these data will be relevant to the combination of stavudine and tenofovir as well?

Dr. Schapiro: d4T (stavudine; Zerit) and AZT have a lot of similarities, and there are some issues of resistance that are similar. However, regarding this issue there is a very big question mark, and I think many experts actually are leaning to think that will not be so. I do not think d4T and AZT are interchangeable in this regard.

[Editor's note: For more information on this topic, Dr. Shapiro suggested abstracts 15-17, 20, 21, 91, and 95. At press time, complete references were unavailable at the conference Web site.]

Medscape: The use of single-dose nevirapine (Viramune) in therapy to reduce mother-to-child HIV transmission has been one of the more controversial HIV interventions in recent years. Some studies have documented that this practice might actually decrease efficacy of subsequent nonnucleoside-containing regimens for the mother. Were there any new data at the workshop on this topic? And if so, are there any other protocols for prevention of mother-to-child transmission that are under investigation that might not have such dire consequences in terms of drug resistance?

Dr. Schapiro: Yes, this was actually a main focus of the workshop. I think many of us were delighted because there is a dilemma that has been evolving, which is of great concern.

On the one hand, we need to prevent mother-to-child transmission, and a single dose of the nevirapine has been shown to save a lot of babies from HIV infection, and that is a wonderful thing. The problem, of course, is that both in the mothers and even in some of those unfortunate infected newborns, there's a consequence of NNRTI resistance. It really has put everyone in a very difficult situation. And as you said, Scott, this is something that has really been controversial, and here we were delighted to see investigators having risen to the challenge. The problem with nevirapine is not only that it selects for a single mutation, which can give resistance to it, but it also is a drug that has a very long half-life.

Even though it's just 1 dose, it stays in the blood for days, and all that the virus needs is 1 mutation to become resistant. There are data showing that actually most women will get some degree of nevirapine resistance with even that 1 dose. The more we look, the more resistance we find, and if you use assays that can look at small minority populations of HIV, you get a lot of resistance -- not only in the mothers, but also in many of those newborns if they get HIV.

So, what is the strategy here? What we need somehow is to "protect" the nevirapine from a resistance perspective; we need to give it in combination in a way that, while we still have nevirapine in the blood, there will be other drugs helping to suppress the virus. This might even help us prevent transmission further because it will reduce viral load even more.

One study took mothers and children and either gave a single dose of nevirapine to the mother and the child, using the standard regimen, or gave the mother the single dose of nevirapine, but the child was also given zidovudine twice a day for 7 days. Or they did this for 7 days in the infant without giving the mother any nevirapine at all. With this last approach, you were able to get a similar reduction of transmission, but not to get resistance in the mother or in the child to a great degree. This way, of course, the mother wasn't exposed to the nevirapine and didn't get mutations. And the baby, who got the nevirapine with the 7 days of zidovudine, had a lower rate of mutations than those who got the other protocol. This is still somewhat controversial, and even the people who did the study agreed that this has to be confirmed in additional studies. A second study gave the single dose of nevirapine to the mother and the child, but then they continued with Combivir [zidovudine/lamivudine] in both of them. When you gave the 4-7 days of Combivir, you got far less resistance, both in the mothers and in the babies.

[Editor's note: For more information on this topic, Dr. Shapiro suggested abstracts 1-4 and 10-13. At press time, complete references were unavailable at the conference Web site.]

Medscape: Regarding another topic of concern for many HIV clinicians, what is the latest data on transmission of drug-resistant HIV, and what implications do they have on clinical management of naive patients?

Dr. Schapiro: The rates of drug-resistant and multidrug-resistant transmission do not seem to be increasing. In fact, in some parts of the world, they even may be decreasing a little bit. There is some difficulty in the reporting, not everybody uses the same resistance assays or includes the same mutations or phenotypic changes, so it is hard to really get a good comparison. However, transmission rates between 5% and 15% have been confirmed now in dozens of trials, and there is no way of running away from the fact that wherever drugs are being given, resistant virus is being transmitted.

One area in which new data have changed our thinking has to do with the fact that these transmitted resistant viruses can persist for years. So the idea that only patients who are recently infected should be tested for resistance really doesn't hold water. The patient could have been infected 2 or 3 years ago, and you can do a resistance test and still catch that mutated virus. The concept that you need to do the resistance test quickly applies to patients who selected for mutations and then stopped taking drug. Among patients with recently acquired, drug-resistant virus, that is usually the only virus the patient has. When it is transmitted, regardless of the drug class, the virus really has to mutate back, and that takes much longer.

An interesting study looked not only at the blood, but also at the semen of infected patients. When resistant virus was transmitted, it persisted in the semen, therefore, if this patient were to infect the next patient, he would again pass on this resistant virus, even if he himself did not receive drug at all.

Another interesting point was that patients with primary infection appear to transmit virus more than patients who have long-term infection, and that if they have resistant virus they pass it right along. In fact, there were a number of studies that actually showed clusters of patients in primary infection, and more and more it looks like during that window when the patient is initially infected and doesn't know it, the patient is a hypertransmitter. This would really speak to the fact that there has to be as much intervention as possible targeted at patients with primary infection.

The importance of resistance testing in naive patients was highlighted in a study looking at patients who were treated during primary infection before resistance testing was used in order to select the initial treatment regimen.. The doctors didn't know the susceptibility of the patient's HIV when they prescribed the initial regimen; they just treated with standard protocols. The current investigators went back and tested these samples for baseline resistance and asked, "Let's see if resistance had any impact on virologic response?." And there was. In those patients who had resistant virus, the response to treatment was not as good.

[Editor's note: For more information on this topic, Dr. Schapiro suggested abstracts 110-118, 122-124, and 127. At press time, complete references were unavailable at the conference Web site.]

Medscape: Genotypic and phenotypic resistance testing is being used fairly widely in the clinic now. How should clinicians approach discordances between the results of these 2 types of tests, and in what type of clinical context is one type more helpful than the other?

Dr. Schapiro: It would be very helpful to see some comparative studies looking at specific clinical situations to give us guidance on any potential advantages of phenotypic testing. Conceptually, we have a number of situations in which we think phenotyping might possibly be better than genotyping, but there actually has never been a randomized study to show any added benefit to phenotype over genotype. Phenotyping is a more expensive test, it takes longer, and is not available worldwide as readily as genotyping. There are more data on genotype studies, showing that using it gives you a better virologic response.

There were a number of studies at this Workshop that looked at interpretation of either phenotype or genotype. There was a very nice study on behalf of the Forum for Collaborative Research, which looked at a number of genotypic-specific interpretations and found that their ability to differentiate between intermediate and full resistance was not good for, ddI and abacavir. Although adherence to therapy could be a potential confounder of this study, it is an important concern that genotypic interpretation systems must address. Interpretation of NRTI resistance has also been a challenge for phenotypic assays. Each of the phenotyping companies uses different strategies for interpreting resistance data. Their older cut-offs are no longer considered accurate, and data were presented at the workshop on the new clinical cut-offs that were developed. .These clinical cut-offs appear to be an important improvement, although considerable challenges remain, such as the variable datasets and virologic outcomes used for different drugs. There was a lot of discussion at the workshop on what clinicians should do. Is that even right to give them clinical cutoffs? Definitely a lot of open questions remain, and I think we have to realize that these interpretation systems of genotypic or phenotypic assays aren't perfect. My view is that NRTI resistance remains the hardest for both of these types of assays to accurately predict.

[Editor's note: For more information on this topic, Dr. Schapiro suggested abstracts 6-9, 24, 29, 37, 51-54, and 56. At press time, complete references were unavailable at the conference Web site.]