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HIV Drug ResistanceHIV Drug Resistance
           
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Resitant to all PIs & almost all NRTIs
Jul 8, 2009

Hello, I have been HIV+ for 25 years and have done pretty well on my HIV therapies which I began about 17 years ago. Last year my viral load began to increase so my doctor & I decided to switch my regimen. My Pheno & Genotype test showed me resistant to all Protease Inhibitors except Prezista and all NRTIs except Tenofovir. I showed no resistance to any drugs in the NNRTI class. At that time (one year ago) my doctor put me on a regimen of Norvir, Prezista, Isentress & Atripla. I have Sulfa allergies (discovered years ago after taking Septra) and after being on the Prezista for one year, have been dealing with rashes and itching which have been increasingly getting worse. Since Prezista is a Sulfa drug, we are assuming it is the culprit. Since it is the only protease inhibitor that I am not resistant to, I have been dealing with the side effects in hopes they will subside. However, the itching is getting unbearable and really affecting the quality of my life. Plus, the more I read about it, it appears it is not good for me to stay on it if it is causing severe rash and itching. Sorry, to go on with so much detail, but I am getting worried about my options moving forward and want to give you as much facts as possible about my situation. I have had three doctor opinions now and all have pretty much concluded that it is a drug reaction. I was hoping for your opinion as to what my drug options are before I talk to my doctor next week about stopping the Prezista. It is scary to me that I am resistant to all the other PIs. My viral load is currently undetectable and my T-cells are at 303. My ratio is 30.3%. So in conclusion, I am resistant to all the remaining PIs, all the NRTIs except Tenofovir and sensitive to all NNRTIs. Am I getting to the end of the road for my options? I am hoping that my only option is not Fuzeon. Please kindly give me your expert opinion. I will be grateful. Thank you so much!

Response from Dr. Sherer

You have done well to tell me a great deal about your situation, but I will caution you and other readers of this website that complex cases with high levels of resistance and a long treatment history are the most difficult to summarize accurately, and even more difficult to interpret effectively. Inevitably, some information is omitted in the history that might be critical to a careful analysis of your situation and the best actions to take. In your case, I would need to know, for example, not only what past regimens you have received, but the short and long term response to those regimens, including any mild or severe side effects that might limit the use or re-use of the drugs in the regimen. And I would need to know specifically if you ever received an NNRTI-containing regimen, such as efavirenz (EFV, Sustiva or Stocrin) or nevirapine (NVP, Viramune), as well as the outcome of that treatment. If you were treated with an NNRTI and failed the regimen, I would not recommend that you use a first generation NNRTI in a subsequent regimen, because there is complete cross resistance between those drugs.

And, importantly, if you had received and failed an NNRTI-based regimen, your most recent genotype and phenotype test results that showed that the dominant strain of your current virus is susceptible to NNRTIs would be incorrect. One of the limitations of both types of resistance tests - both genotype and phenotype tests - is that they only measure the dominant viral strain in your 'swarm' of virus that represents >20% of viral strains, and they miss strains that are present in smaller portions. This phenomenon is called 'archived resistance', and it occurs because the selection pressure of a patient's current ART drugs directly influences the strains that are able to survive in the presence of those drugs. In your case, your current regimen lacks an NNRTI, and so there is no 'selection pressure' by your regimen that would promote the growth of mutant virus that contains the NNRTI resistance mutations that are related to the use of NNRTIs, such as the K103N or the Y181C. Another piece of information that I would like to know is, in any past resistance tests over the past 17 years, were you found to have a viral strain that did contain an NNRTI resistance mutation? The strong likelihood is that you did receive such a regimen, and have indeed at some time developed resistance to the first generation drugs in the NNRTI class.

For all of these reasons, I urge you to take the observations that I share below with you to your next visit with your doctor and discuss it with him or her. And I also apologize for being long winded: There is simply no way to address the complex issues of multi-class resistance and the next options for you and your doctor to consider.

Here are my suggestions in the short version; then below I will explain each one.

1. I agree that a trial that includes stopping the Prezista is warranted, given the consensus among your doctors that you are having a chronic adverse reaction to it.

2. Because resistance to protease inhibitors (PIs) is rarely all or none, you and your doctor can review your resistance tests and consider an alternate PI that still might contribute some anti-viral activity. The merits of this idea will depend on the details of your genotype and phenotype results. I would guess that either tipranavir or lopinavir might still have some activity. As you will see below, you and your doctor can also consider just stopping the Prezista without adding another PI, if your best judgment is that you are susceptible to EFV and have never before been treated and failed an NNRTI.

3. If you have been treated with EFV or NVP in the past and failed that regimen, you and your doctor can review your ART history and resistance tests to see whether you might still receive benefit from the second generation NNRTI etravirine (Intelence).

4. I advise continuing the Isentress. [As you will see below, there are reasons to think that Isentress and Atripla alone may be sufficient...IF you are truly susceptible to EFV and have never been treated and failed an NNRTI in the past.]

5. I agree with continuing the NRTI components of Atripla, i.e. tenofovir and emtricitabine, in the next regimen.

6. Enfuvirtide (T-20) IS an option for you and your doctor that you should consider, though it may well be possible to not use that presently, and to hold that for another time. It might be prudent to start T-20 while you are engaged in this trial, to ensure the optimal response and to maintain your fully suppressed viral load, and then, at some later time (3-6mos), if you maintain full control off Prezista, to withdraw the T-20 to see if you can still maintain control without it.

Similarly, while I would not propose that you try maraviroc (MVC, Selzentry) at this moment, it is another drug that is available to you for consideration. You and your doctor may want to obtain a tropism assay to see if you have an R5 or and X4 virus; maraviroc can only be used to treat R5 viruses.

Comments: The good news in your situation is that your current regimen is currently controlling the virus, and you have a CD4 cell count above 300 cells/ml. You and your doctor can take the time to make the right decision here, although I do understand that the rash and drug reaction are uncomfortable and a reason for prompt action.

In your present regimen, Isentress is an important anchor. In one study from France in patients with high level drug resistance to NRTIs and NNRTIs, but full or partial susceptibility to Prezista, 90% of patients were fully suppressed after one year on the regimen of raltegravir (Isentress), darunavir (Prezista) + ritonavir boosting (Norvir), and Truvada (tenofovir + emtricitabine) or other NRTIs as chosen by the primary physician. As you can see, that regimen is similar to your current regimen, except that you have Atripla instead of Truvada, i.e. you have the extra drug EFV (Sustiva) in your regimen.

In another large cohort study of all highly resistant patients placed on the second generation NNRTI etravirine (ETR, Intelence), two thirds of patients achieved an undetectable viral load, and there was little difference in the outcome among patients treated with each of the following combinations: ETR + DRV + RAL + NRTIs, ETR + DRV + NRTIs, and ETR + RAL + NRTis.

Finally, in the RAL registrational trials, RAL performed surprisingly well after 48 weeks in patients in whom there were no or only one other active drug, achieving full viral load suppression in the majority of patients. However, given that RAL has a level of genetic susceptibility to resistance that is somewhere between boosted PIs and NRTIs, it is best used in the company of two or more active drugs.

In sum, RAL can be used as an anchor in a regimen in someone with highly resistant virus, but it should always be used with 2 or more active drugs. Hence, you and your doctor need to determine what options are available to you as companions to RAL in your current regimen, if you want to stop all PIs, or rely on a less active choice than Prezista.

So the first key question is the EFV and Atripla question: Is your virus susceptible to EFV? Have you ever had NNRTIs before, and did you experience virologic failure? Has a past resistance test ever shown a K103N or Y181C? If not, then you can simply stop the Prezista safely, in my opinion, and use the regimen of Prezista and Atripla. HOWEVER, I am skeptical that this is your situation. I think it's more likely that you did receive and fail an NNRTI in the past, and that you are resistant to the first generation NNRTIs. In that case, you and your doctor can assess whether your NNRTI resistance pattern is such that ETR will be active, and can be added to your regimen. Similarly, as above, I would favor including another boosted PI such as tipranavir or lopinavir if there is sufficient evidence that would make a partial contribution to viral load suppression and, as above, T-20 on a temporary basis.

The sections above on PIs, ETR, and NRTIs speak for themselves, so I will end here and simply reiterate that you have to talk to your doctor and make an informed choice with him or her. I gaurantee that he or she has additional information that I lack that is key to answering some of the questions that I have raised.

Also, many well-experienced HIV clinicians seek second opinions themselves on complex cases like yours, including supplemental interpretations of genotype and phenotype results, and you can reasonably ask your doctor whether he or she has someone that can be consulted for this purpose.


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