A forum for physicians to ask our expert Advisory Board
questions concerning antiretroviral drug resistance and related treatment
issues
Ask The Experts is an open forum in which our site's visitors can receive comprehensive and detailed responses to their questions. Submitted questions should concern antiretroviral drug therapy, drug resistance, and related issues. New questions are selected and answered on an ongoing basis by our Advisory Board. Feel free to submit your own question to the advisory board by filling out the form below.
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I have heard about the emergence of a new K65R mutation that seems to
present in patients on triple NRTI therapy. In the case of a patient on ddI,
tenofovir and 3TC, should I be worried about K65R?
A prior genotype showed M41L and L210L/W, and he is happy on his current regimen with a viral load of approximately 400 copies/mL.
(Wainberg)
Read the response Which genotype kit should be used for detecting drug-resistant mutations in subtype C patients? We are particularly interested in performing tests for mutations conferring resistance to AZT, nevirapine and protease inhibitors. (Katzenstein)
Read the response What regimen would you recommend switching to in a situation involving a patient with evidence of virologic failure to her only regimen - ddI, d4T, nelfinavir - and a resistant genotype report as follows:
Read the response What are the possible ways of overcoming HIV resistance to protease inhibitors and which of those are routinely employed? (Schapiro)
Read the response In the case of a patient who has D67N,T69D,T215Y,G333E,G190A and L10I mutations, who has been taking lopinavir/r, d4T, tenofovir and ddI, and who initially responded but is now rebounding with the current regimen, should one consider dual PI (saquinavir/ritonavir) + ddI + Epivir? Any suggestions? (Conway)
Read the response I am an ID fellow and am seeking advice concerning NRTIs in the case of a patient who was naive to HAART treatment and placed on Combivir and nelfinavir (as you can probably guess). She never became undetectable and escaped viral suppression recently. The following genotype mutations were also present:
Read the response I wanted to inquire about a situation involving a 43-year-old HIV-positive (first screening test in 1985) male coinfected with HCV who was on AZT monotherapy (250 mg twice a day) from 1987 to 1990. In 1990 he stopped therapy. On May 1997 he started AZT + 3TC + SQV (hard capsules / 600 mg x 3). From that time to the present time, viral load was always under detectable levels (<500 copies/mL or <50 copies/mL) and CD4+ ranging from 250 cells/mm3 to 350 cells/mm3.
In this situation, should I:
1) leave the patient on this treatment?
2) simplify the therapy (i.e.: Trizivir)?
3) boost the PI?
(Conway)
Read the response Do you have any knowledge concerning the 101Q mutation? I understand it is an efavirenz mutation.
(Conway)
Read the response What is the latest information on using d4T following AZT failure? (Wainberg)
Read the response Resistance testing is recommended while patients are on therapy. Is there a safe cut off time period during which you could still perform resistance testing? For example, should resistance testing be performed for a patient on ddI+3TC+nelfinavir with a viral.load >50,000 copies/mL who stops his medications on his own 5 days before his visit to the office? (Conway)
Read the response Is a lopinavir/indinavir-based therapy adequate for salvage in the case of a patient who was initially on AZT/3TC for 6 months in 1997 followed by ddI/d4t/IDV combination and who is now in clinical and virological failure? What about adding on an NNRTI - EFZ? Will abacavir be useful here, or will the prior use of ZDV/3TC make it unlikely to be useful? This situation is also in a resource-poor country. (Katzenstein)
Read the response Is it a good idea to use Trizivir twice per day in the case of a patient who, after suspending Zerit/Epivir/Videx therapy for hepatitis for three months in Aug., 2000, developed medium to severe resistance to these antiretrovirals in Dec., 2001(severe resistance developed to Videx)? The virus count grew from 400 copies/mL to 14,000 copies/mL, the CD4 count is 750 cells/mm3, and there is no protease inhibitor resistance. What is the outlook in this situation? (Conway)
Read the response Why are the 333E/D mutations not listed in HIVResistanceWeb's NRTI charts? (Shafer)
Read the response I have a patient with this kind of resistance on June 13th, 2001:
He was taking D4T+3TC+RTV+SQV until June. Since then he has been taking AZT+3TC+EFV+AMP+LPV/r. His viral load was 1,555,662 (6.1 log) in June and his CD4 count was 12 (1.9%).
Two months after change of therapy (August), his viral load was 971,000 and his CD4 count was 65 (5%) in August 30th. One month later, his new VL was 354,000. But now his VL is back up to 1,030,000 and his CD4 count is down to 22 (3.6%). What can I do??? What about a new combination? What about tenofovir? There are few options remaining. There are so many RT mutations that I can't offer another option than AZT+3TC or D4T+3TC. He has already received ddI, ddC, AZT, 3TC,d4T, NFV, SAQ, RTV, IDV, AMP, LPV/r and EFV. What about IL-2 to improve his CD4 count? (Conway)
Read the response A patient started HAART three years ago, with d4T/3TC/nelfinavir. He had not received previous ARV therapy. His HIV RNA has been persistently below 50 copies. He underwent a one month STI and after 15 days of drug suspension, his RNA was 3000 copies/mL, and plasma genotype shows the presence of the M184V and T215Y mutations. How should this be interpreted? Should therapy be changed when it is reinitiated? (Conway)
Read the response I have a new patient, age 20, CD4 261 cells/L, viral load 16,000 copies/mL. He is treatment naive and has no symptoms. Should resistance testing be done now as a guide to selection of initial therapy? (Katzenstein)
Read The response I have a patient who has been on Combivir/nelfinavir for >3 yrs. CD4/VL results: March 15, 2001): CD4=133, VL=8370 c/ml; April 23, 2001: CD4=166, VL=1889. For the past 2 yrs, CD4 has been 130-230, viral load 1800-8000. He states about 90% adherence to meds. A Visible Genetics TruGene genotype on 4/16/01 showed: M184V, L10V, M36I, I54V, A71V. Should I be concerned about this constellation of PI mutations? Would you change therapy (and to what) as his VL is still low, but patient had recent bacterial infections? (Conway)
Read the response I have a new patient, age 20, CD4 261 cells/L, viral load 16,000 copies/mL. He is treatment naive and has no symptoms. Should resistance testing be done now as a guide to selection of initial therapy? (Katzenstein)
Read the response I have a patient who has been on Combivir/nelfinavir for >3 yrs. CD4/VL results: March 15, 2001): CD4=133, VL=8370 c/ml; April 23, 2001: CD4=166, VL=1889. For the past 2 yrs, CD4 has been 130-230, viral load 1800-8000. He states about 90% adherence to meds. A Visible Genetics TruGene genotype on 4/16/01 showed: M184V, L10V, M36I, I54V, A71V. Should I be concerned about this constellation of PI mutations? Would you change therapy (and to what) as his VL is still low, but patient had recent bacterial infections? (Conway)
Read the response We are developing a protocol for NRTI sequencing in our practice. Unfortunately, we do not routinely have access to genotypic testing. Neither abacavir nor didanosine is a good choice in our setting as first line drugs for various reasons. We are considering d4T/3TC as the initial nuke component, followed by AZT/ddI. What are your thoughts on this sequence in terms of the resistance implications? (Wainberg)
Read the response A 5 year old child has been on d4T and 3TC for three years (June 1998 - June 2001). Her viral load was 1,171,084 copies/mL and CD4 percentage was 24% at commencement of therapy. She has been growing well and has not been hospitalized since therapy. She had LIP before initiation of therapy. Since starting ARVs she has not been ill besides the odd URTI and some bronchospasm which resolves with inhaled bronchodilators and inhaled steroids. Her latest viral load, however, is 9, 667 copies/mL and it has been in this range since the initiation of therapy. She never had undetectable virus. Her CD4 percentage increased from 24% to 45%, her latest is 31%.
Her mom wants her to go onto triple therapy to achieve undetectable virus levels. We did a genotypic resistance profile on her at our local lab in South Africa which showed the following mutations: M184V, K70R, D76N, K219Q, signifying ABC resistance, 3TC resistance and low-level AZT resistance.
The question is: should we change her regimen from dual therapy to triple therapy? If so what regimen should we choose? (Katzenstein)
Read the response What would you recommend as the best ARV drug sequence for treatment-naive patients? Would PI-sparing options be preferred in view of their AE profile? (Conway)
Read the response I recently received a patient who has been on virtually all possible available drugs. His viral load was over 100,000 copies/mL and his CD4 count was 45 (10%). He has been without medications for 7 months. When he was in the hospital, a genotype was done: I have not seen the results of that test, but apparently he has multiple primary mutations associated with resistance to PIs and many NRTIs, but not to ddI or to NNRTIs. The ID MD ordered to start the patient on Kaletra only. Can you tell me why? I am going to start the patient in Kaletra/ddI/EFV and then run a genotypic test.
Is Kaletra (alone) is an option in this case? And is ordering a genotypic test before initiation of therapy (after more than 7 months with no therapy) a good idea? (Conway)
Read the response Consider this situation. A patient who started on AZT monotherapy back in 1992, and was on it for several years (shortly after seroconverting). Approximately four years later 3TC was added (Combivir), and then 1 year later when the viral load was noted to be slightly over 500, nelfinavir was added. The patient remains NNRTI-naive. Medicine compliance has always been very good.
In Feb of 2000, full testing including resistances were done. CD4 count was 1400 (43%), CD8 count was 1350 (41%), ratio 1.0. Viral load was 128, and resistance mutations were L10V, K20R/M, and L63P for PIs and K70R and M184V for NRTIs. No mutations were noted for NNRTIs. At the time, given how stable he and his numbers are, we opted to follow him and retest in approx 6 months.
Ten months later, viral load was 425, CD4 was 1600 (48%), CD8 1225 (37%) with a ratio of 1.3. So what to do: the patient has yet to ever test with an undetectable viral load, which would really be the ultimate goal!
Does the M184V really "cancel out" the affects of the K70R, in which case one should leave him on AZT? But should one also leave him on 3TC to continue to select for M184V,or would it make more sense to just switch over to AZT in the hope that we might select for wild type, get rid of M184V, and reselect for genotypic sensitivity to the other NRTIs which technically the patient doesn't have with M184V.
My thoughts would be to change this patient to a regimen of AZT and nelifinavir but substitute efavirenz for 3TC. But I am truly unsure whether it makes more sense to attempt to "keep" M184V and just add efavirenz to the current regimen -- or to completely change the regimen around. Any suggestions on what would make the most sense from a resistance standpoint? Where do you think the increased viral load is coming from? (Wainberg)
Read the response I have a 53-year-old male patient diagnosed HIV+ in 1993. He has been previously treated with multiple agents. The patient presented to me on nevirapine, nelfinavir, saquinavir and ddC. Viral load was 285,000 copies/mL; CD4 count was 5 cells/µL. Genotyping was done and showed resistance to all components of this regimen. The patient’s virus had no mutations associated with resistance to 3TC, d4T, adefovir, amprenavir or lopinavir, but had mutations associated with resistance to all other drugs. The patient was placed on d4T, 3TC, and lopinavir. Repeat labs 3 weeks after change of therapy found viral load of 63,647 and CD4 count of 26 cells/µL. Repeat labs 6 weeks after change shows viral load >500,000, CD4 count of 47 cells/µL. Any thoughts? (Conway)
Read the response I am following a patient who has been on therapy for about 12 years. His therapy has included NRTI's, NNRTI's and PI's. He has had 3 major regimen changes. The last one, 6 months ago, was determined by resistance studies which indicated that PI's were no longer effective. A three drug regimen which included NRTI's and NNRTI's initially reduced his viral load from over 200,000 copies to 60,000 copies and increased his T-cell count from 140 to 250. His last tests indicated that this regimen is losing its effectiveness. What recourse is there for a patient who is no longer benefiting from NRTI's, NNRTI's and PI's? Do you think that fusion inhibitors will be available in the near future,and do you think they will be effective in this patient, who has become resistant to so many other antivirals? (Conway, Wainberg)
Read the responses I am looking for a more complete list of nucleoside reverse transcriptase inhibitors that select for the M184V mutation. The literature always only mentions the four FDA approved drugs ddI, ddC, abacavir, 3TC. I would appreciate if you could name a source where I could find other compounds as well. I'm sure the above four are not the only ones known. (Wainberg)
Read the response Resistance testing seems to be currently limited to demonstrated failures under a specific multi-drug therapeutic regimen (HAART). What percentage of the HIV patients (in the United States) receiving treatment fall into this category? I would imagine that all of these patients should get resistance testing. What percent do you think actually get testing and why is it less than 100%? If the shortfall is an educational or awareness issue, how long do you think it will take to get that number to 50 or 75%? (Conway)
Read the response Other than the VIRADAPT AND GART studies, what published or anecdotal findings support the benefits of resistance testing? (Conway)
Read the response If resistance testing gives insight into the best drugs to use as therapeutic agents, why isn't it the first step to get the treatment off with the best drug combination? The total cost of annual therapy is very high, even without complications. Isn't the up front expenditure worthwhile to make sure the resources are properly applied? Do you think there are circumstances where resistance testing will be an ordinary first course of all HIV treatment? How long do you think it will take for this to occur? (Conway)
Read the response I understand there are two main types of resistance testing, phenotyping and genotyping. Phenotyping actually runs multiple drug response curves against the main viral strains amplified in a laboratory. Genotyping sequences or probes for either known mutations associated with resistance or uses a database to compare mutations against known phenotypic resistance. What are the preferred indications for genotyping versus phenotyping? What is the best way to be sure that the genotype interpretation is highly correlated with anticipated phenotypic expression in the patient? (Conway)
Read the response There are multiple sources for interpretation of rules and databases which may be used to predict resistance. As time passes, how do you see these databases and rules being updated? (Conway) Read the response
L, viral load 16,000 copies/mL. He is treatment naive and has no symptoms. Should resistance testing be done now as a guide to selection of initial therapy? (Katzenstein)