
The Food and Drug Administration (FDA) today (July 12, 2006) approved Atripla Tablets, a new fixed-dose combination of three widely used antiretroviral drugs, to be taken in a single tablet once a day, alone or in combination with other antiretroviral products for the treatment of HIV-1 infection in adults. Atripla is the first fixed dose combination available in the United States to combine two different classes of antiviral drugs in a single pill. This "one-pill-once-a-day" product to treat HIV/AIDS combines the active ingredients of Sustiva (efavirenz) a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), with Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate), two Nucleoside Reverse Transcriptase Inhibitors (NRTIs).

glucose (blood glucose normal). Our ID physician has spoken to a nephrologist who recommended looking at urine protein electrophoresis but basically recommended d/c tenofovir. In the meantime, we had switched his Kaletra to boosted atazanavir (400/100 mg daily) in April as the patient is on a ton of other meds, has chronic diarrhea requiring up to 6 Imodium per day (now resolved), and is at high risk of CHD with lipids not controlled. I had requested an atazanavir trough level from BC which came back at 2 58 ng/mL.

Just wondering what you would do? Double boosted PI? Which one(s)? Would you keep efavirenz? We do not really have access to TDM so would make following levels more difficult...I would probably add 3TC back into the next regimen regardless... 
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This case is complicated and you will get probably several different opinions. Here is mine.First, I would have like to know what was the backbone therapy when he failed NLV. I trust genotyping assay but it tends to miss minority species... Second, I assume that the patient has been on previous AZT and AZT-ddI dual NRTI combination, which would explain the presence of TAMs.
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About the renal dysfunction, some argues that even if TDF is associated with nephrotoxicity, that you should rule out any other possible causes (Again, I assume the patient is not diabetic). Considering the limited options, I would propose to do a biopsy. IF clinically, you feel somewhat unwell with this situation and want to make a switch, I would rely on drug history and the genotyping.
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Considering previous exposure to AZT (Assumed), I doubt that there is any activity left for AZT/d4T. ddI activity will be decreased due to 74V mutation (I guess he had been on it too) 3TC is only a good choice to preserve the 184V and I would also tend to introduce it into the new regime.
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Finally, you don't have many options left. I would throw in ABC (ie Kivexa) as backbone (understanding that the sensitivity is reduced) and keep ATV/r 400/100 + EFV. I would even consider to put in back on Kaletra, despite the lack of lipid control, if drug interaction is an issue.
Good luck Pg
Just to add, he was on AZT mono and then AZT/ddI. I am not 100% sure of his NRTI backbone while on nelfinavir but I know he was on 3TC and possibly d4t (don't have his chart with me now). His genotype back in 2002 makes sense to me based on his previous history.
Good luck Pg
He is not diabetic -we checked his blood glucose again. The nephrologist and our ID physician felt quite strongly that this is a pretty specific tubular issue -the protein electrophoresis is to rule out other causes. Her suggestion is to stop tenofovir. I must say I would rather d/c tenofovir then have to have a kidney biopsy. My debate is whether to try Trizivir or Kivexa + efavirenz + boosted atazanavir or look at some other dual-PI based combination.. Is he a motivated patient wiling to put up with side-effects and compliance issues?
Good luck Pg
It would be good to keep following the renal function and U/A to see if the side-effect reverses once TDF is discontinued.
Good luck Pg
A riskier (but better tolerated) approach would be 3TC plus EFV/Kaletra OR EFV/ATV 400/r100-give a little extra ATV here... (going along with the fact that Kaletra or ATV monotx might be enough in a suppressed patient).
Mich
Case # 2 Hi All, I am familiar with the published data on PI monotx with Kaletra or ATV/r. I am wondering if any of you have actually tried it on any of your patients who really want a very simple regimen and have resistance to NNRTI and NRTIs?
Mich
What has your success rate been? Did you use the step-down approach (i.e. achieve VL < 50 with triple ARVs and step-down to just Kaletra), or did you implement monotx despite high viral loads.
Mich
I have a patient who does not want T-20 and is resistant to NRTIs/NNRTI's. He did not tolerate a double boosted PI regimen (Kaletra caps + ATV) and gave up after only 1-2 weeks on this due to major GI toxicity. We don't have access to other investigational classes of meds here.
Mich
The question will be whether to risk trying PI monotherapy in him (+ 3TC-has the 184V mutation), or to wait until we have more new classes available to construct a more sound regimen. He runs high lipids, smokes, CD4 is 110 (10%), VL > 100,000. He is not a terribly motivated patient and suffers from depression.
Mich
Any opinions? (I would like experience from the other Edmonton folks too!!!) Hi Michelle,
Mich
We have few patients on PI monotherapy as part of Clinical Trials. These patients were naive to treatment and are taking Kaletra. I think the evidence is not strong enough to recommend it widely. In patients were prior resistance, I would be even more cautious and likely not use this option. pg Hi Michelle, I also have never seen PI monotherapy in practice. Coming from BC, we used several meds in salvage regimens although I didn't often see the genotypes of these patients so I do not know the resistance, but I assume there was a lot. Linda 1) You are right that Trizivir with TFV would not lead to the development of K65R, nor would CBV/TFV for that matter, because in the event of failure, the most likely resistance to develop will be M184V, of course, and TAMS. It is rare if never that you will see TAMS and the K65R emerge together under this drug pressure.
Mich
2) The effect of TAMS on TFV and ABC is not to be discounted, however, especially the TAM pathway 1, 215Y, 41L, 210W vs. TAM 2, 67, 70,219. Any 3 of these with M184V = abacavir resistance, and can have an effect on TFV as well.
Mich
3) The problem with using ABC/TFV/3TC is that the resistance to develop will most likely occur in the following order, M184V...K65R, with maybe the 74 mutation in between. What one could possibly sequence after this would be limited to thymidine based with 3TC or FTC and tenofovir.
Mich
4) The premise for the above is that M184V is thought to delay the emergence of TAMS, confer increased susecptilbilty to Tenofovir, (not abacavir) and the K65R is assumed to confer increase susceptibility to TFV. 5) As far as using the 3 agents in question together in a naive patient, with no resistance, (keep in mind primary resistance if infected recently) as a backbone with a strong PI or non-nuke is not out of the question, considering their once daily beauty, but why use the third agent at all? Either TFV or ABC with 3TC or FTC will make a nice backbone and allow for intensification and use of thymidine in the next regimen if needed in this group of patients. ( I personally think that using TFV/CBV after Kivexa makes more sense, however than using Trizivir after Truvada. Tseng, Alice Dr wrote: > Hi everyone, > > Recently, I have received a number of queries from physicians who are > interested in switching patients from tipranavir to other PIs, but worried > about obtaining adequate drug levels. The main concern has been that since > tipranavir is such a potent enzyme inducer, even after stopping the drug the > induction effects could last for around 2 weeks and possibly decrease levels > of the new PI that will to be started. Quite often the physicians do not > wish to interrupt HAART in order to bypass the lag time for the inducing > effects. > > Boerhinger-Ingelheim does not have any recommendations on how to switch or > dose-adjust in this situation, and there are no data currently available. > > Charles and I thought it might be interesting to measure serial plasma > levels in patients undergoing such switches. For instance, in someone > switching from tipranavir/ritonavir to lopinavir/ritonavir, the suggested > dosing schedule might be: > days 1-14:
Mich
d/c tipranavir, continue with ritonavir 200 mg BID, start > lopinavir 400/100 mg BID > thereafter:
Mich
d/c extra ritonavir capsules, continue with regular dose > lopinavir 400/100 mg BID, > with trough concentrations measured at various timepoints before, during and > after the switch-over period. We could look at levels in people making > switches to other PIs too. > > This information would be used for informational purposes only (samples > would be analyzed in batches, rather that done in "real time"), but we think > the accumulated data could be very helpful for understanding more about > tipranavir kinetics and eventually coming up with dose-switching algorithms. > > Has anyone else encountered this situation in clinical practice? Especially > in light of the recent data on intracranial hemorrhage with tipranavir, > hepatotoxicity issues, and expanded access of darunavir, there may be a > number of patients who may be interested in switching from tipranavir to > other agents, so this may be a timely issue to look at. > > If you have any tipranavir patients that you are considering switching to > another PI and who might be interested in having drug levels done, please > let us know the approximate numbers. We are running into this issue often with patients switching off tipranavir and onto TMC-114. As the TMC-114 expanded access specifies that a 2 week washout period is needed between tipranavir and TMC-114 we have been putting patients on another PI (mostly lopinavir at standard doses) temporarily. We haven't done TDM on these patients yet. The results would come in after the switch and therefore would have less clinical relevance to that specific patient.
Mich
I think it would be great to have this data. However, knowing our ethics committee, collecting samples from a group of patients to measure them in batch without it having relevance to clinical care of each specific patient would definitely be considered research and would need to be under the umbrella of a research protocol. Nancy ...that, and knowing our ethics committee they will ask for pharmacogenotyping! It looks like there is some variation between centres on ethics requirements, as I have had other people contact me already wanting to send samples.
Mich
HI everyone, I was following the email trail re: the prolonged induction effect of TPV to take into account when switching to TMC, aware of the 2week suggested washout. My issue with a patient that I need to do this with is that he is finally supressed after 5 years since being on TPV/r/ENF/TFV/3TC for the last year. He is, however, a vasculopath, diabetic, on anticoags, and his TG's are through the roof! He has multi-class resistance, including 47 fold resistance to Kaletra. I am still considering bridging him with 4 caps of Kaletra bid + extra ritonavir. However, would anyone consider the following:
Mich
-just continuing 200mg rtv bid for 2 weeks -starting the TMC114 ( at least after EAP) right away and maintaining the extra 100mg rtv bid x 2 weeks.
Mich
I have brought this subject up to the folks at Tibotec, to hopefully provide me us with some sort of suggestion since their initial market target is going to be the TPV switches. To follow-up on our initial inquiry, attached is a protocol for the tipranavir PK sampling study that Charles, Nancy and myself, along with our HIV resident, Nimish Patel, are proposing. The intent is to assess PI levels in patients switching from tipranavir to another PI, by using lopinavir/ritonavir (and extra ritonavir) for the first 2 weeks immediately following tipranavir discontinuation.
Mich
If you have patients switching from tipranavir to another PI in the near future, and would be interested in participating, please let us know. The attached protocol may be modified as needed for local REB submissions.
Mich
Thanks, Alice, Charles, Nancy, Nimish We will draft something for those centres that require ethics approval. Alice 07/12/2006 l trail re: the prolonged induction effect of TPV to take into account when switching to TMC, aware of the 2week suggested shout. My issue with a patient that I need to do this with is that he is finally supressed after 5 years since being on TPV/r/ENF/TFV/3TC for the last year. He is, however, a vasculopath, diabetic, on anticoags, and his TG's are through the roof! He has multi-class resistance, including 47 fold resistance to Kaletra. I am still considering bridging him with 4 caps of Kaletra bid + extra ritonavir. However, would anyone consider the following:
Mich
-just continuing 200mg rtv bid for 2 weeks -starting the TMC114 ( at least after EAP) right away and maintaining the extra 100mg rtv bid x 2 weeks.
Mich
I have brought this subject up to the folks at Tibotec, to hopefully provide me us with some sort of suggestion since their initial market target is going to be the TPV switches.
Mich
Does anyone have any other suggestions? I guess my issue in this patient is why Kaletra if there is just as much, if not more resistance to it in this patient , than to any other PI. Help! Linda R.
Mich
Hi everyone, To follow-up on our initial inquiry, attached is a protocol for the tipranavir PK sampling study that Charles, Nancy and myself, along with our HIV resident, Nimish Patel, are proposing. The intent is to assess PI levels in patients switching from tipranavir to another PI, by using lopinavir/ritonavir (and extra ritonavir) for the first 2 weeks immediately following tipranavir discontinuation.
Mich
If you have patients switching from tipranavir to another PI in the near future, and would be interested in participating, please let us know. The attached protocol may be modified as needed for local REB submissions. 
RATIONALE
The pharmacokinetics of tipranavir (TPV) / ritonavir (r) are starting to become of greater interest, especially with respect to the strong induction properties of the p-glycoprotein efflux pump and cytochrome P450 3A4 isoenzyme. Reduced lopinavir, saquinavir, and amprenavir levels have been seen with co-administration of TPV/r 1 . In 16 HIV positive patients who received 27 doses of amprenavir/ritonavir 600/100mg twice daily concomitantly with 28 doses of TPV/r 500/200mg twice daily a reduction in pharmacokinetic (PK) parameters of amprenavir/ritonavir was seen: 39% decrease in peak concentration (C max ), 44% decrease in area under the curve (AUC), and 55% decrease in trough concentration (C min ). A similar reduction in PK parameters of lopinavir/ritonavir was seen with 21 HIV positive patients who received 27 doses of lopinavir/ritonavir 400/100mg twice daily with 28 doses of TPV/r 500/200mg twice daily. Lopinavir/ritonavir C max was reduced by 47%, AUC reduced by 55% and C min reduced by 70% when coadministered with TPV/r. In 20 HIV positive patients receiving 27 doses of saquinavir/ritonavir 600/100mg twice daily with 28 doses of TPV/r 500/200mg twice daily saquinavir/lopinavir C max was reduced by 70%, AUC reduced by 76%, and C min reduced by 82%
RATIONALE
1 .
RATIONALE
Higher doses of lopinavir/ritonavir have been studied in patients concomitantly taking TPV/r. In patients taking either lopinavir/ritonavir 400/300mg or 533/233mg twice daily with TPV/r and no other protease inhibitors or non-nucleoside reverse transcriptase inhibitors, target trough concentrations were similar and above the 4mcg/ml target trough for treatment experienced patients on days 1 and 14 with no statistically significant differences noted. The median day 1 trough concentrations for the 400/300mg and 533/233mg twice daily groups were 4.17mcg/ml and 4.77mcg/ml. The median day 14 trough concentrations for the 400/300mg and 533/233mg groups were 7.05mcg/ml and 5.20mcg/ml 2 . Similarly, lopinavir trough concentrations of HIV patients before therapeutic drug monitoring taking lopinavir/ritonavir 533/233mg twice daily with TPV/r 500/200mg twice daily was 4257ng/ml. After therapeutic drug monitoring trough concentrations of lopinavir were 6151ng/ml 3 .
RATIONALE
There are several virologic or pharmacologic markers of response. However, the genotypic inhibitory quotient (GIQ) has been shown to be a better predictor of virologic response when compared to other virologic or pharmacological variables were used. Also a strong, positive correlation between GIQ and viral load reductions has been demonstrated. The GIQ is defined as the quotient between the C min and the number of protease mutations related to resistance to the ARV. Targeted C min for lopinavir in protease inhibitor-experienced patients is 4mg/L 4 . Targeted GIQ are 2.1 for heavily protease inhibitorexperienced patients 5 .
RATIONALE
What remains unclear is the duration of induction properties once TPV/r has been discontinued. Concerns about resistance exist with suboptimal protease inhibitor (PI) concentrations when patients are changed from TPV/r to an alternate PI. This interaction is of greater interest for highly treatment experienced individuals with multi-PI resistance HIV-1, as these patients are most likely using TPV/r. The objective will be to ascertain knowledge of TPV/r's induction effect on other PI's, after TPV/r has been discontinued by examining Cmin and genotypic inhibitory quotients of lopinavir.
RATIONALE
Primary Objective: To determine if the proposed 14 day switch-over lopinavir / ritonavir regimen allows adequate lopinavir minimal concentrations and genotypic inhibitory quotients for three weeks after discontinuing tipranavir / ritonavir.
Secondary: i)
To determine if additional ritonavir (RTV) is effective for achieving adequate lopinavir concentrations during the two-week switchover period. ii) Target GIQs achieved during 2 week switch-over period STUDY DESIGN Design/Methodology: Prospective pharmacokinetic analysis using serial blood concentrations.
Secondary: i)
Patients included in this analysis will have been taking TPV/r 500/200mg twice daily at the time of enrolment for at least 14 days and are being switched to another PI for either toxicity or efficacy reasons. Subjects will be requested to use lopinavir/ritonavir plus additional ritonavir for two weeks following discontinuation of tipranavir. After two weeks, subjects may continue with either regular dose lopinavir/ritonavir or switch to a different PI-based regimen of their physician's choice. The lopinavir/ritonavir dose during the two-week period was selected based on preliminary data suggesting that adequate lopinavir dosages may be achieved in the presence of tipranavir when higher lopinavir and/or ritonavir dosages are used 2, 3 .
Secondary: i)
Upon discontinuation of TPV/r, patients will receive lopinavir/ritonavir (LPV/r) 400/100mg + 200mg ritonavir (RTV) twice daily for 7 days. Subsequently, patients will receive LPV/r 400/100mg + 100mg RTV twice daily for 7 days. After the 14 days of receipt of LPV/r, the patient will receive either LPV/r 400/100mg or be switched to another PI. Morning trough concentrations will be measured on Days 1, 3, 7, 14, and 21. Adherence will be measured using the Simplified Medication Adherence Questionnaire (SMAQ) in Appendix D. A copy of the patient's latest genotype will be submitted to perform GIQ calculations. The GIQ will be calculated by dividing the Cmin by the number of protease mutations related to resistance of lopinavir.
Blood sample collection and preparation procedures
Seven to eight-mL venous blood samples will be collected in heparinised tubes just before ingestion of the next dosage (12 hours after the previous dose). Plasma will be isolated by centrifugation (900 G for 10 min) on the same day and will be stored at -20 to -70C until analysis. Batched analysis will be performed therefore these results will not be used for PI dose adjustments during the study.
Bioanalysis
Concentrations of tipranavir, lopinavir and ritonavir in plasma will be measured by a sensitive and selective high-performance liquid chromatographic method coupled to tandem-mass spectrometry (LC-MS/MS), at The Ottawa Hospital. Sample pre-treatment consists of liquid-liquid extraction of 250 µL of plasma with Methyl-tert-butyl-ether after addition of Ammoniumhydroxide and Internal Standard (6,7-dimethyl-2,3-di-(2-pyridyl)quinoxaline 
SUBJECTS
Patients included in this analysis will be HIV-1 positive treatment-experienced individuals taking TPV/r for at least 14 days. There will be no control group in this pharmacokinetic analysis. All patients must sign informed consent to participate in this analysis. All patients must discontinue the use of all natural health products 2 weeks prior to day 1 of the study.
SUBJECTS
Exclusion criteria for this analysis will be those patients taking concomitant NNRTIs and other enzyme inducers of CYP3A4. Receipt of strong CYP3A4 inhibitors, which may result in significant interactions with study medications, will be excluded per investigator analysis.
Sample size justification:
To examine the pharmacokinetic variability among patients, 6 -10 patients will be required to carry out this analysis.
STUDYINTERVENTIONS

Usual Standard of Care:
Therapeutic drug monitoring is not the standard of care in HIV medicine. It is typically done as an adjunct in complicated cases or special populations. TPV/r is a relatively new agent to the Canadian market and switching to another PI from TPV/r with dose adjustments is done as per clinical judgment.
ETHICALISSUES

Recruitment and Consent:
Clinic physicians wishing to switch their patients off of TPV/r to an alternate PI will identify patients who are eligible for this analysis. Clinic physicians will refer their patients to the Primary Investigator or Co-Investigator to verbally discuss the analysis for consent to be obtained. An informed patient consent form will be given to the patient (Appendix A) to be signed. Only patients capable of offering consent will be included in the analysis. Once consent has been obtained, clinic physicians or an agent on their behalf will fill out a patient history form (Appendix B) and a Pharmacokinetic Test Request form (Appendix C). These forms will be submitted to the Primary Investigator.
Enrolment in Multiple Studies:
Many HIV patients are enrolled in multiple studies. Concurrent enrolment in other studies will not affect safety/welfare of patients for this analysis, as the other studies provide the standard of care for HIV+ patients.
RISK/BENEFITESTIMATES

Benefits:
The benefit to participation in this analysis will be to provide clinicians with a clearer understanding of TPV/r pharmacokinetics and its inductive properties on other PI's. These data may eventually be used to develop dosing algorithms or recommendations to achieve optimal drug concentrations when changing from tipranavir to other PI-based regimens.
Potential Harms:
Seven to eight millilitres of blood will be collected for each trough concentration evaluation. The risk associated with the 40ml of blood taken spread out over 21 days is negligible. At the body site where the blood is taken local reactions or pain might occur which usually disappear shortly after the sample has been taken.
PAYMENTS:
Subjects will not be reimbursed for their participation in this analysis.
PUBLICATION/DISSEMINATION OF RESULTS:
The results of this analysis will be compiled in abstract format and presented as a poster at a national/international meeting. Afterwards, a manuscript will be authored and will be submitted to journals for publication.
COLLECTION AND USE OF PERSONAL HEALTH INFORMATION:
All samples collected will be sent for analysis. Information recorded from laboratory reports will be recorded as de-identified patient information in the database. Only the primary investigator will have a list linking the de-identified data with the identities of the patients. This information will be kept on the primary investigator's password protected computer.
FUNDING AND CONTRACTS Budget:
Anticipated Costs: Blood samples 5 samples per patient x 10 patients = 50 samples $50/sample x 50 samples = $2500 Cost for presentation at a conference and publication $2500 + Total (CAD):
FUNDING AND CONTRACTS Budget:
$5000 Sources of Funds:
FUNDING AND CONTRACTS Budget:
Abbott (MFG of Kaletra) to be approached for funding
Liability:
The subject will be covered by the University Health Network (UHN) insurance policy for damages not covered by the provincial health plan as a direct result of study participation.
Introduction
You are being asked to participate in a research study to investigate the blood concentration effects of changing from tipranavir/ritonavir (Aptivus TM ) to another drug in the same class of anti-HIV drugs known as protease inhibitors. This consent form gives information about the research study. You will be asked to read this consent form and discuss anything that you do not understand with the study staff. Once you understand the study and if you decide to participate, you will be asked to sign this form and you will be given a copy for your records. You are free to choose not to participate or to withdraw from the study at any time, without affecting the care you receive at this institution, either now or in the future.
Introduction
Purpose of the study A growing number of prescribers are switching their patients from tipranavir/ritonavir (TPV/r) to other protease inhibitors (PI's) for a number of reasons: drug interactions, side effects, lack of response, etc. Unlike other PI's, TPV/r has the ability to increase the metabolism (otherwise known as breakdown) of itself and several other drugs, including other anti-HIV drugs. This can result in lower blood concentrations of anti-HIV drugs, possibly leading to an increased risk of drug resistance. What is currently unknown is how long these properties of TPV/r persist after the drug has been discontinued and how this effects blood concentrations of the new PI's.
Introduction
You are currently receiving an anti-HIV drug named TPV/r. Your prescriber wishes to change you to another drug in the PI class of medications. This study will investigate the effects on blood levels of the new PI after discontinuing TPV/r for two weeks.
Introduction
A total of 6 -10 subjects across Canada will be enrolled in the study, which will consist of 6 clinic visits. If you decide to participate, five (5) blood samples will be taken, for a total amount of approximately 35 -40 ml (approximately 3 tablespoons).
Study procedures Screening visit (Visit 1)
If you decide to participate in this study, you will be asked to come for a screening visit. During this visit, you will be examined by a physician. You will be asked to provide information about your medical and medication history. Your doctor will fill out a referral form to determine if you are eligible in the study.
Medication
If you are eligible for participation in the study and if you are taking two 250 mg capsules of Aptivus (tipranavir) with two 100mg capsules of Norvir (ritonavir) twice daily, you will be asked to replace these capsules with three 133.3/33.3mg Kaletra (lopinavir/ritonavir) capsules plus two 100mg Norvir (ritonavir) capsules twice daily for 7 days. On day 8, you will take three 133.3/33.3mg Kaletra (lopinavir/ritonavir) capsules plus 1 (ONE) 100mg Norvir (ritonavir) capsule twice daily for 7 days. On day 15, your doctor will decide to either keep you on Kaletra (lopinavir/ritonavir) or to put you on a different PI. Kaletra and ritonavir should be taken with food, either a full meal or a snack.
Medication
If you are currently using any natural health products (herbal medicines), you will be asked to stop using these products 2 weeks prior to the second study visit.
Study Day 1 (Visit 2)
You will be asked to come to the clinic early in the morning for a seven to eight-millilitre blood sample, 12 hours after your first dose of study medication the evening before. A small plastic needle (intravenous catheter) will be placed in a vein in one of your arms to draw blood. You may take your morning dose of Kaletra and ritonavir after your blood sample has been obtained.
Study Day 3 (Visit 3)
You will be asked to come to the clinic early in the morning for a seven to eight-millilitre blood sample, 12 hours after your dose of study medication the evening before. A small plastic needle (intravenous catheter) will be placed in a vein in one of your arms to draw blood. You may take your morning dose of Kaletra and ritonavir after your blood sample has been obtained.
Study Day 7 (Visit 4)
You will be asked to come to the clinic early in the morning for a seven to eight-millilitre blood sample, 12 hours after your dose of study medication the evening before. A small plastic needle (intravenous catheter) will be placed in a vein in one of your arms to draw blood. You may take your morning dose of Kaletra and ritonavir after your blood sample has been obtained.
Study Day 14 (Visit 5)
You will be asked to come to the clinic early in the morning for a seven to eight-millilitre blood sample, 12 hours after your dose of study medication the evening before. A small plastic needle (intravenous catheter) will be placed in a vein in one of your arms to draw blood. You may take your morning dose of Kaletra and ritonavir or of your new PI after your blood sample has been obtained.
Study Day 21 (Visit 6)
You will be asked to come to the clinic early in the morning for a seven to eight-millilitre blood sample, 12 hours after your dose of study medication the evening before. A small plastic needle (intravenous catheter) will be placed in a vein in one of your arms to draw blood. You may take your morning protease inhibitor dose after your blood sample has been obtained.
Use of Blood Samples
Blood samples will be used to measure the blood concentrations of tipranavir, lopinavir and ritonavir. The blood samples will be kept at Toronto General Hospital and shipped to the Ottawa Hospital for analysis. Blood collected for this study will be destroyed once the results are analysed and published. The blood samples will not be used for future studies, including any future genetic studies.
Use of Blood Samples
Benefits Participation in this study will not be of particular benefit to you. However, the results of this study may give valuable information on the effects on blood concentrations of changing from TPV/r to other PI's. People living with HIV/AIDS may benefit in the future from the knowledge obtained in this study. If you wish, the results of this study can be communicated to you when the results are known.
Risks and discomforts
You may experience some discomfort, pain or bruising on insertion of a needle for the intravenous catheter that will be used for the collection of the blood samples. In rare cases infection may occur.
Participation and withdrawal
Your participation in this study is voluntary. You may withdraw from this study at any time without it affecting the care you receive now or in the future at the Immunodeficiency Clinic at the Toronto General Hospital. The study doctor may choose to withdraw you from the study if you experience a serious reaction to any of the drugs you receive or if you fail to keep appointments. It is important to follow study directions.
Research-related injury
If you are injured as a result of your participation in this study, medical care will be provided to you. Financial compensation for such things as lost wages, disability, or discomfort due to an injury is not routinely available. You do not give up any legal rights by signing this form.
Reimbursement
There will be no financial incentives for your participation in this study.
Confidentiality
All information about participants collected throughout the study will be confidential. If you agree to participate in this study, information that does not identify you by name may be used for medical and scientific purposes including teaching and/or publication. You will be referred to only by a code number and not by name. No records bearing your name will leave the clinic. The ethics committee, which has approved the study at this institution, as well as regulatory authorities, will have access to your medical records, for the purpose only of ascertaining that this study has been performed properly, for a period of five (5) years. A copy of this consent form will be placed in your medical chart so that health care providers at this institution will know that you are participating in a study and what it consists of.
QUESTIONS AND CONTACT PERSONS

Questionsaboutthestudy
For answers to questions relating to this research study, or for information about study procedures you may contact: Alice Tseng at 203-767-3355.
Rightsasaresearchparticipant
If you have questions about your rights as a research participant and wish to discuss this with someone not associated with the study, you may contact the Research Ethics {{EMAIL+PHONE}}.
Research-related Injury
In case of a research-related injury, you should call Alice Tseng at 203-767-3355 during work hours and after hours or in an emergency, you should go to the emergency department and ask for the physician-on-call for the Infectious Disease Department.
Research-related Injury
If you believe that you have been injured as a result of participating in this study, you may contact Alice Tseng at 203-767-3355.
CONSENT FORM University Health Network Toronto General Hospital -Immunodeficiency Clinic
I am being asked to come to the Immunodeficiency Clinic, Toronto General Hospital for blood sampling. The maximum volume of blood taken will not exceed 40mL (equivalent to 8 teaspoons) and the maximal study period will be 21 days. If I agree, I shall come in for hour on the dates of (5 sampling dates) , to have blood samples taken. The amount of blood that will be taken for each sample is 7-8 mL (equivalent to 1.5 teaspoon). The samples will be analyzed for research purposes only. Any information with my name on it will be kept confidential. Procedure to obtain sample: About 8ml of blood should be colleted for drug level analysis using heparinized tubes (green top). Plasma should be isolated the same day by centrifugation at room temperature (10 minutes at 900 G), and stored at -20C (or lower) until shipment. ONLY PLASMA should be shipped for analysis, in a TIGHTLY CLOSED PLASTIC tube, safely packed and shipped at ambient temperature according to the regulations for the shipment of infectious material. Samples should be sent to:
CONSENT FORM University Health Network Toronto General Hospital -Immunodeficiency Clinic
The Ottawa Hospital, General Campus Laboratory N1, mailbox 221 Attn: Jeremy Zhang 501 Smyth Road Ottawa, ON K1H 8L6 Dr. Charles la Porte should be notified via email when the sample has been shipped mmeyer@example.com. The email should include the patient identification number and the date when the sample was obtained. 

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