8th Annual Retrovirus Conference
Pharmacology Review of
the 8th CROI
Therapeutic Drug Monitoring
Written for NATAP by Stephen C. Piscitelli, PharmD, formerly with the National Institutes of Health; now with Virco. Dr. Piscatelli will be conducting trials for Virco to evaluate the utility of TDM
The field of pharmacology, as it relates to HIV infection, has rapidly progressed in recent years. While drug interactions and characterizing the pharmacokinetics of new antiretrovirals remain important topics, pharmacologists are now examining complex issues such as intracellular drug levels, therapeutic drug monitoring, and proteins that are capable of transporting drugs in or out of infected cells. Abstracts on these topics and others were presented at the 8th Conference on Retroviruses and Opportunistic Infections in Chicago.
Therapeutic Drug Monitoring
Therapeutic drug monitoring (TDM) is the individualization of drug doses based on measuring plasma concentrations. Clinicians have used these principles for years to adjust doses of drugs including theophylline, aminoglycosides, digoxin, and anticonvulsants. There is growing evidence that TDM may be useful to ensure HIV-infected patients have adequate blood levels or that their plasma concentrations are not so high that toxicity develops. There are also a number of challenges in using TDM in the clinical setting to change dosing of HIV drugs to adjust drug blood levels and improve viral load response. Whether or not TDM can ultimately be used for this purpose is controversial. While TDM of antiretrovirals has been used commonly in Europe, it has not been well studied, or utilized in the US. However, this year at the 8th CROI, an entire poster session was devoted to the topic and TDM issues also were presented as part of oral presentations on pharmacology of HIV drugs.
It has become clear in recent years that relationships exist between antiretroviral plasma concentrations and antiviral efficacy. A number of papers further described these relationships. Dr. Courtney Fletcher presented the 8 week results of PACTG 382 in HIV-infected children.(1) In this study, children ages 3-16 received nelfinavir, efavirenz, and at least one NRTI. This was an AUC-controlled trial, meaning that patient's doses were adjusted at week 2 of the study in order to obtain an optimal area-under-the-curve (AUC). These investigators demonstrated that those patients with a plasma HIV-1 RNA level less than 400 copies/mL at week 8 had a higher week 2 AUC. In addition, a higher AUC of both nelfinavir and efavirenz had an independent effect on viral load when controlled for each other. This study demonstrates a number of important points. Children generally demonstrate wide variability in pharmacokinetics, and this study showed that a significant number of children required a dosage adjustment at week 2. In addition, it shows that TDM can be effective if performed early into therapy, before drug levels remain low for a significant period of time, leading to the development of resistance.
Two other studies demonstrated relationships with indinavir plasma levels and drug efficacy or toxicity. In the first study, patients receiving zidovudine/lamivudine/indinavir had pharmacokinetic sampling performed on week 4. (2) At week 24, the pharmacokinetic data were evaluated for significant breakpoints with virologic failure or nephrotoxicity. The breakpoint values for virologic failure were an indinavir AUC 14 mg/L*h, Cmax of 7000 ng/mL, and a trough of 100 ng/mL. This trough value is consistent with other studies in naïve patients suggesting that the indinavir trough of around 100-110 ng/ml correlates with antiviral activity. Nephrotoxicty was associated with AUC values greater than 30000 ng/mL*h and a Cmax of 10000 ng/mL. While these data are important, indinavir is now commonly being used with ritonavir to increase its blood concentrations and TDM information is lacking with this combination. The second study examined a number of IDV/RTV combination regimens in 197 patients. (3) Side effects of indinavir were correlated with the indinavir plasma levels (not ritonavir) --Cmin, Cmax & IDV dosage between 400 to 800--and these investigators suggested that lowering of the indinavir dose could improve tolerability of these regimens. They also proposed an algorithm for dosage reduction. In a small subset of patients, indinavir doses were reduced and virologic efficacy was observed or conserved in 76% on a shoert term evaluation. Relationships between indinavir levels and efficacy or toxicity have received the greatest amount of research. Most of this research has been performed with indinavir alone and in naïve patients. These data, although retrospective, provide some insight into how to interpret indinavir levels when used with ritonavir. Additional study and identification of levels that predict toxicity are warranted.
Integrating Phenotypic Resistance &
IVP: In vivo potency index
VIQ: Virtual inhibitory quotient
A major limitation of using only the drug level to guide therapy (other than it doesn't describe long-term adherence) is that the optimal level may vary from patient to patient. Indeed, the highly resistant patient will require higher drug levels than a patient naïve to therapy. Thus, successful attempts at TDM should also take into account a measure of the virus's sensitivity along with the drug level. The use of the IC50 from phenotyping could theoretically provide an optimal target concentration to shoot for in the highly resistant patient. Two posters reported the integration of drug concentration data with the protein binding-corrected IC50 value. The first study examined 8 antiretroviral-naive patients receiving zidovudine/lamivudine/indinavir. (4) Investigators calculated something they called the "in vivo potency index" (IVP). This value was determined by dividing the drug level by the virus's susceptibility. The authors calculated the ratio of free indinavir (no bound to plasma proteins) or intracellular triphosphate concentrations of the NRTIs to the IC90 of the virus at baseline. When the ratios were summed for the three drugs, patients who had a summed ratio greater than the median had a faster time to achieving undetectable plasma HIV-1 RNA levels. Four patients with a higher median ratio achieved undetectable viral load by week 24 vs only 2 of 4 patients with a ratio summed ratio less than the median. The second study was presented by investigators from Abbott Laboratories. (5) They evaluated patients switched from indinavir alone to indinavir /ritonavir (400 mg/400 mg twice-daily). These investigators calculated a "virtual inhibitory quotient" (VIQ) by dividing the Cmin of indinavir by the virtual phenotype from Virco x the serum adjusted EC50 for wild type HIV. This is similar to the IVP except that it corrects for protein binding effects instead of actually measuring free drug. Regardless of the terms, they showed that response rates at weeks 3 and 24 weeks were 18 of 20 and 11 of 17, respectively, for patients with a VIQ greater than 2. By contrast, these response rates were 1 of 8 and 0 of 8, respectively, for patients with a VIQ less than 2.
These two studies were performed retrospectively and in a small number of patients. However, they demonstrate an interesting concept that integration of the phenotype and the drug level may be used to optimize and guide therapy. Much research will still be required to validate the Cmin/IC50 ratio and breakpoints for this ratio will need to be identified. Also, there needs to be consensus on how to best correct for protein binding. With highly bound drugs like lopinavir and saquinavir, it is very difficult to measure free drug levels. A number of correction factors can be used but there remains much disagreement on which is best. Another question is whether the trough level or the AUC is the most important. Still, this appears to be exciting research and may be a tool for monitoring patients in the future.
These studies and others demonstrate that plasma drug levels are associated with antiretroviral effects. The question of whether TDM can be effective when used in the clinical setting requires additional study. PharmAdapt is a study that prospectively evaluates TDM in patients failing therapy for at least 6 months. (6) Patients were randomized to therapy that was modified based on genotypic testing (131 patients), or to therapy that was modified based both on genotypic testing and on trough concentrations of protease inhibitors (125 patients). Patients had their drug levels measured at week 4 and doses were adjusted at week 8. Optimal trough concentrations were defined as levels higher than the protein-adjusted IC50 for wild-type HIV strains. At week 12, there was no difference between the two arms in the percentage of patients with an undetectable viral load (50% vs 43%). Following the presentation, a lively question and answer session ensued that raised a number of important points regarding prospective TDM studies. Turnaround time is likely a major issue in TDM studies as shown above in PACTG 382 where early dose adjustment was shown to be of benefit. In this study, patients did not have their doses adjusted until 8 weeks into therapy. This seems like a long enough period of time that if a patient had low blood levels, they would become resistant to their regimen. In addition, using a wild type IC50 as the target concentration is probably not appropriate in a trial of patients who had failed previous therapies. A number of issues in the study design may have led to the similar results in the two groups.
Which Drugs are Good Candidates for TDM
& Additional Challenges to Using TDM Effectively
Ongoing TDM studies may demonstrate how and when drug levels can be useful to the practicing clinician. A number of limitations / challenges need to be considered. The first involves which drugs should be measured. The greatest amount of data is with protease inhibitors, but NNRTIs have recently been studied and their drug concentrations do appear to correlate with effects. For example, increased efavirenz levels have recently been shown to correlate with CNS adverse effects. The NRTIs are probably not good candidates for TDM since the active triphosphate moieties of these drugs are intracellular and plasma levels do not give an accurate indication of concentrations inside the cell. NRTI levels may be useful from a qualitative standpoint as an adherence check to determine whether or not a patient was taking his/her drugs. In terms of sampling, the trough is considered the most important time point for blood collection. This suggests there is a "critical value" that the drug level needs to be above to inhibit replication. Unfortunately, there are no studies that directly compare the AUC vs the trough for TDM. However, the lesson from BID studies of indinavir showed that even though the AUCs were similar, the BID group had a lower trough and a poorer response, suggesting the trough is most important.
Other problems with TDM involve issues of a single drug measurement to make decisions. A single trough level does not provide information on long term adherence. A patient could not have taken their drugs correctly for weeks but may do so for 2-3 days immediately before their clinic appointment if they know a TDM sample will be taken. The results would show adequate blood levels although the patient may be failing therapy due to nonadherence. Another important issue is intra-subject variability, meaning that diet or other factors could lead to different drug levels on different days in the same patient. If changes in diet, routine or other factors are changing, it may be wise to get at least two levels before making a dosage change. Turnaround time is also significant for correctly performing TDM. Labs running these drug levels should be able to give back results in 2 weeks or less so that changes can be made quickly, and the patient does not have a prolonged period of suboptimal levels. Finally, TDM has generally been used to increase dosages of drugs but as some abstracts at this meeting show, it may also be used to lower drug doses in the face of toxicity. Many clinicians are very uncomfortable lowering doses, especially in resistant patients. However, if the phenotyping is also available, this may provide informative data on whether the dose can be decreased and still keep the level well above the IC50.
Drug Transport Proteins: What are they and what do they do?
A plenary session on drug transporters was presented on Monday afternoon. The term "drug transporter" refers to a group of proteins that affect how drugs get into, and out of cells. Some drug transporters pump HIV drugs out of cells, or inhibit the absorption of HIV drugs in the gastrointestinal tract, thereby decreasing the bioavailability of antiretrovirals. The session was very interesting and the presenters provided a number of thought-provoking studies and concepts. Unfortunately, this field is still relatively in its infancy and most of the work has only been performed in the laboratory. But it does raise some important questions that may help explain the wide variability in response between patients. The first speaker was Richard Kim from Vanderbilt University who has done a great deal of research on P-glycoprotein, a cellular efflux pump encoded by the MDR1 gene that appears to be responsible for low bioavailability of some drugs, including protease inhibitors. P-glycoprotein was initially described in oncology where it was responsible for pumping chemotherapeutic drugs out of the cancer cell, decreasing the effectiveness of chemotherapy. Dr, Kim presented several studies that examined the possible role that P-gp plays in HIV infection. P-gp can be found in a variety of sites in the body, including the brush borders cells of the intestine where it can pump drug back into the gastrointestinal tract, decreasing absorption. In the liver, it may pump drug into bile and is also present in the blood-brain barrier where it can limit the uptake of drugs into the cerebrospinal fluid. This may be especially important in patients with central nervous system manifestations of disease. A number of protease inhibitors are both substrates and inhibitors of P-gp, meaning that they can be affected by this protein but can also inhibit it as well. On the other hand, rifampin and St. John's wort are inducers of P-gp, therapy increasing the efficiency of the transporter. Both potency and selectivity are important factors in determining the effects of P-gp inhibitors in vivo. Studies demonstrate that the protease inhibitors probably do not affect P-gp to the extent that effects are seen clinically. However, a number of other inhibitors are being evaluated for their ability to inhibit P-gp. The proposed benefits of P-gp inhibition include increasing drug bioavailability at lower cost and increasing drug concentrations in sanctuary sites like the CSF, testes, or bone marrow. These effects may ultimately lead to a better outcome. But as you will read below, inhibition of P-gp may also have detrimental effects.
Another transport protein was described by Dr. Arnold Fridland from Gilead Sciences. He presented a number of studies on a drug transporter called multidrug resistance protein (MRP) 4. The expression of this protein in laboratory studies is associated with decreased intracellular phosphorylation of nucleoside reverse transcriptase inhibitors (NRTIs) in vitro. As discussed above, all NRTIs such as zidovudine and stavudine are pro-drugs that must be activated intracellulary through phosphoylation to their active forms. It is currently unknown if this protein is clinically relevant or whether inhibitors of MRP4 would be useful in patients. A great deal of research in this area in continuing.
David Back from the University of Liverpool, described the potential clinical relevance of drug transporters. He described examples where drug transporters have been shown to alter drug disposition. Many of these examples are from the oncology literature, suggesting that HIV research may learn some lessons from the treatment of cancer patients. In addition to intracellular uptake of protease inhibitors, both genetics and ethnicity appear to play a role in drug transporter expression. For example, P-gp exposure was lower in African-Americans compared to Caucasians. However, MRP expression was similar between groups of HIV-infected patients. Back noted that the role of P-gp inhibition is often complicated by pharmacokinetic effects, since many inhibitors of P-gp are also inhibitors of CYP3A4, the isozyme of the cytochrome P450 system responsible for the metabolism of most protease inhibitors. If compounds can be developed that only alter P-gp and not drug metabolism, it would be much easier to identify the specific effects of P-gp inhibition.
As with most issues in science, it is unclear whether P-gp inhibition is beneficial. In fact, inhibiting this protein may be detrimental to patients. Both Back and Dr. Charles Flexner from Johns Hopkins discussed recent studies which show that P-gp expression has a profound impact on HIV replication. In two separate studies, cells expressing P-gp produce at least 40- to 70-fold less HIV. This effect appears to be primarily due to inhibition of HIV entry and/or fusion. These studies set up an interesting controversy on whether P-gp should be altered by inhibitors or inducers. Altering P-gp may result in higher drug concentrations but the fact that P-gp expression may make the cell less susceptible to HIV infection may offset the low concentrations. Dr. Flexner noted that these contrasting effects may be responsible for the prolonged CD4+ cell count benefit observed in some patients despite apparent treatment failure in terms of viral load, They may also contribute to the apparent resistance to HIV acquisition seen in some individuals. The discovery and identification of drug transporters may open new avenues to optimize therapy in HIV infected patients. The presence or absence (or somewhere in between) of these proteins may also help explain why some patients respond very well to therapy while others fail despite no apparent reason.
Opportunistic Infections, New Antiretrovirals, and Alternative Medicines
Three separate drug interaction studies with rifabutin or rifampin were presented. Despite the lower prevalence of opportunistic infections, there are still questions remaining on how to use these agents in combination with antiretrovirals. Data reported last year showed that the dose of indinavir should be increased to 1000 mg q8h when co-administered with rifabutin. In a follow-up to those data, ACTG 365 examined the pharmacokinetics of a rifabutin (150 mg once-daily) when given with simultaneous or staggered indinavir at an increased indinavir dose of 1000 mg every 8 hours in healthy volunteers. (7) Compared to rifabutin given alone at the standard dose of 300 mg once-daily, the AUCs of rifabutin and its 25-desacetyl metabolite were 60%and 125% higher, despite the reduced dose of rifabutin. Separation of the rifabutin administration did not affect its pharmacokinetics compared with simultaneous administration. Adverse effects were not reported but it is likely that patients may experience some rifabutin side effects (uveitis, granulocytopenia) even with a reduced dose. It is possible that the rifabutin dose could be further reduced to 150 mg every other day with an indinavir dose of 1000 mg every 8 hours, and that patients should be monitored for side effects with this regimen.
A retrospective study evaluated rifabutin levels in HIV-infected patients with tuberculosis before and after administration with nelfinavir. (8) Rifabutin was administered as 300 mg twice weekly and concentrations were drawn 2 hours after dosing. Rifabutin levels were not significantly affected after 2 weeks of nelfinavir-based HAART therapy, and nelfinavir concentrations were in the expected range. This study has some limitations in that full pharmacokinetic curves of rifabutin were not collected and also that nelfinavir levels were not collected without concomitant rifabutin. However, this study probably represents a "real life" situation and the data are still meaningful. Based on these data, rifabutin and nelfinavir can likely be used concomitantly with a twice-weekly dose of rifabutin.
A second study in HIV-infected patients with tuberculosis evaluated the effect of rifampin on the pharmacokinetics of efavirenz. (9) The study design included three arms and included 600 mg and 800 mg / day arms with efavirenz. The results demonstrated that rifampin decreased the efavirenz Cmin by approximately 24%. However, there was wide variability, with this interaction ranging from a 7% to 64% change. When efavirenz was given at an increased dose of 800 mg once-daily with rifampin, all patients maintained adequate drug concentrations. The conclusions of this study suggested that the efavirenz dose be increased to 800 mg qd with rifampin. These types of interactions make this reviewer quite nervous since there is such wide variability in the interaction. Any dosage increase should be carefully monitored for efavirenz-related adverse effects and may even warrant the measurement of an efavirenz level to ensure that excessive toxicity does not develop.
BMS-232632 (BMS) is an investigational protease inhibitor that may be useful in resistant strains. To examine the effect of "boosting" with ritonavir, BMS was studied at two doses (200 mg and 400 mg qd) and in combination with either 100 mg or 200 mg BID of ritonavir. (10) As expected with other protease inhibitors, the AUC of BMS was markedly increased by ritonavir. With the lower dose of BMS, increasing the ritonavir from 100 to 200 mg Bid led to an increase in the BMS AUC from 2.3-fold to 5.2-fold. With the higher dose of BMS, the AUC increased 2.3-fold with 100 mg of ritonavir but increasing the ritonavir to 200 mg did not increase the BMS AUC. This study is important since BMS will likely be used with ritonavir if it received FDA approval. It is interesting in that increasing the ritonavir dose only improved the levels at the lower dose of BMS. This may be useful for the design of dosage regimens, but the combination still needs to be studied with NNRTIs since the ritonavir dose is important for interactions a shown below.
The appealing aspects of the new BMS protease inhibitor is that it's dosed once daily, and in preliminary studies it has not led to increased triglycerides & cholesterol, like other protease inhibitors do. The addition of ritonavir would have to be evaluated in light of these characteristics. Bristol Myers Squibb is evaluating the effectiveness of RTV boosting in overcoming PI resistance in PI experienced patients
Amprenavir/ritonavir + NNRTI (Data suggests 200 mg RTV should be used)
The pharmacokinetics of amprenavir 450 mg and ritonavir 200 mg twice-daily were compared in 12 patients receiving a concomitant NNRTI and 5 patients with no NNRTIs (11). When efavirenz or nevirapine was added to this combination, the amprenavir Cmin was not significantly reduced and concentrations were at least 3-fold above those observed with amprenavir alone at standard doses. However, in 5 patients receiving an NNRTI, the dose was changed to amprenavir/ritonavir 600 mg/100 mg twice-daily. Amprenavir levels collected from 21 to 51 days after the switch showed that the amprenavir Cmin was decreased by approximately 80%. Although the median concentration was still higher than for amprenavir alone, this represents a very significant decrease. This decrease may be clinically significant in resistant patients who require higher blood levels for optimum effect. These data are consistent with a number of other studies combining NNRTIs with ritonavir-boosted protease inhibitors. In these studies, 100 mg BID of ritonavir was not enough to prevent decreases in the protease inhibitor levels. When the ritonavir doses of 200 mg BID are used, the NNRTI does not affect the protease inhibitor levels. These data suggest there is a critical dose of ritonavir that should be used when efavirenz or nevirapine are used with boosted protease inhibitors.
Complementary and alternative medicines are widely used in HIV-infected patients despite a general lack of knowledge on their adverse effects and drug interactions. Increased attention has recently been paid to these therapies and two posters at the 8th CROI evaluated herb-drug interactions.
The effect of garlic supplements on the disposition of saquinavir was studied in 10 healthy volunteers. (12) Subjects had plasma samples collected for saquinavir levels on saquinavir alone and then after 3 weeks of a twice daily garlic supplement. Saquinavir levels were again studied alone after a 3-week washout period. Overall, there was a decrease in the saquinavir AUC and Cmin of approximately 50%. The mechanism appeared to be a prolonged induction of metabolism since most patients did not return back to their baseline levels after the washout. Although these data are interesting, this study introduces more questions than it answers. For example, would a decrease be seen when saquinavir is given with ritonavir, as commonly used? What is the actual mechanism, and does dietary garlic affect antiretroviral drug levels? Ongoing studies with other herbs may help to answer some of these issues. Until these questions are better defined, patients should use caution when using garlic supplements along with single protease inhibitors. This interaction may not be as critical in patients taking NNRTIs since their concentrations are very high to begin with and because their metabolism is more complex - nevirapine undergoes autoinduction and efavirenz is a mixed inducer/inhibitor of the cytochrome P450 system.
Marijuana is often used in HIV-infected for a variety of reasons but it is currently unknown if its use affects the pharmacokinetics of protease inhibitors. A study examined the effects of marijuana on the pharmacokinetics of indinavir and nelfinavir in HIV-infected patients. (13) Subjects were randomized to marijuana 4% THC cigarettes, dronabinol, or placebo, (all given three times daily) and plasma samples were collected at baseline and after 14 days. The groups receiving the cigarettes had nonsignificant decreases in indinavir and nelfinavir Cmin of 34% and 12%, respectively. The only statistically significant change was a modest 14% decrease in the indinavir Cmax. The other two treatment groups did not significantly alter any of the indinavir or nelfinavir pharmacokinetic parameters. The pharmacokinetic data in this study was widely variable and there were no significant differences in the trough values, which are likely most important for efficacy. Based on these data, it is unlikely that marijuana cigarettes will markedly affect antiretroviral pharmacokinetics. In addition, there were no changes observed in CD4 count or viral load although changes in these parameters may take longer to be seen.
Abacavir: Once Daily Dosing of NRTIs
Once daily dosing of abacavir has been previously considered based on a long intracellular half-life of the active intracellular component, carbovir triphosphate (CTP). However, a reliable assay method for CTP had not been available until recent. A poster at the 8th CROI examined intracellular CTP levels in six patients receiving 600 mg of abacavir once daily. As expected, CVTP levels were high and sustained with a half-life of in excess of 12 hours. While these data warrant further study using abacavir in a once daily regimen, there may be concerns over the tolerability of such a regimen. The safety of once daily dosing needs to be examined in a large number of patients to discern if the incidence of side effects is increased due to the resulting higher peak levels. In addition, the incidence of hypersensitivity with such a regimen requires evaluation.
3TC Once Daily
Another candidate for once daily dosing is 3TC, also due to a long intracellular half-life of its active triphosphate. The pharmacokinetic results have previously been reported but 24 week results from a clinical trial suggest that once daily 3TC is well tolerated and effective as part of a HAART regimen. The COLA4005 study enrolled 78 patients with viral loads < 50 copies/ml. Subjects also receiving d4T and either indinavir or nelfinavir were randomized to receive standard dosing of 3TC (150 mg BID) or 300 mg once daily. At 24 weeks, virologic results were nearly identical with 82% of patients < 50 copies in the QD group and 81% in the BID group. 3TC was well tolerated in both groups as expected since this agent is one of the antiretrovirals with the best safety profile.
These studies represent the continued progression of longer dosing intervals for antiretrovirals, especially NRTIs. Zidovudine has been reduced to twice daily and didanosine has been reduced to once daily. A once daily formulation of d4T is also being evaluated by Bristol Myers Squibb. Long term safety of these regimens remains an important avenue for study to determine if side effects such as lactic acidosis, steatosis, and other NRTI-related events are increased.
There is much excitement in HIV pharmacology at the present time. Specific topics that will receive much attention in the near future include therapeutic drug monitoring, identification of intracellular mechanisms that affect drug disposition, and understanding complex drug interactions. Just within the past year, a great deal of information has become available on these issues and this trend is expected to continue.
1. Fletcher CV, Fenton T, Powell C, et al.
Pharmacologic characteristics of efavirenz and nelfinavir associated with virologic
response in HIV-infected children. Program and abstracts of the 8th Conference
on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois.
2. Burger D, Felderhof M, Phanupak P, et al. Both short term and virological efficacy and drugs associated nephrotoxciity are related to indinavir pharmacokinetics in HIV-1 infected Thai patients. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 730.
3. Lamotte C, Peytavin G, Perre P, et al. Increasing adverse events with indinavir dosages and plasma concentrations in four different ritonavir-IDV containing regimens in HIV-infected patients. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 738.
4. Fletcher CV, Anderson PL, Kakuda TN, et al. A novel approach to integrate pharmacologic and virologic characteristics: an in vivo potency index for antiretroviral agents. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 732.
5. Kempf D, Hsu A, Jiang P, et al. Response to ritonavir intensification in indinavir recipients is highly correlated with inhibitory quotient. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 523.
6. Clevebergh P, Durant J, Garraffo R, et al. Usefulness of protease inhibitor therapeutic drug monitoring? PharmAdapt: a prospective multicentric randomized controlled trail: 12 weeks results. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 260B.
7. Palma E, Stambaugh J, Akinlobi O, et al. The use of rifabutin with nelfinavir-containing HAART in 48 HIV-infected TB patients. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 741.
8. Hamzeh F, Benson C, Gerber J, et al. Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 259.
9. Lopez-Cortes LF, Ruiz R, Viciana P, et al. Pharmacokinetic interactions between rifampin and efavirenz in patients with tuberculosis and HIV infection. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 32.
10. O'Mara E, Mummaneni V, Bifano M, et al. Steady-state pharmacokinetic interaction study between BMS-232632 and ritonavir in healthy subjects. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 740.
11. Degan O, Kurowski M, Van Lunzen J, et al. Amprenavir and ritonavir: intraindividual comparison of different doses and influence of concomitant NNRTI on steady-state pharmacokinetics in HIV-infected patients. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 739.
12. Piscitelli SC, Burstein AH, Welden N, et al. Garlic supplements decrease saquinavir plasma concentrations. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 743.
13. Kosel B, Aweeka F, Benowitz N, et al. The pharmacokinetics effects of marijuana on nelfinavir and indinavir. Program and abstracts of the 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001, Chicago, Illinois. Abstract 745.