icon- folder.gif   Conference Reports for NATAP  
 
  15th International HIV Drug Resistance Workshop
June 13- 17, 2006
Sitges, Spain
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Everything you wanted to know (almost) about resistance to darunavir; discussion of cross-resistance and comparisons with tipranavir
 
 
  Written By
Mark Mascolini
 
Darunavir, tagged TMC114 as it sailed through clinical trials, got its FDA seal of approval shortly after the Resistance Workshop, where researchers offered a workshop-leading six studies on the Tibotec protease inhibitor (PI). That left a little room to discuss another recently licensed PI, tipranavir, and one still in the pipeline, brecanavir. But while brecanavir perks along, clinicians and people with PI failures on their charts want to know if darunavir or tipranavir will work better for them. This article will attempt at least the first steps toward an answer.
 
Response cutoffs proposed for darunavir
Analysis of the POWER 1, 2, and 3 studies of darunavir in triple-class-experienced people suggested fold-change in susceptibility cutoffsÑand a mutation listÑto predict salvage response to darunavir/ritonavir at 600/100 mg twice daily [1]. These trials enrolled people who had taken two or more nucleosides (NRTIs), one or more nonnucleosides (NNRTIs), and one or more PIs. A PI regimen was failing in all study participants when they signed up for the studies.
 
The response breakdown detailed by Tibotec's Marie-Pierre de Bethune focused on 377 people who took darunavir/ritonavir with NRTIs and possibly enfuvirtide, but not with an NNRTI, for 24 weeks or who dropped out of the study earlier.
 
Among 265 people with a baseline (pre-darunavir) viral fold change in susceptibility to darunavir at or below 10 (compared with nonmutant virus), 50% had fewer than 50 copies/mL at week 24 and the viral load drop averaged 2.08 log copies/mL (see figure below). Among 65 people with a baseline fold between 10 and 40, 25% had a sub-50-copy load at week 24 and the viral load decline averaged 1.08 log copies/mL. For the 46 people with a baseline fold change above 40, only 13% reached a load under 50 copies/mL at week 24 and the viral load drop averaged 0.76 log copies/mL.
 

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On the basis of these findings, Tibotec proposed a lower response cutoff of 10 and an upper cutoff of 40. In other words, they predict a good 24-week virologic response to darunavir/ritonavir in PI-experienced people who start darunavir/ritonavir with a fold-change in susceptibility to darunavir at or under 10, and they see little chance of a good response in people starting darunavir/ritonavir with a fold change in susceptibility above 40. Because these predictors rest on results from trials that enrolled heavily experienced people, they may apply only to similar patient populations.
 
Tibotec researchers also picked out 11 mutations that foretold a poor response to darunavir/ritonavir in people whose virus bore three or more of those mutationsÑV11I, V32I, L33F, I47V, I50V, I54L, I54M, G73S, L76V, I84V, and L89V.
 
Among 94 people who started the trial with only one of those mutations (plus other PI mutations not on the list), 50% notched a viral load below 50 copies/mL by study week 24. Among 113 people with two of those mutations (plus others), 42% had a sub-50-copy response at week 24. And among people with three of these darunavir-damaging mutations, only 22% managed a week 24 viral load under 50 copies/mL. Forty-one people had four or more of these mutations, and only four of them hit the sub-50 target. Another analysis showed that this 11-mutation set predicted response better than the full set of International AIDS Society (IAS)-USA mutations.
 
Working with Bart Winters and Virco colleagues, Tibotec proposed clinical cutoffs for darunavir/ritonavir [2]. This analysis also relied on triple-class-experienced people enrolled in POWER 1, 2, or 3, but here the target was an 8-week 1-log (10-fold) drop in viral load. Because confidence intervals for the lower cutoff, middle range, and upper cutoff overlapped so much, it's hard to guess how useful these cutoffs will prove.
 
Winters started with 402 people who took 600/100 mg of darunavir/ritonavir twice daily in the POWER studies, using 319 of them to define the cutoffs and 83 to validate the cutoffs. The goal was to find baseline fold-change values in susceptibility to darunavir that correlated with a 20% loss of response (the lower cutoff) and with an 80% loss of response (the upper cutoff). The Virco/Tibotec team defined response as a 1-log fall in viral load after 8 weeks of treatment. A linear regression model weighed several baseline variablesÑviral load, phenotypic sensitivity score of the background regimen, fold change in susceptibility to darunavir, and use of enfuvirtide for the first time.
 
The analysis showed that 91% of 170 people with a baseline fold change below 3.4 had a 1-log 8-week response to darunavir, compared with 36% of 14 who had a fold change above 96.9. Among the remaining 218 people with a baseline fold change between 3.4 and 96.9, about 60% had a 1-log viral load drop by week 8.
 
In other words 5 of 14 people with a baseline fold change above the altitudinous 96.9 upper cutoff still had an 8-week response by this definition, while 15 of 170 people under the 3.4-fold lower cutoff didn't respond. Eight-week viral load drops averaged just over 2 log copies/mL among people under the lower cutoff, about 1.5 log in people between the upper and lower cutoffs, and about 1 log in people above the upper cutoff.
 
Cross-resistance among darunavir, tipranavir, and other PIs
Some workshop attendees remained unswayed by the 96.9-fold upper cutoff for darunavir proposed by Virco and Tibotec [2]. They believe such a lofty benchmark lacks clinical value because it would mean just about everyone with some PI-resistant virus has a fair shot at responding to darunavir/ritonavir. Yet the POWER trialsÑand Tibotec's own analysis at the workshop [1]Ñclearly show there are limits to how many people with highly resistant virus darunavir can rescue.
 
But for the sake of argument (and there are sure to be some), if one accepts Virco's lower (3.4) and upper (96.9) cutoffs for darunavir, and if one also accepts upper and lower cutoffs for all other PIs based on the VircoTYPE assay, one can get some handle on cross-resistance among all boosted PIs plus unboosted atazanavir or nelfinavir. Virco's Gaston Picchio offered just such an audit based on 56,018 viral isolates shipped to Virco for resistance testing in 2004 and 2005 [3]. Picchio also vetted the list of darunavir-bruising mutations that Tibotec proposed at the workshop [1].
 
This exhaustive inquest rests on the upper and lower fold-change cutoffs listed in Table 1; for unboosted atazanavir the study used only a biological cutoff of 2.4.
 

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With only one cutoff for atazanavir, Picchio divided susceptibility to this PI into two categories:
 
- Susceptible: Fold change below biologic cutoff
- Resistant: Fold change above biologic cutoff
 
Susceptibility to all the other PIs could be rated three ways:
 
- Maximal response: Fold change at or below the lower cutoff
- Reduced response: Fold change between the lower and upper cutoffs
- Minimal response: Fold change at or above the upper cutoff
 
First Picchio analyzed how the 11 proposed darunavir-specific mutations would affect response to this PI in the submitted viral samples. Notably, 51,939 of the viral isolates analyzed had none of the darunavir-hobbling mutations.
 
Among 2123 samples with only one such mutation, darunavir/ritonavir would have maximal response against about 85% and reduced response against the other 15%. For the 1090 samples with two key mutations, darunavir/ritonavir would have maximal response against 40% and reduced response against 60%. In the 479 samples with three critical mutations, darunavir/ritonavir would exert maximal response against about 10% and reduced response against the rest. Of the 230 samples with four mutations, darunavir/ritonavir would have a reduced response against nearly all viruses and a minimal response against a handful. And for the 157 isolates with five or more of these mutations, darunavir/ritonavir would exert a reduced response against about two thirds and a minimal response against one third.
 
Looking at all 56,018 viral isolates, the Virco team figured how many would have maximal, reduced, or minimal response to each of the eight PIs (Table 2). Darunavir/ritonavir won this rating game in the maximal response and minimal response contests, while placing second in the reduced response comparison. Tipranavir/ritonavir placed second in only the minimal response ranking, while saquinavir/ritonavir finished first in the reduced response bracket and second in the maximal response bracket.
 

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Picchio also used this database and the cutoffs noted in Table 1 to figure how many isolates highly resistant to the eight protease inhibitors would have a maximal response to darunavir, tipranavir, or lopinavir (Table 3). Darunavir came out on top of every comparison except for virus resistant to amprenavir/ritonavir, against which tipranavir held a slight edge; but neither darunavir nor tipranavir had much muscle against amprenavir-resistant virus.
 

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This analysis also yielded the chilling forecast that only 28% of isolates highly resistant to tipranavir will have a maximal response to darunavir. On the other hand, 42% of isolates highly resistant to lopinavir still managed a maximal response to darunavir in this analysis, and 29% of those isolates would have a maximal response to tipranavir. Other analyses suggest less cross-resistance between tipranavir and darunavir (see "Choosing between darunavir and tipranavir" below).
 
Abbott researchers added evidence that may enlighten clinicians pondering a switch from failing lopinavir to either darunavir or tipranavir [4]. Martin King and Abbott colleagues started with 311 PI-experienced people enrolled in clinical trials of lopinavir/ritonavir. Seventy-three of those study participants had an inadequate response to the new lopinavir regimen and available genotypic and phenotypic testing results. King determined that virus from 24 of these 73 became more resistant to lopinavir during treatment by picking up new primary or secondary mutations in protease. Of those 24 people, 18 had archived samples that allowed Monogram Biosciences (formerly ViroLogic) to test the samples for susceptibility to darunavir and tipranavir before and after the lopinavir rescue regimen.
 
Median fold change in susceptibility to darunavir measured 1.4 before lopinavir and 2.7 after lopinavir failure. For tipranavir the median fold change before lopinavir was 1.9 and after lopinavir 1.8. This study was small enough to let King show exactly how many people became more resistant to darunavir or tipranavir during the failing course of lopinavir (Table 4). This person-by-person analysis confirms that viral susceptibility to tipranavir in these 18 people changed little as HIV became more resistant to lopinavir, but the virus became somewhat more resistant to darunavir.
 

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King pointed out that 6 of 9 people whose virus had more than a 2-fold drop in susceptibility to darunavir during failing lopinavir therapy did not have one of the 11 darunavir-specific mutations that Tibotec proposed at the workshop (see "Response cutoffs proposed for darunavir" [1] above). That finding, King suggested, underlines the potential value of phenotyping when planning a darunavir-based salvage regimen.
 
Background regimen impact on response to darunavir
Viral susceptibility to darunavir is hardly the only factor affecting response to a rescue regimen based on this PI. As veteran HIV clinicians well know, any salvage drugÑno matter how potentÑwill eventually give ground to the virus if not backed by other drugs that retain some activity against HIV. Another Tibotec-Virco collaboration highlighted this point in an analysis of 458 people who took 600/100 mg of darunavir/ritonavir twice daily in POWER 1, 2, or 3 [5].
 
To gauge the impact of background regimen drugs, Tibotec's Tony Vangeneugden and colleagues devised a phenotypic sensitivity score (PSS) for all other drugs taken with darunavir (see note 6 to learn how).
 
After 24 weeks of treatment, 42% of people taking darunavir in POWER 1, 2, or 3 reached a viral load below 50 copies/mL, and after 48 weeks, 48% of those in POWER 1 and 2 had a viral load below that mark. (Too few people in POWER 3 had reached week 48 to allow their inclusion in the latter analysis.)
 
Sub-50-copy responses at week 24 tracked closely with PSS of the background regimen. Among people with a PSS at or below 0.5, only 34% had a week 24 viral load under 50 copies/mL, compared with 49% with a PSS of 0.5 to 1.5 and 52% with a PSS above 1.5. Average week 24 viral load drops also correlated with background regimen PSS (Table 5).
 

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A multivariate analysis considering baseline viral load, average duration of HIV infection, median fold change in susceptibility to darunavir, median CD4 count, having three or more primary PI mutations, baseline PSS, time, and the interaction between time and PSS confirmed PSS as an independent predictor of week 24 viral load decline (Table 5).
 
The multivariate analysis also produced the interesting finding that the number of primary PI mutations before beginning darunavir did not independently predict 24-week response. But this study did not weigh the potential impact of proposed darunavir-specific mutations [1].
 
Several other factors correlated with virologic response at week 24, but none as strongly as background regimen PSS (P <0.0001): baseline viral load, baseline fold change in susceptibility to darunavir, mean duration of HIV infection, baseline CD4 count, time (in weeks), and the interaction between time and PSS.
 
Which mutations will darunavir select?
Classic resistance selection experiments performed by Tibotec's Sandra De Meyer [7] showed that:
 
- Mutations arose much more slowly against darunavir than against ritonavir, nelfinavir, saquinavir, amprenavir, lopinavir, atazanavir, or tipranavir.
 
- The mutations eventually evoked by increasing concentrations of darunavirÑR41T and K70E in proteaseÑhave not been linked to resistance to other PIs.
 
- Viral strains constructed to carry these two mutations alone or together remained susceptible to darunavir and to the other PIs studied.
 
- Several substitutions also arose in the gag gene in these experiments. Recombinant viruses engineered to carry both gag and protease mutations remained largely susceptible to darunavir at susceptibility fold changes ranging from 2 to 8.8.
 
These experiments suggest darunavir selects mutant virus along a novel pathway not shared by other PIs. But what this may mean clinically will remain obscure for some time, since darunavir is licensed for PI-experienced people who have already piled up classic protease mutations (and perhaps gag changes as well). And as Tibotec showed in other work discussed above [1], 11 of these classic mutations may impair the response to darunavir. Studies of darunavir in people with little or no antiretroviral experience are under way and may elucidate darunavir's resistance profile in these populations.
 
Gauging tipranavir-related cross-resistance
Demonstrating that response cutoffs vary with the trial population and methods used, Eoin Coakley and Monogram coworkers [8] tendered cutoffs for tipranavir, lopinavir, saquinavir, and amprenavir that differed from those posited by Virco (Table 1 [2]). Monogram's strategy relied on 4-week virologic responses in people who took one of these ritonavir-boosted PIs in RESIST, which enrolled triple-class-experienced people. Notably, Coakley's analysis excluded anyone who took enfuvirtide with their new regimen and anyone continuing the same boosted PI (lopinavir, saquinavir, or amprenavir) that they were taking at study entry.
 
Monogram defined lower clinical cutoff as the fold change in viral susceptibility at which the viral load response first begins to wane and upper clinical cutoff as the fold change above which a clinically meaningful virologic response (more than 0.3 log copies/mL) is unlikely. To set the lower clinical cutoff they compared 4-week virologic responses between two adjacent fold-change brackets (see note 9 for details). To set the upper clinical cutoff they calculated a phenotypic susceptibility score to account for the effect of the background regimen, defined the viral load response attributable to the PI (see note 10 for details), and then defined the fold change in susceptibility associated with a viral load reduction of 0.3 log copies/mL.
 
These methods led to the lower and upper cutoffs listed in Table 6, which also compares the cutoffs from the Virco-Tibotec study (Table 1 [2]).
 

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With the tipranavir cutoffs the mean (and range) viral load drops at week 4 measured 1.3 log copies/mL (-2.8 to -0.3) for 78 people below the lower cutoff (P < 0.0001 versus the intermediate fold-change group), 0.6 log copies/mL (-2.6 to +0.6) for 72 people with susceptibility between the lower and upper cutoffs (P = 0.002 versus the upper cutoff group), and 0.1 log copies/mL (range -1.6 to +0.3) for the 26 people above the upper cutoff.
 
Finally, Coakley tested his cutoffs against baseline viral samples from 563 RESIST participants and found that 53% of these samples were susceptible to tipranavir (below the lower cutoff), 35% had intermediate resistance (between the upper and lower cutoffs), and 12% were resistant (above the upper cutoff). About half of baseline isolates were resistant to each of the other PIs (above the upper cutoffs for those drugs).
 
Among viral isolates with intermediate baseline susceptibility to lopinavir, saquinavir, or amprenavir, 55%, 66%, and 59% respectively were fully susceptible to tipranavir according to these cutoffs.
 
Monogram's Neil Parkin used the cutoffs defined in Coakley's study (Table 6) [8] to calculate cross-resistance between tipranavir and other PIs [11]. For atazanavir/ritonavir he used upper and lower cutoffs of 5.2 and 20, for indinavir 10 and 50, and for nelfinavir a biologic cutoff of 3.6. He classified 3564 viral isolates with at least one protease mutation as sensitive if their fold change in 50% inhibitory concentration lay below the lower cutoff, partially sensitive if the fold change lay between the lower and upper cutoff, and resistant if the fold change lay above the upper cutoff.
 
Of the 3564 viruses analyzed, 55.6% were sensitive to tipranavir/ritonavir, 28.6% partially sensitive, and 15.8% resistant according to this system. Few viruses only partially sensitive to tipranavir would respond to a second PI by this analysis: 23% of such viruses would be sensitive to indinavir/ritonavir, 14% to amprenavir/ritonavir or lopinavir/ritonavir, 11% to saquinavir/ritonavir, 8% to atazanavir/ritonavir, and 3% to nelfinavir. In contrast, more viruses partially sensitive to lopinavir/ritonavir would still be sensitive to tipranavir/ritonavir (49%), indinavir/ritonavir (34%), amprenavir/ritonavir (26%), atazanavir/ritonavir (16%), and saquinavir/ritonavir (17%).
 
All but one viral sample harboring only one major protease mutation remained susceptible to tipranavir/ritonavir with a fold change below 2. The exception was virus with the V82L mutation, in which the fold change in susceptibility to tipranavir crept up to 2.4. Median fold change in susceptibility to tipranavir/ritonavir lay between 2.1 and 2.8 for three mutation clustersÑV31I/M46I/I47V (n = 5), I54V/V82A/L90M (n = 85), and M46IL/I54V/V82A/L90M (n = 56). Parkin determined that 60% to 90% of these isolates retained at least partial susceptibility to tipranavir/ritonavir according to the Monogram cutoffs.
 
Choosing between darunavir and tipranavir
So the question for people with one or more PI failures in their dossierÑespecially if they've already gone through lopinavir and the nonnucleosidesÑis obvious: tipranavir or darunavir? As with all such choices, the decision boils down to a few discrete questions: convenience, cost, resistance, drug interactions, and side effects.
 
Convenience is nearly a tossup. Both PIs require twice-daily dosing, and each dose requires two tipranavir or darunavir pills. Tipranavir needs two ritonavir capsules per dose, darunavir only one. Both drugs must be taken with food.
 
If cost were the sole criterion, darunavirÑat a wholesale tab of about $25 per day (plus the tariff for 100 mg of ritonavir twice daily)Ñwould be the clear winner. Tibotec, now a part of Johnson & Johnson, agreed to set the price substantially lower than those of other recently approved PIs. Darunavir's price beats tipranavir's by about $10 a day.
 
But when is cost ever the sole criterion? The remaining variables in this equation surely count for more when someone has virus resistant to PIs, NRTIs, NNRTIs, and maybe even enfuvirtide. Researchers have worked hard to untangle the still-shaggy resistance profiles of these potent compounds, but both PIs are still so new that much remains to be learned about their activity against resistant virus. And even as more data accumulate, all the predictive schemes in the world may yield only dim forecasts for a person with this many primary PI mutations, that many secondary PI mutations, this many undetectable mutations, that level of commitment to stick with their regimen, this list of non-HIV drugs that may drive darunavir levels up or tipranavir levels down.
 
Still, one must start somewhere in sizing up these two valuable PIs side by side, and since research has yielded lists of protease mutations that threaten response to each drug, why not start there? Table 7 shows that, though both mutation lists are lengthy, the overlap is minimal. This discordance suggestsÑand research so far also suggestsÑthat HIV resistant to one of these PIs will retain at least some susceptibility to the other.
 

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In a study of 9968 HIV isolates presented at the European HIV Resistance Workshop earlier this year, Tibotec found that 93% had decreased susceptibility to lopinavir, 35% to tipranavir, and 22% to darunavir [12]. Among viruses with lowered susceptibility to lopinavir, 77% remained susceptible to darunavir. Among viruses resistant to tipranavir, 70% remained susceptible to darunavir. And among viruses resistant to darunavir, 53% remained susceptible to tipranavir, but almost none (0.5%) to lopinavir. In contrast, a study showcased at the international workshop determined that only 28% of isolates highly resistant to tipranavir will have a maximal response to darunavir (see 3 above). As in all such analyses, results depend on the still-unverified accuracy of cutoffs used for resistance and susceptibility.
 
On the plus side for tipranavir, Abbott's small study at the international Resistance Workshop suggested that HIV does not become more resistant to tipranavir as a lopinavir rescue regimen fails, but it does become more resistant to darunavir (see 4 above).
 
Commercial genotypers and academic algorithm authors are surely hustling to fit the new darunavir data into their predictive engines. Even when they do, relying solely on a machine-made genotype cannot be the best way to plan therapy for salvage PI candidates. A phenotypeÑand counsel with a trusted expertÑwill help.
 
How about drug-drug interactions? Both tipranavir and darunavir depend on the CYP3A4 enzyme for their metabolism. That's why ritonavir, a high-voltage CYP3A4 inhibitor, hoists levels of both drugs into the range needed to slap down resistant virus. But the CYP3A4 connection also means these new PIs may have volatile interactions with other drugs that inhibit or induce this critical enzyme.
 
As a result prescribing information for tipranavir and darunavir features daunting laundry lists of drugs that cannot be taken with these PIs, or whose use is "not recommended" or requires close monitoring (Table 8). Many of these banned or risky drugs are medicines people with HIV depend on. So far tipranavir has the longer list, but possibly only because study of darunavir interactions is at an earlier stage.
 

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Notably, neither lopinavir nor saquinavir should be given with either tipranavir or darunavir, and amprenavir is not recommended with tipranavir.
 
Both tipranavir and darunavir come with their list of side effects, topped by liver toxicity. Tipranavir prescribing information bans use of the PI in people with moderate or severe (Child-Pugh class B or C) hepatic insufficiency, and the FDA's tipranavir prescribing manifesto starts off with a "black box" calling for "extra vigilance" when giving this PI to people with chronic hepatitis B or C infection. The FDA also advises caution when giving darunavir to people with impaired liver function. More work must be done, the FDA says, to figure whether darunavir dose adjustments will be needed in people with a sick liver. But people taking darunavir in clinical trials had fewer liver enzyme jumps than people taking comparison PIs.
 
A few weeks after the workshop, tipranavir's black box got blacker, warning physicians that intracranial hemorrhage may threaten people taking tipranavir/ritonavir. This caution reflects 14 episodes of intracranial hemorrhage, 8 of them fatal, in 6840 people who took tipranavir in clinical trials. Many of the people with this bleeding problem had other medical conditions (central nervous system lesions, head trauma, recent neurosurgery, blood coagulation problems, hypertension, alcohol abuse) or were taking other drugs (anticoagulants, antiplatelets) that may have caused or contributed to the hemorrhages.
 
Tipranavir-induced liver trouble may block its use as a first-line antiretroviral, results of one clinical trial suggest [13]. The study pitted tipranavir/ritonavir at doses of 500/200 mg or 500/100 mg twice daily against lopinavir/ritonavir in 558 antiretroviral-naive people. The trial's independent safety panel recommended closing the 500/200-mg arm at week 48 because of a high rate of symptomatic liver enzyme leaps. At week 60 the safety board advised stopping the trial entirely because 500/100 mg of tipranavir/ritonavir fell just short of lopinavir/ritonavir in controlling HIV.
 
Rash seems to be darunavir's biggest safety threat so far, affecting 7% of people taking the PI in clinical trials. Sometimes fever and climbing liver enzymes accompanied rash, which occasionally arose in severe forms like erythema multiforme or Stevens-Johnson syndrome. Only 0.3% of darunavir trial participants dropped out of the studies because of rash, but the FDA mandates stopping darunavir if severe rash develops. In phase 2 and 3 tipranavir trials, rash reared up in 14% of women and 8% to 10% of men. Rash also flared in 33% of healthy women taking tipranavir/ritonavir after a single dose of ethinyl estradiol. Early rash with either PI could make it tricky to start that drug at the same time as other rash-inducing antiretrovirals.
 
What's the bottom line in picking between tipranavir and darunavir?
Surprisingly, there's one more juicy analysis everyone will want to taste test. Convention-flouting gadfly Andrew Hill (University of Liverpool), ably abetted by Graeme Moyle (Chelsea and Westminster Hospital, London), offered a slick, if naughty, cross-study comparison of 24-week virologic outcomes in the tipranavir RESIST trials and the darunavir POWER trials [14]. Their conclusion: darunavir looks better. Here's how the study worked:
 
Combing through publicly available data on the two RESIST studies and the two POWER studies, Hill and Moyle compared entry requirements, baseline variables, and 24-week outcomes. They confirmed similar entry criteria in RESIST and POWER and comparable baseline age, gender, race, CD4 count, viral load, median number of protease mutations (three), antiretroviral experience, and baseline genotypic and phenotypic resistance.
 
The trials did differ in their background regimens: 23% in control arms of the darunavir studies used double boosted PIs, whereas none did in the tipranavir studies. More people used lopinavir/ritonavir in the control arms of the tipranavir RESIST trials (50%) than in the control arms of the darunavir POWER trials (38%), but more POWER enrollees (32%) used enfuvirtide for the first time than did RESIST enrollees (15%). Whereas 17% of patients in RESIST (all with NNRTI-sensitive virus) used an NNRTI, the POWER protocol barred nonnukes.
 
Despite these differences, 24-week virologic results were comparable in the control arms of POWER and RESIST. But the 24-week treatment benefit of darunavir versus control PIs was greater than the benefit of tipranavir versus control PIs for percent with a 1-log (10-fold) drop in viral load (the primary endpoint of each study), percent below 400 or 50 copies/mL, and CD4 gains.
 
In a subgroup analysis of enfuvirtide-naive study participants, the benefit of darunavir versus the control arm also exceeded the benefit of tipranavir versus control for 1-log drop in viral load and percent below 50 copies/mL at 24 weeks. Darunavir held an edge over tipranavir in the 1-log drop metric for people who did not use enfuvirtide.
 
Readers who want to pick through the details of this pithy analysis can consult the poster online [14].
 
And what about brecanavir?
Still wending its way through clinical trials, brecanavir seems set to emerge as yet another reasonable option for people with heavy PI experience. Analysis of an ongoing GlaxoSmithKline dose-ranging study recorded a brecanavir 50% inhibitory concentration hundreds to thousands times lower (better) than those of other PIs, including tipranavir [15]. But this study by Glaxo's Charles Craig was unable to compare brecanavir's activity with that of darunavir.
 
Craig scrutinized 134 viral samples from people enrolled in the phase 2 trial, which required participants to have two or more multi-PI mutations, defined as the substitutions L10I/F/V/R, V32I, M46I/L, I54V/L/M, V82A/F/T/S, I84V/A/C, and L90M. Virus from these people carried an average 3.2 major PI mutations (including changes at position 46 in 76%, 82 in 63%, and 90 in 62%). If one counts secondary protease mutations, the group's viruses harbored an average 11.2 resistance mutations.
 
In this mutation-burdened viral population, brecanavir had a median 50% inhibitory concentration of only 0.4 nM when the study began. The next best PI was atazanavir (70 nM), followed by saquinavir (110 nM), fosamprenavir (230 nM), tipranavir (244 nM), lopinavir (269 nM), nelfinavir (338 nM), and ritonavir (1641 nM).
 
Figuring median fold changes in susceptibility of resistant virus to these PIs compared with wild-type (nonmutant) virus, Craig found that brecanavir and tipranavir had the lowest median fold changes and the lowest range in fold changes. Next best in this analysis were fosamprenavir and saquinavir. Because Glaxo reported these fold changes on a graph that did not label data points, it's hard to say how brecanavir and tipranavir compare with any more precision. The fold change for tipranavir appears to be a hair lower than that of brecanavir, but both appear to be comfortably below 10.
 
All told, 68% of these highly resistant viral samples had a brecanavir 50% inhibitory concentration below 1.0 nM on day 1 of the study.
 
Mark Mascolini writes about HIV infection
 
References and Notes
 
1. De Meyer SD, Vangeneugden T, Lefebvre E, et al. Phenotypic and genotypic determinants of resistance to TMC114: pooled analysis of POWER 1, 2 and 3. Antivir Ther 2006;11:S83.
 
2. Winters B, Vermeiren H, Van Craenenbroeck E, et al. Development of VircoTYPE resistance analysis, including clinical cut-offs, for TMC114. Antivir Ther 2006;11:S180.
 
3. Staes M, Van Craenenbroeck E, Vermeiren H, et al. Analyses of susceptibility and cross-resistance between TMC114 and other protease inhibitors among >56,000 routine samples, using linear regression model-based fold change predictors. Antivir Ther 2006;11:S33.
 
4. King M, Young TP, Bernstein B, et al. Phenotypic susceptibility to TMC-114 and tipranavir before and after lopinavir/ritonavir-based treatment in subjects demonstrating evolution of lopinavir resistance. Antivir Ther 2006;11:S34.
 
5. Vangeneugden T, Winters B, Bacheler L, et al. Impact of optimised background regimen on virological respone to TMC114 with low-dose ritonavir in POWER 1, 2 and 3, as measured by the phenotypic susceptibility score. Antivir Ther 2006;11:S36.
 
6. Using the VircoTYPE system, Virco and Tibotec developed a background regimen phenotypic sensitivity score (PSS) according to the following rules. Individual NRTIs in a person's regimen were given a PSS of 1 if the fold change in 50% effective concentration predicted for a particular NRTI by VirtualPhenotype was below the lower clinical cutoff, a PSS of 0.5 if the predicted fold change was between the lower and upper clinical cutoffs, or a PSS of 0 if the predicted fold change was above the upper clinical cutoff. Total PSS of the background regimen equaled the sum of PSSs of susceptible NRTIs in the regimen plus 1 if the patient used enfuvirtide for the first time.
 
7. De Meyer SD, Azijn H, Fransen E, et al. The pathway leading to TMC114 resistance is different for TMC114 compared with other protease inhibitors. Antivir Ther 2006;11:S24.
 
8. Coakley EP, Chappey C, Flandre P, et al. Defining lower and upper phenotypic clinical cutoffs for tipranavir, lopinavir, saquinavir and amprenavir co-administered with ritonavir within the RESIST dataset using the PhenoSense assay (Monogram Biosciences). Antivir Ther 2006;11:S81.
 
9. Setting the lower clinical cutoff took four steps: (1) defining two continuous windows adjacent across a given fold change and encompassing the same number of patient data points in each window, (2) computing the median viral load reduction within the adjacent left and right windows, (3) testing for statistical significance of the difference between responses, and (4) moving the cutoff and expanding the windows' limits.
 
10. For example, if the phenotypic susceptibility score (PSS) for background NRTIs was 0 and the PSS for tipranavir/ritonavir was 1, the PIs accounted for 100% of the virologic response. If the PSS for the background NRTIs was 1 and the PSS for tipranavir/ritonavir was 1, the PIs accounted for 50% of the response.
 
11. Parkin NT, Chappey C, Coakley E. Patterns of tipranavir susceptibility and cross-resistance among patient samples submitted for routine resistance testing. Antivir Ther 2006;11:S35.
 
12. De Meyer S, Cao-Van K, Lathouwers E, et al. Phenotypic and genotypic profiling of TMC114, lopinavir and tipranavir against PI-resistant HIV-1 clinical isolates. 4th European HIV Drug Resistance Workshop. March 29-31, 2006. Monte Carlo. Abstract 42.
 
13. Boehringer Ingelheim. Boehringer Ingelheim provides update on Aptivus (tipranavir) clinical trial in treatment-naive HIV-infected patients. June 9, 2006.
 
14. Hill A, Moyle G. Relative antiviral efficacy of TMC114/r and tipranavir/r versus control PI in the POWER and RESIST trials. 12th Annual Conference of the British HIV Association (BHIVA). March 29-April 1, 2006. Brighton. Abstract P1 (http://www.thebody.com/thebody/pdfs/hill_poster.pdf).
 
15. Craig C, Yates P, Flemming J, et al. Resistance-associated amino acid substitutions and drug susceptibility analysis of virus from subjects entering the phase II dose-ranging study of a new protease inhibitor, brecanavir, HPR200001 (STRIVE). Antivir Ther 2006;11:S32.