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ICAAC Report: Evolving Antiretroviral Strategies
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Report 1 from the 14th ICAAC, October 30-November 2, 2004, Washington, DC
Written for NATAP by Mark Mascolini
TOPICS
Trizivir and TDF match Combivir plus efavirenz
Once-daily Trizivir/TDF
Trizivir/TDF ZIPs to the rescue
Truvada goes toe-to-toe with Combivir
Five years of FTC, ddI, and efavirenz
Fixed-dose abacavir/3TC plus efavirenz
Resistance with lopinavir/ritonavir "monotherapy"
Lopinavir/ritonavir once-daily
Lopinavir troughs with & without tenofovir
Is there a role for lopinavir/efavirenz?
Efavirenz versus IDV/RTV in advanced disease
The danger of STIs with NNRTIs
For a dozen years, finding the right kind of antiretroviral regimen has been a balancing act. Even after the first truly active combinations—indinavir or ritonavir plus two nucleosides—wowed the AIDS world in 1995, debate raged for years about whether two unabetted nukes still filled a niche and even whether hydroxyurea-driven ddI deserved a place at the standard-of-care table.
By and by, some experts started dabbling with four- and five-drug regimens, hoping to flog HIV into lifelong submission. But the unpleasant discovery of lipodystrophy and related metabolic maunderings soon forced a retreat to nonnucleoside-driven regimens and—last year—to once-a-day tonics blending the nucleotide tenofovir disoproxil fumarate (TDF) with 3TC and abacavir or ddI. They didn't work (1-4). Even one-pill-twice-daily Trizivir (AZT/3TC/abacavir) came up short when compared with efavirenz-based regimens (5).
But if nuke threesomes flunk the viral load test, and you still have a yen to avoid nonnucleosides (NNRTIs) and protease inhibitors (PIs) in an upfront regimen, how about four nukes? That's the question two groups of British and US clinicians asked—and partly answered—at this year's infectious disease deliberations in Washington, DC, otherwise known as ICAAC.
Trizivir and TDF match Combivir plus efavirenz
The more exacting of the two trials yoked Trizivir to TDF and compared it with a trial-tested standard-of-care regimen, Combivir (AZT/3TC) plus efavirenz, in a 48-week randomized study (6). The more adventurous essay mixed Trizivir and TDF, giving all components—even AZT—once daily (7).
Graeme Moyle and colleagues at London's Chelsea and Westminster Hospital randomized 56 treatment-naive people to Trizivir/TDF and 57 to Combivir/efavirenz (6). Each of these twice-daily regimens relies on only three pills, which may be taken with or without food. Reflecting the Chelsea and Westminster population, most study participants were men. Most had moderately advanced HIV disease:
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By week 48, 17 people (30%) had dropped out of the Trizivir/TDF arm and 16 (29%) gave up on Combivir/efavirenz. Toxicity compelled slightly more people (9, or 16%) to quit Trizivir/TDF than to shelve Combivir/efavirenz (6, or 11%), usually because of abacavir hypersensitivity in the Trizivir group (6, or 10.5%).
Only one study participant, a woman taking Trizivir/TDF, had a virologic failure. The regimen pushed her viral load under 50 copies/mL, but she had a rebound, possibly because of shaky adherence. The rebound brought with it three AZT-related mutations and the 3TC-inspired M184V change. A regimen of ddI, TDF, and lopinavir/ritonavir promptly squelched the rebound.
Putting RNA and CD4 response numbers side by side after 48 weeks, Moyle and confreres discerned no difference between the two regimens:
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Neither of these regimens is perfect, to be sure, but does one outdo the other in any way? Trizivir/TDF's modest advantage in CD4 gains may mean nothing clinically. That group began with fewer CD4s, and people starting a potent regimen with lower T-cell tallies typically gain more than people starting with more CD4 cells.
The oldest drug in the mix, AZT, caused the most side effects (in 7 people or 13%), but there were also 6 suspected hypersensitivity reactions to abacavir in the Trizivir/TDF arm and 2 rashes among people taking efavirenz.
Fasting triglycerides edged up in the Combivir/efavirenz group and edged down in the Trizivir/TDF group, though that small difference lacked statistical significance. But the Combivir/efavirenz group gained 0.8 mmol/L (30 mg/dL) in total cholesterol, while the Trizivir/TDF group lost about 0.2 mmol/L (8 mg/dL), a highly significant difference (P < 0.001).
The bottom line, Moyle offered, is that Trizivir/TDF is a single-class regimen with similar potency to two-class standard therapy. It sure beats three nukes.
The price of once-daily Trizivir/TDF
What could be simpler than the three-pill twice-daily Trizivir/TDF combo concocted by Moyle and coworkers? How about Trizivir/TDF once daily? That's the regimen eyed by Edwin DeJesus (IDC Research Initiative, Altamonte Springs, Florida) and colleagues at other US sites (7).
The rationale for this antiretroviral suite is straightforward. Although 3TC, abacavir, and TDF all have unchallenged once-daily dosing credentials, their combination leads to a high failure rate with 3TC's M184V/I mutation with or without the TDF-tendered K65R. The fourth drug, AZT, complicates HIV's path to resistance because AZT-selected thymidine analog mutations (TAMs) and K65R resolutely shun each other's company (8,9).
Twice-daily Trizivir plus once-daily TDF proved strong enough in Moyle's trial to handcuff HIV in treatment-naive people, so neither TAMs nor K65R emerged in anyone except the woman with possible adherence problems. The gamble in DeJesus' study is that the even greater simplicity of once-daily Trizivir/TDF will offset the possible emergence of AZT-evoked TAMs. Those TAMs make K65R less likely, but is it any better to wind up with a handful of TAMs than with a solitary K65R? Let's find out.
This single-arm open-label study (called COL40263) enrolled 123 treatment-naive people with a viral load above 30,000 copies/mL and any CD4 count. Most (83%) were men, and they started Trizivir/TDF with a median viral load of 5.08 logs (about 120,000 copies/mL) and a median CD4 count of 221 cells/µL (range 20 to 857 cells/µL). Most study participants, 71 (58%), began therapy with more than 100,000 HIV RNA copies/mL; 12 (10%) had AIDS.
As in Moyle's study, Trizivir/TDF proved too toxic for some. Twelve people (10%) quit because of side effects by week 24, which for 8 people meant suspected abacavir hypersensitivity. But 15 other people also dropped out by week 24 for those vaguely defined reasons that may mean almost anything—lost to follow-up, consent withdrawn, protocol violation, and the omnipresent "other." All told, 27 people (22%) had bailed out of the study by week 24, compared with the 34% who stopped twice-daily Trizivir plus once-daily TDF by week 48 in the British trial. So one may wonder whether the added convenience of once-daily Trizivir truly makes the drug more palatable.
The week-24 virologic results fell short of the week-48 results in Moyle's trial (above):
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Eight people met the definition of virologic nonresponse—a confirmed RNA readout of 400 copies/mL or more at week 24 or afterwards. None of these people had the K65R mutation at week 24, but 3 of them had one of more TAMs and another 3 had one or more TAMs plus M184V. Two people with week-24 virologic failure had no apparent resistance mutations. The AZT-provoked TAMs may have headed off emergence of K65R, but they betokened virologic failure all the same.
This study's primary endpoint is the percentage of people who count fewer than 50 copies/mL at week 48. But the week 24 results hint that once-daily TZV/TDF poses too great a risk of TAM resistance.
Trizivir/TDF ZIPs to the rescue
Twice-a-day Trizivir plus TDF also took an ICAAC bow as a rescue regimen after early failure of AZT (or d4T) plus 3TC and a PI or an NNRTI (10). In other words, this trial combined simplification (by subtracting the PI or NNRTI) with intensification (by adding abacavir and TDF), a strategy reflected in the study's name—the Ziagen Intensification Protocol, or ZIP.
Allan Rodriguez (University of Miami) and coworkers from 23 other sites signed up treatment-experienced people still within reach of a simple rescue regimen. Their viral load had to lie between 400 and 10,000 copies/mL, they had to have a CD4 count above 100 cells/µL, they could have only two or fewer nucleoside-induced mutations, and they could not have the K65R mutation. The ZIP team wanted to enroll 100 people, but they wound up with only 51, perhaps because many people prefer a completely new combo to cope with failure. Study findings may change some minds.
Thirty-five enrollees (68%) had a viral load below 5000 copies/mL, and 32 (63%) never suffered an AIDS symptom. The median viral load stood at 3.3 logs (about 2000 copies/mL) and the median CD4 count measured 436 cells/µL (range 142 to 1291 cells/µL). Among the 51 study participants, 80% started with the M184V mutation, 20% had one or two TAMs, 35% had an NNRTI mutation, and 40% had a primary PI mutation.
Eight people left the study by week 24, half of them because of side effects, but no one had a hypersensitivity reaction to abacavir. At week 24 no one met the study definition of failure, a load still above 400 copies/mL or a rebound from under 400 to over 1265 copies/mL (which is a half-log—about 3 times—above 400 copies). Most people had a viral load under 50 copies/mL by week 24:
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The ZIP study will continue through week 48.
Truvada goes toe-to-toe with Combivir
HIV-infected people in the US may now choose from two once-daily fixed-dose nuke duos—Truvada (TDF/emtricitabine [FTC]) and Epzicom (abacavir/3TC). Whether one outperforms the other remains to be seen, but TDF/FTC outdid Combivir (AZT/3TC) after 24 weeks in a randomized trial set to go for another 6 months (11). Everyone in this 509-person multicenter trial outlined by Brian Gazzard (Chelsea and Westminster Hospital, London) also took efavirenz.
These antiretroviral-naive people began therapy with a median viral load of 100,000 copies/mL and median CD4 counts of 233 cells/µL in the TDF/FTC group and 241 cells/µL in the AZT/3TC group. About 40% claimed fewer than 200 cells/µL at study entry, and about 40% were black or Hispanic.
Truvada/efavirenz proved more tolerable than Combivir/efavirenz. Whereas 3% quit the Truvada arm before 24 weeks went by, 9% dumped Combivir. Nausea, vomiting, and anemia harried more people taking AZT/3TC than TDF/FTC:
• Anemia: 14 (5%) taking Combivir and none taking Truvada
• Nausea: 4 (2%) taking Combivir and 1 (<1%) taking Truvada
• Vomiting: 3 (1%) taking Combivir and none taking Truvada
Kidney toxicity rates were low and similar in the two groups. Overall, 21% fled the Combivir/efavirenz arm by week 24 and 11% threw in the towel on Truvada. The higher dropout rate in the Combivir group drove the worse 24-week response in that group, determined by the FDA-sanctioned time to loss of virologic response (TLOVR) algorithm:
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In an on-treatment analysis, nearly everyone in both groups had a 24-week viral load under 400 copies/mL.
Gazzard and colleagues genotyped 10 people in the TDF/FTC arm and 8 in the AZT/3TC group who a confirmed viral load above 400 copies/mL by week 24 or who quit the study early. None of them had AZT-induced mutations and none had the TDF-linked K65R. The only resistance mutations spotted were the 3TC- or FTC-induced M184V and mutations conferring resistance to efavirenz:
• No mutations: 5 (50%) on TDF/FTC, and 3 (38%) on AZT/3TC
• Efavirenz mutations only: 3 (30%) on TDF/FTC, and 4 (50%) on AZT/3TC
• Efavirenz mutations + M184V/I: 2 (20%) on TDF/FTC and 1 (13%) on AZT/3TC
Gazzard noted that most people had reached 48 weeks of follow-up at the time of his report, so final results should show up shortly.
Five years of FTC, ddI, and efavirenz
FTC, a nucleoside similar to 3TC except for a somewhat longer half-life, has also served as a component of once-daily therapy in league with ddI and efavirenz. And it has done so for 5 years in a French trial named back in the days of Franco-American bonhomie, MONTANA (12). This once-a-day medley proved a durable and tolerable regimen, though rates of physician-assessed lipodystrophy climbed curiously high.
A French national AIDS trials team headed by André Furco recruited 40 treatment-naive people with a median viral load of 58,400 copies/mL (interquartile range 34,050 to 108,000 copies/mL) and a median CD4 count of 373 cells/µL (interquartile range 272 to 484 cells/µL). Thus many of the 40 trial participants stood at a disease stage that would probably go untreated today.
Five years after MONTANA started, 23 people (57.5%) are still taking this simple regimen. Of the 17 (42.5%) who stopped, only 2 (5%) did so because of virologic failure and 6 (15%) because of side effects, which researchers blamed on efavirenz in 3 people, on efavirenz and FTC (decreased libido) in 1, and on ddI in 2.
In a 5-year missing-data-equal-failure analysis, 73% had a viral load under 400 copies/mL and 68% slipped under 50 copies/mL. A 5-year on-treatment analysis had 96% below 400 copies/mL and 91% under 50 copies/mL. The median CD4 count ballooned 294 cells/µL since 1999.
Among 9 people with an RNA reading atop 400 copies/mL between months 4 and 60 and genotyped while taking ddI/FTC/efavirenz, 4 had no apparent resistance mutations. The K103N NNRTI mutation showed up in 4, the G190A NNRTI mutation in 2, the FTC-induced M184V in 2, and the ddI-linked L74V in 1. Three other people had AZT-related mutations before treatment began.
Grade 3 or 4 drug-related lab abnormalities included elevated creatinine phosphokinase in 4, high alanine aminotransferase in 1, and lofty triglycerides in 2. Many may assume that lipodystrophy would be rare with this regimen, but at the 5-year mark trial physicians diagnosed lipodystrophy in 5 people (24%), lipohypertrophy in 4 (19%), and lipoatrophy in 3 (14%). Those rates, however, may say more about the aging of the cohort and the fragility of subjective lipodystrophy evaluations than about treatment-induced fat changes.
Fixed-dose abacavir/3TC plus efavirenz
Epzicom (abacavir/3TC), the other fixed-dose, once-daily dual nuke on the US market, made its debut in ESS30009, one of the three studies that discovered the shortcomings of 3TC/TDF/abacavir (1). That trial continued to test fixed-dose 3TC/abacavir plus efavirenz, and Joel Gallant (Johns Hopkins Hospital) spelled out the 24-week results with that regimen (13).
The 169 treatment-naive people in the Epzicom/efavirenz arm forsook their naive status with a median viral load of 4.8 logs (about 63,000 copies/mL) and a median CD4 count of 263 cells/µL. After 24 weeks of treatment, 16 people (9%) had stopped the regimen because of side effects, 1 had a virologic failure, and 15 (9%) had protocol-defined failure because of poor adherence, withdrawn consent, loss to follow-up, or other reasons.
That left 116 of 169 people (69%) with a viral load below 50 copies/mL in a 24-week missing-data-equal failure analysis. In an as-treated analysis, 108 people (86%) had a sub-50 viral load after 24 weeks.
The most frequent grade 2 or higher side effects were drug hypersensitivity (in 10%), rash (in 8%), and insomnia (in 5%). Another 9% had grade 3 or higher hikes in creatinine phosphokinase.
What happened to the people randomized to 3TC/abacavir plus TDF? When researchers closed that study arm because of early failures, most trial clinicians stopped TDF and added a nonnucleoside with or without AZT. Three months after the switch from 3TC/TDF/abacavir, about 60% of that group tallied fewer than 50 copies/mL and about 80% had fewer than 400 copies/mL in missing-data-equal-failure analyses.
Resistance with lopinavir/ritonavir "monotherapy"
Five studies have now sized up lopinavir/ritonavir with no other antiretrovirals, making it the most-probed HAART era "monotherapy" (14-18). One of these studies was a prospective, open-label pilot trial enrolling treatment-naive people (14), while the others included a retrospective analysis (15) and simplification studies involving people with well-controlled HIV (16-18).
The only randomized study in the group, a maintenance trial (18), found no virologic failures among 21 people who continued lopinavir/ritonavir with two nucleosides and three failures (14%) by week 24 in the lopinavir/ritonavir monotherapy maintenance arm. None of these three failures could be tied to emergence of resistant virus—maybe because the assays failed to spot resistance, or maybe because some other mechanism caused the failure.
But resistant virus does emerge during lopinavir/ritonavir monotherapy, the leader of two of these studies reported at ICAAC, even though that emergence is sluggish and seemingly desultory (19). Gerald Pierone (AIDS Research and Treatment Center, Fort Pierce, Florida) counted 4 failures among 15 people (27%) in his retrospectively reviewed cohort (15) and 4 among 18 (22%) in his prospective trial of people who swapped an NNRTI regimen for solo lopinavir/ritonavir (16). He had genotypic and phenotypic diggings for 5 of these people, 3 from the retrospective cohort and 2 from the prospective study. Four of the 5 had resistance mutations before switching to lopinavir/ritonavir, and some rare mutations popped up during monotherapy. One resistance mutation, M36I, is not so rare:
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Pierone tied "documented or presumed nonadherence" to breakthrough viremia in most of these people. Others studying lopinavir/ritonavir monotherapy (14,17) also blamed bad adherence for virologic failure in their studies, a trend indicating that single-drug therapy is not everyone's solution to poor pill taking. The only clear-cut primary mutation that emerged in Pierone's 5 patients, M36I, can confer cross-resistance to indinavir, ritonavir, and nelfinavir. The phenotypic evidence suggested that all of these mutant viruses remained susceptible to lopinavir.
Research on this strategy remains at an inchoate stage that certainly does not support clinical deployment of boosted PI monotherapy. Abbott is studying this tactic in an induction-maintenance trial.
Will lopinavir/ritonavir become a once-daily drug?
Lopinavir/ritonavir monotherapy has a long way to go before winning the aegis of guideline writers, but once-daily lopinavir/ritonavir may be closer to official sanction—for people without resistance to PIs. A 48-week study showed equivalent responses to once-daily and twice-daily lopinavir/ritonavir in treatment-naive people, even though lopinavir troughs dipped lower in the once-daily group (20).
Researchers assigned 115 people to once-daily lopinavir/ritonavir (800/200 mg) plus once-daily TDF/FTC and 75 to the standard twice-daily dose plus TDF/FTC. Mean pretreatment viral load measured 4.8 logs (about 63,000 copies/mL) and mean CD4 count 260 cells/µL (range 3 to 1006 cells/µL). A noncompleter-equals-failure analysis determined that 70% in the once-daily group and 64% in the twice-daily group had a 48-week viral load below 50 copies/mL, a nonsignificant difference. Both groups gained about 185 cells/µL.
Among people with a viral load topping 500 copies/mL after 12 weeks of treatment, researchers managed to genotype virus from 15 people—8 in the once-a-day group and 7 in the twice-a-day group. No one had mutations conferring resistance to lopinavir or TDF, while 2 in the once-daily group and 1 in the twice-daily group had the FTC-linked M184V/I mutation.
Although trough levels of lopinavir (measured just before dosing) proved 60% lower with once-daily dosing, those lower readings did not correlate with week 48 virologic response. Neither did pretreatment viral load or CD4 count. Apparently, the authors conclude, the lower troughs with once-daily lopinavir/ritonavir remain above the threshold of activity for antiretroviral-naive people. (But see the next study review.)
Lower lopinavir troughs with tenofovir
Although once-daily lopinavir/ritonavir kept pace with the standard twice-daily dose in the preceding study, a French trial suggested there may be some risk in combining these PIs with TDF. That study found lower lopinavir troughs in treatment-experienced people starting the PI with TDF than in those starting it without TDF (21).
Dominique Breilh (University Hospital, Bordeaux) and coworkers tracked lopinavir and ritonavir levels in 71 people starting lopinavir/ritonavir after trying multiple PIs and NRTIs. Comparing 17 people who took lopinavir/ritonavir with TDF and 54 people who took the PIs without TDF, they found significantly lower PI troughs (but not peaks) in the TDF group:
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Despite the lower PI troughs with TDF, the groups treated with and without TDF did not differ in virologic or CD4 response. Nevertheless, Breilh and coworkers suggested close lopinavir level monitoring in people taking that drug with TDF and possible upward dose adjustment to 533/133 mg daily.
Is there a role for lopinavir/efavirenz?
US Department of Health and Human Services advisors give their stamp of approval to only two antiretrovirals as "preferred" regimen keystones for treatment-naive people—lopinavir/ritonavir and efavirenz (22). So why not give them both and forget about the nucleosides? That's the question asked by François Raffi (University Hospital, Nantes) and colleagues in the 48-week BIKS (Bitherapy With Kaletra and Sustiva) study (23).
But another question is whether this dynamic duo offers any advantage over standard therapy. The rationale Raffi and coworkers offer for this regimen is that cross-resistance and toxicity complicate treatment with nucleosides, although the same can surely be said for nonnucleosides and PIs. Indeed, lopinavir/ritonavir side effects may be more likely with efavirenz than without it because the PIs must be dosed at 533/133 mg twice daily when served with this NNRTI.
The 16-center BIKS team recruited 65 antiretroviral-naive people and 21 who had taken antiretrovirals but no nonnucleosides. The latter group had a median 5.2 years of treatment history and had tried two to six antiretrovirals. Twelve of the 21 had never taken a PI. They started lopinavir/ritonavir/efavirenz with an average 311 CD4 cells/µL and an average viral load of 4.84 logs (about 70,000 copies/mL).
Twenty-one people (24.4%) bid adieu to this two-drug combo before week 48, only 1 of them because of virologic failure. Seven people (all of them naive at study entry) could not adhere to the regimen or stopped showing up for visits, and another 7 (6 in the naive group) dropped out because of side effects.
In a week 48 analysis that counted discontinuation or missing data as failure, 56 (69%) had a viral load below 50 copies/mL. That success rate is no better—and in some comparisons somewhat worse—than 48-week results with standard lopinavir or efavirenz regimens. Researchers ascribed 3 of 4 virologic failures to poor adherence. Twenty-four people (27.9%) wound up with high cholesterol readings, and 11 (12.8%) came away with high triglycerides. Raffi and colleagues suggested that "NNRTI-PI/r regimens should be optimized to achieve not only immuno-virological efficacy but also improved tolerability."
Efavirenz versus IDV/RTV in advanced disease
Of the 7 people who dropped out of the just-reviewed BIKS study because of side effects, 6 could not tolerate early toxicities tied to efavirenz. But long-term safety profiles probably favor this nonnucleoside over PIs that lash lipids or glucose into the danger zone. A 48-week comparison of efavirenz with indinavir/ritonavir in people with low CD4 counts found less toxicity with the NNRTI—as well as bigger CD4 gains (24).
José Miró (University Hospital Clinic, Barcelona) and coworkers gave efavirenz plus Combivir to 34 treatment-naive people with fewer than 100 CD4 cells/µL and indinavir/ritonavir (800/200 mg twice daily) plus Combivir to 32 people. The pretreatment CD4 quotient stood at a median of 40 cells/µL in both groups, ranging from 6 to 93 cells/µL in the efavirenz arm and from 1 to 99 cells/µL in the indinavir arm. The median viral load measured 5.6 logs with efavirenz and 5.4 logs with indinavir (about 398,000 and 251,000 copies/mL). About half in each group had AIDS.
Four people taking efavirenz died before 48 weeks of treatment, 3 with AIDS diseases and 1 with myocardial infarction. One person in the indinavir group died with end-stage liver disease and cryptococcal meningitis. Three people taking efavirenz (9%) and 8 taking indinavir/ritonavir (25%) stopped or switched treatment because of side effects, a difference that fell just short of statistical significance (P = 0.08). Three people had to swap efavirenz for nevirapine of lopinavir/ritonavir, while 7 traded indinavir/ritonavir for lopinavir/ritonavir or efavirenz.
At the 48-week point, virologic responses looked marginally better in the efavirenz group, but tests of statistical significance did not bear out that apparent advantage. People taking efavirenz gained substantially more CD4 cells than did those taking indinavir/ritonavir, although the between-group difference again fell a tad shy of statistical significance in an on-treatment analysis:
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A secondary analysis found a significant drop in activated (CD38+) CD8 cells after 48 weeks of efavirenz (P < 0.01). Although activated CD8s also dropped in the indinavir/ritonavir arm, that fall from baseline lacked significance.
These results do not say whether the bigger CD4 gains and CD8 soothing in the efavirenz arm mean anything clinically. Although the median CD4 count vaulted from 40 to 254 cells/µL in the efavirenz group (versus from 40 to 157 cells/µL in the indinavir group), the clinical advantage (measured by mortality) broke in indinavir's favor. But the study does confirm that people with precariously low CD4 counts can rely on an efavirenz regimen.
The danger of STIs with NNRTIs
Structured treatment interruptions (STIs) remain an alluring retreat for antiretroviral-weary people, though drug breaks have distinct dangers. People who opt for a drug holiday while taking an NNRTI regimen face a particular risk bestowed by these drugs' slow elimination from the body and quick arousal of resistant virus. Research in the past year showed that both efavirenz and nevirapine may linger in the body for weeks (25,26), long after the nucleosides taken with them have vanished. The result is NNRTI monotherapy with ever-ebbing concentrations of these drugs—a nearly foolproof recipe for resistance. Even when researchers try to outwit HIV by stopping the nonnuke before the nukes, resistance can emerge (27,28).
An ICAAC study confirmed the danger of interrupting a nonnuke regimen (29). This retrospective analysis involved 55 people seen at Madrid's Carlos III Hospital who stopped their antiretrovirals for at least 3 months in 2002. All of them had a viral load under the 50-copy mark and more than 350 cells/µL when they put treatment on hold. Thirty-three people quit an NNRTI regimen and 12 stopped a PI combo. After drug breaks ranging from 3 to 7 months, all restarted treatment at their clinician's behest because of viral rebounds or CD4 drops. Eleven people restarted a PI and 34 an NNRTI.
All 11 people who resumed treatment with a protease drug pushed their viral load back under 50 copies/mL within 6 months, but 15 or 34 people (44%) who resumed with an NNRTI did not, a highly significant difference (P < 0.001). Among the 19 people whose post-STI nonnuke regimen flopped, 13 had successful genotyping. Resistance testing after treatment resumed spotted a nonnucleoside mutation in 10 of these 13 people. Curiously, genotyping 3 months into the STI turned up a nonnucleoside mutation in only 1 of these people, but minority populations of NNRTI-resistant virus can elude detection with standard assays (30).
Mark Mascolini writes about HIV infection (mailmark@ptd.net).
References
1. Gallant JE, Rodriguez AE, Weinberg W, et al. Early non-response to tenofovir + abacavir (ABC) and lamivudine (3TC) in a randomized trial compared to efavirenz + ABC and 3TC: ESS30009 unplanned interim analysis. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. September 14-17, 2003. Chicago. Abstract H-1722a.
2. Farthing C, Khanlou H, Yeh V. Early virologic failure in a pilot study evaluating the efficacy of abacavir, lamivudine and tenofovir in the treatment of naive HIV-infected patients. 2nd IAS Conference on HIV Pathogenesis and Treatment. July 13-16, 2003. Paris. Abstract 43.
3. Landman R, Peytavin G, Descamps D, et al. Low genetic barrier to resistance is a possible cause of early virologic failure in once-daily regimen of abacavir, lamivudine, and tenofovir: the Tonus study. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 52.
4. Jemsek J, Hutcherson P, Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 51.
5. Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 2004;350:1850-1861.
6. Moyle G, Nelson M, Higgs C, et al. A randomised open label comparative study of Combivir + efavirenz (2 class triple therapy) versus Trizivir + tenofovir (single class quadruple therapy) in initial therapy for HIV-1 infection. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Abstract H-1131.
7. DeJesus E, Elion R, Cohen C, et al. Week 24 analysis of once-daily Trizivir and tenofovir DF in antiretroviral-naive subjects (COL40263). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Abstract H-564.
8. Parikh U, Koontz D, Sluis-Cremer N, et al. K65R: a multinucleoside resistance mutation of increasing prevalence exhibits a bi-directional phenotypic antagonism with TAM. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 54.
9. Gil P, Barrios A, García-Benayas T, et al. Rate of virological failure and resistance profiles in patients treated with triple nucleoside regimens. XIII International HIV Drug Resistance Workshop. June 8-12, 2004. Tenerife. Abstract 166.
10. Rodriguez AE, Hill-Zabala CE, Sloan LA, et al. Abacavir/lamivudine/zidovudine + tenofovir in subjects with early virologic failure on an initial regimen of zidovudine or stavudine + lamivudine and a protease inhibitor or non-nucleoside reverse transcriptase inhibitor (ESS30005, ZIP). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Abstract H-653.
11. Gazzard B, DeJesus E, Campo R, et al. The combination of tenofovir DF, emtricitabine (FTC) and efavirenz (EFV) has significantly greater response vs fixed dose zidovudine/lamivudine and EFV in antiretroviral naive patients: a 24 week preliminary analysis. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-1137c.
12. Furco A, Lallemand L, Palmer P, et al. 5-year follow-up of once-daily combination therapy with FTC, ddI, and EFV in treatment naive HIV-infected adults (MONTANA ANRS 091 trial). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-565.
13. Gallant JE, Rodriguez AE, Weinberg W, et al. Efficacy of once-daily abacavir/lamivudine fixed-dose combination (ABC/3TC) + efavirenz and subsequent treatment of tenofovir DF + ABC/3TC non-responders: ESS30009 planned 24 week analysis. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-567.
14. Gathe J, Washington M, Mayberry C, et al. IMANI-1 single drug HAART proof of concept study: pilot study of the safety and efficacy of Kaletra (LPV/r) as single drug HAART in HIV+ ARV-naive patients—interim analysis of subjects completing final 48 week data. XV International AIDS Conference. July 11-16, 2004. Bangkok. Abstract 1057.
15. Pierone G, Mieras J, Kantor C, et al. Kaletra (LPV/r) monotherapy for treatment of HIV Infection. HIV DART. December 15-19, 2002. Naples, Florida. Abstract 076.
16. Pierone G, Mieras J, Fontaine L, et al. Simplification to lopinavir/ritonavir monotherapy from NNRTI-based HAART in HIV-infected patients with complete viral suppression 24 week interim analysis. XV International AIDS Conference. July 11-16, 2004. Bangkok. Abstract 4595.
17. Ruane P, Luber A, Gaultier C, et al. Maintenance therapy using lopinavir/ritonavir alone with well-controlled HIV infection. XV International AIDS Conference. July 11-16, 2004. Bangkok. Abstract 4577.
18. Arribas J, Pulido F, Lorenzo A, et al. Simplification to lopinavir/r single-drug HAART: 24 week results of a randomized, controlled, open label, pilot clinical trial (OK study). XV International AIDS Conference. July 11-16, 2004. Bangkok. Abstract 4486.
19. Pierone G, Mieras J, Kantor C, et al. Genotypic and phenotypic resistance observations among patients with viremia while on lopinavir/ritonavir "monotherapy." 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-183.
20. Yeh V, Barros C, Easterbrook P, et al. Virologic response to a once-daily lopinavir/ritonavir based regimen in ARV-naive patients is not associated with trough lopinavir concentrations or baseline HIV RNA or CD4 count. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-570.
21. Breilh D, Rouzes A, Djabarouti S, et al. Pharmacokinetic drug interaction of lopinavir/ritonavir in combination with tenofovir in experienced HIV+ patients. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract A-445.
22. Department of Health and Human Services panel on clinical practices for treatment of HIV infection. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. October 29, 2004. http://www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=50.
23. Raffi F, Allavena C, Delfraissy JF, et al. 48-Week final results of lopinavir/r-efavirenz combination (BIKS study). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-569.
24. Miró JM, Pich J, Plana M, et al. Immunologic reconstitution in severely immunosuppressed antiretroviral-naive patients (<100 CD4+ T cells/mm3) using a non-nucleoside reverse transcriptase inhibitor- or a boosted protease inhibitor-based antiretroviral regimen: 48 week results (the Advanz trial). 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-574.
25. Taylor S, Allen S, Fidler S, et al. Stop study: After discontinuation of efavirenz, plasma concentrations may persist for 2 weeks or longer. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 131.
26. Muro E, Droste J, ter Hofstede H, et al. Nevirapine plasma concentrations are still detectable after more than 2 weeks in the majority of women receiving single-dose NVP: implications for intervention studies. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 891.
27. Dybul M, Nies-Kraske E, Daucher M, et al. Long-cycle structured intermittent versus continuous highly active antiretroviral therapy for the treatment of chronic infection with human immunodeficiency virus: effects on drug toxicity and on immunologic and virologic parameters. J Infect Dis 2003;188:388-396.
28. Vella S, Palmisano L, Giuliano M, et al. ISS-PART: a prospective, randomized, multicenter clinical trial of intermittent therapy in HIV+ subjects with persistent suppression of viral replication: 48 weeks follow-up. 2nd IAS Conference on HIV Pathogenesis and Treatment. July 13-16, 2003. Paris. Abstract LB47.
29. Barreiro P, De Mendoza C, Camino N, et al. Superior performance of protease inhibitors over non-nucleosides when HAART is resumed after treatment interruptions. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. October 30-November 2, 2004. Washington, DC. Abstract H-576.
30. Mellors J, Palmer S, Nissley D, et al. Low-frequency NNRTI-resistant variants contribute to failure of efavirenz-containing regimens. 11th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2004. San Francisco. Abstract 39.
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