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Second-Line and Salvage Strategies
(Good News and Bad With TMC125)
When to change a failing regimen
Kaletra & Fosamprenavir/r for PI Resistance
How efavirenz affects new lopinavir tablet
Lopinavir/ritonavir inhibits CYP2D6
Omeprazole hoists saquinavir levels
Antiretroviral switch = failure, or not?
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Written for NATAP. A Report from the 10th European AIDS Conference (EACS), November 17-20, 2005, Dublin
Mark Mascolini
Two late-breaker talks at the Dublin EACS meeting laid out phase 2 salvage results with TMC125, the Tibotec nonnucleoside reverse transcriptase inhibitor (NNRTI) that trimmed viral loads by a median 0.89 log copies/mL when given for 7 days to 16 people taking a failing efavirenz or nevirapine regimen [1].
One of the two new studies suggested TMC125 may do something no nonnuke has done before-control HIV replication after failure of another NNRTI. The other study, however, charted an unimpressive difference in antiviral vigor between TMC125 and placebo-but the trial design apparently explains this middling result. Then, a few weeks after EACS, Tibotec called a halt to another phase 2 study because a protease inhibitor (PI) regimen outdid TMC125 in people with NNRTI-but not PI-experience [2].
Two ongoing phase 3 studies-the DUET trials-will determine whether this much-heralded NNRTI will fulfill its potential. In the meantime this report examines the evidence from EACS and the scant data released on the TMC125-versus-PI trial.
Other work headlined at the Dublin gathering featured data on how efavirenz affects the new lopinavir/ritonavir tablets-and how the proton pump inhibitor omeprazole affects saquinavir/ritonavir. Several intriguing analyses addressed two vexing questions of rescue-regimen planning: What does virologic failure mean clinically? And how fast should people switch from an incompletely suppressive regimen?
TMC125-good news and bad news
A 48-week dose-escalation and safety trial of TMC125, presented by the University of British Columbia's Julio Montaner, enrolled 306 people with triple-class experience and a viral load above 1000 copies/mL [3]. With other Canadian and European colleagues, Montaner randomized them to a salvage regimen including 800 or 1200 mg of TMC125 twice daily or placebo.
A crucial trial design feature gave people in the placebo arm a good chance of responding: All enrollees had to have virus sensitive to two or more antiretrovirals that they could add to TMC125 or placebo. Besides placebo or the Tibotec nonnuke, they could start three to four antiretrovirals, including nucleosides with or without lopinavir/ritonavir or saquinavir/ritonavir, and with or without the fusion inhibitor enfuvirtide.
The median starting viral load stood at 4.09 log copies/mL (about 12,300 copies/mL) in the 60 people randomized to placebo and 4.25 log copies/mL (about 17,800 copies/mL) in the 240 assigned to TMC125. So most of these people did not have runaway viral replication. But many people had CD4 counts in or near the danger zone, with median baseline tallies of 230 cells/mL in the placebo group and 211 cells/mL in the TMC125 arm. Both groups had an 11-year history of HIV infection, and almost half in each group had AIDS.
After 24 weeks a noncompleter-equals-failure analysis figured an almost identical viral load drop in the two TMC125 arms, between 1.0 and 1.5 log copies/mL. Confidence intervals almost overlapped with the 24-week drop in the placebo group, which lay between 0.5 and 1.0 log copies/mL. The reasonable treatment options available to the placebo group surely contributed to their decent 24-week response.
A graph of time to treatment discontinuation through more than 50 weeks showed virtually overlapping lines for the placebo group and the TMC125 groups. At the 24-week primary analysis, a slightly higher proportion quit in the placebo arm because of virologic failure, while a much higher proportion stopped TMC125 because of side effects (Table).
Discontinuation of TMC125 or placebo at 24 weeks
Gastrointestinal problems proved the most frequent cause of discontinuation in the TMC125 group. Pancreatitis accounted for three of the six serious toxicities with TMC125. Everyone in whom pancreatitis developed had risk factors for this condition, but Montaner and colleagues could not exclude TMC125 as the cause. Diarrhea was the most common side effect in the NNRTI group, affecting 26% after a median 29 weeks of follow-up.
Overall rates of grade 3 or 4 lab abnormalities did not differ between the TMC125 arm (31% grade 3 and 11% grade 4 after a median 29 weeks) and the placebo arm (29% grade 3 and 12% grade 4 after a median 40 weeks). Grade 3 or 4 pancreatic amylase readings turned up in 5% taking TMC125 and 3% taking placebo.
Phase 3 studies will use a 200-mg twice-daily formulation of TMC125 (two tablets twice daily) that yields TMC125 levels equivalent to those attained with 800 mg twice daily in this trial.
A 48-week trial presented by the University of South Florida's Jeffrey Nadler found better 24-week RNA and CD4 responses to TMC125 than to an "active control" regimen in 199 people with resistance to NNRTIs and three or more primary protease mutations [4]. Nadler and colleagues at other US centers randomized them to take 400 or 800 mg of TMC125 twice daily plus a background regimen or to the control regimen.
Baseline viral loads were similar in the three treatment arms-about 4.7 log copies/mL (50,000 copies/mL)-as was the starting CD4 count-about 100 cells/mL. Two thirds in each treatment group had AIDS.
One trait appeared to favor the TMC125 arms-virus susceptible to more antiretrovirals. More than 40% of people randomized to TMC125 had virus sensitive to two or three antiretrovirals besides the new NNRTI, compared with 25% in the control group. Whereas 40% in each of the TMC125 arms had virus sensitive to only one other antiretroviral, 49% in the control group had only one promising drug to use. While 46% in the 400-mg TMC125 arm and 42% in the 800-mg arm had never tried enfuvirtide and used it as part of their salvage regimen, only 27.5% in the control arm had never tried enfuvirtide and used it in this study.
Yet the TMC125 regimen outperformed the control combination after 24 weeks regardless of how many drugs in the regimen had a phenotypic sensitivity score indicating a good chance of antiviral activity (Table).
Response to TMC125 according to active drugs in regimen
The most-used active drug was enfuvirtide, and its use correlated with virologic response in every treatment arm (P < 0.001). This finding adds to a growing mount of data showing the value of having at least two active drugs in a salvage regimen.
About one third of study participants reached a viral load below 400 copies/mL in a 24-week time-to-loss-of-virologic-response analysis, significantly more than reached that mark with the control regimen (Table). CD4 counts also climbed higher with TMC125.
Time to loss of virologic response and CD4 change at week 24
Rates of grade 3 or 4 side effects proved high but consistent across the three treatment groups-36% with 400 mg of TMC125, 41% with 800 mg, and 38% with the control combo. Grade 3 or 4 lab abnormalities affected about 30% in each group. Twelve people taking TMC125 (8%) had abnormal pancreatic amylase, and pancreatitis cropped up in 3 (2%). Three people (2%) had a TMC125-related rash, 10 (6%) had grade 3 or 4 triglyceride jumps, 9 (6%) had neutropenia, and 5 (3%) had abnormal creatinine.
Five people died during the study, 4 while taking 400 mg of TMC125 twice daily and 1 while taking a control regimen. Researchers blamed TMC125 for one death from cardiopulmonary failure and myocardial infarction.
Nine days after EACS attendees left dear dirty Dublin, Tibotec slammed the brakes on another phase 2 study, this one pitting TMC125 plus two nucleosides against a PI plus two nukes [2]. Unlike the just-reviewed salvage trial, no one in the abandoned trial had tasted a PI before, and only one NNRTI regimen had failed in these people.
After only 12 weeks of follow-up researchers noted that substantially fewer people taking TMC125 reached the primary response target-a viral load below 50 copies/mL. Tibotec scuttled the study and recommended that everyone taking TMC125-even those responding well-switch to a regimen of licensed antiretrovirals. The shutdown will not affect phase 3 studies.
Researchers will look at the potential roles of baseline resistance, the nucleosides used (which were not mentioned in the Tibotec press release), and TMC125 plasma levels attained in the halted trial. Unless they find something striking, the results could mean TMC125 is a second-rate option after failure of efavirenz or nevirapine in people still naive to PIs.
How efavirenz affects new lopinavir tablet
The new lopinavir/ritonavir tablet trims the daily pill count for this PI from six to four. Pharmacologists already knew that efavirenz speeds up clearance of the old lopinavir capsules by 20% and so cuts levels of this PI. To find out whether efavirenz has the same effect on the new table, Abbott recruited 23 healthy volunteers without HIV to take the new PI tablet at a dose of 400/100 mg twice daily for 15 days [5]. Then they started standard-dose efavirenz on day 11. On day 15 they upped the lopinavir/ritonavir dose to 600/150 mg twice daily and took it with efavirenz for 10 days.
Comparing results with an earlier study of lopinavir/ritonavir capsules, Cheri Klein and Abbott colleagues confirmed that two lopinavir/ritonavir tablets (400/100 mg) twice a day yield PI levels equivalent to those reached with three capsules (400/100 mg) twice daily. Efavirenz plus three of the PI tablets (600/150 mg) twice daily raised exposure to lopinavir 36% and to ritonavir 78% compared with efavirenz plus 400/100 mg of the tablet twice daily. But this higher PI exposure did not cause more gastrointestinal grumbles in these healthy volunteers.
Abbott believes two of the tablets twice daily plus efavirenz yield levels of the PIs comparable to those reached when the standard-dose capsule is not taken with CYP3A-inducing drugs like efavirenz. The boost in lopinavir and ritonavir levels with efavirenz plus 600/150 mg twice daily, Abbott proposed, may compensate for the tendency of efavirenz to speed clearance of these PIs.
Lopinavir/ritonavir inhibits CYP2D6
People with HIV take an array of drugs metabolized by the CYP2D6 enzyme, including antidepressants, antipsychotics, and the heart drugs called beta blockers. In a study involving 30 people with HIV, researchers from Cologne, Nijmegen, and Liverpool found that lopinavir/ritonavir inhibits CYP2D6 and so may dangerously boost levels of drugs processed by this crucial enzyme [6].
To gauge CYP2D6 activity, the University of Cologne's Christoph Wyen and colleagues measured levels of dextromethorphan and its metabolite dextrorphan in people before they started lopinavir/ritonavir and two nucleosides and 14 days after they started therapy. Because dextromethorphan metabolism depends on CYP2D6, a lower dexrorphan level and a higher dextromethorphan/dextrorphan ratio after 14 days of the PIs would mean lopinavir/ritonavir inhibits CYP2D6.
And that's what happened. The geometric mean ratio for dextrorphan area under the concentration-time curve (AUC) tumbled about 50%, from 20.1 to 10.1 ng/mL • h, after 14 days of lopinavir/ritonavir. And the dextromethorphan/dextrorphan ratio nearly tripled, zooming from 1.21 before lopinavir/ritonavir to 3.14 after 14 days of therapy.
These results mean lopinavir/ritonavir sliced CYP2D6 activity in half. Such severely truncated CYP2D6 drive would result in pileups of drugs that depend on the enzyme for metabolism.
Wyen's results could explain the MDMA (Ecstasy) intoxication seen in people taking lopinavir/ritonavir, as well as toxic levels of the antidepressant risperidone observed during lopinavir/ritonavir therapy.
Omeprazole hoists saquinavir levels
Another important drug interaction study found that omeprazole, the proton pump inhibitor that quenches stomach acid, greatly raises saquinavir levels when people take the new 500-mg saquinavir formulation in a ritonavir-boosted dose of 1000/100 mg twice daily [7]. In this 15-day study in 18 healthy volunteers, Alan Winston from London's Chelsea and Westminster Hospital charted a 75% jump in saquinavir's peak concentration and an 82% jump in total saquinavir exposure with 40 mg of omeprazole daily. The higher saquinavir levels did not cause more side effects in this short study of people without HIV, but long-term combination of omeprazole and saquinavir/ritonavir may cause problems.
When to change a failing regimen
Several studies show that it's better for people with no good salvage options to continue a failing regimen rather than stop treatment altogether [8-10]. But how fast to abandon a faltering regimen when rescue options exist remains a contentious issue. Four EACS studies addressed this question.
Alessandro Cozzi-Lepri from London's Royal Free Hospital and EuroSIDA cohort colleagues made several trenchant discoveries in their analysis of 110 people who continued a virologically failing three-or-more-drug regimen [11]. Viral loads inched up slowly as the faltering treatment continued, and CD4 counts drifted downward at a languid pace. Those dynamics in individual patients often encourage clinicians to stick with the same regimen rather than shop for options. But the EuroSIDA crew tracked a remorseless rise in resistance-conferring mutations as shaky regimens continued.
Cozzi-Lepri and coworkers studied 110 people who had two genotypes done while their viral load persisted above the 400-copy threshold on the same regimen. They figured a genotypic sensitivity score (GSS) for the failing regimen in which 0 means viral resistance to the regimen components, 0.5 means intermediate resistance, and 1 means sensitivity to the antiretrovirals used.
The median time between the cohort's first and second genotype measured 6 months and ranged from 2 to 28 months. The median year of the first genotype was 1998 with a range from 1996 to 2001. Reflecting that era, almost half of the regimens rested on unboosted PIs, slightly more than 10% used a boosted PI, and slightly fewer than 10% used an NNRTI.
The group's CD4 count averaged 280 cells/mL between the first and the second genotype, dropping about 10 cells/mL monthly. The average viral load inched up 0.14 log copies/mL monthly. But during these apparently tranquil months, 85 of 110 people (77%) picked up at least one resistance mutation, including:
- One or more thymidine analog mutations in 27 (24.6%)
- The 3TC mutation M184V in 7 (6.4%)
- One or more nonnucleoside mutations in 13 (11.8%)
- One or more major PI mutations in 40 (36.4%)
- One or more minor PI mutations in 51 (46.4%)
At the first genotype, on average, the covertly floundering regimens included only 1.1 drugs to which HIV remained susceptible.
A multivariate analysis segregated a single factor that independently predicted evolution of more mutations as the failing regimen continued: People with fewer mutations on the first genotype-the very people with the most rescue regimen options-had the highest risk of gathering more mutations.
A different type of analysis in a different population reached the opposite conclusion-on average, few mutations evolve in people who continue a failing regimen with a modest viral load for 48 weeks [12]. But this finding is not too surprising when seen in the context of this Italian cohort since (1) many study participants had at least one NNRTI mutation (so the virus had no need to evolve new mutations to escape NNRTIs), (2) PI mutations tended to recede from detection (because most people were taking a non-PI regimen), and (3) nucleoside mutations did keep piling up.
The University of Brescia's Paola Nasta ran this analysis as a substudy of the IMPROVE trial, which randomizes lopinavir/ritonavir-naive people to continue an incompletely suppressive regimen or to start a new combination including lopinavir/ritonavir. Everyone had a viral load between 1000 and 20,000 copies/mL for at least 6 months while taking the same regimen, everyone had a CD4 count at or above 200 cells/mL, and two or more regimens had failed in all study participants.
The 74 people randomized to stick with their antiretrovirals and the 76 assigned to try a new mix including lopinavir/ritonavir had similar baseline traits. The groups had taken antiretrovirals for a average 6.6 years, including (on average) 2.9 nucleosides, 0.9 NNRTIs, and 2 PIs. The last regimen before randomization consisted of two nucleosides and an NNRTI in 44.7%, two nucleosides and a PI in 37.3%, and three nucleosides in 17.9%. In the maintenance group 69% were taking a non-PI medley.
The baseline CD4 count averaged 422 cells/mL and the baseline viral load 3.6 log copies/mL. The study group had an average 3.39 nucleoside-related mutations, 3.16 PI mutations, and 0.93 NNRTI mutations (1.01 NNRTI mutations in the maintenance group).
After 48 weeks of follow-up, 11 of 74 people (15%) in the maintenance arm reached a study endpoint-either a viral load jump to 30,000 copies/mL or a CD4 drop below 200 cells/mL. Only 3 people (4%) in the lopinavir/ritonavir switch arm reached one of those endpoints, a significant difference (P = 0.02). While 50 people (66%) in the switch group claimed a viral load below 50 copies/mL at week 48, no one in the maintenance group did. Similarly low proportions dropped out of the study because of side effects-3% in the maintenance group and 4% in the switch group.
Among people maintaining their baseline regimen, median total mutations numbered 7.7 at baseline and 7.7 after 48 weeks. But Nasta reported changes in specific mutation groups over the course of the study in people who stayed with the same drugs: While the median number of thymidine analog mutations stayed stable at 2.3, the median number of all nucleoside-induced mutations rose from 3.4 at baseline to 3.8 at week 48. Median numbers of NNRTI mutations hardly changed, from 1.01 at baseline to 1.06 at week 48. And median PI mutations dropped from 3.2 to 2.8 during the study, as these mutations tended to become undetectable in the 69% of maintainers not taking a PI.
Nasta also figured a genotypic sensitivity score (GSS) for the current regimen and a GSS for future options. On this GSS scale 0 represents the highest level of resistance for each drug and 3 indicates the lowest level for each drug. The final GSS represents the sum of scores for all drugs in a regimen or all drugs still available. While the GSS for the current regimen changed hardly at all, the GSS for future options dropped from 7.6 (+3.9 standard deviation) at baseline to 6.9 (+4.8) at week 48. That ebb, though small, does not appear to support the researchers' conclusion that "future treatment options . . . seem to be preserved" in the population they studied.
PIs resistant to resistance
Even after virologic failure of one, two, or three PI regimens, a hefty majority of viral isolates from Italian and US patients remained sensitive to lopinavir/ritonavir, fosamprenavir, or fosamprenavir/ritonavir in a study by Andrea De Luca from Rome's Catholic University [13].
The analysis involved 643 people in the Catholic University cohort or the Stanford University database who had complete treatment histories on file, the entire protease sequence available for genotyping, and a history of at least one PI failure. Three or more PI regimens had flopped in 271 people (42%), two in 167 (26%), and one in 205 (32%). The most frequently used PIs were indinavir (28%), nelfinavir (22%), saquinavir/ritonavir (19%), lopinavir/ritonavir (8%), ritonavir (7%), and saquinavir (6%).
According to the Stanford genotypic resistance algorithm, which considers lopinavir/ritonavir but only unboosted fosamprenavir, most isolates retained either full sensitivity (34%) or partial sensitivity (20%) to lopinavir/ritonavir, while 46% of isolates were judged resistant. The Stanford algorithm called equivalent proportions fully sensitive (32%) or partially sensitive (18%) to unboosted fosamprenavir, while 49% were judged resistant.
According to the French national AIDS trial group (ANRS) algorithm, which considers boosted fosamprenavir and lopinavir, big majorities of isolates from these cohorts remained fully sensitive to fosamprenavir/ritonavir (91%) and lopinavir/ritonavir (83%). That difference in sensitivity was statistically significant (P < 0.001), but the ANRS formula reckoned that another 12% of isolates had intermediate sensitivity to lopinavir/ritonavir. Among isolates from people in whom three or more PI regimens failed, 87% remained fully susceptible to both boosted PIs, according to ANRS.
Still, a longer antiretroviral treatment history did trim the chances for full sensitivity to fosamprenavir/ritonavir and lopinavir/ritonavir according to ANRS rules. A multivariate analysis figured that each additional failed regimen lowered the chance of full susceptibility to fosamprenavir/ritonavir by 40% (odds ratio 0.60, 95% confidence interval 0.40 to 0.91, P = 0.017). A similar analysis determined that each added month of antiretroviral experience nipped the chance of full susceptibility to lopinavir/ritonavir by 2% (OR 0.98, 95% confidence interval 0.97 to 0.99, P = 0.006).
Earlier ritonavir use tended to lower odds of viral susceptibility to lopinavir/ritonavir after PI failure (OR 0.68, 95% confidence interval 0.42 to 1.08, P = 0.10), and earlier saquinavir use tended to cut the chance of viral susceptibility to fosamprenavir/ritonavir (OR 0.69, 95% confidence interval 0.37 to 1.25, P = 0.22).
Although longer treatment experience meant a higher risk of PI resistance in the Rome and Stanford cohorts, accumulating years of antiretroviral therapy did not translate into deteriorating virologic response in the Spedali Civili HIV clinic in Brescia, Italy [14]. In fact the percentage of people with an undetectable viral load climbed from just under 50% in 2001 to over 70% in 2005, reported Carlo Torti.
The cohort included 1406 people still naive to at least one antiretroviral class and 1341 who had tried the first three classes of antiretrovirals. Among 2449 people with antiretroviral experience, 911 (37.2%) had used more than seven antiretrovirals and 1130 (46.1%) had tried four to seven.
More treatment experience appeared not to curb chances of maintaining an undetectable load in this cohort. Torti could not measure viremia in 79.2% of people on their first regimen, 84.7% on their second or third regimen, and 74.6% trying their fourth or later combination. HIV RNA lay below detection limits in 78.5% of people treated for 6 to 12 months, 85.6% treated for 1 to 2 years, and 84.6% treated more than 2 years.
Torti concluded that in his cohort longer treatment with a wider array of antiretrovirals did not signal "treatment exhaustion." Although regimen switching proved common, continued viral suppression appeared to indicate sustained activity of new and already-used antiretrovirals, and perhaps sharper therapeutic planning by Brescia's HIV clinicians.
Antiretroviral switch = failure, or not?
When figuring virologic success in randomized clinical trials, statisticians often use an intent-to-treat analysis in which a switch from assigned drugs counts as therapeutic failure. But do switchers really fail clinically? No, according to a EuroSIDA cohort analysis by Ole Kirk from the Copenhagen HIV Program [15].
Kirk and EuroSIDA sidekicks reached that conclusion by tracking outcomes in 4784 cohort members starting their first antiretroviral regimen. The EuroSIDA team split them into four groups according to how clinical trial researchers would rate their virologic response and regimen history.
- Group 1: 1998 people with virologic failure (more than one viral load above 400 copies/mL regardless of drug switches)
- Group 2: 1327 with virologic and therapeutic success (all viral loads below 400 copies/mL and no regimen change in the first 12 months of therapy)
- Group 3 (the switchers): 693 people with virologic success but therapeutic failure (all viral loads below 400 copies/mL but a regimen change in the first 12 months of therapy)
- Group 4: 766 people with a missed visit or viral load measurement (classified as treatment failures in some intent-to-treat analyses)
With 21,586 person-years of follow-up starting after 12 months of therapy, Kirk tallied 368 deaths and 594 new AIDS diagnoses. Compared with group 3-the switch = failure group-the virologic and therapeutic success contingent (group 2) had a nonsignificantly lower risk of progression or death, while the people with virologic failure (group 1) had an 86% higher risk of progression or death-a significant difference from the switch group (Table).
Risk of HIV progression in EuroSIDA
Kirk believes the results suggest that a drug switch does not equal virologic failure "in terms of ultimate clinical outcome." He urged careful interpretation of trials that count switches as failures and recommended abandoning that definition of failure in future trials.
Mark Mascolini writes about HIV infection
References
1. Gazzard BG, Pozniak AL, Rosenbaum W, et al. An open-label assessment of TMC 125-a new, next-generation NNRTI, for 7 days in HIV-1 infected individuals with NNRTI resistance. AIDS 2003;17:F49-F54.
2. PRNewswire. Tibotec discontinues exploratory trial with TMC125. November 29, 2005.
3. Montaner J, Domingo P, Junod P, et al. Safety and tolerability of TMC125 in 3-class-experienced HIV-infected patients: 24-week primary analysis of trial TMC125-C203. European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPS3/7B.
4. Nadler JP, Grossman HA, Hicks C, et al. Efficacy and tolerability of TMC125 in HIV patients with NNRTI and PI resistance at 24 weeks: TMC125-C223. European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPS3/7A.
5. Klein C, Zhu T, Chiu YL, et al. Effect of efavirenz on lopinavir/ritonavir pharmacokinetics from a new tablet formulation. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.3/2.
6. Wyen C, Jetter A, Frank D, et al. CYP2D6 is inhibited by lopinavir/ritonavir in HIV-infected patients. European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE4.1/6.
7. Winston A, Back D, Fletcher C, et al. Effect of omeprazole on the pharmacokinetics of saquinavir 500 mg formulation with ritonavir in healthy male and female volunteers. 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract LBPE4.3/16.
8. Miller V, Phillips AN, Clotet B, et al. Association of virus load, CD4 cell count, and treatment with clinical progression in human immunodeficiency virus-infected patients with very low CD4 cell counts. J Infect Dis 2002;186:189-197.
9. Ledergerber B, Lundgren JD, Walker AS, et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004;364:51-62.
10. Kousignian I, Abgrall S, Graba S, et al. Effect of HAART, CD4 cell counts, and viral load on incidence of AIDS-defining events. 12th Conference on Retroviruses and Opportunistic Infections. February 22-25, 2005. Boston. Abstract 592.
11. Cozzi-Lepri A, Phillips AN, Ruiz L, et al. Evolution of drug resistance in HIV infected patients remaining on a virologically failing HAART regimen. European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE17.4/2.
12. Nasta P, Matti A, Gatti F, et al. Are future treatment options reduced in heavily pre-treated HIV+ patients with sustained low level viremia randomized to defer HAART switch? European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE3.4/8.
13. De Luca A, Di Giambenedetto S, Colafigli S, et al. Prevalence of genotypic resistance to boosted fosamprenavir and lopinavir of clinical isolates from patients failing protease inhibitors: influence of genotypic resistance interpretation and number of failed regimens. European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE3.4/11.
14. Paraninfo G, Torti C, Quiros-Roldan E, et al. Antiretroviral drug experience and the treatment response at a population level: is treatment exhaustion really there? European AIDS Conference. November 17-20, 2005. Dublin. Abstract PE7.9/5.
15. Kirk O, Mocroft A, Reiss P, et al. Is there an association between the endpoints in trials of virological efficacy and clinical long-term prognosis? European AIDS Conference. November 17-20, 2005. Dublin. Abstract PS3/4.
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