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Clinical trials of HIV antiretroviral therapy
Paul E Sax, MD (http://www.utdol.com/utd/content/author.do?authorId=265793)
UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.3 is current through August 2007; this topic was last changed on September 11, 2007. The next version of UpToDate (16.1) will be released in March 2008.
INTRODUCTION — This topic reviews the results of some of the major clinical trials of HIV antiretroviral therapy (ART). The clinical use of ART is discussed separately. (See "Initial antiretroviral therapy for HIV infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/22857), and see "Modifying HIV antiretroviral therapy regimens" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/23208), and see "Primary HIV-1 infection: Diagnosis and treatment" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/17081)).
The abbreviations for antiretroviral medications discussed in this topic are shown in Table 1 (show table 1 (http://www.utdol.com/utd/content/image.do?imageKey=id_pix/antire8.htm)).
NRTI MONOTHERAPY
Advanced disease — In a randomized trial in patients with a history of Pneumocystis jiroveci pneumonia (PCP) or advanced AIDS-related complex, fewer of the 145 patients treated with ZDV monotherapy (250 mg every four hours) for 24 weeks died than of the 137 patients treated with placebo (1 versus 19 deaths) and fewer patients developed new opportunistic infections (24 versus 45) [1 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=1)].
Earlier disease
Concorde — Concorde was a randomized trial that compared a strategy of immediate ZDV therapy (250 mg four times daily) with deferred therapy in 1749 asymptomatic patients [2 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=2)]. After a median follow-up of 3.3 years, there was no significant difference in survival with immediate or delayed therapy (92 versus 94 percent) and no difference in a combined end point of death or progression to AIDS (18 versus 18 percent).
This trial suggested that, at least in the era before highly active antiretroviral therapy (HAART), early therapy was not beneficial.
ACTG 019 — A randomized trial compared immediate ZDV therapy (500 or 1500 mg daily in divided doses) versus deferred therapy in 1637 patients with an initial CD4 count http://www.utdol.com/utd/images/characters/ge.gif500 cells/microL [3 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=3)]. Although CD4 counts declined more slowly in patients treated with ZDV, there was no significant difference in the rate of progression to AIDS or death compared with patients who had deferred therapy (3.4 versus 3.6 events per 100 person-years) and no difference in the mortality rate (1.9 versus 2.2 deaths per 100 person-years).
This trial also suggested that in the pre-HAART era, early therapy was not beneficial and ZDV monotherapy should not be given to patients with a CD4 cell count above 500 cells/microL.
COMPARISONS OF NRTI MONOTHERAPY AND DUAL THERAPY
Delta — The Delta trial compared ZDV monotherapy (200 mg three times daily) with combination therapy with ZDV plus either ddI (200 mg twice daily) or ddC (0.75 mg three times daily) in 3207 patients with either symptomatic disease (if AIDS, with a CD4 count above 50 cells/microL) or a CD4 count below 350 cells/microL [4 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=4)]. After a median follow-up of 30 months, 22 percent of patients died. Among patients who had not previously taken ZDV and compared with patients who received monotherapy, the risk of death was reduced in patients who received combination therapy with ddI (hazard ratio [HR] 0.58) or ddC (HR 0.68); among patients with prior ZDV exposure, there was still a reduced risk of death with ddI combination therapy (HR 0.72) but there was no significant decrease in risk with ddC combination therapy.
This trial suggested that treatment with two antiretroviral drugs was superior to monotherapy.
ACTG 175 trial — A randomized trial compared ZDV monotherapy (200 mg three times daily), ddI monotherapy (200 mg twice daily), dual ZDV plus ddI, and dual ZDV plus ddC (0.75 mg three times daily) [5 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=5)]. Compared with patients who received ZDV monotherapy, the risk of progression to the primary combined end point (50 percent decline in CD4 count, AIDS, or death) was reduced with ddI monotherapy (hazard ratio [HR] 0.61), dual ZDV plus ddI (HR 0.50) and dual ZDV plus ddC (HR 0.54).
COMPARISONS OF DUAL AND TRIPLE THERAPY
ACTG 320 trial — A randomized trial compared dual NRTI therapy (3TC 150 mg twice daily plus ZDV 200 mg three times daily or stavudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/247071&drug=true) 40 mg twice daily) with the same regimen plus indinavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/130887&drug=true) 800 mg every eight hours in 1156 patients who had previously received at least three months of ZDV and had a CD4 count no greater than 200 cells/microL [6 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=6)]. The trial was stopped early when the monitoring board found significant differences between the two groups. After a median follow-up of 38 weeks, fewer patients treated with triple therapy reached the primary combined end point of a new clinical AIDS-defining event or death (6 versus 11 percent; hazard ratio 0.50, 95% CI 0.33-0.76) and fewer patients died (1.4 versus 3.1 percent; hazard ratio 0.43, 95% CI 0.19-0.99).
This trial demonstrated the superiority of triple therapy using a dual NRTI backbone plus a third drug compared with dual therapy.
COMPARISONS OF NRTI BACKBONES
ACTG 384 trial — A randomized trial compared NFV 1250 mg twice daily with EFV 600 mg daily in 620 treatment-naive patients who received an NRTI backbone of either ZDV 300 mg twice daily plus 3TC 150 mg twice daily or ddI 400 mg daily plus d4T 40 mg twice daily [7 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=7)]. Patients treated, who failed their first assigned regimen (because of toxicity or virologic failure), were assigned to the other regimen, and the time to failure of the second regimen was the primary end point of the trial. Compared with patients initially treated with ddI/d4T, patients initially treated with ZDV/3TC (with an EFV base, but not with a NFV base) were less likely to reach the primary end point (hazard ratio [HR] 0.68, 95% CI 0.46-1.01). The risk of failure of the first regimen was also lower in patients treated with ZDV/3TC who received EFV (HR 0.35, 95% CI 0.22-0.57) but was not significantly lower in those who received NFV (HR 0.82, 95% CI 0.56-1.20).
This trial showed that not all NRTI backbones achieve equivalent results. The results of the EFV versus NFV base comparison from this trial are discussed below (see "NFV versus EFV (ACTG 384)" below (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/23904&view=text#19)).
TDF versus d4T (Gilead 903) — A randomized trial compared TDF 300 mg daily with d4T 40 mg twice daily in 602 treatment-naive patients who also received 3TC 150 mg twice daily and EFV 600 mg daily [8 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=8)]. After 144 weeks of follow-up, the proportion of patients with a viral load below 50 copies/mL was similar in the TDF and d4T groups (68 versus 63 percent). Patients receiving TDF had less lipodystrophy (3 versus 19 percent) and more favorable lipid profiles.
This trial showed the potency and tolerability of TDF and that d4T caused large increases in triglyceride levels, leading to a less favorable view of d4T as a component of HAART.
FTC versus d4T (FTC301A) — A randomized trial compared FTC 200 mg daily with d4T 40 mg twice daily in 571 treatment-naive patients who also received ddI 400 mg and EFV 600 mg daily [9 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=9)]. The monitoring board stopped the trial early. After a median follow-up of 42 weeks, more patients receiving FTC had a viral load below 50 copies/mL (85 versus 76 percent).
ABC versus ZDV (CNA30024) — A randomized trial compared ABC 300 mg twice daily with ZDV 300 mg twice daily in 649 treatment-naive patients who also received 3TC 150 mg twice daily and EFV 600 mg daily [10 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=10)]. After 48 weeks of follow-up, the proportion of patients with a viral load below 50 copies/mL was similar in the ABC and ZDV group (70 versus 69 percent). In an "as-treated" analysis, the proportion of patients with a viral load below 400 copies/mL was also similar in the two groups (96 versus 98 percent). Withdrawal from the study was less common with ABC (14 versus 18 percent). However, serious adverse events were more common (20 versus 14 percent).
TDF/FTC versus ZDV/3TC (Study 934) — An open label randomized trial designed as a noninferiority study compared TDF 300 mg daily plus FTC 200 mg daily with ZDV 300 mg twice daily plus 3TC twice daily in 517 treatment-naive adult patients who also received EFV 600 mg daily [11 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=11)]. After 48 weeks of follow-up, more patients in the TDF/FTC arm achieved a viral load below 50 copies/mL (80 versus 70 percent) and the mean increase from baseline in CD4 count was greater in the TDF/FTC arm (190 versus 158 cells/microL). Adherence, as assessed by pill counts, was greater in the TDF/FTC arm (90 versus 87 percent) and fewer patients in that arm had adverse events resulting in discontinuation of the study drugs (four versus nine percent). The most common adverse event resulting in discontinuation in the ZDV/3TC arm was anemia (six percent of patients). No patient developed the K65R mutation through 96 weeks of analysis [12 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=12)].
This study of antiretroviral-naive patients gives further support for treatment guidelines, which recommend TDF and FTC as preferred nucleoside analog "backbone" agents within three-drug combination regimens.
COMPARISONS OF PI-BASED AND NNRTI-BASED REGIMENS
NFV versus EFV (ACTG 384) — A randomized trial compared NFV 1250 mg twice daily with EFV 600 mg daily in 620 treatment-naive patients who received an NRTI backbone of either ZDV 300 mg twice daily plus 3TC 150 mg twice daily or ddI 400 mg daily plus d4T 40 mg twice daily [7 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=7)]. Patients treated, who failed their first assigned regimen (because of toxicity or virologic failure), were assigned to the other regimen, and the time to failure of the second regimen was the primary end point of the trial. Compared with patients initially treated with NFV, patients initially treated with EFV (with a ZDV/3TC backbone, but not with a ddI/d4T backbone) were less likely to reach the primary end point (hazard ratio [HR] 0.71, 95% CI 0.48-1.06). The risk of failure of the first regimen was also lower in patients treated with EFV who received ZDV/3TC (HR 0.39, 95% CI 0.24-0.64) but was not significantly lower in those who received ddI/d4T (HR 0.88, 95% CI 0.61-1.29).
The results of the NRTI backbone comparison from this trial are discussed above. (See "ACTG 384 trial" above (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/23904&view=text#13)).
ATV versus EFV — A randomized trial compared ATV 400 mg daily with EFV 600 mg daily in 810 treatment-naive patients who also received open label twice daily ZDV 300 mg plus 3TC 150 mg [13 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=13)]. The proportions of patients achieving an HIV viral load (VL) below 400 copies/mL at week 48 were similar in patients receiving ATV and EFV (70 versus 64 percent) as were the proportions achieving a VL below 50 copies/mL (32 versus 37 percent). Among patients who completed 48 weeks of treatment (an "as-treated" analysis), the proportion achieving a VL below 50 copies/mL were also similar (44 versus 51 percent). The low viral control rates seen in both arms of the study were apparently related to laboratory problems with the type of preservative used for the samples.
The overall frequency of adverse events was similar in the two groups, with rash and dizziness occurring more frequently with EFV, and jaundice and scleral icterus occurring more frequently with ATV. Serious adverse events occurred in 10 percent of each group. Overall, ATV treatment was associated with a more favorable lipid profile with significant differences in the change from baseline in total cholesterol (2 versus 21 percent), LDL-cholesterol (1 versus 18 percent) and triglycerides (-9 versus 23 percent); the increase in HDL-cholesterol was smaller with ATV (13 versus 24 percent). Glucose levels were not significantly changed from baseline in either group.
SQV/RTV versus EFV (FOCUS) — FOCUS is a randomized trial that compared a boosted SQV-based regimen (SQV 1600 mg daily plus RTV 100 mg daily) with an EFV-based regimen in 152 treatment-naive patients [14 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=14)]. In a preliminary report, more patients treated with EFV had a viral load below 50 copies/mL at 48 weeks (71 versus 51 percent).
AMP/RTV versus EFV (CLASS) — CLASS is a randomized trial that compared a boosted AMP-based regimen with an EFV-based regimen (as well as a triple NRTI regimen) in 291 treatment-naive patients [15 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=15)]. In a preliminary report, fewer patients treated with EFV experienced first virologic failure than patients in the other arms of the study.
NFV versus NVP (COMBINE) — A randomized trial compared NFV 1250 mg twice daily with NVP 200 mg twice daily in 142 treatment-naive patients who also received ZDV 300 mg twice daily plus 3TC 150 mg twice daily [16 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=16)]. After 12 months, more patients treated with NVP had a viral load below 20 copies/mL, although the results did not achieve statistical significance (65 versus 50 percent, p = 0.06).
PI versus NNRTI-based strategies versus both (FIRST) — Between 1999 and 2002, 1397 antiretroviral therapy-naive patients at 80 research sites were randomly assigned to a PI, NNRTI, or a PI plus an NNRTI treatment regimen [17 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=17)]. All patients received two nucleoside analogs as part of their combination ART. Over a median follow-up of five years, there was no difference in immunologic or clinical outcomes (AIDS-defining event or death) between an initial PI-based or an NNRTI-based regimen. Furthermore, a 3-class strategy did not offer any additional clinical benefit and was associated with more adverse events.
The comparable clinical outcomes with a PI versus an NNRTI strategy remained valid even in patient subgroups with an HIV RNA level >100,000 copies/mL. Although viral suppression rates were more favorable in the NNRTI arm, this did not translate into a significant clinical or immunologic benefit. Furthermore, most of the patients in the PI arm were taking nelfinavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/177644&drug=true) rather than a ritonavir-boosted protease inhibitor, which is now more commonly used. These results are comparable to the INITIO trial, which had a similar study design. (See "Three- compared to four-drug regimens" below (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/23904&view=text#40)).
PI versus NNRTI-based strategy versus PI plus NNRTI alone (ACTG 5142) — The ACTG 5142 study was a multicenter open-label study of 753 treatment-naive patients who were randomly assigned to receive LPV/r plus two nucleoside analogs (NAs), or EFV plus two NAs, or EFV plus LPV/r alone [18 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=18)]. At 96 weeks, the proportion of patients with <50 copies/mL was significantly lower in the LPV arm (77 percent compared to 89 percent in the EFV arm and 83 percent in the LPV/EFV arm).
However, in the LPV/r arm there was a significantly higher median increase in CD4 cells for the two LPV regimens compared to the EFV regimen (+268 cells with LPV/EFV; +285 with LPV; +241 with EFV). Preliminary resistance analyses demonstrated major resistance mutations in two drug classes in the EFV arm only.
COMPARISONS AND COMBINATIONS OF NNRTIs
EFV and NVP (2NN study) — A randomized trial compared EFV 600 mg daily, NVP 400 mg daily, NVP 200 mg twice daily, and EFV 800 mg daily plus NVP 400 mg daily in 1216 treatment-naive patients who also received d4T 40 mg twice daily and 3TC 150 mg twice daily [19 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=19)]. After 48 weeks of follow-up, there was a trend toward fewer patients having treatment failure (a combined primary end point of virologic failure, disease progression, or change of treatment) with EFV than with once daily NVP, twice daily NVP, or combined therapy (37.8 versus 43.6, 43.7, and 53.1 percent, respectively; difference between NVP twice daily and EFV 5.9 percent, 95% CI -0.9 to 12.8). There were no significant differences among the regimens in reducing viral load or increasing CD4 cell counts. However, the combination of EFV and NVP was associated with more toxicity. Two deaths among the study population were attributed to NVP, one due to hepatotoxicity and one to Stevens-Johnson syndrome.
COMPARISONS OF PI-BASED REGIMENS
LPV/RTV versus NFV (M98-863) — A randomized trial compared LPV 400 mg twice daily plus RTV 100 mg twice daily with NFV 750 mg three times daily in 653 treatment-naive patients who also received d4T 40 mg twice daily and 3TC 150 mg twice daily [20 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=20)]. After 48 weeks of follow-up, more patients treated with LPV/RTV had a viral load below 50 copies/mL (67 versus 52 percent). Patients treated with LPV/RTV had greater increases in triglyceride concentrations than those treated with NFV (125 versus 47 mg/dL [1.4 versus 0.5 mmol/L] increase).
Patients treated with the LPV/RTV-based regimen were less likely to develop resistance mutations related to any of the medications in the regimen [21 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=21)]. In particular, patients with detectable isolates of HIV were much less likely to have PI resistance mutations when treated with LPV/RTV than patients treated with NFV were to have resistance mutations associated with NFV (0 versus 45 percent). (See "Drug resistance testing in the clinical management of HIV infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/17509)).
LPV/RTV versus SAQ/RTV (MaxCmin2 trial) — In this randomized trial, 339 patients were randomly assigned to either lopinavir/ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true) (400 mg/100 mg) twice daily or the soft-gel formulation of saquinavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/226245&drug=true) (1000 mg) plus ritonavir (100 mg) twice daily, both in combination with two nucleoside analogs [22 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=22)]. In an intent-to-treat analysis at 48 weeks, the virologic failure rate was higher in the SAQ than the LPV group (39 versus 25 percent). The differences in efficacy may have been due to high discontinuation rates in the SAQ arm compared to the comparator arm (30 versus 14 percent).
FPV/RTV versus NFV (SOLO study) — A randomized trial compared FPV 1400 mg twice daily plus RTV 200 mg twice daily with NFV 1250 mg twice daily in 649 treatment-naive patients who also received ABC and 3TC twice daily [23 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=23)]. After 48 weeks of follow-up, fewer patients treated with FPV/RTV experienced virologic failure (7 versus 17 percent). However, more patients stopped therapy for other reasons such that the overall success rate (viral load below 400 copies/mL) was the same for both groups (69 versus 68 percent).
FPV/RTV versus LPV/RTV (KLEAN study) — In an open-label, non-inferiority study, 878 antiretroviral therapy-naive patients were randomly assigned to receive either fosamprenavir-ritonavir (700 mg/100 mg) twice daily or lopinavir-ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/25742&drug=true) (400 mg/100 mg) twice daily each with the coformulation of abacavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/23721&drug=true) and lamivudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/140019&drug=true) [24 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=24)]. At week 48, non-inferiority of FPV/RTV was demonstrated in achieving an HIV RNA level <400 copies/microL (73 versus 71 percent). Treatment discontinuations and reported adverse events (such as diarrhea) occurred with similar frequencies in both arms. Both treatment groups also experienced comparable elevations in plasma lipids.
While the results of this study clearly demonstrated the non-inferiority of FPV/r to LPV/r for initial therapy of HIV, an important caveat is that the older soft-gel formulation of LPV/r was used, which is no longer available. The present tablet formulation has a lower pill burden, is more heat-stable, and can be taken with or without regard to food.
RESIST-1 and RESIST-2 — RESIST-1 and RESIST-2 are similar trials comparing TPV 500 mg twice daily plus RTV 200 mg twice daily with another boosted PI-based regimen [25,26 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=25,26)]. RESIST-1 studied 630 patients who had previously received at least three classes of antiretroviral medications including at least two PI-based ART regimens. Patients had at least one PI mutation and a viral load above 1000 copies/mL at baseline. Prior to randomization, an optimized regimen was constructed based on boosted LPV, SQV, AMP, or IDV. Patients were then randomly assigned to the optimized regimen or a TPV-based regimen. At 24 weeks, more patients receiving the TPV-based regimen achieved a viral load below 50 copies/mL (25 versus 10 percent). Similar results were seen in RESIST-2, which included 863 patients. In both trials, adverse events were more common in the TPV arms, including elevated aminotransferases and hyperlipemia.
The resistance profile of tipranavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/104743&drug=true) has been characterized based on genotypic and phenotypic resistance testing in these study patients. Virologic response rates to tipranavir were dependent on the number of amino acid substitutions at the following positions: I13,V32, M36, I47, Q58, D60, V82 or I84 [27 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=27)]. For example, the proportion of virologic responders was 70 percent in those patients who had only one or two of these amino acid substitutions at baseline. In contrast, the proportion of responders declined to only 41 percent in those patients with five or more of these baseline substitutions. In addition, the virologic response rate dropped from 45 to 21 percent if the baseline phenotype had a greater than three-fold shift in the 50 percent effective drug concentration (EC50). These data suggest a role for both genotypic and phenotypic testing in assessing a potential response to tipranavir in patients with extensive treatment experience. (See "Drug resistance testing in the clinical management of HIV infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/17509) and see "Overview of HIV drug resistance testing assays" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/26516)). However, given the complexity of the genotypic patterns in patients with high-level PI resistance, many clinicians prefer to use phenotype testing to assess possible response to tipranavir in this setting.
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ATV/RTV versus ATV/SQV versus LPV/RTV — An open-label randomized trial compared ATV 300 mg daily plus RTV 100 mg daily, ATV 400 mg daily plus SQV 1200 mg daily, and LPV/RTV (400 mg/100 mg) twice daily in 358 patients who had failed at least two prior ART regimens and who were also treated with TDF 300 mg daily plus an NRTI (chosen by phenotypic testing when available) [28 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=28)]. After 48 weeks, fewer patients treated with ATV/SQV than patients treated with LPV/RTV achieved a viral load below 50 copies/mL (26 versus 46 percent); patients treated with ATV/RTV had an intermediate rate of viral suppression (38 percent) that was not statistically different from the other two regimens.
DRV/RTV versus optimized therapy — POWER 1 and POWER 2 were randomized, multinational, phase IIB trials, which compared DRV coadministered with low-dose ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true) to other PIs in a population of highly treatment-experienced patients.
POWER 1 compared the efficacy and safety of four doses of darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true) (TMC114) plus 100 mg ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true) (RTV) with investigator-selected control protease inhibitors (CPIs) in 318 treatment-experienced patients over 24 weeks [29 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=29)]. The mean baseline viral load was 4.48 log(10) copies/mL and the median CD4 cell count was 179 cells/microL. Overall, 63 percent of the patients were resistant to all commercially available protease inhibitors.
Virologic and immunologic outcomes were significantly better in the DRV arms compared to the CPI arm. In the 600 mg DRV twice daily arm, mean CD4 gains were as high as 124 cells at 24 weeks and 53 percent attained an HIV RNA <50 copies/mL; these results led to selection of this dosage for regulatory approval in treatment-experienced patients. Similar efficacy data emerged from the POWER 2 trial [30 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=30)]. (See "HIV protease inhibitors" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/5575)).
In a pooled subset analysis of POWER 1 and POWER 2, the effect of baseline susceptibility on treatment efficacy was examined [34 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=34)]. Forty-seven percent of patients treated with darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true), who had up to eight mutations at baseline, still attained viral suppression. In contrast, only 25 percent of patients who received a control PI with activity against the baseline isolate attained an HIV RNA <50 copies/mL. Of note, at 24 weeks, more than 60 percent of enfuvirtide-naive patients who were treated with enfuvirtide (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/143146&drug=true), in addition to darunavir, achieved undetectable HIV RNA levels [31 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=31)].
In a subsequent larger trial (POWER 3), 327 treatment-experienced patients were treated with darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true)/ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true) plus optimized background therapy in an effort to further evaluate the efficacy of the drug in a larger population of patients with advanced disease and multidrug resistant HIV (median CD4 count 115 cells/microL) [33 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=33)]. No comparator arm was used. Of 324 patients who were treated for 48 weeks, 45 percent achieved HIV RNA reductions to <50 copies/mL.
The efficacy and safety of darunavir-ritonavir was subsequently compared to lopinavir-ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/25742&drug=true) at 48 weeks in treatment-experienced patients in a randomised controlled phase III trial (TITAN) [32 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=32)]. All patients received optimized background regimen according to baseline genotypic and phenotypic testing. Eighty-two percent of the patients were susceptible to four or more protease inhibitors. At week 48, significantly more patients in the darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true) arm had achieved a viral load <400 copies/mL compared to the lopinavir arm (77 versus 68 percent). Side effects included excess rashes in the darunavir group and more diarrhea in the lopinavir group.
TRIPLE NRTI REGIMENS
ACTG A5095 study — A randomized trial compared ABC 300 mg plus 3TC 150 mg plus ZDV 300 mg twice daily with the same regimen plus EFV and with ZDV/3TC plus EFV in 1147 treatment-naive patients [35 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=35)]. After a median follow-up of 32 weeks, the triple NRTI arm of the study was stopped by the monitoring board. In an analysis that combined the two arms containing EFV, virologic failure was more common in patients receiving only ABC/3TC/ZDV (21 versus 11 percent) and time to virologic failure was shorter.
A substudy (ACTG 5166) was designed to evaluate plasma HIV-1 RNA decay rates in 66 study participants in the three different treatment arms [36 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=36)]. Median first-phase viral decay rates at day 10 were significantly faster in subjects receiving the 3-drug EFV regimen compared with those receiving the triple-nucleoside regimen; these differences were even more pronounced in patients with higher baseline viral loads.
These data suggest that early viral dynamic modeling may be a useful tool in predicting treatment efficacy [37 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=37)].
ABC plus 3TC plus TDF (ESS30009) — A randomized, open label, multicenter trial comparing ABC/3TC/TDF with ABC/3TC/EFV in 340 treatment-naive patients was stopped early after an interim analysis [38 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=38)]. Patients treated with ABC/3TC/TDF had a much higher rate of virologic nonresponse than the comparator arm (49 versus 5 percent). Within 12 weeks, high rates of the M184V (98 percent) and K65R (54 percent) resistance mutations were seen in virologic nonresponders in the ABC/3TC/TDF arm. Similar results were seen in another pilot study [39 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=39)]. (See "Drug resistance testing in the clinical management of HIV infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/17509)).
The authors suggested that a low genetic barrier to resistance, produced by synergistic selection pressure from all three drugs, may have contributed to these findings [38 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=38)]. However, only half of the patients developed the K65R mutation, and M184V by itself actually sensitizes HIV to tenofovir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/23224&drug=true) and has only a modest effect on abacavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/23721&drug=true) susceptibility [40 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=40)]. An alternative explanation for the high virologic failure rates and resistance patterns include differential drug localization in various cellular compartments [40 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=40)].
These results suggest that a thymidine analog (ZDV or d4T) is an important component of triple nucleoside regimens.
3TC plus ddI plus TDF — In results presented in a preliminary report, a pilot study of once daily 3TC/ddI/TDF in treatment-naive patients found that after 12 weeks of treatment only one of 22 patients had a virologic response [41 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=41)]. Of 20 patients who had resistance testing, all had the M184V resistance mutation and 10 had the K65R resistance mutation. (See "Drug resistance testing in the clinical management of HIV infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/17509)).
These results similarly suggest that a thymidine analog (ZDV or d4T) is an important component of triple nucleoside regimens.
THREE- COMPARED TO FOUR-DRUG REGIMENS
NFV plus EFV (ACTG 384) — A randomized trial compared four-drug regimens containing NFV 1250 mg twice daily plus EFV 600 mg daily with each drug individually in 980 treatment-naive patients who received an NRTI backbone of either ZDV 300 mg twice daily plus 3TC 150 mg twice daily or ddI 400 mg daily plus d4T 40 mg twice daily [42 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=42)]. After a median follow-up of 2.3 years, the time to first virologic failure was longer with the four-drug regimen compared with NFV/ddI/d4T (hazard ratio [HR] for first virologic failure 0.49), compared with NFV/ZDV/3TC (HR 0.41) and compared with EFV/ddI/d4T (HR 0.57), but not compared with EFV/ZDV/3TC (HR 1.16, 95% CI 0.63-2.14).
EFV versus NFV versus both (INITIO) — An open-label, randomized trial compared ART with two nucleoside analogs (didanosine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/78959&drug=true) and stavudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/247071&drug=true)) plus either efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true) (EFV) or nelfinavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/177644&drug=true) (NFV) or both (EFV plus NFV) in 911 treatment-naive patients [43 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=43)]. At three years of follow-up, a significantly higher proportion of patients in the EFV group had a nondetectable viral load (74 percent) compared to the other two treatment groups (62 percent NFV; 62 percent NFV plus EFV). Patients in the EFV plus NFV group had a shorter time to a treatment modifying adverse event and a shorter time to stopping their initial regimen than the other treatment groups. These results confirm the virologic superiority of EFV-based versus PI-based initial therapy for HIV infection, especially when the comparator is an unboosted PI such as NFV; they also demonstrate that use of all three drug classes as initial therapy is associated with a higher rate of toxicity with no added antiretroviral effect.
Similar to the ACTG trial which also compared EFV, NFV, and EFV plus NFV, the INITIO trial found no difference between the three strategies in terms of immunologic benefit. The applicability of these results to current treatment are somewhat limited by the use of the didanosine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/78959&drug=true) and stavudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/247071&drug=true) NRTI combination, which is no longer recommended due to excess toxicity.
ZDV plus 3TC plus ABC plus EFV (ACTG 5095) — A randomized, double-blind, placebo-controlled trial conducted from 2001 to 2005 compared zidovudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/282056&drug=true) (ZDV) lamivudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/140019&drug=true) (3TC) and efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true) (EFV) to ZDV/3TC/abacavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/23721&drug=true) (ABC) and EFV in 765 treatment-naive patients with a baseline HIV RNA level of 4.86 log(10) copies/mL and a CD4 count of 240 cells [44 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=44)]. After a three-year follow-up, there were no significant differences between the standard three-drug versus four-drug regimens with regard to time to virologic failure, CD4 cell count responses, adverse events or discontinuation rates.
This trial supports the current clinical guidelines that recommend two nucleoside analogs (with one of them 3TC or FTC) plus efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true) for the initial treatment of HIV infection in treatment naive patients; the addition of abacavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/23721&drug=true) provided no additional benefit, regardless of baseline HIV RNA level of CD4 cell count.
DRUG-SPARING STRATEGIES — Issues regarding adherence and adverse effects of chronic antiretroviral therapy have led to interest in studies of simpler maintenance therapies. One such approach is to use a boosted PI alone as a maintenance or simplification strategy after achieving virologic suppression.
LPV-RTV as maintenance therapy (OK study) — A small randomized trial was conducted comparing standard of care therapy with two nucleoside analogs and ritonavir-boosted lopinavir versus simplified maintenance therapy with lopinavir-ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/25742&drug=true) alone in patients who had attained viral suppression for six months [45 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=45)]. HIV RNA levels remained suppressed to below 50 copies/microL in 17 of 21 participants randomly assigned to maintenance therapy at 48 weeks compared to 20 of 21 patients assigned to the standard of care arm. Medication non-adherence was associated with virologic failure in the LPV-ritonavir arm.
The impact of this maintenance strategy on HIV viremia was also studied using an ultrasensitive assay (detection limit 3 copies/mL) in longitudinal plasma samples in the 17 patients who maintained viral suppression [46 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=46)]. The level of persistent viremia, albeit at low levels of detection, did not increase significantly from baseline at any time point after discontinuing NRTI in those patients.
In a larger randomized study, viral suppression was common in both the standard of care arm and the maintenance therapy arms [47 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=47)]; however, the detection of viral levels in the 50 to 400 copies/mL range was more common in the monotherapy group.
These combined data suggest that simplified maintenance may be a viable option for a subset of patients. However, the higher rate of failure in the LPV/r alone arm warrants careful identification of appropriate candidates since missed doses of a ritonavir-boosted PI may have a greater impact on efficacy than the same number of missed doses of a three drug combination [46 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=46)]. Furthermore, research on the utility of using ultrasensitive assays for the identification of maintenance therapy candidates is needed [48 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=48)].
ATV-RTV as maintenance therapy — Regimen simplification has also been attempted with atazanavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/79226&drug=true) (ATV) with conflicting results:
In an open-label 24-week pilot study (ACTG 5201) of HIV-infected patients with viral suppression for 48 weeks or longer on their first protease inhibitor-based regimen, 34 patients were continued on atazanavir (300 mg once daily) and ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true) (100 mg once daily) after a six week induction phase with standard therapy [49 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=49)]. The CD4 count threshold for inclusion in the study was 250 cells/microL; patients with previously documented PI resistance were excluded.Viral suppression occurred in 31 of 33 patients who continued maintenance therapy for 24 weeks. Two of the three patients who had recurrence of viremia had plasma atazanavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/79226&drug=true) concentrations that were low or below detection; no resistance mutations were identified.
In another study, two of 30 patients (7 percent) failed ATV/r monotherapy; none of the study participants had evidence of ATV resistance [50 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=50)]. However, at week 24, three of 20 patients had elevated HIV RNA in CSF despite viral suppression in plasma.
A subsequent study of ATV/RTV monotherapy was terminated after 15 of the planned 30 subjects had been enrolled because five cases of virologic failure had occurred. Plasma ATV concentrations were not associated with the outcome and no PI resistance mutations were found.In light of easy to administer formulations of nucleoside analogs that are well-tolerated, the rationale for using boosted protease inhibitors as monotherapy is becoming less compelling.
AGENTS IN ADVANCED STAGES OF DEVELOPMENT
Integrase inhibitors — HIV-1 integrase is essential for viral replication; integrase inserts viral DNA into the cellular genome through two catalytic reactions. Loss of integrase activity disrupts the viral life cycle.
Raltegravir — Raltegravir (MK-0518) is an investigational integrase inhibitor with potent in vitro activity against both wild-type and multi-drug resistant HIV. It is metabolized by hepatic glucuronidation and has no effect on cytochrome 3A4 [51 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=51)]. Clinical data in both treatment-naive and treatment-experienced patients have demonstrated encouraging results:
In a multicenter, double-blind, randomized, placebo-controlled study, raltegravir was administered to 35 treatment-naive patients in one of four doses (100, 200, 400, and 600 mg) versus placebo twice daily for 10 days [52 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=52)]. On day 10, all patients in the various raltegravir dosing arms experienced a significantly greater decline in viral load compared to placebo (approximately 2-log compared to 0.2 log decline in the placebo arm). Based on these results, a dose-ranging 48 week trial of raltegravir versus efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true) in a combination regimen has been initiated.
A multicenter, double-blind dose-ranging study randomly assigned 179 patients with documented genotypic and phenotypic resistance to each of the three classes of ART to either raltegravir (200 mg, 400 mg, or 600 mg twice daily) or placebo [53 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=53)]. All patients were also given optimized background therapy; however, none received tipranavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/104743&drug=true) or darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true). The study population were heavily treatment-experienced; the median number of previous antiretroviral medications was 12. Of the 166 patients in whom HIV co-receptor tropism was determined at baseline, 68 (41 percent) had dual or mixed tropic viruses, consistent with advanced disease.The primary endpoints were change in viral load from baseline at week 24 and safety. The study was significant for the following findings:
An approximate 2-log decline in HIV RNA was seen in all raltegravir groups as early as two weeks after initiation; this effect was sustained throughout the 24 week period of the study.
Immunologic benefit was seen in all the raltegravir arms, although the magnitude of the CD4 cell count was smaller in the 200 mg dosing group.
Raltegravir had a safety profile comparable to placebo at all doses. However, patients who were seropositive for hepatitis C antibody were excluded so its safety in patients with chronic viral hepatitis is unknown.The efficacy and safety of raltegravir is also being evaluated in a head-to head, naive study against efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true), both using tenofovir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/23224&drug=true)/emtricitabine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/139565&drug=true) (Truvada) as their backbone regimen. Raltegravir is also now available in expanded access programs for patients with limited treatment options. The 400 mg twice daily dose has been selected for future studies. FDA approval of raltegravir, for the treatment of drug resistant HIV, is anticipated in the fall of 2007.
Non-nucleoside reverse transcriptase inhibitors — Etravirine (TMC-125) is a novel NNRTI that maintains activity in viral isolates with some existing NNRTI signature mutations. A randomized dose-ranging study was performed in 79 heavily pretreated patients with both documented NNRTI and PI resistance [54 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=54)]. Viral load responses varied by the number of baseline NNRTI mutations (eg, declines of 1.6 log with one mutation; 1.0 log with 2 mutations; 0.7 log with 3 mutations). However, a study comparing an etravirine-based regimen to a PI-based strategy after NNRTI treatment failure was terminated early due to superiority of the PI arm [55 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=55)].
Subsequently, three larger trials confirmed the efficacy of etravirine [56-58 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=56-58)], as summarized below:
In a multinational double-blind, placebo-controlled phase III trial (DUET-1), 612 patients were randomly assigned to etravirine or placebo [56 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=56)]. Eligible patients were heavily treatment-experienced with documented NNRTI resistance and three or more primary protease inhibitor mutations. All patients also received darunavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/198715&drug=true)/ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true); use of enfuvirtide (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/143146&drug=true) was optional. At week 24, a significantly higher proportion of patients in the etravirine arm attained a viral load of <50 copies/mL compared to those receiving placebo (56 versus 39 percent). In the subgroup of patients with no available active agents, a viral load below 50 copies/mL was achieved by 21 (47 percent ) of 45 patients in the etravirine group compared with four of 46 patients (9 percent) in the placebo group. Rates of viral suppression were similar in the subgroups who used or reused enfuvirtide as background therapy. Side effects related to etravirine were mild and consisted mainly of rash, which resolved with continued drug administration. A second similarly designed trial (DUET-2) confirmed the efficacy and safety of etravirine [57,59 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=57,59)].
An open-label, partially blinded, randomized clinical trial to evaluate the efficacy and safety of two dosages of etravirine (400 mg and 800 mg twice daily) was performed in 199 patients with genotypic resistance to the NNRTI class and at least three primary PI mutations [58 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=58)]. Both groups received an optimized background of at least two nucleoside analogs and/or lopinavir/ritonavir and/or enfuvirtide. Control patients received optimized background alone. The study demonstrated that etravirine led to significant declines in viral load of approximately one log. Few patients developed rash, neuropsychiatric effects, or evidence of hepatotoxicity, as noted with other drugs in this class. However, patients with underlying chronic viral hepatitis and baseline ALT>3x ULN were excluded from the trial.Etravirine (TMC-125) is now available through expanded access programs. Clinicians should be aware that etravirine should NOT be coadministered with tipranavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/104743&drug=true) due to significant drug interactions.
CCR5 antagonists — HIV enters CD4+ T-cells via the chemokine receptor 5 (CCR5) or CXC chemokine receptor 4 (CXCR4 coreceptor [60 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=60)] Viral strains from patients with early stage disease usually use CCR5 coreceptors, whereas approximately one-half of viral strains from patients with advanced immunosuppression enter via either the CXCR4 coreceptor alone, or both the CCR5 and the CXCR4 receptors ("dual/mixed" tropic viruses) [61 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=61)]. (See "Immunology of HIV-1 infection" (http://www.utdol.com/utd/content/topic.do?topicKey=hiv_infe/12850)).
Because CCR5 antagonists are not active against CXCR4 or dual-mixed tropic viruses, a pretreatment screening test has been utilized in study protocols to assess viral tropism. This tropism test is similar to an HIV resistance phenotype, and can determine whether a response from a CCR5 antagonist should be expected. This test is expected to be approved for use when the first CCR5 antagonists become commercially available.
Maraviroc — Maraviroc (UK-427,857, Selzentry), is a selective and reversible CCR5 coreceptor antagonist with a wide range of activity against clinical HIV isolates, including those with multi-drug resistance. Maraviroc was approved for use in treatment-experienced patients by the FDA on August 6, 2007 and will be available in September 2007 by prescription. The FDA is requiring long-term follow-up studies to examine its side effect profile more closely in terms of cardiovascular effects and liver toxicity. Dosing of maraviroc depends on whether or not it is being administered with inducers or inhibitors of cytochrome p450.
Eleven study participants (1.3 percent) who received maraviroc had cardiovascular events including myocardial ischemia during the phase 3 studies; the relationship of these events to maraviroc is uncertain since these patients had either known cardiac disease or cardiac risk factors.
In HIV-infected patients, maraviroc monotherapy for 10 days reduced HIV RNA by up to 1.6 logs with 300 mg daily and 1.8 log with 300 mg twice daily [63 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=63)]. In treatment-experienced patients with CCR5 tropic virus at baseline, Maraviroc treatment plus an optimized background regimen (OBR) was more effective virologically and immunologically than a control arm receiving placebo plus OBR [71,72 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=71,72)]. No adverse effects occurred more commonly in the maraviroc-treated patients than in those receiving placebo. By contrast, in treatment-experienced patients with dual-tropic virus, the addition of maraviroc did not lead to further declines in HIV RNA compared to optimized background therapy alone [64 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=64)]. A trial of maraviroc (300 mg daily or 300 mg twice daily) in combination with zidovudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/282056&drug=true)/lamivudine (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/140019&drug=true) versus efavirenz (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/172151&drug=true) in combination with zidovudine/lamivudine has fully enrolled [65 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=65)].
To date, maraviroc appears to be well tolerated. The most common adverse reactions noted in studies of maraviroc included cough, pyrexia, upper respiratory infections, rash, musculoskeletal symptoms, lightheadedness and abdominal pain.
Severe hepatotoxicity occurred in one of 1300 patients who were enrolled in the phase 2b/3 clinical program [68 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=68)]. However, this patient was also taking other agents with potential hepatotoxicity (isoniazid (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/135645&drug=true) and trimethoprim-sulfamethoxazole (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/20387&drug=true)). On the other hand, the development of aplaviroc was halted due to severe hepatotoxicity, which raises the possibility of a class effect. Subsequent studies of Maraviroc have not identified hepatotoxicity as occurring more commonly than in control arms that did not receive the drug, although the drug has not been studied extensively in patients with underlying chronic viral hepatitis [73 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=73)].
Vicriviroc — Vicriviroc is another investigational CCR5 inhibitor that was evaluated in a double-blind, randomized dose-ranging study (AIDS Clinical Trial Group ACTG 5211) of 118 patients with a median HIV RNA level of 36,380 copies/mL and a median CD4 count of 146 cells/mm3 [70 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=70)]. Patients were randomly assigned to one of three doses of vicriviroc (5,10, or 15 mg) or a matching placebo added to their ritonavir-containing ART. Once daily dosing was feasible due to the inclusion of ritonavir (http://www.utdol.com/utd/content/topic.do?topicKey=drug_l_z/224170&drug=true), which increases plasma concentrations of vicriviroc two to six-fold. The study was significant for the following findings:
At 24 weeks, the mean changes in HIV RNA were -1.51 log (5 mg group), -1.86 (10 mg group), -1.68 (15 mg group) compared to -0.29 in the placebo group.
In subgroup analyses, those patients who had received enfuvirtide (http://www.utdol.com/utd/content/topic.do?topicKey=drug_a_k/143146&drug=true) as part of their optimized background attained the greatest viral load decline, particularly if they were naive to enfuvirtide.
The 5 mg dose was associated with higher rates of virologic failure and more changes in coreceptor usage than in the higher dosing groups.
Ten percent of patients had dual/mixed-tropic virus at study entry; viral load declines in this subgroup were lower than those with R5 virus, but still better than those participants in the placebo arm. Furthermore, CD4 cell counts remained stable.
Diverse types of malignancies occurred in six patients randomized to vicriviroc and in two patients assigned to placebo. The relationship of malignancy to vicriviroc is uncertain.ADJUVANT IMMUNOTHERAPIES — A study of 204 patients with CD4 cell counts ranging from 50 to 350 cells/microL was performed to determine whether interleukin-2 (IL-2) administration is beneficial in patients with moderately advanced HIV infection (AIDS Clinical Trials Group 328) [69 (http://www.utdol.com/utd/content/abstract.do?topicKey=hiv_infe/23904&refNum=69)]. Patients were initially treated with a protease inhibitor-based ART regimen and virologic responders were randomized to open-label continuous infusion IL-2, subcutaneous IL-2, or ART alone at 12 weeks. Patients receiving IL-2 had greater increases in CD4 cell counts at week 84 and had fewer AIDS-defining illnesses.
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| MacArthur, RD, N
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