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Antiretroviral therapy: the main studies
(except 2NN..see separate report)
Dr Graeme Moyle MD, MBBS, Chelsea and Westminster Hospital, London, UK.
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Antiretroviral discussions at the 10th retrovirus conference were not simply about the relative virtues of efavirenz and nevirapine in the 2NN study (http://www.natap.org/2003/Retro/day5.htm),
but also included new information and prolonged follow-up from a number of other key treatment studies. Studies and naive patients of interest included 96 week follow-up of the Gilead 903 study, 48 week outcomes and resistant information from the FTC 301 study and 48 week outcomes of the NEAT study comparing Fos-amprenavir and nelfinavir in initial therapy. Other reported studies of interest included the outcome of the Context study comparing ritonavir boosted Fos-amprenavir with Kaletra in protease inhibitor experienced patients. Additionally a dose selection study for Tipranavir was reported providing information on how the dose selected for the currently recruiting phase 3 studies was chosen.
The Gilead 903 study
This is a randomised, placebo-controlled trial comparing tenofovir and stavudine on the standard care backbone of 3TC and efavirenz in 600 treatment naive individuals. The mean baseline viral load is 81,300 copies/ml and the baseline CD4 count is 279 cells/mm3. The 96 week intent-to treat (ITT) outcomes indicate that, using a virological cut-off of 400 copies/ml, 82% of tenofovir recipients and 78% of stavudine recipients had achieved an undetectable viral load. Using the cut-off of 50 copies/ml, 78 % of tenofovir and 72 % of stavudine recipients were undetectable. These modest numerical differences were not statistically significant. The CD4 responses were 261 cell/mm3 increase in the tenofovir group and a 266 cell/mm3 increase in the stavudine group. Thus, as in the 2NN study, we have two agents performing similarly. Hence, choice of agent will be influenced by adverse event profiles. With regards grade 3/4 adverse events, 23 % of tenofovir recipients and 22 % of stavudine recipients experienced these types of adverse events. Regarding adverse events which may be specifically drug-related, remembering that physicians and patients remain blind to whether they are receiving tenofovir or stavudine, peripheral neuropathy was reported in 3% of tenofovir recipients and 10 % of stavudine recipients, these differences being statistically significant. Regarding investigator-defined lipodystrophy, which could include both atrophy and hypertrophy, only 1% of tenofovir but 12% of stavudine recipients had been assessed by their physician as having lipodystrophy. This difference was also statistically significant. Other aspects which may link with the lipodystrophy syndrome were also more common in the stavudine arm. Limb fat mass at week 96 as measured by DEXA scan was significantly lower in stavudine recipients and although both groups had on average gained weight, weight gain was more modest in the stavudine group. Lipid disturbances were greater in the stavudine group, with significantly larger rises in triglycerides, total and LDL (Ôbad') cholesterol and a smaller rise in the HDL ('good') cholesterol.
Concerns about tenofovir raised from high dose animal toxicity studies have not been borne out over 96 weeks of follow-up in the Gilead 903 study. Changes in creatinine, a marker of renal function, had been uncommon, never > grade 2, and have occurred at similar frequency (< 2%) in the stavudine and tenofovir groups. Similarly, episodes of hypophosphatemia a possible marker of bone and kidney problems have not differed between groups and had been very infrequent events.
In summary the Gilead 903 study indicates that both arms achieved similar suppression in HIV RNA and similar benefits on CD4 cell count. However changes in lipids and reports of peripheral neuropathy and lipodystrophy have been more common in stavudine recipients.
Emtricitabine (FTC) 301 study
The FTC 301 study is a randomised, double-blind, double dummy comparative study of FTC vs d4T with a backbone of didanosine and efavirenz in 571 treatment naive individuals. The study was stopped after an interim analysis performed on data collected through 24 weeks indicated superiority for those individuals randomised to FTC. 48 week results were consistent with the 24 week outcomes with significantly more patients randomised to FTC achieving viral suppression below either 400 or 50 copies/ml and fewer individuals experiencing either a virological rebound or treatment failure (disease progression, drug-related discontinuation or virological rebound).
Resistance in Gilead 903 and FTC 301
These two studies provide one of the first opportunity to investigate resistance outcomes in regimens that spare thymidine analogues. The resistance information at week 48 of the Gilead 903 study were presented at the HIV6 conference in Glasgow in November 2002. In the tenofovir group 29 individuals (9.7% of those randomised) and in the d4T group 25 individuals (8.3%) were defined as virological failure. Mutations associated with efavirenz resistance were found in 16 tenofovir failures and 12 d4T failures. The 3TC signature mutation 184V was found in 12 tenofovir failures and eight d4T failures. Wild type virus was detected in 10 tenofovir failures and 12 d4T failures. In vitro tenofovir is known to select for the K65R mutation, a mutation which is associated with reduced viral fitness but when combined with other mutations may affect the activity of 3TC, abacavir and ddI. K65R was found in association with an efavirenz resistance mutation alone in 2 tenofovir failures and one d4T failure, and in combination with both an efavirenz resistance mutation and 184V in five tenofovir failures and one d4T failure. No patient in either group had the K65R mutation alone. Overall, this meant that seven individuals in the tenofovir group of 29 with virological failure had the K65R mutation compared with 2 of the 25 virological failures in the d4T group. Assessment of these seven isolates from the tenofovir group using both the Virco and ViroLogic phenotype assays was performed. Using the Virco assay, three of the isolates with K65R were resistant to ddI, three resistant to abacavir and four resistant to tenofovir. A number of the isolates showed modest increases in susceptibility to AZT by both phenotypic assays. Thus, in individuals who experienced viral rebound on the tenofovir 3TC efavirenz based regimen, approximately one-quarter had evidence of resistance to all three of these agents and about 10 % of individuals also had resistance to both abacavir and didanosine. As a proportion of the total study participants however this population in who genotype or phenotype results were obtained represents only 10 % of the total population.
In the FTC 301 study, 14 individuals randomised to the FTC arm and 35 individuals randomised to the stavudine arm had virological failure and had genotypes analysed for resistance. NNRTI mutations were present in 71.4% of individuals of randomised to the FTC arm and 88.6% of individuals in the stavudine arm. The M184V mutation associated with resistance to both FTC and 3TC was found in 42.9% of FTC recipients but none of the individuals in the stavudine arm. The mutation characteristic of didanosine monotherapy is the L74V mutation. However, this mutation is not commonly seen when didanosine is used in combination with a thymidine analogue. In the FTC arm of the study L74V mutation was not observed, and this mutation was only seen in 11.4% of samples in the stavudine arm. Thymidine analogue selected mutations (TAMs) were seen in just 1 of 14 samples in the FTC group and 20 % of the stavudine group. Thus, essentially no signature of didanosine resistance was found in the group that received FTC with didanosine and was rarely observed in individuals in the stavudine with didanosine group. Other note, 28.6% of FTC recipients and 2.9% of stavudine recipients experiencing virological rebound were found to have wild type virus.
The results of these two studies would suggest that resistance to NNRTIs and 3TC or FTC arise readily in individuals experiencing rebound on regimens containing these agents. In individuals receiving stavudine as the third agent in the Gilead 903 study additional mutations were only occasionally observed, although when stavudine was combined with didanosine in the FTC 301 study TAMs were seen in approximately 20 % of samples. In individuals receiving tenofovir as the third agent with 3TC and efavirenz the resistance signature of tenofovir was present in approximately 25% of samples from individuals who experienced viral failure, whereas in individuals receiving didanosine with FTC and efavirenz no additional mutations were observed. These data may have implications for physicians considering future treatment sequences in persons initiating thymidine analogue sparing (and also, for both these regimens, once a day) therapies.
Fos-Amprenavir: stands up well in two comparative studies
Fos-amprenavir is a reformulation of amprenavir which dramatically reduces the tablet volume required to achieve therapeutic exposures of amprenavir. The drug has been investigated in a number of different ways including unboosted in treatment naive patients, boosted in a QD regimen, and boosted in a BD regimen.
In 251 treatment naive patients Fos-amprenavir two tablets (1400 mg) BD was compared with nelfinavir 1250 mg BD with a nucleoside analogue backbone of abacavir and 3TC. The randomisation of 2:1 meant that 166 individuals received Fos-amprenavir and 83 individuals received nelfinavir. The median baseline viral load was 4.82 to 4.85 log and the median CD4 cell count 212 to 214 cells/mm3. Using the new FDA mandated analysis of intention to treat with rebound (= blip) and discontinuation = failure, significantly more individuals were virologic successes (using a 400 copies/ml cut-off) in the Fos-amprenavir group (66%) as compared with the nelfinavir group (51%). Less than 1% of patients randomised to Fos-amprenavir never achieved suppression to less than 400 copies/ml whereas 8% of those individuals randomised to nelfinavir did not completely respond. Using the less than 50 copy cut-off, 56 % of Fos-amprenavir and 41 % of nelfinavir patients were virologic responders.
In individuals who entered the study with viral load < 100,000 copies/ml, nelfinavir performed similarly to Fos-amprenavir with 54 % of nelfinavir and 56 % of Fos-amprenavir patients in this category achieving a virological response to less than 50 copies/ml. In individuals who commenced the study with higher viral load the efficacy of Fos-amprenavir was not diminished (55 % less than 50 copies/ml) whereas the effectiveness of the nelfinavir based regimen was markedly diminished (24 % less than 50 copies/ml).
Regarding adverse events, diarrhoea was reported in 5% of Fos-amprenavir recipients and 18% of nelfinavir recipients at a moderate or worse level. Drug hypersensitivity and/or rash were observed in 16 % of Fos-amprenavir recipients and 7% of nelfinavir recipients. This may reflect the difficulty that physicians have in separating the rash associated with amprenavir from the rash associated with abacavir hypersensitivity reactions. Changes in fasting lipid profiles did not differ between the two drug choices although tended to favour the Fos-amprenavir group with moderately greater increases in HDL cholesterol and moderately smaller increases in LDL and total cholesterol.
The second study looking at the clinical utility of Fos-amprenavir, known as the Context study, compared the standard dosage of Kaletra (3 tablets BD) with either Fos-amprenavir 1400 mg QD plus ritonavir 200 mg QD (total 4 tablets QD) and 700 mg of Fos-amprenavir BD plus 100 mg of ritonavir BD (total two tablets BD) in 315 individuals with prior experience of 1 or 2 protease inhibitors. Concomitant use of NNRTIs was excluded during the study. Follow-up over 24 weeks was presented. Baseline viral load was 4.13 to 4.19 copies/ml and CD4 cell count at baseline ranged from 234 to 292 cells/mm3. Baseline prior treatment history tended to favour the Kaletra arm. For example, fewer patients in the Kaletra arm had taken 2 prior protease inhibitors (28 %) compared with the QD (40 %) and BD (34 %) Fos amprenavir arms. Similarly, Kaletra patients had received less prior nucleoside analogue therapy, with 35 % of Kaletra patients only having received 1 or 2 NRTI's, compared with 29 % of the QD and 14 % of the BD Fos-amprenavir groups. These differences in baseline characteristics may have had an important impact on the virological outcomes observed in the study. The mean time-averaged reduction in viral load from baseline was 1.48 log in the QD arm, 1.5 log in the BD arm and 1.66 log in the Kaletra arm. These differences were not statistically significant. The proportion of patients who were virological successes by a 400 copy cut-off were 58% in the QD, 60 % in the BD Fos-amprenavir arm and 69 % in the Kaletra arm. Virological failure, defined as two consecutive values > 400 copies/ml, was observed in 34 % of QD, 27 % of BD Fos-amprenavir recipients and 21 % of Kaletra recipients. Results using a 50 copy assay also favoured the Kaletra group. Grade 3/4 laboratory toxicities and moderate or worse clinical events were observed in similar proportions in each group. Changes in lipids, somewhat surprisingly, did not differ between groups.
Dose selection for Tipranavir
Tipranavir is a new protease inhibitor with a novel chemical structure which has demonstrated in vitro activity against a wide range of viruses resistant to currently approved protease inhibitors and has demonstrated virological activity in mainly small and short-term studies in patients with virus resistant to current protease inhibitors. This drug is now moving into phase 3 clinical development that could potentially lead to approval of this compound.
The phase 2 dose selection study involved 216 individuals experienced with multiple antiretrovirals including at least two approved protease inhibitors randomised in a double-blind matter to receive Tipranavir at doses of either 500 mg with 100 mg of ritonavir, 500 mg with 200 mg of ritonavir or 750 mg with 200 mg of ritonavir all dosed twice-daily. Patients switched from their current PI to Tipranavir for the first two weeks and then modified their background therapy based on results of genotype and phenotype tests.
The study recruited individuals with a median CD4 count of 153 and median viral load of 4.53 log. Baseline susceptibility testing indicated that the majority of patients were resistant to at least Kaletra, nelfinavir, and ritonavir as assessed by the Virco Antivirogram.
By intention to treat, last observation carried forward analysis the 750/200 mg BD dosage group had a greater and more rapid decline in viral load over the first 14 days of therapy with a reduction of approximately 1.2 log at day 14 compared with approximately 0.9 log in the other two treatment groups. By day 28 the viral load decline in the 750/200 mg and 500/200 mg group was approximately 1.4 log and for the 500/100 mg group approximately 1.1 log. In the 750/200 mg and 500/200 mg dosing groups the number of protease inhibitor gene mutations present at baseline did not appear to impact the magnitude of reduction in viral load, even when greater than 20 mutations were present in the protease gene. Adverse events such as grade 3/4 diarrhoea and nausea, were more common in the 750/200 mg dosage group and least common in the 500/100 mg dosage group. After four weeks of therapy 2.7% of individuals dosed with 500/100 mg, 4.2% dosed 500/200 mg and 7% of those dosed 700/200 mg had discontinued therapy. During extended follow-up through 24 weeks, no further patients in the 500/100 mg dosage group discontinued therapy. Overall by 24 weeks 5.8% of 500/200 and 15.5% of 750/200 mg dosed patients had discontinued therapy. Based on the balance between efficacy and tolerability the dose of 500/200 mg of Tipranavir and ritonavir dosed twice-daily will be used in the phase 3 development programme. However, short-term response data in the study may lead some physicians to consider starting at 750 mg of Tipranavir and reducing the dose back to 500 mg if adverse events ensue.
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