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Antiretrovirals: New and novel use thereof
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Reported by Mike Youle, MD, Royal Free Hospital, London, UK
5 Days On HAART, 2 Days off
Kaletra Monotherapy
small molecule entry inhibitors
Maraviroc (formerly UK 427,857)
Vicriviroc (Schering D 417690)
GW873140
synergistic action of Pro 140 with other drugs
enfurvitide (T20)
Reverset
Foscarnet
Thiovir, an oral foscarnet analogue
TMC278
TMC125
TMC120, as a potential microbicide
new NNRTI, BILR 355BS
new NNRTI, GW695634
rev
tipranavir (TPV)
TMC114
new tablet version of Kaletra called Meltrex
PA-457, the first maturation inhibitor
Ok so this is the forum I usually use to air some of my thoughts about the HIV world and this time is no exception. If 4,000 delegates were registered for this conference then I never saw more than 1,000 milling around and some of the sessions were sparsely attended. Part of this was due to the venue, Rio is not easy to get to and especially not from Africa and Asia. The Conference centre itself was an hour from town, but I got the feeling that there were a group of middle-aged care providers (me included) milling around looking for the scraps of data between the rubbish. Perhaps it is a reflection of the fact that almost every presentation showed extremely good response rates (we have the tools) and the really interesting stuff was that mental health and substance abuse issues along with general adherence and poor medical care are high on the reasons for poor outcomes. It seems that the pharmaceutical industry has done its' job in creating a drug pipeline which is still exciting but we providers and the health care industry are fighting against cost and political problems which produce restrictions on how best we can deliver this effective treatment. This was summed up in the slide presentation of Julio Montaner prior to the late breakers when he showed that experienced medical care is as great a factor in the success of treatment as the drugs themselves.
All too easily there has been a sliding towards simple regimens for the developing World which leaves many of us nervous that there is a "tsunami of resistance" building up which will require more complex and costly intervention. That is not to decry the efforts to treat the millions who need it in developing nations but it was comforting to see at least some attempts to use PI based HAART first line with good outcomes using indinavir/ritonavir 400/100 in the NOGOMA study in Bamako, Mali (MoPe11.7C08) supported by Solthis; www.solthis.org, spearheaded by Christine Katlama and her team. Thirty subjects were switched from indinavir (IDV) 800mg TID to 400/100 BID and the problem of refrigeration of ritonavir was overcome by the use of thermos flasks or by the use of unglazed earthenware pots soaked in water (the contents are cooled by the latent heat of evaporation) - I remember my mother using these in the UK many years ago for cooling milk when we did not have a fridge. The results of this boosted PI regimen were as good as in any other studies with 96% having adequate IDV Cmin levels, 93% <400 copies/mL and no PI mutations seen in the two subjects who had detectable viral load.
5 Days On HAART, 2 Days off.
Continuing the theme of 'less is more' the mellifluous Cal Cohen, showed 48 week data of the FOTO study where he adapted the regimen of 30 subjects (10 on efavirenz (EFV), 10 on nevirapine (NVP) and 10 on protease inhibitor (PI) based regimens, all with at least two nucleosides (NRTI's) in their regimen) to take therapy only during the 5 weekdays and to miss the weekend doses (WePe12.4C10). This Pilot study showed that 100% of the EFV based patients' maintained suppression and 90% of the NVP based subjects (the one subject was lost to follow-up after a blip to 511copies/mL. Two of the PI based subjects had rebound but re-suppressed on daily dosing, this may be reflected by the serum levels, which were below adequate trough levels for PI's after 2 days off drug. The dosing schedule was much preferred by the patients and was well tolerated and reduced cost by 28%.
Kaletra Monotherapy.
Jose Arribas had two posters following up on his Only Kaletra (OK) study which assessed what happened if the NRTI backbone was stopped in 21 of 42 subjects (WePe12.3C05). Patients who simplified had been <50 c/ml for a median of 28 months, CD4 before switch was 662, nadir CD4 was 139, and viral load previously was 100,000 c/ml before HAART. Patients who remained on triple-HAART had been <50 c/ml for 15 months, CD4 was 585, nadir CD4 was 90, and viral load previous to HAART was 100,000 c/ml.
At week 48, 81% on Kaletra monotherapy and 95% on triple-HAART had <50 copies/ml (ITT, MD=F). In the triple-HAART there was 1 discontinuation due to hyperlipidaemia, and on Kaletra simplification there were 3 patients who lost viral suppression and 1 lost to follow-up. Viral suppression was defined as 2 viral loads >500 copies/ml 2 weeks apart. All 3 patients with loss of viral suppression added nukes (either AZT/3TC or d4T/3TC) and re-suppressed viral load <50 copies/ml. Preliminary data show that failure of these 3 patients was not associated with the development of primary resistance mutations. One patient had no genotypic mutations; the second patient developed L63P & V77I; the 3rd patient developed V77I. There appeared to be an association with losing virologic control and poor adherence as measured by the validated GEEMA adherence questionnaire.
JE McKinnon reported for his research group, which included John Mellors (WeOa0203), on levels of persistent viraemia after simplification in the OK study using a Roche assay with a limit of 3 copies/ml. For patients who remained <50 copies/ml the levels of virus using the sensitive assay were the same, median 3-6 copies/ml, throughout the 48 weeks. So patients who simplified to Kaletra monotherapy and maintained <50 copies/ml did not have different levels of persistent viraemia when using this sensitive assay. Patients on Kaletra monotherapy had the same percent of undetectable (30%) viraemia as patients remaining on triple-HAART through 48 weeks. However, when comparing patients on Kaletra monotherapy who lost viral suppression to those who did not lose viral suppression: at baseline there was no difference in median viral load, but at week 8 median viral load was higher (not significant) among the 4 failure patients compared to the patients who remained suppressed. At week 12 the difference in median viral load between failures and non-failures appeared a little wider, and by week 24 the failures (n=3) had a statistically significant higher median viral load (about 3 logs) compared to patients who retained viral suppression. This suggests that at least for a few patients monotherapy may not be ideal and it appears this may be for those in whom adherence is an issue.
So now to move on to the new agents in development (and a few old ones):
Jiang and co-workers form the New York Blood Bank presented data on a screening exercise to identify small molecule entry inhibitors against HIV-1 (TuOa0201) . These were mainly N-substituted pyrrole derivatives and may offer new agents to act in this area should they be commercialised.
As has been noted before CCR5 offers an ideal target against HIV since it is well conserved, necessary from transmission and has evidence that reduced activity is protective against HIV infection and progression (_CCR5 homo- and heterozygotes respectively); the potential agents fall into three groups:
1. Large molecules: e.g. PRO 140 (Progenics),
2. Intermediate size molecules: such as modified native ligands (Met-RANTES, AOP-RANTES, NNY-RANTES, etc) which render CCR5 inaccessible,
3. Small molecules: against CXCR4 (AMD3100) or CCR5 (TAK-652, UK427, 857 (maraviroc), SCH D (vicriviroc), CMPD167, GW873140, UCB35625), etc., which interpolate into the membrane binding domain.
An overview of the ongoing studies of Maraviroc (formerly UK 427,857) was presented by Elna van der Ryst from Pfizer in the UK. There have ben 6 studies with a total of 154 healthy volunteers and 66 HIV patients receiving maraviroc either QD or BID in doses from 3-1200mg. Dizziness nausea and tiredness occurred at the higher doses but postural hypotension was dose limiting above the 600mg dose with 3/355 subjects at that dose but 6/9 at the 1200mg dose. This looks to be a very clean drug with no serious adverse events reported and apart from two subjects with postural drop at the higher dose no withdrawals from the studies due to drug related events; also no laboratory abnormalities were reported due to the drug and specifically no QTC prolongation on the ECG which had plagued the Schering compounds. 61/63 (97%) of subjects with CCR5-tropic virus at baseline remained CCR5 at 10 days of monotherapy, 2 showed emergence of CXCR4-using variants under treatment at the 100mg dose. Dan Kuritzkes has previously noted that "the current sensitivity of tropism assays could be called into question..." and that the use or these agents could result in emergence of pre-existing minority variants due to selective pressure against R5 virus. In one patient dual/mixed tropic virus emerged at day 11 but reverted at day 40 to CCR5 tropic; in the second the mixed virus emerged at day 11 and remained mixed with at one year 80% CCR5-tropic virus. Phylogenetics suggests that these variants which emerged were due to pre-treatment R5/X4 virus which could not be detected by the current assay sensitivity. Currently in Phase 2b/3 development in both naive and treatment-experienced patients using doses equivalent to 300 mg QD and 300 mg BID.
Vicriviroc (Schering D 417690) has a molecular weight of 650 making it, relatively small, and therefore hopefully easy and cheap to make; has a long half-life, boosted by ritonavir, and synergy with existing compounds. After a slow start, due to toxicity concerns with the former compound Schering C, this agent seems to be much improved. Francois Raffi presented the data on a phase I/II study where 49 subjects were dosed at 10mg, 20mg or 50mg for 14 days and had intensive PK assessment and then follow-up for 28 days (TuOa205). There were 3 non-drug related serious adverse events but as with maraviroc this seems a very safe drug. The half life is long which could lead to intermittent dosing and viral load drops were good at 10 days and showed a dose response.
As with any new agent there is a flurry of pharmacokinetic and drug interaction studies and this was the meeting to show these data for vicriviroc (TuPe3.1B03, TuPe3.1B05, TuPe3.1B06, TuPe3.1B06, and TuPe3.1B09). I will report the top line data. There is no interaction with tenofovir; and exposure is not affected by the co-administration of zidovudine (AZT) and lamivudine (3TC). Since vicriviroc is metabolised by CYP3A4 the combination with ritonavir increase the exposure to drug by about 500% irrespective of the dose of ritonavir from 100-800mg/day in healthy volunteers and this increase did not seem to yield a higher incidence of side-effects with only a few headaches reported. One study assessed if the use of ritonavir could protect vicriviroc from the effect of CYP3A4 induction by efavirenz and this appeared to be so by using 100mg of ritonavir; it increased vicriviroc exposure but by a reduced amount when all three agents were dosed for 14 days. Finally when using the drug in combination with Kaletra the AUC and Cmax appear to be increased by 2.3 and 4.2 times compared to vicriviroc alone; no additional adverse events were reported.
The third CCR-blocker reported on was GW873140, a spirodiketopiperazine, which was assessed against a panel of clinical isolates resistant to a range of antiretrovirals and to 64 mixed tropic viruses with varying degrees of resistance to HAART (TuPe6.1B13). All isolates were susceptible to the GW873140 (excluding the X4 component of the mixed tropic samples and treatment experienced patient samples appeared more susceptible to the drug (median IC50 of 5.83nM compared to 6.71nM for the antiretroviral naive samples). 95% of samples had an Ic50 <16.5nM which reflects the concentration achievable with the current doses under study.
In an oral presentation Daniel Pevear discussed the synergistic action of Pro 140 with other drugs, which act to block CCR5 (TuOa0206). Pro 140 is a humanized IgG4 monoclonal antibody that binds to a multi-domain epitope on CCR5 and blocks HIV but not chemokine binding to CCR5 and has shown prolonged control of HIV in the SCID mouse model. It acts independently of viral clade and target cell, showing a broad spectrum of inhibition. In the table below a combination index (CI) <1 represents synergy showing that all the current CCR5 inhibitors in development have a favourable interaction when given with Pro 140, opening the door to combination CCR5 blockade. Interestingly this benefit is not seen with the fusion inhibitor enfurvitide.
In a phase 1 study in healthy volunteers no toxicity issue arose and the drug was generally well tolerated (WePe6.2C04). The drug will be given to HIV patients in the fourth quarter of 2005.
T-20
Further data continues to accumulate on enfurvitide (T20) a drug where delivery issues remain a problem. Presentations included use in congenital HIV disease for salvage (MoPe9.2C01); successful use in unsuppressed viraemia in pregnancy (TuPe5.2P06); use of a smaller gauge, smaller bore needle associated with fewer adverse events and better quality of life [Qualite Study] (WePe6.3C09).
Did Injection Issues Change with ENF
Experience in Current Users?
Better response to continued T20 versus stopping after 9 months of suppression (WePe12.3C10); prolonged benefit of the drug, in a Spanish cohort (WePe12.9C05); reduced fear of injection but sustained injection site reactions over time (WePe12.9C13); sustained benefit of the drug in the Swiss AIDS cohort (WePe12.9C21). SEE PIX OF GRAPHS/TABLES BELOW.
Reverset
The only novel nucleoside analogue to be showcased was Reverset (WeOaLB0103). Cal Cohen headed a group, which examined the drug in 199 patients with detectable viraemia on HAART.
The study was placebo controlled dose comparison of 50mg, 100mg or 200mg OD as a two week add on to the failing regimen followed by a 14 week period with an optimised background and then an 8 week cross over. It was conducted in 25 centres in USA, Germany and France.
After two weeks there was variable drop in viral load to around 1log. With the greatest reduction in those who did not take 3TC/FTC. This change was continued out through the optimized background phase and resulted in a statistically significant difference in those who did not have 3TC or FTC in the background regimen.
When the drug was co-dosed with ddI 50% of subjects developed hyperamylasaemia compared to 5% when no ddI was used; 3 subjects developed pancreatitis and use in patients at risk of pancreatitis is not advised.
Foscarnet, a pyrophosphate analogue, continues to make a minor comeback for the treatment of HIV in late stage disease (CD4 <100/mm3, HIV RNA >50,000copies/mL, 3 class drug failure). Christine Katlama presented data on a group of salvage patients in whom she used an induction regimen of 5g iv bid for 6 weeks followed by a maintenance phase, if they achieved a >1log drop in viral load, of 5g iv bid for two days a week (WePe12.9C16). She treated 11 patients in the induction phase and 6 reached maintenance, 2 patients died of HIV disease and lymphoma, only one patients stopped due to marked oedema. Viral load decline in the induction phase ranged from -0.1log to -2.95log with a median of -1.79log at week 6 and a median 50 cell rise in CD4 count. Six subjects started the maintenance phase but 3 had viral load failure whilst the other 3 reached >24 weeks with a CD4 rise of 71 cells/mm3 and a HIVRNA below 6,000copies/mL. Further follow-up was curtailed by the availability of TMC114 which 7 patients commenced. Thus it appears that for cases in extremis, foscarnet may be a useful tool to help patients survive until the next best agent(s) arrives in the clinic.
Thiovir is an oral foscarnet analogue being developed by Adventrx Pharmaceuticals. An in vitro study of the agent against a panel of NRTI and NNRTI resistant strains of HIV showed good activity with synergy with zidovudine and a 2-fold better suppression than foscarnet (TuPe6.1B16). After 13 rounds of replication there was a five-fold increase in IC50 to both thiovir and foscarnet, this is certainly a drug to watch out for in the future.
TMC-278
The new non-nucleoside reverse transcriptase inhibitors (NNRTI) also had some new data on show at the meeting. TMC278, a diarylpyrimidine or DAPY compound had a food effect study in 12 healthy volunteers which showed that food increased the levels of TMC278 by 45% compared to fasted with dose proportional pharmacokinetics from 25-100mg and steady state being reached within one week of dosing (TuPe3.1B10), a dose ranging study is on-going. A second PK study looked at the interaction with tenofovir and found that although TMC278 levels are unaffected the levels of tenofovir rise by approximately 24% in combination (WePe3.3C15).
Figure 4. Geometric mean plasma concentration-time profiles for tenofovir in the presence and absence of TMC278
This is not thought to be clinically significant but the clinical studies will need to examine potential increase in kidney toxicity which theoretically could occur.
TMC-125
The other Tibotec NNRTI, TMC125, is further along in development but had the initial disadvantage of a high pill burden. TMC125 C170 was a randomised single dose crossover study in 45 HIV uninfected individuals to assess the standard granulolayered tablet compared to several novel formulations which reduce the pill load (TuPe3.1B11). All the new formulations were better than the standard one and Tibotec are now deciding which one to move forward with. Another study examined the interaction with didanosine (ddI) and showed that no interaction existed and thus no dose adjustments will be required when the two drugs are given together (WePe3.3C16).
The final NNRTI from the same group, TMC120 is no longer being developed for oral use but is under assessment as a potential microbicide. In a study by the international Partnership for Microbicides the drug was examined for activity in both cell based assays and cervical explant, including migratory cells from the explants (MoPp0105). It was effective both alone and as a gel formulation in semen and cervical fluid did not reduce the effect, biocompatibility with the cervical tissue was excellent. In addition the drug appeared to produce anti-HIV memory effects with activity lasting up to 6 days post treatment and thus seems to be a promising candidate for a microbicide. It would also be important to asses the agent in rectal models since anal intercourse is common and clearly a risk in both men and women. An interesting study from the HIV Center for Clinical and Behavioural Studies in New York assessed acceptability of different volumes of microbicidal gel in 20 HIV uninfected men who were having unprotected anal intercourse (MoPp0206). It was a dose escalation study and the maximal acceptable dose was 50ml in 9 subjects, 35ml in 6 and 20ml for 3, with two lost to follow-up. It appeared that 35ml was the most suitable level to use and that this could be an important prevention tool for men who do not use condoms consistently.
Boehringer-Ingelheim showed data on their new NNRTI, BILR 355BS, a novel 8-substituted dipyridodiazepinone, when the developed a crystallographic model of the interaction with the drug with wild-type virus and with various mutants (WePp0105). This study showed BILR 355BS to be better at binding to the mutants through specific modifications to the core substitution patterns. The drug is now in clinical trials.
The last drug in this class to have data presented was the GSK agent GW695634 (WePe6.2C03). A group headed by Steve Becker from San Francisco performed a double blind, placebo controlled study of 4 doses (100mg, 200mg, 300mg, 400mg BID) for 7 days versus placebo in 46 subjects who had NNRTI resistance. The drug was generally well tolerated although rash occurred in 17%, nausea in 15% and diarrhoea in 11% of subjects. At day 8 median viral load reductions were -1.2, -1.1, -1.6 and -1.3 for the groups on active drug at the doses above and were significant compared to placebo (p<0.001).
A group from Southern Research Institute, Frederick, Maryland showed early data on 12 of a panel of 192 compounds screened out for their activity in blocking rev, the protein which is essential for viral replication, another valuable target to clock replication (WePp0106).
Tipranavir
A number of new presentations on data on tipranavir (TPV) were presented (WeOa0205, WePp0103, TuPe7.8C01, WePe4.4C19, WePe6.2C05, WePe6.3C07, and WePe16.7B07). Valdez and co-workers presented week 24 data from the resist studies by co-use of enfurvitide (T20) and tipranavir inhibitory quotient (IQ). Most of the 450 subjects who received TPV/r at a dose of 500 mg/200 mg BID achieve TPV trough concentrations >60-fold in excess of the TPV IC50 of their isolates
- TPV IQ of 30 or more produces large (>1 log10) early (4 weeks) VL reductions, but these are sometimes not sustained because of lack of background regimens
- This TPV IQ, when used with another active drug (T-20), is able to achieve VL below the limit of detection (BLD, <400 copies/mL) in the majority of these hard-to-treat patients at week 24
- A third of these hard-to-treat patients with TPV IQs 60 achieve a VL below 50 copies/mL at week 24
- The TPV concentrations achieved in most patients are not associated with increased levels of hepatotoxicity
- TDM does not appear necessary when the TPV/r dose of 500 mg/200 mg BID is used among highly treatment experienced patients
TMC-114
After the rather promising data at CROI further information was presented on the continued development of TMC114 from Tibotec. A pharmacokinetic study was conducted in 18 healthy volunteers to assess the effect of omeprazole 20mg or ranitidine 150mg on the levels achieved of TMC114 (WePe3.3C13). There was no discernable effect on drug handling and no change in reported side effects.
Figure 1. Mean Plasma ConcentrationTime Curves of TMC114 on Day 5 per Treatment Session
After the disappointing interaction with atazanavir it is important to know this at an early stage of development since the proportion of HIV-infected individuals that use these drugs is high.
Christine Katlama presented the efficacy data on the Power 1 study, 24 week primary analysis, a randomized 4 dose arm versus best option PI, with all arms receiving optimised background therapy (WeOaLB0102). Two hundred and twenty-five subjects were dosed with TMC114/r and 63 were randomised to the control arm. All had a median of 3 primary PI mutations and 8 PI resistance mutations (mainly L90M V82A, M46I/L and L33F/I).
Figure 1. Mean Plasma Concentration-Time Curves of TMC114 on Day 5 per Treatment Session
Approximately 44% of subjects received T20 in the optimised backbone. Results showed the 600mg plus 100mg ritonavir to be the best dose with a -2.03 median reduction in viral load and a CD4 rise of 124cells/mm3 at 24 weeks.
There no adverse events seen more commonly in the TMC114/r arms and liver and lipid events were reported in <10% of subjects. Sub-group analysis suggested that the concurrent use of enfuvirtide (T20) was beneficial as was having <3 primary mutations to PI's.
In a further late-breaker poster the safety data for this study was presented and essentially showed that there was no difference in adverse events between the arms compared to control (WePeLB6.2C01). The rates of nausea, diarrhoea and headache however were reduced in the TMC arms. This is a difficult population to assess for safety and the studies in earlier stage patients will likely reveal the true toxicity rates of the agent at the chosen dose of 600mg BID. Ongoing studies will address the pharmacokinetics and utility of combining TMC114/r with TMC125, a combination which may prove highly beneficial to patients with late stage HIV disease.
Kaletra: new tablet
The new tablet version of Kaletra called Meltrex (melt-extrusion) which reduces the pill burden from 6 to 4 pills daily, does not require refrigeration), and hopefully the gastro-intestinal side effects, had an oral presentation from George Hanna, Abbott Laboratories (WeOa0206). In 141 healthy volunteers in 3 studies the drug was evaluated in various food states and with single and multiple doses. The tablet formulation met bioequivalence criteria compared to the soft gel capsule (Kaletra) and there was less food effect than with the old formulation
Undoubtedly this agent will be now the gold standard against which other PI's will be compared and this means that several of the ongoing studies comparing the new Saquinavir 500mg tablet formulation (Gemini study) and the naive study compared to atazanavir (in development) must consider their comparator formulation carefully if they are to get the best information from the studies.
PA-457 is the first molecule of a new and exciting class of compounds, called maturation inhibitors, which interfere with the creation of new virions prior to them budding from the surface of the infected cell. It prevents the conversion of the HIV-1 capsid precursor, CA-SP1 (p25) to mature capsid proteins (p24) resulting in defective core condensation and release of non-infectious viral particles. Further PK modelling was presented from the double blind, placebo controlled single dose study, which evaluated doses of 75mg, 150mg and 250mg and placebo in 4 groups of 6 patients who were antiretroviral naive or off therapy for at least four weeks, first presented at CROI in Boston [Abstract 159] (TuPe3.1B01). The half-life was 60.3 hours with linear pharmacokinetics suggesting a possibility of a less than daily dosing schedule.
So, in conclusion, the future for HIV therapy is rosy and now what we must deal with is developing effective therapies for hepatitis C, where the story is much less favourable and late HIV diagnosis, which remains a socio-political issue.
Thank you for those investigators who shared slides from their presentations. This article will also appear in the next edition of the Journal of Viral Entry.
Mike Youle
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