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ICAAC San Diego 2002: new therapy approaches; hormones and metabolics
Reported by Mike Youle, MD, Royal Free Hospital, London
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There was an oral session at ICAAC where several speakers delivered interesting talks about future treatments for HIV. This is a review of that session. Some of the information, particularly about the Merck integrase inhibitor program, was presented at this Summer's Resistance Workshop. Dr Youle's report below on metabolics will be followed up with more on body changes presented at ICAAC.
New anti-HIV therapy and approaches
This was a conference in which there were several promising agents discussed with in vitro and animal data available but that have not yet reached the clinical setting. Other than T20 and tipranavir novel drugs for patients with multi-drug resistant virus are few and far between and one wonders if the FDA really have a concept of what it is to be desperate for a new therapy to treat with. As the most recent presentation on atazanavir versus efavirenz [Study A1424-034] showed [Abstract H-1076] when the new FDA criteria for efficacy are applied to a study very few subjects manage to achieve what is classed as success. As clinicians, however we know that many patients exhibit some viral load blips without ever failing treatment over a long period of time so attempting to equate utility with these efficacy parameters gives a false cut-off that lacks clinical relevance. One wonders how studies will be judged when the ultra-ultra-sensitive <3 copy assay becomes the new gold-standard of suppression.
The last day gave the best overview of what lies around the corners, both near and far. The initial presentation discussed the pitfalls and processes of development of new antiretroviral agents against the protease and reverse transcriptase and focused on the non-nucleoside reverse transcriptase inhibitor TMC125 and the protease inhibitor TMC114 [abstract 1781]. Rudy Pawels explained the high throughput screening process used at Tibotec (now part of Johnson and Johnson) and how compound optimisation results in new agents that have better efficacy profiles. As yet there is a limited ability to isolate toxicity in the pre-clinical phase and this is a challenge for drug development since more and more side-effects limit the utility of particular therapies. He presented data on TMC125 and especially on the hydrogen bond strength of this agent at the binding site. These novel DAPY NNRTIs appears to complement those of the available ones such as efavirenz and so combination studies might yield greater efficacy. The TMC114 protease inhibitor data suggested that it will have a log better activity than lopinavir, data derived from time to breakthrough experiments. This drug is currently in phase II studies.
ENTRY INHIBITORS. Robert Doms next discussed the action and possibilities of combination approaches to entry and fusion inhibitors [abstract 1782]. He and the group of Eric Arts had wondered why some subjects given T20 did not have such good responses as others. One of the factors that appeared to be linked to this poorer viral load reduction appeared to be variability in the V3 loop of envelope. Although not directly related to the action of T20 this determines differences in envelope protein-co-receptor density and binding, that appear to be rate limiting for the action of T20. Thus virus that is most resistant to T20 binds to the co-receptor with greatest affinity. It would appear that high gp120-CCR5 affinity equals fast fusion and low affinity results in slow fusion. The faster the fusion process the less time T20 has to bind to the HR2 domain and inhibit the process. Having said that he went on to explain that co-receptor antagonists might therefore help by reducing R5 expression and aiding the effect of T20. As he said it makes" all the sense in the world to use co-receptor antagonists and fusion inhibitors together". This is good news for future therapeutic strategy.
INTEGRASE INHIBITORS. Daria Hazuda from Merck Research Laboratories showed data regarding the original diketobutanoic acid derivatives that appeared to successfully act at the strand transfer level of HIV integration into the host cell genome [abstract 1783. These compounds however have problems with their utility as drugs that render them "intractable for further development". She then described the new generation of agents called the 1,6-naphthyridine 7-carboxamides which appear to be much more likely to make the grade.
There has been a study of one candidate L870812 conducted in rhesus monkeys infected with a rapidly pathogenic simian virus SHIV89.6. The treated animals had minimal decline in T4 cells so by day 87 they had 520 T4 cells compared to a median of only 39 in those who received no integrase inhibitor. In addition the viral load of the treated animals went below detection in 4 of the 6 monkeys and in the other two they achieved a 1-2 log drop and had T4 cells of 261 and 1267 respectively. The two poorer responders had low levels of drug suggesting that at higher doses they may have done better. They both developed a signature mutation at codon 155 but did not show an increase in viral load when this appeared. At day 87 the untreated animals were given active drug for 21 days and showed a 2 log drop in viral load but which rebounded at day 10, although the virus recovered was wild-type. Hazuda argued that the drug had better activity before T cell decline and that higher doses need to be studied.
The mutants that were selected for also seemed to be replication deficient suggesting that they would be unlikely to infect and would not integrate either.
The candidate agent L870810 is now in phase I studies and shows an IC95 of 110ng/mL similar to currently used anti-HIV agents and has good oral bioavailability and a longer half life suggesting twice daily dosing is possible
MORE PRELIMINRY RESEARCH. Finally, in this session, Bryan Cullen from Duke University took us on a magical mystery tour of non-traditional targets for HIV suppression [abstract 1784]. He concluded the first part of his talk by saying that the tat and rev genes were ideal targets for future agents since they are essential components for ongoing replication. He noted that there are already agents such as flavopyridole, used in oncology, which may have utility and that against rev some agents are active but have too high a cell toxicity to use.
He was keener on the use of RNA interference and in an elegant talk described how artificially or virally introduced double stranded RNA's could block the replication of HIV by degradation of homologous messenger RNA species. This process uses a technique that is important in the development of an organism to switch off the production of a particular set of genes and gene products so that, for instance, a butterfly can evolve for a caterpillar rather than the genes merely leading to a larger caterpillar. Although a long way off and with major delivery challenges this seemed intuitively a fascinating approach to controlling HIV at the cellular level with potentially very low toxicity.
Workers from a joint venture between the Swedish Karolinska Institute and Medivir AB presented new information concerning a novel NRTI that seems to work effectively in vitro against multi-drug resistant strains of HIV [abstract H-172]. The compound, 3'-Fluoro-2',3'-Dideoxyguanosine (FLG) has been previously shown to be active against both HIV and Hepatitis B virus (HBV) which makes it valuable for co-infected patients, along with compounds such as lamivudine and tenofovir.
The antiviral effects of the agent were determined in several cell lines that permit HIV replication. Activity was assessed, as IC50 values, which represent the levels at which the agent will inhibit 50% of the virus, so were not at the 90% level that is a much more stringent assessment of efficacy. FLG appeared to have extremely good action against MDR isolates with a decreased susceptibility, in these assays, of less than 1.5 fold for the five isolates with Q151M and 2.1 fold for those with T69S double insertions. FLG also showed activity against variants with mutations M41L, D67N, L210W and T215Y at levels that are close or below those of 1.0microM i.e. the EC50 for wild-type virus for FLG. In experiments to attempt to produce resistance to the drug virus after 28 passages produced two dominant variants, which included codon changes at position 35 and 133, which cause resistance to the drug. Some cross-resistance to lamivudine but not zidovudine was seen with these strains.
A pro-drug of FLG (MIV-210) has in a phase one study showed excellent oral uptake and high plasma levels of FLG. A study was also conducted in woodchucks, an animal model for hepatitis that showed dramatic reduction in woodchuck hepatitis virus load of up to 7.8log after 10 weeks of treatment at a dose of 60mg/kg, with good tolerability [abstract F-1695]. If this agent is safe it could represent a vital option for those who have NRTI resistance as well as an attractive first-line dual action capability.
Perspectives on hormonal and metabolic changes
The great white charger against lipid and metabolic abnormalities has to be atazanavir since all these studies to date have suggested this agent to have little of the negative profile that other protease inhibitors have. It remains to be seen how the lipodystrophy story pans out since no controlled data on this agent compared to others has yet been presented. A lot of the data that came out of this meeting has had previous airings notably at the Lipodystrophy Workshop held during the previous week. However some new information made its' way into the Monday poster session.
Work by a Spanish group suggested that the level of free thyroid hormone levels built on earlier data that suggested that around 13% of HIV patients have some thyroid dysfunction [Grappin et al AIDS 2000,14:1070-1072]. In 202 subjects prospective assessments of thyroxine (FreeT4) the hormone that controls energy levels were performed as we as the hormone TSH that stimulates production [Abstract H-910]. There was tight correlation of T4 with CD4 count with abnormally low levels in 1.3% of subjects. Higher levels were associated with a lack of an AIDS diagnosis and in subjects without concurrent hepatitis with the TSH level also being predictive of the Free T4 levels. In addition further data supported the higher rate of dysfunction when Calza and co-workers assessed 84 subjects (49 on HAART) [Abstract H-1911]. In the HAART treated individuals 12.2% had low FreeT4 whilst none of the treatment naive subjects did (p<0.05). In this study no association was seen with a particular antiretroviral (exposure >27 months), although reports have previously been made of hypothyroidism with efavirenz.
Another hormone that is poorly monitored in patients with HIV by many units and irregularly replaced is testosterone. Cohan and his group at Pacific Oaks in Los Angeles looked at the efficacy and utility of Androgel, a topical testosterone product in 30 hypogonadal subjects who were stable on intra-muscular injections of testosterone cypionate [Abstract H-1912]. After 8 weeks of topical therapy quality of life assessments showed a 10% improvement in physical and emotional well being as well as more stable serum levels of testosterone as well as greater patient acceptability.
Continuing on the hormonal trail, two abstracts further evaluated the aspects of human growth Hormone (HGH) in childhood development and HIV related lipodystrophy. Ezeanolue and colleagues described 3 African-American children in whom growth failure was identified, 2 HIV+ and one HIV- [Abstract H-1913]. They also had HGH deficiency and ILGF-1 levels below normal, an uncommon condition. On MRI their pituitary glands were small but with exogenous HGH they have regained their growth curves. The authors mused on the link between this phenomenon and the exposure to nucleoside analogues since their mothers had all been exposed to AZT during pregnancy. Moyle reported the effect of maintenance low-dose alternate day therapy with HGH used to treat lipodystrophy in 12 subjects who were given 4mg/kg daily for twelve weeks followed by a blinded phase of placebo, alternate day or twice weekly 1mg/kg doses [Abstract H-1935]. The sustained responses over 12 weeks of higher dose were lost on placebo and both fat free mass and visceral adipose tissue gains were maintained on the alternate day dosing.
New fill is a physical intervention involving injections of polylactic acid into the face to correct areas of subcutaneous fat loss [Abstract H-1934]. Developed in France it has gained popularity in Europe but has been effectively banned in the USA, a source of some consternation. In a small study of this approach, 30 patients were randomised to immediate injections or delayed treatment. Self-perception, visual analogue scores of self assessed appearance and standard depression tools all showed a benefit for the immediate treatment group, which was sustained through 24 weeks. This further confirmed previous work from France on the acceptability of this intervention for facial wasting.
Thromboembolic complications are one of the least understood adverse events in HIV. It has become increasingly obvious that clotting disorders, such as protein S deficiency and embolic events, especially deep-vein thromboses are common in HIV disease, and not all attributable to long flights across the Atlantic. In one study presented 25 subjects without haemophilia and on PI based regimens were assessed for a wide range of markers of coagulation [Abstract H-1937]. Contrary to published reports these subjects showed increases in circulating anticoagulants although the thrombin time was significantly reduced after one month (p<0.05). Many of those with reported episodes have been on nucleoside analogues for a long period so further studies where the classes are distinguished may added to the knowledge base concerning these problems.
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