Fusion inhibitors
New drug presentations at this year's Workshop on HIV Drug Resistance and Treatment Strategies covered a variety of classes of compounds. P. Sista and colleagues and GD Miralles et al (abstracts 2 and 3, respectively) presented new data on the fusion inhibitors T20 and T-1249, both of which have impressive anti-HIV activity against viruses resistant to inhibitors of reverse transcriptase (RT) and protease [1,2]. Further, data presented separately by these two groups demonstrated the activity of both T-20 and T-1249 against non-clade B viral isolates. In addition, it was demonstrated that patients who possess viruses resistant to NRTI, NNRTI or PI can respond well to T-1249, confirming the absence of cross-resistance among these four classes of antiviral molecules.

On the more technical side, W.A. O'Brien and colleagues demonstrated that the sensitivity of HIV-1 to fusion inhibitors such as T-20 involves distinct regions of gp41 (abstract 17) [3]. Of particular interest are sequences that constitute the first heptad repeat of gp41 and the importance of interactions between gp120 and co-receptors. These findings highlight the types of interactions involved in viral fusion and the likely complexity of events that may underlie resistance to fusion inhibitors such as T-20 and other members of this class.

Protease inhibitors
Presentations on a novel series of second-generation PI, named DPC681 and DPC684, were presented by L.T. Bachelor (abstract 6) [4]. These compounds were demonstrated to be active at low concentrations against wild-type viruses and, in addition, were shown to be highly effective against nelfinavir-resistant viruses containing the D30N mutation and saquinavir-resistant viruses containing M48V/L90M, among other isolates. In addition, the fact that these novel compounds maintained high pharmacologic levels suggests the possibility that they may result in suppression of virtually all PI-resistant clinical isolates described to date, including those resistant to indinavir, saquinavir, lopinavir, and nelfinavir.

NNRTI
Abstract 7 was presented by M.P. de Béthune of the Tibotec-Virco group [5]. It documented results obtained with the second generation NNRTI, TMC120 and TMC125. TMC120, when studied in tissue culture selection protocols, yielded mutations at positions Y181C and Y188L after ten days of replication at 200 nM, while a G190E substitution was observed after 10 days in the presence of 1 M of drug. TMC125 yielded a variant containing L100I and Y181C after 21 days. It is noteworthy that the occurrence of resistance in these cases required at least one additional week compared with development of resistance to either nevirapine or efavirenz. This is probably because the emergence of resistance to these novel compounds usually required the presence of two distinct mutations.

In abstract 10, the antiviral NNRTI capravirine was again demonstrated to be highly effective against a broad range of viral isolates that displayed resistance to other NNRTI [6]. Unfortunately, this novel compound has been reported to cause vasculitis in beagle dogs. Other animal safety studies are now in progress and hopefully will lead to a re-evaluation of the clinical utility of this compound, following the decision by the company to decelerate the development of this drug for human usage.

Nucleoside/nucleotide analogs
In abstract 5, F. Rousseau presented data on FTC and documented that the likelihood of selection of a M184V mutation associated with resistance was less than that associated with resistance to 3TC [7]. Similar results were obtained in regard to clinical trials on suppression of hepatitis B virus. These studies warrant further study of this molecule in the clinic.

In abstract 8, M.D. Miller et al presented data on tenofovir (PMPA), a nucleotide RT inhibitor, and confirmed earlier findings on a lack of cross-resistance between tenofovir and previously approved NRTI and NNRTI [8].

In abstract 11, R.C. Bethell of Biochem Pharma presented data on an exiting new nucleoside analog termed BCH-10618 [9]. It is commonly understood that this molecule is the negative enantiomer of dOTC that had previously been reported in the context of a racemic mixture. In brief, BCH-10618 was demonstrated to be highly effective at low drug concentrations against viral replication using both wild-type viruses and those containing mutations associated with resistance to other NRTI. Despite the emergence of mutations at positions K65R, V75I or M184V, in the aftermath of ongoing replication, BCH-10618 remained highly effective in most cases against viral recombinants containing the aforesaid mutations. In contrast, BCH-10618 was less effective against viral isolates containing inserts at position 69 or against viruses containing the Q151M substitution. These findings warrant further study of BCH-10618 in clinical trials.

In abstract 14, J. Jeffrey et al presented data on amdoxovir (DAPD) which is the pro-drug of DXG [10]. This compound was shown to be effective against a wide array of HIV strains resistant to other forms of nucleoside therapy and also warrants further study in the clinic. In abstract 12, the same group demonstrated that both mycophenolic acid and ribavirin may have the potential to synergize with the DAPD in antiviral effectiveness.

Integrase inhibitors
In abstract 9, D. Hazuda presented data on novel integrase inhibitors that have been developed by Merck research laboratories [11]. She has shown how a series of diketo compounds that possess antiviral activity can select for resistance in tissue culture. Moreover, the acquisition of a series of mutations in sequence led to increased diminution in anti-viral activity. However, this resistance was marked by a loss of viral replicative capacity in single cycle infection assays. Hopefully, compounds that warrant clinical study will be available soon, in contrast to the lead compounds that have suffered from problems of non-specific protein binding and bioavailability.

References
Abstracts can be accessed by hyperlink after registering for the 5th International Workshop on HIV Drug Resistance & Treatment Strategies Webcast at Mediscover.net

Sista P, Melby T, Dhingra U, N Cammack, McKenna P, Dehertogh , Matthews T. The fusion inhibitors T-20 and T-1249 demonstrate potent in vitro antiviral activity against clade B HIV-1 isolates resistant to reverse transcriptase and protease inhibitors and non-B clades. Antiviral Ther. 2001;6(Suppl 1):2. Abstract 2
GD Miralles, R DeMasi, P Sista1, T Melby, F Duff, T Matthews for the T1249-101 Study Group. Baseline genotype and prior antiretroviral history do not affect virological response to T-1249. Antiviral Ther. 2001;6(Suppl 1):3. Abstract 3
Derderyn CA, Decker JM, Sfakianos JN, Zhang Z, O'Brien WA, Ratner L, Shaw GM, Hunter E. Sensitivity of HIV-1 to fusion inhibitors targetted to the gp41 first heptad repeat involves distinct regions of gp41 and is consistently modulated by gp120 interactions with co-receptor. Antiviral Ther. 2001;6(Suppl 1):17. Abstract 17
LT Bacheler, S Jeffrey, K Logue, S Garber, S Diamond, R Kaltenbach, G Trainor, D Getman and S Erickson-Viitanen. Resistance profiles of second generation HIV protease inhibitors DPC 681 and DPC 684. Antiviral Ther. 2001;6(Suppl 1):6. Abstract 6
de Béthune M-P, Azijn H, Andries K, Janssen P, Pauwels R. In vitro selection experiments demonstrate reduced development of resistance with TMC120 and TMC125 compared with first generation NNRTI. Antiviral Ther. 2001;6(Suppl 1):7. Abstract 7
Alexander TN, Leavitt MC, Rudy JJ, Isaacson JS, Hertogs K, Larder BA, Patick AK. Antiviral activity of the HIV-1 NNRTI caparavine against HIV-1 variants from NNRTI-experienced patients. Antiviral Ther. 2001;6(Suppl 1):10. Abstract 10
Rousseau F, Fang L, Sykes A, Rigney A, Mondou E. Emtricitabine: antiviral efficacy and lack of development of resistance in patients treated 1 year for chronic hepatitis B virus infection parallel results in HIV infection. Antiviral Ther. 2001;6(Suppl 1):5. Abstract 5
Miller MD, McKenna P, Larder BA, Harrigan PR. Characteristics of tenofovir phenotypic susceptibility. Antiviral Ther. 2001;6(Suppl 1):8. Abstract 8
Z Gu1, N Nguyen-Ba, C Ren, JM De Muys, B Allard, MA Wainberg, P McKenna, DL Taylor, RC Bethell. BCH-10618, a new heterosubstituted nucleoside analogue against HIV-1 infection. Antiviral Ther. 2001;6(Suppl 1):11. Abstract 11
J Jeffrey, K Borroto-Esoda, J Feng, S Fleming, P Furman, J Mewshaw, F Myrick, R Qi, L Rimsky, D Wakefield. Amdoxovir, a nucleoside reverse transcriptase inhibitor, is active against HIV mutants resistant to standard nucleoside therapy. Antiviral Ther. 2001;6(Suppl 1):14. Abstract 14
D Hazuda, W Schleif, L Gabryelski, J Grobler, P Felock, K Stillmock, A Espeseth, R Danzeisen, R Danovich, M Miller, M Witmer. Resistance to integration inhibitors: evolution of active site mutations, relationship to fitness and enzyme co-factor utilization. Antiviral Ther. 2001;6(Suppl 1):9. Abstract 9