Since the 7th Conference on Retroviruses and Opportunistic Infections last January/February, the anti-HIV drug development landscape has become clearer. Several drugs that were in clinical development just a few months ago have been dropped from clinical development, while the role of others is coming into focus. Drugs that have been dropped include the nucleoside RT inhibitor (NRTI) lodanesone (F-ddA) due to problems of toxicity (lactic acidosis and hepatotoxicity), and the nonnucleoside RT inhibitors (NNRTIs) emivirine (MKC-442) and GW420867 due to rash and hepatic induction of protease inhibitors, respectively. The drugs discussed at the Workshop included the protease inhibitors lopinavir, tipranavir, BMS-232632, and DMP-450, and the NRTIs tenofovir and DAPD. Several compounds in preclinical development were also described. Drugs in clinical development that were not discussed include the NRTIs DOTC and FTC, the NNRTI, AG-1549, and the fusion inhibitors.

Lopinavir
Dale Kempf presented two abstracts on the genetic mechanisms and clinical consequences of resistance to lopinavir (ABT-378). In the first (Abstract 38), he described a study in which protease isolates obtained from patients who failed treatment with one or more of the currently approved PI were sequenced and tested for their susceptibility to lopinavir [1]. Susceptibility ranged from 0.6 to 96-fold resistant (compared to wild-type HIV-1). Mutations at 11 positions (codons 10, 20, 24, 46, 53, 54, 63, 71, 82, 84, 90) were associated with lopinavir resistance. High-level resistance generally required 6 mutations (6-7 mutations: median, 14-fold resistance; 8-10 mutations: median, 44-fold resistance).

In his second presentation (Abstract 89), Kempf described an open-label phase II study of ritonavir/lopinavir + efavirenz + investigator-selected NRTI salvage therapy in NNRTI-naive patients who had otherwise been heavily treated [2]. Nearly all patients (24/25) whose virus isolates had 0 to 5 of the PI mutations described above achieved plasma HIV-1 RNA levels 400 copies by week 24. In contrast, rates of virologic response to therapy were significantly lower for patients whose virus isolates had 6 PI resistance mutations.

These two abstracts suggest that the genetic mechanisms of resistance to lopinavir are similar to the genetic mechanisms of resistance to most other PI, and that most PI resistant isolates (with the probable exception of nelfinavir-resistant isolates containing D30N) are likely to have some degree of reduced susceptibility to lopinavir. However, these data also demonstrate that high-level lopinavir resistance requires multiple PI mutations. This high genetic barrier to resistance for lopinavir is partly intrinsic to the compound and partly related to the high levels achieved in vivo. These resistance data are consistent with the clinical findings that patients receiving lopinavir as part of their initial regimen are likely to achieve prolonged virologic suppression and that patients who fail treatment with other protease inhibitors will often achieve some virologic benefit with lopinavir salvage therapy.

Tipranavir
Sharon Kemp presented an abstract describing the results of in vitro selection experiments with tipranavir (Abstract 40) [3]. In the presence of escalating concentrations of tipranavir, HIV isolates with 10-fold tipranavir resistance were selected. These isolates consistently contained at least two major mutations (generally at codons 82, 84, or 90), one flap mutation (generally at codon 46 or 54), and two or more accessory mutations (e.g. at codons 10, 20, 36, 71).

Tipranavir has less anti-HIV activity in vitro than lopinavir and also has bioavailability problems. The potency of tipranavir in vivo has not yet been described. Based on this abstract, the dynamic range in susceptibility between wild-type isolates and tipranavir-resistant isolates is only about 10-fold. This makes it difficult to assess recent claims that most PI-resistant clinical isolates retain susceptibility to tipranavir.

BMS-232632
BMS-232632 is reported to have potent anti-HIV activity in vitro with IC50 values of 3-5 nM. It is also reported to have a favorable pharmacokinetic profile allowing once daily dosing and potent antiviral activity in vivo [4,5]. It is currently in phase III clinical trials.

At the Sitges Workshop, Richard Colonno described the susceptibility of BMS-2326332 to approximately 50 clinical isolates obtained from patients failing other protease-inhibitor containing regimens (Abstract 8) [6]. BMS-232632 susceptibilities ranged from 0.5- to 82-fold resistant (most highly resistant isolates were 20-40 fold resistant). The most highly resistant isolates generally had two major mutations at codons 82, 84, or 90, as well as, mutations in the protease flap (e.g. codons 46 and 54) and accessory mutations (e.g., 10, 63, 71). It is difficult to agree with the abstract's claim that the resistant profile of BMS-232632 differs significantly from that of currently available PI. Nonetheless, the potency and pharmacokinetic profile of this compound make it a promising candidate for further clinical studies. In addition, the raw data from their study, described in detail in a thorough poster, provide valuable data on genotype-phenotype relationships among the PI and may help clinicians in deciding when to use BMS-232632 should it eventually be approved.

DMP-450 J. Sierra described the results of a phase I/II study of DMP-450 a protease inhibitor under clinical development by Triangle Pharmaceuticals (Abstract 6) [7]. Previously untreated patients were treated with DMP-450 in combination with stavudine and lamivudine and by week 4, >2 log RNA reductions were observed at the highest does studied, including one of the b.i.d. dosages. No drug resistance data on this compound were presented.

Tenofovir
Michael Miller described the anti-HIV susceptibility to tenofovir of a panel of NRTI-resistant clinical samples (Abstract 4) [8]. Isolates containing an insertion at codon 69 were the most resistant (approximately 25-fold), whereas most other isolates, including those with the multiple classical AZT resistance mutations or with the previously described mutation K65R, were found to be 3- to 4-fold resistant [9]. As in the case of adefovir, the M184V mutation was found to confer tenofovir hypersusceptibility. Tenofovir has demonstrated remarkable antiretroviral activity in the SIV model of acute and chronic infection. If clinical trials demonstrate that this compound has greater potency and less toxicity than its predecessor, adefovir, tenofovir may prove a useful addition to the NRTI class of compounds.

DAPD
DAPD is under development by Triangle Pharmaceuticals for the treatment of HIV and hepatitis B virus (HBV). DAPD, diaminopurine dioxolane, is converted in vivo to a guanosine analog, DXG (dioxolane guanosine). Steve Deeks presented preliminary clinical data from a 2 week dose-finding study of DAPD used as monotherapy in previously untreated and previously treated patients (Abstract 9) [10]. Among the treatment-naive patients, there was a 1.5 log RNA reduction at the highest doses used. Among the previously treated patients there was a 1.1 log RNA reduction at the highest doses used.

Finally, Phillip Furman reported in vitro data on the susceptibility of DAPD to known NRTI-resistant isolates (Abstract 4) [11]. Isolates with the uncommon, multinucleoside-resistance mutation Q151M consistently had decreased susceptibility to DAPD (about 5-fold) and one isolate with K65R + Q151M had approximately 40-fold decreased DAPD susceptibility. However, isolates with the more common NRTI resistance mutations (e.g. M184V, the 3TC-resistance mutation, and M41L, D67N, K70R, T215Y, and K219Q, the classical AZT-resistance mutations) remained susceptible to DAPD. DAPD's potent activity in vivo and its in vitro activity against HIV-1 isolates with most common NRTI resistance mutations make this a promising a new anti-HIV compound.