DPC 083 is a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) under development until recently by Bristol-Myers Squibb .

The drug has been shown to be active against single resistance mutations associated with high level resistance to NNRTIs, including the K103N mutation, and against double mutation patterns such as K103N and Y181C, K103N and V108I, and K103N and P225H.

Week 8 results of a study in NNRTI-experienced individuals have been reported. Fifty-one individuals were treated, and 57% had viral loads below 400 copies/ml at week 8 after starting with a mean baseline viral load of 7000 copies/ml. The mean viral load reduction was 1.28 log₁₀, and response was correlated with the number of new nucleoside analogue reverse transcriptase inhibitors (NRTIs) added. Forty per cent of the patients who did not add a new NRTI achieved a viral load below 400 copies/ml (Ruiz 2002).

The main side-effect noted is skin rash, although incidence has not been reported. Participants in trials are being prescribed an antihistamine for the first 28 days on treatment since the rash tends to appear soon after starting treatment, and is responsive to antihistamine treatment, unlike the rash associated with nevirapine (Viramune) treatment.

The development of DPC 083 was suspended in May 2003 due to the side effect profile and the lack of strong evidence that DPC 083 will be an effective NNRTI for people who have already failed efavirenz (Sustiva) or nevirapine.

Key research

Week 8 results from a study of DPC 083 in people who have experienced failure of an NNRTI-containing regimen were reported by Ruiz. Fifty one patients (mean age 40, 94% male) with mean baseline viral load of 3.85 log (around 7,000 copies /ml) and 473 CD4 cells/mm3 were randomized to receive either 100mg or 200mg of DPC 083 once daily. Baseline resistance profiles were available for 48 individuals; 94% had at least one NNRTI resistance mutation, including mutations at positions 101 (44%), 103 (52%), 181 (17%), and 190 (25%). Fifteen patients had at least two NNRTI resistance mutations. The pooled (100 and 200 mg) on-treatment (OT) response rate at week 8 (< 400 copies/mL) was 57%. The mean change in VL from baseline was -1.28 log. The pooled OT response rates varied according to the number of new NRTIs used: no new NRTI 40% (4/10), 1 new NRTI 72% (13/18), and 2 new NRTIs 67% (10/15). The discontinuation rate due to adverse events was 16% (8/51).

Ruiz reported a dose ranging study in treatment-naﶥ patients; the study compared the efficacy of various doses plus two NRTIs against efavirenz plus two NRTIs. 134 patients with mean baseline viral load of 33,113 copies were randomised to receive either 50mg, 100mg or 200mg of DPC 083 or efavirenz. All participants received Combivir (AZT plus 3TC). After 24 weeks, the proportion of patients with viral load below 50 copies (undetectable) was similar in each arm (79% (50 mg), 67% (100 mg), 72% (200 mg), and 78% (EFV). However, there was a trend towards higher discontinuation rates in the efavirenz group and in those who received the highest DPC 083 dose. Premature discontinuation rates were 14% (50 mg), 17% (100 mg), 24% (200 mg) and 22% (EFV) (p > 0.05). The most frequent side effects were dizziness and rash. Dizziness was less frequent with DPC 083 (11-18%) than with EFV (32%). The frequency of rash was 15% (50 mg), 33% (100 mg), 53% (200 mg), 38% (EFV).

References

Jeffrey S. New second generation NNRTIs: improved resistance and cross-resistance profiles. Thirteenth International AIDS Conference, Durban, abstract TuPpA1145, 2000.

Ruiz N et al. Study DPC 083-203, a Phase II Comparison of 100 and 200 mg Once Daily DPC 083 and 2 NRTIs in Patients Failing a NNRTI Containing Regimen. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 7, 2002.

Ruiz N et al. Study DPC 083-201: A Phase II Double-Blind (DB) Comparison of 3 Once Daily Doses of the NNRTI DPC 083 vs 600 mg Efavirenz (EFV) in Combination with 2 NRTIs in HIV Anti-Retroviral (ARV) Treatment Naﶥ-Patients. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 7, 2002.