IAS: New NRTI D-d4FC active in treatment-experienced patients

The new nucleoside reverse transcriptase inhibitor (NRTI) D-d4FC (Reverset) is active in patients with substantial treatment experience and NRTI resistance, according to the results of a phase IIb study presented at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro on July 27^th.

The study also showed that the drug should not be used with ddI (didanosine, Videx / VidexEC), due to an elevated risk of side-effects.

D-d4FC is currently under development by Incyte and Pharmasset. It has previously been shown to be active against NRTI-resistant HIV in the test tube. As well as having the potential to be active against HIV in patients who have failed NRTI-based therapy, the drug also persists for a long period in the body, with a half-life of 17 hours.

Early studies also suggested that it may not cause mitochondrial toxicity or raised lactate levels, side-effects that occur with other drugs in the same class.

The investigation presented in Rio de Janeiro set out to test the efficacy of the drug in HIV-positive patients when used in combination with other drugs.

“Reverset 200mg is active in antiretroviral-experienced patients and generally well tolerated,” the researchers concluded. “Because of the risk of elevated lipase and pancreatitis, Reverset should not be used with ddI."

“Data support the continued development of Reverset,” they said.

The investigators recruited 199 patients from 25 sites in the United States, France and Germany. The patients were treatment-experienced with a mean baseline viral load of 31,600 copies/ml and many NRTI-associated mutations: 60% had the M184V mutation, 60% had M41L, 50% had between four and six thymidine analogue mutations (TAMs) and 6% had K65R.

During the first two weeks of the trial, the patients were randomised to add placebo or one of three doses of D-d4FC to their failing drug regimen. At the end of this period, patients taking placebo had a mean viral load fall of 0.03 log₁₀.

However, those taking 200mg of the drug once daily had a mean drop of 0.7 log₁₀. This was significantly greater than the placebo group (p

The effect of adding D-d4FC to a failing regimen was unaffected by inclusion of tenofovir (Viread), AZT (zidovudine, Retrovir) or abacavir (Ziagen). However, its activity was reduced if it was combined with either 3TC (lamivudine, Epivir) or FTC (emtricitabine, Emtriva).

After omitting the results from patients taking either of these drugs, the mean viral load drop was 1.1 log₁₀. This is unsurprising, as FTC and 3TC have a similar chemical structure to D-d4FC, so their combination may not be as powerful as using two or more drugs that target different sites within the HIV’s genetic material.

The activity of the 200mg dose was undiminished by the presence of TAMs, M41L or M184V alone. However, the combination of TAMs with M184V, L74V/I or K65R caused the anti-viral effects of the drug to be reduced.

After the two-week add-on phase of the study, the patients continued to take placebo or their assigned dose of D-d4FC alongside a background regimen of drugs that was optimised for each patient based on their drug resistance profile.

At the end of week 16, the patients taking 200mg D-d4FC once daily had a mean viral load of 1.2 log₁₀ below baseline, with 54% achieving a drop of at least 1 log₁₀. These values compared to 0.4 log₁₀ and 14% in the placebo group.

Omission of the values from patients taking 3TC or FTC in their background regimen again resulted in more impressive results, with a mean viral load reduction of 1.4 log₁₀ and 80% of the patients achieving a drop of 1 log₁₀ or more.

Side-effects were mild in the study, and included headache, fatigue, nausea and diarrhoea, and were found at similar rates in all four arms.

However, combination of D-d4FC with ddI led to a high frequency of hyperlipasaemia, the presence of the enzyme lipase in the blood. This may be a sign of damage to the pancreas. In the 200mg dose, two (5%) of the 37 patients not taking ddI had elevated lipase levels, compared to seven (50%) of the 14 who were taking ddI. There were also four cases of pancreatitis, or inflammation of the pancreas, although these only occurred in the 100mg group.

Dr Cal Cohen, presenting, said that the other severe side-effects seen, including elevated blood fats and low blood cell levels were probably attributable to other drugs being taken by the patients.

Phase III trials of D-d4FC are currently being planned. Phase III trials are the final steps in the clinical trial process before a licence for a drug can be applied for. They are usually large, long-lasting studies comparing the drug of interest to another drug as part of an antiretroviral therapy regimen.