Bristol-Myers Squibb, the manufacturer of ddI, has written to health care providers in the United States warning of early virologic failure in patients who begin antiretroviral treatment with regimens that combine ddI and tenofovir with either efavirenz or nevirapine.
The findings are derived from two data sets of treatment-naïve patients. In a randomised study which compared ddI EC 250mg/tenofovir plus efavirenz to ddI/tenofovir/efavirenz/lopinavir/ritonavir, six of 14 patients in the ddI/tenofovir/efavirenz arm experienced protocol-defined virologic failure after three months on treatment, compared to none of the twelve patients in the lopinavir-containing arm. All patients who experienced virologic failure had high baseline viral load (>100,000 copies/ml) and CD4 cell counts below 200 cells/mm3. Resistance patterns that included G190E/S (n=3), L74V/I (n=4), and K65R (n=2) mutations were observed at failure (Podzamczer).
The second piece of evidence comes from an unpublished retrospective database analysis of 5000 treatment-naïve HIV patients in whom therapy was initiated between October 2002 - March 2004. Fourteen patients were identified as having received a regimen of ddI EC 250 mg once daily and TDF 300 mg once daily, plus either EFV 600 mg once daily (n=10) or NVP 400 mg once daily (n=4).
After 12 weeks of therapy, five of 14 patients (36%) experienced suboptimal (plasma viral load drop
At baseline, virologic failure patients had a median viral load of 5.8 (range, 4.7-6.0) copies/ml and a median CD4 cell count of 126 (range, 24-281) cells/mm3. Four of the virologic failure patients exhibited the K65R and L74V mutations and all seven exhibited one or more of the following mutations: L100I, K103N/R/T, Y181C, and G190E/Q/S.
Data not cited by Bristol Myers Squibb were also presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy two weeks ago in Washington DC.
An open-label comparative trial in which patients were randomised to receive ddI and efavirenz with either tenofovir or 3TC was stopped early because higher rates of treatment failure were seen in patients taking tenofovir, according to data presented by Dr Graeme Moyle of London's Chelsea and Westminster Hospital.
After four weeks of treatment 97% of patients randomised to receive 3TC (n=36) had achieved a 1 log10 fall in their viral load, compared to only 88% of the individuals taking tenofovir (n=41). After twelve weeks of treatment the investigators noted that none of the patients taking 3TC had experienced rebound in their viral load or had primary resistance mutations. By contrast, 13.8% of the tenofovir recipients had either an increase in their viral load of at least 0.5 log10 or had developed resistance mutations.
In further analysis, the investigators established that all these viral rebounds had occurred in patients who had a baseline CD4 cell count below 200 cells/mm3 and a pre-treatment viral load above 100,000 copies/ml.
Treatment failures were not related to poor adherence, which Memscaps data indicated was 100%.
Advice to prescribers
Bristol Myers Squibb warns doctors that ddI/tenofovir plus efavirenz or nevirapine should be used with caution in patients with high baseline viral load, but also points out that in treatment-experienced patients there is no evidence that the combination of ddI and tenofovir is associated with higher rates of virologic failure. The company cites a post-hoc analysis of its BMS 045 study of atazanavir/ritonavir versus lopinavir/ritonavir or atazanavir/saquinavir in PI-experienced patients, which shows no difference in rates of virologic failure between those who received ddI/tenofovir in their nucleoside analogue backbone and those who did not.
The analysis excluded atazanavir/saquinavir-treated patients and included only those with baseline viral load above 100,000 copies/ml. The two combined arms of ATV + RTV and LPV/RTV demonstrated a 33% (8/24) virologic failure rate§ through Week 48 in the ddI-treated group compared to 52% (16/31) in the non-ddI-treated group.
The company also points out that in two studies in treatment-naïve patients (Gilead 903 and Study 301A), the combinations of tenofovir, efavirenz and 3TC or FTC respectively were not associated with higher rates of virologic failure when compared to the control arms.
Podzamczer D et al. Early virologic failure with a combination of tenofovir, didanosine and efavirenz. Antiviral Therapy 2004 9:S172, Poster 156 presented at the 13th International HIV Drug Resistance Workshop; June 2004; Tenerife Sur, Spain.