First randomised trial shows clinical benefit of TDM for people using nelfinavir or indinavir containing combinations

Report by Simon Collins, HIV i-Base

The Second International workshop on Clinical Pharmacology of HIV Therapy took place on 2-4 April in Noordwijk, the Netherlands. Of the 80 or so presentations and posters, results from the first randomised study showing the benefits of TDM will have the most important effect on use of therapeutic drug monitoring.

No one seems to doubt that achieving optimum results from the currently available antiretroviral drugs involves a complicated and multifactorial process. With results from most studies over the last few years falling well below 100% achievement of maximal viral suppression even in treatment naïve individuals, this should send a major signal that greater care needs to be given to each key area.

Along with potency, activity, adherence and tolerability, achieving the concentrations that are necessary for each drug to work is an essential component that is acknowledged, but rarely acted upon.

The reluctance for clinicians, even with access to low cost, validated, fast turnaround assays to utilise this service has often been due to a lack of evidence from randomised clinical trials. With the long protracted UK OPIUM study still not enrolling patients, despite access to world class research at Liverpool University, the results from the Dutch ATHENA study were therefore keenly awaited.

TDM is routinely available for all patients using a PI or NNRTI-based combination in the Netherlands. The importance of establishing the degree of clinical benefit nevertheless led to this large study, even though running a randomised clinical trial looking at the benefits of TDM would provide people with a sub-optimal standard of care for Dutch patients. (Interestingly this was the reason given last year by the MRC for not supporting the OPIUM study, although less than 3% of patients who could benefit from TDM currently access these tests in the UK.)

ATHENA has enrolled 600 patients (50% naïve, 50% experienced) from 22 Dutch sites and randomised them 1:1 into an intervention or control arm. The intervention arm involves drug concentrations being determined at regular intervals and the results reported to the treating physicians, together with advice from a pharmacologist; in the control arm the results are not reported.

At last year’s Noordwijk meeting, preliminary results from the first 400 or so patients enrolled showed approximately a quarter of people using indinavir, nelfinavir, ritonavir or saquinavir were recording sub-optimal concentration ratios (<75% of population values) leading to a recommendation to provide adherence support or increase dosing levels. Additionally, 5-10% of patients achieved levels >200% of population values leading to a recommendation to dose reduce if toxicity was reported as an issue. With patients using nevirapine levels were sub-optimal in 10% of samples and excessive in 3.5%. [4]

For this year’s meeting, David Burger from UMC Nijmegen presented clinical results with one-year follow-up on treatment naïve patients using either indinavir or nelfinavir based regimens. [5, 6]

Blood was sampled at each out-patient visit and analysed for IDV or NFV by validated HPLC at a central lab. Because of the random sampling times, the concentration ratio (CR) – calculated as an individual concentration divided by the time-adjusted population value – was calculated and advice was reported to the physician within 4 weeks of sampling.

Results from 92 randomised patients using nelfinavir 1250mg BID were presented and a CR <0.90 determined whether an intervention was necessary. The rules for intervention for patients using nelfinavir was to discuss intake with food with a first result <0.90. A second CR < 0.90 lead to a dose increase to 1500mg q12h and a third CR < 0.90 to increase dose to 1750mg q12h or add low-dose RTV.

Overall, after one year of follow-up, there were 35 discontinuations in the TDM-blind arm compared to 12 discontinuations in the TDM arm (p = 0.01). There were 18 and 2 discontinuations due to treatment failure in each arm respectively (p=0.02). The proportion of patients with a successful response (viral load < 500 copies/ml) was 97% and 82% at 6 months (p=0.06), which reached statistical significance at 12 months at 80% and 60% (p=0.03), in the TDM and control arms respectively.

The analysis in this study showed that the odds for virological success in treatment naïve patients using nelfinavir-based regimens is higher if their monitoring included TDM.

In the 55 people randomised using indinavir-based combinations, 16 were using indinavir as sole PI dosed at 800mg TID, 20 were using indinavir/ritonavir dosed at 800mg/100mg BID and 19 were using indinavir/ritonavir dosed at 400mg/400mg BID.

Interventions for indinavir concentrations in each of these combinations were instigated if outside the following range:

IDV 800mg tid: 0.75 – 2.0 CR

IDV/rtv 800/100mg bid: 0.25 – 2.0 CR

IDV/rtv 400/400mg bid: > 0.50 CR

After one year of follow up in this group, overall rates of discontinuations in the TDM vs. control group were 25% and 48% respectively (p=0.07) although in these cases discontinuations were driven largely by toxicity. This achieved statistical significance at 10% and 40% (p=0.03) when looking at the 36 patients on 800mg TID or 800mg/100mg regimens – those most associated with indinavir toxicity.

The proportion of patients with a successful response (viral load < 500 copies/ml) was 92% and 74% at 6 months (p=0.06) which reached statistical significance at 12 months at 75% and 48% (p=0.04), in the TDM and control arms respectively.

Comment

Based on these results, patients currently using either of these regimens could improve their clinical care through access to TDM.

Patients starting a nelfinavir-based combination are less likely to see their treatment fail.

Patients using indinavir either as a sole PI in TID regimens or using ritonavir boosted BID regimens (dosed at 800/100) are less likely to discontinue due to toxicity if their dosing is managed by TDM.

In the UK, TDM for nelfinavir, saquinavir and indinavir is available at no cost to clinicians through the pharmacology department of Liverpool University thanks to programmes sponsored by Roche and Merck.

The importance of longer term follow-up (ie to a year) showed a clear benefit to using TDM for these agents and in this population. Prompt reporting of results (within 4 weeks) is likely to also have ensured that the a dose outside the optimal range could be adjusted in order before either development of resistance or discontinuation due to toxicity.

It was reassuring to hear that clinicians used a first low results as an opportunity for adherence support, and that the investigators place benefits from TDM as only one of many crucial factors for achieving optimum results.

References:

Reports from First International Workshop on Clinical Pharmacology – HIV Treatment Bulletin Vol 1, No 2, May 2000.
PK and TDM studies at 7th Retrovirus Conference. DrFax 83, Feb 2000.
Marzolini et al – Efavirenz plasma levels can predict treatment failure and CNS side effects in HIV-infected patients. AIDS 2001 Jan 5; 15(1):71-5.
Burger D, Hoetelmans R, Hugen P et al – ATHENA: A Randomised, Controlled Clinical Trial to Evaluate whether Therapeutic Drug Monitoring (TDM) Contributes to Reduced HIV-related Morbidity and Mortality. First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk. Abstract 6.6
Burger D et al – Therapeutic drug monitoring (TDM) of indinavir in treatment naïve patients improves therapeutic outcome after 1 year: results from ATHENA. Second International workshop on Clinical Pharmacology of HIV Therapy, 2-4 April 2001. Noordwijk. Oral presentation and poster 6.2a.
Burger D et al – Therapeutic drug monitoring (TDM) of nelfinavir 1250mg BID in treatment naïve patients improves therapeutic outcome after 1 year: results from ATHENA. Second International workshop on Clinical Pharmacology of HIV Therapy, 2-4 April 2001. Noordwijk. Oral presentation and poster 6.2b.