The most important predictor of successful ITI is the inhibitor titre at the start of ITI, which affects both the likelihood of success and the time taken to achieve tolerance. An inhibitor titre <10 BU/ml at the time of initiation of ITI significantly correlated with successful outcome in both the NAITR and the IITR (p=0.004 and 0.001 respectively) (Mariani et al, 1994; DiMichele et al, 1999 and 2000). The success-rate and time to success for patients starting ITI with an inhibitor titre <10BU/ml was 85% and 11 months, which compared to 33% and 15 months in patients with high titre inhibitors >10BU. Most other studies show a similar relationship between the starting inhibitor titre, outcome and the time taken to achieve tolerance (Mauser-Bunschoten et al, 1996; Kreuz et al, 1995).

A low peak historical inhibitor titre prior to ITI has been said to predict successful ITI but this variable is far less strongly related to outcome than the starting inhibitor titre (Mariani et al, 1994, DiMichele et al, 1997). Very high starting inhibitor titres > 500 BU/ml are associated with a poor response to ITI. Mariani et al, 1994; Kreuz. et al, 1995; Mauser-Bunschoten et al, 1995; DiMichele et al, 1997).

Although it is widely believed that ITI should start as soon as possible after the inhibitor is detected, there is no firm scientific basis for this approach. A short interval between inhibitor detection and the initiation of ITI predicted a successful outcome in some studies (Mariani et al, 1994; Kreuz et al, 1995) but not others (Mauser-Bunschoten et al, 1995; DiMichele et al, 1999 and 2000). If ITI is initiated as soon as possible after the presentation of the inhibitor, as is common current practice, then ITI will often start shortly after some treatment with factor VIII, at a time when the immune system has been stimulated and when the inhibitor titre is rising. The inhibitor titre at this point will commonly be greater than 10 BU/ml, a starting level above which the response to ITI has been shown to be less good. The chance of achieving successful ITI should be enhanced by deliberately deferring the initiation of ITI until the inhibitor titre has declined below 10 BU/ml. There is also some evidence that waiting until the inhibitor titre is below 5BU/ml may improve response further but this has yet to be firmly established (Mauser-Bunshoten et al 1995, DiMichele et al, 2000). This is achieved by avoiding factor VIII, by treating all bleeds on-demand with bypass therapy, preferably using a bypassing agent that does not cause anamnesis in the high titre inhibitor patient. True cohort studies in which the start of ITI was deferred, either deliberately or through circumstance, until the inhibitor titre was < 10BU/ml have been notably successful (Mauser-Bunschoten et al, 1995; Smith et al, 1999; Rocino et al, 2000). These authors report similar success-rates of 88-100% despite using widely varying factor VIII dose-rates.

The influence of the dose of factor VIII used is disputed. The IITR suggested that larger doses are significantly more effective, particularly in patients with inhibitor titres >10 BU/ml at the start of ITI (Mariani et al, 1994). In contrast, neither the NAITR nor the GITR were able to demonstrate such a dose-relationship (DiMichele et al, 1999 and 2000; Lenk et al, 1999). A meta-analysis of the ITI registries reported by Kroner (1999) showed that, in patients with a starting inhibitor titre of <10 BU/ml and historical titres between 50 and 200 BU/ml, there was no relationship between the success-rate of ITI and the dose of factor VIII used. Furthermore, the van Creveld low-dose regime has been reported to achieve a success rate of 88% amongst a cohort in whom the inhibitor titre had declined from pre-treatment peak-levels as high as 177 BU/ml to < 10BU/ml prior to the initiation of ITI (Mauser-Bunschoten et al, 1995). Many of these patients inhibitor titres had actually fallen to < 5 BU/ml before ITI was started. These results are similar to those reported by Smith (1999) and Rocino (2000) using a high-dose regimen but deliberately deferring the start of ITI until the inhibitor titre had fallen to < 10 BU/ml. It would appear that if the inhibitor titre is allowed to fall to < 10 BU/ml (and possibly lower) before ITI is initiated, then the outcome of ITI is independent of the dose of factor VIII used.

Tolerance may be induced more easily in younger patients whose inhibitors are not long-established (Mariani et al, 1994; Mauser Bunschoten et al, 1995; Kreuz et al, 1995), although this is disputed by DiMichele (1999 and 2000).

There is no convincing data to suggest that any particular type or brand of factor VIII concentrate is more or less effective for ITI. Although Kreuz has suggested that patients may be more readily tolerised using intermediate-purity factor VIII concentrate, this data is inconclusive and is based on uncontrolled observations in six patients (Kreuz et al, 1996*). Furthermore, others have demonstrated similar success using high-purity or recombinant factor VIII concentrates (Smith et al, 1999; Rocino et al, 2000).

Many low-level inhibitors will disappear spontaneously without ITI, although troublesome inhibitors may also present with a low titre.

Tolerance is achieved by the regular administration of factor VIII or IX over a period of time that varies from a few months to two or more years, in resistant cases, until tolerance is achieved. Most patients are tolerised within 6 to 9 months but some may take up to one or two years to achieve tolerance. The IITR database suggests that 95% of all patients who achieved tolerance, did so within 30 months (Mariani et al, 1994).

Widely differing doses of factor VIII have been used to achieve tolerance. The Van Creveld regimen employs low doses of factor VIII of 25 IU/Kg three times weekly (Mauser-Bunschoten, et al, 1995). At the other extreme, the Bonn Regimen uses doses of factor VIII of 100 IU/kg BID (Brackmann et al, 1996). Following publication of the initial analysis of IITR data, daily doses of approximately 100 IU/kg have also been widely used with success. High dose regimens may require the insertion of a central line, although low-dose regimes are commonly administered through peripheral veins without the use of a central venous catheter.

Interruption of ITI and intercurrent infection during the course of ITI should be avoided if possible, since they may also adversely influence both success and the time taken to achieve tolerance (Kreuz, et al 1995, Brackmann, et al 1996, Lenk, et al, 1999). Intercurrent infection commonly causes non-specific stimulation of the immune-system leading to a rise in inhibitor titre. This risk is a major disadvantage of the use of central venous catheters during ITI and has led Brackmann and his group to attempt intensive ITI without the use of central lines.

In North America, ITI is discontinued and factor VIII prophylaxis started as soon as tolerance has been demonstrated (DiMichele et al, 1998). In Europe it is more usual to continue ITI for several months after tolerance is established and then to tail the factor VIII dose down over three months before starting normal prophylaxis (Mariani et al, 1994; Kreuz et al, 1995; Brackmann et al, 1996; Lenk et al, 1999). This tailing-off procedure is not of proven value, given that the rate of relapse is very low regardless of whether ITI is stopped abruptly or tailed off once tolerance has been demonstrated (DiMichele et al, 2000).

The optimum approach to immune-tolerance induction has not been agreed. Although high-dose regimens may achieve tolerance more rapidly, it is not clear that their overall success-rate is superior to low-dose regimens. Low-dose regimens may be administered more readily without the use of central lines than high-dose regimens. These questions will have to be settled by a randomised clinical trial. The number of patients available for study is limited, however, and international collaboration is necessary for such a study to succeed.

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