GigaHAART study shows benefit of treatment interruption prior to treatment with >7 drugs in highly treatment experienced patients

2 November 2001. Related: Conference reports, Drug resistance, EACS 8th Athens 2001.

Simon Collins, HIV i-Base

ANRS 097 was an open label randomised trial comparing the efficacy of an immediate versus deferred multidrug salvage regimen in highly treatment experienced patients with severe immunological and virological failure defined as CD4 <200 cells/mm3 and HIV RNA >50,000 copies/ml.

The study evaluated the safety and benefit of both an 8-week treatment interruption and subsequent use of GigaHAART therapy with >8-drugs.

All participants were on a currently failing ARV treatment including >3 drugs. All were experienced to RTIs, NNRTIs and PI drug classes. Exclusion criteria included any acute opportunistic infections or intolerance to any drug class.

Randomisation at baseline was either to immediate treatment or deferred treatment following a 8-week washout period. Primary endpoint was the percentage of patients with >1 log decrease at week 12 and 20 in the immediate and deferred arms respectively . Secondary endpoints included follow up results at weeks 24 and 32 in each arm, CD4 response, genotypic and phenotypic resistance changes, correlation between efficacy and plasma drug levels and general safety and tolerability.

Of 70 randomised patients, 2 never took study drugs. Of 68 patients (n=34 in each arm), 30 and 32 were available for the week 12 and week 20 evaluation and 27 and 25 for the week 24 evaluation in the immediate versus deferred arms respectively.

Baseline characteristics are shown below:

* All median values

Baseline resistance for the whole study group (not separated by treatment arm) were:

The GigaHAART regimen recommended included 3-4 NRTIs (from ddI, d4T, AZT, 3TC, ABC), plus hydroxyurea (500mg BID) plus one NNRTI (NVP, EFV or DLV) plus 3 protease inhibitors. PI arms were either 400mg ritonavir/600mg amprenavir BID OR 300mg ritonavir+400mg lopinavir BID plus ONE of either 400mg indinavir, 600mg saquinavir or 1250mg nelfinavir (all BID).

One person used 6 drugs, 40 people used 7 drugs and 21 people (31%) used combinations with 8 drugs. Hydroxyurea was included in 48 (71%) of the regimens.

Virological efficacy is shown below:

The virological response for each arm was a fall from over 5 logs to approximately 4 log over the first two weeks, but while this gradually rebounded in the immediate treatment arm to leave only a -0.4 log drop from baseline at week 12, the deferred treatment arm continued to decline to −1.9log below baseline.

Resistance changes between baseline and week 8 for the deferred treatment arm showed some evidence of reversion to wild type similar to that observed previously in short term interruption studies. For example 21%, 38% and 24% of people showed a loss of at least one mutation in the PI, RTI and NNRTI classes respectively. Although 16 (55%) people showed no evidence of mutation reversal, 4 (14%), 7 (24%) and 2 (7%) people experienced changes in one, two and three classes of drugs respectively.

Results from monitoring trough levels of the PI and NNRTIs in the combination found a slightly lower proportion of people achieving adequate levels in the immediate compared to the deferred arm (74% vs 80%). However when results from the resistance testing were correlated with either adequate or low drug levels, a better virological response was associated with detection of reversed mutations, when adequate drug levels were detected.

Safety and tolerability are always raised as a concern for regimens using >6 drugs and this study showed a generally low level of toxicity for such an advanced group. Grade 3- toxicities and HIV-related events were similarly distributed between the two arms, with slightly higher events reported in the immediate treatment arm, although numbers were small.

Follow-up results at 24 and 32 weeks are of significant importance in strategy studies in treatment experienced patient and these further results will be keenly awaited. Nevertheless, these results provide important early results from a short treatment interruption followed by a generally tolerable regimen for patients in this difficult situation where treatment decisions become more critical.

Comment

The results from the French ANRS 097 were eagerly awaited, given that this study had been stopped early due to significantly improved benefit shown in the treatment interruption arm. The management of patients in this setting is especially difficult.

Currently the tri-national Optima Study, including 25 sites in the UK, will aim to provide a more definitive answer to both the importance of multiple drug therapies and closely monitored treatment interruptions in this setting and provide longer term results. Although the GIGHAART study produced significant benefits to the treatment interruption arm at relatively short term follow-up, for those patients achieving maximal suppression <50 copies by this strategy, you would expect this success to continue. Given that low levels of resistance can quickly return it will be important to know whether these results lead to clinical benefit in the longer term. It nevertheless provides important information for people whose clinical health would benefit from closer individualised treatment outside the setting of a randomised study such as Optima.

Further confirmation of the importance of adequate drug levels should make routine use of TDM – as critical as resistance assays, for all treatment experienced patients recycling previously used medications.

Reference:

Katlama C et al. GIGHAART (ANRS 097): A prospective randomised trial comparing the efficacy of a salvage regimen administered with or without treatment interruption in patients with severe biological failure and extensive prior therapy. 8th ECCATH, Athens 2001. Abstract O16.