Indinavir/ritonavir at 400/400 mg or 800/100 mg as intensification

16 July 2000. Related: Conference reports, Antiretrovirals, Intl Drug Resistance Workshop 4 Sitges 2000.

It has previously been reported that in patients with incomplete virological suppression on indinavir based combination therapies intensifying treatment by substituting indinavir/ritonavir 800/200 mg BID may lead to better virolgical control (see HTB Vol 1, No 2).

Of concern when dosing indinavir / ritonavir at 800/200 mg BID are the high peak levels (Cmax) of indinavir which may be more likely to produce indinavir related toxicities (nephrolithiasis, dry skin, chapped lips, hair loss). The 400/400 mg BID dosing does not lead to higher peak levels of indinavir (IDV) (in fact Cmax is reduced by 51%), but does raise trough levels (Cmin) 3.7-fold. Andrew Zolopa of Stanford University presented data from a study which attempted to determine whether the increase in the trough concentrations of IDV achievable with 400/400 mg IDV/RTV BID will produce greater virologic suppression in subjects with detectable viraemia while receiving an IDV-based triple regimen [1].

Thirty five subjects with HIV RNA between 50 and 50,000 copies/mL (median 3.2 log copies/mL) who had been receiving IDV 800 mg Q8H with 2 NRTIs for more that 3 months (median 32.1 months) were switched from IDV 800 mg to IDV/RTV 400/400 mg with dose escalation of ritonavir over 6 days. Subjects were naive to ritonavir and were also allowed to switch NRTIs after week 3. Virologic response at Week 3 was defined as a decline in plasma HIV RNA by >0.5 log copies/mL or a Week 3 viral load <50 copies/mL.

At Week 3, 60% (21/35) were classified as responders by the above definition and (40%) 14/35 were non-responders. Of the responders approximately half were <50 copies/mL, the other half having had >0.5 log decline. Stepwise logistic regression revealed that responders had a significantly higher IDV Cmin that non-responders at week 3. The median decline in HIV RNA was also found to be greater in those subjects with Cmin higher than the median. The number of PI mutations prior to switch was also a significant predictor of virologic response at week 3. Virologic response was observed in 85% of subjects with 0 – 3 baseline mutations and 33% of subjects with 4 – 7 baseline mutations.

The presenters concluded that the additional virological response obtained in some patients indicates that the trough level of the protease inhibitor is the most important indicator of in vivo potency (as IDV AUC was unchanged and the Cmax reduced). Total number of PI mutations at baseline and trough level of indinavir achievable by co-dosing with ritonavir are significant predictors of virologic response and IDV/RTV (400/400 mg BID) demonstrates activity against HIV with a certain degree of resistance to indinavir.

A similar study using IDV/RTV at 800/100 mg BID was presented by Ana Moreno on behalf of a group from the Ramon y Cajal Hospital, Madrid [2]. This was a prospective study of 59 patients treated using a salvage regimen including IDV/RTV 800/100 mg BID plus two NRTIs after previous failure of multiple PI-based therapies. Virological response measured by HIV RNA <50 copies/mL (a stringent criteria in salvage settings) was 63% at 3 months and 38% at 6 months (on treatment analysis). A gain in CD4 T-lymphocytes of 126 cells/mm3 was also seen at 6 months.

There was a trend to a better virological response in patients achieving higher IDV levels and the VL decrease was greater in those whose HIV did not contain the V82A mutation in at baseline. Tolerability, however, was poor with 48% of patients discontinuing study medication and a further 15% requiring a dose adjustment. Overall level of nephrotoxity (undefined) was 33% and was more frequent in patients with a higher exposure to indinavir. The investigators suggest that the high interindividual variability, and the relationship between IDV levels, efficacy and toxicity suggest the usefulness of therapeutic drug level monitoring (TDM) in patients receiving this combination.

References:

1. Zolopa AR, Shulman N, Havlir D et al. Ritonavir intensification of indinavir-containing antiretroviral regimens: the effect of increasing indinavir trough concentration and protease resistance on virological response. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 95.
2. Moreno A, Casado JL, Sabido R et al. Increased plasma drug levels using twice daily ritonavir-indinavir at 100-800mg correlate with virological response in a salvage therapy. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 118.