Treatment interruption and salvage therapy
Dr Mike Youle for HIV i-Base
The temporary interruption of therapy is common in clinical practice due to forgetfulness, unforeseen circumstances, ambivalence of the individual to treatment, intercurrent illness and a host of other factors.
What the consequences of temporary treatment interruptions are will only become apparent for controlled clinical studies but there are already data accumulating around these issues. Several more studies were presented at ICAAC and also data on what can be done if therapies cease to be effective and the patient falls into the nebulous category of salvage.
The non-nucleoside class of compounds has several interesting characteristics that may be of importance in these two areas. With regard to treatment interruption the long half-life that these drugs have may offer a degree of protection if temporary interruption of therapy occurs. An analysis of the efavirenz study DMP-006  where a group of 129 subjects who interrupted therapy for toxicity was compared to 515 subjects who had no treatment interruptions found no significant differences in rates of eventual virologic failure . A hyper-susceptibility to the use of efavirenz was reported in a prospective phenotype study undertaken by Haubrich and co-workers . Eighteen to 24% of subjects with extensive exposure to NRTI agents showed this phenomenon, defined as an NNRTI ratio of [IC50patient/IC50 control] <0.4, resulting in significantly better viral load suppression at month 3 in patients treated with efavirenz.
Data was presented by several groups examining the benefits of dual PI in those experienced and failing on single PI regimens. In the French study from Piroth and co-workers  31 subjects were randomised to saquinavir 600mg q12h plus ritonavir 200mg q12h versus saquinavir at the same dose with nelfinavir 100mg q12h. Pharmacokinetic studies did not show a relationship with serum level and response. More worrying was that in this study with relatively preserved CD4 cell count (median at baseline of mid 300”) only 20% in the saquinavir/ritonavir arm and 12.5% in the saquinavir/nelfinavir arm were <200copies/mL at week 24, a rather dismal outcome.
Better results were obtained in the cohort study of Grossman and his US colleagues  where the combination of indinavir/ritonavir at either 800/200mg or 400/400mg q12h seemed to produce response rates of 52% and 33% respectively. The higher doses of ritonavir were associated with changes in serum lipids whereas the 800/200mg dosage gave skin problems.
One interesting presentation examining the change in sensitivity of the virus under the effect of “baby-dose” ritonavir was presented by Challiou . In this study subjects who were receiving saquinavir 600mg q12h with ritonavir 100mg q12h were followed for one year with sequential resistance assays. At baseline in the 34 subjects 9/34 (26%) harboured V82A/F/T mutations and 4/34 (12%) had M46/I/L. During follow-up 23% acquired the V82A/F/T mutations and 15% the M46I/L codon changes. Median trough concentration of ritonavir was close, at 0.47_g/mL to the EC50 for wild-type strains of the virus (0.96_g/mL). The patients in this study must have had detectable virus at points during the follow-up to measure resistance, However, the acquisition of new mutations associated with resistance to ritonavir and by cross-resistance to indinavir raises the concern that the pharmacokinetic boosting of PI’s may not be without risk of developing resistance to the low-dose ritonavir component. Further work needs to assess this risk.
The last combination PI work to be presented was from the ABT-378/ritonavir experienced study presented by Steve Becker from San Francisco . In this study multiple PI experienced subjects with 68% showing >4-fold resistance to 3 licensed PI’s were given efavirenz and ABT-378/r as a new combination. Whilst the on treatment success rate was 86% at week 24 the intent to treat was 71%.
These data although hopeful are not disimilar to data seen with indinavir/ritonavir when an NNRTI is added as a first NNRTI and the head to head studies of ritonavir boosted PI’s are vital to assess their relative worth. The MaxCmin study, open in several UK centres and co-ordinated by the CHIP group from Copenhagen is currently assessing indinavir/ritonavir versus saquinavir /ritonavir and a further study including ABT-378/ritonavir is in the offing
- Staszewski S et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med. 1999 Dec 16;341(25):1865-73.
- Ruiz NM et al. Temporary interruption (TI) of SUSTIVA (Efavirenz, EFV) containing therapy does not impact virological Response Rates. Abstract I-479. 40th ICAAC, Toronto, Canada, Sep 2000.
- Haubrich R et al. Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility (HS) is common and improves short-term virologic response. Abstract I-481. 40th ICAAC, Toronto, Canada, Sep 2000.
- Piroth L et al. Randomised salvage therapy with saquinavir-ritonavir (SQV-RTV) versus nelfinavir-ritonavir (NFV-RTV) for highly experienced HIV-infected patients. Abstract I-543. 40th ICAAC, Toronto, Canada, Sep 2000.
- Grossman H et al. Response with twice daily (BID) crixivan plus norvir based regimen (IDV-RTV) in patients failing protease inhibitor (PI) therapy. Abstract I-545. 40th ICAAC, Toronto, Canada, Sep 2000.
- Chaillou S et al. Does ritonavir “baby dose” induce specific mutations in salvage combination therapy? A VIRADAPT sub-study. Abstract I-1267. 40th ICAAC, Toronto, Canada, Sep 2000.
- Becker S et al. ABT378/ritonavir (ABT-378/r) and efavirenz: 24 week safety/efficacy evaluation in multiple PI experienced patients. Abstract I-697. 40th ICAAC, Toronto, Canada, Sep 2000.