Seventh International Congress on Drug Therapy in HIV Infection Glasgow, UK - 14-17 November 2004

Int Cong Drug Therapy HIV 2004 Nov 14-18;7:Abstract No. PL1.4

Julio Montaner
B.C. Centre for Excellence on HIV/AIDS, Vancouver, Canada

Three potentially overlapping rationales for STI have been proposed, including autoimmunization, reversion to wild-type virus and decreased drug exposure. These principles have now been tested in the settings of primary infection, salvage and chronic infection, with rather disappointing results.

STI in Primary infection An early study of STI in patients with primary HIV infection showed evidence of increased CTL and HIV-specific CD4+ responses. Also, a number of patients appeared to be able to maintain control of viremia off therapy in this study. (Rosenberg ES, et al. Nature. 2000 Sep 28;407(6803):523-6.) However, continued follow-up of these patients showed evolution of CTL escape mutants, decreasing CD4+ counts and increasing HIV-RNA plasma levels. (Kaufmann D, et al. 11th CROI; Abst 24.) Subsequent studies have failed to demonstrate a substantial benefit of STI in this setting. (Markowitz M, et al. J Infect Dis. 2002;186:634-643; Smith DE, et al. AIDS. 2004 Mar 26;18(5):709-18. Fidler S, et al. AIDS. 2002 Oct 18;16(15):2049-54.) Based on these results STI is not recommended in patients who initiated HAART during primary HIV infection.

STI in Salvage Patients on a failing HAART regimen with multiple drug-resistance who stop therapy may experience a rapid reversion in virus population toward wild type. This was initially reported to be associated with a better virological response in at least some patients when therapy was re-initiated. (Miller V, et al. AIDS. 2000 Dec 22;14(18):2857-67). It is now clear that the reversion to wild-type virus, as described above, is associated with an increase in HIV-RNA load and a decrease in CD4+ count. (Deeks SG, et al. N Engl J Med. 2001 Feb 15;344(7):472-80.) Three prospective trial have further evaluated this issue. Early positive results from the small short term ANRS 097 study (Katlama C, et al. AIDS. 2004 Jan 23;18(2):217-26.) failed to be confirmed by the results of Retrogene (Ruiz L, et al. J Infect Dis. 2003 Oct 1;188(7):977-85.) or CPCRA 064 (Lawrence J, et al. N Engl J Med. 2003 Aug 28;349(9):837-46.). The later study actually showed that treatment interruption was associated with not only significant CD4+ cell depletion, but also an increase in clinical events. Based on the demonstrated risk and lack of consistent benefit of STI in salvage, this practice is not currently recommended.

STI in Chronic HIV Infection The Swiss-Spanish Intermittent Therapy Trial (SSITT) evaluated STI in chronic HIV infection. (Fagard C, et al. Arch Intern Med. 2003 May 26;163(10):1220-6.). 133 patients with viral load below 50 copies/mL for at least 6 months on HAART underwent cycles of 2 weeks STI followed by 8 weeks on HAART. After 4 cycles, patients stopped therapy until viral load rebounded to > 5,000 copies/mL. 17% and 8% of patients maintained viral loads below 5,000 copies/mL at 52 weeks and 96 weeks, respectively. Failure of STI in chronic HIV infection has also been reported using a 7 days on/7 days off approach. (Ananworanich J, et al. AIDS. 2003 Oct 17;17(15):F33-7.). Based on these results STI is not recommended in chronic infection.

In an attempt to limit drug exposure (for reasons such as adherence, toxicity, cost) several groups are currently evaluating CD4+ guided therapy interruptions. This form of intermittent or pulse therapy is not expected to provide a direct immunologic or virologic benefit. To date, this approach appears to be comparable to the continuous therapy arm in several ongoing studies. However, concerns have emerged regarding premature development of resistance in highly adherent patients following such treatment interruptions. Consequently, full evaluation of long-term results of such strategy studies will be needed before the possible role of this approach is fully understood. Until then, the only acceptable use of treatment interruptions in clinical practice today pertains to allow recovery from side effects or co-morbidities.

SESSION 1: TREATMENT STRATEGIES

2004-11-14
PL1.4

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