Effective Salvage Therapy for HIV-1 Infection – An Unmet Challenge

59 Widespread use of combination antiretroviral therapy has led to dramatic decreases in AIDS-related morbidity and mortality in Europe and North America [1]. The limitations of current therapies, however, have become increasingly evident in the last few years. One major limitation is incomplete suppression of viral replication in 10–40% of treatment-naive patients initiating therapy as a consequence of limited drug potency, suboptimal drug pharmacokinetics, and difficult medication adherence (because of the large numbers of pills, the requirement for frequent dosing and side effects). Partial virus suppression allows the evolution of viral resistance and cross-resistance, which reduces drug activity and restricts future treatment options. The net result is that resistance to two or more drug classes has developed in many treatment-experienced patients, thus focusing attention on the need for effective ‘rescue’ or ‘salvage’ treatment regimens. This need was highlighted at the Second International Workshop on Salvage Therapy for HIV Infection held in Toronto, Canada, 19–21 May, 1999. A review of the activity of different salvage regimens in protease inhibitor-experienced patients reveals that virus suppression to below 400 HIV RNA copies/ml is achieved in only 20–40% of patients at 24 weeks [2]. This is in sharp contrast to success rates of up to 90% for initial therapy. As for initial therapy, the effectiveness of salvage regimens is reduced by pre-existing drug resistance, incomplete medication adherence, and complex drug–drug interactions. The latter was underscored by the finding of an unexpected interaction between adefovir and delavirdine in AIDS Clinical Trials Group (ACTG) Protocol 359 [3]. Although the mechanisms underlying this interaction remain to be defined, adefovir lowered the serum levels of delavirdine by approximately 50%. In turn, this reduced the favourable effect of delavirdine on saquinavir pharmacokinetics, resulting in lower saquinavir levels and less antiretroviral activity. Other factors associated with failure of salvage therapies include high plasma viral load and low CD4 cell count at the time of initiation of salvage therapy [4]. The duration and extent of prior therapy and the time on a failing regimen were also associated with lower rates of response to salvage therapy. The latter argues for an early switch away from a failing therapy, although this has not been tested prospectively. Several groups have reported the use of multiple drug regimens for salvage therapy [5–8]. In general, heavily pretreated and advanced patients were offered combination regimens containing up to nine drugs including up to four nucleosides, two non-nucleosides, two protease inhibitors and in some instances, hydroxyurea. Moderate to severe adverse effects were common, often leading to changes in the drug regimen. Despite this, a substantial antiviral response was observed in 30–50% of patients. Overall, increasing the number of active (sensitive) drugs in a salvage regimen improved the rate of success. Identification of ‘active’ drugs was prospectively shown to be increased by the use of HIV drug resistance testing [9,10]. Whether multiple drug regimens for salvage therapy of heavily pre-exposed patients can be optimized using HIV drug resistance testing remains to be determined. An intriguing observation has been reported [5] about the effect of drug ‘holidays’ (discontinuations of failing antiretroviral regimens) on subsequent treatment response in the context of initiating multiple drug regimens for salvage therapy. In this retrospective study, a drug holiday was often associated with a shift in the circulating virus from multidrug-resistant to drug sensitive. Furthermore, this shift in drug sensitivity was associated with a greater likelihood of subsequent viral suppression. These provocative data need to be confirmed in controlled clinical trials. Cautious optimism for the future can be derived from the more than 20 new drugs in various stages of clinical development [11]. These include agents in all three drug classes (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors) as well as two new drug classes – nucleotide analogue reverse transcriptase inhibitors and fusion inhibitors, which Effective salvage therapy for HIV-1 infection – an unmet challenge