The success of salvage therapy depends on the clinical status of the patient and on the choice of salvage therapy regimen. Regimens that contain at least one drug belonging to a previously unused class of drugs have the greatest chance of long-term success. The likelihood of durable virus suppression is therefore lower in patients who have already received nucleoside RT inhibitors (NRTI), nonnucleoside RT inhibitors (NNRTI), and protease inhibitors (PI).

Both the DHHS and the IAS recommend that a change in regimen because of treatment failure should be guided by results of resistance testing. Yet, although there have been many recent reports of diverse salvage therapy regimens in patients with diverse treatment histories, few of these reports have been accompanied by the baseline genotypic data that are needed to stratify patients according to the extent of drug resistance prior to salvage. The absence of such crucial data forces physicians to play a guessing game in choosing salvage therapies. If instead the baseline, pre-salvage genotypic data were routinely published, the choice of salvage therapy could be made more rationally.

The following sections will review recent abstracts on salvage therapy presented at the 8^th Conference on Retroviruses and Opportunistic Infections (8^th CROI). Although the clinical development of fusion inhibitors, the fourth class of anti-HIV drugs, continues apace, there have been no recent clinical reports on the use of these compounds in salvage therapy. Recent reports have instead examined the role of new NRTIs, NNRTIs, and PIs or have attempted to clarify the extent of cross-resistance between currently approved drugs. Most of these reports are preliminary and their full value will be realized with the release of their primary data and their publication in peer-reviewed journals.

Nucleoside RT Inhibitors
Costaglio et al (abstract 449) reported data from the NARVAL ANRS 088 trial showing that the presence of three or more classical AZT resistance mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) impaired the virologic response to salvage therapy with ddI and d4T even when these were prescribed together with a PI or NNRTI.¹ The presence of multiple AZT resistance mutations appeared to cause less impairment of abacavir-containing salvage therapy regimens. The impairment of ddI/d4T salvage therapy is consistent with the reports of several other groups. However, the lesser impairment of abacavir-containing salvage therapy regimens is surprising and appears to conflict with data reported two years ago at the 6^th CROI by Lanier et al.² The baseline genotypic data from the current study and from the study by Lanier et al must be made publicly available so that physicians can determine which patients with AZT resistance mutations are likely to benefit from the inclusion of abacavir in salvage therapy regimens.

Shulman et al (abstract 437) shed additional light on the genotypic correlates of d4T resistance.³ She examined the correlation between baseline genotype and follow-up RNA levels in 31 AZT-treated patients who were subsequently treated with d4T monotherapy during the pre-HAART era. Seven of eight patients who had the K70R mutation alone were considered to have responded virologically at week 8 (0.3 log RNA reduction). Patients with isolates containing other NRTI mutations such as (e.g. T215Y, M41L/T215Y, D67N/K70R/K219Q) did not respond to d4T. This study suggests that patients whose viruses contain the ZDV-resistance mutation, K70R, may still benefit from d4T. In contrast, the benefit from d4T will be lower in patients whose viruses have T215Y and other combinations of ZDV-resistance mutations.

Frenkel et al (abstract 463) reported provocative results about the RT mutation, M184V.⁴ In PACTG 366, children with and without M184V were evaluated for their response to salvage therapy with a combination of four antiretroviral drugs selected based on a child's previous drug history. The presence of M184V at baseline was associated with a significantly better virologic response to salvage, with 34 of 70 (49%) patients with the M184V and 15/51 (29%) patients without M184V achieving an RNA level <400 copies/mL at week 12. Clearly, this abstract raises more questions than it answers and additional data are needed to know whether M184V provided clinical benefit or was linked to clinical benefit in some other way. For example, was M184V an indication of adherence to therapy or did children with M184V receive more active drugs.

Miller et al (abstract 441) presented data from Gilead Sciences Study 902, a phase II, placebo-controlled, double-blind study evaluating 3 doses of tenofovir added to stable regimens in 189 heavily treated patients.⁵ Despite the presence of NRTI mutations in nearly all of the patients at baseline, there was a mean HIV RNA reduction of 0.58 logs which persisted through week 48.

Nonnucleoside RT Inhibitors
Wolfe et al (abstract 323) presented preliminary data on the new NNRTI, capravirine (AG1549).⁶ In a phase II, double-blind, placebo controlled trial of 75 PI-naive patients failing an NNRTI containing regimen, at least one half of the patients receiving capravirine had a plasma HIV-1 RNA level <400 copies/mL by week 12. Capravirine is highly potent in vitro and is active in vitro against viruses containing the most common NNRTI resistance mutations, K103N, and Y181C. This study provides the first glimmer of hope that patients failing an NNRTI-containing regimen, may still benefit from a second NNRTI. However, because the patients in this trial also received nelfinavir and two NRTI, the data presented by Wolfe et al must be followed up with the baseline genotypic data of the study participants, the data comparing the outcomes of those receiving capravirine with those receiving placebo, and the week 24 RNA levels.

Pfizer recently suspended clinical trials of capravirine after dogs receiving high doses were found to develop vasculitis in a 12-month toxicology study. However, vasculitis has not been reported in >600 patients who have received capravirine in clinical trials and, should capravirine emerge as a non-cross-resistant NNRTI, further clinical development of the compound or a closely related compound will continue.

Protease Inhibitors
There were two studies describing the use of ritonavir/lopinavir as part of salvage therapy. Clumeck et al (abstract 525) presented the week 48 follow-up of 57 PI-experienced, NNRTI-naive patients treated with regimens containing ritonavir/lopinavir and efavirenz.⁷ In the intent-to-treat analysis, 65% had RNA < 400 copies/mL and 56% had RNA <50 copies/mL. In the on-treatment analysis, these values were 80% and 70%, respectively. While these data are impressive, it remains essential for Abbott to publish the pre-therapy protease sequences so that physicians will be able to predict with a higher degree of certainty which patients have the best chance of responding to ritonavir/lopinavir and which patients may need additional drugs to increase the likelihood of successful salvage.

Reitmayer (abstract 328) presented efficacy data on 4317 heavily treated patients with advanced disease were provided with early-access ritonavir/lopinavir.⁸ Surprisingly, 50% of patients failing 2 PIs and 30% failing 3 or 4 PIs were able to suppress RNA to <500 copies/mL by week 16. Not surprisingly, patients who were NNRTI-naive (a minority of this population) and thus able to benefit from NNRTI were more likely to achieve virologic suppression.

Gulick et al (abstract 338) reported the final results of the ACTG 359 trial which compared six regimens for treating patients with virologic failure after receiving an indinavir-containing regimen.⁹ Salvage therapy included dual PIs (ritonavir 400 mg bid /saquinavir 400 mg bid vs. nelfinavir 750 mg tid / saquinavir 800 mg tid) and either delavirdine or adefovir or delavirdine + adefovir. In a factorial analysis, the two dual-PI regimens were equivalent and delavirdine was superior to adefovir. But overall virus suppression was disappointing with only 77of 254 (30%) patients achieving RNA <500 copies/mL by week 16. To what extent the weaker virus suppression in this study compared with the ritonavir/lopinavir/efavirenz study was due to differences between the patients or to differences in the regimens will become clearer when these studies are published in their complete form.

References