Report on salvage therapy from the 39th annual meeting of the IDSA

2 November 2001. Related: Antiretrovirals, Drug resistance.

By Daniel R. Kuritzkes, MD for HIV&hepatitis.com

Phase II trials with lopinavir/ritonavir (LPV/r) for salvage therapy were performed mostly in non-nucleoside RT inhibitor (NNRTI)-naïve patients. Thus, the extent to which success of LPV/r in salvage depends on patients being NNRTI-naïve has been uncertain.

Preliminary results from the LPV/r expanded access program, reported at the 8th Conference on Retroviruses and Opportunistic Infections, suggested that efficacy of this drug might be less impressive in highly treatment-experienced patients as compared to those enrolled in formal clinical trials [1].

Data regarding experience with LPV/r in the community setting were provided by several abstracts presented at the 39th Annual Meeting of the Infectious Diseases Society of America (San Francisco, October 25-28, 2001). In general, the abstracts were based on results in small numbers of patients treated at individual centres.

Falusi et al [2] described the experience at Rush-Presbyterian-St. Luke’s Medical Center in Chicago with use of LPV/r to treat heavily pre-treated patients. Results with 23 patients with a mean plasma HIV-1 RNA of 5.3 log10 copies/mL were presented. Patients were all NNRTI experienced and had received a median of 3 prior PI’s. The median number of PI resistance mutations was 6.

In patients for whom results of a phenotypic resistance test were available the IC50 for LPV was increased 10- to 30-fold above control for three or more PI’s; in five patients, IC50’s were increased >30-fold. Fifty-four percent (8/15) patients showed less than a 0.5-log10 reduction in plasma HIV-1 RNA by week 12.

Patients with fewer PI resistance mutations and lower levels of PI resistance by phenotype were more likely to show an initial reduction in virus load, but these responses were short-lived, as only 33% of patients whose virus had <5 PI resistance mutations or an IC50 that was <30-fold greater than control maintained a >1-log10 decline in virus load by week 12. Nine patients had plasma HIV-1 RNA levels <50 copies/mL at week 4 or 12.

Lieu et al [3] reported the of the Kaiser-Permanente Medical Care Program in San Diego with this regimen. During the first 10 months that the drug was available, 35 treatment-experienced patients were placed on a LPV/r-containing regimen. The patients had received a median of more than five previous regimens.

In contrast to the experience of Falusi et al described above, 13/29 evaluable patients reached an undetectable plasma HIV-1 RNA within three months (<50 copies/mL by the version 3.0 bDNA assay). Success was associated with a fewer number of previous treatment regimens, being NNRTI-naïve (along with use of an NNRTI in the salvage regimen), a CD4 count at time of switch that was >300 cells/mm3, and a virus load <10,000.

Similarly encouraging results were observed in 13 patients by Badri et al (Cook County Hospital, Chicago) [4]. The baseline CD4 count for these patients was 165 cells/mm3 and the mean virus load was 4.7 log10 copies/mL. Patients had received a mean of 3.2 prior PI’s, and their viruses harboured and average of approximately 6 PI resistance mutations; most were NNRTI-experienced with a median of 1 NNRTI resistance mutation per isolate.

Despite these seemingly unfavourable characteristics, patients experienced a mean decline in plasma HIV-1 RNA level of 1.6 log10 copies/mL at 12-16 weeks, and 46% had a >2-log10 decline in virus load. In addition, a mean increase in the CD4 count of 87 cells/mm3 was found.

Patients whose virus carried <6 PI resistance mutations were more likely to show a virologic response to the LPV/r-containing salvage regimen. Of note, 7/13 patients received amprenavir in addition to LPV/r, and it is interesting to speculate on the contribution of the second “boosted” PI to success of the regimen.

Additional data on patients from the San Diego area who received LPV/r as part of the Abbott Early Access Program were presented by Keese et al (UC San Diego) [5]. Fifty-eight patients enrolled in the open-label study, with a mean baseline CD4 count of 154 cells/mm3 and a mean plasma HIV-1 RNA titre of approximately 5.4 log10 copies/mL. Four percent of patients were forced to discontinue drug due to adverse events, and 19% were lost to follow-up.

The mean reduction in plasma HIV-1 RNA was significantly greater for patients who had received fewer than 5 NRTI’s vs those who had received more than 5 NRTI’s in past regimens (1.9- vs 1.1-log10 reduction, respectively; p<0.05). Of note, the CD4 nadir prior to adding LPV/r was a better than absolute CD4 in predicting success if the salvage regimen.

Although much attention has focused on the use of LPV/r for salvage, pharmacologic enhancement of other PI’s by RTV can also be useful in this setting. One poster presentation at the meeting reported on the use of indinavir (IDV)/RTV combination therapy for highly treatment-experienced patients [6].

Seventy-six patients received IDV/RTV (62 at a dose of 800 mg/200 mg bid and 14 at a dose if 400 mg/400 mg bid). On averaged, patients had received nearly four years of prior antiretroviral therapy, including a median of two prior PI’s (43 were IDV-experienced), but 10 were PI-naïve. In 16 cases, patients were NNRTI-naïve or had no genotypic evidence of NNRTI resistance. The mean plasma HIV-1 RNA level at baseline was 4.24 log10 copies/mL and the mean CD4 count was 246 cells/mm3. Overall, 61% achieved a plasma HIV-1 RNA level <50 copies/mL at 6 months.

However, 19 patients discontinued the regimen due to treatment-related toxicities (hyperlipidemia [7], nephrolithiasis [4], lipodystrophy [3]) or subsequent treatment failure (5). Multivariate analysis showed that baseline plasma HIV-1 RNA, magnitude of the CD4 increase, number of prior antiretroviral agents overall, and number of prior PI’s were each significant predictors of treatment response.

Another salvage strategy includes the use of delavirdine (DLV) to help boost protease inhibitor levels. In contrast to nevirapine (NVP) and efavirenz (EFV), both of which lower protease inhibitor levels by inducing CYP3A4, DLV is a competitively inhibits PI metabolism by the CYP system.

Owen and Stein [7] presented data on use of DLV in 14 NNRTI-naïve patients in combination with single- or dual-PI regimens. All of the patients had received treatment with at least one prior PI, and nine had received two PI”s. The median plasma HIV-1 RNA prior to initiation of DLV was approximately 4.6 log10 copies/mL, and the median CD4 count was 195 cells/mm3. Eleven of 14 patients achieved a plasma HIV-1 RNA level <500 copies/mL by 24 months; 11/13 remained suppressed to <500 copies/mL at 30 months, and 11/12 had virus loads <50 copies/mL after 36 months.

These results are consistent with other published data on the use of DLV in combination with PI’s [8]. Comparative studies are needed to determine the relative benefits of using DLV in place of NVP or EFV as a component of salvage therapy. Also intriguing is the question of whether DLV can be used even in NNRTI-experienced patients as an alternative to RTV to boost PI levels in patients with substantial hyperlipidemia.

The question of sequencing protease inhibitors was addressed in part by an abstract from Becker et al [9], who studied the use of amprenavir (APV) after nelfinavir (NFV) in patients enrolled in CHORUS, a longitudinal cohort study. They identified 23 patients who received NFV as their first PI, followed by APV or APV/RTV. Patients received APV for a mean duration of one year, and 48% included an NNRTI in the regimen.

Of 16 patients for whom baseline and follow-up laboratory data were available, 81% achieved an undetectable plasma HIV-1 RNA level, with a median drop in plasma HIV-1 RNA of 1.6 log10 copies/mL at six months. Although genotype and phenotype data were not presented in the published abstract, these preliminary data are consistent with previous studies that have shown persistent APV susceptibility among isolates that are NFV resistant.

These results suggest that APV may be useful after failure of a NFV-containing regimen.

In summary, no major breakthroughs in salvage therapy were reported at this year’s IDSA meeting. Only limited conclusions can be drawn from the relatively small studies presented at the meeting, many of which were retrospective.

Nevertheless, it is clear from the data that LPV/r is likely to be less effective in highly treatment-experienced patients than in the phase 2 studies reported to date, particularly when the drug is used in NNRTI-experienced patients. More new drugs are needed if we are to make substantial progress in designing effective salvage regimens.

References:

1. Reitmayer R, Rode R, Bernstein B, et al. Initial Efficacy Results from the KALETRA (Formerly Known as ABT-378/r) Early- Access Program [Abstract 328]. 8th Conf Retroviruses and Opportunistic Infections, Chicago, February 4-8, 2001.
2. Falusi O, Smith KY, Huang D, et al. Efficacy of lopinavir (LPV) in heavily pre-treated patients [abstract 675]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
3. Lieu D, Nguyen C, Furlano J, et al. Community experience with the introduction of lopinavir-ritonavir in an antiretroviral experienced HIV-positive population [abstract 676]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
4. Badri S, Falusi O, Blake M, Barker D. Efficacy of lopinavir/ritonavir (lop/r)-containing salvage regimens in HIV-1 infected patients [abstract 677]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
5. Keesee KS, Ballard C, Mathews WC, Barber E. Lopinavir/ritonavir: eficacy in an expanded access program at the UCSD Owen Clinic [abstract 678]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
6. Horberg MA, Klein D. Long term efficacy of indinavir/ritonavir (IDV/RTV) in highly ART experienced patients [abstract 681]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
7. Owen WF, Stein C. Delavirdine combined with protease inhibitors: Durability and efficacy for salvage therapy in AIDS [abstract 679]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.
8. Kuritzkes DR, Bassett RL, Johnson VA, et al. Continued lamivudine vs delavirdine in combination with indinavir and zidovudine or stavudine in lamivudine-experienced patients: results of Adult AIDS Clinical Trials Group protocol 370. AIDS 2000;14:1553-61.
9. Becker SL, Dieterich DT, Fusco GP. Clinical experience of amprenavir (APV) following nelfinavir (NFV) use [abstract 694]. Abstracts of the IDSA 39th Annual Meeting, San Francisco, October 25-28, 2001.

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