Medical Consultant
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ISSUE 69 Conference Report Special |
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19-21 May, 1999 - Toronto, Canada.
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OTHER NEWS |
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2nd International Workshop on Salvage Therapy for HIV Infection19-21 May, 1999 - Toronto, Canada. |
Conference Reports: Paul Blanchard, ATP.
The 2nd International Workshop on Salvage Therapy for HIV Infection presented information on the treatment approaches currently being explored after virological failure of multiple previous regimens. AIDS Treatment Projects "Doctor Fax" provides the following reports which highlight presentations giving the most up-to-date data on the efficacy and durability of these often complex regimens.
Although much of the data appears disappointing, the complex histories of the patients in these studies must be kept in mind. Indeed the very diversity of both their disease and treatment histories makes the execution and interpretation of these studies all the more difficult. Michael Saag of the University of Alabama highlighted this very difficulty in his observations of his clinical cohort [1]. Amongst 114 patients experiencing virological failure attending the University of Alabama clinic, a staggering 1067 regimen 'events' were utilised (defined as use of a regimen by any patient for more than 14 days). In contrast a 'unique' regimen was defined as any combination of drugs used at least once by any patient for more than 14 days. In total, 242 unique regimens were identified as having been used, over 89 of which contained 4 or more antiretroviral drugs. When sequencing of unique regimens was considered it was found that 93% (107 patients) had used a sequence of regimens unique to themselves.
Additionally many of these patients represent those who entered earlier clinical trials of what were clearly, in retrospect, woefully inadequate antiretroviral therapies. As pioneers at the frontier of anti-HIV drug development most had reluctantly entered the therapeutic arena in the face of advancing disease, the numerous deaths occurring amongst their peer group and lack of any other options. Diversity is perhaps the keyword to bear in mind when considering any data from these patient cohorts: diversity of disease history, diversity of response to prior regimens, diversity of type and sequence of prior regimens and diversity of reasons for poor response. Proscriptive treatment guidelines become nonsensical in this extraordinary arena and individualised approach a necessity. This is not, however, to be taken as a license for prescribing anarchy. Indeed, the large number of different salvage regimens represents this individuation - a key point to salvage that is not random choice or prescription anarchy. As will be seen, general rules regarding resistance testing, switching early in failure and which drugs NOT to combine or sequence are emerging. Intriguing hints at the utility of planned drug holidays, cycling of combinations and activities of new compounds also need further investigation. It may not be at all clear exactly how to proceed with this group of patients yet, but knowing what to avoid doing is of great importance to avoid damaging even further their potential for future treatment response.
References 1. Saag M, Raper J, Chatham A et al. Optimum design of salvage protocols: lessons from a clinical cohort. [Abstract 032] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
A number of presentations at the Salvage Therapy workshop reported largely observational data on the tolerability and virological efficacy of a variety of multidrug combinations. A summary table of the best defined of these is reproduced on the following page.
As can be seen virological responses vary widely across these studies and apart from one [Abs. 018] tend to cluster in the range of 30 to 40% effectiveness in achieving HIV plasma RNA levels <200 to < 500 copies/mL out to 24 to 52 weeks.
The outstanding study in terms of virological efficacy is that of a cohort of 63 patients at the Royal Free Hospital, London whose ongoing results were presented at this meeting by Dr Mike Youle [Abs. 013]. A Kaplan-Meier Intent-to-Treat analysis of these patients was presented showing an impressive 70% achieving below 400 copies/mL plasma viral load at week 24. An updated analysis including the week of presentations data (median 37 weeks of follow-up) showed 82% (52/63) <400 copies/mL and 62% (39/63) <50 copies/mL (again, on treatment analysis). Using the drop-out figures given in the presentation a "pseudo" Intention to Treat analysis would still give a response rate of 68% (43/63) achieving less than 400 copies/mL out to the week of presentation.
Looking at this cohort more closely a number of features should be noted. Although the median number of prior antiretrovirals may be slightly less than that of the comparable studies, the population was disadvantaged in terms of baseline viral load and CD4 count. Indeed, 31 of the 63 subjects had viral loads higher than the assay quantification level (>750,000 copies/mL) at baseline. This cohort was also unique amongst those in the table below in that patients were taken off all antiretrovirals for more than 4 weeks prior to starting the MDRT regimen (median duration of time off therapy was 8 weeks). Viral rebound off therapy undoubtedly contributed to these very high baseline viral loads. Additional features included an intensive support package consisting of:
PI dose and hyperlipidaemia
Interestingly when an analysis of PI used and dose was performed there was found to be a significant correlation between higher doses of ritonavir within the dual protease combination and larger rises from baseline of both triglyceride and cholesterol AUC. This was not found to be the case for the dose of indinavir. It was also reported anecdotally that modifying the dose of ritonavir in the regimen could lead to a lowering of blood lipids in individual patients (i.e. switching from 400/400mg bd or 600/200mg bd to 800/100mg bd of IND/RTV).
Considering the number of agents in these MDRT regimens reported tolerability and adherence was remarkable. A separate poster presentation by Howard Grossman concluded that these regimens are surprisingly well tolerated by motivated patients with no new toxicity's noted and can be maintained in the majority for extended periods [Abs. 023]. A further observation made is that many of these regimens did not contain any novel agents and that genotypic resistance to many of the components was not predictive of non-response. Indeed, Grossman observed that with regard to prior NNRTI-experience and contrary to expectations those NNRTI-experienced subjects experienced a greater increase in CD4+ cells and a greater decrease in viral load than those who were NNRTI-naïve. This appears counter intuitive and requires further data. Doug Mayers in his plenary session reported that the viral suppression contribution for each drug in these MDRT regimens was approximately -0.17 log for each drug inactive by genotype and -0.37 log for each drug active by genotype [Abs. 025].
[SEE PAGE 8 FOR STUDY SUMMARY CHART]
References
1. Youle M, Mocroft A, Johnson M, Tyrer M et al. Surrogate marker responses to multidrug combinations comprising hydroxyurea, efavirenz, double protease inhibitors (PI) and nucleoside analogues in PI failures. [Abstract 018] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
2. Shulman N, Zolopa A, Murlidharan U et al. Salvage therapy with an efavirenz and adefovir-based regimen in antiretroviral experienced patients. [Abstract 013] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
3. Grossman H, Frechette G, Reyes F. Mega-HAART: complex protective regimens for HAART failure. [Abstract 023] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
4. Mayers D. Plenary: The role of diagnostic/monitoring technologies in salvage therapy. [Abstract 025] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
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Large numbers of agents in MDRT regimens has been seen as 'kitchen sink' therapy. However, those in need of salvage require a last shot at maximal viral suppression and may be unwilling to risk more targeted regimens. Of course, it is the accuracy of the targeting which is at issue here. As Doug Mayers comments, even drugs not expected to contribute by genotypic resistance results do have minimal activity, if 3 or 4 of these "non-contributing" agents are combined a useful degree of suppression may be produced. Ultimately tolerability and toxicity's determine the true utility of these regimens.
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In vitro experiments have hinted for some time now that the mutation in the reverse transcriptase gene of HIV at codon 184 may have the potential to confer advantages for the HIV-infected host. There is evidence for increased fidelity of reverse transcriptase when this mutation is present as well as reduced biological fitness.
A presentation by Michael Miller, Gilead Sciences, of the data from study 408 highlighted again the role of the 184 mutation in those treated with the nucleotide analogue adefovir dipivoxil (ADV) [1]. This study enrolled 442 subjects who received either adefovir or placebo added to stable (8 weeks or more) background antiretroviral therapy for 24 weeks. After 24 weeks open-label ADV was offered to all subjects.
Prior to study entry more than 90% of patients had received zidovudine (ZDV) and 85% had received lamivudine (3TC). Virology subset studies of 142 subjects examined in detail both genotypic and phenotypic resistance at baseline and week 24 and its relationship to virological response. Baseline median plasma viral load value for the 142 subjects in this subset was 4.5 log copies/mL.
Overall, the week 24 mean virological response in the subset study patients receiving active ADV was approximately -0.4 log with no obvious viral load rebound out to 48 weeks. 53% of these ADV treated subjects had the M184V mutation and high-level zidovudine (ZDV-Hi) resistance mutation (M41L, T215 Y/F), 15% had just M184V and 14% had ZDV-Hi alone.
At 24 weeks those with ZDV-Hi resistance alone (n=10) experienced a mean HIV RNA change of -0.05 log while those with ZDV-Hi and M184V at baseline (n=39) experienced a change of -0.51 log copies/mL. This difference in response was significant with a p-value of 0.037.
M184V mutation was present at baseline in 108/142 subjects and was still present in 98 of these 108 at week 24 (91%). 3TC therapy was maintained over these 24 weeks in 92/108 (85%) and 16/108 (15%) discontinued 3TC. Loss of the M184V mutation was seen in 10/108 (9%) by week 24. Additionally a multivariate linear regression analysis was performed in which the presence of this mutation at baseline was independently predictive of an increased virological response of 0.38 log, whereas ZDV-Hi mutation alone independently predicts a reduced response of 0.62 log.
Although the predictor of enhanced response identified was presence of M184V at baseline the majority of these patients maintained that mutation mostly in the face of continued administration of 3TC. It would seem reasonable to assume that the continued presence of M184V would be necessary for continued virological advantage while using concomitant adefovir and this should be explored with further analysis.
Further hints at the utility of maintaining selective pressure on the M184V mutation came in 2 other presentations at this meeting. In her presentation of an efavirenz + adefovir based salvage regimen [2] (see study summaries chart) Nancy Shulman of Stanford University also identified this factor as a predictor of success. 81% of this cohorts subjects had the M184V mutation at baseline and analysis revealed that concurrent lamivudine or abacavir (both giving M184V selection pressure) was a predictor of achieving a viral load less than 500 copies/mL. Lack of nucleoside analogue support in the ACTG 359 study [3] presented by Roy Gulick on behalf of the ACTG 359 study team may also have been a factor in the low response rates seen unexpectedly across all arms (see study summaries chart). Unexpected adverse drug interactions were discovered in this trial (see later article in this issue of ATP's "Doctor Fax"), however even those arms that did not contain the interacting drugs performed poorly. Although genotypic data was not presented incidence of M184V mutation in this group is likely to be high due to their previous treatment history. Here there was no maintenance of selective pressure on this mutation.
References
1. Miller MD, Margot NA, Lamy PD et al. Adefovir dipivoxil is active in patients with lamivudine- or zidovudine/lamivudine-resistant HIV. [Abstract 004] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
2. Shulman N, Zolopa A, Murlidharan U et al. Salvage therapy with an efavirenz and adefovir-based regimen in antiretroviral experienced patients. [Abstract 013] 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
3. Gulick RM, Katzenstein D, Hu J et al. Salvage therapy with saquinavir soft gel capsules in combination with ritonavir or nelfinavir and delavirdine, adefovir dipivoxil, or both: ACTG 359. [Abstract 020]. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
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Whilst adefovir is currently being positioned with a role in salvage therapy, and particularly those patients with ZDV and 3TC related resistance, its own effects on resistance should also be observed. Oral PMPA, another nucleotide analogue in development with Gilead appears (at this stage) more promising than adefovir with increased virological potency. Reassurance is required, and with some urgency, that prior adefovir treatment will not compromise future response to PMPA. The UK COLATE study will investigate if continuing 3TC after resistance arises has any benefit. This is a randomised, open label study for patients failing their first line 3TC containing combinations. The participants will be randomised into 2 groups: The first group will discontinue 3TC and begin a new combination which must include a protease inhibitor. The second group will continue taking 3TC along with the new combination which must also include a protease inhibitor. The new combination regimen must consist of at least 3 anti-HIV drugs.
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As mentioned above, the ACTG 359 trial results reported by Roy Gulick identified a previously unreported and unexpected adverse pharmacologic interaction between three of the components in this multi-drug regimen.
Two of the arms of this six arm randomised partially double blinded trial co-administered the p450 CYP3A4 inhibiting NNRTI delavirdine and the nucleotide analogue adefovir. Drug level monitoring in these arms identified a 50% reduction in the levels of delavirdine compared to the non-adefovir containing arms. Additionally the reduction in levels of delavirdine led to reduced enhancement of the saquinavir component of this regimen. Consequently the reduced CYP3A4 inhibition subsequent to the reduction in levels of delavirdine led to a 50% reduction in saquinavir levels in the adefovir containing arms.
Virological responses in this complex trial of indinavir experienced, NNRTI-naïve subjects receiving a salvage therapy regimen using saquinavir soft gel capsules (Fortovase) revealed no demonstrable difference between using ritonavir or nelfinavir as the second protease inhibitor; delavirdine had greater efficacy than adefovir; and the combination of delavirdine/adefovir was no better than delavirdine alone at 16 weeks of follow-up.
Ref: Gulick RM, Katzenstein D, Hu J et al. Salvage therapy with saquinavir soft gel capsules in combination with ritonavir or nelfinavir and delavirdine, adefovir dipivoxil, or both: ACTG 359. [Abstract 020]. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
Veronica Miller presented results on 558 patients from the Frankfurt HIV Clinic Cohort investigating the association between CD4 count (at baseline and during follow-up) and duration of viral load suppression using so-called highly active antiretroviral therapy (HAART). The 558 selected patients had all experienced viral load declines to less than 500 copies/mL within 36 weeks of starting their 3-drug HAART treatment. HAART was PI-based in 74% and NNRTI-based in 26%; results did not differ amongst these 2 types of regimen. Although these subjects were not a pure "salvage" population (nearly half were antiretroviral naïve) the observations from this cohort may be of value in their implications for those with low CD4 counts.
Higher CD4 counts prior to antiretroviral treatment had previously been identified as being associated with reduced virological rebound. However, the relationship between baseline CD4, on treatment CD4 and duration of virological suppression is unknown. If higher baseline CD4 counts "protect" against future viral rebound it is reasonable to ask if larger treatment induced CD4 cell rises might also offer similar protection.
Baseline measures for the 558 patients in this study included median CD4 of 188 cells/mm3 and a median HIV RNA viral load of 5 log copies/mL. As mentioned 48% of patients were antiretroviral naïve. During the period of follow-up 306/588 (52%) of subjects experienced a viral load greater than 500 copies/mL after being previously suppressed to below 500 copies on their initial HAART combination. Amongst all 306/588 subjects the Kaplan-Meier estimate of experiencing such viral rebound was determined to be 42.5% at 24 weeks and 64.3% at 84 weeks.
Cox proportional hazards modelling identified both baseline CD4 count and change from baseline CD4 count to be independently associated with risk of viral rebound (see table for relative hazards - RH).
RH of rebound for baseline CD4*
| RH | 95% CI | |
| <20 | 2.85 | (1.45-5.58) |
| 20-99 | 2.01 | (1.08-3.75) |
| 100-299 | 2.36 | (1.30-4.26) |
| 300-500 | 1.51 | (0.80-2.86) |
| >500 | 1.00 |
p<0.001
*adjusted for number of new drugs and time to VL <500.
RH of rebound for change in CD4 from baseline*
| RH | 95% CI | |
| <0 | 2 | (1.3-3.1) |
| 0-49 | 1.2 | (0.08-1.08) |
| 50-99 | 1.1 | (0.7-1.7) |
| 100-200 | 1.3 | (0.9-2.0) |
| >200 | 1.00 |
p<0.003
*adjusted for number of new drugs, time to VL <500 and baseline CD4.
RH of rebound for last updated CD4 count*
| RH | 95% CI | |
| <20 | 5.4 | (2.3-2.7) |
| 20-99 | 2.5 | (1.5-4.2) |
| 100-299 | 2.4 | (1.5-3.7) |
| 300-500 | 2 | (1.3-3.2) |
| >500 | 1.00 |
p<0.001
*adjusted for number of new drugs and time to VL <500.
This study concluded that patients with higher baseline CD4 counts and greater CD4 cell count rises subsequent to HAART experience a substantially reduced risk of viral rebound. The possible role of increased numbers of CD4 cells in contributing to host mediated suppression of HIV replication was mooted as a mechanism for this observed effect.
Ref: Miller V, Staszewski S, Sabin C. CD4 lymphocyte count as a predictor of the duration of HAART-induced suppression of HIV-1 virus load. Gulick RM, Katzenstein D, Hu J et al. Salvage therapy with saquinavir soft gel capsules in combination with ritonavir or nelfinavir and delavirdine, adefovir dipivoxil, or both: ACTG 359. [Abstract 020]. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
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It must now be asked how this data fits with that of increased risk of virological failure with large CD4 cell rises and the target cell hypothesis? Of course, the higher CD4 rises may only be a marker of good response but not part of the mechanism for maintained durability. |
Planned treatment breaks after failure of an antiretroviral regimen have been used for some time now. Various rationales have been advanced for their utility including "wash-out" periods to prevent drug-drug interactions between drugs in the old regimen and those in the new, giving the liver a break and simply giving the patient a rest from frequently demanding schedules. Additionally the observation was made by some that a period off all antiretroviral treatment appeared to be associated with an improved virological response on introduction of the new regimen. This observation remained to be further defined.
Veronica Miller from the Klinikum der JW Goethe Universitat, Frankfurt, presented results from a study of the effects of such treatment breaks in subjects with previous failure to multiple previous treatment regimens. A total of 94 subjects were analysed to assess the treatment response in relation to baseline resistance, viral load, CD4 cell count and any effect of a "drug holiday" prior to initiation of a multidrug rescue therapy regimen (MDRT).
Baseline median viral load in these 94 subjects was 5.21 log copies/mL, baseline median CD4 count was 108 cells/mm3. The MDRT treatment resulted in a maximum viral load reduction of 2.7 log (median of 12 months follow-up). Baseline susceptibility (phenotypically determined) was associated with a virological response (defined as achieving and maintaining viral load <500 copies/mL). In those subjects with viral populations sensitive to at least four of the drugs in the MDRT regimen 67% were responders. However, 70% of subjects never achieving less than 500 copies were found to have viral populations which were sensitive to a maximum of 3 drugs in the new regimen. Ten patients had taken a "drug holiday of more than 2 months and 6 of these showed a shift to wild type in their HIV population. The observation was made that patients who had taken a treatment break and whose viral population had shifted to wild type were more likely to be responders. Increases in viral load and reductions in CD4 counts were also observed during the time off therapy.
This observation was investigated further in fifty subjects to better define the effects of change in viral susceptibility, CD4 count and viral load during treatment interruption. All fifty of these patients had received antiretroviral treatment since 1/1/96 with a variety of regimens including at least 2 prior protease inhibitor containing regimens and had more than one year of PI experience. A treatment interruption of greater than 2 months was enforced before introduction of an MDRT regimen. Resistance assay results before the interruption and at a second time point just prior to introduction of MDRT were available for 39/50 patients.
In all 50 subjects, during the drug holiday, viral load increased by a median of 0.71 log (5.07 to 5.87 log copies/mL) and CD4 cell counts declined by a median of 89 cells/mm3 (155 to 49 cells/mm3).
In those with resistance analysis available 26/39 showed a shift to wild type HIV and the remaining 13/39 maintained a phenotypically similar population between the first and second resistance testing time points. The mean number of prior antiretroviral drugs was 8 in both shifters and non-shifters.
The following table compares viral load and CD4 response during treatment interruption between those with HIV shift or no shift to wild type.
Shifting to wild type (n=26)
| VL just prior to initiation of MDRT | Change in VL off treatment | Change in CD4 off treatment | |
| All (n=26) | 4.98 log | +0.98 log | -122 |
| >500 VL on MDRT (n=8) | 5.66 log | +0.26 log | -121 |
| <500 VL on MDRT (n=18) | 4.47 log | +1.34 log | -129 |
Not shifting to wild type (n=12)
| VL just prior to initiation of MDRT | Change in VL off treatment | Change in CD4 off treatment | |
| All (n=12) | 5.46 log | +0.34 log | -29 |
| >500 VL on MDRT (n=10) | 5.79 log | 0.0 log | -24 |
| <500 VL on MDRT (n=2) | 3.95 log | +1.72 | -88 |
8 weeks after initiation of MDRT those with HIV shifts to wild type experienced a median viral load reduction of 2.9 log, whereas those without a shift had a median 0.7 log reduction.
Miller concluded that complete treatment interruptions might lead to shifts in the viral population, with a change to wild type as the dominant variant in the majority. These changes in phenotypic sensitivity may be associated with better initial virological response to MDRT. However, large rises in viral load and reductions in CD4 counts need to be closely monitored during any drug holiday.
Ref: Miller V, Rottman C, Hertogs K et al. Mega-HAART, resistance and drug holidays. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
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Interestingly, those experiencing better virological response (<500) after treatment interruption and introduction of MDRT also appears to be those who experienced the largest rebound in VL off therapy. As well as shift to wild type, might higher peaks of viraemia be associated with better response to MDRT? This phenomenon might be similar to acute primary HIV infection and host response needs to be looked at in these subjects. Anti-HIV responses may be being induced in these subjects by large quantities of HIV antigen ("autoimmunisation"). |
| SalvageRegimen | StudyType | Subjects | Prior antiretrovirals | Baseline CD4 (cells/mm3) | Baseline VL (log copies/mL) | NNRTI naïve? | HIV RNA response | Abstract |
| SQV/RTV required + 2 NA's | Retrospective review | N=58 | One PI only (RTV, SQV, IND) + NA's | 256 | 4.0 | Yes | 48.3% <200 at 52 weeks (ITT-LOCF) | 007 |
| ADV/EFV required + PI's + NA's | Retrospective review | N=33 | No limits. Median prior ARV's = 8 | 102 | 5.1 | Yes - 66% | 29% <500, 17% <20 at 24 weeks (ITT, NC=F) | 013 |
| Up to 9 ARV's including 2 PI's, 2 NNRTI's, HU, up to 4 NNRTI's | Observational study | N=82 | No limits. Median prior ARV's = 7. | 185 | 4.7 | Not required | 45% <400 at 30 weeks (ITT) | 015 |
| Double PI, EFV, HU + NA's | Observational study | N=63 | No limits. Median prior ARV's = 5 | 128 | 4.8 | Yes - 86% | 70% <400 copies at week 24 (ITT) | 018 |
| NVP/NFV + NA's (11% ABC) | Observational study | N=92 | 2 NRTI's + at least one PI | 232 | 4.7 | Yes | 24% <200 copies at 52 weeks (OT) | 019 |
| SQV/RTV or SQV/NFV + DLV/ADF or DLV or ADV | Randomised partially double blinded | N=277 | IND, (<2 weeks RTV or SQVhgc), no prior NFV, AMP or ADV | 229 | 4.5 | Yes | 30% <500 copies at week 16 over all arms | 020 |
ADV=Adefovir, AMP=Amprenavir, ARV=Antiretroviral, DLV=Delavirdine, EFV=Efavirenz, HU=Hydroxyurea, NA=Nucleoside Analogue, NFV=Nelfinavir, NNRTI=Non-Nucleoside Reverse Transcriptase Inhibitor, NVP=Nevirapine, PI=Protease Inhibitor, RTV=Ritonavir, SQV=Saquinavir.
[Abstract 007] Paredes R, Puig T, Arno A et al. High-dose saquinavir plus ritonavir-containing HAART salvage therapy: long-term efficacy in protease inhibitor-experienced patients and predictors of virological response. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
[Abstract 013] Salvage therapy with an efavirenz and adefovir-based regimen in antiretroviral experienced patients. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
[Abstract 015] Montaner JSG, Harrigan PR, Jahnke NA et al. Multidrug rescue therapy for HIV-infected individuals with prior virological failure to multiple regimens: results from an initial cohort. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
[Abstract 018] Youle M, Mocroft A, Johnson M et al. Surrogate marker responses to multidrug combinations comprising hydroxyurea, efavirenz, double protease inhibitors (PI) and nucleoside analogues in PI failures. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
[Abstract 019] Pumarola T, Martinez E, Buira E et al. Salvage therapy with nevirapine and nelfinavir in HIV-1 protease inhibitor-experienced patients. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
[Abstract 020] Gulick RM, Katzenstein D, Hu J et al. Salvage therapy with saquinavir soft gel capsules in combination with ritonavir or nelfinavir and delavirdine, adefovir dipivoxil, or both: ACTG 359. 2nd International Workshop on Salvage Therapy for HIV Infection, 19-21 May 1999, Toronto, Canada.
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OTHER NEWS
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Paul Blanchard, ATP. A number of new drugs under development are targeted at the co-receptors that HIV uses to enter and infect cells. Two of these co-receptors, CCR5 and CXCR4 have been intensively investigated. Different strains of HIV have differential ability to utilise these co-receptors, and some HIV strains cannot enter cells if one or either of these co-receptors is absent. However, the observation has been made that evolution of HIV during the course of infection may allow switching in its ability to use different co-receptors. Rapid progression in HIV-disease has been associated with such a switch in HIV co-receptor use from CCR5 using to CXCR4 using strains.
Mosier et al report their findings on two new CCR5 co-receptor antagonists (AOP-RANTES and NNY-RANTES) in the May issue of the Journal of Virology. The researchers explored the in vivo efficacy of these two receptor antagonists in an animal model of HIV infection: severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice). The drugs were tested for their ability to prevent infection with a CCR5 using (R5) strain of HIV-1 that requires only one amino-acid mutation to become dually tropic for the CCR5 and CXCR4 co-receptor, and only three mutations to become an exclusively CXCR4 co-receptor using virus.
Although efficient blocking of HIV was observed in this model the expected switch in co-receptor usage by the R5 strain of HIV occurred rapidly. With NNY-RANTES co-receptor switch HIV variants appeared during the one-week treatment period in two challenged animals. Interestingly, these were not the dual-tropic variants a single amino-acid change would have created. In both cases there was the same three-position mutation into a CXCR4 using virus.
The authors warned that... "The emergence of viruses capable of using CXCR4 under the selective pressure of the concentrations of NNY-RANTES used in these experiments demonstrates that the inappropriate use of CCR5 antagonists could generate more pathogenic variants, since there is general agreement that the course of disease progression is accelerated with the switch from R5 to R5X4 viruses."
"These results strongly reinforce the view that clinical use of blocking agents for CCR5 alone would be unwise and that cocktails of antagonists directed toward known co-receptors or antagonists with broader specificity will be required for safe and effective therapy of HIV-1 infection in humans."
Ref: Mosier et al. Highly Potent RANTES Analogs either Prevent CCR5-Using Human Immunodeficiency Virus Type 1 Infection In Vivo or Rapidly Select for CXCR4-Using Variants. J Virol, May 1999;73(5):3544-50.
London-based investigators report the case of a patient with advanced HIV infection who developed symptoms of type III hyperlipidemia (dysbetalipoproteinemia) after starting combination antiretroviral therapy that included a protease inhibitor. The man presented with "florid-yellow-orange papules" of the back of his hands, which were histologically confirmed as eruptive xanthomata, Dr. R. K. Lister and colleagues at the Royal Free Hospital report. A few months earlier, his viral load was 750,000 RNA copies/mL and his CD4 count was 16 cells per microlitre. The patient, who had failed treatment with nucleoside analogue combinations, was started on highly active antiretroviral therapy (HAART), which included two protease inhibitors (ritonavir and indinavir).
The xanthomata occurred after a good response to HAART, which was marked by an increase in CD4 count to 145 cells per microlitre and a decrease in viral load to less than 400 RNA copies/mL. Laboratory findings indicated a serum cholesterol value of 29.3 mmol/L and a triglyceride value of 27.5 mmol/L. These values had been 3.3 mmol/L and 2.2 mmol/L, respectively, prior to HAART. Following discontinuation of ritonavir, his lipid profile normalised and the xanthomata resolved. "Further investigation showed that the patient was homozygous for apolipoprotein E2 (phenotype E2,E2)," the clinicians report in the May 15th issue of The Lancet, and plasma levels of beta-very low-density lipoprotein (VLDL) were high.
Dr. Lister's group concludes that dysbetalipoproteinemia, which had been latent in this patient, was precipitated by protease inhibitor therapy. This case suggests that patients may benefit from a general lipid profile and apoE2,E2 phenotype screen prior to initiation of protease inhibitor therapy.
Ref: Lancet 1999;353:1673. Source: Reuters Health.
Based on a second interim analysis of a phase III trial of Remune, an investigational immune system-based HIV therapy, an independent Data Safety Monitoring Board (DSMB) has recommended that the trial be concluded, according to a joint statement issued by the Immune Response Corporation in Carlsbad, Calif, and Agouron Pharmaceuticals, Inc., in La Jolla, Calif.
The panel members found no differences in clinical end points between the treatment groups in the 2,500-subject trial, and concluded that it was unlikely that any statistically significant differences would emerge in the near-term if the trial were extended. "The number of HIV-associated clinical endpoints observed in the trial was far less than originally anticipated," the statement continued. This is attributed to the increased use of highly active antiretroviral therapy (HAART) after the trial began.
However, in a separate evaluation of 250 subjects, who were randomly pre-selected for surrogate marker analysis, company investigators detected significant differences. After 48 and 96 weeks, they found significant reductions in viral load and increases in lymphocyte proliferation among subjects receiving Remune.
The US Food and Drug Administration (FDA) previously agreed that a marketing application for Remune could be submitted based on favourable virologic end points. Therefore, Agouron is planning 2 more phase III surrogate marker trials of Remune.
"While HAART, which became the standard of care after we initiated this trial, has been an enormous benefit to HIV patients, it has made it exceedingly difficult to conduct a trial based upon reaching clinical endpoints," Dr. Dennis J. DeCarlo, Immune Response CEO, commented. The company hopes to initiate a rollover study, pending FDA clearance, within 2 to 3 months.
Source: Aegis.com
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In retrospect this appears to the wrong study of a promising therapeutic candidate. Effect on time to virological failure would seem the most rational marker for future prospective studies. |
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Source: Business Wire.
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