Strategies for salvage therapy
Simon Collins, HIV i-Base
On of the most clinically relevant oral presentations was an overview of approaches to salvage therapy focusing on When to switch and How to wait that was given by Steven Deeks, from University of California. 
The session started by highlighting the lack of detail provided by current treatment guidelines for management of highly treatment experienced patients. They recognise the balance between minimising resistance to an existing failing treatment by switching once viral rebound is confirmed, but also that using a new treatments as it becomes available will limit treatment options to include the subsequent new drug, which if both were used together could provide more durable protection. However, they generally remain vague about clinical decisions. This talk therefore analysed recent data to help decide when to change and how to weigh the balance of advantages and disadvantages using new treatments.
How to switch: use two new sensitive drugs
Guidelines also generally display a pessimistic outlook for achieving viral suppression to <50 copies/mL in triple-class experienced patients. This was another main issue that Deeks challenged saying that the paradigm for salvage therapy has completely shifted over the last year. The recent tipranavir and TMC114 trials in treatment-experienced patients showed that significantly higher percentages of patients achieve viral suppression to <400 or <50 copies/mL when T20 was included in the optimised background therapy: 53% of patients in the tipranavir studies, achieved <400 copies/mL at 24 weeks; and 67% of patients using TMC114 (in an interim analysis of 118 patients) achieved viral load <50 copies/mL. These responses are approaching those seen in treatment naive individuals with other established regimens.
The availability of two drugs to which the virus is sensitive an entry inhibitor and a new protease inhibitor hopefully with additional residual activity of one or two nukes, perhaps also using the reduced fitness from maintaining the M184V mutation by including 3TC or FTC, has provided a much more optimistic outlook for salvage therapy. However, new drugs will still largely only become available in a sequential manner, and even a 67% response isnt the 90% or higher that we should be aiming for.
Data from these new drug trials provide greater confidence on how to switch but they dont clarify which patients should switch early and which patients should wait. When should new drugs be used in the setting of triple-class MDR HIV?; and, if a decision is made not to switch, what should be done in the meantime?
Using resistance tests to predict when to switch
It should be possible to give more helpful guidance, based on resistance test results, on when to wait before switching, in patients who are currently clinically stable, and who are not dependent on immediate life-saving benefits of T20 or the newer PIs.
Analysis of the initial 2-weeks of functional monotherapy in the BI1182:52 study found that a cut off above 4-fold phenotypic resistance to tipranavir, using the Virologic Phenosense (Virologic) assay, correlated with 2-week viral load response. This can be used to help decide when NOT to use T20 with tipranavir. The cut-off for sensitivity with the AntiVirogram (Virco) assay, are <3-fold for sensitivity and >10-fold for resistant. Results >4-fold on with Virologic or >10-fold with Virco indicates that tipranavir will not generate a virological response.
Although phenotypic resistance tests are generally more strongly recommended in direct relation to treatment experience, analysis of genotypic resistance also have been reported to correlate with response to tipranavir.
For the full study cohort, there was an inverse relationship between the number of mutations at codons 33, 82, 84, or 90 and viral load reduction at week 24. Patients with 0, 1, 2 and 3 mutations at these codons demonstrated a -1.51, -0.76, -0.62 and -0.13 log10 copies/mL reductions and there was a dose-related response for patients with 3 or more mutations at codons 33, 82, 84, or 90.
A second genotypic analysis suggested that presence of 0-4, 5-8 and >8 mutations at baseline (from L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D or I84V) produced a >1log reduction in viral load at week 24 in 45%, 21% and 0% of people not using T20, and that this correlated with phenotypic cut-offs of <3-fold, 3 to 10-fold and >10-fold, with the AntiVirogram assay.
Resistance data from non-responders using TMC114 will require similar analysis as soon as it becomes available,
Risks of waiting
Considering CD4 count is clearly critical but also complicated. Delaying any switch until the CD4 count drop to <100 cells/mm3 or possibly lower, will maximise the chance that more new drugs are available, but if it falls below this level, the chance of treatment success are also reduced.
In an early analysis by Deeks of patients maintained on virologically failing PI-based regimens, viral load level 12-weeks after virological rebound correlated with rate of reduction in CD4 counts. It also occurred at a significantly reduced rate compared to rate of CD4 reduction in an historical treatment-naive control group.  Also, although the proportion of people who fail immunologically (defined as CD4 return to baseline) steadily increases with time since virologic failure, the risk of clinical progression has not been clearly defined for any given CD4 or viral load level in the context of multi-drug resistance (MDR). 
Response rates to salvage regimens have been shown to be predicted by disease stage. For example the TORO studies showed that baseline CD4 >100 cells/mm3 and viral load <100,000 copies/mL were both highly statistically significantly associated with likelihood of achieving viral suppression to <400 at week 24 (OR of 2.4 and 1.8 respectively) in patients receiving T20 plus optimised background regimens. 
Baseline CD4 count <50 cells/mm3 at time of treatment modification predicted a significantly poorer virologic response to salvage therapy compared to patients at any count above 50 cells/mm3 in an analysis of patients in the tipranavir/r study presented at the Rio meeting, both for patients receiving tipranavir or a comparitor PI (although responses to tipranavir were significantly higher). 
Other risks from a delayed switch are difficult to quantify. Rates of development of additional mutations have not been clearly described for patients with MDR who maintain virologically failing treatment. Viral tropism shift from R5 to X4 or mixed tropism, increases as CD4 levels drop below 100 cells/mm3 and is more likely to limit the chance to benefit from future use of CCR5 inhibitors.
A summary of when to switch was:
- If two (or preferably) three well-tolerated and effective drugs are available then an early and aggressive switch should be considered.
- When to switch requires access to resistance test with well defined genotypic and/or phenotypic cut-offs.
- If not, benefits of preserving novel treatment classes may outweigh benefits of switching, particularly if CD4 is still >100 cells/mm3; substantial resistance to existing classes already exists; or virus is already dual tropic/X4.
How to wait and which drugs to maintain
The discussion of how to wait – for patients who have higher CD4 counts, or who only have one active drugs available – focused on the choice of drugs to use in a failing treatment.
Residual activity of 3TC after development of M184V is now well highlighted due to the E-184V study, whose 48-week results were reported in Rio. 
The mechanism for this may be a mixture of residual antiviral activity and reduced fitness, as other studies have shown discontinuation of 3TC produces a rapid viral load rebound prior to the reversion of the viral population back to wild-type at 184.
Earlier work by Deeks has shown that maintaining nucleosides maintains viral suppression compared to maintaining only protease inhibitor components of a failing regimen, and that both PIs and probably T20 both have residual benefit on viral load mediated through impaired viral fitness (or reduced pathogenicity). NNRTIs have not been shown to have any residual antiviral effect once NNRTI resistance is confirmed.
The strategy for maintaining partial suppression is to maintain NRTIs that often have residual activity against resistant HIV pending availability of more effective regimens and to use NRTIs in the backbone of salvage regimens. Other drugsparticularly protease inhibitors and/or enfuvirtidemay no longer exert a direct antiviral impact, yet still have residual benefit via its impact on the maintenance of mutations that reduce fitness and/or virulence
Finally, perhaps optimistically from the viewpoint of delaying a treatment switch, are more recent data from the observational PLATO study published last year in the Lancet showing that CD4 declines more slowly in treated patients with multi-drug resistance than in treatment naive patients and also that continued protease inhibitor inclusion in the failing regimen has a more beneficial clinical effect and is independent of viral load. 
In summary of how to wait:
- Factors associated with persistent immunologic and clinical benefit in setting of drug resistant HIV have not been defined.
- Observational data suggest durable CD4+ T cell count benefits are due in part to continued use of protease inhibitors, and this effect is independent of viral load.
- Continued protease inhibitor therapy and perhaps T20 should be considered in advanced immunodeficiency. The slides from this presentation – http://www.ias-2005.org/planner/Presentations/ppt/3471.ppt
- Deeks S. Switching therapy: strategic approaches: when to switch and how to wait. Forum presentation. 3rd IAS Conference, July 2005. Rio de Janeiro. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract WeFo0201.
- Deeks SG, Barbour JD, Martin JN et al. Sustained CD4+ T Cell Response after Virologic Failure of Protease Inhibitor-based regimens in patients with HIV Infection. JID 2000; 181:946-53
- Deeks SG, Barbour JD, Grant RM et al. Duration and predictors of CD4 T-cell gains in patients who continue combination therapy despite detectable plasma viremia. AIDS 2002; 16:201-207.
- Montaner J, DeMasi R, Dleehanty J et al.Analysis of virological response of enfuvirtide in TORO: implications for patient management. 2nd IAS Conf HIV Pathology and Treatment, Paris 2003. Abstract 116.
- Hicks et al. 3rd IAS Conf HIV Pathology and Treatment, Rio de Janeiro 2005. Tipranavir/ritonavir demonstrates superior immunologic response to comparitor PIs in a PI-experienced population with advanced HIV disease. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract WePe16.7B07.
- Castagna A, Danise A, Menzo S et al. E-184V study. Lamivudine monotherapy vs treatment interruption in failing HIV-1 infected subjects, harbouring the M184V mutation: 48-week final results. 3rd IAS Conference on HIV Pathogenesis and Treatment, Rio de Janeiro, 2005. Abstract WeFo0204.
- The PLATO Collaboration. Predictors of trends in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004; 364: 5162