6.9. Salvage Therapy

– Christian Hoffmann –


The term “salvage therapy” is not clearly defined in HIV medicine. As in oncology the term is currently used to refer to varying situations. Some speak of salvage only if all drug classes have failed, whereas others employ the term from second-line therapy onward. Today, many clinicians talk about salvage when there is resistance to at least two or three antiretroviral drug classes.

TCR (Triple Class Resistance) is present when viral resistance mutations against the three conventional drug classes NRTIs, NNRTIs and PIs have developed. TCF (Triple Class Failure) means that the viral load remains detectable although these three drug classes have been implemented. Analogous to MDR tuberculosis, triple class resistant viruses with additional resistance mutations are also referred to as MDR, multi-drug resistant viruses. However these terms are not uniformly defined.

Significant progress has been made for patients with TCR and/or MDR viruses over the last few years, changing therapy dramatically within a few months. For years lopinavir, T-20 and tipranavir/r were the only TCR drugs, then, within a short period in 2007/08, four new drugs were licensed. Darunavir, maraviroc, raltegravir and etravirine all have remarkable effects in the presence of multiple resistance mutations, which allow us to be optimistic and change our goals. Even with intensely pre-treated patients there is no reason not to get viral loads to below the limit of detection.

The number of patients with TCR viruses is in decline and not, as often presumed, increasing (Lohse 2005+2006, Napravnik 2007). In an analysis involving 30,000 patients from North America the proportion of patients whose second ART had virologically failed decreased from 95/100 in 1996-97 to only 13/100 person years in 2004-05 (Deeks 2008). The majority of patients with TCF originally received antiretroviral treatment with mono- and duo-therapies (Lederberger 2004). In an analysis of almost 46,000 patients in Europe the TCF rate was only 2.1%. Five and nine years, respectively, after initiation of ART the rate increased to 3.4% and 8.6% (Plato 2010). The number of patients not achieving a viral load below 50 copies/ml due to TCF remains low (Basnio 2010).

Given that this patient group is small, it is difficult to do studies with sufficient power. Homogenous populations do not really exist and every patient has his own individual therapy history and resistance pattern. In larger centers as many as 50 different combinations are used. This makes it difficult to test new salvage agents in phase II/III studies. The design of these studies is another problem: as the single use of an experimental drug within a failing regimen is ethically questionable, ART must always be optimized (OBT, optimized background therapy). If the OBT is too good, the effect of the new drug may be hidden, as many patients achieve a good viral suppression just on OBT. If the OBT is poor, the effect of the new drug may only be temporary or too weak – the window through which the efficacy of a new salvage drug can be seen is small.

The recent failure of the CCR5 antagonist vicriviroc (Gathe 2010) is only one of many examples. This shows how difficult it has become to bring a salvage agent to the market.


First a few words about daily practice: it should not be forgotten that patients with TCF, who often have a long history of being on treatment and who now find themselves once again on a precipice, need encouragement. It is important not to leave these patients without hope. It usually takes years to progress from virologic treatment failure to immunologic and finally clinical failure (see Principles of Therapy). Fortunately these patients – most having been treated for ten or fifteen years, having experienced a lot – are often not nearly as nervous as the often young HIV doctor. They have learned that there is almost always more to come.

Much is possible now in individual cases. Table 9.1 shows an example illustrating the history of antiretroviral therapy – although treatment always remained up to date, viral load of less than 100,000 copies/ml was not always achieved over the years. Finally, with the application of a new agent the patient experienced their first success after more than a decade of having a high level plasma viremia. Viral load has now been below the limit of detection for three years.

Table 9.1. Case report showing what is possible today.
Date ART

CD4 cells

Viral load

Jun 95 AZT (later, ddC, ddI)



Jun 96 AZT+ddC+RTV



Okt 96 D4T+3TC+IDV



Jul 97 D4T+ddI+3TC+NVP+IDV



Jan 99 D4T+ddI+ABC+3TC+SQV/r



Sep 99 D4T+ABC+3TC+DLV+LPV/r



Dez 01 TDF+ddI+DLV+HU



Jun 03 TDF+3TC+FPV/r



Okt 03 TDF+3TC+ddI+TPV/r



Mai 04 AZT+3TC+TDF+LPV/r+T-20+DLV



Dez 04 AZT+3TC+TDF



Dez 07 AZT+3TC+TDF+DRV/r+RAL+T-20



Jan 08






Mar 11



Comment: Not all treatment modifications are shown. The switch in 2007 was deferred until DRV and RAL were available in order to use both agents simultaneously. T-20 was recycled when resistance testing did not clearly show if darunavir was still active. Although not foreseeable how long this therapy success will last, the complete suppression of the patient’s viral load is remarkable after so many years in the six figure range. A de-escalation of the current treatment (13 pills, 7 agents) seems risky at present.

Patients with TCF probably have a worse prognosis than patients without TCF (Lohse 2007). In a population-based study from the Danish HIV Cohort on all patients who experienced TCF between 1995 and 2004, the total number of genotypic resistance mutations and specific single mutations predicted mortality. In a regression model adjusted for CD4 T cell count, HIV RNA, year of TCF, age, gender and previous ART regimen, harboring at least 9 (versus less) mutations was associated with increased mortality. In contrast, other studies did not find an association between number of resistance mutations and mortality (Lucas 2004). With good CD4 T cell counts, even despite TCR viruses, the risk of developing AIDS is relatively small (Ledergerber 2004). TCR viruses have less ability to replicate and are probably less aggressive (Prado 2005). And, newer classes of drugs may be on the horizon. So, in cases of TCR or MDR, be patient. It is, however, important that patients with MDR viruses are very carefully monitored and undergo regular (monthly) full-body exams – something that is often neglected these days in the discussions on blood values and resistance testing, etc. Loss of weight, Stage B symptoms, oral candidiasis, OHL and cognitive worsening are early signs of disease progression that need to be watched for. If possible, these patients should be treated in large centers that have access to clinical studies.

Salvage with the newer drugs

A wide range of agents for the treatment of patients with limited options has been licenced in the last few years. These agents include the PIs tipranavir/r and darunavir/r (which now also has an indication for naïve patients), the NNRTI etravirine, the CCR5 anatgonist maraviroc and the integrase inhibitor raltegravir (also with an indication for naives). They have revolutionized salvage therapy and have become indispensable in the struggle against resistant viruses. Other strategies have proved less effective. The most important results on salvage therapy from large-scale studies within the last few years are shown in Table 9.2 and Table 9.3.

Table 9.2. The large randomized studies in salvage therapy.

Study (Agent)

Main inclusion criteria
Lalezari 2003, Lazzarin 2003, Nelson 2005

TORO 1+2

TCF or TCR or both, VL >5,000
Hicks 2006


TCF and 1-2 primary PI-resistance, VL >1,000
Clotet 2007


TCF and ≥ 1 primary PI-resistance, VL >1,000
Lazzarin 2007, Madruga 2007, Katlama 2009

DUET 1+2

≥1 NNRTI-resistance and ≥3 primary PI-resistance, VL >5,000
Gulick 2008, Fätkenheuer 2008


TCR or TCF or both, VL >5,000 (prior treatment interruption at baseline allowed), only R5-tropic viruses
Cooper 2008,
Steigbigl 2008


TCR, VL >1,000
TCR=Triple Class Resistance, TCF=Triple Class Failure, VL=Viral load

Of note, inclusion criteria for these studies varied widely. In some studies inclusion was coupled to certain resistance mutations, others included triple class failure. There were great differences in patient populations and the definition of TCF was not consistent. The proportion of patients additionally receiving T-20 ranged from 20-44%. Different resistance scores were also used in order to determine the number of active agents in background therapy.

Accordingly, response rates vary considerably even in the placebo arms. The rates of all patients with a plasma viremia less than 50 copies/ml at 48 weeks ranged from 10% to 40%, with addition of T-20 from 11% to 62%. The response rates of patients who had received only one active agent and placebo varied from 1-24%.

Cross-trial comparisons regarding the efficacy of the new agents need to be avoided. Although this is attempted for marketing reasons: According to these trials, darunavir/r is not better than tipranavir/r. Raltegravir does not have a higher efficacy than maraviroc. The individual study matters greatly,


Table 9.3. The large randomized studies in salvage therapy, main results.






Agent tested






Total n






Baseline characteristics

Median VL, log RNA/ml






Median CD4 T cells/µl






0-1 active drug, %*







With de novo T-20, %






With darunavir, %






With tipranavir, %






Response at 48 Wo*

In total, %

45 vs. 10

23 vs. 10

44 vs. 17

64 vs. 34

61 vs. 40

With de novo T-20, %

58 vs. 11

28 vs. 14

61 vs. 27

84 vs. 62

71 vs. 59

0-1 active drug, %

37 vs. 1


37 vs. 6***

48 vs. 12

57 vs. 24

*Definition of an active drug varied considerably (different resistance scores were used); **Response at 48 weeks defined as viral load <50 copies/ml;  ***Data at week 24. n.a.=not applicable

What to do in patients with TCR

First of all, a resistance test should be available that was not done during a treatment interruption. Older resistance tests should also be reviewed. Resistance mutations detected earlier presumably still exist even if they are no longer detected. It is also important to check incompatibilities of the last years to spare the patient unnecessary side effects and dangerous re-exposure.

Some pilot studies report success when only new drugs are used. In the French TRIO study, 103 extensively pre-treated patients with TCF were treated with the combination RAL+ETV+MVC, out of which 86% achieved plasma viremia below 50 copies/ml at 48 weeks (Yazdanpanah 2009). In a smaller Italian study with 28 patients on the same combination RAL+ETV+MVC it reached 92% (Nozza 2010+2011).

Does it necessarily have to be new drugs? Before switching, physicians should go over the classes, one by one, depending on the individual resistance profile, even the old ones. Table 9.4 shows an overview of the major salvage strategies with regard to each class.

Table 9.4. Salvage strategies in patients with TCR to NRTIs, NNRTIs and PIs.
Drug Possible strategies, remarks
NRTIs Try to conserve mutations that reduce replication fitness, such as M184V with 3TC or FTC. Consider AZT and TDF simultaneously, due to diverging resistance pathways
NNRTIs At <3 NNRTI mutations consider etravirine (approved only with a boosted PI/r), otherwise discontinue NNRTIs
PIs Darunavir/r (good data with etravirine) or tipranavir/r
Maraviroc Tropism test? Due to non-detected dual-tropic viruses, use 2 definitively active agents such as raltegravir and T-20 (if nothing else works), remember doses adaptions when boosting with PIs
Raltegravir At least 1-2 active agents additionally needed, be aware of rapid resistance development
T-20 Consider when uncertain that at least one other agent than raltegravir and maraviroc is active

NRTIs: Even if 3TC or FTC  are no longer effective according to the resistance test, it might make sense in many cases to continue treatment with them. In this way, HIV is forced to conserve the M184V mutation, which reduces the replication fitness (Eron 2004, Campbell 2005, Castagna 2006). Due to diverging resistance pathways, another consideration may be to use AZT and TDF. This also applies when patients have already been treated with these substances. By adding AZT, viral load can be decreased under detection level in the presence of resensitising K65R (Stephan 2010).

Recycling with ddI is also possible. In the Jaguar study, 168 patients with over 1000 copies/ml and a median of 4 NRTI mutations on stable ART additionally received ddI or placebo (Molina 2005). The decrease of viral load was 0.60 logs after 4 weeks although 68% of the patients had previously received ddI. Even with these patients, the viral load decreased by 0.48 logs. However, a more recent study questions improvement of salvage regimens containing at least three new drugs by the addition of NRTIs with reduced activity according to resistance tests (Imaz 2011).

NNRTIs: In the case of NNRTIs, with less than three NNRTI resistance mutations, etravirine seems to be a good option in combination with a boosted PI (most effective with darunavir/r). In other cases it is recommended to discontinue NNRTIs. There is little doubt that once generated, resistance remains. However, with pregnant women who have received nevirapine once for transmission prophylaxis there was no elevated rate of treatment failure on nevirapine-containing regimens if ART was initiated more than 6 months after delivery – at least theoretically, it seems possible for NNRTI resistances to disappear provided one waits a longer time (Lockman 2007). However, there is no other data on recycling NNRTIs besides those for transmission prophylaxis.

PIs: In the case of PIs, the boosted PIs darunavir and tipranavir are strongly recommended, which probably have distinct resistance profiles. When resistance findings are unclear, they should be discussed with the treating physician or the virologist. If darunavir/r and tipranavir/r are not available or if they are not tolerated, one can try lopinavir/r; other PIs are probably not suitable.

Raltegravir, maraviroc, T-20: If at least one other agent is still active, it seems sufficient to treat with only one of the new agents, either maraviroc or raltegravir, to reduce the viral load to below the limit of detection. That way, one could keep the option with the other drug that could be then combined with T-20 in the future. In the case of maraviroc, a recent tropism test should be available. If maraviroc or raltegravir are the only active agents according to the resistance test, they could and should be administered together. Fortunately, there is no relevant interaction (Baroncelli 2010). If maraviroc can not be used due to tropism, one should consider T-20.

It is also important to strategize. What comes after the current regimen, and what can you do if that fails? To what extent is the patient standing with his back against the wall, immunologically? How high is the risk of progression to AIDS? The lower the CD4 T cells and the higher the viral load the more active agents are required to control the virus. If CD4 T cells are very low, it may be better to put all stakes onto one option with as many active agents as possible (at least two), instead of saving up for future options.

Such complex decisions should be discussed in a team of experienced HIV-physicians with a virologist, who can shed some light onto the resistance situation. The treating physicians should be present as well, as they are familiar with the individual situation, know the patient’s adherence history and understand what can be expected from the patient.


Practical tips for salvage therapy

  • First question: what is the treatment history, what level of success was there and for how long? Perform resistance testing (not during treatment interruption).
  • Choose as many new active drugs as possible when changing therapy.
  • Do not add one new drug to a failing regimen. If the clinical and immunological situation allows, wait for a second active drug.
  • Do not wait too long to switch, thus giving the virus the opportunity to develop further mutations – the higher the viral load at the time of switch, the more difficult the chances for success.
  • Do not be too demanding from the patient! Not everyone is suitable for Mega-ART.
  • Patients should be treated in larger centers where new drugs and experience are available.
  • Encourage the patient. New treatments may become available soon. A “watch and wait” approach may be possible.
  • Do not allow reversion to wild-type virus – even a failing regimen should be continued in the absence of further options.

The following strategies were used with some success pre-2007. Today, after the introduction of new drugs, they have a minor role to play.

Double PI salvage regimens

Since the introduction of darunavir/r and tipranavir/r, double PI regimens have lost their standing in salvage therapy. They will briefly be discussed because some patients are still being treated with double PI regimens.

Lopinavir/r + saquinavir/r: in vitro they have synergetic effects (Molla 2002). In the LopSaq study, 128 treatment-experienced patients were treated for different reasons (resistance, toxicity) with a nuke-free combination consisting of lopinavir/r  plus saquinavir. At week 48, 61% had reached a viral load below 400 copies/ml. However, the response in patients with numerous PI resistance mutations and low CD4 counts was poor (Staszewski 2006, von Hentig 2007).

Atazanavir/r + saquinavir/r: PK parameters for saquinavir are significantly improved by atazanavir. Response in pretreated patients was good (von Hentig 2007, Winston 2007, Manosuthi 2008). Despite the fact that saquinavir levels are elevated by atazanavir, this combination must be given with ritonavir (Haas 2003, Johnson 2005). Given the poor results in treatment-naïve patients, this combination is unlikely to play any further role  (Landman 2008).Table 9.5 gives an overview of other double PI combinations.

Conclusion: There is no longer any reason to put a patient on a double PI. Simplifying therapy should be considered for patients on a double PI regimen. One newer study showed that patients with stable viral suppression on double PI can change to darunavir/r monotherapy without risk (Cohen 2009). This would also be saving costs as darunavir, albeit the most expensive PI, is still less expensive than two older PIs together.

Table 9.5. Double PI combinations with supporting data.
Combination Daily Dose/comment Source
More favorable
Lopinavir/r + saquinavir 800/200/2000 Staszewski 2006
Atazanavir/r + saquinavir 300/200/2000 von Hentig 2007
Saquinavir/r + fosamprenavir 2000/200/1400 Boffito 2004
Lopinavir/r + indinavir 800/200/1600 Staszewski 2003
Less favorable
Lopinavir/r + fosamprenavir Poor PK data Kashuba 2005
Lopinavir/r + atazanavir Poor activity Ulbricht 2008
Lopinavir/r + nelfinavir Poor PK data, diarrhea Klein 2003
Atazanavir + indinavir Elevated bilirubin Chisolm-Burns 2007
Atazanavir + fosamprenavir Poor activity Landman 2009
Atazanavir + saquinavir without /r Poor activity Johnson 2005
Tipranavir + LPV/APV/SQV Poor PK data Walmsley 2004
Indinavir + nelfinavir Relatively poor activity Riddler 2002

Mega-ART with T-20, treatment interruptions

Intensified treatment combinations with more than three drugs – often described as mega- or giga-ART – may indeed be effective. Only well-informed and highly motivated patients can be considered for mega-ART regimens, and such approaches are often unrealistic in clinical practice. There is some evidence from the small INTENSE study that, in some cases, induction with T-20 is of benefit (Clotet 2008).

So, do structured treatment interruptions (STI) before initiation of such intensified regimens provide additional benefit? The answer is clearly no. After some encouraging results from the early GIGHAART Study (Katlama 2004) there is an overwhelming amount of data showing that STIs do not have a positive effect in heavily pretreated patients. In the CPRC064 Study in which patients interrupted treatment for four months prior to going on a salvage regimen no differences were found between patients who took an STI and those who had not (Lawrence 2003). However, it was disconcerting to see that patients who interrupted treatment not only had worse CD4 counts but also had a significantly higher frequency of severe clinical events during the follow-up period. Other randomized studies did not find any virologic benefit by interrupting treatment prior to starting an intensified salvage regimen (Ruiz 2003, Beatty 2006, Benson 2006, Walmsley 2007, Holodiny 2011). This approach is no longer an option.

Utilizing NNRTI hypersusceptibility

Viral strains are considered “hypersusceptible” to certain drugs if the IC50 (50% inhibitory concentration) for the drug is lower than that of the wild-type in phenotypic resistance tests. NNRTI hypersusceptibility was first described in January 2000 (Whitcomb 2000). It generally occurs very rarely with NRTIs but quite frequently with NNRTIs, and mostly in viruses that have developed resistance mutations against NRTIs (Albrecht 2001, Haubrich 2002). In an analysis of more than 17,000 blood samples the prevalence of hypersusceptibility in NRTI-naïve patients to efavirenz and nevirapine was 9% and 11%, respectively. In NRTI-experienced patients, it was 26% and 21% (Whitcomb 2002). Studies show that NRTI mutations, predominantly at codons 215, 208 and 118, are independently associated with NNRTI hypersusceptibility (Shulman 2004, Clark 2006).

There seems to be some evidence that patients with NNRTI hypersusceptibility have better virologic response. Of 177 highly treatment-experienced (but NNRTI-naïve) patients, 29% exhibited this type of lowered IC50 for one or several NNRTIs (Haubrich 2002). Of the 109 patients who received a new NNRTI-containing regimen, those with NNRTI hypersusceptibility achieved better results. Viral load was significantly lower even after 12 months, and the CD4 T cell count was also higher. The replicative fitness, however, does not seem to be important here (Clark 2006). Even if the real significance and molecular correlate for NNRTI hypersusceptibility remain uncertain, the consequence is clear: patients with NRTI mutations and without NNRTI resistance should receive an NNRTI if possible.

Watch-and-wait or even simplifying ART

Sometimes even the most intensified salvage regimen is not effective. Viral load cannot be suppressed to undetectable levels. What should be done in these cases? The answer is to keep going as long as the patient can tolerate the therapy. Multi-drug resistant viruses are typically slightly less aggressive than wild-type, at least for a certain period of time. A drug such as 3TC also has a positive effect on the viral load even in the presence of a confirmed M184V resistance. In a small study, in which 6 patients with MDR virus stopped only 3TC, the viral load increased by 0.6 logs (Campbell 2005). An Italian study enrolled 50 patients with a viral load of at least 1000 copies/ml on a 3TC-containing regimen, with evidence of the M184V mutation and at least 500 CD4 T cells/µl (Castagna 2006, Gianotti 2008). Patients were randomized to completely interrupt treatment or to continue with 300 mg 3TC alone because the M184V mutation reduces the replicative fitness of HIV. Patients on 3TC indeed had a significantly lower increase in viral load (0.6 versus 1.2 logs) and lost significantly less CD4 T cells (73 versus 153/µl). The M184V mutation was maintained in all patients on 3TC, and no other mutations accumulated. In contrast, a shift to wild-type was observed in all patients without 3TC. The benefit was sustained until week 144 (Castagna 2007) when 3TC was continued on a daily basis. Regarding FTC, daily doses also seems to be effective, but not when given weekly (Soria 2010).

However, ART should not be stopped completely in very immunocompromised patients who are then at risk of developing opportunistic infections. In fact, all efforts should be made in such cases to at least partially control the virus. Waiting, even on a suboptimal regimen, is a strategy that can be used to gain valuable time until new drugs are available. In such cases, ART is not being taken in vain: suboptimal ART is better than none at all, and some suppression of viral load better than none. Patients benefit even with only a slight reduction in viral load (Deeks 2000). A trial of patients with at least 2500 copies/ml on ART who were randomized to interrupt or continue ART for at least 12 weeks showed an immunological benefit for those who remained on their regimen. CD4 T cells dropped only by 15, compared to 128 cells/µl in patients on an STI (Deeks 2001). In a large cohort study, CD4 T cell counts did not drop as long as the viral load remained below 10,000 copies/ml, or at least 1.5 logs below the individual set point (Lederberger 2004).

Table 9.6. Example of a successful watch-and-wait strategy for almost three years.
Date (HA)ART

CD4 T cells

Viral load

until 1997 AZT, AZT+ddC, AZT+ddI

40 (nadir)





Oct 97 d4T+3TC+SQV+NFV



Jun 98 d4T+3TC+NVP+IDV/r









Sep 02 d4T+ddI+3TC+NVP+LPV/r



Nov 02*



Jan 03



Feb 03 AZT+3TC+ABC



May 03



Dec 04 AZT+3TC+ABC+TDF**



Jan 06



*Resistance testing showed a total of 20 mutations, with genotypic resistance against all drugs tested. Compliance was very good and plasma levels were always adequate. **TDF was added because of chronic HBV infection. Note: the patient’s viral load has been below the limit of detection since April 2006, when he started AZT+3TC+TDF+TPV/r+RAL.

How intensively should treatment be continued? Which drugs can be discontinued in this watch-and-wait setting? Quadruple nukes seems to be safe, as indicated by a retrospective study (Llibre 2008). NNRTIs such as nevirapine or efavirenz can be stopped if resistance mutations are found, because replicative fitness is not influenced by NNRTI mutations (Piketty 2004). Moreover, accumulation of further resistance mutations should be avoided as these may compromise newer NNRTIs such as etravirine. The same is probably true for integrase inhibitors (Wirden 2009).

What about PIs? There is data from a small pilot study showing that PI discontinuation may be safe (Deeks 2005). 18 patients, in whom the viral load remained high despite more than 6 months on ART (good compliance, appropriate efficacy), had the PIs removed from their respective ART regimens while the NRTIs were continued. Within the first two weeks, none of the patients had an increase of more than 0.5 logs, and even after 16 weeks, no increase was observed in most patients (in only 5/18 patients was there an increase of between 0.5 and 1.0 logs; in the others there was no increase, maybe even a fall). A negative immunological effect was also seen in a few patients, but this was only moderate. Repeated resistance tests showed that all PI mutations persisted in all patients in the first 12 weeks, although PIs were not being taken. One retrospective study on HIV-infected children, in which the PIs had been discontinued, was based on the same idea as the Deeks Study. Here, it was also seen that on continuous NRTI therapy, there was no increase in viral load (LeGrand 2005). Another study, however, showed that PIs maintained activity (Opravil 2009).

Results from one of our own patients where this approach has been successful for almost three years are shown in Table 9.6. Resistance testing after two years showed that there were no changes in the MDR virus. Watch-and-wait on a simple NRTI regimen seems feasible in some patients for a limited period of time. The reasons for this phenomenon, however, are still not understood but it is possible that multiresistant viruses cannot easily mutate back. With PI therapy alone, this does not appear to be effective – in 5/5 patients, in whom only the nucleoside analog was stopped, viral load increased significantly (Deeks 2005). As total patient numbers are still very small in the data presented to date, many observers remain skeptical. The main question is how long and in which patients these strategies might be successful. It is thus advisable to monitor CD4 T cells at short intervals.


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