– Christian Hoffmann –
Changing a regimen that is successful but intolerable due to side effects is usually easy. The suspected drug is replaced with another drug of the same class. It becomes more difficult if alternate drugs are contraindicated because of potential toxicity or if resistance mutations to these drugs are suspected. In such cases, changes need to be individualized.
This is particularly true in those subjects with a treatment history of 10 or 15 years, who probably harbor multiresistant viruses. Even physicians with lots of experience in treatment should discuss these complex individual cases with their colleagues. In many large centers, so called weekly ART meetings have been established. At these meetings, both virologists (to translate resistance testing) and clinicians (with personal experience of the individual patient’s situation) can discuss these complex cases.
This chapter discusses two important reasons for switching where certain principles should apply: changing due to virologic failure, and changing to simplify the regimen. Switching due to possible side effects has been discussed in previous chapters.
Switching due to virologic failure
The same principles apply as when initiating therapy: compliance, dosing issues, concurrent diseases, co-medications and drug interactions. It is also essential to consider treatment history and possible existing resistance mutations. Although desirable before any change in treatment, resistance tests in cases of virologic failure are not always practical. It is therefore useful to become familiar with the most important resistance mutations, particularly for nucleoside analogs:
|Table 8.1. Expected resistance mutations with different nuke backbones.|
|Failing nuke backbone||Mutations|
|AZT/d4T+3TCAZT+3TC+ABC||M184V and then successive TAMs, the longer one waits|
|TDF+3TC/FTC||K65R and/or M184V|
|ABC+3TC||L74V, less frequently K65R and/or M184V|
|AZT/d4T+ddI||TAMs, Q151M, T69ins|
The basic principles for changing therapy in cases of virologic failure apply: the faster the change, the better; the virus should be given as little time as possible to generate more resistance mutations. Resistance patterns become more complex the longer one waits (Wallis 2010). In addition, the more drugs that are changed, the higher the likelihood of success for the new regimen.
The situation with NNRTIs is more straightforward. There is usually complete cross-resistance. Continuation in the presence of these resistance mutations is of no use as they have no impact on the replicative fitness of the virus. Moreover, accumulation of further resistance mutations may compromise the efficacy of second generation NNRTIs such as etravirine. The NNRTI should be stopped as soon as possible if there is evidence of resistance.
There are also relevant cross-resistance mutations for PIs. For switching and sequencing PIs refer to the salvage section of the next chapter. Table 8.2 provides a rough guide on how to proceed without knowledge of resistance mutations. One must note that data is not sufficiently available for all options. On account of the promising monotherapy studies with lopinavir/r and darunavir/r, which usually are sufficient on their own, the regimen need not be totally changed in cases of limited resistance mutations and accordingly rapid switch to these boosted PIs. One study showed that if the frequent NRTI mutation M184V is detected alone, cytidine analogs 3TC or FTC can be continued, provided a boosted PI is initiated. The effect of the boosted PI is enough to achieve virlogical success – 3TC seems to be able to conserve M184V that in turn lowers viral fitness (Hull 2009). Presently there are ideas about developing a fixed combination of a boosted PI and 3TC.
Table 8.2. Changing first-line therapy without knowledge of resistance mutations*.
|Failing initial therapy||Potentially successful change|
|3 NRTI||Instead of 3rd NRTI one PI/r (rapid switch) or 1-2 new NRTIs plus NNRTI or RAL|
|2 NRTI + NNRTI||Instead of NNRTI, one PI/r (rapid switch) or 1-2 new NRTIs plus RAL or MVC*|
|2 NRTI+ 1 PI/r||1-2 new NRTIs plus NNRTI plus new PI/r or RAL or MVC**|
*In individual cases, other modifications or simply waiting may be advisable. All PIs should be boosted = PI/r. ** Maraviroc only with tropism test. For complex cases, see the chapter on Salvage Therapy.
In some cases of virologic failure, the addition of one agent alone can make sense. Whether this applies to abacavir is being discussed. In contrast to a placebo-controlled study (Katlama 2001), in clinical practice there was no sustained virologic effect with the addition of abacavir alone to a failing regimen (Cabrera 2004). Addition of tenofovir also seems possible in certain cases (Khanlou 2005, Schooley 2002). Our experience with this approach has been good in cases with minimal increases in the viral load (up to 500 copies/ml) and in the absence of TAMs.
In patients who have been treated exclusively (and over a prolonged period) with NNRTIs, the above strategy has mostly not been successful. Extensive resistance mutations usually exist and a complete change of ART is necessary. In all patients previously treated with NRTIs or NNRTIs over a longer period, a boosted PI must be used. In the presence of a failing PI regimen, a new NNRTI alone is often not sufficient (Abgrall 2007, Khaykin 2008). With respect to resistance mutations and prior ART exposure, the addition of a new drug such as raltegravir and maraviroc should be considered. For complex resistance situations see the next chapter.
Simplification – do maintenance therapies work?
Can HIV infection be treated in a similar fashion to microbacterias, with a sequence of intense induction therapy followed by less toxic (and less expensive) maintenance therapy? The idea is appealing, and has circulated almost since the existence of combination ART. Between 1998 and 2003, the answer was clearly that maintenance therapies do not work. Three randomized studies (Trilège, ADAM, ACTG 343) destroyed any hope that ART might be reduced to two or even one drug. By today’s standards, one could object that outdated substances, such as saquinavir, indinavir or nelfinavir were used (Havlir 1998, Reijers 1998, Flander 2002).
In the last few years, better drugs have been licensed. In particular, lopinavir and darunavir with high resistance barriers cast a different light on the negative image of maintenance therapies. Randomized studies already exist for lopinavir/r and darunavir/r, but other boosted PIs have also been investigated as PI/r monotherapy (see Table 8.3).
The studies show that in most cases virologic suppression remains when simplifying to a PI/r monotherapy. In the OK04 study with lopinavir/r, a reduction of lipoatrophy rates was achieved. The observation period has now been extended to four years (Cameron 2007, Pulido 2008). However, some patients on lopinavir/r show low levels of viremia, especially in combination with low CD4 T cells and as expected, they show poor compliance (Campo 2007, Pulido 2008, Gutman 2010). The same was observed with therapy-naïve patients (see above).
For darunavir, the results of two large randomized studies MONET and MONOI with identical design are published (Katlama 2010, Arribas 2010). In MONET, non-inferiority of the monotherapy could not completely be shown after 96 weeks, at least regarding primary endpoints. 81% of patients were below detection in the standard-arm at week 96, compared to 75% in this on darunavir monotherapy. When virologically successful therapies were not evaluated as a failure, a difference was not observed. The results can be explained by a possibly low adherence in the mono-arm (with significantly more HCV-coinfected patients). In MONOI, lipoatrophy improved (Valantin 2010). At week 48, no significant difference in efficacy was found. However, there were isolated cases of virologic failure. At week 96, transient viremia was more frequent on monotherapy and a permanent control under 50 copies/ml without blips was observed in 59% versus 70% of patients (Valantin 2011). Darunavir resistance mutations were not observed either in MONET or in MONOI. Possibly, darunavir levels are lower without NRTIs (Garvey 2010).
Less data is available for other PIs. For atazanavir/r there is a one-arm pilot study, in which the agent showed weak results in monotherapy. Another pilot study on atazanavir/r was prematurely interrupted after virologic failure occurred in 5/15 patients (Karlstrom 2006). The Ataritmo study observed an elevated viral load in cerebrospinal fluid within some patients on atazanavir with otherwise well suppressed viral loads. In the OREY study, 9/63 patients developed virlological failure (Pulido 2009). There is also a pilot study for saquinavir (Patricia 2010).
Conclusion: Monotherapies with boosted PIs such as lopinavir/r and darunavir/r are slightly less effective than classic therapies. Often lower viremia without resistances appears that disappears upon intensification. Risk factors for a failure of monotherapy are poor compliance and low CD4 T cell nadir. Monotherapies as a theoretical strategy can not be justified at this time. In some individual cases, however, they can reduce adverse events.
Table 8.3. Newer studies on maintenance therapies (PI/r monotherapy).
|Less than 50 copies/ml?|
|Nunes 2009 (KalMo)||
|LPV/r versus 2 NRTIs+LPV/r||
|80% vs 87% (ITT, VL < 80)|
|Campo 2009 (M03-613)||
|LPV/r versus CBV+EFV||
|60% vs 63% (ITT), but low-level viremia more frequently|
|Pulido 2008 (OK04 Study)||
|85% vs 90% (ITT), Non-inferiority shown, but more frequent low level viremia|
|LPV/r vs ART-continuation||
|84 vs 88% (ITT), Non-inferiority not shown, more frequent low viremia|
|LPV/r vs ART-continuation||
|21% VF on Mono. Especially those with low CD4-Nadir, study discontinued.|
|DRV/r versus 2 NRTIs+DRV/r||
|84% vs 85% (ITT), Non-inferiority shown
|DRV/r versus 2 NRTIs+DRV/r||
|VF 0 vs 3%, Non-inferiority shown|
|92%, 1 discontinuation, no failure|
|94%, 1 case of VF|
|VF 33%, study discontinued prematurely|
|Vernazza 2007 (ATARITMO)||
|92%, no resistance or VF|
|Wilkin 2009 (ACTG 5201)||
|88%, no resistance|
|79% under 400 copies/ml, however at least 14% VF|
All patients had less than 50 (75) copies/ml for at least six months. VF = Virologic failure,ITT = Intention-to-treat
Switching to simplify – triple-nukes revisited
Triple nuke therapy, though now fairly obsolete for first-line therapy, may be justifiable for maintenance therapy. Several randomized studies have not detected any virologic disadvantage (Katlama 2003, Bonjoch 2005, Markowitz 2005, Sprengler 2010).
In the ESS40013 Study, a total of 448 patients were treated with AZT+3TC+ABC plus efavirenz. After 36 or 44 weeks, 282 patients with undetectable viral load were randomized to continue with the same therapy or to stop efavirenz. After 96 weeks, 79% versus 77% of patients were still below 50 copies/ml, proving that triple nuke was not inferior (Markowitz 2005). In a Spanish study, 134 patients with an undetectable viral load for at least 24 weeks were randomized to receive either Trizivir® or Combivir® plus nevirapine (Bonjoch 2005). At 48 weeks, the percentage of patients with an undetectable viral load was comparable across arms (71% versus 73%, ITT). Similar results were also seen in the TRIZAL and FREE study, in which 209 patients were randomized (Katlama 2003, Sprenger 2010). In the Swiss Cohort, the failure rate was low in 495 patients with suppressed viral load and switch to Trizivir®. Patients with earlier exposure to mono- or dual-NRTI therapy, low CD4 T cell count at time of switch, or AIDS were at increased risk of treatment failure, limiting the use of Trizivir® in these patient groups (Wolbers 2007). Some long-term data for the quadruple nuke strategy with Trizivir® plus tenofovir (d’Ettore 2007, Llibre 2008) also exist.
The approach taken in the French COOL Study failed. In this trial, 140 patients were randomized to TDF+3TC+efavirenz or TDF+efavirenz for 48 weeks. Inclusion criterion was ART with a viral load below 50 copies/ml for at least three months; patients with prior treatment failure were excluded. There were no restrictions on CD4 T cell counts. An analysis showed a significantly worse outcome for patients on the dual therapy. Moreover, there were no differences in the toxicity rates between arms. Thus, 3TC seems to be important in maintaining viral suppression. Its discontinuation, however, has no effect on tolerability (Girard 2006).
Maintenance therapy using Trizivir® seems feasible. However, the benefit remains questionable. Three or four NRTIs are possibly more toxic than other strategies. Strategies such as monotherapy with boosted PIs are not yet justifiable outside clinical trials.
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