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Change due to virological 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 are not always practical. It is therefore useful to become familiar with the most important resistance mutations, particularly for nucleoside analogs (see Table 8.1). The basic principles for changing therapy in cases of virological failure apply: the faster the change, the better; the virus should be given as little time as possible to generate more resistance mutations. In addition: the more drugs that are changed, the higher the likelihood of success for the new regimen. Table 8.1: Expected resistance mutations with different nuke backbones Failing nuke backbone Mutations AZT/d4T+3TC AZT+3TC+ABC M184V and then successive TAMs, the longer one waits TDF+3TC/FTC K65R and/or M184V ABC+3TC L74V > K65R and/or M184V AZT/d4T+ddI TAMs, Q151M, T69ins TDF+ABC/ddI K65R 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. There are also relevant cross-resistance mutations for PIs. Resistance testing is therefore recommended here. At the latest after the second PI, the area of salvage begins, which is discussed in more detail in the next chapter. Table 8.2 provides a rough guide on how to proceed without knowledge of resistance mutations. Table 8.2: Changing first-line therapy without knowledge of resistance mutations* Failing initial therapy Potentially successful change 3 Nukes 2 new nukes plus NNRTI or PI 2 new nukes plus NNRTI plus PI possibly also: with high viral load 2 Nukes + 1 NNRTI 2 new nukes plus PI PI + NNRTI 2 nukes + PI 2 Nukes + 1 PI 2 new nukes plus NNRTI plus possibly new boosted PI, or boost present PI, if this was not already the case * Note: there is insufficient data available on all these changes. In individual cases, other modifications or simply waiting may be advisable. Apart from nelfinavir, all PIs should be boosted. If the increase in viral load is minimal, treatment success may also be achieved with simple changes - if one acts quickly. In the case of two NRTIs plus an NNRTI, for example, treatment may possibly be intensified simply by the addition of abacavir (Degen 2000, Katlama 2001 Rozenbaum 2001). In a placebo-controlled study, 41 % of patients on stable ART with a viral load between 400 and 5,000 copies/ml achieved a viral load below 400 copies/ml at 48 weeks after addition of abacavir alone (Katlama 2001). Such results could possibly be even better with "more rigorous" entry levels (for example, not waiting to change therapy until 5,000 copies/ml are reached, but acting already at 500 copies/ml). Addition of tenofovir also seems possible in certain cases (Khanlou 2005). Tenofovir reduced the viral load under stable HAART by 0.62 log (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 nukes, this strategy is not promising. Extensive resistance mutations usually exist, so that a complete change of HAART is necessary. At least two randomized studies (some blinded) have shown that most benefit is achieved by switching to an NNRTI plus a PI plus at least one new NRTI. This has been shown for both nelfinavir plus efavirenz and indinavir plus efavirenz (Albrecht 2001, Haas 2001). In patients previously treated with NRTIs or NNRTIs, a boosted PI must be used. Change to simplify - do "maintenance therapies" work? Can HIV infection be treated in a similar fashion to some hematological diseases or tuberculosis, with a sequence of intense induction therapy, which is then followed by less toxic (and less expensive) maintenance therapy? The idea is appealing, and has circulated almost since the beginning of HAART. Before 2003, the answer was clearly that maintenance therapies did not work. By 1998, three randomized studies (Trilège, ADAM, ACTG 343) had already destroyed all hope that HAART might be reduced to two or even one drug. In the French Trilège Trial, 279 patients adequately treated with HAART were randomized to three arms of different intensity (Pialoux 1998, Flander 2002). At 18 months, the viral load had increased to above 500 copies/ml in 83 patients - 10 on AZT+3TC+indinavir, but 46 on AZT+3TC and 27 on AZT+indinavir. However, temporary dual therapy had no negative consequences, and resistance did not develop (Descamps 2000). In the ADAM Trial (Reijers 1998), patients who had been treated with d4T+3TC plus saquinavir+nelfinavir for several months either stopped or continued their nucleoside analogs. The study was already doomed at interim analysis: in 9/14 (64 %) patients, simplifying therapy already had a detectable viral load at 12 weeks, versus 1/11 (9 %) of those continuing on the previous regimen. The third study, finally led to the end of the notion of maintenance therapy was ACTG 343. 316 patients, with a viral load below 200 copies/ml for at least two years, either continued to take AZT+3TC+indinavir or a simplified regimen of AZT+3TC or indinavir. The failure rate (viral load above 200 copies/ml) was 23 % versus 4 % on continued therapy (Havlir 1998). In the last few years, newer better drugs have been licensed. In particular, lopinavir with its antiviral potency and concurrent high resistance barrier casts the negative image of maintenance therapies in a different light. Other boosted PIs have also been tried, and several smaller studies on the simplification of therapy have been conducted with "PI/r monotherapy" (see Table 8.3). Table 8.3: Newer studies on changing to "maintenance therapies" Source n "Maintenance" Week Less than 50 copies? LPV/r-mono Arribas 2005 (OK04 Study) 198 LPV/r versus 2 NRTIs+LPV/r 48 81 versus 95 % (ITT). Failure mainly due to poor adherence Delfraissy 2006 (MONARK) 136 LPV/r versus CBV+EFV 48 71 versus 75 % (ITT), 84 versus 98 % (OT), lower viremia in mono-arm Cameron 2006 (M03-613) 155 LPV/r versus CBV+EFV 24 50 versus 61 % (ITT), lower viremia in mono-arm Nunez 2006 (KalMo) 60 LPV/r versus 2 NRTIs+LPV/r 48 83 versus 87 % (ITT, VL<80) Other "mono" Kahlert 2004 12 IDV/r 48 92 %, 1 dropout, no failure Vernazza 2006 (ATARITMO) 28 ATV/r 24 92 %, no resistance or failure Swindells 2006 (ACTG 5201) 34 ATV/r 24 91 %, no resistance Karlstrom 2006 15 ATV/r 16 33 % treatment failure, study interrupted Other Girard 2006 (COOL Trial) 143 EFV+TDF versus EFV+3TC+TDF 24 82 versus 97 % OT = on treatment; ITT = intention to treat They show that in most cases virological suppression is maintained when there is a switch to PI/r monotherapy. In one study with lopinavir/r, lipoatrophy was even reduced (Cameron 2007). Resistances seldom occurred (Arribas 2007). However, in a few patients, low viremia was observed, especially with low CD4-cell counts or, not unexpectedly with reduced compliance (Campo 2007). Overall, monotherapy with lopinavir/r seems to be somewhat less potent than the earlier triple combinations. There is much less data available for the other PIs than there is for lopinavir/r. A pilot study with atazanavir was interrupted after 5/15 patients demonstrated virological failure (Karlstrom 2006). In the Prometheus Study, PI- and d4T-naïve (including some completely treatment-naïve) patients were randomized to a regimen of saquinavir/r plus/minus d4T. After 48 weeks, 88 versus 91 % of patients in the on-treatment analysis were below 400 copies/ml. However, patients with high viral loads were not stable on this treatment (Gisolf 2000). In the French COOL Study, 143 patients were randomized to TDF+3TC+efavirenz or TDF+efavirenz for 48 weeks. Inclusion criterion was HAART 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 counts. A recently presented appraisal showed a significantly poorer response under double- compared to triple-therapy. It was also important that there was no difference in the toxicity in both arms - the additional administration of 3TC obviously had a very important effect on viral suppression, but did not increase the frequency of side effects (Girard 2006). Conversion in order to simplify - triple nuke revisited Triple nuke therapy, though now fairly obsolete for first-line therapy (see "Which HAART to start with"), may be an option for maintenance therapy. At least three randomized studies could not detect any virological disadvantage (Katlama 2003, Bonjoch 2005, Markowitz 2005). In the ESS40013 Study, 448 patients were treated with AZT+3TC+ABC plus efavirenz. After 36 or 44 weeks, 282 patients with undetectable viral load at this time 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). After 48 weeks, the viral load in both arms often remained undetectable (71 versus 73 % in the ITT analysis). Similar results were also seen in the TRIZAL study, in which 209 patients were randomized (Katlama 2003). References on changing and simplifying therapy 1. Albrecht MA, Bosch RJ, Hammer SM, et al. Nelfinavir, efavirenz, or both after the failure of nucleoside treatment of HIV infection. N Engl J Med 2001, 345:398-407. http://amedeo.com/lit.php?id=11496850 2. Arranz Caso JA, Lopez JC, Santos I, et al. A randomized controlled trial investigating the efficacy and safety of switching from a protease inhibitor to nevirapine in patients with undetectable viral load. HIV Med 2005, 6:353-9. http://amedeo.com/lit.php?id=16156884 3. Arribas JR, Pulido F, Delgado R, et al. Lopinavir/ritonavir as single-drug therapy for maintenance of HIV-1 viral suppression: 48-week results of a randomized, controlled, open-label, proof-of-concept pilot clinical trial (OK Study). J AIDS 2005, 40:280-7. http://amedeo.com/lit.php?id=16249701 4. Arribas J, Pulido F, Delgado R, et al. Drug resistance outcomes at 48 weeks in the OK04 trial: a comparative trial of single-drug maintenance therapy with lopinavir/ritonavir vs triple therapy with LPV/r. Abstract 638, 14th CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/28387.htm 5. Barreiro P, Soriano V, Blanco F, et al. 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Cameron W, da Silva B, Arribas J, et al. A two-year randomized controlled clinical trial in antiretroviral-naive subjects using lopinavir/ritonavir (LPV/r) monotherapy after initial induction treatment compared to an efavirenz (EFV) 3-drug regimen (Study M03-613). Abstract THLB0201.XVI IAC 2006, Toronto. 10. Cameron DW, da Silva B, Arribas J, et al. Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction followed by LPV/r monotherapy compared with EFV + ZDV/3TC. Abstract 44, 14th CROI 2007, Los Angeles. Abstract. http://www.retroconference.org/2007/Abstracts/30523.htm 11. Campo R, da Silva B, Cotte L, et al. Predictors of loss of virologic response in subjects who deintensified to lopinavir/ritonavir monotherapy after achieving plasma HIV-1 RNA <50 copies/ml on LPV/r plus zidovudine/lamivudine. Abstract 514, 14th CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/29790.htm 12. 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