More? HIV Medicine 2007, Chapter 5.9: Download

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Nevertheless, there are many problems. Salvage studies are becoming increasingly more difficult as patients with MDR viruses are becoming less frequent (Lohse 2005). Homogenous patient populations are scarce as each one has an individual history of therapy, a different distribution of resistances and therefore varying prerequisites. In large HIV centers, often more than 50 different combinations are used. This makes it difficult to test new salvage substances in Phase II/III trials. It is also hard to find the correct study design: as the single use of an experimental drug in a failing regimen is ethically questionable, the appropriate 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 too 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. Background First: it should not be forgotten that patients with MDR viruses, who often have a long therapeutic history, and who now presumably find themselves once again on a precipice, need encouragement. It is important not to deny anyone hope. Although some studies have shown that patients with MDR viruses have a worse prognosis than patients without resistances (Hogg 2005, Zaccarelli 2005), data are not unequivocal. In the GART Study, the risk of progression for patients with more than six resistance mutations was not increased in contrast to patients with less than twomutations, (Lucas 2004). Despite MDR viruses, the risk of developing AIDS with good CD4-cell counts is relatively small (Ledergerber 2004). MDR viruses have a weaker ability to replicate and are probably less aggressive (Prado 2005). Furthermore, progress is continuing. New classes of drugs will arrive. So, for MDR, simply - be patient! Until then, one should accept that even today there are patients in whom one has to say goodbye to the primary aim of therapy of reducing the viral load to undetectable levels - especially if despite better compliance the only response to intensification of therapy is more side effects. Sometimes it is better to step back and wait for new options (see below). If possible, these patients should be managed in large centers, in which the new possibilities are usually available sooner, and where there is more experience with complex salvage regimens. A single new medication should ideally not be used alone - use as many effective substances as possible! It usually takes years to progress from virological to immunological, and finally to clinical treatment failure (see also "Principles of Therapy"). It is, however, important that patients with MDR viruses are very carefully observed and undergo regular (monthly) full body examination - something that is often neglected today in the long discussions about blood values and resistance testing for many HIV patients. Loss of weight, B-symptoms, oral candidiasis, OHL, and cognitive worsening are early signs of disease progression that should not be missed. The following is a discussion about a few salvage therapy strategies, which when used alone or in combination, are promising. · Salvage with lopinavir/r, tipranavir/r, darunavir/r and T-20 · Double PI regimens · Mega-HAART, with or without treatment interruptions · Utilizing NNRTI "hypersusceptibility" · Salvage through recycling · Just waiting, and even simplifying ART · Experimental salvage drugs Salvage with lopinavir/r, tipranavir/r, darunavir/r and T-20 The three boosted PIs lopinavir (Kaletra™), tipranavir (Aptivus™) and darunavir (Prezista™) have significantly improved salvage therapy. The resistance barriers are high, so that the response rates, even in the presence of multiple PI resistance is often still good. Although the occurrence of dyslipidemia is sometimes disturbing, the three substances should be considered following failure of the first PI. Lopinavir/r: was, in 2001, the first important salvage drug. At least 5-7 mutations are necessary for failure of lopinavir/r (Kempf 2001, Masquelier 2002). In 70 patients on a failing PI regimen, the viral load fell by 1.4 logs after two weeks following the substitution of the PI with lopinavir/r (Benson 2002). However, two large studies have shown that the virological effect on PI-resistant viruses is only marginally better than other boosted PIs such as atazanavir/r and fosamprenavir/r - a difference could only, if at all, be seen when multiple PI resistances were present (Elston 2004, Johnson 2006). Table 9.1: Patient example of the success of lopinavir/r in salvage therapy Date (HA)ART CD4+ T-cells Viral load Mar 1993 AZT (later +ddC) 320 N/A May 1996 AZT+3TC+SQV 97 N/A Feb 1997 d4T+3TC+IDV 198 126,500 Aug 1997 d4T+3TC+NFV 165 39,500 Mar 1998 d4T+ddI+SQV/RTV+HU 262 166,000 Sep 1998 238 44,000 Jul 2000 AZT+3TC+NVP+LPV/r 210 186,000 Oct 2000 385 < 50 Oct 2004 569 < 50 Note the insufficient responses to new regimens after failure of the first PI; insufficient viral suppression over two years with surprisingly stable CD4-cell levels; and finally a durable response to lopinavir/r - after more than four years of suboptimal PI-treatment! NNRTI hypersusceptibility may have possibly been present in this case (see below). On switching to lopinavir/r, genotypic and phenotypic resistance to various NRTIs and PIs were present. Tipranavir/r: In the RESIST studies, 1,483 intensively pre-treated patients with optimized therapy received either tipranavir/r or a boosted comparison PI (Hicks 2006). The patients had a viral load of more than 1,000 copies/ml and at least one primary PI mutation. After 48 weeks, tipranavir was immunologically and virologically superior to the comparison PI. However, the difference actually also occurred because some patients had already been pre-treated with lopinavir/r - when this was not the case, there was no longer a significant benefit. In other words, if lopinavir/r is still effective, tipranavir/r is not much better, but when the lopinavir/r card has been played, it can still be effective. Darunavir/r: two large Phase IIb studies, POWER-1 and -2, led to the licensing in the USA in 2006. Almost 600 intensively pre-treated patients were included. In the 600 mg group (600/100 darunavir/ritonavir bid) the viral load in 46 % remained at less than 50 copies/ml after 48 weeks (Lazzarin 2006) - a significantly better result than the control PI (10 %), and a result that had so far never been seen in a patient group with extremely limited options. The effect of darunavir is of course not limitless. A total of 11 resistance mutations have been identified; above 3 mutations, the efficacy decreases significantly (DeMeyer 2006). All three PIs are more successful, the greater the number of additional active substances available. In the RESIST- and POWER-studies, the proportion of patients, who had a viral load below the level of detection increased when T-20 was given in addition to tipranavir or darunavir (Lazzarin 2006, Hicks 2006). If tipranavir or darunavir are being considered, T-20 should therefore always be contemplated, too. Double PI salvage regimens Not only lopinavir but also other PIs can be boosted with low doses of ritonavir. With the introduction of new substances, these double PI strategies have lost some of their standing. They do, however, need to be briefly discussed as etravirin, maraviroc or raltegravir are not available everywhere. Lopinavir/r + saquinavir/r: in vitro they have synergistic effects (Molla 2002). There do not seem to be any unfavorable interactions (Ribera 2004). In the LopSaq Study, for various reasons (resistance, toxicity), 128 intensively pre-treated patients received a nuke-free combination consisting of lopinavir/r (400/100 mg bid) plus saquinavir (1,000 mg bid). At week 48, 61 % had achieved a viral load of less than 40 copies/ml. However, the response in the presence of numerous PI resistance mutations and low CD4 counts was poor (Staszewski 2006). Atazanavir/r + saquinavir/r: under 300 mg atazanavir, 100 mg ritonavir and 1,600 mg saquinavir, not only the trough levels, but also the intracellular levels of saquinavir increase significantly (Boffito 2004, Ford 2006). In the ATSAQ study (Rottmann 2004), 40 heavily treatment-experienced patients were treated with a nuke-free combination of 300 mg atazanavir, 100 mg ritonavir and 2 x 1,000 mg saquinavir. After 32 weeks, 85 % had reached a viral load below 400 copies/ml. Three further studies are currently underway. Despite the fact that saquinavir levels are elevated by atazanavir, ritonavir is also required. The unboosted combination is relatively weak (Haas 2003, Johnson 2005). Saquinavir/r + fosamprenavir: was one of the first PI combinations (Eron 2001) and is still interesting due to its partially overlapping resistance profile. Fosamprenavir reduces saquinavir levels somewhat, but this is compensated by the administration of 200 mg ritonavir bid (Boffito 2004). Lopinavir/r + indinavir: in vitro, there is synergy. The combination has been tested in different doses (Staszewski 2003, Isaac 2004). But, in view of the considerable tolerability and the improved salvage options available today, indinavir is rarely used. . However the data is not completely clear-cut, and case numbers are fairly low. An additional ritonavir dose is possibly necessary, and TDM is recommended. Indinavir and lopinavir do not usually seem to require dose adjustment. Other double PI combinations: initial pilot studies have shown that advantageous interactions seem to exist between atazanavir and fosamprenavir (Zilly 2005, Khanlou 2006). This also applies to lopinavir + atazanavir (Langmann 2005), a combination that is currently under investigation in the LORAN study. Unfavorable double PI combinations: atazanavir + indinavir should be avoided as both drugs cause hyperbilirubinemia. Severe diarrhea is to be expected when combining lopinavir/r + nelfinavir, and the lopinavir levels also decrease (Klein 2003). Indinavir + nelfinavir have relatively weak activity (Riddler 2003). Unfavorable interactions exist between tipranavir and other PIs. The levels of lopinavir, saquinavir and amprenavir are reduced (Walmsley 2004). Even the combination of lopinavir/r + fosamprenavir, which has a very promising resistance profile, cannot be considered because of the unfavorable PK data - possibly the plasma levels of both drugs are significantly reduced through a complex interaction (Mauss 2002, Kashuba 2005). It should be noted that increasing the dose of ritonavir does not change anything (Mauss 2004, Taburet 2004). Double PI combinations are not routine treatments. They should only be considered in salvage patients who are suffering from NRTI side effects (mitochondrial toxicity), and should be administered by experienced clinicians with access to therapeutic drug monitoring, so that dose adjustment is possible if required. Table 9.2: Double PI combinations with sufficient supporting data Combination Daily Dose/comment Source More favorable Lopinavir/r + saquinavir 800/200/2,000 Staszewski 2006 Atazanavir/r + saquinavir 300/200/2,000 Boffito 2004 + 2006 Lopinavir/r + atazanavir 800/200/300 Langmann 2005 Saquinavir/r + fosamprenavir 2,000/200/1,400 bid Boffito 2004 Lopinavir/r + indinavir 800/200/1,600 bid Staszewski 2003 Less favorable Lopinavir/r + fosamprenavir Poor PK data Kashuba 2005 Atazanavir + saquinavir Poor activity Johnson 2005 Tipranavir + LPV/APV/SQV Poor PK data Walmsley 2004 Lopinavir/r + nelfinavir Poor PK data, diarrhea Klein 2003 Atazanavir + indinavir Elevated bilirubin Indinavir + nelfinavir Relatively poor activity Riddler 2002 Mega-HAART with and without treatment interruptions Intensified treatment combinations with five or more drugs - described as "mega"- or "giga"-HAART - may indeed be effective. However, only well-informed and motivated patients can be considered for mega-HAART regimens. Potential drug interactions are often difficult to predict. Nevertheless, mega-HAART will become less important with the introduction of new drugs and new drug classes. So, do treatment interruptions produce any effect? In the GIGHAART Study, 68 heavily treatment-experienced patients were randomly allocated to eight weeks of treatment interruption or not (Katlama 2004). All patients were subsequently switched to a combination of 7-8 drugs: 3-4 NRTIs, hydroxyurea, 1 NNRTI and 3 PIs. In the treatment interruption group, efficacy after 24 weeks was significantly better, and viral load dropped by 1.08 versus 0.29 logs. The helper cells also increased significantly. These effects were still visible after 48 weeks, although less marked. However, the results of the GIGHAART Study have not remained uncontradicted, and these days, there are a greater number of studies that have found treatment interruptions to have unfavorable effects. In CPRC064, in which treatment was interrupted for four months prior to the salvage regimen, no differences were found between patients with or without a treatment interruption (Lawrence 2003). However, it was disconcerting to see that patients who interrupted treatment not only had worse CD4-cell counts, but also a higher frequency of severe clinical events. Other randomized studies did not find any virological benefit in interrupting treatment prior to a salvage regimen (Haubrich 2003, Ruiz 2003, Beatty 2006, Benson 2006), so that this strategy cannot be recommended at present (see "Treatment interruptions"). Utilizing NNRTI "hypersusceptibility" Treatment-experienced but NNRTI-naïve patients often still respond surprisingly well to NNRTIs. In 56 patients in a small, randomized study, the proportion of patients with less than 200 copies/ml after 36 weeks increased from 22 to 52 %, as long as two new NRTIs and nelfinavir were given in addition to nevirapine (Jensen-Fangel 2001). In ACTG 359, delavirdine increased the virological response rate to a new PI from 18 to 40 % (Gulick 2002). "NNRTI hypersusceptibility" may be responsible for this. Viral strains, in which the IC50 (50 % inhibitory concentration) is lower than that of the wild-type in phenotypic resistance tests, are considered "hypersusceptible". This phenomenon, which was first described in January 2000 (Whitcomb 2000), and for which the biochemical correlate is still the subject of debate (Delgrado 2005), very rarely occurs with NRTIs, but quite frequently with NNRTIs - in particular in viruses that have developed resistance mutations against NRTIs. NRTI hypersusceptibility has been described in several prospective studies (Albrecht 2001, Haubrich 2002, Katzenstein 2002, Mellors 2002). In an analysis of more than 17,000 blood samples, the prevalence in NRTI-naïve patients to, efavirenz and nevirapine was 9 and 11 %; in NRTI-experienced patients, it was notably 26 and 21 % (Whitcomb 2002). In particular, mutations on the codons 215, 208, and 118 are associated with NRTI hypersusceptibility (Schulman 2004). There is some evidence that patients with NNRTI hypersusceptibility have better responses to treatment. Of 177 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 NNRTI-containing regimen, the viral load in NNRTI hypersusceptibility was significantly lower after 12 months, and the CD4-cell count was much higher. The replicative fitness does not seem to be important here (Schulman 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 always receive a NNRTI in their new regimen if at all possible. Salvage through recycling of older drugs One can occasionally also make use of drugs that have already been used in the past as, for example, in the Jaguar Study (Molina 2003). 168 patients with more than 1,000 copies/ml and a median 4 NRTI mutations on stable HAART received either ddI or placebo. The viral load was reduced by 0.60 logs after 4 weeks. 68 % of patients had previously received ddI, and even in these patients, viral load was still reduced by 0.48 logs. New salvage therapies should not only contain as many new active substances as possible, but should also contain drugs that force the virus to preserve the resistance mutations, which at the same time inhibits the replicative fitness. Thus, it may be reasonable to conserving the M184V mutation by continuing with 3TC or FTC (see below and section on resistances). "Watch and wait" or even simplifying ART Sometimes even the most intensified salvage protocol is not effective. Despite the use of T-20, darunavir and other antiretroviral drugs, viral load cannot be suppressed to undetectable levels. What should be done with such patients? The answer is: keep going, as long as the patient tolerates therapy! Multidrug-resistant viruses are typically slightly less aggressive than the wild-type, at least for a certain period of time. Therefore, 3TC for example still 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 viruses stopped only 3TC, the viral load increased 0.6 logs (Campbell 2005). For this reason, very immunocompromised patients who are at risk of developing opportunistic infections should not stop HAART completely. In fact, all efforts should be made, particularly in such cases, to at least partially control the virus. Just "waiting" even on a suboptimal regimen is therefore a strategy that can be used to gain valuable time until new drugs become available. HAART is not being taken by these patients without good reason: suboptimal HAART is better than none at all, and some viral suppression is still better than none. Patients benefit even with only a slight reduction in viral load (Deeks 2000). In a randomized study, patients with a viral load of at least 2,500 copies/ml on HAART either interrupted or continued their therapy for 12 weeks. It showed a significant CD4-cell benefit in those who remained on the failing HAART - the CD4 cells fell by merely 15 versus 128/µl in the interrupted group (Deeks 2001). In a large cohort, CD4-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). How intensive does the treatment have to be whilst in the waiting period? Some drugs can certainly be discontinued. The NNRTIs such as nevirapine or efavirenz should in principle be stopped if resistance mutations have been found, because replicative fitness is not influenced by the NNRTI mutations (Piketty 2004), and the occurrence of further NNRTI mutations, which would compromise future second generation NNRTIs such as etravirine, should be avoided. Following the results of a pilot study, this probably also applies to the removal of PIs when resistances arise. 18 patients, in whom the viral load remained high despite more than 6 months on HAART (good compliance, appropriate efficacy), had the PIs removed from their respective therapies, whilst the NRTIs were continued (Deeks 2005). 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, there was an increase of between 0.5 and 1.0 logs; in the others, there was no increase, or even a fall). A negative moderate immunological effect was only seen in a few patients. Repeated resistance tests showed that all PI mutations persisted in all patients for the first 12 weeks, in the absense of PIs. One retrospective study in HIV-infected children, in which the PIs had been discontinued. Here, but NRTI therapy continued, demonstrated an increase in viral load only after a long period of time (LeGrand 2005). The course of one patient, in whom this approach has been successful for years, is shown in Table 9.3. Resistance tests showed that there were no changes in the MDR virus. The approach of "watch and wait" on a simple NRTI regimen thus seems feasible in some patients for a certain period of time. The reasons for this phenomenon, however, are still not understood. It is of note that with PI therapy alone, this does not appear to be effective - in 5/5 patients, in whom only the nucleoside analog was stopped, the viral load significantly rapidly increased (Deeks 2005). Table 9.3: Example of a successful "wait and watch"-strategy over three years Date (HA)ART CD4+ T cells Viral load until 1997 AZT, AZT+ddC, AZT+ddI 40 (nadir) 107,000 Mar 97 AZT+3TC+SQV-HGC 84 259,000 Oct 97 d4T+3TC+SQV+NFV 211 67,000 Jun 98 d4T+3TC+NVP+IDV/r 406 1,200 Jan 00 AZT+3TC+ABC+NVP+IDV/r 370 1,030 Mar 02 AZT+3TC+ABC+TDF+NVP+IDV/r 429 3,350 Sep 02 d4T+ddI+3TC+NVP+LPV/r 283 5,000 Nov 02* 348 7,600 Jan 03 315 16,400 Feb 03 AZT+3TC+ABC 379 6,640 May 03 241 2,400 Dec 04 AZT+3TC+ABC+TDF** 298 4,200 Jan 06 323 5,800 *Resistance testing showed a total of 20 mutations, with genotypic resistance against all drugs tested. Compliance of the patient is very good, and plasma levels were always adequate. **TDF was added because of chronic hepatitis B infection. An Italian study took another innovative approach (Castagna 2004). 50 patients with a viral load of at least 1,000 copies/ml on a 3TC-containing regimen, a M184V mutation and at least 500 CD4 cells/µl either completely interrupted treatment or continued with 3TC alone. The rationale: the M184V mutation reduces the replicative fitness of HIV. And in reality - patients on 3TC had a lesser increase in viral load (0.6 versus 1.2 logs) and lost less CD4 cells (73 versus 153/µl) over 24 weeks. 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 advantageous effect of 3TC could be observed over a period of up to 144 weeks (Castagna 2007). As patient numbers are still very small in the data presented to date, some questions remain. How long and in which patients can these strategies remain successful? It is advisable to monitor CD4 cells at short intervals. Nevertheless, if such approaches could be confirmed in larger studies, they would be very attractive. In addition to better tolerability and simpler dosing, the approach with NRTI therapy alone would have the advantage of removing the selective pressure from the virus so that it does not generate further PI or NNRTI mutations - new drugs, which do not have unlimited efficacy for salvage, would not be compromised. Specific New Salvage Drugs Integrase inhibitors as well as CCR5-antagonists, attachment- or maturation inhibitors are the new classes of drugs that have already been shown to decrease the viral load in HIV patients. In addition, new NRTIs and second generation NNRTIs such as SPD-754, etravirine or rilpivirine, are relatively far in their development (see "HAART 2007/2008"). In 2007, three Expanded Access Programs will be run: included are the second generation NNRTI etravirine, the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc. Other substances are being tested in Phase III studies. Where possible, patients with MDR viruses should be included in these studies. However, the problem is that it is only possible to take part in either a study or an EAP. Cooperation between firms is an exception, as each company only tests its preparation with licensed drugs. It would be ideal if at least two new active substances were used in salvage therapy. Practical tips for therapy of MDR viruses 1. First question: which previous treatment has been used, with what level of success and for how long? 2. Choose as many new (active) substances as possible. 3. Don't wait too long, thus giving the virus the opportunity to develop further resistance mutations - the higher the viral load at the time of switch, the lower the chance of success. 4. Use lopinavir/r, tipranavir/r or darunavir/r! In addition, simultaneous therapy with T-20 should be considered. 5. Has the patient ever taken an NNRTI? If not, it's high time! If so, stop the NNRTI if there is resistance! 6. Don't demand too much from the patient! Not everyone is suitable for mega-HAART. 7. Don't exploit a single new drug - if the clinical condition and the CD4 cells allow, try and wait for a second active drug. 8. Endeavor for EAP (maraviroc, etravirine, raltegravir) or introduce the patient to a larger center. 9. Encourage the patient! There is no such thing as having no more therapeutic options. A "watch and wait" approach is often possible. 10. Don't allow reversion to wild-type virus - even in the absence of further options, a "failing" regimen should be continued. References on salvage 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. Beatty G, Hunt P, Smith A, et al. A randomized pilot study comparing combination therapy plus enfuvirtide versus a treatment interruption followed by combination therapy plus enfuvirtide. Antivir Ther 2006; 11: 315-9. http://amedeo.com/lit.php?id=16759047 3. Benson CA, Deeks SG, Brun SC, et al. Safety and antiviral activity at 48 weeks of lopinavir/ritonavir plus nevirapine and 2 nucleoside reverse-transcriptase inhibitors in HIV type 1-infected protease inhibitor-experienced patients. JID 2002, 185:599-607. http://amedeo.com/lit.php?id=11865416 4. Benson CA, Vaida F, Havlir DV, et al. A randomized trial of treatment interruption before optimized antiretroviral therapy for persons with drug-resistant HIV: 48-week virologic results of ACTG A5086. J Infect Dis 2006; 194: 1309-18. http://amedeo.com/lit.php?id=17041858 5. Boffito M, Dickinson L, Hill A, et al. Steady-state pharmacokinetics of saquinavir hard-gel/ritonavir/fosamprenavir in HIV-1-infected patients. J AIDS 2004, 37:1376-1384. http://amedeo.com/lit.php?id=15483467 6. Boffito M, Kurowski M, Kruse G, et al. Atazanavir enhances saquinavir hard-gel concentrations in a ritonavir-boosted once-daily regimen. AIDS 2004, 18:1291-7. http://amedeo.com/lit.php?id=15362661 7. Boffito M, Maitland D, Dickinson L, et al. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses 2006; 22: 749-56. http://amedeo.com/lit.php?id=16910830 8. Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis 2005, 41:236-42. http://amedeo.com/lit.php?id=15983922 9. Castagna A, Danise A, Carini E, et al. E-184V. Pilot study to evaluate immunological response to lamivudine monotherapy vs treatment interruption in failing HIV-1 infected subjects, harbouring the M184V mutation. Abstract WeOrB1286, 15th Int Conf AIDS 2004, Bangkok. 10. Castagna A, Danise A, Galli L, et al. 144-week clinical and immunological outcome of HIV-1-infected subjects receiving lamivudine monotherapy or treatment interruption. Abstract 516, 14th CROI 2007, Los Angeles. Abstract: http://www.retroconference.org/2007/Abstracts/28962.htm 11. Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with HIV infection. J Inf Dis 2000, 181:946-53. http://amedeo.com/lit.php?id=10720517 12. Deeks SG, Wrin T, Liegler T, et al. Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001; 344: 472-80. http://amedeo.com/lit.php?id=11172188 13. Deeks SG, Hoh R, Neilands TB, et al. Interruption of Treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection. J Inf Dis 2005, 192:1537-44. http://amedeo.com/lit.php?id=16206068 14. Delgado J, Shulman N. Drug resistance. NNRTI hypersusceptibility. AIDS Read 2005, 15:28-30. http://amedeo.com/lit.php?id=15685732 15. De Meyer S, Vangeneugden T, Lefebvre E, et al. Phenotypic and genotypic determinants of TMC114 (darunavir) resistance: POWER 1, 2 and 3 pooled analysis. Abstract P196, 8th ICDTHI 2006; Glasgow, Scotland. 16. Elston RC, Yates P, Tisdale M, et al. GW433908 (908)/ritonavir (r): 48-week results in PI-experienced subjects: A retrospective analysis of virological response based on baseline genotype and phenotype. Abstract MoOrB1055, XV Int AIDS Conf 2004; Bangkok. 17. Eron JJ Jr, Bartlett JA, Santana JL, et al. Persistent antiretroviral activity of nucleoside analogues after prolonged zidovudine and lamivudine therapy as demonstrated by rapid loss of activity after discontinuation. J AIDS 2004, 37:1581-1583. http://amedeo.com/lit.php?id=15577413 18. Eron JJ, Haubrich R, Lang W, et al. A phase II trial of dual protease inhibitor therapy: amprenavir in combination with indinavir, nelfinavir, or saquinavir. J AIDS 2001, 26:458-61. http://amedeo.com/lit.php?id=11391165 19. Ford J, Boffito M, Maitland D, et al. Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients. J Antimicrob Chemother 2006; 58: 1009-16. http://amedeo.com/lit.php?id=16984898 20. Gulick RM, Hu XJ, Fiscus SA, et al. Durability of response to treatment among antiretroviral-experienced subjects: 48-week results from ACTG Protocol 359. J Inf Dis 2002, 186:626-33. http://amedeo.com/lit.php?id=12195349 21. 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