Treatment-Experienced Patients

Updated October, 2009

Rami Kantor, M.D., Karen T. Tashima, M.D.

First Edition (2003):  Andrew R. Zolopa, M.D. and Joel Gallant, M.D., M.P.H.

               Antiretroviral treatment failure may be caused by drug toxicity or virologic failure. Virologic failure may occur because an antiretroviral treatment regimen fails to reduce plasma HIV RNA levels to undetectable levels (<20-50 RNA copies/ml) or because plasma HIV RNA levels rebound following an initial decrease to undetectable levels. The success rate of antiretroviral therapy is lower in patients who have already experienced virologic failure on an earlier treatment regimen than in previously untreated persons.

               The goals of management of treatment-experienced patients with virologic failure differ according to circumstances related to prior treatment exposure and drug resistance. In limited or intermediate prior drug exposure, with adequate or some treatment options, the goal is to re-establish maximal virologic suppression. In extensive prior drug exposure, with few or no adequate treatment options, the goal is preservation of immune function and prevention of clinical progression, and expert advice is critical (6). If two or more fully active drugs can be identified, however, the goal of treatment for the patient with highly resistant virus is to achieve viral suppression to below 50 copies/mL (11). This goal is more readily achievable with the use of enfuvirtide and new protease inhibitors designed to have activity against multiple PI-resistant viruses (11, 33). Etravirine is a new NNRTI with activity against virus containing the K103N reverse transcriptase resistance mutation. Other recently developed drugs include drugs in new classes such as the integrase inhibitor raltegravir and the CCR5 antagonist maraviroc, which inhibits cell entry.

               In patients experiencing drug toxicity, it is appropriate to substitute one or more drugs of similar potency but with different side effects. Often it will be possible to substitute drugs of the same class but occasionally it may be necessary to substitute an equally potent drug from a different drug class. Drug toxicity must be anticipated and recognized early because it is a common cause of non-adherence leading to virologic failure. When toxicity cannot be confidently attributed to a single drug and is severe enough to require temporary discontinuation of therapy, all agents in the combination should be stopped (11).

Causes of Virologic Failure

               In patients with continued HIV replication despite antiretroviral therapy, it is essential to determine whether virologic failure is due to non-adherence, pharmacological factors, or pre-existing or acquired HIV drug resistance. This requires a detailed history of drug-taking behavior and possibly drug-resistance testing. Drug resistance testing is particularly important in patients who have been partially adherent or have received a drug to which drug resistance can emerge rapidly, such as 3TC or an NNRTI.

               Drug resistance testing is not necessary in patients who have not taken any of their prescribed antiretroviral drugs, and may or may not be necessary in patients who have discontinued all of their drugs simultaneously. In patients receiving a protease inhibitor-based regimen, resistance is unlikely to develop if all drugs are discontinued simultaneously. However, in patients receiving an NNRTI-based regimen, simultaneous discontinuation of all drugs may lead to prolonged exposure of the patient's virus to the NNRTI alone at subtherapeutic levels, since the two most commonly used NNRTIs – nevirapine and efavirenz – each have a much longer half-life than those of the NRTIs.
Review Article:  Hirsch MS, et al.  Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA Panel.  Clin Infect Dis 2008;47:266-285.

Management of Virologic Failure Due to Nonadherence or Pharmacokinetic Factors

               The absence of detectable drug resistance in a patient failing an antiretroviral regimen strongly suggests inadequate drug levels due either to non-adherence or interfering pharmacological factors. Decreased drug levels increase the risk for resistance, particularly if the virus is exposed to some but not all of the drugs in a treatment regimen. Decreased drug activity is often correctable by improving adherence or by modifying therapy to increase bioavailability. Strategies to improve adherence are outlined in "Initial Treatment of HIV Infection".

Antiretroviral Drug Resistance

               The presence of resistance to one or more of the drugs in a regimen before starting therapy is an independent predictor of virologic response to that regimen. In addition, several prospective controlled studies have shown that patients whose physicians have access to drug resistance data, particularly genotypic resistance data, respond better to therapy than control patients whose physicians do not have access to these assays. The accumulation of such retrospective and prospective data has led expert panels to recommend the use of resistance testing in the treatment of HIV-infected patients.

               Drug resistance tends to be cumulative for a given individual and reliance on a single test can result in an underestimation. Thus all prior treatment history and resistance test results should be taken into account when determining a sequential regimen (6, 12, 15).

Management of Virologic Failure Caused by Drug Resistance

               There are several strategies for managing antiretroviral therapy in treatment-experienced patients with detectable plasma viremia and drug resistance. These include: 1) maintaining the failing treatment until clinical or immunologic progression force a change in therapy, 2) intensifying the current regimen with the addition of a single drug, or 3) changing the entire regimen. When the decision to change therapy is based on viral load determination, the viral load result should be confirmed with a second test. Clinicians have also often opted to temporarily discontinue therapy in some patients to reduce the level of resistance in an attempt to maximize the response to subsequent therapy but the risks and potential benefits of this strategy are controversial (11).

Guideline: Hammer SM, et al.  Antiretroviral Treatment of Adult HIV Infection. 2008 Recommendations of the International AIDS Society-USA Panel.  JAMA 2008;300(5):555-570.

Maintaining Treatment in Persons with Transient Low-Level Viremia

               Transient low-level viremia, now referred to as a "blip", is defined as the occurrence of a plasma HIV RNA level >50 copies/ml on at least one occasion followed by a subsequent measurement of <50 copies/ml. Blips occur in up to 40% of patients receiving antiretroviral therapy. The causes of blips are likely to be heterogeneous and may include a temporary decrease in drug exposure (e.g. due to decreased drug absorption, increased drug metabolism, or a change in plasma binding proteins), a temporary increase in release of virus caused by activation of the latent virus reservoir, or a higher steady state of low-level virus replication because of a weak antiretroviral regimen or pre-existing drug resistance.                Viral blips can provide therapeutic dilemmas for clinicians, however their biological significance remains unclear with conflicting data. Patients with persistently detectable low-level viremia (>50 copies/ml) have been observed to be at increased risk of virologic rebound (i.e. viral load >5,000 copies/ml with subsequent return of viral load towards baseline). Frequent blips may be associated with the accumulation of new drug-resistance mutations and the risk of frank relapse may be higher in patients receiving drugs such as the NNRTIs, to which resistance can develop by the acquisition of a single mutation. However, isolated blips were not associated with virologic failure in a short-term study of patients receiving Zidovudine (ZDV)-Lamivudine (3TC)-indinavir. Moreover, in an intensive study of a small group of patients most blips appeared to represent normal biological and statistical variation around mean levels that are below 50 copies/ml rather than clinically significant elevations in the level of viral replication (28).

               A patient experiencing frequent blips should be counseled about the importance of adherence although is has been suggested that its importance is negligible (26). It may also be necessary to assess the potency, dosing schedule, and pharmacokinetics of the drug regimen, and to consider whether the patient could have pre-existing resistance to one or more of the drugs in the combination. Treatment intensification is an option for those patients believed to be at risk for virologic failure, but the selection of an additional drug may have to be made in the absence of drug susceptibility results, since most resistance assays may not be able to detect resistance when the viral load is very low.

Maintaining Treatment in Persons with Persistently Elevated Plasma HIV RNA Levels

               It is often possible to select a second completely suppressive regimen for patients experiencing their first virologic failure. However, because patients with more treatment experience are less likely to respond fully to a new regimen, many clinicians base their changes on the patient's clinical and immunologic status and the extent, rather than the presence, of virologic failure. Even a partial virologic response can increase CD4 counts and substantially decrease the rate of clinical progression. Many patients with virologic rebound also continue to maintain elevated CD4 counts — a phenomenon of unknown durability that has been referred to as RNA-CD4 discordance.

               Physicians may be hesitant to change therapy in patients with stable CD4 counts despite detectable viremia because of the risk of new toxicities, adverse reactions, or new problems with adherence. However, patients with ongoing viremia on failing therapy may develop higher levels of resistance to the drugs in their regimen and cross-resistance to other drugs within the same class. If resistance testing indicates that options are available to fully suppress HIV replication, then a change in therapy is indicated as early as possible (17). However, if few or no active drugs are available, it may be most appropriate to continue current therapy while weighing the patient's prognosis, the degree of HIV resistance, and the prospect of new drug availability to determine whether the benefit of RNA-CD4 discordance outweighs the risk of additional resistance. It may not be appropriate to use NNRTIs in any non-suppressive regimen, in part because most of the cohorts in whom RNA-CD4 discordance has been described have been receiving protease inhibitor-based therapy (29).

Petersen, ML et al. Long-term Consequences of the Delay Between Virologic Failure of Highly Active Antiretroviral Therapy and Regimen Modification. AIDS. 2008 Oct 18;22(16):2097-106.

Intensification

               Intensification is the addition or substitution of a single antiretroviral agent to a regimen on which a patient has measurable viremia. It has been studied primarily in heavily treated patients with established virologic failure and plasma HIV RNA levels >1,000 copies/ml. Intensification should be considered for patients with low-level plasma viremia, in whom either resistance testing or low plasma HIV RNA levels suggest that most of the administered drugs are still active. For example, patients who have developed the 3TC-associated mutation M184V may have low-level viremia on 3TC-containing regimens without developing resistance to other components of the regimen. Blind intensification (i.e. without resistance testing) is necessary in patients with low viral loads (e.g. <1000 copies/ml), in whom resistance testing often cannot be obtained, but should be avoided in patients failing therapy with higher viral loads, since resistance testing in these patients can provide specific information about resistance to the drugs in the failing regimen.

               If intensification proves ineffective, it can lead to resistance not only to the drugs in the original regimen, but also to the drug used for intensification. To minimize this risk, clinicians should avoid adding drugs that would be key components of future regimens, such as drugs from entirely new classes. Intensification is usually considered only in two situations, neither of which is associated with extensive resistance: (i) HAART has recently been initiated and plasma HIV RNA levels have decreased but remain detectable; (ii) a patient has developed low-level virologic rebound after having already achieved an undetectable viral load. In these situations, drug resistance, if present, is likely to be minimal, and usually affects only one component of the regimen.

               Most studies of intensification have involved the addition of a third NRTI or tenofovir DF to a HAART regimen already containing two NRTIs, or the addition of a second protease inhibitor to a HAART regimen already containing one protease inhibitor. Intensifying a protease inhibitor-based regimen with an NNRTI or vice versa has not been studied and is generally not advised. The most commonly studied NRTIs used for intensification are abacavir and tenofovir. Abacavir has been shown to mostly benefit NRTI-experienced patients with limited resistance to NRTIs. It is notably highly effective for patients who have a dominant virus with only the M184V mutation (19). Intensification of partially suppressive regimens with tenofovir can achieve both a sustained virologic response and reduction in the emergence of new resistance mutations (25, 27, 31). When used as a single protease inhibitor, indinavir is associated with wide variations in Cmax and Cmin, and intensification with ritonavir, a potent inhibitor of cytochrome P450, in patients on long-term indinavir regimens has been shown to improve virologic response. With the exception of nelfinavir, all available PIs should be pharmacologically enhanced with ritonavir boosting, providing consistently higher drug levels over the dosing interval (6, 9, 11).

Choosing a New Regimen

               Before the widespread use of resistance tests, it was commonly assumed that virologic failure signaled resistance to all drugs in the regimen. However, several recent clinical trials have shown that most patients developing virologic failure on their first HAART regimen usually have resistance to only one of the drugs in the regimen, usually those with the lowest genetic barrier to resistance. A resistance test, which should be performed while patients are still on the failing regimen or within 4 weeks after regimen discontinuation (6), can help determine which drugs are no longer likely to be effective and which may retain antiretroviral activity.

               The standard approach to managing virologic failure to an initial HAART regimen is to use at least two or three new drugs, including at least one drug belonging to a new class (6, 11). The relative lack of resistance in patients with early virologic failure on their first HAART regimen suggests that a less complete change in therapy may be possible. The DHHS guidelines currently advise that a single drug substitution (made on the basis of resistance testing) can be considered, but is unproven at this setting. When resistance to and toxicity of NRTIs or NNRTIs limits the availability of non-protease inhibitor drugs, use of a double-boosted PI (2 active PIs and low-dose ritonavir) has been proposed for study, without much available data (5, 11).

               The success of salvage therapy decreases with increasing antiretroviral experience because of the high levels of cross-resistance within each of the three drug classes. Preliminary data suggest that patients switching from one dual NRTI combination will generally have some virologic response as long as high-level resistance to the first combination has not yet emerged. Because of the high-level of cross-resistance between ZDV and d4T, it is unlikely that substituting one drug for the other will be highly effective. There appears to be less clinical cross-resistance between ddI and 3TC, and a regimen that involves the substitution of one of these drugs is likely to have some activity. Although there have been several studies describing the use of abacavir and tenofovir for intensification, there are fewer data on the use of these drugs as part of salvage therapy. Nonetheless, because of the potency of these drugs — in untreated persons, they reduce plasma HIV RNA levels by 1.5 logs — they should be considered for use in salvage therapy.

               Because of the high-level of cross-resistance within the NNRTI class, patients developing virologic failure during treatment with one NNRTI are unlikely to benefit from any of the other currently available NNRTIs. However, the NNRTI efavirenz has proved to be useful in the salvage of NNRTI-naïve patients.

               For patients who have multiple genotypic resistance mutations in the NRTI and PI classes, a phenotypic resistance test should be considered. The phenotypic resistance test measures the ability of the virus to grow in the setting of different concentrations of drug and can show which antiretroviral agents may have relatively more activity. For example, patients in whom nelfinavir-resistant isolates arise after nelfinavir therapy often respond to a regimen containing another protease inhibitor, because D30N, the most common nelfinavir-resistance mutation, confers little cross-resistance to other protease inhibitors. However, because as many as 15%-25% of nelfinavir failures may be associated with other mutations, including L90M, which is associated with protease inhibitor cross-resistance, virologic failure on nelfinavir does not guarantee susceptibility to other protease inhibitors.

               Enfuvirtide, or T-20 (Fuzeon), the first of fusion inhibitors, has been shown to have potent antiretroviral activity in both phase I, II, and III clinical trials (18, 23, 33). Adverse reactions associated with T-20 include injection site reactions following subcutaneous administration. The optimal time to initiate T-20 is when a strong and sustained virological response can be predicted on the basis of treatment history, resistance data and viro-immunological parameters, and is best considered at the time of the second, third, or fourth failure, depending on the number of active drugs that remain as options. Maximum sustainable response may best be achieved in patients whose virus retains at least partial activity to two drugs or more, ideally from different antiretroviral classes, and who present with CD4>100 and VL<105. The availability of only a single agent deemed active should not be considered a contraindication for T-20 use. Weighing the risks and benefits of using a single active drug in the heavily treatment-experienced patient is complicated, and consultation with an expert is advised (1, 2, 11).

               In patients infected with highly multidrug-resistant viruses, the durability of response is usually brief. However, sustained antiviral responses have been observed when T-20 is combined with at least one other active antiretroviral drug. Because of its expense—it has been priced at $20,000 per year—and its requirement for subcutaneous administration, T-20 is used only for salvage therapy.

               Using a single active antiretroviral drug in a new salvage regimen is not recommended because of the risk of rapidly developing resistance to that drug. However, in patients with advanced HIV disease with a high likelihood of clinical progression, adding a single drug may reduce the risk of immediate clinical progression. Weighing the risk (e.g., selection of drug resistance) and benefits (e.g., antiretroviral activity) of using a single active drug in the heavily treatment-experienced patient is complicated, and consultation with an expert is advised (6).

               The success of multi-drug rescue therapy, or "mega-HAART", in patients who have failed several prior antiretroviral drug regimens and have multidrug-resistant HIV strains is limited by large pill burdens and poor adherence, toxicity and pharmacological interactions. Dual protease inhibitor regimens should also be avoided for these same reasons (11).

Treatment Interruptions in Patients with Persistent Viremia

               When faced with untreatable drug resistance, many physicians and patients have elected to stop therapy prior to initiating a salvage regimen, presumably to allow replacement of highly resistant virus with wild-type virus. Although this approach has been shown to be beneficial in some studies (6, 16), re-treatment of such patients with drugs to which they were once resistant rapidly selects for the re-emergence of resistant virus. Treatment interruption has been associated with greater disease progression and did not confer immunologic or virologic benefits or improve the overall quality of life and is therefore not recommended (6, 7, 11, 20, 21, 30).

Recently Approved and New Drugs

               Recently approved drugs that can be considered in treatment-experienced patients include the fusion inhibitor enfuvirtide (see above), and the protease inhibitors atazanavir, tipranavir and darunavir. Atazanavir has a unique resistance profile and does not increase lipids. Although in patients with high level resistance to other PIs, susceptibility to atazanavir is often reduced (13), recently published 48-week results show that in a moderately treatment experienced population, ritonavir-boosted atazanavir appeared comparable to lopinavir plus ritonavir with advantages on lipid changes and pill burden (11).

               Tipranavir and darunavir (formerly TMC-114) are the two newest protease inhibitors, used only with ritonavir-boosting, designed to have activity against multi-PI-resistant virus. Studies using tipranavir or darunavir in patients with PI-, NNRTI-, and NRTI-class failures showed greater HIV-1 RNA and CD4 cell count responses compared with another PI in optimized background regimens. The responses to either drug were doubled if one of the agents in the background regimen was enfuvirtide, in patients who had not taken enfuvirtide in the past. The percentage of patients achieving viral load below 50 copies/mL was as high as 36% for tipranavir (Farthing et al. 46th ICAAC abstract H-1385) and 60% for darunavir, if enfuvirtide was also used (4, 14).

               These encouraging results, that are presumably due to improved - yet unique - resistance profiles of these new medications, raise the possibility that the highly-experienced patient population may also be likely to achieve complete viral suppression if medications are chosen carefully. Side effects to tipranavir/ritonavir include nausea, diarrhea, rash, hyperlipidemia and liver enzyme elevations, particularly in patients with hepatitis B or C coinfection. Patients with advanced liver disease should not use tipranavir. Fatal and nonfatal intracranial hemorrhage has been reported among patients taking tipranavir/ritonavir. Side effects to darunavir/ritonavir include rash, nausea, diarrhea and hepatitis, more frequent in patients with hepatitis B or C.

               Impressive results have been seen in patients taking darunavir/ritonavir with etravirine, an NNRTI with acritivity against the K103N containing virus. In the DUET studies, 65% of highly treatment experienced subjects achieved viral suppression at one year follow-up when using the two drugs in a new regimen (22, 24). The drug interaction between tipranavir/ritonavir and etravirine is significant, therefore the use of these two drugs in combination is to be avoided.

               Raltegravir targets integration of virus into the host genome and represents the first drug in the integrase inhibitor class. The drug is well tolerated and highly effective in combination with one or two other active agents such as darunavir/ritonavir and enfuvirtide (3, 32).

               Maraviroc, a co-receptor antagonist, prevents HIV entry by preventing binding of CCR5-using virus to the co-receptor CCR5. The drug is not active against virus utilizing co-receptor CXCR4. A tropism test should be performed if maraviroc is being considered, and maraviroc should be given only if the patient’s virus uses the R5 receptor exclusively. In phase III studies, maraviroc added substantial activity to regimens with one or two other active drugs. Tipranavir/ritonavir can be administered with maraviroc. Depending on co-administered drugs, maraviroc dosing requires adjustment and should be carefully considered (8, 10).

               Multiple new combinations of these drugs are possible but not all have been evaluated in prospective studies. The additional virologic benefit to adding NRTIs in this setting may be limited since most patients will have developed significant resistance to all drugs in the NRTI class. Studies are ongoing to further define the role of NRTIs in this setting. In summary, an increasing number of new regimens are available for use and are very likely to improve the outcomes of treatment for the highly treatment experienced patient.

DeCastro N, et al.  Switch Enfuvirtide to Raltegravir in Virologically Suppressed Multidrug-Resistant HIV-1-Infected Patients: A Randomized Open Label Trial.  Clin Infect Dis 2009;49:1259-1267.

REFERENCES

1. Clotet B, Raffi F, Cooper D, et al. Clinical management of treatment-experienced, HIV-infected patients with the fusion inhibitor enfuvirtide: consensus recommendations. Aids 2004;18:1137-46. [PubMed]

2. Cooper DA, Lange JM. Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. Lancet Infect Dis 2004;4:426-36.  [PubMed] 

3. Cooper DA, Steigbigel RT, Gatell JM, et al. Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med 2008;359:355-65.  [PubMed] 

4. De Meyer S, Azijn H, Surleraux D, et al. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005;49:2314-21.  [PubMed]   

5. Deeks SG. Treatment of antiretroviral-drug-resistant HIV-1 infection. Lancet 2003;362:2002-11. [PubMed]

6. DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents, 2008. [PubMed]

7. El-Sadr WM, Lundgren JD, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-96.  [PubMed]

8. Fatkenheuer G, Nelson M, Lazzarin A, et al. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med 2008;359:1442-55.  [PubMed] 

9. Gallant JE. Protease-inhibitor boosting in the treatment-experienced patient. AIDS Rev 2004;6:226-33. [PubMed]

10. Gulick RM, Lalezari J, Goodrich J, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med 2008;359:1429-41.  [PubMed] 

11. Hammer SM, Eron JJ, Jr., Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. Jama 2008;300:555-70.  [PubMed]

12. Harrigan PR, Wynhoven B, Brumme ZL, et al. HIV-1 Drug Resistance: Degree of Underestimation by a Cross-Sectional versus a Longitudinal Testing Approach. J Infect Dis 2005;191:1325-30.  [PubMed]

13. Havlir DV, O'Marro SD. Atazanavir: new option for treatment of HIV infection. Clin Infect Dis 2004;38:1599-604. [PubMed]

14. Hicks CB, Cahn P, Cooper DA, et al. Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 2006;368:466-75. [PubMed]

15. Hirsch MS, Gunthard HF, Schapiro JM, et al. Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clin Infect Dis 2008;47:266-85.  [PubMed] 

16. Jaafar A, Massip P, Sandres-Saune K, et al. HIV therapy after treatment interruption in patients with multiple failure and more than 200 CD4+ T lymphocyte count. J Med Virol 2004;74:8-15. [PubMed] 

17. Kantor R, Shafer RW, Follansbee S, et al. Evolution of resistance to drugs in HIV-1-infected patients failing antiretroviral therapy. AIDS 2004;18:1503-11. [PubMed]

18. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003;348:2175-85. [PubMed]

19. Lanier ER, Ait-Khaled M, Scott J, et al. Antiviral efficacy of abacavir in antiretroviral therapy-experienced adults harbouring HIV-1 with specific patterns of resistance to nucleoside reverse transcriptase inhibitors. Antivir Ther 2004;9:37-45. [PubMed]

20. Lawrence J, Hullsiek KH, Thackeray LM, et al. Disadvantages of structured treatment interruption persist in patients with multidrug-resistant HIV-1: final results of the CPCRA 064 study. J Acquir Immune Defic Syndr 2006;43:169-78. [PubMed]

21. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. N Engl J Med 2003;349:837-46.  [PubMed]

22. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007;370:39-48.  [PubMed] 

23. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. N Engl J Med 2003;348:2186-95.  [PubMed]

24. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet 2007;370:29-38.  [PubMed] 

25. McColl DJ, Margot NA, Wulfsohn M, Coakley DF, Cheng AK and Miller MD. Patterns of Resistance Emerging in HIV-1 From Antiretroviral-Experienced Patients Undergoing Intensification Therapy With Tenofovir Disoproxil Fumarate. J Acquir Immune Defic Syndr 2004;37:1340-50.  [PubMed]

26. Miller LG, Golin CE, Liu H, et al. No evidence of an association between transient HIV viremia ("Blips") and lower adherence to the antiretroviral medication regimen. J Infect Dis 2004;189:1487-96. [PubMed]

27. Miller MD, Margot N, Lu B, et al. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis 2004;189:837-46.  [PubMed]

28. Nettles RE, T.L. K, Kwon P, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005;293:817-29. [PubMed]

29. Petersen ML, van der Laan MJ, Napravnik S, Eron JJ, Moore RD and Deeks SG. Long-term consequences of the delay between virologic failure of highly active antiretroviral therapy and regimen modification. Aids 2008;22:2097-106  [PubMed] 

30. Ruiz L, Ribera E, Bonjoch A, et al. Role of structured treatment interruption before a 5-drug salvage antiretroviral regimen: the Retrogene Study. J Infect Dis 2003;188:977-85.  [PubMed]

31. Squires K, Pozniak AL, Pierone G, Jr., et al. Tenofovir disoproxil fumarate in nucleoside-resistant HIV-1 infection: a randomized trial. Ann Intern Med 2003;139:313-20. [PubMed]

32. Steigbigel RT, Cooper DA, Kumar PN, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med 2008;359:339-54.  [PubMed] 

33. Youle M, Staszweski S, Clotet B, et al. Concomitant use of an active boosted protease inhibitor with enfuvirtide in treatment-experienced, HIV-infected individuals: recent data and consensus recommendations. HIV Clin Trials 2006;7:86-96.  [PubMed]