Approach to the Treatment-Experienced Patient

Infect Dis Clin N Am 21 (2007) 85–102

Approach to the Treatment-Experienced Patient Joel E. Gallant, MD, MPH Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 443, Baltimore, MD 21205, USA

Despite the efficacy of highly active antiretroviral therapy (HAART), discussed elsewhere in this issue, treatment failure and drug resistance continue to occur frequently in HIV-infected individuals. In some cases, this is a consequence of pre-existing drug resistance, resulting either from prior nonsuppressive therapy or primary infection with resistant virus. Other patients fail because of inadequate drug concentrations, usually caused by poor adherence, but sometimes by inadequate bioavailability, drug-drug or drug-food interactions, or individual variation in drug metabolism. Many of these factors are less relevant now than they were in the early years of the HAART era. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) and ritonavir-boosted protease inhibitors (PIs) have excellent bioavailability and are less subject to pharmacokinetic variability than the unboosted PIs that were the cornerstone of early HAART regimens. Adherence has become less challenging now that more once-daily regimens and drugs with lower pill burdens are being used. In addition, there are many more agents to choose from today, including drugs that are either better tolerated and less toxic than earlier agents, or that are effective against drug-resistant virus because of their unique resistance profiles or mechanisms of action. Nevertheless, many treatment-experienced patients still require the use of complex regimens that are associated with side effects and long-term toxicity. Adherence to such regimens can be challenging, especially for patients with mental illness, substance abuse, and homelessness, who are disproportionately represented among those failing therapy. In the last year, Dr. Joel E. Gallant received research support from Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck & Co., Panacos, Pfizer, Roche Pharmaceuticals, and Tibotec; he received consultant fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck & Co., Panacos, Pfizer, Tibotec, and Monogram Biosciences; he received honoraria from Abbott Laboratories, Gilead Sciences, and Roche Pharmaceuticals. E-mail address: [email protected] 0891-5520/07/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2007.01.003

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Traditionally, antiretroviral therapy has been less effective in treatmentexperienced patients who have failed previous therapy than in previously naive individuals [1–3]. The challenge of successfully treating experienced patients requires an understanding of the toxicities, resistance profiles, and pharmacokinetic characteristics associated with each agent, and a familiarity with the investigational agents in development. It also requires a relationship between clinician and patient that fosters adherence, especially to the more complex combinations likely to be used in ‘‘salvage therapy.’’ Defining treatment failure There are three categories of treatment failure: 1. Virologic failure: failure to achieve or maintain maximal virologic suppression 2. Immunologic failure: progressive decline in CD4 cell count 3. Clinical failure: progression of clinical disease In resource-rich countries, where viral load can be monitored, the emphasis is on virologic failure, defined as an incomplete virologic response to antiretroviral therapy. Reduction of the plasma HIV-1 RNA level (viral load) to below the limit of detection (less than 50-75 copies/mL) typically occurs within the first 24 to 36 weeks of therapy, with the time to suppression varying depending on the baseline viral load and the potency of the treatment regimen. Virologic failure includes both lack of suppression to undetectable levels or rebound to detectable levels following initial suppression. The Department of Health and Human Services (DHHS) guidelines define virologic failure as a confirmed viral load measurement above 400 copies/mL after 24 weeks or above 50 copies/mL after 48 weeks [4]. Immunologic and clinical definitions of failure are rarely considered in patients whose viral load is fully suppressed on antiretroviral therapy, because a poor CD4 response or the occurrence of new clinical events despite virologic suppression is unlikely to be caused by the regimen chosen. Exceptions include the blunted CD4 count response that has been associated with the use of zidovudine or with the combination of tenofovir DF plus full-dose didanosine [5,6]. There is also evidence that lopinavir-ritonavir (and possibly other ritonavir-boosted PI-based regimens), although not virologically superior to efavirenz-based regimens, is associated with a greater CD4 count response [7]. In most cases, however, such discordant responses are caused by late initiation of therapy rather than by the specific drug regimen chosen [8,9]. Initial approach to treatment failure Clinicians evaluating patients with treatment failure must determine the reason for failure, because the solution is dependent on the cause.

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Nonadherence Clinicians should ask about adherence in an open-ended and nonjudgmental fashion. Laboratory evidence for nonadherence includes viral rebound despite wild-type virus on resistance testing, or subtherapeutic or undetectable plasma concentrations of the agents prescribed. In cases where indications for therapy were equivocal, treatment interruption is sometimes an appropriate approach to failure caused by nonadherence. When treatment is necessary, however, simplification may help improve adherence, provided it can be achieved without jeopardizing potency. Counseling and referral to adherence support programs may also be beneficial. Substance abuse, inadequate housing, and mental illness, including depression, decrease the likelihood of adherence, and should be actively addressed. Drug toxicity Side effects, especially those that are not anticipated by the patient, can cause treatment failure because of their affect on adherence. Some, such as efavirenz-related rash or neuropsychiatric side effects, are common but improve with ongoing use. In such cases, reassurance and symptomatic therapy may be enough. Other side effects are common but easily managed. PIassociated diarrhea, for example, responds readily to fiber supplements. Patients vary in their ability or willingness to tolerate side effects. Open communication channels are critical, and the clinician must provide assurance that the regimen will be modified if the side effect becomes intolerable to the patient. It is usually clear which drug is causing the side effect, allowing a different drug of similar or greater potency but with a different side effect profile to be substituted, provided there is no drug resistance. Modification of therapy to deal with toxicity is simple in patients on early regimens, but it becomes more challenging in patients with drug resistance, for whom the choice of drugs is more limited. Pharmacokinetic factors Patients can fail therapy despite excellent adherence because of inadequate drug levels, although this is less common with the regimens used today. With some agents, the timing of doses and adherence to food restrictions are relevant, and should be discussed. Patients should also be asked about use of concomitant medications, including nonprescribed drugs or complementary therapies that could interact with antiretroviral agents. Drug absorption can be impaired by vomiting or diarrhea. PIs should be pharmacokinetically boosted with low-dose ritonavir whenever possible. Ritonavir increases the levels and prolongs the half-lives of all PIs except nelfinavir. Drug resistance Drug resistance can be either the cause or the effect of treatment failure. Resistance can be transmitted at the time of infection, and possibly later

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because of superinfection. Resistance can also be acquired as a result of nonsuppressive therapy. Resistance testing is indicated in patients failing therapy with viral loads of at least 500 to 1000 copies/mL [4,10]; however, virologic failure is often identified much earlier. The approach to low-level viremia is discussed next. Low-level viremia and ‘‘blips’’ A ‘‘blip’’ is an isolated viral load above 50 copies/mL, usually at low levels, in a patient whose viral load is otherwise suppressed. Most evidence suggests that blips are common and not associated with an increased risk of virologic failure or evolution of drug resistance, at least in the short-term [11,12], although some studies suggest a link between frequent blips and virologic failure [13,14] or nonadherence [15]. Blips may be caused by the release of nonreplicating virus from the latent reservoir [16] or laboratory variability around the lower limit of detection, especially with highly sensitive viral load assays, such as the Roche Amplicor (Basel, Switzerland) (reverse transcriptase polymerase chain reaction) version 1.5 assay. False-positive results can occur because of improper specimen handling; specifically, when blood is drawn in a plasma preparation tube (PPT) tube and then frozen and stored before processing [17]. Unfortunately, defining a viral load as a blip requires that it be repeated, because it is only a blip if the next viral load is undetectable. In contrast, persistent low-level viremia is clearly associated with treatment failure and drug resistance [18–25]. Unfortunately, resistance can emerge when the viral load is still too low to allow for resistance testing. One solution to this problem is to continue the failing regimen until a resistance test can be obtained. This increases the likelihood of resistance, however, especially to such drugs as lamivudine, emtricitabine, and the NNRTIs, for which a single mutation confers high-level resistance. Intensification is sometimes used in such situations to prevent resistance. Intensification Intensification, the addition or substitution of a single antiretroviral agent, can be considered in the case of low-level viremia when evidence suggests that most of the drugs in the regimen remain active, based either on a low viral load or resistance test results. Because ineffective intensification can lead to further resistance, resistance testing should be performed first whenever the viral load is adequate. Clinical trials of this strategy have generally studied the addition of a third nucleoside–nucleotide reverse transcriptase inhibitor (NRTI) to a regimen already containing two NRTIs. It has been most successful in patients with low viral loads and limited drug resistance [26–28]. Modification of antiretroviral therapy based on drug resistance testing Clinicians are sometimes reluctant to change therapy in patients with stable CD4 counts who are doing well clinically because of concerns about

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exhausting future treatment options or of increasing drug toxicity or resistance. Ongoing viremia on a failing regimen can lead to higher levels of resistance, however, which may compromise future options because of cross-resistance [24,25]. When resistance test results suggest that a fully suppressive option is available, which is the case for an increasing proportion of treatment-experienced patients, a switch to the suppressive regimen is usually preferable to continuation of failing therapy. Current guidelines from DHHS and from the International AIDS Society-USA now state that the goal of therapy in treatment-experienced patients is maximal virologic suppression (to viral loads less than 50 copies/mL) [4,10], a more ambitious goal than in past guidelines, reflecting the improved treatment options available to treatment-experienced patients. When there are no fully suppressive options, continued therapy with a nonsuppressive regimen is still beneficial, an approach discussed later in this article. Patients failing therapy with viral loads above 1000 copies/mL usually have some degree of resistance to one or more of the drugs in the regimen. The presence of wild-type virus in a patient experiencing virologic failure is strong evidence of nonadherence or of other causes of subtherapeutic drug levels. Before the availability of resistance testing, patients failing a drug regimen were typically switched to an entirely new regimen. It is now known, however, that resistance first affects drugs in the regimen with the lowest genetic barrier to resistance [29–33]. A resistance test, preferably performed while patients are still on therapy or within 4 weeks of discontinuation, can help determine which drugs may retain activity, and whether a partial change in therapy may be possible. Multiple clinical trials have shown that resistance testing helps clinicians to select more effective regimens in treatment-experienced patients [34–40], and other studies have shown that resistance test results are highly predictive of response to subsequent therapy [41,42]. Treatment guidelines now recommend the routine use of resistance testing in patients who are failing therapy [4,10,43]. There are two categories of resistance tests: genotypes and phenotypes (Table 1). Genotype tests report the presence of mutations associated with drug resistance, along with an interpretation typically generated based on a computer-based algorithm. Phenotype testing involves exposing a recombinant created from the patient’s virus to varying concentrations of antiretroviral agents, with measurement of the IC50 and the fold-change (the degree to which the IC50 of the patient’s virus differs from that of a drug-susceptible virus). It is a more direct measure of susceptibility, but is also more expensive and time consuming. Although clinical trials comparing the two approaches have not demonstrated a clear benefit of phenotype testing, many experts prefer this approach in patients with more extensive resistance because it assesses interactions among mutations, especially for PIs and NRTIs, and provides a quantitative measure of susceptibility. Genotypes are more sensitive than phenotypes, however, at detecting resistance because of ‘‘mixtures’’ of mutant and wild-type virus, an argument that supports the

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Table 1 Advantages and disadvantages of genotypic and phenotypic resistance tests Testing method

Advantages

Disadvantages

Genotypic

n Faster n Lower cost n Detection of mutations may precede phenotypic resistance n More sensitive than phenotype for detecting mixtures of resistant and wild-type virus

Phenotypic

n Provides direct and quantitative measure of resistance n Methodology can be applied to any antiretroviral agent, including new drugs n Assesses interactions among mutations n Accurate with non-B HIV subtypes

n Indirect measure of resistance n Relevance of some mutations unclear n Unable to detect minority variants (!20%–25% of viral sample) n Complex mutational patterns may be difficult to interpret n Genotypic correlates of resistance not as well defined for new agents or non-B subtypes n Susceptibility cut-offs not standardized between assays n Clinical cut-offs not defined for some agents n Unable to detect minority variants (!20%–25% of viral sample) n Complex technology with longer turnaround n More expensive

use of both tests or a combined assay whenever phenotyping is being ordered. Nucleotide reverse transcriptase inhibitor resistance There are a variety of pathways to NRTI resistance in patients failing NRTI-containing regimens (Table 2). Thymidine analogue mutations (TAMs) are mutations at codons 41, 67, 70, 210, 215, and 219, which are selected only by the thymidine analogues, zidovudine and stavudine, but which cause varying degrees of cross-resistance to all NRTIs. The amount of resistance and cross-resistance depends on the drug, the number of TAMs, and the specific TAM pathway. The combination of mutations at codons 41, 210, and 215 is associated with higher levels of NRTI resistance than mutations at codons 67, 70, and 219. M184V is selected by lamivudine and emtricitabine and causes high-level resistance to both. It also causes modest decreases in susceptibility to abacavir and didanosine, although this is not clinically significant when the mutation is present alone. M184V increases susceptibility to stavudine, tenofovir, and zidovudine, an effect that can partially reverse resistance caused by other mutations. M184V delays the emergence of TAMs in patients taking thymidine analogue–containing regimens. K65R can be selected by abacavir, didanosine, and tenofovir when not combined with zidovudine. Although it is the ‘‘signature mutation’’ for tenofovir, it seems to be selected less frequently with the combination of

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Table 2 Summary of NRTI resistance mutations Mutation

Selected by

Effects on other NRTIs

M184V

3TC, FTC

n Loss of susceptibility to 3TC, FTC n Y susceptibility to ABC, ddI (clinically insignificant when no other mutations present) n Delayed TAMs and [ susceptibility to ZDV, d4T, TDF

TAMs

ZDV, d4T

n Y susceptibility to all NRTIs n Degree of resistance depends on number of TAMs and TAM pathway n Greater loss of susceptibility with 41/210/215 pathway than with 67/70/219 pathway

Q151M, T69ins

ZDV/ddI, ddI/d4T

n Both: resistance to all NRTIs

K65R

TDF, ABC, ddI

n Variable Y susceptibility to TDF, ABC, ddI (and 3TC, FTC)

n T69ins: TDF resistance

n [ susceptibility to ZDV L74V

ABC, ddI

n Y susceptibility to ABC, ddI n [ susceptibility to ZDV, TDF

E44A/D, V118I

ZDV, d4T

n [ NRTI resistance (with 41/210/215 pathway)

Abbreviations: 3TC, lamivudine; ABC, abacavir; d4T, stavudine; ddI, didanosine; FTC, emtricitabine; NRTI, nucleotide reverse transcriptase inhibitor; TAMs, thymidine analog mutations; TDF, tenofovir; ZDV, zidovudine.

tenofovir-emtricitabine than with tenofovir-lamivudine [44]. It causes variable loss of susceptibility to abacavir, didanosine, tenofovir, lamivudine, and emtricitabine, but increases susceptibility to zidovudine. L74V is selected by abacavir and didanosine, resulting in variable loss of susceptibility to both but retained or increased susceptibility to zidovudine and tenofovir. Failure of abacavir-containing regimens that do not include zidovudine may lead to emergence of either K65R or L74V, but L74V seems to be more common. The activity of tenofovir in the presence of L74V after failure of abacavir- or didanosine-containing regimens has not been well studied clinically. Multinucleoside resistance mutations include the T69 insertion mutation and the Q151M complex, both of which cause broad NRTI cross-resistance. They have been associated primarily with use of zidovudine-didanosine and stavudine-didanosine in the pre-HAART era. These are no longer common mutations, presumably because either lamivudine or emtricitabine are a component of virtually all antiretroviral regimens. The T69 insertion

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mutation causes resistance to tenofovir, whereas tenofovir susceptibility is partially retained with the Q151M complex. A far more common cause of multinucleoside resistance is the presence of multiple TAMs. E44A/D and V118I are accessory mutations that further decrease NRTI susceptibility when combined with TAMs in the 41/210/215 pathway. TAM-mediated resistance emerges gradually because of the inhibitory effect of M184V and because no single TAM causes high-level resistance. It should not occur if patients are not allowed to remain on zidovudineor stavudine-containing regimens with ongoing viral replication, and as a result, TAMs should be viewed as preventable mutations. In contrast, M184V emerges early in patients failing lamivudine- or emtricitabinecontaining regimens. K65R or L74V can also emerge early in patients taking combinations that select for them. Nonnucleoside reverse transcriptase inhibitors resistance Cross-resistance among the first three NNRTIs (nevirapine, delavirdine, and efavirenz) is broad and widespread, because the common NNRTI mutations cause high-level resistance and can emerge quickly. K103N is the most common mutation affecting this class. Y181C is sometimes seen in patients failing nevirapine-based therapy, although K103N is favored when zidovudine is included in the regimen, because Y181C improves susceptibility to zidovudine. A number of other, less common mutations also occur in NNRTI-treated patients, including mutations at codons 100, 106, 108, 188, 190, 225, and 227. Some (eg, G190A/S/E) cause hypersusceptibility to delavirdine, although there are no clinical data on the efficacy of that drug in patients who have experienced failure of another NNRTI with these mutations. Because most NNRTI mutations cause high-level resistance with minimal effect on viral fitness, there is no benefit to continuing NNRTIs if the viral load is not fully suppressed, a practice that could allow accumulation of additional NNRTI mutations that could lead to cross-resistance to the later use of the second-generation NNRTIs in development. Etravirine (TMC125) has activity against virus expressing K103N and other NNRTI mutations. No single NNRTI mutation causes significant resistance to etravirine. Response to etravirine is attenuated, however, as the number of NNRTI mutations increases [45]. Y181C seems to have a greater effect on etravirine susceptibility than the more common K103N mutation. Protease inhibitor resistance Some primary PI mutations are unique to specific drugs. For example, D30N, which is selected only by nelfinavir, does not cause cross-resistance to other PIs. I50L is selected by atazanavir when it is used without ritonavir boosting in PI-naive patients [46]. In contrast, other primary PI mutations, such as those at codons 82, 84, and 90, are selected by numerous PIs, causing broad cross-resistance within the class [47]. Now that most PIs are being

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combined with low-dose ritonavir for pharmacokinetic ‘‘boosting,’’ these distinctions have become less important, because patients with early virologic failure on ritonavir-boosted PIs typically have no PI mutations [48,49]. Patients with extensive PI resistance usually developed it while taking unboosted PIs in the early years of the HAART era, when it was not uncommon to leave patients on failing regimens. There are now treatment options for many such patients within the PI class, with the recent approval of tipranavir and darunavir, two second-generation PIs with demonstrated efficacy in PI-resistant patients. Tipranavir, which is always boosted with ritonavir, is approved for use in highly treatment-experienced patients or those with HIV strains resistant to multiple PIs. Its efficacy in PI-experienced patients was demonstrated in the RESIST trials, in which patients taking ritonavir-boosted tipranavir plus an optimized background regimen achieved significantly greater mean reductions in viral load at 48 and 96 weeks than those taking comparator PIs [50]. Patients treated with tipranavir-ritonavir who used the fusion inhibitor enfuvirtide for the first time in their background regimens had the best response, emphasizing the importance of including a fully active second agent in a new regimen for a treatment-experienced patient. Susceptibility to tipranavir can be assessed genotypically using a mutation score determined by adding up the number of the following mutations: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, and 84V. In the RESIST trials, patients with a baseline score of 0 to 1 had the best response to therapy with tipranavir-ritonavir, those with scores of 2 to 7 had an intermediate response, and scores of 8 or higher were associated with minimal response [51]. Phenotyping may provide a more accurate assessment of susceptibility to tipranavir, as with any new drug for which genotypic correlates of resistance have not been fully characterized. Tipranavir should not be combined with PIs other than ritonavir, because it is a potent inducer of CYP3A4 metabolism, significantly reducing plasma concentrations of other PIs. It is associated with greater hepatotoxicity and hyperlipidemia than other PIs, which may be caused in part by the higher dose of ritonavir required for boosting (200 mg twice daily). The US Food and Drug Administration also issued a warning about an increased risk for intracranial hemorrhage in patients taking tipranavir. Most of the cases reported have occurred in patients with other medical conditions or taking medications that could have increased the risk of bleeding. Darunavir (formerly TMC114) was approved by the Food and Drug Administration in June 2006 for use in treatment-experienced patients. Like tipranavir, it is active against PI-resistant virus and also requires boosting with ritonavir, although with a lower dose (100 mg twice daily). In the POWER studies, multiclass-experienced patients treated with darunavir/ ritonavir, 600/100 mg twice daily, plus an optimized background regimen experienced significantly greater viral load reductions and rates of suppression

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to less than 50 copies/mL at 24 and 48 weeks than those taking comparator PIs [52]. The toxicity of darunavir-ritonavir in the POWER studies was similar to that observed with comparator PIs. In the POWER studies, baseline phenotypic susceptibility to darunavir was the strongest predictor of virologic response, with the best response being associated with a fold change of less than or equal to 10 [53]. Genotypic mutations associated with decreased response were 11I, 32I, 33F, 47V, 50V, 54L/M, 73S, 76V, 84V, and 89V. The presence of three or more of these mutations at baseline was associated with a decreased virologic response. The concomitant use of enfuvirtide provided additional benefit overall, although patients with less treatment-experience or with baseline phenotypic susceptibility to darunavir derived less additional benefit from use of enfuvirtide. Lacking a head-to-head trial, it is difficult to compare tipranavir and darunavir. Both have been shown to be superior to comparator PIs in multiclass-experienced patients with varying degrees of PI resistance. Although a larger proportion of participants achieved undetectable viral loads in the POWER trials than in the RESIST trials, there is considerable variation in the degree of treatment experience and drug resistance and in the selected background regimens, making cross-study comparisons difficult. Comparing toxicity is more straightforward. The toxicity profile for darunavir-ritonavir in the POWER studies was similar to that of the comparator PIs, whereas tipranavir-ritonavir caused significantly more hyperlipidemia and hepatotoxicity than the comparator PIs in the RESIST trials. When faced with a patient with resistance to other PIs, resistance testing provides the best means for choosing between tipranavir and darunavir. Although there is some overlap (eg, mutations at codons 33F, 54M, and 84V), their resistance profiles, discussed previously, differ considerably. Phenotyping may be preferred when assessing susceptibility to new PIs, because early genotypic algorithms are refined over time. If resistance testing demonstrates susceptibility to both drugs, then darunavir is preferred because of toxicity and cost considerations. Approach to patients with limited treatment options Because of the high levels of cross-resistance within each of the antiretroviral drug classes, the success of so-called ‘‘salvage therapy’’ has traditionally decreased with increasing antiretroviral experience. Although patients failing initial or second regimens have generally had suppressive options available, those with greater treatment experience and drug resistance were sometimes unable to achieve complete suppression using available agents. This is beginning to change now, with the availability of a fusion inhibitor, second-generation PIs and NNRTIs, integrase inhibitors, and CCR5 inhibitors. DHHS and International AIDS Society-USA treatment guidelines now state that the goal of therapy is virologic suppression to less than 50 copies/mL for all patients, not just those with less treatment

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experience [4,10]. Nevertheless, there will probably always be some patients for whom complete suppression is unrealistic. Strategies for the management of such patients are discussed next. Continued nonsuppressive therapy When virologic suppression to undetectable levels is no longer possible, the goal of therapy is to suppress viral load as much as possible and to prevent CD4 count decline and clinical progression. In most cases, patients are better off on nonsuppressive therapy than on no therapy at all, because even a partial virologic response can help to maintain clinical and immunologic stability. The phenomenon of viral load-CD4 ‘‘discordance,’’ in which patients with incomplete virologic suppression may experience stable or increasing CD4 cell counts, and may be caused by a combination of partial suppression of the viral load below baseline levels and by decreased viral replicative capacity resulting from the presence of resistance mutations [54–56]. There are drawbacks to continued nonsuppressive therapy, however, the most important of which is further accumulation of resistance mutations [21,22,24,25]. The evolution of further resistance with nonsuppressive therapy may occur less rapidly in patients who already have significant resistance, however, than in those failing earlier regimens [24,57]. Moreover, further accumulation of resistance mutations may be inconsequential. For example, a patient with five thymidine analogue mutations is unlikely to be harmed by emergence of a sixth. In other cases, however, new mutations may decrease future treatment options because of their effect on susceptibility to agents in development. Patients without access to at least two active agents are unlikely to experience a sustained response to therapy. It is generally preferable to wait until two active agents are available rather than to use a fully active agent along with drugs to which the patients’ virus is no longer susceptible. In such cases, the use of a partially active ‘‘holding regimen’’ is usually advisable, the goal being to maintain resistance mutations and decrease replication capacity to prevent or slow disease progression. When selecting a holding regimen, there are several important considerations: NNRTIs should not be used because NNRTI mutations have no significant impact on replication capacity, and the accumulation of new NNRTI mutations might preclude later use of second-generation NNRTIs, such as etravirine. Lamivudine or emtricitabine should usually be included in the regimen, because they are safe, well-tolerated agents that do not select for additional mutations after emergence of M184V and that provide partial virologic suppression despite resistance [58,59]. Maintaining M184V is beneficial, because it decreases replication capacity and increases susceptibility to stavudine, tenofovir, and zidovudine. The use of PIs or other NRTIs depends on the patient’s resistance pattern and the consequences of further viral evolution, although it should be noted that there is some evidence for the benefit of continued NRTIs despite extensive NRTI resistance (see section on

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treatment interruption). In addition to these considerations, ‘‘holding regimens’’ should also be chosen to minimize side effects and toxicity. Multidrug rescue therapy Multidrug rescue therapy, or ‘‘mega-HAART,’’ involves the use of six or more drugs in patients who have failed several prior regimens and have multidrug-resistant virus [60,61]. The rationale for this approach is the assumption that no single virion is likely to be resistant to all drugs in the salvage regimen, regardless of the degree of resistance present in the overall viral population. These regimens have generally been difficult to tolerate and maintain, although it has become easier to prescribe multiple drugs now that pill burdens have decreased and coformulated products have become available. Pharmacologic interactions are often impossible to predict, and there is a risk that some combinations may result either in subtherapeutic drug levels or excessive toxicity. Treatment interruptions in patients with persistent viremia At one time, there was some enthusiasm for complete treatment interruption before the initiation of salvage therapy in highly treatment-experienced patients. The rationale for this approach was that it would allow for replacement of resistant virus with drug-susceptible wild-type virus. Although there was some short-term success with this strategy [60,62,63], it later became clear that reinitiation of drugs to which the virus is resistant results in rapid selection of pre-existing resistant mutants [64], and that treatment interruption results in marked declines in CD4 cell counts and an increased risk of opportunistic infections and other clinical events [54,65,66]. This strategy can be dangerous in patients with advanced disease, but it may be viable in a subset of patients with earlier stage disease, who may be able safely to defer reinitiation of therapy until a more suppressive regimen can be constructed. An alternative approach is ‘‘partial treatment interruption.’’ In a small study, discontinuation of PIs with continued NRTI therapy resulted in short-term stability in a small trial [67]. In addition, the use of lamivudine monotherapy in patients already resistant to lamivudine was associated with a slower CD4 decline compared with complete treatment interruption [68]. The patients who benefited from lamivudine monotherapy had high CD4 counts at nadir and at the time of treatment interruption, however, so the results of this study are not applicable to highly treatment-experienced patients with advanced disease.

Use of novel or investigational agents The development of new agents is the best hope for patients with broad, multiclass resistance. Drugs in development include agents in existing classes

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that have unique resistance profiles and agents from classes with novel mechanisms of action. The decision to use a new agent can be challenging. Combination therapy is always required to prevent resistance; however, multiple new agents may not be available simultaneously. The choice is often between the lesser of two evils: premature use of a new agent in a nonsuppressive regimen, which may result in rapid emergence of resistance to that drug, versus deferring its use, with the potential for CD4 decline and adverse clinical outcomes. The fusion inhibitor enfuvirtide provides an illustration of this dilemma. The combination of enfuvirtide with at least one other active agent leads to sustained virologic response, which has been demonstrated in the original TORO trials [41,42], and in subsequent studies using tipranavir [50], darunavir [52], and MK-0518 [69] in highly treatment-experienced patients. However, enfuvirtide is expensive, requires twice-daily subcutaneous injections, and can cause painful injection site reactions. Clinicians are often reluctant to use it when they believe they can construct effective salvage regimens with other agents. These regimens are often unreliable in highly experienced patients, however, because of decreased susceptibility. When the salvage regimen fails, the amount of resistance is even greater, making it more difficult to find active drugs to combine with enfuvirtide. Like any new agent, enfuvirtide is less effective if it is reserved for ‘‘deep salvage’’ therapy. Recent data suggest that it has a low genetic barrier to resistance. High-level enfuvirtide resistance can emerge rapidly in the face of continued viral replication [69,70], and failure of enfuvirtide-containing regimens may be associated with rapid virologic rebound and questionable residual clinical benefit [70,71]. Many of these same considerations apply to virtually any new agent. A discussion of specific investigational antiretroviral agents is prone to rapid obsolescence, because new data emerge and investigational agents become approved drugs. As of February 2007, there are three investigational agents available through expanded access programs that are expected to be approved before the end of the year: MK-0518, an integrase inhibitor; etravirine, a second-generation NNRTI; and maraviroc, which blocks viral entry by inhibiting binding to the CCR5 coreceptor. All three have shown promising activity in treatment-experienced patients with highly resistant virus. Other investigational agents currently in clinical trials include but are not limited to GS-9137 (integrase inhibitor); vicriviroc (CCR5 inhibitor); TNX355 (monoclonal anti-CD4 antibody); and bevirimat (maturation inhibitor). Phase IIb and III clinical trials have allowed treatment-experienced patients access to investigational drugs to achieve virologic suppression that would be unlikely or impossible using only commercially available drugs. The benefit to study participants has been reflected in the results of studies like POWER, TORO, RESIST, and studies involving etravirine and MK0518. Before referring a patient to a clinical trial, however, the clinician

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must weigh the risks and benefits of trial participation for the individual patient. The design of these trials typically involves the use of an ‘‘optimized background regimen’’ composed of approved drugs selected by the investigator versus the optimized background regimen plus the investigational agent, sometimes at varying doses. Factors to consider when deciding whether to refer a patient to a trial include (1) the patient’s prognosis without suppressive therapy, which is a function of CD4 count, viral load, rate of CD4 decline, and clinical status; (2) the study design of the trial, including the odds of being randomized to the control arm; (3) the likelihood that the optimized background regimen will be active if the patient is randomized to the control arm or to an arm that includes a subtherapeutic dose of the study drug; and (4) the possibility that use of an active agent in the optimized background regimen arm will lead to resistance to that drug, with loss of future options, should the patient not achieve completely virologic suppression. For some patients, especially those with low and falling CD4 counts, clinical trials may provide the only opportunity to achieve resuppression and to prevent adverse clinical outcomes, and the risk of randomization to a nonsuppressive arm is a risk worth taking. Waiting for drug approval or expanded access may be a safer option for other patients, however, especially those with higher CD4 counts who are clinically stable and whose optimized background regimen may not be fully suppressive without an investigational drug.

Summary The management of treatment-experienced patients is complex and challenging. Fortunately, new agents continue to be developed that offer hope to those who have developed resistance to currently available agents. Knowing when, how, and in whom to use new agents is never easy and highlights the importance of expert care for HIV-infected patients. The management of treatment-experienced patients requires considerable expertise, especially now that even patients with highly resistant virus can hope to achieve full virologic suppression.

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