Changing Antiretroviral Therapy: Why, When, and How

Source : http://hivinsite.ucsf.edu/InSite?page=kb-03-02-06
(See Reference and Table 1-3)

HIV InSite Knowledge Base Chapter
June 2006

Timothy Wilkin, MD, MPH, Weill Medical College of Cornell University
Marshall Glesby, MD, PhD, Weill Medical College of Cornell University
Roy M. Gulick, MD, MPH, Weill Medical College of Cornell University


Introduction

Once antiretroviral therapy (ART) is initiated, patients generally remain on medications indefinitely. A change in the ART regimen is often necessary because of both acute and chronic toxicities, concomitant clinical conditions, and development of virologic failure. The approach to patients who need to change ART will differ depending on several issues, including the reason for change, the amount of previous ART experience, and the available treatment options. For example, when patients develop an adverse effect to a drug during their first ART regimen, effective treatment may be easily accomplished by substituting another agent for the offending drug in the regimen. At the opposite end of the spectrum are patients with advanced HIV disease who have experienced toxicities, virologic failure, and drug resistance during multiple past treatment regimens and thus require a new treatment regimen. This chapter reviews these circumstances and provides clinical evidence and strategies for changing therapy.


Acute Toxicities

Toxicities from ART are common and may necessitate changes in medications (Table 1). These toxicities are typically not life threatening but can affect quality of life and negatively affect patients' willingness to adhere to their regimens. In fact, several cohort studies have suggested that toxic effects are a more common reason for changing ART than are virologic failures.(1-4) A review of published cohort studies that examined modification of initial ART regimens found that antiretroviral intolerance and toxicity were the most common reasons for changing therapy in 8 of 11 studies.(4) Gastrointestinal disturbance such as nausea, vomiting, and diarrhea was the most frequently cited toxicity leading to a change in an initial ART regimen, and this has been confirmed in a separate cohort study.(3) Most of the modifications due to intolerance in these studies occurred within 3 months of starting ART.(4) The large majority of the patients in these cohort studies were taking protease inhibitor-based regimens.

Investigators monitoring an Italian cohort of HIV-infected patients examined the outcomes of patients whose first ART regimens were based on nonnucleoside reverse transcriptase inhibitors (NNRTIs).(5) They found that clinical drug toxicity, which occurred in 18% of patients starting a nevirapine-based regimen and in 10% of patients starting an efavirenz-based regimen, was the most common reason for changing an initial ART regimen. In contrast to gastrointestinal disturbance with protease inhibitor-based regimens, hypersensitivity (eg, rash and hepatitis) was the most common reason for discontinuing a nevirapine-based regimen (12%), and central nervous system toxicity was the most common reason for discontinuing an efavirenz-based regimen (5%). In addition to the toxicities mentioned above, rash, headache, fatigue, and abnormalities in hematologic and liver function tests are common toxic effects leading to a change in ART.(3) In some resource-constrained settings, where ART regimens usually consist of an NNRTI (typically nevirapine) in combination with either zidovudine or stavudine plus a second nucleoside analogue, high rates of acute toxicities necessitating antiretroviral changes have been reported (6-8) These adverse effects include rash, hepatotoxicity, and anemia.

No absolute guidelines exist for determining when to change regimens if these toxicities occur. Given that many patients improve within a few weeks of starting ART, providers often attempt to control adverse effects with short-term palliative medicine (eg, loperamide for diarrhea and prochlorperazine or metoclopramide for nausea). Efavirenz-associated central nervous system toxicity often subsides within a few weeks after starting the medication (9) and is usually managed by reassuring the patient. In the case of acute toxicity attributable to a specific antiretroviral drug, same-class substitution of a drug with a differing toxicity profile is accepted clinical practice, based largely on anecdotal experience and descriptive data from clinical trials (eg, abacavir or tenofovir for zidovudine-related gastrointestinal intolerance). The decision to change antiretroviral medications is based on consideration of the severity of symptoms, efficacy of palliative medications, options for substitution, and risks associated with those options. The occurrence of adverse effects has been associated with reduced adherence,(10) and providers generally should offer a change in medications for patients who report diminished adherence due to toxicity. Modification of ART because of toxicity in patients who are starting an initial ART regimen does not seem to be associated with subsequent virologic failure.(11,12)


Chronic Toxicities

Certain toxicities emerge months to years after the initiation of antiretroviral medications. These include neuropathy, changes in body composition (commonly termed lipodystrophy), and metabolic toxicities (eg, dyslipidemia and insulin resistance) that are associated with an increased risk of cardiovascular events. Researchers have shown great interest in the strategy of changing antiretrovirals to manage these chronic toxicities. The presumed multifactorial etiology of such complications makes their study a challenge because >1 drug or class of drugs in a regimen may contribute pathogenetically to the toxicity. Nonetheless, investigators have addressed chronic toxicities by substituting drugs that have been linked epidemiologically to specific adverse effects.


Lipoatrophy

Lipoatrophy (eg, loss of subcutaneous fat in the face, extremities, and buttocks) is a component of lipodystrophy. Thymidine analogue use has been associated with lipoatrophy, and, in particular, stavudine use has been identified as a risk factor in several studies.(13,14) Although fat loss was once thought to be irreversible, small proof-of-concept studies have suggested that substituting zidovudine or abacavir for stavudine was an approach worthy of further examination.(15,16) In a landmark study, subjects with lipoatrophy were randomized to continue stavudine or zidovudine or to switch the thymidine analogue to abacavir. Those who switched had statistically significant increases in both subcutaneous abdominal tissue volumes by computed tomography and peripheral fat mass by dual-energy X-ray absorptiometry (DEXA) scanning at 24 weeks of follow-up.(17) Although these short-term changes were not clinically significant, further follow-up to 2 years demonstrated continued improvements in lipoatrophy.(18) Other studies have demonstrated improvements in lipoatrophy after substituting abacavir,(19,20) tenofovir,(20) or zidovudine (19) in place of stavudine, suggesting that this approach may be reasonable to consider if a patient's treatment history permits safe substitution. A patient with a history of abacavir hypersensitivity or documented resistance to abacavir would not be an appropriate candidate for this switch. Similarly, a history of single or dual nucleoside analogue therapy is associated with an increased risk of virologic failure after changing to abacavir, probably because of preexisting nucleoside resistance mutations, and precludes such a switch.(21)

Observational data have suggested that protease inhibitors may act synergistically with nucleoside analogues in the development of lipoatrophy.(22) Several small, randomized controlled studies in which a protease inhibitor was switched to an alternative agent, however, have not shown objective improvements in lipoatrophy.(22,23,24) For example, among 77 subjects randomized either to switch from a protease inhibitor to nevirapine or efavirenz or to continue the protease inhibitor, the 58 subjects with lipodystrophy at baseline showed no changes in body composition by DEXA or anthropometric measurements after 1 year of follow-up.(22) Contrasting results came from a subgroup analysis of a larger trial in which 8 subjects taking a regimen containing zidovudine and a protease inhibitor switched their protease inhibitor for abacavir. On average, these subjects gained small amounts of leg fat over 48 weeks, as assessed by DEXA, compared with 7 control subjects who remained on a zidovudine-based regimen that included a protease inhibitor.(25) Taken together, these data suggest that substituting another agent for a protease inhibitor is not likely to have a clinically significant impact on lipoatrophy, at least in the short term.


Central Fat Accumulation

Because increased truncal (visceral) fat has been linked epidemiologically to protease inhibitor use, the effect on truncal fat of switching to regimens that do not contain a protease inhibitor has been explored in several small studies, most of which have lacked a control group and objective end points.(26-28) In 1 randomized study, subjects with increased visceral abdominal tissue volume at baseline had greater reductions after switching from a protease inhibitor-containing regimen to abacavir, nevirapine, adefovir, and hydroxyurea compared with controls who stayed on protease inhibitor-containing regimens.(29) Lipoatrophy, however, worsened in those randomized to the change in regimens. In a metabolic substudy of a large randomized trial, no significant improvement was found in body composition abnormalities 24 months after patients switched from a protease inhibitor to abacavir, nevirapine, or efavirenz.(24) Overall, the approach of switching from protease inhibitors has not proven successful and cannot be recommended as a strategy for addressing increased truncal fat. Specific therapies for this condition are an active area of research.


Dyslipidemia

Hypertriglyceridemia and hypercholesterolemia have been clearly associated with the use of specific protease inhibitors and may occur within weeks after initiation. These toxicities have been managed successfully by switching within the protease inhibitor class or by switching to drugs from other antiretroviral classes. As an example of the first approach, replacing ritonavir with nelfinavir or nelfinavir plus saquinavir improved lipid profiles in a small, randomized study.(30) Similarly, substituting atazanavir for a protease inhibitor improved lipid profiles in uncontrolled studies (31,32) and in a randomized comparison with lopinavir-ritonavir.(33) The effect of substitution of a protease inhibitor with the combination of atazanavir and low-dose ritonavir is less clear; in 1 randomized study, atazanavir-ritonavir appeared to affect total cholesterol and triglycerides favorably, whereas lopinavir-ritonavir appeared to worsen these parameters.(34) Several studies have examined the approach of switching a protease inhibitor to an NNRTI or abacavir. These studies are reviewed in detail elsewhere.(35) In general, substitution of nevirapine (24,36) or abacavir (21,24,37) has had favorable effects on triglycerides and often on total cholesterol, whereas substitution of efavirenz has yielded mixed results.(27,36,38). However, in a randomized study, triglyceride levels decreased in the first 12 months after substitution of efavirenz, nevirapine, or abacavir for a protease inhibitor, but returned to baseline by 24 months.(24) Changing to efavirenz or nevirapine may increase high-density lipoprotein cholesterol,(35,36) but may have variable effects on low-density lipoprotein (LDL) cholesterol.(24,36)

Nucleoside analogues also may contribute to dyslipidemia in HIV-infected patients. Stavudine has been associated with greater adverse lipid effects in 2 randomized, controlled studies when compared with zidovudine or tenofovir, in conjunction with lamivudine and efavirenz or nelfinavir.(39,40) Several studies have suggested that substituting tenofovir for stavudine may improve total cholesterol and LDL cholesterol; the effect on triglyceride levels is less clear.(20,41)


Insulin Resistance/Diabetes Mellitus

The effect of drug substitution has been characterized less well for insulin resistance than for dyslipidemia. Whereas indinavir clearly causes decreased insulin sensitivity when administered to healthy, HIV-uninfected volunteers,(42,43) the relative effects of other protease inhibitors have not been clearly discerned in vivo. In vitro data concerning insulin resistance (44) and diabetes mellitus associated with protease inhibitor use,(45) however, do suggest that certain other drugs within the class may induce insulin resistance directly or indirectly. Switching a protease inhibitor to abacavir,(24,46) efavirenz,(24,27) or nevirapine (24,26) appears to have a favorable effect on insulin resistance; few data exist on the effect of substituting atazanavir for another protease inhibitor. Substituting an alternative drug for a protease inhibitor may therefore be a reasonable strategy for patients with other risk factors for diabetes mellitus, such as obesity and positive family history,(47) although no data are available on the efficacy of such a strategy in preventing the development of diabetes mellitus. Because insulin resistance is associated with increased cardiovascular risk in the general population,(48) reducing insulin resistance may have long-term benefits.



Life-Threatening Toxicities

Life-threatening toxicities are rare, but remain an important reason for changing ART. Severe rash such as Stevens-Johnson syndrome or erythema multiforme is an indication to change ART.(49) These rashes have been reported most commonly with NNRTIs: delavirdine (rarely), efavirenz (0.1%), and nevirapine (1%).(50-52) Lactic acidosis is potentially fatal and is most commonly associated with stavudine, but it has been reported with all nucleoside reverse transcriptase inhibitors.(53,54) In the case of symptomatic hyperlactatemia or lactic acidosis, retrospective data suggest that it is generally safe to change the presumed offending agent (typically stavudine or didanosine) to an alternative nucleoside analogue considered to have similar virologic activity but less propensity to injure mitochondria (typically abacavir, lamivudine, or tenofovir).(55) This substitution is generally made after a treatment interruption to allow resolution of the initial toxicity. Other potentially fatal toxicities include didanosine-associated pancreatitis (56) and abacavir hypersensitivity.(57) Rechallenge with the offending agent after the onset of any of these life-threatening toxicities should not be attempted.


Adherence/Quality of Life

Much progress has been made in simplifying ART so that regimens are easier for patients to take in a consistent manner. In the mid- to late 1990s, combination ART involved taking medications at least 3 times a day, often with food and water restrictions and high numbers of pills. These complex regimens are gradually giving way to simpler regimens involving fixed-dose combination pills, newer drugs or formulations that can be taken once daily, and the use of ritonavir for pharmacokinetic enhancement of other protease inhibitors (Table 2). Given these new options, many patients with stable virologic suppression on more difficult regimens can change to regimens with lower pill burdens and minimal dosing complexity, thus improving adherence and quality of life.

Investigators have studied many approaches to simplifying complex ART regimens with the aim of improving adherence and quality of life, and thereby reducing rates of virologic failure. The most widely studied approach has been replacing a protease inhibitor with nevirapine, efavirenz, or abacavir in patients with full virologic suppression while taking a protease inhibitor-based regimen. In 2 studies, adherence improved in subjects randomized to switch from a protease inhibitor to efavirenz (58) or to abacavir (37) compared with those who continued the protease inhibitor-based regimen. In both studies, time to virologic failure was delayed in the switch arms, suggesting that the improvement in adherence was clinically relevant. Other investigators have reported improvements in quality of life, as assessed by questionnaires, in 2 randomized studies in which protease inhibitors were switched to nevirapine (59) or to either nevirapine or efavirenz (22) compared with continuing the protease inhibitor.

Clinicians who are contemplating changing an ART regimen for quality-of-life considerations should keep in mind the potential for adverse effects of the new regimen. In a large, randomized study that assessed the efficacy of simplifying protease inhibitor-based regimens by substitution with abacavir, efavirenz, or nevirapine, approximately 50% of subjects had new adverse events, although few of those events resulted in discontinuation of the regimen.(60) With the advent of several simpler protease inhibitor regimens that include options for once-daily dosing with decreased pill burden and fewer adverse effects, clinicians may have less need for the strategy of replacing protease inhibitors merely for the purpose of simplification.


Changing ART in Patients with Virologic Suppression

When considering changing an ART regimen for any of the reasons discussed above in a patient with virologic suppression, it is critical to examine the patient's treatment history. Previous virologic failure on an NNRTI, whether or not resistance testing was performed, or documented resistance to this class of agents is a contraindication to switching to nevirapine or efavirenz. Similarly, previous monotherapy or dual therapy with nucleoside analogues increases the risk of virologic failure when changing to abacavir because of selected nucleoside resistance mutations. Of note, substituting abacavir for a protease inhibitor or NNRTI typically results in a triple nucleoside regimen, which has been shown to be virologically inferior to efavirenz-based regimens as initial therapy.(61) Although switching a virologically suppressed patient to a triple-nucleoside regimen may differ from using such a regimen as initial treatment, a randomized simplification trial in which subjects on protease inhibitors were switched to abacavir, nevirapine, or efavirenz showed a trend toward a greater rate of virologic failure in the abacavir arm.(60) Thus, drug substitution that results in a triple-nucleoside combination without additional drugs cannot be recommended for most patients.


Concomitant Medical Conditions

A patient's changing clinical status often mandates a change in ART. For example, certain antiretroviral medications are less favored in pregnancy. Efavirenz is teratogenic in animals and was linked to birth defects in several reported cases,(62,63) so this agent should be substituted with nevirapine or an appropriate protease inhibitor-based regimen in pregnant women.(63) Caution should be used with nevirapine in pregnancy because it has been associated with an increased risk of fatal hepatitis in pregnant women, especially in women with higher CD4 counts; nevirapine generally should not be initiated in women whose CD4 count is >250 cells/µL.(64) The oral solution of amprenavir should not be used in pregnant women because of the high content of polyethylene glycol,(65) and hyperbilirubinemia induced by atazanavir and indinavir is a theoretical risk for the newborn.(66,67)

Medications used to treat comorbid illnesses often interact with antiretroviral agents. A prime example is the interaction of rifampin, a first-line drug for the treatment of tuberculosis, with both NNRTIs and protease inhibitors.(68) This interaction may be avoided by substitution of efavirenz for nevirapine, perhaps by dose adjustment of efavirenz,(69) or by substitution of rifabutin for rifampin in the case of protease inhibitors.(68) Other important drug interactions include cholesterol-lowering "statins" with protease inhibitors,(70) oral contraceptives with NNRTIs or protease inhibitors,(71) and ergot derivatives with protease inhibitors.(72) The activity of tenofovir, emtricitabine, and lamivudine against hepatitis B has encouraged many providers to include these medicines in the ART regimens of patients with chronic hepatitis B.(73-75) (See chapter "Coinfection with Hepatitis Viruses and HIV.")


Suboptimal Immunologic Response

Patients starting ART may fail to have a significant increase in CD4 cells despite control of viral replication. Investigators from the Swiss HIV Cohort Study reported that 38% of patients with stable suppression of HIV during ART for >5 years failed to reach a CD4 count of at least 500 cells/µL.(76) In some cases, the particular ART regimen may be problematic; several studies have shown suboptimal increases, or even decreases, in the CD4 count in patients treated with virologically suppressive ART regimens that include the combination of didanosine and tenofovir.(77,78) Generally, however, the causes and clinical significance of this phenomenon are unclear, but remain a concern for both patient and provider. Treatment intensification (supplementing an existing regimen with additional antiretroviral drugs) in the setting of poor CD4 recovery has not been shown to increase the CD4 count.(79) Interleukin-2 has been shown to increase CD4 cells, but its relationship to clinical outcomes has been lacking and adverse effects are common.(80) The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) study is a large ongoing trial that is assessing clinical end points (eg, death, new opportunistic infections) with subcutaneous interleukin-2 versus placebo in patients taking ART. However, this study is limited to individuals who have CD4 counts >300 cells/µL at baseline. Without additional data, the best strategy for patients with virologic suppression and suboptimal immunologic response is probably to continue their current regimens.


HIV-Related Clinical Events

Clinical events such as opportunistic infections or AIDS-associated malignancies are uncommon in patients with virologic suppression during ART. The ART Cohort Collaboration, involving 13 cohort studies of patients starting a first ART regimen, estimated the risk of an AIDS-defining illness or death within 3 years of starting ART. Among those patients with virologic suppression 6 months after starting ART, the estimate of risk ranged from 14% for those with a 6-month CD4 count of <25>350 cells/µL.(81,82) Limited data are available on whether to change ART for patients who develop AIDS-defining illnesses. Certainly, a regimen should be changed if the patient has detectable viremia and if viable alternatives exist to ensure maximal suppression of HIV and to enhance immune reconstitution. Other infections such as herpes simplex virus reactivation, herpes zoster, pneumonia, and human papillomavirus-associated squamous intraepithelial lesions (eg, cervical and anal dysplasia) can occur in patients with stable virologic suppression during ART and do not indicate a need for changing ART.

Caution should be used in interpreting clinical events that occur soon after the initiation of ART (eg, within 3 months). During this period, patients starting ART with lower CD4 cell counts, especially <100>Changing ART for Virologic Failure

The treatment guidelines of the U.S. Department of Health and Human Services suggest criteria for assessing virologic failure: HIV RNA >400 copies/mL at 24 weeks of therapy, HIV RNA >50 copies/mL by 48 weeks of ART, or repeated detection of viremia after virologic suppression.(71) A single elevated HIV RNA level should be confirmed with a second measurement because an isolated increase ("blip") in HIV RNA may occur in up to 40% of patients and is not associated with virologic failure.(84) However, repeated or sustained increases in HIV RNA levels are associated with an increased risk of virologic failure.(85)


Cause of Failure

Once a patient has experienced virologic failure, the cause of the failure should be explored. If adherence, toxicity, and pharmacokinetic reasons can be excluded, then virologic failure of the current regimen has been established. The initial approach to treatment failure is to carefully review the patient's antiretroviral history, including each specific drug (noting the formulation) and each previous regimen, the duration of each regimen, any adverse effects or toxicities, and the response in HIV RNA levels and CD4 cell counts (if known). This information is essential for assessing the likelihood of archived resistance mutations to individual drugs or drug classes. The patient should be encouraged to continue the current regimen during the assessment of virologic failure because discontinuing ART, even in the setting of virologic failure, may lead to both a rapid increase in HIV RNA level and a decrease in CD4 cell count, with or without clinical events.(86)


Resistance Testing

Resistance testing gives information only about the most prevalent viral strain circulating at the time the blood specimen is obtained. Therefore, resistance testing should be performed while the patient is taking the failing treatment regimen, because virus that harbors resistance mutations may not be detected readily after the selective pressure of drug is removed, but nevertheless will remain archived in tissue reservoirs. In separate studies, both genotypic testing (87,88) and phenotypic testing (89) led to significantly improved virologic responses with the subsequent ART regimen as compared with the strategy of using the antiretroviral history alone in selecting the regimen. (See chapter "Genotypic Testing for HIV-1 Drug Resistance.") Although current guidelines recommend the use of resistance testing in the management of antiretroviral failure,(71,90) it is not clear whether the optimal test is a genotype, a phenotype,(91) or both.(92) Used together, a careful ART history and resistance testing yield the most complete assessment of both archived and present resistance mutations, and this strategy optimizes selection of the next ART regimen.


Expert Advice

Evaluation and management of antiretroviral-experienced patients are complicated. Because HIV clinicians may have limited knowledge about resistance testing,(93) expert advice is recommended. In the Havana study, resistance testing and expert advice for selecting subsequent ART regimens were each associated with improved virologic responses.(94) Current guidelines suggest obtaining expert advice when managing treatment-experienced patients.(71)


Pharmacokinetics

Drug concentrations are associated with virologic responses in treatment-experienced patients. For example, as part of the Viradapt study, protease inhibitor concentrations were measured in patients taking combination regimens and were assessed as optimal or suboptimal (<2-fold>Selecting the Next Regimen.

For a patient experiencing virologic failure, how is the next ART regimen optimally designed? The initial approach was simply to use drugs that the patient had not yet taken, but in early clinical studies such as AIDS Clinical Trials Group studies 359 and 398, this strategy achieved maximal virologic suppression in only about 30% of patients.(101,102) However, these early studies did suggest factors that were associated with better virologic responses, including a lower baseline HIV RNA level at the time of regimen change; use of 2 protease inhibitors, rather than 1, in the next regimen; and use of a new class of agents (eg, NNRTIs). The initial studies of resistance testing also led to the recommendation that the new ART regimen for a patient experiencing virologic failure should contain at least 3 active (on the basis of resistance testing) antiretroviral agents to achieve an optimal virologic response.(71,87)

One study incorporated several of these factors in its design by enrolling 70 patients who had experienced failure of only 1 protease inhibitor, had not taken NNRTIs, and had HIV RNA levels ranging from 1,000 copies/mL to 100,000 copies/mL.(103) The subjects substituted lopinavir/ritonavir (at either of 2 randomly assigned doses) for their current protease inhibitor and also added nevirapine (introducing a new drug class for these subjects) and at least 1 new nucleoside analogue.(103) At 48 weeks in an intent-to-treat analysis, 70% of subjects had HIV RNA levels <400>

Conclusions

Changing an ART regimen is common in clinical practice for patients with either suppressed virologic replication or virologic failure. Those with virologic suppression usually have changes in ART in an attempt to alleviate acute toxicities, control chronic toxicities, or improve quality of life. This strategy generally appears safe as long as relevant issues such as previous ART use are considered. The benefits of changing ART must be weighed against the possibilities of encountering new toxicities and increasing the risk of virologic failure. The management of virologic failure among treatment-experienced patients has improved over the last several years. The establishment of clear criteria for assessing virologic failure, the development and availability of HIV resistance testing, the identification of factors leading to improved virologic responses in subsequent regimens (eg, 3 active drugs in the regimen), the development of new antiretroviral agents with activity against resistant virus, and the exploration of therapeutic drug monitoring have contributed to progress in the field.