A n t i ret ro v i r a l T h e r a p y Treatment-experienced Individuals Katya R. Calvo,
MD
a
, Eric S. Daar,
MD
b,
*
KEYWORDS Treatment experienced HIV resistance Treatment simplification Antiretroviral failure KEY POINTS Modifying antiretroviral therapy (ART) requires knowledge of efficacy and tolerability of prior regimens, resistance test results, and careful assessment of ART adherence. Individuals experiencing suboptimal virologic response on ART should be assessed for modifiable factors that relate to the individual (eg, adherence) and the drugs (eg, absorption, drug-drug and drug-food interactions) before treatment modification. Once suboptimal virologic response is confirmed, a delay in modifying therapy is associated with worse virologic and clinical outcomes. There are strategic differences in modifying therapy in individuals failing first-line failure versus those who are highly treatment experienced. ART simplification in virologically suppressed individuals should take into consideration potential or known archived drug-resistant virus.
INTRODUCTION
Managing antiretroviral therapy (ART)–experienced individuals requires a systematic approach in order to optimize outcomes. Consideration must be given to the different reasons for switching or modifying therapy in a given person. These reasons range from the management of suboptimal virologic response, poor tolerability, to enhance convenience, or to minimize interactions with other medications or food. This article categorizes individuals as those planning to modify therapy for suboptimal virologic response or while maintaining virologic suppression.
a Division of HIV Medicine, Department of Internal Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, CDCRC 203, Torrance, CA 90502, USA; b Division of HIV Medicine, Department of Internal Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, CDCRC 205, Torrance, CA 90502, USA * Corresponding author. E-mail address: [email protected]
Infect Dis Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.idc.2014.06.005 0891-5520/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
id.theclinics.com
2
Calvo & Daar
The goal of therapy for ART-experienced individuals remains the same as for those who are starting therapy for the first time: to suppress plasma human immunodeficiency virus (HIV) RNA to undetectable levels. There are numerous highly effective and well-tolerated options for those initiating therapy for the first time.1,2 This therapeutic goal becomes more challenging in ART-experienced persons with histories of drug intolerance or resistance. This article provides guidance for clinicians managing ART-experienced individuals. ART-EXPERIENCED INDIVIDUALS WITH SUBOPTIMAL VIROLOGIC RESPONSE
Although there are no standardized definitions for virologic response, there is a consensus that plasma HIV RNA should ideally be suppressed to below the limits of detection of the available assays. Nevertheless, responses vary and each situation needs to be defined in order to address specific management strategies. Although such definitions may change with time, conceptualizing what is meant by each is important and they have been proposed in the current treatment guidelines and are summarized in Table 1.1 For the purposes of this article, suboptimal virologic response is defined as incomplete virologic response or rebound. The causes of suboptimal virologic response can be separated into factors related to the individual and those related to the antiretroviral regimen.6–8
Table 1 Definitions of virologic response Term
Definition
Comment
Virologic suppression
Plasma HIV RNA below the lower limits of detection of the available assay
—
Virologic failure
Inability to achieve or maintain suppression of plasma HIV RNA levels to 200 copies/mL after 24 wk of ART
The time to this goal may vary depending on baseline plasma HIV RNA and type of ART initiated
Virologic rebound
Confirmed plasma HIV RNA >200 copies/mL after virologic suppression is achieved
—
Virologic blip
Isolated detectable plasma HIV RNA level after virologic suppression, followed by return to virologic suppression
This does not seem to be an increased risk for virologic failure
Antiretroviral Therapy
Causes of Suboptimal Virologic Response
The causes of suboptimal virologic response may vary from person to person and require different management approaches, some of which are summarized in Table 2 and later in this article. Starting with higher plasma HIV RNA, with which it may take longer than 24 weeks to achieve full virologic suppression9 Having inadequate drug levels resulting from poor adherence, or drug-drug or drug-food interactions Using a regimen with inadequate potency either because of intrinsic properties of the drugs or the presence of drug-resistant virus acquired at the time of infection and/or selected for during the course of therapy Defining which of these factors may be contributing to suboptimal virologic response is a critical first step in the management of these individuals. If the suboptimal response is a result of taking the medication incorrectly then further instruction and adherence counseling may suffice. It is critical to identify reasons for poor adherence so that they can be managed. Common barriers to adherence include substance abuse, psychiatric illnesses, or unstable living situations, which need to be addressed as soon as possible or there is a risk of jeopardizing success with future regimens. If poor adherence is related to medication intolerance, then substitution of another drug usually is sufficient. Suspected Drug Resistance
If suboptimal virologic response persists after careful review and management of the modifiable causes outlined earlier, drug resistance testing should be obtained while patients are taking their current regimens or within 4 weeks after regimen discontinuation.1 Resistance tests are most reliable when plasma viral load is greater than 1000 copies/mL; however, testing can sometimes be performed successfully in patients with plasma HIV RNA less than 1000 copies/mL,10 although for technical and logistical reasons this is not always possible. Genotypic drug resistance testing is preferred for patients failing first-line or second-line regimens. Genotypic testing yields pertinent results regarding protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and nucleoside reverse transcriptase inhibitor (NRTI) resistance. The same is true for integrase strand transfer inhibitor (InSTI) resistance, although often this needs to be ordered separately. The role of phenotypic drug resistance testing is limited to patients with complex drug resistance patterns, especially to the PIs. In select situations additional testing may be ordered to assess resistance to the fusion inhibitor enfuvirtide or for viral tropism in Table 2 Common reasons for suboptimal virologic response Drug Related
Patient/Virus Related
Intolerance Pharmacologic (eg, drug-drug or drug-food interactions) Complex dosing schedule Suboptimal potency
High baseline plasma HIV RNA Low baseline CD4 cell count Transmitted or acquired drug resistance mutations Comorbidities (eg, substance abuse, psychiatric illnesses, neurocognitive deficits) Poor adherence Missed appointments Poor access to medications
3
4
Calvo & Daar
patients considering the use of, or experiencing virologic failure on, a CCR5 antagonist. Useful resources to assist clinicians in interpreting the results of drug resistance testing are available from the International Antiviral Society–USA (iasusa.org) and Stanford University Drug Resistance Database (hivdb.stanford.edu). Management of Suboptimal Virologic Response
Confirmed persistent plasma HIV RNA, especially when greater than 200 copies/mL, often results in the emergence of drug-resistant virus. A delay in treatment modification can be associated with increasing accumulation of resistance conferring mutations to drugs in the current regimen that often are cross-resistant to drugs not in the current regimen.11 As a result, viral suppression is more likely to occur when a therapeutic switch occurs in patients with low plasma HIV RNA and/or high CD4 T-cell counts.12 Once a decision is made to modify ART, guidelines traditionally recommend that patients with suboptimal virologic response be changed to a regimen that includes at least 2, and preferable 3, fully active drugs.1,13,14 The less potent the regimen (ie,
MD
a
, Eric S. Daar,
MD
b,
*
KEYWORDS Treatment experienced HIV resistance Treatment simplification Antiretroviral failure KEY POINTS Modifying antiretroviral therapy (ART) requires knowledge of efficacy and tolerability of prior regimens, resistance test results, and careful assessment of ART adherence. Individuals experiencing suboptimal virologic response on ART should be assessed for modifiable factors that relate to the individual (eg, adherence) and the drugs (eg, absorption, drug-drug and drug-food interactions) before treatment modification. Once suboptimal virologic response is confirmed, a delay in modifying therapy is associated with worse virologic and clinical outcomes. There are strategic differences in modifying therapy in individuals failing first-line failure versus those who are highly treatment experienced. ART simplification in virologically suppressed individuals should take into consideration potential or known archived drug-resistant virus.
INTRODUCTION
Managing antiretroviral therapy (ART)–experienced individuals requires a systematic approach in order to optimize outcomes. Consideration must be given to the different reasons for switching or modifying therapy in a given person. These reasons range from the management of suboptimal virologic response, poor tolerability, to enhance convenience, or to minimize interactions with other medications or food. This article categorizes individuals as those planning to modify therapy for suboptimal virologic response or while maintaining virologic suppression.
a Division of HIV Medicine, Department of Internal Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, CDCRC 203, Torrance, CA 90502, USA; b Division of HIV Medicine, Department of Internal Medicine, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, 1124 West Carson Street, CDCRC 205, Torrance, CA 90502, USA * Corresponding author. E-mail address: [email protected]
Infect Dis Clin N Am - (2014) -–http://dx.doi.org/10.1016/j.idc.2014.06.005 0891-5520/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
id.theclinics.com
2
Calvo & Daar
The goal of therapy for ART-experienced individuals remains the same as for those who are starting therapy for the first time: to suppress plasma human immunodeficiency virus (HIV) RNA to undetectable levels. There are numerous highly effective and well-tolerated options for those initiating therapy for the first time.1,2 This therapeutic goal becomes more challenging in ART-experienced persons with histories of drug intolerance or resistance. This article provides guidance for clinicians managing ART-experienced individuals. ART-EXPERIENCED INDIVIDUALS WITH SUBOPTIMAL VIROLOGIC RESPONSE
Although there are no standardized definitions for virologic response, there is a consensus that plasma HIV RNA should ideally be suppressed to below the limits of detection of the available assays. Nevertheless, responses vary and each situation needs to be defined in order to address specific management strategies. Although such definitions may change with time, conceptualizing what is meant by each is important and they have been proposed in the current treatment guidelines and are summarized in Table 1.1 For the purposes of this article, suboptimal virologic response is defined as incomplete virologic response or rebound. The causes of suboptimal virologic response can be separated into factors related to the individual and those related to the antiretroviral regimen.6–8
Table 1 Definitions of virologic response Term
Definition
Comment
Virologic suppression
Plasma HIV RNA below the lower limits of detection of the available assay
—
Virologic failure
Inability to achieve or maintain suppression of plasma HIV RNA levels to 200 copies/mL after 24 wk of ART
The time to this goal may vary depending on baseline plasma HIV RNA and type of ART initiated
Virologic rebound
Confirmed plasma HIV RNA >200 copies/mL after virologic suppression is achieved
—
Virologic blip
Isolated detectable plasma HIV RNA level after virologic suppression, followed by return to virologic suppression
This does not seem to be an increased risk for virologic failure
Antiretroviral Therapy
Causes of Suboptimal Virologic Response
The causes of suboptimal virologic response may vary from person to person and require different management approaches, some of which are summarized in Table 2 and later in this article. Starting with higher plasma HIV RNA, with which it may take longer than 24 weeks to achieve full virologic suppression9 Having inadequate drug levels resulting from poor adherence, or drug-drug or drug-food interactions Using a regimen with inadequate potency either because of intrinsic properties of the drugs or the presence of drug-resistant virus acquired at the time of infection and/or selected for during the course of therapy Defining which of these factors may be contributing to suboptimal virologic response is a critical first step in the management of these individuals. If the suboptimal response is a result of taking the medication incorrectly then further instruction and adherence counseling may suffice. It is critical to identify reasons for poor adherence so that they can be managed. Common barriers to adherence include substance abuse, psychiatric illnesses, or unstable living situations, which need to be addressed as soon as possible or there is a risk of jeopardizing success with future regimens. If poor adherence is related to medication intolerance, then substitution of another drug usually is sufficient. Suspected Drug Resistance
If suboptimal virologic response persists after careful review and management of the modifiable causes outlined earlier, drug resistance testing should be obtained while patients are taking their current regimens or within 4 weeks after regimen discontinuation.1 Resistance tests are most reliable when plasma viral load is greater than 1000 copies/mL; however, testing can sometimes be performed successfully in patients with plasma HIV RNA less than 1000 copies/mL,10 although for technical and logistical reasons this is not always possible. Genotypic drug resistance testing is preferred for patients failing first-line or second-line regimens. Genotypic testing yields pertinent results regarding protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and nucleoside reverse transcriptase inhibitor (NRTI) resistance. The same is true for integrase strand transfer inhibitor (InSTI) resistance, although often this needs to be ordered separately. The role of phenotypic drug resistance testing is limited to patients with complex drug resistance patterns, especially to the PIs. In select situations additional testing may be ordered to assess resistance to the fusion inhibitor enfuvirtide or for viral tropism in Table 2 Common reasons for suboptimal virologic response Drug Related
Patient/Virus Related
Intolerance Pharmacologic (eg, drug-drug or drug-food interactions) Complex dosing schedule Suboptimal potency
High baseline plasma HIV RNA Low baseline CD4 cell count Transmitted or acquired drug resistance mutations Comorbidities (eg, substance abuse, psychiatric illnesses, neurocognitive deficits) Poor adherence Missed appointments Poor access to medications
3
4
Calvo & Daar
patients considering the use of, or experiencing virologic failure on, a CCR5 antagonist. Useful resources to assist clinicians in interpreting the results of drug resistance testing are available from the International Antiviral Society–USA (iasusa.org) and Stanford University Drug Resistance Database (hivdb.stanford.edu). Management of Suboptimal Virologic Response
Confirmed persistent plasma HIV RNA, especially when greater than 200 copies/mL, often results in the emergence of drug-resistant virus. A delay in treatment modification can be associated with increasing accumulation of resistance conferring mutations to drugs in the current regimen that often are cross-resistant to drugs not in the current regimen.11 As a result, viral suppression is more likely to occur when a therapeutic switch occurs in patients with low plasma HIV RNA and/or high CD4 T-cell counts.12 Once a decision is made to modify ART, guidelines traditionally recommend that patients with suboptimal virologic response be changed to a regimen that includes at least 2, and preferable 3, fully active drugs.1,13,14 The less potent the regimen (ie,
