Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults

doi:10.1016/S1473-3099(06)70550-3

The Lancet Infectious Diseases

Volume 6, Issue 8, August 2006, Pages 496-507

https://doi.org/10.1016/S1473-3099(06)70550-3 Get rights and content

Summary

Despite dramatic declines in HIV-associated morbidity and mortality as a result of highly active antiretroviral therapy, management of heavily treatment-experienced patients remains complex and challenging. Treatment response rates with subsequent antiretroviral regimens are lower than with initial antiretroviral therapy. Additionally, increased mortality has been associated with multidrug-resistant HIV. We review data relevant to management of such patients and offer a systematic approach to constructing a salvage antiretroviral regimen.

Introduction

The availability of potent antiretroviral drugs and their use in three or more drug combination regimens—highly active antiretroviral therapy (HAART)—has led to a dramatic decline in the morbidity and mortality associated with HIV infection.1, 2, 3 In spite of this, many HIV-infected patients receiving HAART are unable to achieve sustained levels of plasma HIV RNA below contemporary limits of detection. In particular, patients that initiated antiretroviral therapy before the HAART era have been exposed to serial ineffective monotherapy regimens as well as stepwise additions of single new agents to a failing antiretroviral regimen. Issues such as tolerability, adherence, and broad cross resistance within each class of antiretroviral drugs have further complicated the situation, resulting in the current common dilemma of clinical HIV care whereby a substantial number of HIV-infected patients have multi-antiretroviral class failure with limited options for future therapy.

By contrast with the 70–90% success rates commonly observed in clinical trials,3, 4, 5 only approximately 50% of patients who received HAART therapy in a non-clinical trial setting were reported to achieve the goal of viral suppression.6, 7, 8, 9 Response rates achievable with subsequent regimens prescribed after failure of primary HAART therapy are considerably lower. The prevalence of heavily treatment-experienced patients with multiclass resistance is variable and not well reported. In over 8500 patients in the EuroSIDA cohort, 413 (5%) were reported to have failed virologically two HAART regimens and experienced all three main drug classes.¹⁰ Richman and colleagues,¹¹ however, estimated resistance to all three drug classes to be present in 13% of adults receiving care in the USA with plasma viraemia over 500 copies per mL. Patients with multidrug-resistant HIV infection are believed to be at increased risk for mortality. In various studies, the hazard ratio for increased mortality attributable to drug resistance has ranged from 1·8 for resistance to any antiretroviral agent to 5·34 for triple-class resistance.12, 13, 14

In this review, we present data relevant to constructing an antiretroviral therapy regimen in heavily treatment-experienced HIV-infected adults with multiply resistant virus. For the purpose of this review, it is assumed that the potential causes that might have led to the development of drug resistance and treatment failure—eg, non-adherence, drug-related toxicity, and pharmacokinetics—have been addressed. Thus our focus will be on the process of selection of an appropriate antiretroviral regimen with a reasonable chance of success.

Section snippets

Treatment failure

Treatment failure is a general term that encompasses various reasons for an antiretroviral regimen to be deemed inadequate. Clinical failure indicates progression of clinical symptoms or the emergence of a new opportunistic infection, condition, or death while on an antiretroviral therapy. Virological failure indicates the loss of control of viral replication (ie, rebound in viral load). In this review, we use salvage therapy to describe treatment regimens for people who have failed more than

Antiretroviral treatment history

Current guidelines recommend resistance testing to optimise drug selection after treatment failure.15, 16, 17 However, current resistance testing options have been found to be insensitive in identifying minor viral species that constitute less than 10–20% of the circulating virus population.¹⁸ When the selective pressure on drug-resistant populations is relieved by withdrawal of drugs, wild-type virus re-emerges as the predominant virus population.19, 20, 21 This reversion to wild-type usually

Resistance testing

Two types of commercial assays are currently available to assess antiretroviral drug resistance.²⁴ Phenotypic drug susceptibility assays amplify the pol region of the patient's HIV-1, which encodes the viral enzymes reverse transcriptase and protease, and incorporates it into a laboratory virus that lacks this region. The resulting virus is called a recombinant virus and is cultured in the presence of increasing concentrations of an antiretroviral drug to determine the concentration required to

Replication capacity

The term replication capacity refers to the ability of a virus to replicate compared with that of a wild-type drug sensitive control virus. Replication capacity is expressed as a percentage of wild-type virus, in which 100% is defined as the median replication capacity of a population of wild-type clinical isolates. A commercial replication assay is now available that measures the replication capacity of HIV from patient plasma samples and provides the results along with results of genotypic

Residual antiviral activity and viral fitness

Patients who continue antiretroviral therapy in the face of ongoing viral replication often maintain some degree of viral suppression.76, 77 Alternatively, when patients discontinue a regimen that has clearly failed to lead to complete virological suppression, rebounds in HIV-1 RNA and declines in CD4 cell count have been observed.78, 79 These observations suggest that these presumably failing regimens, or at least some of their components, had provided additional benefit in maintaining at

Incorporation of new agents into an antiretroviral regimen

Results from pivotal phase III trials of recently approved antiretrovirals have provided some insight into how best to incorporate new antiretrovirals into a regimen for the treatment of heavily treatment-experienced patients.

TORO (T-20 vs Optimized Regimen Only) I and II were open-label randomised clinical trials in which treatment-experienced patients were randomised to receive enfurvitide (T-20) plus an optimised background regimen or the optimised background regimen alone.87, 88 RESIST

Double-boosted protease inhibitors

The use of low-dose ritonavir to enhance the pharmacokinetics of PIs—ie, boosting—so that they become more effective and more convenient to take (fewer pills, longer dosing intervals) has become standard clinical practice.95, 96 All currently licensed PIs are commonly prescribed as boosted agents with the exception of nelfinavir, which is not reliably augmented by ritonavir. Several randomised studies have confirmed the utility of different boosted-PI regimens in treatment-experienced

Structured treatment interruption

Structured treatment interruption is a treatment strategy based on the premise that treatment interruption allows reversion of a highly resistant virus population to wild-type virus and thus increases the likelihood of obtaining durable virological suppression and immunological benefit after reintroduction of antiretroviral therapy. The feasibility of this approach was preliminarily tested in uncontrolled virological studies that reported wild-type reversion in several patients within 4 months

Mega-HAART

Mega-HAART, also referred to as multiple drug rescue therapy (MDRT), is an antiretroviral treatment strategy that involves the administration of several (more than five) antiretroviral drugs in combination to HIV-infected patients with prior virological failure to multiple antiretroviral regimens.119, 120, 121, 122 These MDRT regimens were often very complex and included combinations of several drugs within each class—in one report, up to four NRTIs, two PIs, two NNRTIs, and hydroxyurea were

Therapeutic drug monitoring and the inhibitory quotient

Therapeutic drug monitoring (TDM) has been proposed as a useful tool for the optimisation of antiretroviral therapy.¹²³ The use of TDM could be useful to identify subtherapeutic drug levels, interperson variability in drug elimination, genetic polymorphisms, non-adherence, drug interactions, and toxicity.124, 125, 126, 127, 128, 129, 130 Although there are few data correlating TDM with improved clinical outcomes, TDM has been shown in some studies to improve or predict outcomes.131, 132 A more

Continuing a failing regimen

In situations where there are no or few treatment options in the armamentarium of licensed antiretrovirals, it might be reasonable to continue the same antiretroviral regimen until newer and presumably active agents become available.¹⁶ The goal of therapy in this case is preservation of immune responses and delay of clinical progression rather than complete viral suppression. The major risk of this approach is ongoing viral evolution and the loss of future drug options. In a recent analysis of

Conclusions

We have presented available data relevant to the management of heavily treatment-experienced HIV-infected adults that are experiencing multiclass virological failure. Our interpretation of existing data has led us to formulate the following approach in managing such patients.

First, as a result of the availability of new and potent agents and our improved understanding of how best to incorporate these agents into a new antiretroviral regimen, a paradigm shift is occurring in the management of

Search strategy and selection criteria

Data for this review were obtained from papers published in the English language identified by searches of Medline, Current Contents, and references from relevant articles. The search terms used were “salvage therapy”, “treatment failure”, “HAART”, “antiretroviral”, “resistance testing”, “replication capacity”, “viral fitness”, “structured treatment interruption”, and “mega HAART”. We reviewed data presented at major HIV-related meetings including Conference on Retroviruses and

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ReviewApproach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults

Summary

Introduction

Section snippets

Treatment failure

Antiretroviral treatment history

Resistance testing

Replication capacity

Residual antiviral activity and viral fitness

Incorporation of new agents into an antiretroviral regimen

Double-boosted protease inhibitors

Structured treatment interruption

Mega-HAART

Therapeutic drug monitoring and the inhibitory quotient

Continuing a failing regimen

Conclusions

Search strategy and selection criteria

Lancet

J Clin Virol

Lancet

J Biol Chem

Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection

N Engl J Med

Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviralnaïve patients: a 3-year randomized trial

JAMA

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV

J Acquir Immune Defic Syndr

Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection

N Engl J Med

HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy

AIDS

Virological treatment failure of protease inhibitor therapy in an unselected cohort of HIV-infected patients

AIDS

Durability and predictors of success of highly active antiretroviral therapy for ambulatory HIV-infected patients

AIDS

Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions

Ann Intern Med

Response to antiretroviral therapy among patients exposed to three classes of antiretrovirals: results from the EuroSIDA study

Antivir Ther

The prevalence of antiretroviral drug resistance in the United States

AIDS

Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients

AIDS

Predictors of death, and response to therapy in patients with multi(three)-class drug resistant HIV in the UK

Antivir Ther

Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel

JAMA

Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents

British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy

Worldwide evaluation of DNA sequencing approaches for identification of drug resistance mutations in the human immunodeficiency virus type 1 reverse transcriptase

J Clin Microbiol

Pre-existing L74V is a risk factor for virological non-response and development of K65R in patients taking tenofovir DF (TDF)

Antivir Ther

Clinical use of genotypic and phenotypic drug resistance testing to monitor antiretroviral chemotherapy

Clin Infect Dis

Susceptibilities of human immundeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reverse transcriptase inhibitors

Antimicrob Agents Chemother

3′-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors

Antimicrob Agents Chemother

Mutations in the non-nucleoside binding-pocket interfere with the multi-nucleoside resistance phenotype

AIDS

Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase

Proc Natl Acad USA

Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase

Science

Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates

AIDS

The clinical relevance of non-nucleoside reverse transcriptase inhibitor hypersusceptibility: a prospective cohort analysis

AIDS

Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens

J Infect Dis

Nelfinavir-resistant, amprenavir-hypersusceptible strains of human immunodeficiency virus type 1 carrying an N88S mutation in protease have reduced infectivity, reduced replication capacity, and reduced fitness and process the gag polyprotein precursor aberrantly

J Virol

A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir

J Virol

Mutations in HIV-1 reverse transcriptase potentially associated with hypersusceptibility to nonnucleoside reverse-transcriptase inhibitors: effect on response to efavirenz-based therapy in an urban observational cohort

J Infect Dis

Phenotypic hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in treatment-experienced HIV-infected patients: impact on virological response to efavirenz-based therapy

AIDS

Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs

Review
Approach to salvage antiretroviral therapy in heavily antiretroviral-experienced HIV-positive adults