Treatment of HIV/AIDS in Patients Failing Their First HAART Regimen

By Peter J. Piliero, MD
Dr. Piliero is Associate Professor of Medicine, Director of Research of the Division of HIV Medicine and Medical Director of the Clinical Pharmacology Study Unit at Albany Medical College.

ABSTRACT
INTRODUCTION
FACTORS LIMITING THE SUCCESS OF PROTEASE INHIBITOR-BASED HAART
    - Poor adherence
    - Drug-resistant HIV variants
    - Viral reservoirs
    - Suboptimal pharmacokinetic potency of PI-based HAART
CURRENT STRATEGIES FOR RESCUE THERAPY
    - Genotype- and phenotype-guided treatment
    - Pharmacokinetic boosting by combining PIs
ADVANCES IN ANTIRETROVIRAL THERAPY
    - Atazanavir (Reyataz™)
    - Fosamprenavir (Lexiva™)
    - Tipranavir
    - TMC114
CONCLUSIONS
TABLE 1 - Ritonavir-boosted Combination PI HAART Regimens as Rescue Therapy: Findings from Clinical Trials
TABLE 2 - Hyperlipidemia with Combination-PI Regimens: Findings from Clinical Trials

References

ABSTRACT

A substantial number of HIV-infected patients experience treatment failure while on their initial highly active antiretroviral therapy (HAART) regimen. The development of an effective secondary, or rescue, antiretroviral drug regimen is a complex process that involves consideration of several factors.

These factors include the ability of the patient to diligently adhere to potentially complex, restrictive, and toxic rescue drug regimens; HIV resistance to the current drugs and any associated cross-resistance to agents in the same class; and the presence of lingering viral reservoirs undergoing active replication. Such reservoirs may harbor HIV variants with resistance patterns differing from those currently predominating in the bloodstream.

Sub-optimal adherence in combination with variability in drug pharmacokinetics within HIV-infected individuals can alter drug efficacy, leading to the emergence of resistant HIV variants. These HIV variants persist during all subsequent regimens, potentially compromising rescue therapy. Individually or in combination, such factors can lead to failure of the first-line HAART regimen as well as lead to sub-optimal potency of the rescue therapy.

Strategies aimed at optimizing rescue antiretroviral drug regimens include assessment of HIV genotype and/or phenotype, and the utilization of either protease inhibitor regimens that incorporate ritonavir to improve pharmacokinetics or agents to which the patient has not been previously exposed.

Currently, several new drugs are being made available that produce rapid and sustained virologic and immunologic responses, especially against HIV variants resistant to more established drug regimens.

The combination of simplified dosing schedules, fewer pills per dose, and improved metabolic side effect profiles of rescue regimen agents may facilitate adherence by increasing tolerability.

INTRODUCTION

Highly active antiretroviral therapy (HAART) can suppress plasma HIV RNA levels to below the limits of detection by the most sensitive assay technologies currently available as well as increase the CD4+ cell count. Both of these effects delay progression to AIDS and decrease morbidity and mortality.^1-3 Unfortunately, a substantial number of HIV-infected patients experience treatment failure while on HAART, with their levels of circulating HIV rising to detectable or even to pretreatment levels.⁴ In a recent study done in a primary care facility, only 47% of patients achieved an HIV RNA level of 500 copies/mL or less 7 to 14 months after HAART initiation.⁵

Various characteristics of HAART can hinder its long-term efficacy. Poor patient adherence is the primary factor leading to virologic failure. This frequently results from complex dosing regimens involving many pills per dose and from emergent pharmacotoxicity that can reduce the patient’s willingness to remain on the regimen. As a result, treatment regimens may also fail to fully suppress HIV in all viral reservoirs.^6-9

Patients who experience failure of a primary regimen usually require a second, or rescue, regimen. Since further lapse in patient adherence can reduce the likelihood of a response to the rescue regimen, thus limiting its efficacy, clinicians must address the non-adherence that led to the initial therapy failure prior to initiating the rescue regimen. The rescue regimen must address the antiretroviral resistance selected by the failing drug regimen, and thus resistance testing is an essential step in constructing the new regimen.

This review describes major factors contributing to HAART failure and outlines both current strategies and novel drugs for secondary, or rescue, HAART regimens.

FACTORS LIMITING THE SUCCESS OF PROTEASE INHIBITOR-BASED HAART

Poor adherence

Poor patient adherence to the HAART regimen is the key obstacle to successful antiretroviral therapy.¹⁰ Poor adherence can facilitate the emergence of resistant variants and impede virologic responses to treatment.^9,11 The permissible margin of error for HAART regimen success is very small.¹² In a 6-month study of 99 HIV-infected patients,¹¹ poor adherence to antiretroviral therapy regimen was significantly associated with treatment failure (p<0.001; Figure 1).

Adherence was measured using an electronic monitoring system (MEMS^® TrackCap; APREX; Union City, California) and was quantified as a percentage (number of doses taken vs the number prescribed). The best virologic outcomes require at least 95% adherence to therapy, but several reports suggest that few patients achieve this.^11,13,14

Patient-related reasons for poor adherence can range from simply forgetting to take their medication to more complex and diverse psychosocial issues.^15,16 The patient-provider relationship also plays an important role. Treatment-related reasons for poor adherence include high pill burden, complicated administration requirements, and toxicity contributing to poor tolerability.

For example, protease inhibitor (PI) regimens such as amprenavir require 8 pills to be taken 2 times daily, for a total of 16 pills. Indinavir must be taken 1 hour before or 2 hours after meals three times a day and requires that approximately 48 ounces of fluid be consumed each day. All of these factors reduce patient willingness to remain on the regimen.^17-19 Strategies intended to improve adherence include modification of existing antiretroviral regimens and pharmacokinetic enhancement with ritonavir. The development of agents that permit once-daily dosing may also improve adherence.

Drug-resistant HIV variants

The error-prone nature of reverse transcription permits emergence of HIV variants that are resistant to current drugs.^20,21 Studies of HIV resistance to antiretroviral monotherapy have demonstrated characteristic genotypic resistance patterns for each drug class.^22-24

HIV resistance to PIs tends to develop more slowly than does resistance to nucleoside reverse transcriptase inhibitors (NRTIs) or non-NRTIs (NNRTIs).⁷ Fortunately, high-level cross-resistance to PIs appears to require 3 or more mutations in the protease gene. Replication of HIV variants that emerge under drug pressure may be attenuated (i.e., replication capacity or viral fitness impaired), compared with replication of wild-type HIV.²⁵

Subsequent removal of drug-selective pressure may actually increase HIV replication by permitting the re-emergence of the wild-type HIV associated with improved replication capacity.

A pivotal study by Deems and coworkers²⁶ confirmed that continuing antiretroviral therapy even in the presence of drug-resistant HIV variants can be beneficial. Although this does not suggest that modification of a failing HAART regimen is unnecessary, complete treatment cessation is probably unwise.

Variants with resistance mutations that have emerged during first-line treatment failure persist when second- and third-line regimens are initiated, although they may represent only a minor population of the entire viral pool. In one study, this was observed for both NRTI and PI treatments, compromising the efficacy of subsequent rescue regimens, but the same phenomenon has been seen with NNRTI-based treatments.²⁷

Viral reservoirs

Several reports have documented CD4+ cell and other anatomic viral reservoirs in HIV‑infected patients even in the presence of undetectable plasma HIV RNA levels and long‑term HAART.^8,28 Such reservoirs are thought to maintain a “library” of archived viral quasispecies that replicate slowly and emerge under selective pressure from antiretroviral therapy.²⁹

Thus, despite HAART, each patient remains a potential source of drug-resistant HIV variants. Recent evidence suggests that distinct populations of HIV with varying drug sensitivities can be identified in blood and semen of patients receiving therapies re-initiated after interruption.

This observation supports the hypothesis that distinct HIV reservoirs exist³⁰ (e.g., in the genital tract) and underscores the difficulty in preventing emergence of drug-resistant variants. Ideally, antiretroviral therapies should penetrate these viral reservoirs to optimize viral suppression during initial treatment.

Suboptimal pharmacokinetic potency of PI-based HAART

Some unboosted PI-based HAART regimens have suboptimal potency.^25,31 Due to their pharmacokinetic limitations, such regimens can yield low and inconsistent drug exposure, facilitating the emergence of drug-resistant virus. For example, saquinavir (hard-gel capsules) and indinavir are extensively metabolized in the intestines and liver by cytochrome P450 (CYP) enzyme system, which limits their bioavailability.

Potency of PI-based HAART can also be impaired by drug-drug interactions whereby either concomitant antiretroviral agents or other medications the patient is taking reduce the PI drug level. Thus, although reverse transcriptase resistance mutation burden is predictive of therapy failure, inadequate PI plasma concentrations exacerbate loss of response to HAART.³²

CURRENT STRATEGIES FOR RESCUE THERAPY

Genotype- and phenotype-guided treatment

The selection of a rescue HAART regimen is most effective when both the patient’s treatment history and data pertaining to protease and reverse transcriptase resistance are factored into therapeutic design.^33-37 However, while resistance testing is now considered the standard of care for the management of patients experiencing virologic failure in North America and Western Europe, failure to detect resistance by genotypic or phenotypic assays does not confirm the absence of drug-resistant HIV.^35,38,39

Although testing can identify the predominant viral variants within an HIV-infected patient, resistant variants may go undetected because their concentrations are below current detection limits.

Genotypic assays can detect the presence of resistance-related mutations using nucleotide sequence analysis.^6,40 Genotypic testing is rapid and provides indirect evidence of resistance relatively quickly, usually within 7 to 12 days. Although genotypic testing is inexpensive, complex mutational patterns resulting in resistance can require expert interpretation to improve clinical outcomes.

Phenotypic testing measures the drug susceptibility of patient-derived viruses in culture assays and provides direct evidence of resistance that is easier to interpret. Unfortunately, the test is labor intensive, requiring 2 to 5 weeks, and it is more expensive than genotypic testing. Another shortcoming of phenotypic testing is variance in definitions of susceptibility for each specific drug, some of which have yet to be established. Clearly, virologic response parameters for each drug tested requires standardization.

However, the development of resistance determined by longitudinal phenotypic testing may be an earlier prognostic marker of regimen failure than viral load.⁴¹ Although it has not yet been determined whether the best tests are genotypic or phenotypic, independent prospective studies show that both types of tests are useful.^33,34,42 Additional studies are needed to assess the relative utility of these assays in guiding clinical therapy decisions.

Additionally, a virtual phenotype test (VPT) (Virtual Phenotype^™; Tibotec-Virco; Yardley, Pennsylvania) has been developed. VPT determines resistance by matching the patient’s HIV genotype with genotypes in a large database of samples for which there is paired phenotypic data. An estimate of the phenotype of the patient's virus is then calculated from the inhibitory concentration (IC₅₀) of viruses in the database with similar genotypes.

Studies comparing measured phenotype and virtual phenotype have shown a very good correlation between the 2 test results (r²=.72).^43-45 Viral phenotypes, estimated by VPT, appear to be useful predictors of treatment response.⁴⁴ Although VPT is simpler and cheaper than phenotypic testing, its reliability depends on several factors, including the specific mutations that are put into the search for a match, the number of matches found, and the distribution of drug susceptibility among the matches. Randomized clinical trials are currently under way to further assess the clinical utility of VPT.

Pharmacokinetic boosting by combining PIs

Current PIs are metabolized predominantly by the 3A4 isoenzyme of the CYP450 system.^40,46 Ritonavir is a potent inhibitor of CYP3A4 and is thought to increase drug bioavailability through its inhibition in the gut wall. It may also reduce drug elimination by inhibiting CYP3A4 in the liver.^40,46-48 Ritonavir’s inhibition of CYP3A4 has been exploited to increase drug levels of concomitantly administered PIs, a so-called “boosting” effect, which can be of particular value in rescue regimens.^46,49

For example, the combination of ritonavir and amprenavir can potentially reduce the required dosage (and therefore pill burden) of amprenavir from 1200 mg twice daily to 600 mg twice daily while improving tolerability. Table 1 summarizes the results of some studies with dual PI–based regimens.^50-55

A critical issue associated with the use of boosted-PI therapy, however, is the increased potential for adverse events, including hyperlipidemia, which can be marked and sustained.^56,57 This has been observed in several studies of ritonavir-based PI combinations (Table 2).^52,58-62 Moreover, treatment of ritonavir-associated hyperlipidemia is complicated because many statins are metabolized by CYP3A4. Ritonavir-induced inhibition of CYP3A4 can result in elevated statin blood levels and associated side effects. Pravastatin, which is not metabolized by CYP3A4, is the statin of choice for treating PI-associated hyperlipidemia.

ADVANCES IN ANTIRETROVIRAL THERAPY

Arguably, the best hope for rescue therapy lies in the availability and development of novel antiretroviral agents. Current strategies in PI research focus on improving the potency and pharmacokinetic and resistance profiles of these agents. Newly available PIs are atazanavir (Reyataz™, ATV) and fosamprenavir (Lexiva™, FPV). 

PIs under clinical investigation include tipranavir and TMC114. The addition of new members to the existing antiretroviral drug classes, along with discovery of drugs having novel mechanisms of action, including immunomodulators and entry inhibitors, is critical to advancing treatment of HIV infection and AIDS.

Atazanavir (Reyataz™)

Atazanavir is a PI with a low pill burden (2 capsules once per day) and a distinct resistance profile in the PI-naïve patient.⁶³ A single daily dose of atazanavir 400 mg achieves adequate serum levels over a 24-hour time period, and, in combination with NRTIs, rapidly and durably suppresses HIV RNA and increases CD4+ cell count in both treatment-naïve and treatment-experienced patients.

Atazanavir as a sole PI has not been observed to be as efficacious as 400 mg of lopinavir boosted with 100 mg of ritonavir twice daily in moderately treatment-experienced patients when each PI regimen was co-administered with 2 NRTIs for 24 weeks.⁶⁴ However, when boosted with ritonavir, minimum serum levels of atazanavir can be increased 5 to 8-fold.⁶⁵

In a study of highly treatment-experienced patients failing at least 2 prior HAART regimens that contained at least 1 PI (BMS-045),⁵⁵ the combination of 300 mg of atazanavir boosted with 100 mg ritonavir once daily resulted in HIV RNA suppression to <400 copies/mL in 64% of patients and to <50 copies/mL in 39% of patients at 24 weeks of treatment (Table 1).

The proportions of patients responding were comparable to those responding to 400 mg of lopinavir boosted with 100 mg of ritonavir twice daily in the same trial (<400 copies/mL, 62%; <50 copies/mL, 42% at 24 weeks). Furthermore, treatment with atazanavir/ritonavir resulted in a reduction or stabilization of lipid levels in these patients (Table 2). The lipid effects of treatment with atazanavir/ritonavir may be associated with a reduction in the risk of cardiovascular events associated with use of PIs.⁶⁶

Fosamprenavir (Lexiva™)

Fosamprenavir is a prodrug of amprenavir with improved pharmacokinetic characteristics that permit reduced pill size and pill count.⁶⁷ The CONTEXT study compared fosamprenavir/ritonavir once daily or twice daily with lopinavir/ritonavir twice daily in 320 patients who had failed 1 or 2 previous PI-containing regimens.

Patients were randomized into 3 treatment groups: fosamprenavir/ritonavir 1400 mg/200 mg once daily; fosamprenavir/ritonavir 700 mg/100 mg twice daily; or lopinavir/ritonavir 400 mg/100 mg twice daily. At 48 weeks, the mean change in viral RNA from baseline was –1.49 log₁₀ copies/mL for once-daily fosamprenavir/ritonavir, –1.53 log₁₀ copies/mL for twice-daily fosamprenavir/ritonavir, and –1.76 log₁₀ copies/mL for twice-daily lopinavir/ritonavir.⁶⁸

Fewer patients on once-daily fosamprenavir/ritonavir achieved an undetectable viral load, so when using fosamprenavir/ritonavir in PI-experienced patients, twice daily dosing should be used.

Tipranavir

Tipranavir is an investigational PI in Phase 3 clinical trials that has potent in vitro activity against HIV variants that are resistant to multiple PIs.⁶⁹ Ritonavir boosting significantly increases the bioavailability and antiretroviral activity of tipranavir. In a recent Phase 2 clinical study, tipranavir/ritonavir combination therapy demonstrated activity in 261 highly treatment-experienced patients.^70,71

These patients were randomly assigned to receive 1 of 3 doses of tipranavir/ritonavir twice daily (Group A, tipranavir/ritonavir 500 mg/100 mg; Group B, tipranavir/ritonavir 500 mg/200 mg; Group C, tipranavir/ritonavir 750 mg/200 mg). Median decreases in HIV RNA levels from baseline were –0.9 log₁₀ copies/mL in Group A, –1.0 log₁₀ copies/mL in Group B, and –1.2 log₁₀ copies/mL in Group C after 2 weeks.

Modest side effects including some diarrhea and nausea were observed. Due to better tolerability, the 500 mg/200 mg tipranavir/ritonavir is the dose being used in the Phase 3 studies.

TMC114

Designed to exhibit high potency with low specificity, TMC114 appears not to permit emergence of drug-resistant variants as readily as current PIs. For this reason, TMC114 has been termed a “resistant-repellent PI.”⁷² In a recent Phase 2 open-label study, TMC114 showed significant antiviral activity in multiple PI-experienced HIV patients failing PI therapy.⁷³ In this study, 50 patients were randomized into 3 treatment cohorts and 1 control cohort. In the 3 treatment cohorts, failing PIs were replaced by 1 of 3 TMC114/ritonavir regimens: 300 mg/100 mg twice daily; 600 mg/100 mg twice daily; 900 mg/100 mg once daily. All other antiretroviral regimens remained unchanged. Patients in the control cohort continued with their failing regimen. The median change in plasma HIV RNA from baseline to end point in the 3 treatment cohorts and the 1 control cohort was –1.24, –1.50, –1.13, and +0.02 copies/mL, respectively. The median reduction in plasma viral load was –1.35 log₁₀ copies/mL HIV RNA after 14 days of treatment with TMC114/ritonavir.⁷³ Phase 2 studies are now underway to evaluate long‑term safety and efficacy and to define the optimal dose of TMC114.

CONCLUSIONS

Factors leading to the failure of an initial HAART regimen include poor patient adherence that may be due to regimen complexity or drug toxicity, the emergence of resistant HIV variants, viral reservoirs, and sub-optimal pharmacokinetic characteristics of PIs.

Although current antiretroviral rescue therapies have limitations, novel antiretroviral agents hold promise for greater control, rapid and durable virologic suppression, and sustained immunologic recovery.

Characteristics of new PIs such as atazanavir, fosamprenavir, and tipranavir (all given in combination with ritonavir), which may improve the response to rescue therapy include: 1) efficacy against resistant HIV variants, 2) improved toxicity profile, and/or 3) simplified dosing and administration to improve patient adherence.

Specifically, atazanavir plus ritonavir requires once-daily administration of only 3 capsules, and uncommonly causes hyperlipidemia associated with PI therapy.

Fosamprenavir allows for a reduced pill burden and shows efficacy when combined with ritonavir in highly treatment-experienced patients.

Tipranavir plus ritonavir also has shown clinical efficacy in patients who have developed significant PI cross-resistance after failing prior regimens. Further development of HAART regimens for rescue therapy will likely include the use of novel PIs in conjunction with other investigational therapies such as entry inhibitors.

[ TABLE 1 ]   

Ritonavir-Boosted Combination PI HAART Regimens as Rescue Therapy*: Findings from Clinical Trials
	Dose and Schedule (PI mg/ritonavir mg)	Findings	Sources
Saquinavir/ ritonavir	600 mg/400 mg bid 400 mg/400 mg bid	20% had HIV RNA <200 c/mL at week 12 65% had HIV RNA <500 c/mL at week 24 38% had HIV RNA <50 c/mL at week 24	Fatkenheur50 Tebas51
Indinavir/ ritonavir	400 mg/400 mg bid 800 mg/100 mg bid	50% had HIV RNA <50 c/mL at week 36 62.5% had HIV RNA <400 c/mL at week 36 37.2% had HIV RNA <500 c/mL at week 12 21.6% had HIV RNA <500 c/mL at week 24	Hsu52 Barreiro53
Atazanavir/ ritonavir	300 mg/100 mg qd	64% had HIV RNA <400 c/mL at week 24 39% had HIV RNA <50 c/mL at week 24	FDA briefing doc.55
Lopinavir/ ritonavir	400 mg/100 mg bid	65% had HIV RNA <400 c/mL at week 48 56% had HIV RNA <50 c/mL at week 48	Clumeck54
Fosamprenavir/ ritonavir	1400 mg/200 mg qd 700 mg/100 mg bid	50% had HIV RNA <400 c/mL at week 48 58% had HIV RNA <400 c/mL at week 48 46% had HIV RNA <50 c/mL at week 48	Vertex Pharmaceuticals74
*Regimens may have also included NRTIs or NNRTIs

[ TABLE 2 ]   

Hyperlipidemia with Combination-PI Regimens: Findings from Clinical Trials
Combination	Lipid Parameter Results	Source
Lopinavir/ritonavir vs nelfinavir	Fasting TG >750 mg/dL 11% for lopinavir/ritonavir vs 2% for nelfinavir TC >300 mg/dL 10% for lopinavir/ritonavir vs 6% for nelfinavir	Ruane62
Indinavir/ritonavir vs indinavir	TC >300 mg/dL 22% for indinavir/ritonavir vs 13% for indinavir Fasting TG >750 mg/dL 12% for indinavir/ritonavir vs 3% for indinavir Fasting TG levels higher in combination groups than with indinavir alone 22/37 patients had grade 3/4 cholesterol or      TG elevations	Harley61 Visnegarwala60 Hsu52
Atazanavir/ritonavir ARV failure; Switched from ³1 PI	Mean changes from baseline: TC –8%, fasting LDL-C –10%, fasting TG –2%	Lichtenstein59
Atazanavir/saquinavir ARV failure; Switched from ³1 PI	Mean changes from baseline: TC –9%, fasting LDL-C –11%, fasting TG –14%	Lichtenstein59
Switch from nelfinavir to atazanavir	Mean change at 24 weeks, mg/dL: TC=202 to 169; fasting LDL-C= 132 to 99; fasting TG = 127 to 102	Murphy58
Lopinavir/ritonavir ARV failure; Switched from ³1 PI	Mean changes from baseline: TC +3%, fasting LDL-C –4%, TG +31%	Lichtenstein59

Figure 1. Degree of adherence is significantly associated with virologic failure (HIV RNA level >400 copies/mL).¹¹ Adherence of 95% or greater was associated with the greatest percentage of virologic success. *p<0.001 vs both lower rates of adherence.

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