Trends in HIV Care, Part 2: Antiretrovirals in the Pipeline, HIV/Hepatitis C Virus Coinfection, and Pharmacokinetics of Treatment Adherence-A Roundtable Discussion

This is the second part of a 2-part article on trends in HIV care. Part 1 focused on issues related to newly available antiretroviral agents, anal dysplasia, and diagnostic testing reimbursement and was published in the December 2008 issue.

This is the second part of a 2-part article on trends in HIV care. This month's Research Focus is a summary of a roundtable discussion with 4 health care providers from the AIDS Community Health Center (ACHC) in Rochester, NY. The ACHC is a not-for-profit HIV medical clinic that provides specialty and primary care to 600 patients with HIV/AIDS.

Here, 3 current topics of interest to HIV care providers are presented and discussed using the evidence available to date with an eye toward the future of HIV care. The topics presented are antiretroviral agents in the pipeline, trends in HIV/hepatitis C virus (HCV) coinfection, and the pharmacokinetics of treatment adherence.

ANTIRETROVIRAL AGENTS IN THE PIPELINE
This discussion focuses on 3 antiretroviral agents in development that have reached phase 3 clinical trials. These agents, discussed below, are vicriviroc (Schering-Plough), a coreceptor anatagonist; rilpivirine (Tibotec), an NNRTI; and elvitegravir (Gilead Sciences), an integrase inhibitor. The addition of these antiretrovirals to the more than 20 currently approved agents will help fill unmet needs of persons with HIV/AIDS, which, in turn, will improve quality of life and longevity, especially for treatment-experienced patients.

Vicriviroc
Patients enrolled in the phase 2 Vicriviroc (SCH 417690) in Combination Treatment With Optimized ART Regimen in Experienced Subjects (VICTOR-E1) study¹ (including patients in the placebo arm) and the AIDS Clinical Trials Group (ACTG) 5211 study² were eligible to continue on open-label vicriviroc with optimized background therapy at the completion of 48 weeks of treatment in an extension for each study.³ The vicriviroc dose for all patients was escalated to 30 mg once daily during the open-label treatment period. Because there were no dose-related differences in the safety profile, data for all patients receiving vicriviroc were pooled for analysis regardless of the original starting vicriviroc dose. The mean duration of vicriviroc treatment for all patients (N = 205) was 96 weeks (range, 1 to 216 weeks).

Analyses were done on data from all patients who completed at least 12 weeks of vicriviroc treatment (n = 196). Virological response to regimens containing vicriviroc was evidenced within 12 weeks by a significant decrease in HIV RNA detectable in blood; this decrease was sustained long-term. Median change from baseline HIV RNA level was –2.1, –2.2, –2.3, and –2.3 log₁₀ copies/mL at weeks 48, 96, 144, and 168, respectively. Mean change from baseline CD4⁺ cell count was +121/μL, +144/μL, +158/μL, and +143/μL at the same time points.

Rilpivirine
This second-generation NNRTI is about to enter phase 3 clinical trials. In Study C204, which was a phase 2 head-to-head trial in treatment-naive patients, rilpivirine performed equally well when compared with efavirenz in terms of virological and immunological outcomes.⁴ After 96 weeks, 71% to 76% of patients taking rilpivirine had HIV RNA levels below 50 copies/mL, compared with 71% taking efavirenz. All groups experienced similar increases in their CD4 counts: from 146/μL to 172/μL for patients taking rilpivirine versus 160/μL for those taking efavirenz. In Study C204, there was a lower rate of rash, CNS adverse events, and sleep disturbances and fewer lipid abnormalities in patients who received rilpivirine than in those who received efavirenz.

Additional benefits include an apparently higher genetic barrier to resistance than other NNRTIs, although complete resistance data are not yet available in patients in whom rilpivirine treatment failed.

Elvitegravir
Elvitegravir has completed phase 2 studies, and a phase 3 trial is under way. In treatment-experienced patients, Zolopa and colleagues⁵ conducted a phase 2, randomized, dose-ranging study that compared ritonavir-boosted elvitegravir in varying doses with a ritonavir-boosted protease inhibitor (PI), each combined with an optimized background regimen (OBR) based on resistance testing.

Using the primary end point of time-weighted average change from baseline in HIV-1 RNA level through 24 weeks, the boosted elvitegravir 50-mg and 125-mg groups were determined to be noninferior to the comparator PI group. Furthermore, results from the 125-mg dose group were shown to be statistically superior to the comparator PI group at weeks 16 and 24. Through week 24, approximately 11% to 13% of patients in each arm discontinued the study, with 3% to 4% of those discontinuations attributable to issues concerning safety, tolerability, or efficacy. However, there was no evidence of increased grade 2, 3, or 4 adverse events in elvitegravir-exposed patients versus the comparator PI group.

In a further analysis of the boosted elvitegravir 125-mg group, patients with no active agent in the OBR had a reduction in HIV-1 RNA level of 0.7 log₁₀ copies/mL at week 24.⁶ Those who had 1 or more active agents in their OBR had a reduction in HIV-1 RNA level of 1.7 log₁₀ copies/mL. Patients in whom the fusion inhibitor enfuvirtide was being used for the first time with or without active NRTIs had a reduction in HIV-1 RNA level of 2.9 log₁₀ copies/mL. However, preliminary data have demonstrated cross-resistance between elvitegravir and the recently approved integrase inhibitor raltegravir, which may limit the use of this new class of drugs.⁷

Table 1 lists other candidate antiretrovirals in earlier stages of development.^8-21 All of these agents have shown some promise in efficacy, and many of them are first in their class, such as the attachment inhibitors TNX-355 and TRI-1144 and the maturation inhibitor bevirimat. Others represent new generations of the NRTI, NNRTI, and PI classes. However, it is unlikely that all of them will make it through the pipeline to final approval for use in patients. For example, trials of AMD-11070, a first-in-class, small-molecule antagonist against the HIV coreceptor CXCR4,^10,22 have been halted recently because of drug-related liver toxicity, making this agent's future uncertain. It may be abandoned completely or returned to clinical trials as a modified agent, or it may be evaluated at lower doses to address its liver toxicity. While there are other candidates with activity against X4 strains of HIV-1, all are in much earlier stages of development.

HIV/HCV COINFECTION: NEW STRATEGIES TO IMPROVE OUTCOMES
Several key themes designed to improve outcomes are a part of our future management of HIV/HCV coinfection. In addition to the development of new drugs for HCV infection treatment, new monitoring strategies will likely change our approach to care of patients with hepatitis C.

Studies in both HCV monoinfection²³ and HIV/HCV coinfection^24,25 have established pegylated interferon and ribavirin as standards of care in both. Despite this advance in care, patients with HIV/HCV coinfection have lower rates of sustained virological response (SVR) overall than do monoinfected patients, particularly those infected with the harder-to-treat genotype 1 HCV.

One strategy to increase SVR in coinfected patients is the use of higher, weight-based dosages of ribavirin (1000 to 1200 mg/d) instead of the lower dosage of 800 mg/d, to maximize the contribution of ribavirin to SVR.²⁶ The preliminary results of the Peginterferon Ribavirin Espaa Coinfection (PRESCO) trial have shown an end-of-treatment virological response in HIV/HCV-coinfected patients similar to that seen in those with HCV monoinfection.^23,26 To date, the end-of-treatment virological responses are 50%, 85%, and 44% in patients with HCV genotypes 1, 2/3, and 4, respectively. Until the results for SVR are available, the authors emphasize that the following are all crucial for a satisfactory response to hepatitis C therapy in HIV/HCV-coinfected patients: proper patient selection for treatment, the use of ribavirin 1000 to 1200 mg/d, and good treatment adherence. (The PRESCO study results for SVRs are expected in mid-2009.)

"Direct Antivirals" to Optimize Hepatitis C Treatment
The use of so-called direct antivirals involves direct, potent inhibition of HCV replication that can result in rapid decreases in HCV RNA levels.²⁷ This strategy is particularly attractive in view of the lower SVR seen in HIV/HCV coinfection than in monoinfection, particularly for HCV genotype 1.²⁴

It is anticipated that the addition of direct antivirals to the current standard of care of pegylated interferon and ribavirin will reduce the risk of viral breakthrough and increase the likelihood of SVR. While this approach offers opportunities for improved outcomes, the addition of these agents to standard regimens may increase the risk of drug resistance and treatment-related adverse events, beyond that seen with the current standard of care. Thompson and colleagues²⁷ have also cited other issues to be addressed, including duration of therapy, reassessment of early stopping rules, treatment of previously treated patients, and the proper combinations of agen

ts to optimize therapy in addition to pegylated interferon and ribavirin. In addition, since trials of direct antivirals are done first in HCV-monoinfected patients, knowing their benefits in HIV/HCV-coinfected patients will require additional study.

A summary of direct antiviral candidates currently under development is shown in  Table 2.^28-44

Patient Assessment and Monitoring: New Technologies
The accurate diagnosis of HCV-related fibrosis is crucial for prognostication and treatment decisions. Liver biopsy remains the gold standard to assess fibrosis, but this procedure has limitations, including its invasiveness, sampling error, risk of complications, and variability in interpretation. Several noninvasive alternatives to liver biopsy to assess cirrhosis have been developed, including FibroSURE (BioPredictive, Paris) and FibroScan (Echosens, Paris). Both tests are in use in Europe and both are in limited clinical use in the United States, even though neither has been approved by the FDA. A comparative clinical trial is being organized in the United States that should help position these tests for appropriate clinical use and lead to FDA approval. (For more information, see http://clinicaltrials.gov/ct2/show/NCT00708617.) In the meantime, FibroSURE is available from commercial laboratories in the United States under license from its European manufacturer.⁴⁵

FibroSURE is a composite of 5 serum biochemical markers (α₂-macroglobulin, apolipoprotein A-I, haptoglobin, γ-glutamyltransferase, and bilirubin) of hepatic fibrosis developed by Poynard and colleagues.⁴⁶ FibroScan employs an ultrasound-based technique known as transient elastography that measures the speed of propagation of elastic waves through the liver. The velocity of these waves is directly correlated with liver stiffness, such that fibrotic livers generate higher FibroScan measurements.⁴⁷

Both diagnostic tests have performed well in clinical settings for the identification of HCV-related cirrhosis in patients with HCV monoinfection.⁴⁸ In HIV/HCV coinfection, Myers and colleagues⁴⁹ reported that these serum markers of fibrosis had a negative predictive value of 93%, had a positive predictive value of 86%, and could eliminate the need for liver biopsy in 55% of patients with moderate to high levels of fibrosis. While both provide an alternative to liver biopsy, there are some limitations to these noninvasive procedures, including cost and reimbursement issues; difficulty in determining intermediate stages of fibrosis; and inability to exclude other conditions, such as hepatic steatosis.⁴⁸

Early Virological Response
The rate of HCV decay or decline has emerged as an essential monitoring tool to assess treatment response in both monoinfected ²³ and coinfected patients.⁵⁰ Virological response to hepatitis C therapy after 4 weeks appears to predict which HIV-positive persons coinfected with HCV genotype 1 or 3 will have a successful response to a full course of treatment.^51,52 The obvious clinical advantages to predicting a patient's response to therapy are avoiding treatments that are unlikely to result in SVR, avoiding treatment-emergent adverse events, and avoiding the associated costs.

Also, early virological response may actually be a surrogate marker for resistance to pegylated interferon and/or ribavirin. In Japan, studies of patients with the harder-to-treat genotype 1b have shown that genetic mutations in the interferon sensitivity determining region (ISDR) of HCV correlate with decreased efficacy of interferon therapy. In the United States and Europe, the correlation between amino acid mutations in the ISDR and interferon efficacy is not as clear and is under study.^53,54

An important question in the medical care of HIV/HCV-coinfected patients is who should deliver the HCV component of care. The newly implemented HIV/HCV-coinfection program at the ACHC is designed to manage HCV infection in the patient's HIV "medical home" (ie, the place where the patient receives health care on an ongoing basis), in the context of his or her HIV therapy. This grant-funded program includes both group and individual patient visits. The goals of treatment support are to maintain patient adherence to HCV therapy, because most HIV/HCV-coinfected patients are taking antiretrovirals concurrently. We believe that this approach best serves our patients, and we plan to assess patient outcomes in this program once it is fully subscribed.

PHARMACOKINETICS AND TREATMENT ADHERENCE
The mantra that "drugs don't work in patients who don't take them" is widely attributed to former US Surgeon General C. Everett Koop and remains the cornerstone of treatment adherence.⁵⁵ Adherence to a medication regimen is generally defined as the extent to which patients take medications as prescribed by their health care providers. The term "adherence" is preferred by many health care providers because "compliance" suggests that the patient is passively following the doctor's orders and that the treatment plan is not based on a therapeutic alliance or contract established between the patient and the provider, according to Osterberg and Blaschke.⁵⁵ Both terms, however, are imperfect descriptions of medication-taking behavior.

In addition to reinforcing the importance of taking medications as directed, drug pharmacokinetics help explain the link between adherence and clinical outcomes, and reinforce another mantra: adherence is a process and not a single event.⁵⁶ Pharmacokinetics may vary from person to person because of, for example, differences in genetic background, diet, concomitant medication, and coinfections. In HIV medicine, the degree of viral resistance and viral fitness also play important roles.^57,58

Beyond the individual patient, there are public health implications to adherence as well. Debates about providing antiretroviral therapy to the developing world have centered on the relationships between patient adherence to treatment, the risk of drug resistance, and the antiretroviral classes used.⁵⁶

Nonadherence leads to drug-resistant HIV infection-or at least this is what we have been trained to believe.⁵⁷ The widely accepted premise that nonadherence breeds resistance has been challenged, at least as it pertains to some anti-HIV therapies.⁵⁸ In fact, some research indicates that the relationship between adherence and HIV drug resistance is more complicated than assumed initially. For some regimens, resistance may be more likely in those who take more rather than less of their medications. For others, the opposite may be true.⁵⁸

Bangsberg and colleagues⁵⁷ suggest that each antiretroviral therapeutic class has a unique adherence-resistance relationship. Historically, resistance to single, unboosted PI therapy occurred most frequently at moderate to high levels of adherence, presumably because of low-level or intermittent viral replication in the face of ongoing exposure to the drug.

In the current era, boosted PIs appear to be remarkably "resistance resistant."⁵⁹ In terms of today's clinical decision making, the identification and development of antiretroviral drug combinations that have a high pharmacokinetic or genetic barrier to resistance are critical to the long-term management of HIV infection, especially in treatment-experienced patients who harbor resistant strains to earlier treatment regimens.

Direct adherence-resistance relationships appear strongest for unboosted PIs; these relationships have been observed for most NRTIs as well.^60-62 Data from study cohorts of HIV-infected persons with well-characterized measures of adherence suggest that resistance to both PIs and NRTIs occurs primarily in highly adherent patients. Gallego and colleagues⁶⁰ found that PI resistance was limited to those patients who reported more than 90% adherence. In separate studies, Walsh and colleagues⁶¹ and Howard and colleagues⁶² confirmed this linear and direct association between adherence and the number of resistance mutations. These investigators estimated that any regimen that durably suppresses plasma viral load to undetectable levels (less that 50 copies/mL) in 95% of perfectly adherent patients will reduce the population burden of resistance by 45% compared with historical regimens with which patients had less than 95% adherence.

No such relationship has been observed for the NNRTIs. Resistance to NNRTI therapy occurs at low to moderate levels (approximately 60%) of adherence.⁶³ Parienti and colleagues⁶³ reported that NNRTI resistance was most often associated with interruptions of therapy in their NNRTI-treated cohort and concluded that these dynamic relationships are important considerations in balancing the individual and public health benefits of therapy.

Similarly, Sethi and colleagues⁶⁴ found that resistance to NNRTI therapy occurred at lower levels of adherence than did resistance to PI therapy. A different adherence-resistance relationship for NNRTIs is also consistent with reports of resistance to these medications occurring after single-dose therapy given during perinatal HIV prevention trials. It appears, therefore, that the NNRTIs have an adherence-resistance relationship wherein almost any exposure in the absence of full viral suppression is sufficient to cause resistance.

The obvious question is why would the relationship between adherence and resistance differ substantially between drug classes? Substantial in vivo data and theoretical considerations suggest that NNRTIs have several characteristics that might result in an unfavorable adherence-resistance relationship, including the following:
1. NNRTI potency exerts a strong anti-HIV selective pressure.
2. NNRTIs act at a site distant from the active site of their target enzyme. Therefore, mutations that confer drug resistance do not dramatically impact enzymic efficiency and, by extension, viral replicative capacity (or viral fitness).
3. NNRTIs have long half-lives and remain in plasma for extended periods after several missed doses.
4. Resistance to one NNRTI confers some level of cross-resistance to other NNRTIs.

In clinical terms, patients and clinicians should be aware of the importance of stopping NNRTI therapy at least 7 days before stopping NRTI therapy to avoid "functional monotherapy" in drugs with different half-lives.⁶⁵

Based on these arguments, it would appear that widespread use of NNRTIs in the face of treatment nonadherence would likely have greater public health costs than the widespread use of ritonavir-boosted PIs.

In summary, the relationship between adherence and resistance to HIV antiretroviral therapy is more complex than simply "nonadherence increases the risk of drug resistance." For unboosted PI–based regimens, most drug resistance occurs in patients who take most of their medications, and there is likely to be a bell-shaped relationship between adherence and resistance. For regimens with a ritonavir-boosted PI, limited resistance occurs at any level of adherence, hence the term "forgiveness." For NNRTIs, resistance mutations are uncommon in highly adherent patients but occur more often in patients with any level of adherence insufficient for full viral suppression. Moving forward, these relationships will need to be confirmed with newly introduced NNRTIs.

This discussion, however, should not be interpreted as meaning that maximal adherence is bad. Instead, we need to recognize 2 important facts: (1) the generation of patients treated with unboosted, first-generation PIs are likely to harbor high levels of antiretroviral resistance and (2) proper selection of antiretroviral agents that suppress viral load maximally, including boosted PIs and newer agents (as discussed in our first roundtable66 and above), is essential to support the most favorable adherence-resistance relationship possible.

Dr Corales reports the following relationships: advisor and speaker for Gilead Sciences, Bristol-Myers Squibb, Tibotec, and Merck, and speaker for Abbott Laboratories. Dr Valenti reports acting as a consultant to Roche Pharmaceuticals and Roche Diagnostics. No potential conflict of interest relevant to this article was reported by the other coauthors. Dr Valenti moderated the roundtable on which this article is based and prepared the first draft of the manuscript from the transcript of the discussions. Each coauthor prepared and presented his or her individual discussions and contributed to and edited the final draft of the manuscript.

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