Switching Antiretroviral Therapy Part I

A decade ago, at the dawn of the HAART era, many people with HIV considered it a victory to find an antiretroviral regimen that reduced their viral loads to an undetectable level and raised their CD4 cell counts out of the danger zone--even if that meant putting up with agonizing side effects and difficult dosing schedules.

Today, given an improved understanding of HIV treatment and an array of new agents, it is often possible to devise regimens that both suppress HIV and are relatively easy to live with. Treatment veterans may see treatment-naïve individuals starting therapy with simpler, less toxic regimens--like the newly approved one-pill, once- daily Atripla (tenofovir/ emtricitabine/efavirenz)--and wonder: Is it time for me to switch?

While treatment-experienced individuals typically have fewer options than those starting therapy for the first time, many can still benefit from revising their treatment plans. This article will examine motivations for changing therapy and recent innovations in antiretroviral treatment. It will review some of the switch studies that support changing regimens--and also look at why, in some cases, it may make sense to stick with what's already working.

Reasons for Switching

People with HIV may be motivated to switch drugs for a variety of reasons, including:

• Inadequate virological control
• Intolerable or bothersome side effects
• Metabolic and mitochondrial abnormalities
• Inconvenience and poor adherence

At the XV International AIDS Conference in 2004, Brian Boyle, MD, and colleagues presented the results of a survey of 357 readers of a publication for HIV positive people (POZ magazine) asking about their interest in and experience with switching antiretroviral therapy. Switching was common, with 40% saying they had changed their regimen during the past year, and 20% saying they had made two or more changes. The most frequent reasons for wanting to switch were to reduce side effects (44%), improve potency (27%), and enhance convenience (20%).

Inadequate Potency

The most urgent reason for changing therapy--and one few doctors or patients will argue with-- is poor virological control. The goal of antiretroviral therapy is to suppress HIV viral load to an undetectable level, ideally below 50 copies/mL. When even low-level viral replication continues in the presence of a drug, resistance mutations can emerge. This not only may reduce HIV's susceptibility to current drugs, but can also confer cross-resistance to similar agents--in the worst case rendering an entire class of drugs ineffective.

With the selection of antiretroviral agents now available, most HIV positive people--even those with some prior treatment experience--have a good chance of keeping the virus in check. According to Ronald Mitsuyasu, MD, of the University of California at Los Angeles Medical Center, patients starting their second or third regimen typically should achieve full HIV suppression within three months or so. Individuals with more extensive prior treatment histories may not achieve complete virological suppression, but still should see some improvement.

In addition to suppressing viral load, a potent antiretroviral regimen typically also raises CD4 cell counts out of the danger zone--below 200 cells/mm3--where the risk of opportunistic illnesses begins to rise. According to the current U.S. federal HIV treatment guidelines, 350 cells/mm3 is an acceptable level, though recent studies suggest that the risk of disease progression is lower if antiretroviral therapy is started early and CD4 count is maintained at a higher level (see "News Briefs"). After initiating therapy, it is not uncommon for CD4 counts to increase more slowly than viral load declines; some patients, especially those with a low CD4 nadir (lowest-ever level), may have difficulty reaching an optimal level.

If viral load does not fall or CD4 cell count does not rise within a reasonable period of time (about 3--6 months), further testing is indicated to determine the reason. As a rule, the sooner such problems are detected, the easier they are to fix. However, viral load "blips" (transient spikes) are common, and most research suggests they are harmless; in addition, various factors can temporarily alter CD4 counts. Therefore, many experts prefer to wait until a patient has had at least two consecutive tests showing a trend of increasing viral load and/or declining CD4 count before changing therapy.

If treatment is failing to suppress HIV, the cause may be low drug levels in the body, perhaps due to suboptimal adherence or individual variations in how drugs are processed. Therapeutic drug monitoring (TDM) can show whether this is the case.

Another possibility is that drug resistance has developed; even people who have never used antiretroviral therapy may have been infected with a drug-resistant strain of HIV. Resistance testing can show if this is why certain drugs are not working, and what might be the best options for a switch. Standard genotypic testing involves analyzing HIV genetic material for known resistance mutations. In the more expensive phenotypic assay, an individual's virus is exposed to a drug in a test tube to determine how well that agent works against that particular strain of HIV.

People who started treatment in the pre-HAART era may have a history of suboptimal therapy with nucleoside reverse transcriptase inhibitor (NRTI) monotherapy or dual-NRTI therapy and may have developed resistance to multiple drugs. For these individuals, decisions about switching therapy are more complex--and there is less room for error if they have advanced HIV disease and low CD4 cell counts. (See the Winter 2003 issue of BETA for an in-depth discussion of "salvage" therapy for heavily treatment-experienced patients.)

Side Effects and Toxicities

Drug-related toxicity is one of the most common reasons for modifying antiretroviral therapy. In Boyle's survey, adverse events were the most frequently cited reason for wanting to change drugs. (Some of the most common and most worrisome antiretroviral side effects are listed below.)

NRTIs: nucleoside/nucleotide reverse transcriptase inhibitors
NNRTIs: non-nucleoside reverse transcriptase inhibitors
PIs: protease inhibitors

Most medications can cause some side effects in some people, especially when they are first introduced. Some of the typical symptoms associated with antiretroviral therapy--nausea and vomiting, diarrhea, fatigue--often go away as the body adjusts to a drug. Therefore, it is important not to give up on a new regimen too soon.

According to Mitsuyasu, most side effects of this sort should dissipate within several weeks. If they persist longer than a couple of months, it may be time to think about making a switch. (Note: In rare cases, common mild-to-moderate side effects--especially occurring in certain clusters-- may be signs of a more serious hypersensitivity reaction; individuals taking abacavir [Ziagen] or nevirapine [Viramune] should familiarize themselves with hypersensitivity symptoms and report these to a health-care provider without delay. See "News Briefs" for information about an abacavir hypersensitivity test currently in development.)

The respondents in Boyle's survey differed in terms of what side effects they found most difficult to live with: 75% said diarrhea, followed by nausea (49%), fatigue (47%), body shape changes (45%), peripheral neuropathy (41%), headaches (25%), and elevated cholesterol (12%). And side effects need not be severe to interfere with quality of life. Michael Saag, MD, of the University of Alabama at Birmingham Center for AIDS Research notes that patients sometimes neglect to tell their physicians about "subtle toxicities" such as persistent loose stool, mild headaches, or general malaise, but these, too, might improve with a well-considered switch. Because there is no "one size fits all" regimen that is optimal for everyone, HIV positive people should work with their providers to find an individually tailored combination that offers the best balance of potency and tolerability.

Metabolic and Mitochondrial Manifestations

While "garden variety" side effects such as gastrointestinal symptoms and fatigue often improve over time, some more worrisome long-term manifestations associated with antiretroviral therapy have emerged since effective treatment has allowed HIV positive people to live longer. These fall into two broad categories:

• Metabolic manifestations: lipodystrophy (body shape changes), hyperlipidemia (elevated blood cholesterol and triglycerides), blood glucose abnormalities (insulin resistance, diabetes mellitus)
• Mitochondrial toxicity and associated conditions: lactic acidosis, lipoatrophy (loss of fat in the face, limbs, and buttocks), hepatomegaly with steatosis (enlarged fatty liver), peripheral neuropathy, pancreatitis.
  

Metabolic manifestations are most often associated with the protease inhibitor (PI) class, while mitochondrial toxicity is linked with NRTIs, especially ddI (didanosine, Videx EC), d4T (stavudine, Zerit), and AZT (zidovudine, Retrovir). Both sets of conditions are poorly understood, however, and have also been observed in HIV positive individuals who have never taken antiretroviral therapy.

Body shape changes--whether abdominal fat accumulation associated with PIs or peripheral fat loss linked to NRTIs--are among the most distressing side effects of antiretroviral drugs, and are commonly cited reasons for switching therapy. And it's not all about vanity: visceral fat accumulation, elevated blood lipids, and insulin resistance are all associated with increased risk of cardiovascular disease. And, though rare, lactic acidosis and liver failure related to mitochondrial toxicity can be life threatening.

Convenience and Adherence

Given that so many people with HIV have struggled over the years merely to find a regimen that keeps the virus under control and prevents immune system decline, convenience may seem like a trivial reason for switching.

But ease of use is a crucial factor contributing to good adherence. Research has shown that near-perfect adherence is necessary to maintain virological suppression and prevent the emergence of drug-resistant virus. And studies have found that simpler regimens do indeed promote better adherence. For example, a study by Tracy Glass and colleagues reported in the March 2006 Journal of Acquired Immune Deficiency Syndromes (JAIDS) showed that complex therapy--in particular, use of a boosted PI regimen-- was associated with poorer adherence.

Saag is among the experts who believe that if a patient is having difficulty sticking to a regimen, it's better to "nip the problem in the bud" by switching to an easier combination before treatment failure occurs.

Individuals who have been on antiretroviral therapy for many years remember the challenges of the earliest anti-HIV regimens. When AZT was first introduced, it had to be taken six times daily. The discontinued unboosted formulation of saquinavir (Fortovase) required eight capsules at a time, twice daily. Unboosted indinavir (Crixivan) had to be taken every eight hours. It was not uncommon for an individual's regimen to include some drugs that had to be taken with food, while others had to be taken on an empty stomach. Ritonavir (Norvir) and the old formulation of lopinavir/ritonavir (Kaletra) required refrigeration--a serious drawback in much of the developing world, but bad enough for people who take their medications during the workday.

While most antiretroviral combinations no longer consist of handfuls of pills, and HIV positive people typically no longer require several additional medications to prevent or treat opportunistic illnesses, high "pill burden" remains a common complaint. Along with their anti-HIV drugs, many people also take adjunct medications-- such as lipid-lowering agents and antidepressants-- to manage treatment side effects, as well as complementary therapies such as vitamins and supplements. Thus, many patients and physicians feel, the fewer pills in an antiretroviral regimen, the better.

In addition to reduced pill burden, several newer antiretroviral agents can be taken just once daily, and it is now possible to construct a few complete once-daily regimens. As is the case with side effects, convenience is also in the eye of the beholder. Nearly two-thirds of Boyle's survey respondents said that they would prefer a simpler regimen, assuming it could control HIV equally well. But simplicity meant different things to different people: about half said they would rather take three or four pills at a time once daily, while 40% preferred one or two pills at a time twice daily. Here again, HIV positive people should work with their providers to devise an individualized regimen that is convenient and promotes optimal adherence, without sacrificing antiretroviral potency.

Evolution of Antiretroviral Therapy

Over the past decade, several innovations have made antiretroviral therapy not only more effective, but also easier to tolerate and simpler to fit into one's life:

• New antiretroviral agents
• Reformulations of older drugs
• Fixed-dose combination pills
• Once-daily regimens
• Protease inhibitor boosting
• Class-sparing regimens
• Improved treatment strategies

Numerous switch studies have compared older drugs and treatment strategies with newer ones that researchers hoped would offer better or more durable virological suppression, fewer side effects, and greater convenience. Many such studies include participants who have achieved good virological control on an existing regimen, with the aim of examining other aspects of therapy-- typically simplified dosing or reduced long-term toxicity.

When dramatic treatment advances occur--such as the use of ritonavir to boost levels of other PIs--most HIV specialists will review their patients' existing regimens and suggest appropriate changes. But practitioners who have less experience in the field may find it difficult to keep up with incremental changes; therefore, it may be helpful for patients to gather information explaining the potential benefits and risks of switching.

Some HIV positive people, following the "if it ain't broke, don't fix it" principle, have chosen to stay on the same regimens for years. As discussed below, the urge to stick with the "tried and true" is often reasonable, since there is no guarantee that switching will prove advantageous for any specific individual. But in many cases, patients may be needlessly missing out on the latest innovations in antiretroviral therapy.

New Agents, and More to Come

While the drug development process often seems agonizingly slow to people who need new medications now to construct viable antiretroviral regimens, the HIV treatment field has actually progressed remarkably rapidly. A total of 22 antiretroviral agents have been approved since the appearance of AZT in 1987, although two--ddC (zalcitabine, Hivid) and amprenavir (Agenerase)--have since been pulled off the market following the development of superior alternatives.

While new agents in existing drug classes are continually working their way through the development pipeline (for example, the experimental NNRTI TMC-125), novel agents that attack HIV by entirely different mechanisms hold the most promise, especially for people with extensive resistance to current drugs. Some of the agents in novel classes now moving through the pipeline include CCR5 coreceptor antagonists such as maraviroc, other types of entry inhibitors, integrase inhibitors such as MK-0518 and GS-9137 (see "Drug Watch"), and the viral maturation inhibitor bevirimat (PA-457).

New Formulations

Along with novel agents, manufacturers have also developed new formulations of drugs. For example, the original version of ddI (Videx), discontinued earlier this year, contained a buffering agent that restricted which other drugs could be taken at the same time; the new formulation, Videx EC, is not affected by stomach acid. Some drugs have been reformulated to contain larger doses, allowing for a lower pill burden; for example, people used to have to take five of the old 250-mg nelfinavir (Viracept) tablets at a time to get the same amount of medicine they can now get in two 625-mg tablets.

Saquinavir--the first PI on the market, approved in 1995--has come full circle. The original hard-gel tablet (Invirase) was poorly absorbed, and thus less potent in suppressing HIV. A new soft-gel capsule (Fortovase), released two years later, was better absorbed, but required six pills three times daily. With the discovery that ritonavir could be used to boost saquinavir levels in the blood, Invirase made a comeback. Today, the standard dose is two 500-mg Invirase tablets plus one 100-mg ritonavir capsule twice daily; Fortovase was recently taken off the market.

Amprenavir (Agenerase), a less potent PI that was usually taken eight pills at a time, was replaced with its more powerful pro-drug, fosamprenavir (Lexiva); the original amprenavir formulation, too, was recently discontinued. A new formulation of the Kaletra lopinavir/ritonavir combination pill allows patients to take fewer pills per day, has no food restrictions, and no longer requires refrigeration--which will be a boon in resource-limited settings.

Substituting a new formulation of an older drug is one of the most conservative switch strategies. Since people already have an idea how well the drug works for them and whether they can tolerate its side effects, benefits such as simplified dosing may be achieved with minimal risk.

Fixed-Dose Combination Pills

Using a fixed-dose coformulation that contains two or more drugs in a single pill is perhaps the easiest way to reduce pill burden, and changing from two or three separate medications to a coformulation is one of the most popular and low-risk switch strategies. In order to gain Food and Drug Administration (FDA) approval, studies must show that a combination pill is "bioequivalent" to the separate drugs used together--that is, it is processed the same way in the body and works equally well. As an added benefit, most insurance companies consider fixed-dose combinations as a single medication requiring just one co-payment.

So far, most fixed-dose coformulations contain only NRTIs (see sidebar at right). The first, Combivir (AZT/3TC), was released in 1997, and there are now four all-NRTI combinations on the market. Because of its once daily dosing schedule and good side effects profile, the Truvada (tenofovir/emtricitabine) combination pill is now the most frequently prescribed medication for patients starting first line antiretroviral therapy. The Kaletra pill contains the PI lopinavir plus a boosting dose of ritonavir.

The newest fixed-dose combination, approved on July 12, is Atripla, a three-in-one coformulation containing Gilead Science's tenofovir (Viread) and emtricitabine (Emtriva) plus Bristol-Myers Squibb's efavirenz (Sustiva). Atripla is the first-ever complete one-pill, once-daily antiretroviral regimen.

In wealthy countries, the development of coformulations has been limited by patent issues. Typically, brand name combination pills contain drugs manufactured by a single pharmaceutical company. For example, Abbott Laboratories holds the patent on ritonavir, allowing the company to produce the Kaletra coformulation, while PIs produced by other manufacturers must be taken with a separate dose of ritonavir.

Some foreign generic drug-makers have produced fixed-dose combination pills containing agents patented by multiple companies--for example, Triomune, manufactured by Cipla in India, contains Glaxo's 3TC, Bristol- Myers Squibb's d4T, and Boehringer Ingelheim's nevirapine. The FDA recently approved a three-in-one, twice-daily AZT/3TC/nevirapine coformulation, produced by India's Aurobindo, for use in developing countries. The Gilead/Bristol-Myers Squibb effort to develop Atripla is the first successful cooperative venture among drug manufacturers in the HIV field, and the first multiclass coformulation available in the United States.

Once-Daily Dosing

While the approval of Atripla has generated considerable excitement, it was already possible to put together complete regimens that require as few as two to four pills once daily. Once-daily dosing is feasible if a drug has a long enough half-life (the amount of time it takes for the concentration of an agent to be reduced by one-half in the body) to remain potent for 24 hours.

NRTIs were the first once-daily drugs to come on the market. Some agents that were originally prescribed twice daily, such as 3TC and abacavir, were later shown to work equally well when taken once daily. The NNRTI efavirenz may also be taken once per day. Atazanavir (Reyataz) was the first approved once-daily PI, and boosting with ritonavir also allows some older PIs to be taken once per day. With some drugs, however, once daily dosing is recommended only for people starting antiretroviral therapy for the first time, while treatment experienced patients should take them more often. In Boyle's survey, more than 80% of respondents expressed interest in a once-daily regimen. Among the reasons they gave for preferring less frequent dosing: getting their pill taking out of the way so they don't have to think about HIV for the rest of the day; concern about forgetting doses later in the day; ease of fitting pills into their daily schedule; and greater privacy--for example, not having to take drugs at work.

Studies have shown that such self-reported preferences translate into improved adherence and more effective therapy. For example, at the 2005 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Edwin DeJesus, MD, and colleagues presented preliminary data from COMET (Combination of Efavirenz and Truvada), a Phase IV post-marketing study that included 411 patients with suppressed HIV who switched from twice-daily Combivir to once-daily Truvada while remaining on efavirenz; 86% said they switched for regimen simplification, 6% hoped for reduced toxicity, and 8% cited both reasons. After 24 weeks, significantly more patients who switched maintained virological suppression; participants also experienced fewer side effects and reported increased convenience and greater overall satisfaction with the Truvada regimen.

In Abbott's open-label study M02-418, presented by Richard Rode, PhD, and colleagues at the same conference, 190 treatment-naive participants were randomly assigned to receive either 800/200 mg once-daily or 400/100 mg twice-daily lopinavir/ritonavir plus once-daily tenofovir and emtricitabine. After 96 weeks, efficacy was similar in both groups. However, patients in the once-daily arm achieved better adherence, assessed using pill bottles with electronic monitors; furthermore, the difference in adherence widened over time, falling from 97% to 93% in the once-daily arm, but from 92% to 81% in the twice-daily arm.

Data from another PI switch study were presented by Jose Gatell, MD, at the 2005 European AIDS Clinical Society (EACS) conference. In the open-label Phase III SWAN study, 419 participants with undetectable viral load were randomly assigned to remain on their current boosted or unboosted PI-based regimen--which contained at least three pills taken twice daily or more--or switch to a once-daily atazanavir-based regimen. After 48 weeks, 16% in the continued regimen arm experienced virological rebound, compared with 7% in the atazanavir switch arm.

Overall, these and other studies suggest that switching to once-daily regimens--especially those with reduced side effects--improves adherence, resulting in higher rates of treatment success. The drawback to once daily dosing is that near-perfect adherence and correct timing (taking medications at the same time every day) becomes even more important. Once-daily drugs are typically less "forgiving" because the virus potentially has a whole day, rather than 8--12 hours, to begin replicating if a dose is missed.

Protease Inhibitor Boosting

One of the most beneficial advances in antiretroviral therapy was the realization that small doses of ritonavir could be used to boost blood levels of other PIs. This approach takes advantage of ritonavir's action as an inhibitor of the CYP3A4 enzyme, which processes many drugs in the liver. This causes ritonavir to interact with several classes of medications-- sometimes dangerously raising their levels in the body--but it also means co-administration of ritonavir can raise blood levels of other PIs, conferring increased potency and allowing fewer pills to be taken less often. For example, unboosted indinavir required four capsules three times daily on an empty stomach, while boosted indinavir can be taken two pills at a time twice daily with or without food.

Numerous studies have demonstrated the advantages of boosted PI regimens. In the SWAN study, for example, most cases of treatment failure occurred among patients taking unboosted PIs. In a meta-analysis of 64 studies with more than 10,000 treatment-naive patients taking nearly 100 different HAART regimens, John Bartlett, MD, and colleagues found that virological suppression was achieved more often with triple combinations that included a boosted PI (64%) or an NNRTI (63%) than with regimens that included an unboosted PI (44%) or three NRTIs (51%).