Noncompliance crippling treatment gains
Pharmacist interventions needed
The honeymoon is over for protease inhibit -ors. Rightly touted two years ago as a breakthrough later supported in federal guidelines, aggressive triple-combination therapy is showing some vulnerabilities that threaten to counter the gains, say researchers who attended this year's 12th World AIDS Conference in Geneva.
Topping the list of concerns is patient noncompliance with the often complicated dosing regimens. Taking protease inhibitors alone can mean from six to 18 pills per day with a host of restrictions.
A national survey reports that nearly half of all patients responding either miss or skip doses on a regular basis, in part because they're feeling better or because they can't keep up with the schedule. That is leading to fears that protease inhibitor-resistant strains will develop, or rather continue to develop, as cases of resistance were reported at the AIDS conference.
Toxic side effects from protease inhibitors also are emerging, contributing to noncompliance: Lipodystrophy, the wasting of fat from the face, limbs, and upper trunk; highly elevated cholesterol levels; type II diabetes; and an untenable alternative to lipodystrophy, called "buffalo hump," the accumulation of fat on the spine, are all being reported.
Renewed focus on compliance
Taken together, the call to arms coming from Geneva was two-pronged: a renewed emphasis on compliance and the development of alternative drugs and therapies toward simpler dosing regimens and to counter any protease inhibitor resistance on the way.
"Everyone is at least aware that adherence is an issue and are trying to get something in place to enhance it. That was obviously a big focus at the conference," says Lidia Gajewski, PharmD, manager of the managed health care division of Stadtlanders Managed Pharmacy Services in Pittsburgh and assistant professor of pharmacy and therapeutics at the University of Pittsburgh School of Pharmacy. Gajewski attended the Geneva conference as part of her role as developer and coordinator of HIV/AIDS clinical management at Stadtlanders. "Getting to the actual reason for noncompliance, be they side effects, knowledge deficiencies, or a regimen that's not compatible with the patient's lifestyle, is a big role of the pharmacist, whether in a hospital or outpatient setting. Monitoring and counseling are the keys."
On the drug therapy side of compliance, where combination therapy is still the rule, a pair of non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine, have been successful in clinical trials as a protease alternative. Other drugs are being reformulated into a daily dose, including the non-nucleoside reverse transcriptase inhibitor (NNRTI) didanosine, or ddI.
Already on the market, the nucleoside reverse transcriptase inhibitor (NRTI) Combivir, merging AZT and 3TC, is being widely prescribed for its efficacy and easy administration of one pill, twice a day. Another NRTI, abacavir, is before the FDA following its own successful early trials.
Testing is being done both as an alternative to protease in terms of dosing regimens, resistance, and side effects, as well as for treatment options in cases of therapy failure with protease inhibitors.
"These drugs are in different classes [than protease inhibitors] and work on different parts of the replication cycle. Up until now, the NNRTIs didn't necessarily produce as potent results as protease inhibitors, but the data on newer drugs in the class look as good or better in some patients," says Gajewski. She cautions that the data are preliminary. "The studies are encouraging, but down the road, we don't know the durability," she says, noting that some of the most encouraging data presented at the conference were from trials of just 24 weeks.
Along with compliance concerns, another reason different drugs are being considered for optional first-line treatment is that current combination therapies mixing protease inhibitors and NNRTIs and NRTIs are making patients better, but they are not completely eradicating the virus, researchers confirmed at the conference. Even with undetectable levels of viral loads, latent pockets of active, often mutating virus remain in the system. That has framed the short-term goal of treatment into one of maintaining good health with combination therapies, while finding ways to boost the immune system to possibly wipe out the virus, especially since a viable vaccine remains decades away. And with the newer alternative drugs not yet available, compliance with current regimens is the only way to keep the disease in check.
'Drug holidays' a widespread problem
Along with the complicated dosing regimens, complacency brought by the success of protease inhibitors also has become a factor in patient noncompliance. A national survey of HIV patients and doctors shows just how widespread noncompliance can be. Titled "Adherence to Antiretro viral Regimens in HIV Infected Patients: Results of a Survey among Patients and Physicians," the poll found that nearly half of all patients admitted to not taking medication as prescribed at some point.
Twenty-six percent of patients responding reported "prior day" noncompliance at the time they were contacted, while 43% reported noncompliance during the "prior week." Fifty-four percent also said they knew other HIV patients who've gone off their regimens because of complicated dosing schedules.
Pollsters conducting the study, printed in full in the May issue of the Journal of the International Association of Physicians in AIDS Care, also confirmed the emergence of "drug holidays" among 23% of the patients contacted. Drug holidays are periods where patients simply stop taking their drugs altogether, and the survey found that patients who've been taking drugs longer also take longer drug holidays. Specifically, patients on therapy between two and 12 months averaged drug holiday durations of 6.2 days, while patients taking drugs more than 25 months skipped an average of 14.4 consecutive days.
For their part, 42% of physicians polled said they learn of noncompliance directly from their patients. The majority of physicians, 62%, said they realize patients have been noncompliant when their viral loads increase during periodic checks, although the speculative nature of that conclusion has been criticized by AIDS advocacy groups reviewing the survey.
Still, 84% of physicians said they have limited the availability of certain drugs to patients based on fears that noncompliance leads to resistant strains, although they admit preexisting resistance or ineffective regimens also may increase viral loads or CD4 counts. When asked for solutions, 74% of physicians chose simplification of dosing regimens as the most important intervention.
Pharmacists must bridge provider gap
Until new drugs and therapies aimed at decreased dosage become available, pharmacists must bridge the gap between physicians and patients, Gajewski says. She and her colleagues at Stadtlanders submitted three posters that were accepted and published at the conference. All three centered on pharmacist intervention toward drug regimen compliance.
Using established dosing guidelines for the protease inhibitor indinavir, a clinical pharmacy specialist was identified to review prescriptions falling outside the guidelines. Indinavir can be dosed as 600 or 800 mg q8h or 1,200 mg bid. In those cases, information on the drug's dosing and viral resistance was sent to the prescribing physician, along with a physician action form seeking any clinical or lab data or related justifications for the prescription, to be returned within 24 hours.
The procedure was evaluated after one year, finding that 92% of patients (351 of 381) originally given prescriptions outside the guidelines had fallen into place. Then a six-month follow-up study found that "suboptimal" prescribing had "decreased dramatically."
A similar program was set up for the combination prescribing of indinavir and nevirapine at an 86.5% (96 of 111 patients) success rate. Another system was set up for direct patient compliance to protease inhibitor therapy that includes a monthly checklist forwarded into a patient's database that assigns three levels of compliance with matching intervention and follow-up procedures. Patients are contacted by telephone if the monthly checklists are not returned.
The system tracks the amount of monthly screenings, any changes in self-reported compliance, viral loads, and CD4 counts. Any prior interventions also are charted. The system is overseen by a multidisciplinary education, counseling, social service, and physician consult team.
Alternative therapies show promise
If the loose prescribing that conference posters describe is happening, it begs the question of why. Here Gajewski offers a context that also can apply to the average contact most hospital pharmacists have with AIDS patients: "It's not so much the HIV specialists but the general practitioner who may only have a handful of patients and is finding it hard to keep up with the literature and the changes," she says. "They may say, 'Well, this is what I did a year ago,' and that's why pharmacist oversight on dosing and then compliance is important. I can tell you from the conference, there were lots and lots of posters on compliance. That was really at the forefront, and I brought home piles of them."
Several drugs before the Food and Drug Admin istration have shown encouraging results as alternatives to standard protease inhibitor-led combinations. The once-daily, non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (Sustiva, by Merck) has been promising on several fronts. One study combined the drug with Combivir - dosed as one tablet twice a day combining AZT and 3TC - along with the protease inhibitor indinavir as a quadruple therapy consisting of only three different pills. Doctors with Kaiser Permanente in San Francisco reported that 184 patients were enrolled in the 24-week study, which resulted in undetectable HIV levels in 74% of patients, compared with 45% on triple-combination therapy without efavirenz. AZT and 3TC are nucleoside reverse transcriptase inhibitors (NRTIs), meaning the trial allowed the introduction of one of the newer NNRTIs into the regimen without increasing the number of pills given.
Sustiva also has proved successful in early trials combining it with AZT and 3TC, compared with indinavir alone and the two NRTIs, furthering Sustiva's potential as a direct alternative to a protease inhibitor and its side effects or resistance factors. Another ongoing trial with Sustiva matches it solely with indinavir as a two-drug regimen, with Sustiva given once daily and indinavir every eight hours.
Another new NNRTI, nevirapine (Viramune, by Boehringer) is being touted as a protease substitute and for its possibilities as part of an initial therapy regimen. Indicated as a twice-daily tablet with or without food, the drug was given with the NRTIs d4T and ddI, resulting in undetectable viral loads in 85% (17 of 20) patients at 16 weeks. The drug is being tested with ddI and AZT as a non-protease inhibitor combination therapy option.
[For more details or to obtain full reprints of the pharmacy compliance initiatives by Stadtlanders, call (888) 588-6891.]
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