Experts examine latest HIV options

Drug Store News, August 24, 1998 by Kim Roller

Scientists left the 12th World AIDS Conference, held earlier this summer in Geneva, Switzerland, with new understanding of the precarious nature of both prevention and treatment of HIV disease. Tactics for the former have been diminished by the sheer scope of the epidemic, in which 16,000 new infections are estimated to occur each day, largely in the developing world.

Reports on the enormous strides in HIV treatment were tempered by the increasing and discomforting knowledge that efficacy of new therapies relies on a non-existent margin of error. Several major reports discussed the importance of the pharmacist in this issue of medication adherence, noting that the incorporation of the pharmacist into the HIV care team had a significant impact on patient outcome. While numerous studies reported that immune reconstitution in HIV-infected individuals may be possible with prolonged reduction of the HIV viral load through highly active anti-retroviral therapy, new cross-resistant strains of the virus are being transmitted that have resulted from noncompliance with that therapy. Although new drugs may soon be available that might simplify treatment regimens and increase tolerability, the conference ended with the sobering pronouncement that there is "no end in sight" for the epidemic. Of the reports presented in Geneva, the question of how to ensure adherence to complex, life-long drug regimens with uncertain safety profiles emerged as the single most important and harrowing challenge to the future of effective HIV therapy. There are now 11 anti-HIV drugs approved by the Food and Drug Administration; the number may soon rise to 15. They are used in regimens so complex that even experts admit difficulty keeping track of therapeutic advances. An estimated 800,000 Americans are infected with the HIV virus; 36.6 million people are infected worldwide. HAART The rate of AIDS deaths in the United States dropped 44 percent in 1997, the first decline since the epidemic was reported in 1981. This decline is widely attributed to HAART, the potent triple drug combination therapy of protease inhibitors and non-nucleoside reverse transcriptase inhibitors. These triple combinations have been able to achieve long-term suppression of the HIV plasma viral load to undetectable levels--less than 500 copies/ml, which has become the therapeutic standard target. Said Dr. Michael Saag of the University of Alabama, an international authority on HIV, "HAART has created a paradigm whereby HIV is now viewed as a chronic, manageable disease." The era of triple drug therapy began in 1996 with the introduction of protease inhibitors and now includes a variety of other drugs added to two-drug combinations. The relative aggressiveness of initial therapy has, in general, been proportioned to the plasma HIV RNA level, although researchers caution that literally every patient's experience is different. Many reports also noted that HAART is arguably the most cost-effective major new medical technology that has been introduced in the past decade. "In the long term, we project an incremental cost-effectiveness ratio that is highly favorable compared to almost any other technology in the United States," said Dr. John Bartlett of Johns Hopkins. Although HAART has produced high-level suppression of HIV replication and a decreased occurrence of opportunistic infections, as well as decreased mortality, medical care providers are faced with mounting problems dealing with resistance to anti-retroviral drugs, lack of patient adherence to complex and costly drug regimens, the emergence of troubling side effects and possible toxicities, pharmacokinetic interactions, and anticipating changes in the event of drug failure. Because intermittent adherence to medical regimens can lead to more rapid development of resistance and thus restrict what drugs may or may not be used in the future, many physicians are reluctant to initiate aggressive anti-retroviral therapy, saving the most potent agents for later utilization. The medical community remains sharply divided on this issue. And, the serious side effects of P1 therapy have become a troubling concern. These include lipodystrophy (abnormal fat distribution, including "buffalo humps" and what has become known as "protease paunch"), pancreatitis, diabetes and possibly cardiovascular disease. The question remains whether prolonged suppression of HIV replication will permit profound immune recovery or whether the subclinical immune deficiencies that are now prevalent in HIV infected persons will place persons at a heightened risk for different opportunistic complications, such as malignancies. New studies have shown replication-competent virus isolated from the blood of suppressed patients receiving HAART. Rapid rebound of HIV in vivo also has been documented after prolonged suppression. Researchers agree viral loads should be monitored closely and attempts should be made to catch viral rebounds early--which may indicate resistance to only one drug and allow the opportunity to prevent progressive resistance. In addition, new genotypic and phenotypic resistance assays may now be used to predict zidovudine and protease inhibitor resistance, adding to the tools available. "Regardless of which therapeutic strategy, one thing is certain: Each decision regarding HIV therapy has ultimate implications on which therapies can and cannot be used in the future," said Saag. "HIV clinicians are obliged to think about the consequences of each therapeutic intervention at the time therapy is initiated." HIV has both a high turnover and a high mutation rate, complicating attempts at long-term suppression. This has led to the urgent need for new and more potent agents, both to simplify treatment regimens (thereby improving compliance) and to address growing concerns over the problem of cross-resistance. What follows are some new drugs that show particular promise. New drugs Abacovir, a novel nucleoside analogue, which is highly bioavailable when given orally, crosses the blood brain barrier well, is synergistic or additive with many other antiretrovirals and has produced viral load reduction greater than that seen with other nucleoside RT inhibitors. Adefovir, a nucleotide analog reverse transcriptase inhibitor, has shown both anti-HIV and anti-CMV activity. Cross resistance with other antiretrovirals has not been observed. A related agent, PMPA, has shown considerable activity in a simian AIDS model and is beginning human trials. Efivarenz is a new NNRTI with which resistance appears more slowly than for other NNRTIs. A pilot study suggested suppression of plasma HIV-RNA levels below the level of detection for 48 weeks in more than 80 percent of trial participants. Phase III trials are under way. Abacovir, adefovir and efavienz are available in expanded access programs for patients with advanced disease who have failed other regimens. "Second-generation" PIs in phase III clinical trials include amprenavir and ABT-378. Amprenavir has shown considerable antiviral activity in vitro, and in preliminary clinical studies demonstrates sustained suppression of HIV replication in combination with ZDV-3TC. It may be possible, in combination with ritonavir, to achieve very high levels of ABT 378 above concentrations required to inhibit resistant viruses. Hydroxyurea, although having little anti-HIV activity of its own, potentiates the activity of certain nucleosides, particularly didanosine. Hydroxyurea has extensive clinical experience in cancer therapy and is relatively well-tolerated. Studies have suggested a lower HIV plasma RNA by ddI plus hydroxyurea than ddI alone. New data also indicate that combination therapy with reverse transcriptase inhibitors may represent a viable alternative for AIDS patients who can no longer tolerate protease inhibitors. Researchers also reported on a multi-drug "rescue therapy" for HIV-infected individuals with prior virologic failure to multiple regimens. Preliminary results were obtained with regimens using up to eight drugs: three nucleosides, two protease inhibitors, two NNRTIs and hydroxyurea. The MDRS achieved substantial antiviral effect in 40 percent of heavily pre-treated patients and suggests that relying on historical, clinical and laboratory evidence may not be sufficient to rule out a possible antiviral response. The new phenotypic and genotypic assays may help to characterize predictors of response. HIV pharmaceutical specialists key to bolstering compliance The incorporation of a pharmacist into the HIV care team has a significant impact on patient outcome, according to several reports at the international conference that dealt with the specialized role of the pharmacist in HIV counseling and education, particularly with regard to the key issues of adherence and compliance. A study from a pharmacist-based HIV medication adherence referral clinic at North Broward County Hospital in Ft. Lauderdale, Fla.; reported that after three months of highly active anti-retroviral therapy with pharmacist counseling, 50 percent of the patients who had a history of severe noncompliance had achieved an HIV plasma viral load at undetectable levels. A study from the Immunodeficiency Clinic at Erie County Medical Center in Buffalo, N.Y., described the addition of an HIV pharmaceutical care specialist to an HIV care team. Dr. Lori D. Esch, PharmD., who co-authored the Geneva report, is the PCS at the clinic on a team with three ID specialists, three ob/gyns, nurse practitioners and physicians assistants. Approximately 700 patients are involved with the clinic. The role of the HIV/PC S is to evaluate patients with a complex drug regimen who are facing barriers to successful care make the appropriate interventions and follow patients on a long-term basis. Counseling includes patients with suboptimal adherence records, adverse drug reactions and patients who are just starting HAART. Esch noted that any patient starting medication for the first time comes to the clinic for at least two counseling visits after the treatment has been decided "What we look at, in terms of compliance, is the lifestyle issue," she said. "We don't want to give medication that has to be given with food to someone who eats irregularly. We look at whether people work strange hours; whether they have small children, whether they are actively using drugs -- these patients will probably not have a good adherence. So our job is to find something that works. "Some people would rather be on a twice-daily regimen-even if that means taking 19 or 20 pills at one times," Esch continued. "In fact, this is the regimen that has the best adherence record. But, there are some people who would rather take two pills every single hour of the day." Esch said the most important thing is to pair-up the pill taking with an activity the patient does every day. "One patient I spoke with said the only thing that she does every single day is to have a cigarette in the morning. So that would be the logical time for her schedule. Another woman picks up her children at the school bus stop every day. Weekends, of course, are the prime times for missing doses. "The most important time frame is the first week, the first three days," the doctor noted. "This is when people forget, or some of the side effects kick in, and they just stop right away. If you wait longer than a week, you're lost." To a patient just starting HAART, Esch advised that the two most important things, unequivocally, are to reinforce, over and over, adherence (not missing a single dose) and to advise the patient of side effects--and to tell them the side effects can be managed. "In terms of adherence, you really have to do more than just dictate. It means trying to prevent them from getting into situations where they will forget. And, the side effects of therapy--this is extremely important where HIV is concerned," she said, noting that patients must be told "all the side effects, the likelihood and how to manage them. Often, we minimize the side effects and say, 'Well, this is unlikely.' With this kind of medication it is extremely important that the patient be told these side effects can be managed. For instance, with ritanovir a patient will often get tingling, or even a trembling sensation, and some patients think they are having a stroke or a seizure. But, if they've been told about the side effects, that this is completely normal, they'll be more likely to continue with the medication and to face other side effects head on," said Esch. Dr. Kathleen Graham from North Broward Hospital also emphasized that the pharmacist has to act as a "medication coach." "If you forget to take your medication in the evening, for even just several evenings, you're exposing the virus to sub-therapeutic levels, and your body becomes resistant. Now there is cross-resistance. So, if your body become resistant to crixivan, it can also be resistant to Norvir, another protease inhibitor. Eventually nothing will work," she said.