OOCCUUVolume 13 Number 3 February 1998

FF A Guide toAIDSResearch and Counseling

SSNew treatment options present people

with HIV disease with exciting opportuni-ties as well as unanticipated challenges.Recent data support the commonly heldbelief that strict adherence is crucial inorder to achieve long-term viral suppres-sion1,2,3 and, presumably, durable clinicaleffectiveness. Other studies suggest thatviral eradication and a cure are most like-ly unattainable with the currently availa-ble classes of antivirals.4,5,6 While data are limited about the long-term efficacy of treatment initiated at any stage of HIVinfection—including very early infection—many researchers and providers believethat patients with acute HIV infectionshould initiate antiviral therapy as soon as possible. Finally, HIV antiviral drugshave significant short-term, and unknownpotentially long-term, side effects.

Complex treatment decisions musttherefore be driven by personal prefer-ence, common sense, rapidly accumulat-ing data, changes in communityprescribing patterns, and, perhaps mostimportant, a comfort with uncertainty.This article reviews the factors clientsmight consider when making treatmentdecisions, focusing on issues of adherenceand duration of effect.

Deciding to Initiate Therapy: EfficacyThe decision to initiate therapy should

be based on an understanding of the risks(for example, toxicity and effects onlifestyle) and benefits (for example,improved survival and quality of life) of aspecific treatment option. Publishedguidelines provide a useful framework forconsidering these risks and benefits, buteach individual will value and weigh these

issues in unique ways. The guidelinesregarding the initiation of antiviral thera-py rely on increasing data that suggestthat there is virologic (decreased viralload), immunologic (increased CD4+ cellcounts), and morbidity and mortalitybenefits associated with antiviral combi-nations that include two nucleoside ana-logues and a potent protease inhibitor ora non-nucleoside reverse transcriptaseinhibitor (NNRTI). The duration of thispositive effect, however, is not known.

Efficacy can be evaluated on severallevels. For patients with early HIV infec-tion, long-term efficacy will be mostimportant. For those with advanced dis-ease, shorter-term goals may be morerelevant. For most people, improved quali-ty of life and extended life span are theexplicit hopes. However, for many others,an unspoken goal may be total viral eradi-cation and cure.

Recent data from three different labora-tories show that even with prolongedsuppression of detectable virus in theblood, there remain latently infectedresting CD4+ cells (non-replicating; notproducing virus). These cells, when acti-vated, are capable of producing infectiousvirus, thus serving as a reservoir of infec-tion even in those who have had nodetectable virus in their blood for up to30 months. The bottom line is that peopleusing currently available combinationswill likely need to continue treatmentindefinitely in order to keep the virus incheck. While cure with the currently avail-able drugs is not a realistic goal, it is stillpossible that people will live long enoughto try newer drugs that may eventuallyachieve this goal.

Toxicity, Side Effects and Quality of LifePatients also experience medication

toxicities in unique ways. Considering theside effect profile of a given combination

Antiviral Adherence DilemmasMichelle E. Roland, MD

is important, as the possibility of certainside effects may direct specific treatmentchoices. For example, the possibility ofside effects such as fatigue, nausea, diar-rhea, or headache may be unacceptable tosome. Still, patients may tolerate commonside effects more easily when warnedabout them in advance.

Some undesirable consequences ofhighly active antiviral therapy (HAART;that is, the use of potent drug combi-nations) may, ironically, result fromimproved immune function. Theseinclude: rapidly progressive hepatitis B or C (liver destruction is largely immunemediated) and worsening immune throm-bocytopenia purpura (ITP; immune medi-ated destruction of platelets). Body

composition changes, including buffalohumps (fat collections in the upper back)and abnormal fat collections around thetorso, as well as a number of endocrino-logic changes, including hypertriglyceri-demia (elevated lipid subset) and possiblydiabetes mellitus, are less well under-stood.

Some of these side effects can be life-threatening. Others can be disfiguring.The long-term effects of hypertriglyc-eridemia for example, heart disease or pancreatitis) are unknown, and it is possible that serious long-term sideeffects may develop for those who live for many years.

Other issues may affect quality of lifewhile taking these antiviral medications.

FOCUS2 February 1998

The newest AIDS buzzwordsare “treatment adherence.”Everywhere you listen peopleare talking about the hope forviral eradication and the fear ofviral resistance, and the bottomline is always adherence.

The media does pay lip ser-vice to the idea that combinationtherapy is a pill-popping chal-lenge. But, as it becomes clearthat strict adherence is essen-tial, it becomes clearer still thatstrict or even consistent adher-ence is not merely a challenge, it is abnormal.

I was talking to Gail, the moth-er of a woman with HIV abouther daughter’s reactions to herdrug regimen and the difficul-ties of both tolerating sideeffects and adhering perfectly toher treatment schedule. The daybefore, someone had told meabout new data and anecdotalevidence that suggest that forsome people with HIV, missingeven a few doses can result inrapid increases in viral load anddrug resistance.

When I told Gail about thesestudies, her immediate reactionwas anger. Gail has been an activeadvocate for HIV funding, goingto Washington each year to lobbyCongress, and her otherwise mild

manner becomes animated whenshe talks about AIDS.

The press, she said, would havea field day with this news: theywould blame people with HIV for not adhering and label themfailures. But how many of thosereporters, or the doctors for thatmatter, were getting up in the weehours to pop a dose of Crixivan,she demanded? I replied, wait!(her passion required an exclama-tion to interrupt): If the studyfindings stood the test of time,wouldn’t it be important for peo-ple on these drug combinations to know that only a few misseddoses might lead to resistance?

Dose-Difficult ExperiencesGail eventually agreed that

the information itself was notthe problem; it was the tiredperception that somehow peoplewho become infected, or fail toadhere to their regimens, orchoose not to try the regimensat all somehow deserve theirfate. It’s not a position that mostpeople will voice when talkingabout an individual—a friend, ason, a partner—but it’s a simpleone to express when talkingabout those “other” people who,if they just took their pills,could “get on with their lives.”

In this month’s issue of FOCUS,Michelle Roland is particularlyeffective in presenting the scien-tific data about drug adherence,the real challenges to adherenceposed by everyday living, andthe shared responsibility ofprovider and client to designattainable treatment plans. Andin our second article, our anony-mous author is poetic in hisevocation of “dose-difficult”experiences—too many pills toooften—with which we can allempathize, HIV-positive or not.

It’s easy to exhort people to beresponsible—to take their medsand be thankful for the opportu-nities they have—easier still toblame them for the opportunitiesthey might seem to be squander-ing. But, think about living withHIV and dealing with all thechallenges that we’ve writtenabout in these pages for the past13 years, and then add theprospect of popping those pillsat all hours without exception forthe rest of your life. Doesn’t theissue seem to go way beyond thescience of treatment adherence?

I hold out hope for a timewhen the doses are fewer and the consequences of missing oneare less dire. Until then, momentsof empathy, encouragement, andsupportive problem-solvingwould be more appropriate thanthe befuddlement or indignationthat appear to be the more fash-ionable response.

Editorial: Bucking the NormRobert Marks, Editor

ReferencesDeeks S, Loftus R,Cohen P, et al.Incidence and predic-tors of virologicfailure to indinavirand/or ritonavir in anurban health clinic.37th InterscienceConference onAntimicrobial Agentsand Chemotherapy.September/October1997. Abstract LB 2.

FOCUS3 February 1998

Patients must be seen and monitoredregularly with laboratory studies. Theymust be especially vigilant not to run

out of medications.Those with insur-ance or AIDS DrugAssistance Program(ADAP) restrictionsmay leave the phar-macy empty-handedif they attempt toget refills early or if there are paperwork problems.

Taking intoaccount an indivi-dual's lifestyle isextremely importantwhen recommend-ing a potential com-bination. Somemedications need tobe taken with mealswhile others areonly absorbed on anempty stomach. Onedrug must be refrig-erated; the others

should not be. Some can be taken threetimes a day during waking hours, whileanother must be taken every eight hours.

Although protease inhibitors are gener-ally more potent than the non-nucleosidereverse transcriptase inhibitors, in somecases starting with an NNRTI might be agood choice. In a motivated patient with ahistory of adherence problems, adherencecan be assessed with an NNRTI-containingregimen. The advantage of this approachis that if the patient is not able to adhereto the regimen and develops a detectableviral load, he or she will not have devel-oped protease inhibitor resistance. If thepatient is able to stabilize and restartmedications in the future, the proteaseinhibitors will still be an option.

There are even circumstances whenusing two nucleoside analogues alonemight be a reasonable choice. Althoughdestined to "fail" eventually as HIVbecomes resistant to the double combina-tion, this approach can slow disease pro-gression and diminish adherenceproblems and pill burden.

Finally, several once-a-day drugs arecurrently in clinical trials. For those whoare doing relatively well clinically, waitinga few more months for a-once-a-day regi-men may be a reasonable alternative.Close monitoring of the CD4+ count andviral load is important if patients andproviders choose this option.

A Commitment to AdherenceOne of the reasons for viral break-

throughs is non-adherence. Becauseadherence studies are limited at this time,it is not clear how many doses an individ-ual may miss in a given time periodbefore resistance will develop to one or more of the drugs. Such studies haveshown an association between an increasein a person’s viral load and notes in his orher medical records suggesting non-adherence; a direct relationship betweenthe likelihood of developing a detectableviral load and delays in refilling medica-tions; and an increase in viral load inindividuals who have missed three days of medication. Cross-resistance is com-mon within both the protease inhibitorsand the NNRTI classes, which means thatresistance to one drug is likely to conferresistance to other drugs in that class.Because taking these medications requiressuch a tremendous commitment, it’s cru-cial to take the time to be sure the deci-sion to begin treatment is the right one.

Clinicians and patients may attempt tomaximize adherence by discussing cues toremember to take medications, anticipat-ing changes in the patient's daily patterns,and reviewing medications in the clinicprior to starting them. Helping to stabilizeissues such as homelessness, active men-tal health problems, and substance usebefore starting therapy is often but notalways essential.

Strict adherence may be the mostimportant component of any treatmentstrategy. Adequate time and resourcesmust be invested to assist each individualin making the decisions most likely toenable that person to adhere to his or hermedications. Physicians need to learnadherence evaluation and education tech-niques that they may have never beentaught before.

In addition, new health care deliverymodels may be necessary. Pharmacy-runmedication clinics can assess and supportadherence before and after medicationshave been prescribed. In addition, nurseeducator or directly observed therapy(DOT) models or both may be adapted to HIV settings. For example, diabetesnurse educators have constructed individu-al and group education systems that maybe useful in HIV care. The tuberculosismodel of DOT could be combined withmethadone maintenance, food delivery, or homeless outreach programs (or anycombination of these), whereby patientscould be given their daily medication doses in monitored settings.

Vanhove GF, SchapiroJM, Winters MA, et al.Patient compliance anddrug failure in pro-tease inhibitor mono-therapy (letter).Journal of theAmerican MedicalAssociation. 1996;276(24): 1955-1956.

Cohen V, Maggio C,Triplett JW, et al.Relationship betweenantiretroviral prescrip-tion compliance andimmunologic, virologic,and clinical outcomes.American College ofClinical PharmacyAnnual Meeting,November 1997.Abstract 67.

Wong JK, Hezareh M,Gunthard HF, et al.Recovery of replica-tion-competent HIVdespite prolongedsuppression of plasmaviremia. Science.278(5341):1291-1295.

Finzi D, HemankovaM, Pierson T, et al.Identification of areservoir for HIV-1 inpatients on highlyactive antiretroviraltherapy. Science.278(5341): 1295-1300.

Clinicians and patients can

maximize adherence by identifying cues

to help remind patients to take medications,anticipating changes in daily patterns, and

reviewing medicationsin the clinic prior to

starting them.

Chun TW, Stuyver L,Mizell SB, et al. Pre-sence of an inducibleHIV-1 latent reservoirduring highly activeantiretroviral therapy.Proceedings of theNational Academy ofScience USA. 1997; 94:13193-13197.

Carptenter CC, FischlM, Hammer SM. Anti-retroviral therapy forHIV infection in 1996:Recommendationsfrom an internationalpanel. Journal of theAmerican MedicalAssociation. 1996;276(2): 146-154.

Panel on ClinicalPractices of HIVInfection. Guidelinesfor the use of anti-retroviral agents inHIV-infected adultsand adolescents.Federal Register.1997; 62(118): 33417-33418.

AuthorsMichelle E. Roland, MDis Project Manager ofthe Post-ExposurePrevention Program,an Adjunct Instructorof Medicine in theUniversity of CaliforniaSan Francisco AIDSProgram at SanFrancisco GeneralHospital, and a clini-cian on the hospital’soutpatient AIDS ward.

More Urgent Treatment DecisionsThere are a few situations when starting

therapy may be more urgent. Patients withvery high or rising viral loads (or both)and falling CD4+ cell counts or rapiddisease progression are likely to benefitfrom prompt initiation of therapy. For avery ill patient with advanced disease,whose only hope of extended life is near-immediate antiviral therapy, the decisionto begin must be made in the context ofthe importance of quality versus quantityof life; and any decision to start therapyshould be seen as flexible and reversible.

The other circumstance in which theremay be a sense of urgency is for the patientwith acute HIV infection, a conditiondefined by a detectable viral load plus anegative or indeterminant antibody testresult. It is not yet known if the very earlytreatment of acute HIV will achieve the goalsof preserving immune function, preventinginfection of sanctuary tissue sites such asthe central nervous system, lowering viralload and increasing longevity, and achievinglong-term viral suppression. Nor is it knownif this very early treatment might have thepotentially negative consequence of reduc-ing the natural effective immune responseto early HIV infection. However, many clini-cians and researchers believe that the theo-retical reasons to treat people with acuteHIV as soon as possible are compelling.

When someone is diagnosed with acuteHIV infection, they are likely to feel over-whelmed. They may remember the eventthat exposed them to HIV and feel guilt,shame, or anger related to that exposure.They will have to deal with the impact of a life-threatening diagnosis. And then they may be presented with a very com-plex, "high tech" treatment decision, per-

haps after never having had any signifi-cant experience with the health care sys-tem. The language that providers andlong-term patients have become familiarwith, for example, viral load, T-cell counts,and antivirals, may be completely foreign.

In most other cases, there is no urgencyto start medications immediately. It ismost important to start them at the rightmoment for each individual, taking thetime to counsel carefully, select the rightmedications, and provide the necessaryresources to maximize adherence.

ConclusionsWhile the encouraging results of

ongoing clinical trials and HAART-relateddecreases in HIV morbidity suggest that a subset of people with HIV can and arebenefiting from treatment advances,recent data on viral latency and theimportance of adherence may be discour-aging to some clients. Unfortunately, thereare no data available to inform peopleabout exactly how adherent they must be.

The task of health care and mental healthproviders is to help individuals explore allof the complex issues related to the deci-sion to use these medications and to sup-port strict adherence as best we can—without creating an unbearable burden forpatients. This counseling must occur in thecontext of the knowledge that, for now,therapy must be indefinite. Advances in theunderstanding of the basic science of HIV,while discouraging at the moment, willenable scientists to construct rationalapproaches to the ongoing control of HIVinfection. And, while we know that somecells remain latently infected with HIV, aslong as the virus is suppressed by adequatelevels of potent antivirals, this latent infec-tion is not likely to pose a problem.

FOCUS4 February 1998

References Anastasio CJ. HIV and tuberculosis:Noncompliance revisited. Journal ofthe Association of Nurses in AIDS Care.1995; 6(2): 11-23.

Bangsberg D, Tulsky JP, Hecht IM, et al.Protease inhibitors in the homeless.Journal of the American MedicalAssociation. 1997; 278(1): 63-65.

Besch CL. Compliance in clinical trials.AIDS. 1995; 9(1): 1-10.

Haynes RB, McKibbon KA, Kanano R.

Systematic review of randomized trialsof interventions to assist patients tofollow prescriptions for medications.The Lancet. 1996; 348(9024): 383-386.

Healton CG, Messeri P. The effect ofvideo interventions on improvingknowledge and treatment compliancein the sexually transmitted diseaseclinic setting. Lesson for HIV healtheducation. Sexually TransmittedDisease. 1993; 20(2): 70-76.

Katzenstein, DA. Adherence as a partic-ular issue with protease inhibitors.

Journal of the Association of Nurses in AIDS Care. 1997; 8(supp): 10-17.

Lyons C. HIV drug adherence: Specialsituations. Journal of the Association of Nurses in AIDS Care. 1997; 8(supp):29-36.

Molla A, Korneyeva M, Gao Q, et al.Ordered accumulation of mutations in HIV protease confers resistance toritonavir. Nature Medicine. 1996; 2(7):760-766.

Muma RD, Ross MW, Parcel GS, et al.Zidovudine adherence among individu-als with HIV infection. AIDS Care. 1995;7(4): 439-447.

O’Brien WO. Resistance to antiretroviral

Clearinghouse: HIV Drug Adherence

FOCUS5 February 1998

My prized pill collection is shrinking.Two years ago, I maintained the usualarsenal of a person with HIV: a coupleantivirals—but hoards of antifungals andantibiotics, a hodgepodge of cold sorecompounds, diarrhea fighters, and pills,potions, and creams to combat variousitches, rashes, and scratches. Don't forgetabout the necessary selection of sedatives

and antidepressants to help mecope with it all.

The good news is that thesedays, I have little need for any-thing but two nukes (aka nucleo-side analogue reverse trans-criptase inhibitors) and a pro-tease inhibitor. My labs are good.I feel great. The pressure's off.

So I go get this new job and it'sreally demanding. I'm trying to eatbetter, sleep more, and work outthree times a week. My off-hoursare spent dealing with healthinsurance, taxes, credit ratings,and student loans, along with thesimple tasks of washing dishesand buying groceries. If I'm lucky,

I have time to go on a date once in awhile.I'm starting to feel like a normal person.

On Being SupermanThe problem is that normal people,

generally, don't take a handfull of pillstwo or three times a day. They don't havefood restrictions. They don't secretlystash medicine bottles in the refrigerator.You never see a normal guy chewing bigchalky tablets, toting pillboxes, or search-

ing his pockets to separate non-nucleosidereverse transcriptase inhibitors NNRTIsfrom lint balls.

Although I'm swallowing fewer pills innumber, the timing and food restrictionsfor the remaining few is a real ball-buster.Was that take two tablets two hours aftereating or take two tablets two hours beforeeating? Do I take the white ones threetimes a day and the red and triangle onesonly twice a day, or the other way around?Did I even take my pills this morning?

I definitely remember the first time Iswallowed my Crixivan. At first it was abreeze. Taking those capsules every eighthours was no problem—for about a week.Then it hit me: a wave of nausea while onthe bus headed to work. The scent ofcoffee gave me the dry heaves. I felt toxic.For two weeks straight, my mouth tastedlike I was sucking on a dirty penny. Thewhites of my eyes became yellows. Finally,I called my doctor and said I can’t take it! I can’t live like this forever.

His response: Your T-cells have doubledand your viral load is below the limits ofdetection. Who could argue with thatpayoff? I pressed on, and with time theside effects subsided.

Now if I remember to bring my "candy"with me to work, it’s not the side effectsthat get me, but the dosing schedule. I'mnot about to pop a protease snack in themiddle of a staff meeting. Try timingmedicine and food restrictions around aneggnog toast at a Thanksgiving dinner.Imagine landing in Peru for work while yourluggage (and meds) land in Colombia. I'm afairly organized guy, but I'm no Superman.

Meanwhile, I keep hearing the buzzabout how strict adherence is absolutely,unquestionably, necessary. If I miss justone dose, they say, viral resistance will

Popping Pills for LifeAnonymous

Sometimes Iremember thedread. That’s

the bestreminder for

me to take my pills.

drugs. BETA. San Francisco AIDSFoundation. 1997; January: 11-14.

Singh N, Squier C, Sivek C, et al.Determinants of compliance withantiretroviral therapy in patients withhuman immunodeficiency virus:Prospective assessment with implica-tions for enhancing compliance. AIDSCare. 1996; 8(3): 262-269.

Ungvarski P. Adherence to prescribedHIV-1 protease inhibitors in the homesetting. Journal of the Association ofNurses in AIDS Care. 1997; 8 (supp):37-45.

Wall TL, Sorenson JL, Batki SL, et al.Adherence to zidovudine among HIV-infected methadone patients: A pilot

study of supervised therapy anddispensing compared to usual care.Drug and Alcohol Dependence. 1995;37(3): 261-269.

Wells EK. Adherence to HIV treatments.HIV Frontline. 1997; Sept/Oct (30): 1-4.

Weust, J. Removing the shackles: Afeminist critique of noncompliance.Nursing Outlook. 1993; 41(5): 217-224

Williams A. Antiretroviral therapy:Factors associated with adherence.Journal of the Association of Nurses inAIDS Care. 1997; 8 (supp): 18-23.

ContactsRick Hecht, MD, UCSF AIDS Program,San Francisco General Hospital,

Building 80, Ward 84, 995 PotreroAvenue, San Francisco, CA 94110, 415-476-4082, ext. 431.

Catherine Lyons, MSN, NP, MPH, UCSFAIDS Program, San Francisco GeneralHospital, Building 80, Ward 84, 995Potrero Avenue, San Francisco, CA94110, 415-476-0828.

Michelle Roland, MD, UCSF AIDSProgram, San Francisco GeneralHospital, Building 80, Ward 84, 995Potrero Avenue, San Francisco, CA94110, 415-476-4082, ext. 432.

See also references cited in articles in this issue.

develop. I'll fail the drugs. I'll be left withno options. Then, I'll be back to where Iwas two years ago: getting offers for mylife insurance policy.

The Adherence EnforcerOn one hand, I know that treatment

adherence is important. On the otherhand, the everyday boring task of living a productive life is no cakewalk. I gettired. Sometimes I'm lazy. I forget littlestuff here and there.

A while back, my doctor asked if Imissed doses of medicine. I said "yes." Helooked disappointed, wrote something inmy chart, and then delivered a four-minutespeech that left me with anxiety and guilt.

Now when my doc asks the same ques-tion, I think for a moment. Do I want thespeech or not? I’m sure I miss a doseabout once every two weeks, but I don'tadmit to it. It's just easier.

An acquaintance of mine pleads the Fifthat every doctor visit. Not only does he missmeds for the usual reasons, but he occasion-ally takes these extended drug and alcoholgetaways. He's a party boy; loves thosecircuit parties where it's easy to buy under-ground drugs such as cocaine, Special K,Ecstasy, or crystal (methamphetamine). Atsome point, the guy heard it's bad to mixHIV meds with street drugs. He opts for thestreet drugs and lies to his doctor.

Another friend of a friend is this earthy-crunchy type. Wears open-toed sandals.He's big into vitamins, herbs, and visual-ization. He's always talking about pharma-ceutical propaganda, toxic buildup, andthe need to "cleanse." He maintains thistheory that the human body needs to"purify" at times. So he takes "drug holi-days." He stops all his meds and doesherbal tea for several days. He claims itmakes him feel better.

I once heard this story about how theexecutives of a pharmaceutical companywere instructed to eat M&Ms three timesduring a day to simulate the experience ofthe typical "AIDS patient." Clever. Perhapsa more realistic experience is vomiting inpublic. Or getting a surprise attack ofdiarrhea in a car during rush hour.

I'm not demeaning the pharmaceuticalcompanies. To the contrary, they saved mylife. Believe me, I'm grateful. In a relativelyshort period, they brought to market someamazing therapies. I love hearing storiesabout empty hospital beds. I was grantedthe good fortune to witness a renaissancein HIV treatment. I thank God every eighthours, one hour before a meal or twohours after. Or as needed.

It's just the whole pill thing. Sometimesit's hard to connect the abstract adherencemessages with the indigestion-causingpills in my pocket. It's not impossible, it's just hard.

Somewhere under my stacks of late billsis a shiny brochure about adherence. Iglanced at it once: it described somethingor other about the importance of takingyour medicine on time. I really should readit. Sometimes, my pharmacist brings up thetopic of adherence: blah, blah, blah. In oneear, out the other. (Between you and me, I'mfar more honest with my friends than withmy pharmacist or my doctor. In that order.)

The Memory of Dread I don’t talk much with my regular shrink

about adherence. He doesn’t ask and I don’ttell. These days, we talk most about mydestructive lifestyle habits, stress levels,and my mom. There was a time when our50-minute hour was spent dealing with theday-in-day-out, gun-to-your-head terror ofdying from AIDS.

Sometimes I remember the dread. That’sthe best reminder for me to take my pills.

It also helps to sit down about once aweek and organize my pills in these cheapcolor-coded containers. What's left overfrom the previous week determines if I'vebeen good or bad. Then I stash tablets inmatchboxes, small aspirin containers, andpacks of cigarettes. I hide them in my gymbag, the glove compartment of my car, andthe bottom drawer of my desk at work. Ihand over mini-supplies (along with apart-ment and car keys) to my closest friends. I tend to lock myself out of things.

What works for me, probably won't workfor someone else. But it works for me. Fornow. I'd love to stay and debate the mosteffective strategy for promoting adherenceamong patients, but I have to run. It's thattime of the day. I have to take a few pills.

FOCUS6 February 1998

AuthorsThe author of thisarticle, who prefers to remain anonymous,has had HIV for 12years. He is a firmbeliever that—throughself-education, self-empowerment, andpersistence—patientshave far more controlover their own healththan conventionalwisdom would predict.

Comments and Submissions We invite readers to send letters

responding to articles published inFOCUS or dealing with current AIDSresearch and counseling issues. Wealso encourage readers to submit arti-cle proposals, including a summary ofthe idea and a detailed outline of thearticle. Send correspondence to:

Editor, FOCUSUCSF AIDS Health Project, Box 0884San Francisco, CA 94143-0884

FOCUS7 February 1998

The Price of Non-AdherenceMirken B. How much does it really matter if youtake your pills on time? BETA. 1997; September: 9-16. (San Francisco AIDS Foundation.)

The advent of potent antiviral combina-tions heightens the negative consequencesof missing doses, taking doses improperlywith respect to eating, and varying the timeperiod between doses, according to a reviewof new studies on treatment adherence.

Antiviral drugs place “selection pressure”on HIV to mutate, giving new drug-resis-tant virus an advantage over original, non-resistant strains. Only replicating virus canmutate, and no regimen has yet beenproven to suppress viral growth complete-ly. Weaker regimens, comprised of onlynucleoside analogue reverse transcriptasedrugs—for example, zidovudine (ZDV; AZT)or didanosine (ddI])—exert weaker selec-tion pressure than stronger regimens con-taining a protease inhibitor as a componentof a three-or-more-drug combination. Ifblood levels of drugs in these potent com-binations fall temporarily, allowing moreviral production, resistant strains canemerge and overtake the original strains.

Adherence is particularly important for another reason related to the way inwhich protease inhibitors and non-nucleo-side analogue reverse transcriptaseinhibitors (NNRTI) are metabolized by thebody. The less potent nucleoside analoguedrugs require the addition of phosphatemolecules to activate them. These “tri-phosphate” drugs remain in HIV-infectedcells for much longer periods of time thando the newer drugs, which can diffuseeasily in and out of cells and whose levels,therefore, may quickly change and varyover time.

Several recent studies offer compellingsupport for strict adherence. Definingadherence as taking at least 60 percent to 85 percent of prescribed doses, thesestudies show that those participants whoadhered to dosing instructions were morelikely to achieve and maintain viral loadsbelow detectable levels and less likely todevelop resistant virus. Although therewere individual exceptions within thesestudies, indicating that non-adherence isnot the only factor that can undermine aregimen, these results reinforce the impor-tance for both patients and providers ofunderstanding the instructions for takingprescribed medications. This is even moresignificant because of the possibility of a

person developing not only resistance to a single drug, but also cross-resistanceto similar drugs not yet taken.

Latent HIV in People with Low Viral LoadFinzi D, Hermankova M, Pierson T, et al. Identifica-tion of a reservoir for HIV-1 in patients on highlyactive antiretroviral therapy. Science. 1997;278(5341): 1295-1300. (Johns Hopkins University;Aaron Diamond AIDS Research Center, New York;and University of California San Diego.)

A 30-month-long study of 22 patientsfound “compartments” of replication-com-petent latent HIV in the resting CD4+ cellsof patients on triple or quadruple combina-tion therapy. Notably, the recovered HIV didnot demonstrate mutations that wouldindicate resistance to the HIV medicationsused in the treatment combinations.

Researchers do not know whether suchlatent HIV can be reactivated, however, theexistence of a stable reservoir of latentlyinfected cells should be a consideration indeciding whether to continue, reduce, oreven stop antiviral treatment in peoplewith no other evidence of persistent virus.

Subjects were selected according to veryspecific criteria: both patient- and physi-cian-reported strict adherence to aggressivehighly active antiretroviral therapy (HAART)regimens, rapid decline in viral load to lessthan 200 copies per milliliter, and contin-ued undetectable viral load levels on sever-al measurements throughout the durationof the study. In all of the research subjects,long-term suppression of viral replicationto undetectable levels was achieved.Additionally, as a result of treatment, CD4+counts in most patients increased, andthere was a lack of viral mutation.

The number of CD4+ cells harboringreplication-competent HIV was low, and,compared to other study populations, lowerthan the number in patients not on HAART.The fact that this number did not decreaseover the course of treatment suggests thatthe HIV reservoir has a slow decay rate.

Surveying AdherenceBowers M. Adherence and the HIV community.BETA. 1998; January: 9-26 . (San Francisco AIDSFoundation.)

Two national studies—one of people withHIV disease, the other of physicians—found strikingly high rates of non-adher-ence to antiviral regimens and concernsabout the number of doses per day and thenumber of pills per dose in these regimens.

Conducted by telephone by pharmaceuti-cal company DuPont Merck, the first studysurveyed 665 patients who were taking atleast two antiretroviral medications; the

Recent Reports

FOCUS8 February 1998

second surveyed physicians, each whotreated at least 50 people with HIV disease.

Nearly all of the patients said that theirphysicians had educated them aboutadherence, and more than half said theirproviders had explained the importance of treatment adherence and the meaningof viral resistance. However, 26 percentadmitted to non-adherence within the pastday, and more than 40 percent reportednon-adherence within the past week.

Respondents were more likely to miss adose of all of their medications or to takeall of their medications at the wrong timethan they were to miss a single pill, take asingle pill at the wrong time, or fail tofollow dietary requirements. Reasons fornon-adherence included sleeping througha dose, forgetfulness, not having a dose onhand when it was due, and being too busyto take the dose at the scheduled time. The most common suggestions to improveadherence were to use an alarm with theirpill box and to have fewer pills per dose.

More than half of the physicians said thenumber of doses per day was the greatestcontributing factor to non-adherence andlisted other reasons as: side effects, thenumber of pills, and dietary requirements.Physicians thought that patients had only apartial understanding of the importance ofregimen adherence, even though 82 per-cent of respondents reported talking aboutadherence or giving patients educationalmaterials about adherence.

Compliance and HIV DiseaseCrespo-Fierro M. Compliance/adherence and care management in HIV disease. Journal of theAssociation of Nurses in AIDS Care. 1997; 8(4): 43-54. (Visiting Nurse Service, New York.)

Supervised therapy, a strong nurse-client relationship, and conscientiouspatient education all play important rolesin adherence to HIV antiviral therapy,according to a review of the literature.

Among the psychosocial factors thatinfluence adherence are trust, communi-cation, internal conflict or stress, pater-nalistic provider behavior, mental healthproblems, and control. One study foundthat four medication-related attitudesaffected adherence: degree of skepticismabout the treatment, degree of concernabout HIV disease, perceived severity ofillness, and barriers to taking medication.

Ethnocultural factors also affect adher-ence. Among these are: language and litera-cy barriers, the motivation of some ethnicgroups to please or distrust authority, andthe “locus of control,” that is, whether aperson believe control comes from within

themselves or is determined by externalforces. Many providers make the assump-tion that people with external loci of con-trol are “hard to reach” or “non-compliant”and that people of color are likely to befatalistic; however, research reveals thatmany people of color actively participate intheir health care, and that health care work-er attitudes can sabotage this participation

The literature suggests approaches toadherence including supervised therapy and case management; the establishment oftrust, acceptance, and good communication;individualized treatment; and cultural com-petence. In terms of patient education, flexi-ble short-term goals, patient reminders, andoutreach may all help achieve adherence.Health care providers who are more pro-active and optimistic about their ability tohelp clients are generally more effective inimproving adherence; approaching carewith the constellation of attitudes thatcomprise an “I can” versus an “I can’t” posi-tion will facilitate this strategy.

Finally, directly observed therapy (DOT),used primarily in the treatment of tubercu-losis (TB), has regained popularity in recentyears as a means for improving compliance.However, because HIV treatment is morecomplicated, requires medication through-out the day and night, and can last a life-time, DOT may not be a cost-effectiveoption. One form of DOT may offer somelessons; by employing a surrogate familymodel and including field trips, hot meals,support groups, and clinic and home visits,providers achieved high rates of adherence.

Next MonthLast month, we promised that the

February issue of FOCUS would coverHIV and methamphetamine use. Dueto unforseen circumstances, we ranarticles on adherence instead.

In the March issue of FOCUS,Michael Gorman, PhD, MSW, aresearcher and clinician with theUniversity of Washington’s Alcoholand Drug Abuse Institute, will chartthe courses of the HIV and drug useepidemics, discussing, in particular,methamphetamine use. In addition,Michael Siever, MPhD, Director ofthe Stonewall Project, a program ofthe Department of Addiction Medicineof San Francisco General Hospital, willdiscuss clinical interventions formethamphetamine users.

Executive Editor; Director,AIDS Health ProjectJames W. Dilley, MD

EditorRobert Marks

Staff WritersSusan LaCroixJohn Tighe

Founding Editor; AdvisorMichael Helquist

Medical AdvisorStephen Follansbee, MD

DesignSaul Rosenfield

ProductionAndrew TavoniShauna O’Donnell

CirculationShauna O’Donnell

InternsGloria ChungJesse Ritvo

FOCUS is a monthly pub-lication of the AIDSHealth Project, affiliatedwith the University ofCalifornia San Francisco.

Twelve issues of FOCUSare $36 for U.S. residents,$24 for those with limitedincomes, $48 for individu-als in other countries, $90for U.S. institutions, and$110 for institutions inother countries. Makechecks payable to “UCRegents.” Address sub-scription requests and cor-respondence to: FOCUS,UCSF AIDS HealthProject, Box 0884, SanFrancisco, CA 94143-0884. Back issues are $3each: for a list, write to theabove address or call(415) 476-6430.

To ensure uninterrupteddelivery, send your newaddress four weeks beforeyou move.

Printed on recycled paper.

©1998 UC Regents: Allrights reserved.

ISSN 1047-0719

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