OOCCUUVolume 12 Number 5 April 1997

FF A Guide toAIDSResearch and Counseling

SSPart of the burden of HIV disease is

having to make extraordinarily difficultdecisions about medical treatment: whento begin and halt treatment, whether tojoin clinical trials and how faithfully tofollow them, and whether to try alternativetherapies and how to interpret experiencewith them. For many other health-relateddecisions, there is broad consensus in themedical community about what peopleought to be doing. It is common for medi-cal providers to do whatever it takes to getpatients to take actions consistent withthis consensus. This might involve overtadvocacy for the medical standard andmore subtle deprecation of alternatives.

HIV-related treatment decisions areoften less tidy. They involve gambles withvaried consequences and great uncertain-ty. Rarely can medical providers confi-dently predict the outcomes of treatmentsor even in the age of protease inhibitorsand triple combination therapy, prescribea standard approach. New medicines areinherently less certain than old ones, andtreatments “in the pipeline” may seem themost uncertain, yet the most promising.

Under these circumstances, the best thathealth professionals can do is to helppatients to understand their choices. Thegoal is no longer to advocate for fixedtreatments but to give patients the bestshot at achieving the outcomes they valuein a way that leaves them feeling empow-ered. This article first looks at the deci-sion-making process, and then applies it toHIV-related treatment dilemmas, with thegoal of helping mental health and medicalpractitioners guide people with HIV. This

strategy may seem formulaic and does, in fact, employ a formula, but it is mostimportantly a structured tool to helpclients clarify values and a complement to more typical counseling approaches.

Decision-Making TheoryAlthough HIV-related decisions are var-

ied, they share common elements. Eachpresents possible actions, possible conse-quences of taking those actions, and uncer-tainties about which of those consequenceswill actually occur. Decision theory offers acalculus for identifying the best course ofaction. Using it, however, requires clearlycharacterizing a decision’s components.Provider and patient must define optionssharply enough to assign probability esti-mates to each possible consequence and toreveal the—often difficult—tradeoffs thatthese consequences imply. For example,how much suffering of type X will a persontolerate over the next six months in orderto achieve a 10 percent increase in theprobability of being alive five years fromnow with a comparable quality of life?

Corporate or government decisions withlarge financial stakes often undergodetailed decision analyses conducted bywell-paid consultants. This luxury is sel-dom available for the life-and-death deci-sions of ordinary people. Even if it were,not everyone would be comfortable trust-ing their fate to calculations, especiallythose based on uncertain data.

But the principles underlying decisionanalysis can help people with HIV diseaseto structure their decisions so that they canget further into their dilemmas beforethrowing up their hands and going withtheir guts. Knowing in detail what it meansto make a calculated decision allows peopleto decide how calculating they want to be.These potential insights can be organizedaccording to the core concepts of “options,”“uncertainties,” and “consequences.”

Decision-Making Theory and HIV DiseaseBaruch Fischhoff, PhD and Julie S. Downs, PhD

OptionsThe first step in the process of decision

making is to define the options. In practice,individuals rely on health professionals toidentify the field of alternatives. This pro-cess is not perfect, because practitionersmay not wish to discuss treatment optionsthat they cannot provide or do not trust, or with which they are not familiar. Underideal circumstances, clinicians would layout all the options, along with the reasonswhy they favor some and cannot (or willnot) advocate others. This is particularlyimportant because options that individualsperceive as “omitted with intent to conceal”may, ironically, acquire more credibilitythan clinicians may believe they deserve.The clinician’s rationale provides patientswith an orderly framework for determiningchoices. This increases the chance thatunconventional treatments receive thesame scrutiny as mainstream ones.

Getting all the options out on the tableshould also mitigate the natural tendency

to neglect “opportunity costs,” that is, thechances that are forgone when one courseof action precludes others. For many peoplewith HIV disease, the greatest risk fromtreatment may not be its direct side effects,but having to forgo other treatments orinterfering with natural healing processes.

Once the options have been identified,they must be understood. Technical jargonprovides one obvious threat to comprehen-sion. A more subtle risk arises when peoplewith HIV disease attain fluency in the lan-guage of treatment, without fully under-standing the technical terms or theirimplications. For example, patients mightnot realize that what seems like a singletreatment option—for instance, “proteaseinhibitor”—is actually a family of possibili-ties. As a result, they may not appreciate the clinician’s ability to tailor treatments topatient needs by varying doses or ameliorat-ing side effects. Nor may they understandthe opportunities in awaiting the outcomesof research or field trials that might make

FOCUS2 April 1997

Indecision is a familiar state ofbeing for me. I am all too awareof the options, and am quick tointerrogate them one after anoth-er, critiquing and discardingthem, and adopting them aftercareful re-examination.

It must be true for some peo-ple with HIV disease, whosechoices involve much higherstakes than mine do, that theytoo experience indecision inresponse to an abundance ofinformation and a paucity ofcertitude. Organizations likeACT-UP and Project Inform andpublications like AIDS TreatmentNews, GMHC’s Treatment Issues,and the San Francisco AIDSFoundation’s BETA have made thescience of HIV infection accessi-ble, revealing HIV-related treat-ment in all its complexity topeople with HIV disease andtheir loved ones.

The resulting population of lay-experts has the advantage ofbeing able to identify and under-stand the treatment options andthe burden of being able to dis-

sect and assess each one. Is therea template to help them maketreatment decisions, a guide forthe all-too-initiated?

The answer is, of course, notan unequivocal “yes.” This issueof FOCUS looks at HIV treatmentdecision making with the goal ofilluminating this process. It pro-vides a bird’s-eye view of the twosides of the decision equation—the provider’s and the patient’s—a perspective that can help coun-selors help their clients.

The anchor of the issue is anintroduction to decision-makingtheory. Baruch Fischhoff and JulieDowns apply decision science toHIV treatment dilemmas, an exer-cise absent from the AIDS litera-ture. As they stress, the result isnot a cut-and-paste formula—though I am bound to disclosethat there is math involved—but a lens through which to perceiveand master the decision-makingprocess. In some ways, under-standing this process may be asimportant as understanding thescience behind each treatment.

Ironically, for many people, thenew treatment “paradigm” has notmade the choices obvious. In hisarticle, Steven Deeks identifies arange of concerns that complicatetreatment decisions: from sideeffects and toxicity to overwhelm-ing treatment regimens. In adiscussion of the approachesclinicians take when advisingtheir patients about treatment,Deeks distinguishes between thelimited guidelines of “cookbook”medicine—past recipes employ-ing CD4+ cell counts, symptomprofiles, and limited drug combi-nations—and broader principlesof the new paradigm. These fun-damental principles enable us toharness the new conception ofHIV infection, more precise mea-sures of progression, and a widerarray of treatments.

These articles cannot lead tocrystal-clear decisions. Too manyquestions about the new treat-ment approach remain unan-swered, and every individualfacing these choices has differentgoals and values. But, the authors,like therapists, have equipped us with the tools to help clientsreach informed decisions: princi-ples, information, and process.

Editorial: In DecisionRobert Marks, Editor

FOCUS3 April 1997

treatment options look different. Inresponse, clinicians should be aware ofcommon misconceptions, aggressivelysolicit questions about options, and encour-age patients to bring friends to appoint-ments to help them process information.

UncertaintiesOnce clients understand their options,

they can focus on how likely it is that theconsequences of these options will come to

pass. In expressing likelihoods,we often describe events usingterms such as “rare,” “uncom-mon,” or “likely.” But, there is no real substitute for expressingthis information numerically.While clinicians might beuncomfortable speaking precise-ly about issues that are poorlyunderstood, only numericalterms communicate uncertaintyin the standardized way neededfor decision making. If sciencecan say no more than that theside effect rate from a treatmentis anywhere from 3 percent to30 percent, then clients arebetter off knowing this rangethan they are with vaguedescriptors like “possible.”

To give them an intuitive feeling forwhere these numbers come from and whythey are so uncertain, patients need tounderstand something about the underly-ing science. This context should helpthem to interpret their own “post-deci-sion” experience, so that they can tellwhen things are going awry and when thedecision might need revisiting. It may alsoenable them to follow public discussion ofthe issue, so that they have a betterchance of distinguishing among scientificevidence, anecdote, and rumor.

The research literature finds that peopleare good at remembering—and keeping arough count of—individual occurences thatthey themselves have witnessed. However,most of us place too much confidence insmall samples and are easily misled byunrepresentative samples. The literaturealso finds that misconceptions can co-existwith correct beliefs, undermining theirusefulness. Once identified, though, these“bugs” in people’s “mental models” canoften be corrected with common-senseexplanations. For this to happen, cliniciansneed to consider carefully what additionalinformation is really necessary to helptheir patients. Finally, patients need toknow about opportunities for reducinguncertainty, for example, by running tests

to determine susceptibility to side effectsor by acknowledging clinical trials that mayproduce relevant results in the near future.

ConsequencesTreatment dilemmas often pose irrecon-

cilable tradeoffs. For example, does onewant a drug that extends life at the priceof persistent nausea and disrupted sleep?The full set of consequences that patientsneed to consider might include changes inhealth status, self-esteem, personal rela-tions, and finances. For effective decisionmaking, these consequences must be asspecific as possible, so that patients knowexactly what they are evaluating. Forinstance, a possible future health statecould include more energy, less nausea,less pain, weight gain, decreased viralload, and an increased CD4+ cell count.

Highlighting these tradeoffs and makingthem a matter of individual choice canmake the decision process an opportunityrather than a burden. Providers should helppatients understand the real-life effects ofpotential consequences. One way of doingthis is to relate them to a patient’s pastexperiences or to those of people whom thepatient knows. Many patients may haveexperienced similar side-effects from otherdrugs or have dealt with episodes of regretor social pressure; these experiences caninform the process. Patients who havefriends with HIV disease may be all too wellacquainted with the consequences of treat-ment. Patients who have neither direct norvicarious experience may benefit frommeeting people who have, or by readingaccounts that describe what it was like forthem—recognizing the difficulty of imagin-ing physical or psychological states.

Throughout this process, it will be achallenge for patients to realize that it istheir values that matter when weighingalternative outcomes. This process can befrustrating, but, ultimately, it can lead topersonal growth, as people determinewhat really matters to them and assertcontrol over their lives.

Putting It All TogetherAlthough it may be unnerving to consign

one’s fate to a formula, it can still beinstructive to “run some numbers,” in orderto get a sense of the combined influence ofthe uncertainties and consequences associ-ated with each option. The logic of thesecomputations is straightforward: calculatethe expected utility of each option, thenchoose the option with the highest score(or, one of the best, if the very best cannotbe clearly distinguished). Expected utility

ReferencesBursztajn H, Fein-bloom R, Hamm R, etal. Medical Choices,Medical Chances:How Patients, Fami-lies, and PhysiciansCan Cope withUncertainty. NewYork: Routledge, 1990.

Fischhoff B. Givingadvice: Decisiontheory perspectives onsexual assault. Ameri-can Psychologist.1992; 47(5): 577-588.

Fischhoff B, Downs J.Accentuate the rele-vant. PsychologicalScience. In press.

Janis I. Counseling onPersonal Decisions.New Haven: Yale Univ-ersity Press, 1982.

Plous S. The Psychol-ogy of Judgment andDecision Making. NewYork: McGraw-Hill,1993.

It is a challengefor patients

to realize thatit is their values

that matterwhen weighing

variousoutcomes.

AuthorsBaruch Fischhoff, PhDis Professor of Socialand Decision Sciencesand Professor of Engi-neering and PublicPolicy at CarnegieMellon University inPittsburgh,Pennsylvania.

Julie S. Downs, PhD isResearch Associate inSocial and DecisionSciences at CarnegieMellon University.

is computed by taking each possible out-come of an action, estimating how good orbad it would be (its “utility”), assessing theprobability of its occurrence, multiplyingthe two (to get the expected utility associ-ated with that outcome), and then addingthe products from all the outcomes (to getthe overall expected utility of the action).

Often, the hardest part of this procedureis assigning the utilities. It requires hard,frank thinking to say just how attractive oraversive different outcomes would be.Texts on the topic offer various proce-dures for structuring this task to the levelof precision that people feel comfortableproducing. The simplest analysis is to givescores of +1 to all good outcomes and -1 toall bad outcomes, and then multiply themby a factor reflecting their likelihood.

For example, in considering DrugCombination X, a patient—let’s call himPeter—might focus on two factors:decreasing viral load and peripheral neu-ropathy. Decreasing viral load would be+1 (because it is a positive outcome) x 0.5percent (because 50 percent of subjects in trials experienced this increase) for avalue of 0.5. Peripheral neuropathy wouldbe -1 (because it is a negative outcome) x0.2 (because 20 percent of the subjects intrials experienced this side effect) for avalue of -0.2. Were these the only twofactors, the final score would be 0.5 plus -0.2, or 0.3. If Peter is confident that theratings represent his feelings and beliefs,the positive overall score recommendsCombination X.

Where the values are uncertain, as willoften be the case, or where greater speci-ficity might be helpful, one can repeat thecalculation with a wider range of numbers.

For example, one might array the possibili-ties along a rating scale anchored by thevery best and very worst possible outcomes(equal, say, to +100 and -100, respectively).Using this approach, Peter might rate as+100 the dramatic decreases in viral loadproduced by Combination X. He might rateperipheral neuropathy -5 because it hadproven to be mild, causing only modestdiscomfort for most people. However, ifPeter had once had a severe case of periph-eral neuropathy and feared repeating thisexperience, he might rate the condition -25.The critical point is that Peter gets to assignvalues that make sense to him.

This process may be useful even if aperson has no intention of being bound bythe mathematical results. Doing some calcu-lations can help get a fix on complex issuesthat might otherwise overwhelm a person.Simply writing things down can reduce therisk of neglecting an issue. It can summa-rize a person’s thinking for others whomight provide advice and support.Discussing the analysis can clarify thepatient’s and clinician’s respective roles in selecting the appropriate treatment.

Finally, creating a record can protectone, in the future, against “hindsightbias,” the tendency to exaggerate howpredictable the outcomes of a decisionwere when it was made. It can also protectagainst “outcome bias,” the tendency toevaluate decisions by how things turnedout, rather than by how wisely the situa-tion was analyzed when the choice wasmade. Either bias can add a needlesselement of regret. When people engage incareful and thoughtful decision-makingprocesses, their decisions should be moresystematic and less vulnerable to biases.

FOCUS4 April 1997

ReferencesCollier AC, Coombs RW, SchoenfeldDA, et al. Treatment of human immun-odeficiency virus infection withsaquinavir, zidovudine, and zal-citabine. New England Journal ofMedicine. 1996; 334(16): 1011-1017.

Condra JH, Schleif WA, Blahy OM, et al. In vivo emergence of HIV-1 vari-ants resistant to multiple proteaseinhibitors. Nature. 1995; 374(6522):569-571.

Inouye RT, Hammer SM. Update ondevelopments in antiretroviral therapy.Improving the Management of HIV

Disease. 1997; 4(5): S7-S15.

Japour AJ. Measurement of HIV-1 RNAin clinical practice: An initial manage-ment algorithm. Journal of the Inter-national Association of Physicians inAIDS Care. 1996; 2(11): 16-19.

Carpenter CJ, Fischl MA, Hammer SM,et al. Antiretroviral therapy for HIVinfection in 1996: Recommendations of an international panel. Journal ofthe American Medical Association.1996; 276(2): 146-153.

MacDougall DS. Quantitative measure-ment of HIV RNA: Techniques andclinical applications. Journal of the

International Association of Physiciansin AIDS Care. 1996; 2(11): 9-14.

Mellors JW, Rinaldo CR, Gupta P, et al.Prognosis on HIV-1 infection predictedby the quantity of virus in plasma.Science. 1996; 272(5265): 1167-1170.

Morgan RA. Gene therapy for HIV infec-tion. Clinical and Experimental Immu-nology. 1997; 107(Suppl. 1): 41-44.

Nabulsi A, Revicki D, Conway D, et al.Quality of life consequences of addingritonavir to current antiviral therapy foradvanced AIDS patients. Presentation atthe XI International Conference on AIDS,Vancouver, Canada, July 1996.

Perelson AS, Essunger P, Markowitz M,et al. How long should treatment begiven if we have an antiretroviral

Clearinghouse: The New Paradigm

FOCUS5 April 1997

The use of antiretroviral therapies totreat HIV disease has, until recently, beenbased on clinical guidelines. For example,recent guidelines suggested that as CD4+cell counts fall to 500, patients shouldbegin treatment with zidovudine and,after a year or two, switch to didanosine.However, since the field has evolved sodramatically over the past year, suchclinical guidelines—cookbook medicine—are no longer appropriate. Instead, clinicaldecision-making is increasingly based onmuch broader principles of therapy.

As part of this shift, clinicians andresearchers have articulated new goals forHIV-related antiretroviral treatment. Formost of the past decade, antiretroviraltherapies aimed at delaying disease pro-gression. Today, the goal of treatment is to stop progression: to fully suppress viralreplication. The logic is relatively simple.By preventing HIV from replicating, muta-tions in its DNA cannot occur, making viralresistance to any combination of drugsimpossible. Since these combinations pre-vent resistance, they can work indefinitelyand halt disease progression. For somepatients, this goal may be achievable. Thechallenge is to find potent combinationsthat patients can tolerate and which resultin enduring suppression of viral replication.

To understand resistance, it is importantto understand mutation. Mutation refers tospecific changes in the HIV “genome” or

DNA. Every time HIV replicates in an indi-vidual’s body, it makes mistakes andmutates. Occasionally, a mutation allowsHIV to replicate more easily in the presenceof a particular antiretroviral treatment.Since the treatment is effective in blockingthe replication of other strains of HIV—onlythose that have not mutated—the resistantstrain quickly takes over and becomes thedominant strain. Once resistance develops,it is probably permanent, and the moreoften mutation occurs, the more difficult itbecomes to find an effective drug regimen.

Hit Hard: Use Three Drugs “Hit hard, hit early” describes the evolv-

ing paradigm of HIV treatment. The firstprinciple, “hit hard” is becoming widelyaccepted: in order to fully suppress thevirus, patients should initiate treatmentwith combinations of drugs all at the sametime. Typically, these combinations includetwo nucleoside analogs, for example,zidovudine (ZDV; AZT) and lamivudine(3TC) plus a powerful protease inhibitor.These drugs should be taken at their fulldoses and started within no more than acouple of weeks of each other. The goal ofthis approach is to render HIV unable toreplicate and force it into a “dormant” state.

It is no longer appropriate to start offwith a single drug like ZDV. In such cases,the virus is able to mutate and becomeresistant to the drug in a matter of weeks. In fact, many experts recommend againsttherapy with two similar antiretroviraldrugs—such as the popular combination of ZDV and 3TC—since this tentative, lessaggressive approach allows HIV to replicateand stilll easily mutate. Adding a proteaseinhibitor to a failing regimen is tantamount

regimen that completely blocks HIVreplication? Presentation at the XIInternational Conference on AIDS,Vancouver, Canada, July 1996.

Perelson AS, Neumann AU, MarkowitzM, et al. HIV-1 dynamics in vivo: Virionclearance rate, infected cell life-span,and viral generation time. Science.1996; 271(5255): 1582-1586.

Singh N, Squier C, Sivek C, et al.Determinants of compliance withantiretroviral therapy in patients with human immunodeficiency virus:Prospective assessment with implica-tions for enhancing compliance. AIDSCare. 1996; 8(3): 261-269.

Volberding PA. HIV quantification:Clinical applications. Lancet. 1996;347(8994): 71-73.

ResourcesThe following newsletters and otherpublications are devoted to HIV-relatedtreatment issues:

AIDS Treatment News, P.O. Box 411256,San Francisco, CA 94141; 800-TREAT12 or415-255-0588; aidsnews@aidsnews.org.

The Bulletin for ExperimentalTreatment for AIDS (BETA), publishedby the San Francisco AIDS Foundation,PO Box 2189, Berkeley, CA 94702-0189;800-959-1059.

Project Inform publishes fact sheets on a variety of treatment-relatedtopics, 1965 Market Street, Suite 220,San Francisco, CA 94103; 800-822-7422(national hotline), 415-558-9051 (SFhotline), 415-558-0684 (fax).

Treatment Issues, published by the GayMen’s Health Crisis in New York, 129 West20th Street,2nd Floor, New York,NY 10011.

Contacts Baruch Fischhoff, PhD, Department ofSocial and Decision Sciences, CarnegieMellon University, Pittsburgh, PA 15213,412-268-6971, baruch@andrew.cmu.edu.

Steven G. Deeks, MD, AIDSProgram/Oncology Services, SanFrancisco General Hospital, Building80, Ward 84, 995 Potrero Avenue, SanFrancisco, CA 94110.

See also references cited in articles in this issue.

Principles of HIV-Related Medical CareSteven G. Deeks, MD

to using that protease inhibitor alone,resulting in mutation and rapid resistance.

A corollary to the “hit hard” principle isthat compliance with medication regimens

is crucial to the overall goal ofcomplete viral suppression. Toprevent resistance, the virusmust be suppressed continuous-ly. While it is clear that missinga few doses every month or sois safe, the more doses missed,the more likely it is that thevirus will have a chance to repli-cate in the absence of the drugand become resistant. If a drugmust be stopped in response toside effects, it is best to switchimmediately to a replacement atits fully prescribed dose. Takinglow doses allows HIV replicationin the presence of the drug andis no longer an appropriateresponse to side effects.

In short, there is substantialclinical evidence to support theprinciple to “hit hard.” Patientswho are not taking antiretrovi-ral drugs have two options:suppress the virus completely

or leave it alone. Patients currently onnon-aggressive but effective regimens,such as ZDV plus 3TC, can continue aslong as they are doing well. However, ifthey experience a decline, they will proba-bly need to switch to two other nucleosideanalogs plus a protease inhibitor.

Hit Early?The second fundamental principle is that

clinicians should initiate treatment as earlyin the disease process as possible, even forpatients with normal CD4+ cell counts.Although the premise to “hit early” is basedon some clinical data, it is more controver-sial than the “hit hard” approach. It is diffi-cult to justify exposing otherwise healthyindividuals to the expense, potential toxici-ty, and complexity of medical regimens.

Hitting the virus early in the diseaseprocess is based primarily on three theoret-ical concerns. First, when a person is initial-ly infected with HIV, the pool of virus in thebody is relatively homogeneous. After yearsof replication and the inevitable mutationsthat follow, the body becomes host to mul-tiple strains of the virus. Second, early inthe disease process, HIV spreads through-out the body, seeding different organ sys-tems such as the genitals and the brain.Treating HIV in these “sanctuaries” may bedifficult as HIV disease progresses. Third,early treatment will likely prove beneficial

because HIV-related immune destructionmay not be reversible. Until research con-firms otherwise, a patient can expectantiretroviral therapy to do no more thanmaintain the immune system at the level itwas when he or she began that treatment(even if CD4+ cell counts increase).

The extreme example of “hitting early” isthe practice of initiating combination thera-py in patients who have been recentlyinfected, that is, within the three monthspreceding treatment. However, the numberof people who know they are infected withina month or two of contracting HIV is verysmall. Barring this knowledge, clinicians usequantifiable measures of infection—viralload and CD4+ cell counts—to determinewhen to start therapy. Today, there is clearconsensus that people with a viral loadgreater than 10,000 to 30,000 copies of HIVRNA per milliliter and CD4+ cell counts ofless than 350 should definitely begin treat-ment. People who have viral loads above10,000 and CD4+ cell counts below 500should probably begin treatment. Peoplewho have CD4+ cell counts above 500should probably not begin treatment unlessviral load is above the 10,000 range.*

Some virologists and clinical expertshave gone beyond these guidelines, advo-cating that every seropositive patientshould be aggressively treated with three-drug combinations. For people whose CD4+cell counts are relatively high and whoseviral load is relatively low, this may not bean attractive option: it is understandablethat an otherwise healthy, asymptomaticperson might delay treatment when con-fronted with the possibility of a lifetimecommitment to ingesting a handful ofpills—each of which can cause a variety ofside effects—three to four times a day. Insuch cases, experts recommend close moni-toring of viral load and CD4+ cell counts.Until there are better data, deciding whento initiate therapy is dependent on individ-ual preferences and personal experience.

Clouding the issue is the fact that thescience of treatment is advancing daily, anddecisions made today might be regrettedsix months from now. A year ago, cliniciansroutinely recommended starting treatmentwith two drugs, and adding a third whenHIV disease progressed. Today, many clini-cians regret this approach, since it appearsnow to encourage drug resistance. Forhealthy people with early stage disease,waiting for science to catch up remains areasonable option. Those in the middle andlate stages of AIDS, however, cannot affordto wait. Hitting hard is important at whatev-er point therapy is initiated, but hitting

FOCUS6 April 1997

*Viral load is expressedin terms of the amountof viral RNA per milli-liter of blood. When theviral load of a seropos-itive person is “unde-tectable,” the numberof viral particles is at a level below the lowerlimits of detectionusing current assays.However, when accu-rate research tests areused to retest “unde-tectable” results, virusis always detected.Researchers andclinicians are clear thatan “undetectable” read-ing of the test meansthat a person’s immunesystem should remainstable, and that HIVdisease progressionshould not occur. Anundetectable level alsoimplies that the risk ofdeveloping drug resis-tance is very low. ForHIV prevention pur-poses, the implicationsof an undetectablereading are unknown:undetectable does notmean “virus free,” andinfectious virions arecertainly present.

“Hitting early”is more contro-

versial than“hitting hard”:deciding when

to initiatetherapy

is dependenton individual

preference and experience.

FOCUS7 April 1997

very early may be too stringent a criterionto be held up as a standard.

Are All Combinations Created Equal?Combination therapy and the advent of

the protease inhibitors have reinvigoratedHIV antiretroviral therapy. However, with10 drugs currently available, there arehundreds of possible combinations. Whenthey confront the daunting task of identi-fying the best combination for a particularpatient, clinicians consider side effects,drug interactions, dosing regimens, cost,and the possibility of viral resistance.

Combination therapy usually includestwo nucleoside analogs such as ZDV and3TC plus a protease inhibitor. Among theprotease inhibitors, there are now fouroptions. In the United States, indinavir(Crixivan) has been the most popular ofthese. However, it can cause kidney stonesand requires adherence to a complicatedregimen. Indinavir must be taken everyeight hours on an empty stomach, forcingpatients to be ruled by an alarm clock.

Ritonavir (Norvir) is a powerful drug. Itis the only protease inhibitor with conve-nient twice-daily dosing. But, ritonavir hassignificant side effects, particularly duringthe first few weeks of treatment. (Many ofthese side effects may be prevented byescalating dosage gradually over twoweeks.) In addition, ritonavir interacts witha number of other drugs further complicat-ing treatment. The third option, saquinavir(Invirase), is safe and well-tolerated, but itis not as potent as the other options, pri-marily because only 4 percent of the drugis absorbed. Recently approved by theFood and Drug Administration, nelfinavir(Viracept), the fourth option, appears to be safe, well-tolerated, and potent.

Recent research suggests that patientsmay now have a fifth option: the combina-tion of ritonavir and saquinavir. Because ofunique interactions between these drugs,they can be administered at low doses andare particularly effective. Over the nextyear, other options are certain to emerge.

The nucleoside analog drugs include ZDV,3TC, didanosine (ddI), zalcitabine (ddC), andstavudine (d4T). The combination of ZDVand ddI or ZDV and 3TC may be the bestcombination for patients who have neverreceived therapy in the past. However, inthe HIV epicenters such as San Francisco,Los Angeles, and New York, many if notmost people with HIV disease have alreadytaken ZDV and the other nucleoside analogs.Theoretically, such patients may already beresistant to these drugs. For them, it isdifficult if not impossible to apply the prin-

ciple—articulated below—of starting three“new” drugs. In these cases, clinicians mustapply experience and knowledge of resis-tance to select the optimal combination.

Changing Therapy A clinician may suggest changing a drug

for a variety of reasons, including sideeffects and difficulties with compliance.However, the most common reason isdrug failure, typically manifesting as anincreasing viral load. In these instances, it is possible that a patient’s virus hasbecome resistant to his or her medicalregimen. In response, the fundamentalprinciple is to avoid replacing a singledrug. If a combination has truly “failed,”and the development of drug resistance isa genuine concern, it is probably best tochange the entire antiretroviral regimen.

Unfortunately, there is little clinicaldata to guide clinicians when resistance toa protease inhibitor develops. For exam-ple, we do not know if a virus resistant toone protease inhibitor will respond to asecond administered subsequently. Untilsuch data exist, clinicians should considera patient’s first regimen—including aprotease inhibitor—as the patient’s bestchance for “complete” viral suppression.

ConclusionOver the next few years, researchers and

clinicians will publish guidelines on how to treat patients using antiretroviral thera-pies. These guidelines will represent thebest recommendations at the time and willbe valuable as clinical tools. While experi-ence suggests that these guidelines willchange with time—incorporating new medi-cations and treatment options—it is likelythat the broader principles of therapy willevolve more slowly and that preventingdrug resistance will remain the cornerstoneof future treatment decision making.

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

ReferencesCarpenter CC, Fischl M, Hammer SM, et al.Antiretroviral therapyfor HIV infection in1996: Recommenda-tions from an Interna-tional Panel. Journal ofthe American MedicalAssociation. 1996; 276(2): 146-154.

Coffin JM. HIV popula-tion dynamics in vivo:Implications for geneticvariation, pathogene-sis, and therapy.Science. 1995;267(5197): 483-489.

Deeks S, Smith M,Holidniy M, et al. HIV-1 protease inhibitors:A review for clini-cians. Journal of theAmerican MedicalAssociation. 1997;277(2): 143-153.

Gullick R, Mellors J,Havlir D, et al. Potentand sustained anti-retroviral activity ofindinavir (IDV), zido-vudine (ZDV), andlamivudine (3TC).Presentation at the XIInternational Confer-ence on AIDS, Vancou-ver, Canada, July 1996.

Ho DD. Time to hitHIV, early and hard(editorial). NewEngland Journal of Medicine. 1995;333(7): 450-451.

AuthorsSteven G. Deeks, MD isand Assistant ClinicalProfessor of Medicineat the AIDS Programof the University ofCalifornia San Fran-cisco, and is anattending physician inthe AIDS clinic at SanFrancisco GeneralHospital.

Cathy Hultin, a UCSFAIDS Health Projectintern, aided in thedevelopment of thisarticle.

FOCUS8 April 1997

Viral LoadSaag MS, Holonit M, Kuritzkes DR, et al. HIV viral loadmarkers in clinical practice. Nature Medicine. 1996; 2(6): 625-629. (University of Alabama at Birmingham;Stanford University; University of California SanFrancisco; and the International AIDS Society—USA.)

Although CD4+ cell count remains thebest predictor of the development ofopportunistic conditions, plasma HIV RNAlevel, or “viral load,” appears to be the bestpredictor of long-term clinical outcome forpeople with HIV disease, according to anoverview of appropriate clinical use of viralload testing. Viral load can indicate risk ofdisease progression, timing and efficacy ofantiviral treatment, and treatment failure.

Viral load—which is quantifiable invirtually all HIV-infected people—is usefulbecause it exhibits a wide dynamic range,correlates significantly with clinical stage,and provides data that can inform treat-ment decisions. High viral load corre-sponds to lower baseline CD4+ cell counts,more rapid declines in CD4+ cell counts,and more rapid disease progression.

The CD4+ cell count remains an essen-tial index for making decisions aboutopportunistic infection prophylaxis andfor evaluating the immunological effectsof antiretroviral therapy. CD4+ cell countalone, however, is inadequate to deter-mine prognosis and to measure responseto antiretroviral therapy, and is subject to substantial variability.

Viral load, as is CD4+ cell count, isexpressed as a quantity per milliliter ofblood, in this case the number of copies ofHIV RNA. Initially, clinicians should obtaintwo viral load readings two to four weeksapart and subsequent measurements everythree to four months. At critical decisionpoints, for example when changing treat-ment, clinicians should increase frequencyto every three to four weeks.

Studies have shown that patients whoseviral loads exceeded 100,000 within sixmonths of seroconversion were more likelythan those with lower viral load to progressto AIDS within five years. Patients whomaintained viral loads of less than 10,000did not progress to AIDS during the nextfive years. High viral load (from 30,000 to 50,000) warrants the start of therapy,regardless of CD4+ cell count. The minimalresponse indicating effective antiviral treat-ment is a three-fold reduction in viral load,a magnitude that reflects biologically sig-nificant changes in viral replication.

Protease Inhibitor ReviewDeeks S, Smith M, Holidniy M, et al. HIV-1 pro-tease inhibitors: A review for clinicians. Journal ofthe American Medical Association. 1997; 277(2):143-153. (University of California San Francisco;Kaiser Family Foundation; and Stanford University.)

Long-term studies of the proteaseinhibitors have only recently been complet-ed and, therefore, results have not under-gone peer review. But since there is such ademand for protease inhibitors, this tech-nical review of conference and meetingpresentations provides a rational approachto prescribing these drugs.

The review explains how proteaseinhibitors work, their interactions withother drugs, and their safety, efficacy, andcost. Protease is an enzyme that acts as a“molecular scissors,” cleaving large proteinchains into smaller ones that enable HIV tomature. Protease inhibitors block the partof the protease molecule that clips thesechains, thus preventing HIV from maturing.

The annual cost of treatment with a pro-tease inhibitor, two reverse-transcriptaseinhibitors, and viral load testing is well over$10,000. The federal ADAP program wasmeant to fill a gap by paying for medica-tions for those with advanced HIV diseaseuntil they qualified for Medicaid. But theprospect of providing long-term medicationsupport for tens of thousands of people hasprovoked a crisis in the program. Likewise,Ryan White CARE Act services, which areaimed at those with advanced disease, maybecome less necessary, but only if combina-tion therapy is affordable.

Next MonthAs studies of protease inhibitors are

too recent to have been published inpeer-reviewed journals, so it is that“data” on psychosocial adjustment tothe new treatment paradigm arises fromfirst-person accounts. In the May issueof FOCUS, Ron Henderson, Director ofTraining and Education at HealthInitiatives for Youth in San Francisco,describes his own experience dealingwith the shift in AIDS care and recountsthe stories of four others facing differ-ent situations but similar decisions.

Also in the May issue, JeffreyMoulton Benevedes, PhD discusseslife as a San Francisco therapist treat-ing people whose lives and perspec-tives of life are rapidly changing.

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

EditorRobert Marks

Staff WriterJohn Tighe

Founding Editor; AdvisorMichael Helquist

Medical AdvisorStephen Follansbee, MD

DesignSaul Rosenfield

ProductionShauna O’DonnellSaul Rosenfield

CirculationShauna O’Donnell

InternsCathy HultinSari KasperCandice Meng

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.

©1997 UC Regents: Allrights reserved.

ISSN 1047-0719

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