determinants of virological response to antiretroviral therapy: implications for long-term...

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Determinants of Virological Response to Antiretroviral Therapy: Implicationsfor Long-Term Strategies

Steven G. Deeks From the Department of Medicine,University of California San Francisco

A variety of factors can contribute to the failure of combination antiretroviral therapy todurably suppress viral replication in patients infected with human immunodeficiency virus(HIV). Patients who have a low CD4+ T cell count or high plasma viral load before therapyis initiated are at high risk for subsequent virological failure. Previous therapy is also a strongdeterminant of subsequent virological response, presumably because of pre-existing viral re-sistance. Drug exposure, as determined by adherence, drug absorption, and drug metabolism,has a significant impact on future long-term virological responses. Although definitive proofis lacking, some tissues may have limited drug penetration, thus allowing for ongoing viralreplication. Understanding why combination therapy fails for HIV-infected patients may allowclinicians to individualize treatment strategies. Unfortunately, almost any factor (drug, host,or viral) that leads to virological failure of an initial combination regimen is likely to per-sist—and perhaps become more challenging—once a salvage regimen is initiated.

The goal of antiretroviral therapy is to “improve the lengthand quality of the patient’s life” [1]. On the basis of our currentunderstanding of HIV pathogenesis, the optimal way to achievethis goal is by long-term suppression of viral replication to thelowest level possible. Within 4–6 months of initiation of ther-apy, plasma viral load should decrease to below the level ofquantification (usually 20–200 copies/mL) and remain at thatlevel indefinitely [1, 2]. If this specific goal is not achieved fora patient, therapy is considered to be failing. Although theclinical significance of virological failure remains unclear, a de-tectable viral load implies ongoing viral replication and thecontinued selection of drug-resistant virus. If long-term viralsuppression is not achieved, virally mediated CD41 T cell de-pletion and disease progression theoretically become inevitable.

Managing HIV infection requires long-term planning. De-termining for which patients a specific drug regimen is likelyto fail—before treatment is initiated or modified—may allowclinicians to develop more effective long-term strategies (table1). Similarly, once therapy is initiated, early signals of impend-ing drug failure—particularly, a limited reduction in plasmaHIV RNA levels—may allow early intervention.

Are Current Drugs Sufficiently Potent to Fully SuppressViral Replication?

The current goal of therapy is to completely suppress viralreplication. However, it is increasingly unclear whether this goal

Reprints or correspondence: Dr. Steven G. Deeks, University of CaliforniaSan Francisco, 995 Potrero Ave., San Francisco General Hospital, San Fran-cisco, CA 94110 ([email protected]).

Clinical Infectious Diseases 2000;30(Suppl 2):S177–84q 2000 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2000/3006S2-0011$03.00

can be achieved with standard regimens, even when all otherfactors are optimized. For example, Zhang and colleagues [3]analyzed 8 highly selected patients who had undetectable HIVRNA levels (!50 copies of RNA/mL) during combination ther-apy for 2–3 years. In 6 of the 8 patients, there was no evidenceof evolution in proviral sequences, which suggested that com-plete viral suppression had been achieved. Two patients, how-ever, had evidence of sequence evolution, which indicated on-going viral replication. Although the degree of replication inthese 2 patients was insufficient to allow for the selection ofdrug resistance, these data suggest that viral suppression maybe only partial in some patients with long-term undetectableHIV RNA levels [3].

Martinez-Picado and colleagues [4] also found evidence ofongoing viral replication in highly selected patients who had along-term virologic response to therapy (HIV RNA !50 copies/mL). Clonal analysis of replication competent viruses recoveredfrom peripheral blood mononuclear cells revealed the emer-gence over time of significant drug resistance mutations. No-tably, these mutations were more common in subjects who hadtransient episodes of viremia (“blips”).

Collectively, these observations and others [5, 6] suggest thatvirus replication persists in some patients, even when an optimalresponse has apparently been achieved. Virologic failure mayoccur in some patients because current regimens are not suf-ficiently potent to completely suppress viral replication.

Baseline CD4+ T Cell Count and Viral Loadas Predictors of Outcome

Both a low baseline CD41 T cell count and high baseline viralload are independent predictors of virological failure with a pro-tease inhibitor–including regimen. In a large, prospective clinicaltrial (Adult AIDS Clinical Trials Group [ACTG] 320), use of the

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S178 Deeks CID 2000;30 (Suppl 2)

Table 1. Determinants of virological outcome with combination therapy.

Factor Implication

Low baseline CD4 T cell count Initiate therapy early (1350 CD4 cells/mm3; viral load, !10,000–20,000 copies/mL)High baseline plasma viral load Consider 4-drug therapy for patients presenting with baseline viral loadPrior therapy

Viral resistance Avoid sequential use of antiretroviral therapy; initiate therapy with drugs that confer limited cross-resistanceto other drugs, thus allowing for therapy as needed; consider baseline resistance testinga

Cellular resistance Avoid concurrent use of zidovudine and stavudineDrug exposure

Pharmacokinetics Individualized drug monitoringa

Adherence Adherence monitoring (MEMS capsa; others); adherence interventions; delay therapy until patient is able tocommit to therapy; delay therapy until simplified regimens become available

Increased target-cell availability Frequent viral-load monitoring with early intensificationb

Tissue sanctuaries Use CNS-penetrating agents in combination therapy

a Use of these technologies has not been validated in prospective studies.b Early intensification of treatment for patients who experience early virological rebound has not been validated in prospective clinical studies.

combination of zidovudine, lamivudine, and indinavir was eval-uated for patients with advanced immunodeficiency (CD4 T cellcount !200/mm3; mean baseline CD4 T cell count, 87/mm3) [7].Among the 577 patents initially randomized to receive the triple-drug combination, the outcome was successful for 51% (definedas a viral load !500 copies/mL at weeks 24 and 40). Notably,the outcome was successful for only 39% of patients who had abaseline CD4 T cell count !50/mm3, compared with 58% of thosewith a baseline CD4 T cell count between 51/mm3 and 200/mm3

[7].The importance of the baseline CD4 T cell count is further

illustrated by a comparison of 2 pivotal clinical trials (035 and039) sponsored by Merck (Rahway, NJ), in which the activityof zidovudine, lamivudine, and indinavir was evaluated in zi-dovudine-pretreated patients. Patients enrolled in trial 039, whohad baseline CD4 T cell counts !50/mm3 (median, 14/mm3),had response rates of 60% and 38% at week 24 and week 60,respectively [8]. In contrast, among patients in trial 035, whosebaseline CD4 T cell counts were between 50/mm3 and 400/mm3

(median, 144/mm3), response rates were ∼90% and 78% at week24 and week 100, respectively (by use of a more conservativeintent-to-treat analysis) [9].

In cross-sectional analyses, there is a weak but significantinverse association between CD4 T cell count and viral load[10]. Because of the significant predictive value of a low CD4T cell count on virological response, it is not surprising thatpatients with high baseline HIV type 1 (HIV-1) RNA levels areat increased risk for drug failure. The degree to which baselineviral load contributes to treatment failure, independent of theCD4 T cell count, is difficult to assess, particularly in studiessuch as ACTG 320, in which the CD4 T cell count range waslimited. To determine the predictors of virological response ina diverse group of patients, we performed an observationalstudy of patients who were receiving long-term treatment withprotease inhibitor–including regimens at San Francisco GeneralHospital [11].

Only 170 (50.2%) of the 337 patients studied had an unde-tectable HIV RNA level (!500 copies/mL) after 48 weeks of

therapy. The risk of failure increased incrementally as the base-line HIV RNA level increased; this became most apparent atplasma HIV RNA levels 14.5 log10 copies RNA/mL. Similarly,as the baseline CD4 cell count decreased, the risk of virologicalfailure increased. In a multivariate analysis (controlling forbaseline CD4 cell count, baseline HIV RNA level, and previousexposure to nucleoside analogues), both CD4 cell count andviral load remained strong independent predictors of virologicaloutcome [11].

Why would baseline CD4 T cell count and/or viral load be animportant determinant of virological response to combinationtherapy? First, the ability of the immune system to recognize andsuppress viral replication may be a critical component of anysuccessful therapeutic strategy. Initiating therapy early in thecourse of the disease may preserve the immune response againstHIV [12]. Second, HIV infection is characterized by a high levelof virus turnover and frequent mutations, which result in therapid development of countless quasi species. Patients with earlydisease may harbor a less heterogeneous population of HIV-1and therefore have a reduced risk of drug-resistant virus at base-line [13]. Third, clinical experience with zidovudine over the pastdecade has indicated that this drug is better tolerated in early-stage disease. Drug adherence, a critical factor for determiningtreatment outcome, may therefore be more difficult for patientswith advanced disease. Other factors associated with advanceddisease that might impact virological outcome include the con-current use of numerous medications, which result in drug-druginteractions, and the possible presence of gastrointestinal disease,which results in drug malabsorption.

These observations indicate that antiretroviral therapyshould be initiated before the CD4 T cell count decreases tolow levels (although precisely how low is unclear). Similarly, asthe viral load increases to levels 110,000–20,000 copies/mL,therapy should be strongly considered [1, 2]. Finally, the stageof disease may also guide treatment strategy. For example, pa-tients with a low baseline CD4 T cell count and/or a highbaseline viral load may benefit from more-aggressive therapythan the currently recommended standard triple-drug regimens.

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CID 2000;30 (Suppl 2) Determinants of Virological Response to Antiretroviral Therapy S179

Previous Therapy

The role of pre-existing viral resistance. The response totriple-drug therapy is improved when administration of thedrugs is initiated simultaneously, rather than sequentially. Ofthe 32 patients who were treated simultaneously with zidovu-dine, lamivudine, and indinavir in Merck trial 035, 25 (78%)had a durable virological response. In contrast, of the 33 pa-tients who began therapy with zidovudine and lamivudine andthen had indinavir added 24–52 weeks later, only 10 (33%) hada durable response (intent-to-treat analysis) [9]. Similarly, thecombination of zidovudine, didanosine, and nevirapine wasalso highly effective in treatment-naive patients [14] but hadonly a transient effect in patients who were previously treatedwith nucleoside analogues [15]. These observations suggest thatprevious drug exposure, with the emergence of resistance andcross-resistance, is an important cause of subsequent virologicalfailure.

In several clinic-based cohort studies of combination therapy,the virological response rates varied from 40% to 60%. This isin contrast to the 70%–90% response rates observed in clinicaltrials. The sequential introduction and use of antiretroviraldrugs in clinical practice may account for much of these dif-ferences. When protease inhibitors became widely available inearly 1996, many patients simply added them to a pre-existingstable nucleoside-analogue regimen. This was clearly seen atSan Francisco General Hospital, where most patients wereextensively nucleoside-analogue–treatment-experienced whenprotease inhibitors became available. For this reason and sincemany of them had advanced disease, virological failure oc-curred in ∼50% of our patients [11].

There is growing interest in the use of resistance assays todetect resistance before the initiation or modification of com-bination antiretroviral therapy [16]. Data obtained from ret-rospective studies indicate that the presence of viral resistance,as measured by genotypic and/or phenotypic assays, predictsresponse to protease inhibitor–including regimens [17, 18]. Pro-spective, randomized clinical trials indicate that knowledge ofbaseline resistance patterns in treatment-experienced patientsallows clinicians to design more effective salvage regimens [19].

Finally, several cohort studies have demonstrated that resis-tance to nucleoside analogues, nonnucleoside reverse transcrip-tase inhibitors, and protease inhibitors can exist in treatment-naive patients (usually at prevalence rates of !5%). Presumably,these resistance patterns reflect naturally occurring genetic poly-morphisms or were transmitted during primary infection [20,21]. The degree to which pre-existing resistance causes subse-quent virological failure in treatment-naive patients receivingcombination therapy is unknown.

The role of cellular resistance. The development of viralresistance and cross-resistance to antiretroviral therapy does notaccount for all of the failures observed among previouslytreated patients. For example, antiretroviral therapy may in-

duce or select for long-term changes in host cells, which resultsin a diminished ability of a drug to inhibit HIV replication.

Nucleoside analogues undergo intracellular phosphorylationto an active triphosphate metabolite. Phosphorylation and ac-tivation of the thymidine analogues (stavudine and zidovudine)is more efficient in activated CD4 T cells. In contrast, the non-thymidine analogues (lamivudine and didanosine) are efficientlyphosphorylated in resting as well as activated cells.

The thymidine analogues share a common intracellular ac-tivation pathway that involves phosphorylation by thymidinekinase. The monophosphate form of zidovudine has been foundto inhibit the activity of this enzyme. Since thymidine kinasephosphorylation is rate-limiting for stavudine (but not zido-vudine), zidovudine may prevent stavudine activation. This hy-pothesis was examined in the ACTG 290 trial, in which patientswere treated concurrently with stavudine and zidovudine nu-cleoside analogues [22]. As predicted, the triphosphate form ofstavudine was lower than normal. Patients treated with thiscombination experienced a rapid decline in CD4 T cell levels,which presumably was a consequence of this negative drug-drug interaction.

Although the clinical relevance of these observations is un-known, the results of the ACTG 290 trial illustrate an importantconcept that drugs may fail in previously treated patients forreasons other than the development of genotypic resistance.Other poorly understood factors, such as cellular resistance,may also play important roles in determining virological re-sponse to therapy. More research in this area is necessary.

Drug Exposure

Adherence. Medication adherence is another important de-terminant of outcome [1, 2]. Theoretically, inconsistent adherenceto therapy could result in suboptimal drug concentrations, thusallowing for viral replication to proceed in the presence of thedrug. This creates an ideal situation for selecting drug resistance.Complicated drug schedules, drug toxicity, and, as detailed below,patient-specific factors all contribute to adherence.

Progress in determining the quantitative relationship betweenadherence and the virologic response has been limited by thelack of a validated adherence measure. To address this issue,Bangsberg and colleagues [23] administered three independentadherence measurements to a group of marginally housed HIVinfected adults. All were receiving a protease inhibitor basedregimen. There was a strong correlation among the measure-ments, with adherence reported to be 89% (self-administeredquestionnaire), 73% (unannounced pill counts at subjects res-idence) and 73% (eclectronic medication monitor). As expected,there was a strong negative correlation between any single ad-herence measure and absolute viral load (the correlation co-efficient ranged from 20.60 to 20.81). In a multivariate modelthat considered several factors, adherence remained a strong

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predictor of absolute viral load. For every 10% decrease inadherence (as measured by pill count), there was a doubling ofthe absolute viral load.

Haubrich et al. [24] at the California Collaborative TreatmentGroup (CCTG) administered a 24-item questionnaire to 173patients enrolled in a prospective study of frequent versus in-frequent viral-load monitoring. As a substudy, patients wereasked about their medication-adherence patterns over the pre-ceding 4 weeks. When adherence was categorized on the basisof patients’ estimated number of doses taken (!80%, 80%–95%,95%–99%, and 100%), viral load reduction was strongly as-sociated with each patient’s self-reported degree of adherence.It is notable that the primary care provider’s assessment of thepatient’s adherence did not correlate with either the patient’sself-reported adherence or with the virological response to ther-apy [24].

The observation that adherence predicts the virologic re-sponse to therapy is not surprising. The next step is to definelevel of adherence necessary to achieve a durable virologic re-sponse, and level of adherence below which resistance does notemerge. As regards this latter point, Bangsberg [23] observedthat patients with less than 50% adherence had no detectabledrug resistance. There may be a level of drug exposure at whichthe selective pressure for the emergence of resistance is greatest,and any decrease in drug exposure (adherence) below thisthreshold results in less resistance.

Hecht et al. [25] at San Francisco General Hospital reportedsimilar results in a cross-sectional study. Approximately one-third of the patients to whom a questionnaire was administeredreported having missed at least 1 dose over the preceding 3days. A number of reasons were given for nonadherence, in-cluding “forgot” (40%), “slept through the dosing time” (37%),“change in routine” (27%), “too busy” (22%), “too sick” (13%),“side effects” (10%), and “depressed” (9%). The missing ofdoses was found to be associated with virological failure (oddsratio, 4.7; 95% confidence interval, 1.1%–20.6%). Taken as awhole, these studies and others suggest that adherence is animportant determinant of outcome with protease inhibitor–based regimens.

Although definitive data regarding the importance of ad-herence will be difficult to obtain, risk factors for nonadherenceare well known. In the CCTG study, recreational drug use andalcohol use, but not sex, ethnicity, HIV risk group, or education,correlated with self-reported adherence (since the study pop-ulation was predominantly white and homosexual, the gener-alizability of these results may be limited) [24]. Chesney et al.[26], who participated in the ACTG and used a self-adminis-tered questionnaire, reported that increased alcohol intake pre-dicted nonadherence. They also found that working outside thehome was an important predictor of nonadherence (presumablybecause such patients were missing their midday doses) [26].

Several interventions to improve medication adherence areundergoing prospective clinical evaluation. One available op-

tion is to defer therapy, either until the patient is able to committo long-term adherence or until well-tolerated twice-daily oreven once-daily regimens are developed [1, 2]. Similarly, oncenonadherence becomes an issue, the clinician and patient mayconsider stopping therapy and then reinitiating it once im-proved adherence is possible.

Pharmacokinetics. Drug exposure is an important deter-minant of virological outcome, particularly with protease in-hibitors. Plasma clearance, peak plasma concentration, troughplasma concentration, and area under the curve have all beenproposed as possible determinants of the virological response.Attention has been focused on the role of the trough plasmaconcentration in determining virological outcome.

Indinavir has a complex pharmacokinetic profile. Because ofits rapid clearance from plasma (mediated by cytochrome P450CYP3A isoenzyme), high peak and low trough concentrationsoccur, which result in the need for dosing every 8 h. To evaluatethe role of the trough concentration on virological response, across-sectional study of patients receiving treatment with anindinavir-including regimen was performed. Twenty-three pa-tients underwent careful pharmacokinetic evaluation. Patientswith evidence of persistent viral replication had lower median8-hour area under the curve measurements than patients whoachieved evidence of durable viral suppression [27].

These observations were subsequently confirmed in a largerprospective study on indinavir combination therapy (ACTG343). Indinavir trough concentration 4 weeks after beginningan indinavir-based regimen was predictive of both the 4-weekand 24-week virologic response [28]. A maximal virologic re-sponse required an indinavir trough concentration of at least110 ng/mL. Such detailed pharmacokinetic studies should ide-ally be performed for each antiretroviral drug. Because of thetime and expense involved, it is unlikely if such studies will beperformed.

The importance of indinavir trough concentrations for pre-dicting virological outcomes was perhaps most definitively dem-onstrated in Merck 067, a study of 2 nucleoside analogues plusindinavir (either 800 mg every 8 h or 1200 mg every 12 h;indinavir trough concentrations were predicted to be muchlower in the twice-daily regimen). The study was stopped pre-maturely because virological failure occurred in a higher pro-portion of patients receiving twice-daily doses [29]. Finally, inearly clinical trials of ritonavir, there was a negative correlationbetween ritonavir trough concentrations and the emergence ofresistance to ritonavir [30].

Suboptimal plasma concentrations of protease inhibitorsmay occur under specific clinical conditions. For example, pa-tients with gastrointestinal disease may have difficulty absorb-ing antiretroviral drugs, which results in suboptimal plasmadrug concentrations. Drug-drug interactions may also affectdrug levels. Rifampin, for instance, induces the activity of P450CYP3A, the key hepatic enzyme involved in the metabolism ofeach of the 4 currently available protease inhibitors. Use of

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rifampin with a protease inhibitor results in enhanced drugmetabolism, subtherapeutic drug levels, and increased risk fordrug failure (for review, see [31]).

The relationship between drug pharmacokinetics and viro-logical outcome is complex and poorly understood. Because ofthe very dynamic nature of viral replication, achieving contin-uous therapeutic drug levels may be necessary for completeviral suppression. The impressive virological data associatedwith efavirenz and lopinavir/ritonavir may be due, in part, toprolonged half-lives and high trough concentrations (relativeto the predicted concentration of drug required to inhibit viralreplication by 90% [IC90]) [32, 33]. Since there may be markedinterpatient and even intrapatient variability in drug metabo-lism [31, 34], individual drug monitoring may become a nec-essary clinical tool for managing HIV disease.

The role of viral reservoirs. The majority of HIV resides intissue, particularly lymph nodes, tonsils, and gut-associatedlymphoid tissue. In general, decay rates in lymphoid tissuesclosely parallel those in plasma, which suggests that antiretro-viral therapy is highly effective for clearing HIV from thesetissues [35].

Concerns remain that other body sites, such as the CNS andthe genital tract, may serve as tissue sanctuaries for viral rep-lication [36]. If drugs do not adequately penetrate these tissues,viral replication will persist indefinitely and make HIV eradi-cation theoretically impossible. Furthermore, resistance will de-velop if viral replication occurs in the presence of subthera-peutic drug concentrations.

Attention has focused on the ability of antiretroviral agentsto cross the blood-brain barrier, since HIV infects the CNS.Zidovudine penetrates the CNS, reduces CSF levels of HIV-1RNA, and prevents AIDS dementia complex [37]. Lamivudineand stavudine also cross the blood-brain barrier [38]. Prelim-inary data indicate that CSF concentrations of indinavir arecomparable with or exceed plasma protein-free concentrations[39]. Despite these observations, discordant virological re-sponses to antiretroviral therapy in plasma and CSF have beenreported. In 1 study, some patients exhibited slower viral decayin the CSF than in plasma [40]. Two explanations for this ob-servation were postulated: (1) effective concentrations of drugswere not achieved in the CSF, and (2) viral turnover in theCNS may be compartmentalized, which results primarily fromautonomous virus production by long-lived macrophages.

The genital tract may also serve as an anatomic sanctuaryfor viral replication. Similar to the blood-brain barrier, a blood-testes barrier exists in men. In general, the viral load in responseto antiretroviral therapy is similar in both semen and plasma,which suggests that viral replication in the genital tract is notnecessarily compartmentalized [41]. This remains controversial,as some investigators have reported a discordance in viral phe-notype between plasma and semen, as well as a lack of cor-relation between plasma HIV RNA levels and the ability toculture virus from semen [42, 43].

Despite observations that suggest that some tissues serve asprotected sanctuaries for viral replication, there is no convinc-ing evidence that viral resistance and virological failure occurbecause of these sanctuaries. Targeting specific tissues with an-tiretroviral therapy, although reasonable, is not generally rec-ommended. These issues require further investigation.

Early Viral Load Response as a Predictorof Subsequent Failure

The initial virological response to therapy appears to predictthe long-term response. In the ACTG 320 trial, the viral load4 weeks after initiation of treatment with zidovudine, lamivu-dine, and indinavir was the strongest independent predictor ofvirological suppression at weeks 24 and 40 [44]. The slope ofviral decay over the first few weeks of therapy may be a goodmarker of the relative potency of a regimen. Indeed, this slopehas been advocated as a rapid and relatively safe means fordetermining the virological activity of novel compounds inHIV-infected study subjects [45].

How low a viral load is required to ensure durable suppression?Several recent studies have indicated that viral suppression ismore likely to endure when the viral load decreases to !20–50copies/mL than when it decreases to !500 copies/mL but remains150 copies/mL. In a large phase II/III study of zidovudine, la-mivudine, and nelfinavir combination therapy, up to 90% of pa-tients whose viral load had decreased to !50 copies/mL for 2consecutive visits remained at this level for 48 weeks. In contrast,only 13% of patients whose viral load had decreased to !400copies/mL but remained 150 copies/mL did the viral load remain!400 copies/mL through week 48 [46]. Similar observations weremade in trials that evaluated the long-term efficacy of nevirapine[47] and ritonavir [48].

Based in part on these observations, a large retrospectivestudy was performed within the ACTG to determine whetherthe early virologic response to therapy predicted the 24-weekoutcome. On the basis of the viral decay curves, patients wereclassified as “on track” or “off track” for a successful virologicresponse. Surprisingly, the vast majority of patients who ex-perienced virologic failure by week 24 were initially “on track”.Virologic failure tended to be abrupt, with rapid rebounds inviral load after an initial successful response. Only a minorityof subjects (!20%) had a slow initial decline in viral load. Asexpected, virologic failure in this subgroup was common [49].These data question the prevailing opinion [1, 2] that the earlyvirologic response is a surrogate of regimen activity, and suggestthat close monitoring of viral load will not reliably provideearly evidence of virologic failure.

These observations have clinical implications. Patients shouldachieve at least a 0.5- to 0.75-log decline in viral load by weeks4–8 and have an undetectable viral load (!500 copies/mL) byweeks 12–16. Failure to achieve a viral load that is undetectable(!50 copies/mL) by means of an ultrasensitive assay by week 24

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may be associated with an incomplete response and subsequenttreatment failure. The lack of a robust virological response totherapy should prompt the clinician to consider whether the reg-imen is failing. Possible therapeutic strategies for such a lack ofresponse include continued therapy with close observation, earlyintensification with an additional agent, stopping therapy andreassessing at a later date, or changing to an entirely new regimen.

Target Cell Availability and Virological Failure:Predator/Prey Model

A model has been proposed that may provide an alternativemechanism for virological failure. The life cycle of HIV involvesa continuous cycle of cell infection and cell death. HIV (the“predator”) therefore requires a continued supply of target cells(the “prey”) for ongoing viral replication. In the face of highlyactive antiretroviral therapy (HAART), the absolute numberof activated CD41 T cells (the presumed target cells) may in-crease, thus leading to a more permissive environment for viralreplication [50, 51]. In this model, previously effective drugconcentrations become less effective as T cell expansion occurs.Drug-susceptible virus then begins to replicate. This modeltherefore predicts that patients with larger increases in CD41

T cell counts may have a higher risk for subsequent virologicalfailure and that initial viral rebound will be associated withwild-type virus.

Evidence supporting this model was observed in ACTG 343,a large, prospective trial designed to evaluate the concept ofinduction/maintenance. After a 6-month “induction” periodwith zidovudine, lamivudine, and indinavir, patients were ran-domized to receive continued triple-drug therapy or “mainte-nance” therapy with indinavir monotherapy or zidovudine/la-mivudine. Viral rebound was more likely to occur in patientsrandomized to 1 of the 2 maintenance regimens, thus leadingto early termination of the study. It is interesting that indinavirmonotherapy was most likely to fail for patients with the mostrobust increase in CD41 T cell counts during the inductionperiod, a finding that is consistent with the predator/prey model[52].

ACTG 375 evaluated the complex relationship between pro-tease inhibitor mediated viral suppression and the CD4 T cellresponse. In this small study [53], subjects who had computedtomography evidence of abundant thymic tissue had greaterincreases in naı̈ve CD4 T cells. Interestingly, these subjects werealso more likely to experience virologic failure. These prelim-inary data provide additional support that increased target cellsmay contribute to subsequent virologic failure.

Virological Failure and Clinical Progression

The most widely accepted definition of drug failure is basedon viral load. However, several cohort studies have suggestedthat CD4 T cell counts can remain elevated after virological

failure, at least for the first 1–2 years of follow-up [54, 55]. Themechanism of this increased CD41 T cell count in the presenceof ongoing viral replication remains unclear, but presumablythe increase is due, in part, to persistent but incomplete viralsuppression.

Ledergerber et al. [56] recently studied clinical progression(AIDS events and deaths) among 2674 patients followed in theSwiss HIV Cohort. After controlling for a variety of baselinefactors, they found that the estimated probability of clinicalprogression over 30 months was similar among patients whohad either a durable virological response (HIV RNA level !400copies RNA/mL) or a transient virological response (HIV RNAlevel !400 copies/mL, followed by a sustained rebound) [56].Although more research is needed, it appears that there may asignificant delay between virological failure and either immu-nologic or clinical progression.

Conclusion

For the multiple reasons discussed above, long-term viralsuppression may be difficult or impossible to achieve for manypatients receiving combination therapy. Baseline characteristics,such as disease stage, plasma viral load, and drug resistance,contribute to determinations of patients’ responses to therapy.Once therapy is initiated, factors that influence the exposure ofdrug to the virus (such as adherence, drug metabolism, anddrug distribution to potential tissue sanctuaries) have signifi-cant effects on the durability of the virological response. Unlesseach of these issues is addressed, virological failure is possible.Unfortunately, many of these factors are likely to persist whensalvage therapy is initiated, which suggests that many patientswhose first regimen fails will have a poor response to any sub-sequent regimen.

References

1. US Department of Health and Human Services, Henry J. Kaiser FamilyFoundation. Guidelines for the use of antiretroviral agents in HIV infectedadults and adolescents. MMWR Morb Mortal Wkly Rep 1998;47:43–82.

2. Carpenter CC, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults:updated recommendations of the International AIDS Society–USA Panel.JAMA 2000;283:381–90.

3. Zhang L, Ramratnam B, Tenner-Racz K, et al. Quantifying residual HIV-1replication in patients receiving combination antiretroviral therapy. NEngl J Med 1999;27:1605–13.

4. Martinez-Picado J, DePasquale MP, Kartsonis A, et al. Selection of anti-retroviral resistance in the latent reservoir of human immunodeficiencyvirus type 1 during successful therapy [abstract 238]. In: 7th Conferenceon Retroviruses and Opportunistic Infections (San Francisco), 2000.

5. Ramratnam B, Mittler JE, Zhang L, et al. The decay of the latent reservoirof replication competent HIV-1 is inversely correlated with the extent ofresidual viral replication during prolonged antiretroviral therapy. Nat Med2000;6:82–5.

6. Grossman Z, Polis M, Feinberg MB, et al. Ongoing HIV transmission duringHAART. Nature Med 1999;5:1099–1104.

7. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of twonucleoside analogues plus indinavir in persons with human immunode-

at University of C



Dow

nloaded from



ficiency virus infection and CD4 cell counts of 200 per cubic millimeteror less. N Engl J Med 1997;337:725–33.

8. Hirsch M, Steigbigel R, Staszewski S, et al. A randomized controlled trialof indinavir, zidovudine, and lamivudine in adults with advanced humanimmunodeficiency virus type 1 infection and prior antiretroviral therapy.J Infect Dis 1999;180:659–66.

9. Gulick RM, Mellors JW, Havlir D, et al. Simultaneous vs. sequential initiationof therapy with indinavir, zidovudine and lamivudine for HIV-1 infection:100 week follow-up. JAMA 1998;280:35–41.

10. Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA.Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.Science 1996;272:1167–70.

11. Deeks SG, Hecht FM, Swanson M, et al. HIV RNA and CD4 cell countresponse to protease inhibitor therapy in an urban AIDS clinic: responseto both initial and salvage therapy. AIDS 1999;13:F35–43.

12. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1–specificCD41 T cell responses associated with control of viremia. Science 1997;278:1447–50.

13. Coffin JM. HIV population dynamics in vivo: implications for genetic var-iation, pathogenesis, and therapy. Science 1995;267:483–9.

14. Montaner J, Reiss P, Cooper D, et al. A randomized, double-blind trialcomparing combinations of nevirapine, didanosine, and zidovudine forHIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canadaand Australia Study. JAMA 1998;279:930–7.

15. D’Aquila RT, Hughes MD, Johnson VA, et al. Nevirapine, zidovudine, anddidanosine compared with zidovudine and didanosine in patients withHIV-1 infection: a randomized, double-blind, placebo-controlled trial.Na-tional Institute of Allergy and Infectious Diseases AIDS Clinical TrialsGroup protocol 241 investigation. Ann Intern Med 1996;124:1019–30.

16. Hirsch MS, Brun-Vezinet F, D’Aquila RT, et al. Antiretroviral drug resistancetesting in adult HIV-1 infection: recommendations of an InternationalAIDS Society–USA Panel. JAMA 2000;283:2417–26.

17. Deeks SG, Hellmann N, Grant RM, et al. Novel four-drug salvage treatmentregimens after failure of a protease inhibitor–containing regimen: antiviralactivity and correlation of baseline phenotypic drug susceptibility withvirologic outcome. J Infect Dis 1999;179:1375–81.

18. Zolopa AR, Shafer RW, Warford A, et al. HIV-1 genotypic resistance patternspredict response to saquinavir-ritonavir therapy in patients in whom pre-vious protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-21.

19. Durant J, Clevenbergh P, Halfon P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet 1999;353:2195–9.

20. Boden D, Hurley A, Zhang L, et al. HIV-1 drug resistance in newly infectedindividuals. JAMA 1999;282:1135-41.

21. Little SJ, Daar ES, D’Aquila RT, et al. Reduced antiretroviral drug suscep-tibility among patients with primary infection. JAMA 1999;282:1142-49.

22. Sommadossi JP, Zhou XJ, Moore J, et al. Impairment of stavudine (d4T)phosphorylation in patients receiving a combination of zidovudine andd4T (ACTG 290) [abstract 3]. In: Program and abstracts of the 5th Con-ference on Retroviruses and Opportunistic Infections (Chicago). Alex-andria, VA: Foundation for Retrovirology and Human Health, 1998.

23. Bangsberg DR, Hecht FM, Charlebois ED, et al. Adherence to proteaseinhibitors, HIV-1 viral load, and development of drug resistance in anindigent population. AIDS 2000;14:357–66.

24. Haubrich RH, Little SJ, Currier JS, et al. The value of patient-reportedadherence to antiretroviral therapy in predicting virologic and immuno-logic response. AIDS 1999;13:1099–107.

25. Hecht FM, Colfax G, Swanson M, Chesney MA. Adherence and effectivenessof protease inhibitors in clinical practice [abstract 15]. In: Program andabstracts of the 5th Conference on Retroviruses and Opportunistic In-fections (Chicago). Alexandria, VA: Foundation for Retrovirology andHuman Health, 1998.

26. Chesney M, Ickovics J, Chambers D, for the Recruitment Adherence and

Retention Committee of the Adult Clinical Trials Group (ACTG) (1997).Adherence to combination therapy in AIDS clinical trials. In: AnnualMeeting of the AIDS Clinical Trials Group (Washington, DC), 1997.

27. Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concen-trations and antiviral effect. Pharmacotherapy 1999;19:708–12.

28. Acosta EP, Havllir DV, Richman DD, et al. Pharmacodynamics (PD) ofindinavir (IDV) in protease-naive HIV-infected patients receiving ZDVand 3TC [abstract 455]. In: 7th Conference on Retroviruses and Oppor-tunistic Infections (San Francisco), 2000.

29. Merck Pharmaceuticals, West Point, PA. Letter to investigators. 18 September1998.

30. Molla A, Korneyeva M, Gao Q, et al. Ordered accumulation of mutationsin HIV-1 protease confers resistance to ritonavir. Nat Med 1996;2:760–6.

31. Flexner C. HIV-protease inhibitors. N Engl J Med 1998;338:1281–92.32. Murphy R, King M, Brun S, et al. ABT-378/ritonavir therapy in antiretro-

viral-naive HIV-1–infected patients for 24 weeks [abstract 15]. In: Programand abstracts of the 6th Conference on Retroviruses and OpportunisticInfections (Chicago). Alexandria, VA: Foundation for Retrovirology andHuman Health, 1999.

33. Staszewski S, Morales-Ramirez J, Tashima KT et al. Efavirenz plus zido-vudine and lamivudine, efavirenz plus indinavir plus zidovudine and la-mivudine in the treatment of HIV-1 infection in adults. Study 006 Team.NEngl J Med 1999341:1865–73.

34. Merry C, Barry MG, Mulcahy F, et al. Saquinavir pharmacokinetics aloneand in combination with ritonavir in HIV-infected patients. AIDS 1997;11:F29–33.

35. Cavert W, Notermans DW, Staskus K, et al. Kinetics of response in lymphoidtissue to antiretroviral therapy of HIV-1 infection. Science 1997;276:960–4.

36. Schrager LK, D’Souza MP. Cellular and anatomical reservoirs of HIV-1 inpatients receiving potent antiretroviral combination therapy. JAMA 1998;280:67–71.

37. Price RW. Neurological complications of HIV infection. Lancet 1996;348:445–52.

38. Foudraine NA, Hoetelmans RM, Lange JM, et al. Cerebrospinal-fluid HIV-1 RNA and drug concentrations after treatment with lamivudine pluszidovudine or stavudine. Lancet 1998;351:1547–51.

39. Stahle L, Martin C, Svensson JO, et al. Indinavir in cerebrospinal fluid ofHIV-1–infected patients. Lancet 1997;350:1823.

40. Staprans S, Marlow N, Glidden D, et al. Time course of cerebrospinal fluidresponses to antiretroviral therapy: evidence for variable compartmen-talization of infection. AIDS 1999;13:1051–62.

41. Vernazza PL, Gilliam BL, Flepp M, et al. Effect of antiviral treatment onthe shedding of HIV-1 in semen. AIDS 1997;11:1249–54.

42. Coombs RW, Speck CE, Hughes JP, et al. Association between culturablehuman immunodeficiency virus type 1 (HIV-1) in semen and HIV-1 RNAlevels in semen and blood: evidence for compartmentalization of HIV-1between semen and blood. J Infect Dis 1998;177:320–30.

43. Eron Jr JJ, Smeaton LM, Fiscus SA, et al. The effects of protease inhibitortherapy on human immunodeficiency virus type 1 levels in semen (AIDSClinical Trails Group Protocol 850). J Infect Dis 2000;181:1622–28.

44. Demeter L, Hughes M, Fischl M, et al. Predictors of virologic and clinicalresponses to indinavir (IDV), ZDV 1 3TC or ZDV 1 3TC [abstract 509].In: Program and abstracts of the 5th Conference on Retroviruses andOpportunistic Infections (Chicago). Alexandria, VA: Foundation for Re-trovirology and Human Health, 1998.

45. Kilby JM, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 rep-lication in humans by T-20, a peptide inhibitor of gp41-mediated virusentry. Nat Med 1998;4:1302–7.

46. Powderly WG, Saag MS, Chapman S, et al. Predictors of optimal virologicalresponse to potent antiretroviral therapy. AIDS 1999;13:1873-80.

47. Raboud JM, Montaner JS, Conway B, et al. Suppression of plasma viralload below 20 copies/mL is needed to achieve long-term virologic sup-pression. AIDS 1998;12:1619–24.

at University of C



Dow

nloaded from



48. Kempf DJ, Rode RA, Xu Y, et al. The duration of viral suppression duringprotease inhibitor therapy for HIV-1 infection is predicted by plasma HIV-1 RNA at the nadir. AIDS 1998;12:F9-14.

49. Huang W, De Gruttola V, Fischle M, et al. Patterns of plasma HIV RNAresponses in antiretroviral treatment success and failure [abstract 451]. In:7th Conference on Retroviruses and Opportunistic Infections (San Fran-cisco), 2000.

50. McClean AR, Nowak MA. Competition between zidovudine-sensitive andzidovudine-resistant strains of HIV. AIDS 1992;6:71–9.

51. Bonhoeffer S, Coffin JM, Nowak MA. Human immunodeficiency virus drugtherapy and virus load. J Virol 1997;71:3275–8.

52. Havlir DV, Marschner IC, Hirsch MS, et al. Maintenance antiretroviral ther-apies in HIV-infected subjects with undetectable plasma HIV RNA aftertriple-drug therapy. N Engl J Med 1998;339:1261–8.

53. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restor-

ation in patients with human immunodeficiency virus infection after 48

weeks of zidovudine, lamivudine and ritonavir therapy. J Infect Dis

2000;181:141–7.

54. Kaufmann D, Pantaleo G, Sudre P, Telenti A. CD4 cell count in HIV-1

individuals remaining viraemic with highly active antiretroviral therapy

(HAART). Swiss HIV Cohort Study. Lancet 1998;351:723–4.

55. Deeks SG, Barbour J, Martin J, Swanson M, Grant RM. Sustained CD4 T

cell response after virologic failure of protease inhibitor based regimens

in HIV infected patients. J Infect Dis 2000181:946-53.

56. Ledergerber B, Egger M, Opravil M, et al. Clinical progression and virological

failure on highly active antiretroviral therapy in HIV-1 patients: a pro-

spective cohort study. Lancet 1999;353:863–8.

at University of C



Dow

nloaded from


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