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Antiretroviral therapy: ‘the state of the art’
Biomed & Pharmacother 0 Elsevier, Paris
1999 ; 53 : 63-72
Update
Antiretroviral
therapy:
‘the state of the art’
J.S.G. Montaner, V. Montessori, R. Harrigan, M. O’Shaughnessy, R. Hogg
Summary -The field of antiretroviral therapy is evolving at a very rapid pace. At this time. the initiation and optimization of antiretroviral therapy is based on serial plasma viral load determinations which aim to suppress viral replication to as low as possible for as long as possible, thus preventing disease progression. Currently available antiretrovirals require combination therapy with at least three agents to achieve this goal. Increasing availability of newer and more potent antiretroviral regimens will continue to enhance and simplify the number of therapeutic options available in the not too distant future. 0 1999 Elsevier, Pari\ AIDS
/ antiretroviral
THE
GOAL
therapy
i HIV
OF ANTIRETROVIRAL THERAPY
The objective of antiretroviral therapy is to prevent disease progression, and thus prolong and improve the
quality of life [7]. In practical terms,this impliesthe use of triple drug combination therapy regimensto reduce plasmaviral load asmuch aspossiblefor aslong aspossible[ 131.To achievethis, the useof antiretroviral drugs with minimal or no overlapping toxicity, and at least additive (if not synergistic) antiviral activity shouldbe encouraged.This can help to maximize the magnitude and duration of the antiviral response.Given the need for maximal long-term adherenceto currently available treatments, prescribing providers should carefully explore with the patient the feasibility of a proposed treatment. Beyond the obvious medical, pharmacokinetic, and safety issues, the patient’s lifestyle, motivations, and resourcesshouldalsobe considered. TREATMENT-NAIVE
INDIVIDUALS
Partial suppressionof viral replication (usually in the context of antiretroviral therapy with two nucleoside analogues)hasled to substantialimprovementsin morbidity and mortality among HIV-infected individuals. One suchexample pertainsto the decreasein mortality that has been seenin British Columbia (BC) over the last 24 months, even before protease inhibitors and triple drug regimenswere introduced in the summerof
1996.Similar effects werenoted in the recently reported CAESAR trial [9]. Newer data strongly suggest,however. that more powerful regimens are warranted in order to enhancethe magnitudeandthe durability of the therapeutic benefit. A recently completed analysis of plasmaviral load profiles amongpatientswho initiated therapy sincethe summerof 1996within The BC Centre’s Drug Programclearly illustratesthe issue.In brief, patients who started therapy using two nucleosides.as recommendedby the Centre’s former guidelines,generally reached their maximal antiviral effect within a few weeks, This was followed by an increasein the median plasma viral load in the ensuing weeks and months. On the other hand, patients treated with triple drug regimens, despite having a substantially higher plasmaviral load and a lower CD4+ count at baseline, showeda steadydeclinein the medianplasmaviral load to below 500 copies/ml over the sametime period. These results suggestthat partial suppressionof viral replication, suchasthat seenwith dual nucleosidetherapy, leadsto an earlier reboundin viral replication. This rebound (which is often accompaniedby the development of resistance to one or more drugs within the regimen) is ultimately responsiblefor the premature virological failure of a given regimen [21, 231. Recent evidence also suggests that the durability of the antiretroviral effect of a given regimen is proportional to the maximal level of suppressionof viral replication (nadir) that is achieved early on after the initiation of treatment 1361.The use of more sensitiveviral
64
J.S
G. Montaneret al
load tests, with limits of quantification down to 20 to 50 copies/ml, has allowed us to appreciate that only those patients who exhibit a maximal reduction in plasma viral load had sustained antiviral responses to therapy. In the context of maximally suppressive ‘strategies. strict adherence to the therapeutic regimen is critical to maximize the magnitude and durability ofthe treatment effect [22]. In fact, lack of adherence to the therapeutic regimen is likely to become one of the most important determinants of early treatment failure [ 121.It is there-fore particularly important to optimize the circunstances under which treatment is initiated. Given the prospect for long-term therapy with often cumbersome regimens, it is therefore reasonable to delay lhe initia-, tion of therapy if the patient is not ready to commit to it. Also. it is critically important to recogrlize that tanpering with a powerful triple drug regimen (i.e., altering dose, schedule, or dietary and drug restrictions) m ;ay allow sufficient viral replication to occur and promote the emergence of HIV resistance and in turn, premature virological failure. If for any reason a patient must stop one or two of the drugs in a triple drug regimen, inhrruption of the entire regimen is recommended. In this context, viral load will increase significantly. but the patient will retain the ability to respond to the regimen at a later date as it is less likely that drug resistimce will have developed. Given the currently licensed antiretroviral agents, sustained high level suppression of viral replication can only be reliably achieved with triple drug regimens. Combinations with limited or no overlapping toxicity and with additive. or even synergistic antiviral effects are preferred [ 19, 401. When planning the long-term treatment strategy, downstream implications should be carefully considered. In other words, the impact of a given regimen on the number and quality of remaining therapeutic options, should the initial reginlen fall, Table
I.
Selected
should be proactively considered. Use of monotherapy or dual nucleoside therapy is not recommended. Tub/e I summarizes options for initial therapy. Tnhlrs /I to IV list the FDA-approved antiretrovirals with dosages and potential side effets. Figure I illustrates the mechanism of action of these antiretroviral agents. Although the most experience has been in using combinations of two nucleosides (NRTI) plus either a protease inhibitor or a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), research has also explored regimens including two protease inhibitors, usually (but not always) with reverse transcriptase inhibitors. The additional potent antiviral suppression is often welcome for very high viral loads or in patients for whom another regimen has already failed [8, IS]. The most widely studied dual protease inhibitor combination is that of ritonavir and saquinavir [ 61. Two-yea1 follow-up data was recently presented on over 140 treatment nai’ve patients whose initial CD4+ count was between 100-500 cells/mmi. All but 27 of the patients (I 9%) remained on only the two Pls for 60 weeks (the entire cohort had a median number of two prior antivirals, but were PI-naive). Treatment-received analysis of 89 out of 100 evaluable patients (89%) demonstrated maintenance of an undetectable viral load, less than 200 copies/ml, at 60 weeks. Full results of this study, including an intent-to-treat analysis using the most sensitive viral load assay now available, is awaited before this approach can be compared with more traditional triple drug regimens. There were four original dosing arms in this study; however, the dose of 400 mg hid of each protease inhibitor has been reported as providing the best balance of safety and efficacy. Therefore, a combination of 400 mg hid of each ritonavir plus saquinavir (with possibly a reverse transcriptase inhibitor, generally a nucleoside), can be considered as a valid protease-containing antiretroviral regimen. Other dual protease combinations being studied include
first-line regimens.
Zidovudine 200300 + didanosine 200 mg or + lamivudine 150 or Stavudine 40 mg hi& + didanosine 200 mg or + iamivudine 1SO
mg hick hid’ mg hid
indinavir
800 mg y&
Or
ritonavir
600 mg, hid
Or
hid’ mg hid
netinac ir 7.50 mg titf5 or saquinavir-SGC I .200 mg tid
nevirapine 200 mg qd x 14 days. then 200 mg hid (or 400 mg qd) or delavirdine 400 mg tid Or
efavirenz
600 mg qd
PI: protease inhibitor; NNRTI: non-nucleoside reverse tlanscriptase inhibitor. ’ 125 mg hid if < 60 kg once daily dosing available soon; z 20 mg hid if < 60 kg; i consider dual PI use (i.e., ritonavir 400 mg PO bid and saquinavir 400 mg PO hid + third drug) and triple nutleoside (i.e., AZT + 3TC + abacavir); 4 saquinavir in originally approved form (InviraseY. dosage of 600 mg y8h. not on list of potent Pls (due tl) poor bioavailability); ‘dosing at 1,250 mg hid currently under evaluation.
Antiretroviral therapy
Table
When to start treatment
II. Modifying therapy due to failure. Potential
selec,ted
0pptiorz.s
Antiretroviral therapy should be considered for all HIV-infected individuals, with the possible exception of those who have a low plasma viral load (< 5,000 copies/ml) and a clearly normal and stable CD4+ count (> 500 cells/mm’). Clinical trials are currently underway to determine the role of therapy in this group of patients. Currently, antiretroviral therapy should be offered to any HIV-infected individual whose plasma RNA is > 5,000 copies/mL or whose CD4+ count is < 500 cells/mm’ (or the CD4+ percentage consistently < 25%), regardless of symptoms. If this approach is followed, clinical criteria will play a limited role in initiating therapy, since symptoms are exceptionally rare in individuals who have normal CD4+ count and very low viral load. Nevertheless, the optimal time to initiate therapy remains controversial. Available clinical evidence from virology and immunologic studies indicates that treatment should be encouraged before immuno-deficiency develops. This is usually judged by a full evaluation of the medical history, a physical exam and the prognostic laboratory markers (CD4+ count and plasma viral load). However, the ultimate decision of when to start therapy will also be affected by personal factors, such as the patient’s preference. lifestyle, and readiness to
2 new NRTIs/PI
2 NRTIs/PI 2 N RTls/NNRTI 2 PIs/‘NRTI 2 PIs/NNRTI# NRTI/PI/NNRTI’
2 new NRTIs/NNRTI 2 PIs/NRTI 2 new NRTIs/NNRTI 2 PIs/2NRTI 2 Pls/NNRTI 2 new NRTIs/PI 2 PIs/NRTI 2 new NRTIs/NNRTI 3 new NRTI (‘9
Changes in therapy should be monitored with viral load immediately before and within the first 4-6 weeks of therapy, so that the expected effect on viral load can be confirmed. “Inclusion of a PI and NNRTI
in a combination severely constrains options for rescue therapy. indinavir 1,200 mg hid plus nelfinavir 1,00&l ,250 mg hid. and nelfinavir 1,000-l ,250 mg bid plus saquinavir 1,000 mg hid [ 16, 20,271. In summary, it is recommended that triple drug therapy consisting of two nucleosides plus either a potent protease inhibitor or a non-nucleoside reverse transcriptase inhibitor be offered as first-line therapy. Consideration could be given to using dual protease based regimens or triple nucleoside therapy as well. Table
65
III. FDA-approved antiretrovirals -dosage and potential loxicity of nucleoside reverse transcriptase inhibitors (NRTIs).
Generic nume hr-und numeQ (FDA-uppml,edi
Zidovudine: AZT or ZDV retrovir” (1987)
300 mg hid* (lower doses of 200 mg hid are often used)
Didanosine: dd1 videxE (1991)
> SO kg : 200 mg hid 3549 kg : 100 mg bid
(possible new dosing : 400 mg for > 50 kg, 200 mg qd for 3549 kg)
qd
> 10%: nausea, anemia. neutropenia. headache, insomnia < 10%: fi CPK (+ clinical myositis), hyperpigmentation of nails, l? liver enzymes > 10%: peripheral neuropathy, pancreatitis. nausea, vomiting, diarrhea, headache l-IO%‘: 0 liver enzymes, anemia, neutropenia take 1 h before or 2 h after meal
Zalcitabine: ddC hivid@ (1992)
0.75 mg rid
Stavudine: d4T zeritB (1994)
>60kg:40mghid < 60 kg: 30 mg hid
Lamivudine: 3TC epivip (1995)
150 mg hid
> 10%: oral ulcers. peripheral neuropathy l-IO%: nausea, vomiting, diarrhea, pancreatitis take with food > IO%: peripheral neuropathy l-IO%: dysphoria, insomnia, other mood disturbance, nausea, vomiting, pancreatitis take with food nausea, headache, neutropenia, malaise, fatigue
Zidovudine 300 mg
I tab hid
(see entries for component
+ lamivudine 150 mg combivir@ (I 997)
drugs above)
---___
* While currently available data suggest that zidovudine 300 mg once daily can have a favorable effect on surrogate markers, the clinical effectiveness
of this dose has not been established.
66
J.S.G. Montaner
Table IV. FDA-approved
antiretrovirals
Neviraoine: NVP ViramuneCm (1996)
Delavirdine: Rescriptor”
- dosage and potential
toxicity
200 me od x 2\rk>. then BII) (alternative”ddse: 400 mg yd. prcferabl) at night because it may haw mild sedative effect! 400 mg rid (possibl q 600 ml; PO hid)
DLV ( I Y97)
commit to long term therapy. If initiation of therapy is deferred for whatever cause,the issueshouldbe revjsited frequently. taking into account trends in the patient’s clinical and laboratory profile as well as emergingdata. Every eligible patient should be offered antiretro\liral therapy. The natureof the treatment andthe needfor strict adherenceto the regimen must be discussedin detail with all patients. The possibleconsequencesof poor adherenceto the regimen (i.e., treatment failure, viral resistance, cross-resistanceto other drugs and thus, decreasedtreatment options) should be clearly and specifically discussed. The regimen should be specifically selectedto facilitate adherence.Care-givers
et al
of non-nucleoside
reverse
transcriptase
inhibitors
> 10%: rash. neutrooenia < l-IO%: GI: nausea, diarrhea. n transaminases other: fever, headache; 0.5%: Steven’s Johnson > 10%: rash, 2Zlf.K: nausea, vomiting. fatigue, lt transaminases
diarrhea.
(NNRTls).
syndrome headache,
and patients must recognize that the number of treatment options currently available is very limited. Proteaseinhibitor-containing regimens are fairly strict in terms of the dosing requirements. In contrast, NonNucleoside ReverseTranscriptaseInhibitor (NNRTI)basedregimens are lessdemanding. Preliminary data suggest that a triple nucleoside (NRTI) regimen may also be a viable and lessdemandingoption. No completed study, however, has yet compared the relative merits of starting therapy with two nucleosidesplus a potent protease inhibitor or two nucleosides plus a NNRTI or thee nucleosides.This is a critical issue, which will hopefully be addresseddefinitively in the next severalmonthsonce the resultsof studiesbecome available. TREATMENT-EXPERIENCED INDIVIDUALS
CD4tT Cell
When to change therapy
transcriptase /
&tease inhihitors work here
Nbn-nucleoside and nucleoside reversetranscriptase inhibitors work here Figure 1. Mechanisms of action of antiretroviral agent:.. HIV is a retrovirus. To reproduce. it uses the reverse transcriptase enzyme Lo convert RNA into DNA. DNA then enters the nucleus 3f the cell and makes many copies of the original virus. New viral particles are then modified, assembled and leave the cell able to Infect new cells. Nucleoside analogues cause the cell to produce incomplete DNA by incorporating themselves into the DNA of the virus ard thus stopping the replication process. Non-nucleoside rc,erse trdw scriptasc inhibitors bind directly to the reverse transcriplaie enLyme and prevent it from functioning. Protease inhibitors prevent nw progeny HIV particles from being assembled and releas~:d.
A numberof variables can impact the decisionof when to change treatment. Obviously, the specific reason(s) leading to a change of therapy will often place severe constraints on the available options. In general, patients developing toxicity to a given agent shouldbe advisedto changeto a secondagent which haslimited or non overlapping toxicity. Similarly, when clinical or virologic failure are the motivation for change, issues of cross-resistancewill become the critical determinants. The following provides a practical, though not necessarily all-encompassing, perspective on when and how to change treatment under different clinical circumstances. Modifying therapy - intolerance, adverse effects or drug interactions The developmentof intoleranceoften dictates an early change in the antiretroviral therapy regimen. Fortu-
Antiretrovird
nately, a number of agents are available which have only limited overlapping toxicity. Drug interactions can also dictate a change in therapy. This is particularly the case when chemotherapeutic agents are required for treatment of associated conditions. The known effect of protease inhibitors on cytochome P4.50 is responsible for a lengthy list of potential drug interactions that should be carefully reviewed before using these compounds. Drugs such as alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride. clorazepate, clozapine, diazepam, dihydroergotamine, encainide, ergotamine, flecainide, flurazepam, meperidine, midazolam, pimozide, piroxicam, propafenone. propoxyphene, quinidine, rifabutin, terfenadine, triazolam, and zolpidem are not to be taken with ritonavir. Although drug interactions have been best characterized in the context of ritonavir use, it is likely that this issue also plays a role with other potent protease inhibitors. It is important to emphasize that intolerance to agiven antiretroviral agent in the distant past, even if due to a well-documented adverse effect, does not necessarily preclude rechallenging with the same agent if clinically indicated. Obviously, this should always be done under controlled circumstances and in consultation with an experienced physician. Patients presenting a well-characterized intolerance or adverse effects to a single agent, in the context of sustained full suppression of viral replication. can be offered a direct switch of the offending agent. Under other circumstances, a change of regimen will be necessary. Metabolic disorders and body fat redistribution have now been recognized in substantial numbers of patients receiving long term treatment with protease inhibitors containing regimens 1251.A hypothesis has been put forward linking these to an underlying protease inhibitor-induced insulin resistance status. The ultimate clinical significance of these adverse effects has not yet been elucidated. Similarly, the best strategy to deal with these problems has not yet been defined. Modifying
therapy - due to treatment
failure
Prior to defining treatment failure it should be noted that short term variability is at least in the order of 3fold for plasma viral load (pVL) and about 30% for CD4 count. Furthermore, variability may be increased by intercurrent illnesses, vaccinations, or stimulants in general. On the other hand, variability decreases with repeated testing. It is therefore important to obtain duplicate measuretnents at baseline and prior to taking any active therapeutic steps. While treatment fail-
ther;lpy
67
ure has traditionally been defined in terms of the development of a new AIDS-defining illness, opportunistic infections, development of symptoms, or a decline in CD4+ counts, the current understanding of the pathophysiology of HIV disease mandates a change in antiretroviral therapy prior to clinical disease progression or immunological deterioration 133, 391. Within the context of this pVL-driven therapeutic strategy, treatment failure is best defined in quantitative terms. Currently, drug failure is defined mainly in virological terms (i.e., substantial and confirmed rebound of pVL in the absence of another likely reason). Once treatment failure has been confirmed, one should consider the following principles: - change to thee new drugs; - a\ oid using drugs likely to be cross-resistant to previously failed agents; - changing a single drug within a failing regimen is not acceptable; - always consider the downstream implications of a given change in therapy, (i.e., a change in therapy virtually always decreases future therapeutic options). The initial goal of therapy is to achieve sustained maximal suppression of viral replication; this implies the reduction of pVL to below the limit of quantitation of the most sensitive clinical assay available. From a technical standpoint, anything less than maximal suppression of viral replication represents virological failure. However, there is now ample evidence that partial suppression of viral replication is associated with substantial improvements in clinical outcomes. In addition, the number of non cross-resistant triple drug combinations that can be offered, given the number of drugs currently available, is probably limited to two and certainly not more than thee. Thus, if sustained maximal suppression of viral replication cannot be achieved, a given regimen should be continued as long as there is evidence of partial suppression of viral replication and that there is no reason to suspect that its continued use will compromise the ability to benefit from the next available regimen. If there is a viable alternative treatment available. a change to a new regimen will be warranted if there is rebound of viral replication to detectable levels (greater than 400 copies/ml) , or evidence of a declining CD4+ count. Under these circumstances, the decision of what to change to has typically been based on a thorough understanding of the past exposure to antiretroviral drugs and the possible cross resistance and/or synergy of the available agents. However, the issue of cross-resistance appears to be more critical when agents such as protease inhibitors
68
J.S.G. Montaner et al.
or non-nucleoside reverse transcriptase inhibitors are considered. Again, drug interactions can potentially place important constraints on the number of options
available. Table V outlines someselectedoptions for a change in therapy given the failure of a specific regimen. It should be emphasized that there are very limited data available regarding this issue at present. Thus, it isdesirable that changes in therapy be monitored with viral load immediately before and within the first 4-8 weeks of therapy so that the expected effect on viral load can be confirmed. It should also be emphasized that the best
strategy regardingwhen to changetherapy asa resull of treatment failure is not fully defined at present.Specifically the risk-benefit
ratio of a change in therapy, at dif-
ferent thresholdsof rebound viral replication, has not been established. At all times one must consider the implications of continuing therapy on the presenceof active viral replication, as this will allow continued evolution of the virus and therefore a higher level of crossresistance to related agents. On the other hand, changing therapy before it is strictly necessary may rapidly decrease the number of treatment options available ar a
time in which these are rather limited. In this context,
it is particularly important to appreciatethe fact that a clinical benefit hasbeendemonstratedeven when modestand transientvirologic effects were present.In other words, that a clinical benefit hasremainedevenbeyond the time when rebound viral replication first occurred. This apparent ‘dissociation’ betweenlaboratory markersand clinical benefit wasfirst apparentin clinical trals involving dual nucleoside therapy, such asDelta or ACTG 175 and more recently the CAESAR trial [93. Not surprisingly a similar and probably more dramatic ‘dissociation’ betweenviral rebound while on therapy, and persistent immunologic and clinical benefit has beenobservedin clinical practice when the more powerful triple drug therapy regimens have been used.
currently
available
It is therefore useful to separate virologic failure from treatment failure. Virologic failure occurs when a patient who has continuously adheredto the regimen and has had plasmaHIV RNA levels below the lower limit
of detection
of the assay (whatever
the limit of
sensitivity of the assay) presents with consistently detectable plasma HIV RNA. Virologic failure may also be identified in a patient with a plasmaviral load that increasessignificantly from a baselinethat may
Table V. FDA-approved antiretrovirals: dosage and potential tcxicity of protease inhibitors. Generic name hrund name@ (FDA-crpproved/
U.rual
adult
dosage
All approved Pls
Indinavir: IDV crixivan@ (1996)
Side
&em/toxicity
(food
requrrements)
fat redistribution (including ‘buffalo hump’, ‘protease paunch’) lipid abnormalities (e.g. hypertriglyceridemia) glucose intolerance/diabetes mellitus 800 mg y8h
GI: nausea, diarrhea, abdominal pain, benign hyperbilirubinemia (-10%) +/-jaundice, GU: crystalluria, flank pain, kidney
stones. Other: rash. Take with low fat/protein snack or on empty stomach;
RitDnavir: RTV norvir@ ( 1996)
600 mg bid dose escalation as follows: 300 mg bid x 3 da) s, 400 mg hid x 2-3 days. COO mg hid x
2-3 days, 600 mg hrd thereafter
store pills with desiccant
GI: nausea, vomiting, taste perversion, diarrhea, n transaminases (ALT, AST) neuromuscular. Circumoral and peripheral paresthesias, headache, muscle weakness, fi CPK. General aathenia refrigerate medication
Nelfinavir: NFV viracept” (1997)
750 mg tid
(possible new dosing: 1,250 mg hid)
< 10%: nausea, vomiting, flatulence, or CPK take with snack or light meal
Saquinavir-HGC: SQV-HGC invirase@(1995) Saquinavir-SGC: SQV-SCC fortovasem(1997)
400 mg PO hid (when used with ritonavir 400 mg PO hid) 1,200 mg qXh
GI: nausea, abdominal oral ulcers
> 10%: diarrhea
discomfort/pain,
asthenia,
fl transaminases
anorexia,
diarrhea,
CNS: headache, dizziness, asthenia neuromuscular and skeletal: numbness/tingling in limbs, muscle aches, muscle and bone pain hamatological: Neutropenia other: rash, pruritus if used with RTV, take with a fatty snack. Store saquinavir soft-gel in refrigerator
Antiretroviral
never have reached the lower limit of detection. The need for an urgent change in therapy would be substantially greater if continuation on the same regimen is felt to increase the likelihood of cross-resistance to other therapeutic alternatives. This is probably most important in patients who are taking protease inhibitor based regimens. In such an instance, one could retain Table
VI. 1998 Investigational
antiretrovirals:
Usual
Nucleoside Abacavir: expanded
FIG
analog reverse
transcriptase
IS92U89 access
inhibitors
transcriptase
CNS: headache, asthenia. insomnia GI: nausea allergic: potentially life-threatening anaphylaxis; if allergic reaction (usually fever, malaise, nausea f rash) develops. drug is discontinued; do not o-challenge (deaths reported) ‘,
inhibitors
Adefovir dipivoxil: bis-POM-PMEA prev,eon” investigational
120 (pass. 60) mg qd used in conjunction with L-carnitine
pmpa investigational
not yet determined (doses used in early trials with SIV-infected macaques have ranged from 30-75 mg/kg yd)
Non-nucleoside
500
reverse
transcriptase
inhibitors
(NNRTIa)
600 mg qd
MKC-442 investigational
not yet determined (doses used in early human trials have ranged from loo-350 mg bid) *development has been discontinued* --~--
Table
VII.
1998 Investigational
ABT-378 investigational
Other medications
antiretrovirals:
rash, dizziness, ‘hangover’ (j/l3 pregnant monkeys given efavirenz do not use in pregnant women)
dosages and potential
not yet determined (doses used in early human trials have ranged from 200-600 mg hid) used with RTV 50 mg qd-bid 1,200 mg hid
Amprenavir: 141 W94 = VX-478 investigational
nausea. diarrhea, headache. sinusitis lab: fi liver enzymes, CPK, creatinine
mg qd
Efavirenz: DMP-266 sustiva” expanded access
Loviride: LVD not available -
toxicity.
(NTRIs)
200 mg qd
analog reverse
the two nucleosides while switching from a single to a dual protease inhibitor containing combination. The issue is less clear if the patient is being treated with two nucleosides plus a non-nucleoside reverse transcriptase inhibitor (NNRTI). For the NNRTI’s, resistance tends to behave as more of an all or none phenomenon.
udrrlt dosup
300 mg hid
investigational
Nucleotide
dosages and potential
69
therapy
(possible
synergy
have had birth defects;
with AZT. dd1. SQV)
toxicity.
diarrhea
nausea and vomiting
(IO-IS%).
diarrhea
(S-IO%),
rash
(< 5%)
(not developed
Hydroxyurea: hydrea” available for rescue therapy
as antiretrovirals 500 mg hid
onlv
but shown to have adjutant
anti-HIV
effect)
ncutropenia (associated with blunted CD4+ responses direct effect of the drug on the bone marrow)
due to
70
J.S.G.
Montaner
Hydroxyurea agent has been used to treat leukemia and sickle cell disease for several decades. More recently, hydroxyurea has been shown to play a role in the management of HIV infection [3 1. 381. Its proposed mechanism of action is related to its known inhibition of ribonucleotide reductase, a cellular enzyme noi specific 1‘01 retroviruses. In vitro studies done earlier this decade have shown the ability ofhydroxyurea to decrease HIV activity when used in combination with ddI and possibly d4T, or 3TC. The fact that it does not work against HIV-specific enzymes minimizes the chance of resistance developing as a result of its use. Hydroxyurea is most commonly used at a dose of 500 nlg PO hid in combination with nucleosides (chiefly ddl, but also d4T and 3TC). Enhanced pVL suppression can be easily demonstrated with hydroxyurea as ;an adjuvant. However, hydroxyurea is known to have a suppressive effect on bone marrow and can cause not only ncutropenia but may also diminish the increase in CD,Jcells usually seen with pVL suppression The precise role of hydroxyurea within the current thrrapeutic strategy remains to be established in prospectively controlled clinical trials, many of which are currenrly underway. This
SIMPLIFICATION
OF THER.$PY
It has become clear over the last couple of’ years that the rate of success of triple drug therapy can be compromised by a variety of factors. Among them are adequacy of the treatment regimen. pre-existence of drug resistance, very advanced immune deficiency. and incomplete adherence. Of all of the above, rhe I,ltter has become one of the most frequent determinant: of treament failure in the clinical setting. The currently available regimens are often complex and associ:.ted wrth potential side effects. Beyond that. treatments often have a substantial impact on the patienl’s I fe-style. Restrictions regarding what patients should and should not eat and what medicines may or may not be used may sound trivial at first glance, but they after becotme insurmountable obstacles in the long term. It is for this reason that attempts have been initiated towards the development of simplified regimens. Amotlg them, combining AZT and 3TC in a single tablet ::an allow for the back bone of the nucleoside therapy to be Irovidcd by one tablet, taken twice daily. Also, recent data suggests that effectiveness may be at least preserved when nelfinavir is given as I.250 mg hid, rathrr than in its conventional rid regimen [241.
et al
Several drugs of proven antiviral efficacy are currently being evaluated for simplified once daily regimens.Among them are 3TC 300 mg qd, ddI400 mg qd and nevirapine 200 mg qd for 14 days increasing to 400 mg qd thereafter. Furthermore, several new drugs suchasadefovir, possibly PMPA andefavirenz arecurrently being developedfor once daily therapy. In addition, ABT-378, a new potent proteaseinhibitor, may be given as a qd regimen if combined with low dosesof ritonavir [291.TablesVI andVII describeinvestigational antiretroviral dosagesand potential toxicity. CONCLUSIONS The field of antiretroviral therapy continues to evolve at a very rapid pace. Currently, we are in a position to guide the initiation and optimization of antiretroviral therapy basedon serial plasma viral load determinations. Preliminary data strongly suggestthat plasma viral load driven antiretroviral therapy representsa significant improvement over treatment based on CD4+ decline, the developmentof symptoms.or the development of minor or major HIV-related diseases.With increasing experience in the use of plasma viral load determinations, it is likely that our recommendations will needto be revised. Furthermore. increasingavailability of newer andmorepotent antiretroviral regimens will continue to enhanceand simplify the number of therapeutic options available in the not too distant future. REFERENCES Arribas JR. Gonzalez-Garcia J. Ibanez C, Ruin B. Peiia JM, Esteban C. et al. Acute hepatitis in AIDS patients during ritonavir treatment [Abslract 4 I7 1. 5th Conference on Retroviruses and Opportunistic Infections: 1908. Bar] PA, Rizard CiP. Gallant S. Welbon C. Graziosi C. Chave JP, et al. Comhination lSY2/141 WY4 therapy in HIV-Iinfected antiretroviral naive subjects with CD4counts > 400 cells/p1 and viral load > S.000 copies/ml [ Abhlract 36.51. 5th Confcrencc on Retrovirusc\ and Opportunistic Infections; 1998. 3 Beach RS. Wohlfeilcr MB. SilvaA. IndinaviriNevirapine conbination therapy in advanced HIV- I infection [Abstract 42X]. 5th Conference on Rctroviruses and Opportumstic Infections: 199x. 4 Borleffs JC on behalf of the CHEESE Study Team. First comparative study of saquinavir soft gel capsulks versus indinavir as part of triple therapy regimen (CHEESE) [Abstract 387bl. 5th Confereke on R&ovik~es and Opportunistic Infections; I YYX. 5 Bouhamdan M. Duan LX. Pomerantr RJ. Inhibition of human immunodeticiency virus type A replication by expression of fusion protein, vpr-
Antiretroviral
6 Cameron DW, Japour A, Mellors J. Farthing C, Cohen C. Markowitz M, et al. Antiretroviral safety and durability of ritonavir-saquinavir in protease inhibitor-naive patients in yea,two of follow-up [Abstract 3881. 5th Conference on Retroviruses and Opportunistic Infections, 1998. 7 Carpenter. Cdi, Fischl MA. Hammer SM. Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1997 : updated recommendations of the International AIDS Societv-USA Panel. JAMA 1997 ; 277 (24) : 1962-9. 8 Casano P, Hermans P, Sommereijns, B, de Wit S. Kabeya K. O’Doherty E, et al. Combined quadruple therapy with ritonavir-saquinavir + nucleosides in patients who failed triple therapv with RTV. SOV or Indinavir [Abstract 423 I. 5th Confere&e on Retroviruies and Opportunistic Infections; 199X. 9 CAESAR Coordinating Committee. Randomized trial ofaddition of lamivudine plus loviride to zidovudine-containing regimens for patients with HIV-I infection: the CAESAR trial. Lancet 1997 ; 349 : 1413-21. 10 Cohen CJ. Hellinger JA, Stein AJ. Gathe J, Keiser P. Can Nelfinavir substitute for other protease inhibitor(s) in persons with plasma HIV- I RNA below 500 copies/ml before the substitution? [Abstract 3871. 5th Conference on Retroviruscs and Opportunislic Infections; 1998. P. Viral load I I Deeks S, Beatty G, Cohen PT. Grant R, Volberding and CD4’ T-cell changes in patients failing potent protease inhibitor therapy [Abstract 4191. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 12 Deeks S, Loftus R. Cohen P. Chin S. Grant R. Incidence and predictors of virologic failure to indinavir and/or ritonavir in an urban health clinic [Abstract LB- 21. 37th ICAAC: 1907. 13 Department of Health and Human Services. Guidelines tor the use of antiretroviral agents in HIV-infected adults and adolescents. Panel on clinical practice\ for treatment of HIV infection: 1997. II Eron J. Haubrich R. Richman D, Lang W. Tisdale M, Myer:, R. et al. Preliminary assessment of 14lW94 in combination with other protease inhibitors [Abstract 61. 5th Conference on Retroviruses and Opportunistic Infections; 1998. IS Gallant JE, Hall C, Barnett S. Raines C. Ritonavir/saquinavil as salvage therapy after failure of initial protease inhibitor regimen [Abstract 4271. 5th Conference on Retroviruses and Opportunistic Infections; 199X. 16 Gallant JE, Heath-Chiozzi M. Rainea C, Anderson R. Katz T, Fields C, et al. Safety and efficacy of nelfinavirritonavir combination Therapy [Abstract 394-A]. Sth Conference on Retroviruses and Opportunistic Infections: 1998. 17 Gerard M. de Wit S, Sprecher S, de Cock F. Van Laethem Y, Hermans P. et al. Salvage anti HIV triple therapy with foxcarnet in combination with nelfinavir and nevirapine in heavily pretreated patients [Abstract 4241. 5th Conference on Ketroviruses and Opportunistic Infections: 1998. IX Harris M. Whaley M, de Wet JJ. Raboud J, Rat S, Conway B. ct al. One year follow-up of HIV patients treated with nevlrapine, indinavir and lamivudine [Abstract 429aJ. 5th Conference on Retroviruses and Opportunistic Infections; 199X. I!, Havlir DV, Friedland G. Pollard R, Tierney C. Smeaton L. Fox L. ct al. Combination zidovudine (ZDV) and stavudine (d4T) therapy versus other nucleosides: report of two randomizcd trials (ACTG 290 and 29X) [Abstract 21. 5th Conference on Retroviruses and Opportunistic Infections : 199X. 20 Havlir DV. Riddler !S: Squirea K, Winslow D. Kerl- B, Nguyen BY, et al. Co-administration of indinavir (IDV) and nelfinavir (NFVI in a twice daily regimen: Preliminary safety, pharmacokinetic and anti-viral activity results [Abstract 3931. 5th Conference on Retroviruses and Opportunistic Infection\; I Y9X.
therapy
71
21 Hazelwood D, Koel JL. Nail CD, Marangos M, Smith R. Miles S, et al. Multi-drug resistant HIV-I isolates from patients with rising plasma viral burden during double or triple combination therapy in clinical practice [Abstract 4211. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 22 Hecht FM, Colfax G. Swanson M, Chesney JA. Adherence and effectiveness of protease inhibitors in clinical practice [Abstract 1511. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 23 Hertogs K, Mellors JW, Schel P, Van Cauwenberghe A. Larder B, Kemp S, et al. Patterns of cross-resistance among protease inhibitors in 4X3 clinical HIV-I isolates [Abstract 395].5th Conference on Retroviruses and Opportunistic Infections; 1998. 24 Johnson M for the European Viracept Clinical Trial Group. Comparison of BID and TID dosing of VIRACEPT@ (nelfinavir; NFV) in combination with stavudine (d4T) and lamivudine (3TC) [Abstract 373].5th Conference on Retroviruses and Opportunistic Infections: 199X. 25 Keruly JC. Chaisson RE, Moore RD. Diabetes and hyperglycemia in patients receiving protease inhibitors [Abstract 4 IS 1, 5th Conference on Retroviruses and Opportunistic Infections: 1998. 26 Kost R, Cao Y, Vesanen M, Talal A. Hurley A, Schluger R. et al. Combination therapy with abacavir (1592),141 W94. and AZT/3TC in subjects acutely and chonically infected with HIV [Abstract 3631. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 21 Kravcik S, Farnsworth A, Patick A, Duncan I, Hawley-Foss N. Anderson R. et al. Long-term follow-up of combination protease inhibitor therapy with neltinavirand saquinavir (soft gel) in HIV infection [Abstract 394-C]. 5th Conference on Retroviruaes and Opportunistic Infections; 1998. 2X Kuritzkes DR, Marschner IC, Johnson VA, Bassett RL, Eron JJ. Fischl MA, et al. A randomized. double-blind, placebo-controlled trial of lamivudine (3TC) in combination with zidovudine (ZDV), stavudine (d4T). or didanosine (dd1) in treatment nai‘vc patients IAbstract I I. 5th Conference on Retroviruaes and Opportunistic Infections; 199X. 2’) Lal R, Hsu A, Granneman GR. El-Shourbagv T. Johnson M. Lam W, et al. Multiple dose safety. tolerability and phamuLokinetics of ABT-378 in combination with ritonavir [Abstract 6471. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 30 Lawrence J, Schapiro J. Winters M. Montoya J, Zolopa A, Pesano R. et al. Salvage therapy with indinavir plus nevirapine in patients previously treated with two other protease inhibitors and multiple reverse iranscriptase inhibitors [Abstract 4221. Sth Conference on Retroviruses and Opportunistic Infections: 1998. 31 Lori F, Jessen H. Clerici M, Lieberman J, Lisziewicz J. Right S. et al. Consistent, sustained HIV suppression without rebound by hydroxyurea, dd1. and a protease inhibitor prevents loss of immunological functions [Abstract 6551. 5th Conference on Ketroviruses and Opportunistic Infections; I998. 32 Mellora J, Lederman M, Haas D. Horton J, Haubrich R. Stanrord J. et al. Antiretroviral effects of- therapy combining abaccavir ( 1592) with HIV protease inhibitors (Pis) [Abstract 41. 5th Conference on Retroviruses and Opportunistic Infections; I Y98. 33 Mellors JW, Munoz A. Giorgi JV, Margolick JB, Tassoni CJ. Gupta P. et al. Plasma viral load and CD4+ Ivmohocvtc.\ as pr&nostic markers of HIV- I infection. Ann In&m’Med 1097 ; I26 : 946.54. 34 Moorman A, Delaney K. Palella F. Ashman D and the HIV lOutpatient Study Group. Recent patterns of antiretroviral lherapy and clinical response in ambulatory HIV patients
72
35
36
37
3X
J.S.G. Montaner
lAbstract 1441. 5th Conference on Retroviruses zrd Opportunistic Infections; 1998. Opravil M, on behalf of the SPICE study team. Study of Protease Inhibitor Combination in Europe (SPICE): Saquinavir soft gelatin capsule and nelfinavir in HIV-infected individuals [Abstract 394-B]. 5th Conference on Retroviruses .md Oppz tunistic Infections; 1998. Raboud JM, Montaner JSG, Conway B, Rae S, Reiss P, Vella S. et al. Suppression of plasma viral below 20 copies/ml. is needed to achieve a long term antiretroviral response. AIDS (in press 1998). Rozenbaum W, Adda N, Wirbel E, Hadacek B, Schneider V. Costagliola D. Predictors and incidence of failure in 500 advanced stage HIV patients treated witt indinavit ]Abstract 4201. 5th Conference on Retroviruses ;nd Opp’Jrtunistic Infections; 1998. Rutschmann OT, Opmvil M. Iten A, Malinverni R, Vernazza P. Bucher H, et al. ddI + d4T +/- hydroxyurea for HIV-1 infec-
et al.
tion [Abstract 6561. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 39 Shaefer M, Shaker-Irwin L, Maude C, Williams V, Morales D. Thommes J, et al. Progression of disease in the Pacific Oaks Population Study (POPS) since the introduction of protease inhibitors and use of highly active antiretroviral therapy [Abstract 1921. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 40 Sommadossi JP, Zhou XJ, Moore J, Havlir DV, Friedland G. Tiernev C. et al. Impairment of stavudine (d4T) ohospho_ . rylation in patients receiving a combination of zidovudine (ZDV) and d4T (ACTG 290) [Abstract 31. 5th Conference on Retroviruses and Opportunistic infections; 1998. 3 I Workman C, Mussen R. Sullivan J. Salvage therapy using six drugs in heavily pretreated patients [Abstract 4261. 5th Conference on Retroviruses and Opportunistic Infections; 1998.
1999 ; 53 : 63-72
Update
Antiretroviral
therapy:
‘the state of the art’
J.S.G. Montaner, V. Montessori, R. Harrigan, M. O’Shaughnessy, R. Hogg
Summary -The field of antiretroviral therapy is evolving at a very rapid pace. At this time. the initiation and optimization of antiretroviral therapy is based on serial plasma viral load determinations which aim to suppress viral replication to as low as possible for as long as possible, thus preventing disease progression. Currently available antiretrovirals require combination therapy with at least three agents to achieve this goal. Increasing availability of newer and more potent antiretroviral regimens will continue to enhance and simplify the number of therapeutic options available in the not too distant future. 0 1999 Elsevier, Pari\ AIDS
/ antiretroviral
THE
GOAL
therapy
i HIV
OF ANTIRETROVIRAL THERAPY
The objective of antiretroviral therapy is to prevent disease progression, and thus prolong and improve the
quality of life [7]. In practical terms,this impliesthe use of triple drug combination therapy regimensto reduce plasmaviral load asmuch aspossiblefor aslong aspossible[ 131.To achievethis, the useof antiretroviral drugs with minimal or no overlapping toxicity, and at least additive (if not synergistic) antiviral activity shouldbe encouraged.This can help to maximize the magnitude and duration of the antiviral response.Given the need for maximal long-term adherenceto currently available treatments, prescribing providers should carefully explore with the patient the feasibility of a proposed treatment. Beyond the obvious medical, pharmacokinetic, and safety issues, the patient’s lifestyle, motivations, and resourcesshouldalsobe considered. TREATMENT-NAIVE
INDIVIDUALS
Partial suppressionof viral replication (usually in the context of antiretroviral therapy with two nucleoside analogues)hasled to substantialimprovementsin morbidity and mortality among HIV-infected individuals. One suchexample pertainsto the decreasein mortality that has been seenin British Columbia (BC) over the last 24 months, even before protease inhibitors and triple drug regimenswere introduced in the summerof
1996.Similar effects werenoted in the recently reported CAESAR trial [9]. Newer data strongly suggest,however. that more powerful regimens are warranted in order to enhancethe magnitudeandthe durability of the therapeutic benefit. A recently completed analysis of plasmaviral load profiles amongpatientswho initiated therapy sincethe summerof 1996within The BC Centre’s Drug Programclearly illustratesthe issue.In brief, patients who started therapy using two nucleosides.as recommendedby the Centre’s former guidelines,generally reached their maximal antiviral effect within a few weeks, This was followed by an increasein the median plasma viral load in the ensuing weeks and months. On the other hand, patients treated with triple drug regimens, despite having a substantially higher plasmaviral load and a lower CD4+ count at baseline, showeda steadydeclinein the medianplasmaviral load to below 500 copies/ml over the sametime period. These results suggestthat partial suppressionof viral replication, suchasthat seenwith dual nucleosidetherapy, leadsto an earlier reboundin viral replication. This rebound (which is often accompaniedby the development of resistance to one or more drugs within the regimen) is ultimately responsiblefor the premature virological failure of a given regimen [21, 231. Recent evidence also suggests that the durability of the antiretroviral effect of a given regimen is proportional to the maximal level of suppressionof viral replication (nadir) that is achieved early on after the initiation of treatment 1361.The use of more sensitiveviral
64
J.S
G. Montaneret al
load tests, with limits of quantification down to 20 to 50 copies/ml, has allowed us to appreciate that only those patients who exhibit a maximal reduction in plasma viral load had sustained antiviral responses to therapy. In the context of maximally suppressive ‘strategies. strict adherence to the therapeutic regimen is critical to maximize the magnitude and durability ofthe treatment effect [22]. In fact, lack of adherence to the therapeutic regimen is likely to become one of the most important determinants of early treatment failure [ 121.It is there-fore particularly important to optimize the circunstances under which treatment is initiated. Given the prospect for long-term therapy with often cumbersome regimens, it is therefore reasonable to delay lhe initia-, tion of therapy if the patient is not ready to commit to it. Also. it is critically important to recogrlize that tanpering with a powerful triple drug regimen (i.e., altering dose, schedule, or dietary and drug restrictions) m ;ay allow sufficient viral replication to occur and promote the emergence of HIV resistance and in turn, premature virological failure. If for any reason a patient must stop one or two of the drugs in a triple drug regimen, inhrruption of the entire regimen is recommended. In this context, viral load will increase significantly. but the patient will retain the ability to respond to the regimen at a later date as it is less likely that drug resistimce will have developed. Given the currently licensed antiretroviral agents, sustained high level suppression of viral replication can only be reliably achieved with triple drug regimens. Combinations with limited or no overlapping toxicity and with additive. or even synergistic antiviral effects are preferred [ 19, 401. When planning the long-term treatment strategy, downstream implications should be carefully considered. In other words, the impact of a given regimen on the number and quality of remaining therapeutic options, should the initial reginlen fall, Table
I.
Selected
should be proactively considered. Use of monotherapy or dual nucleoside therapy is not recommended. Tub/e I summarizes options for initial therapy. Tnhlrs /I to IV list the FDA-approved antiretrovirals with dosages and potential side effets. Figure I illustrates the mechanism of action of these antiretroviral agents. Although the most experience has been in using combinations of two nucleosides (NRTI) plus either a protease inhibitor or a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI), research has also explored regimens including two protease inhibitors, usually (but not always) with reverse transcriptase inhibitors. The additional potent antiviral suppression is often welcome for very high viral loads or in patients for whom another regimen has already failed [8, IS]. The most widely studied dual protease inhibitor combination is that of ritonavir and saquinavir [ 61. Two-yea1 follow-up data was recently presented on over 140 treatment nai’ve patients whose initial CD4+ count was between 100-500 cells/mmi. All but 27 of the patients (I 9%) remained on only the two Pls for 60 weeks (the entire cohort had a median number of two prior antivirals, but were PI-naive). Treatment-received analysis of 89 out of 100 evaluable patients (89%) demonstrated maintenance of an undetectable viral load, less than 200 copies/ml, at 60 weeks. Full results of this study, including an intent-to-treat analysis using the most sensitive viral load assay now available, is awaited before this approach can be compared with more traditional triple drug regimens. There were four original dosing arms in this study; however, the dose of 400 mg hid of each protease inhibitor has been reported as providing the best balance of safety and efficacy. Therefore, a combination of 400 mg hid of each ritonavir plus saquinavir (with possibly a reverse transcriptase inhibitor, generally a nucleoside), can be considered as a valid protease-containing antiretroviral regimen. Other dual protease combinations being studied include
first-line regimens.
Zidovudine 200300 + didanosine 200 mg or + lamivudine 150 or Stavudine 40 mg hi& + didanosine 200 mg or + iamivudine 1SO
mg hick hid’ mg hid
indinavir
800 mg y&
Or
ritonavir
600 mg, hid
Or
hid’ mg hid
netinac ir 7.50 mg titf5 or saquinavir-SGC I .200 mg tid
nevirapine 200 mg qd x 14 days. then 200 mg hid (or 400 mg qd) or delavirdine 400 mg tid Or
efavirenz
600 mg qd
PI: protease inhibitor; NNRTI: non-nucleoside reverse tlanscriptase inhibitor. ’ 125 mg hid if < 60 kg once daily dosing available soon; z 20 mg hid if < 60 kg; i consider dual PI use (i.e., ritonavir 400 mg PO bid and saquinavir 400 mg PO hid + third drug) and triple nutleoside (i.e., AZT + 3TC + abacavir); 4 saquinavir in originally approved form (InviraseY. dosage of 600 mg y8h. not on list of potent Pls (due tl) poor bioavailability); ‘dosing at 1,250 mg hid currently under evaluation.
Antiretroviral therapy
Table
When to start treatment
II. Modifying therapy due to failure. Potential
selec,ted
0pptiorz.s
Antiretroviral therapy should be considered for all HIV-infected individuals, with the possible exception of those who have a low plasma viral load (< 5,000 copies/ml) and a clearly normal and stable CD4+ count (> 500 cells/mm’). Clinical trials are currently underway to determine the role of therapy in this group of patients. Currently, antiretroviral therapy should be offered to any HIV-infected individual whose plasma RNA is > 5,000 copies/mL or whose CD4+ count is < 500 cells/mm’ (or the CD4+ percentage consistently < 25%), regardless of symptoms. If this approach is followed, clinical criteria will play a limited role in initiating therapy, since symptoms are exceptionally rare in individuals who have normal CD4+ count and very low viral load. Nevertheless, the optimal time to initiate therapy remains controversial. Available clinical evidence from virology and immunologic studies indicates that treatment should be encouraged before immuno-deficiency develops. This is usually judged by a full evaluation of the medical history, a physical exam and the prognostic laboratory markers (CD4+ count and plasma viral load). However, the ultimate decision of when to start therapy will also be affected by personal factors, such as the patient’s preference. lifestyle, and readiness to
2 new NRTIs/PI
2 NRTIs/PI 2 N RTls/NNRTI 2 PIs/‘NRTI 2 PIs/NNRTI# NRTI/PI/NNRTI’
2 new NRTIs/NNRTI 2 PIs/NRTI 2 new NRTIs/NNRTI 2 PIs/2NRTI 2 Pls/NNRTI 2 new NRTIs/PI 2 PIs/NRTI 2 new NRTIs/NNRTI 3 new NRTI (‘9
Changes in therapy should be monitored with viral load immediately before and within the first 4-6 weeks of therapy, so that the expected effect on viral load can be confirmed. “Inclusion of a PI and NNRTI
in a combination severely constrains options for rescue therapy. indinavir 1,200 mg hid plus nelfinavir 1,00&l ,250 mg hid. and nelfinavir 1,000-l ,250 mg bid plus saquinavir 1,000 mg hid [ 16, 20,271. In summary, it is recommended that triple drug therapy consisting of two nucleosides plus either a potent protease inhibitor or a non-nucleoside reverse transcriptase inhibitor be offered as first-line therapy. Consideration could be given to using dual protease based regimens or triple nucleoside therapy as well. Table
65
III. FDA-approved antiretrovirals -dosage and potential loxicity of nucleoside reverse transcriptase inhibitors (NRTIs).
Generic nume hr-und numeQ (FDA-uppml,edi
Zidovudine: AZT or ZDV retrovir” (1987)
300 mg hid* (lower doses of 200 mg hid are often used)
Didanosine: dd1 videxE (1991)
> SO kg : 200 mg hid 3549 kg : 100 mg bid
(possible new dosing : 400 mg for > 50 kg, 200 mg qd for 3549 kg)
qd
> 10%: nausea, anemia. neutropenia. headache, insomnia < 10%: fi CPK (+ clinical myositis), hyperpigmentation of nails, l? liver enzymes > 10%: peripheral neuropathy, pancreatitis. nausea, vomiting, diarrhea, headache l-IO%‘: 0 liver enzymes, anemia, neutropenia take 1 h before or 2 h after meal
Zalcitabine: ddC hivid@ (1992)
0.75 mg rid
Stavudine: d4T zeritB (1994)
>60kg:40mghid < 60 kg: 30 mg hid
Lamivudine: 3TC epivip (1995)
150 mg hid
> 10%: oral ulcers. peripheral neuropathy l-IO%: nausea, vomiting, diarrhea, pancreatitis take with food > IO%: peripheral neuropathy l-IO%: dysphoria, insomnia, other mood disturbance, nausea, vomiting, pancreatitis take with food nausea, headache, neutropenia, malaise, fatigue
Zidovudine 300 mg
I tab hid
(see entries for component
+ lamivudine 150 mg combivir@ (I 997)
drugs above)
---___
* While currently available data suggest that zidovudine 300 mg once daily can have a favorable effect on surrogate markers, the clinical effectiveness
of this dose has not been established.
66
J.S.G. Montaner
Table IV. FDA-approved
antiretrovirals
Neviraoine: NVP ViramuneCm (1996)
Delavirdine: Rescriptor”
- dosage and potential
toxicity
200 me od x 2\rk>. then BII) (alternative”ddse: 400 mg yd. prcferabl) at night because it may haw mild sedative effect! 400 mg rid (possibl q 600 ml; PO hid)
DLV ( I Y97)
commit to long term therapy. If initiation of therapy is deferred for whatever cause,the issueshouldbe revjsited frequently. taking into account trends in the patient’s clinical and laboratory profile as well as emergingdata. Every eligible patient should be offered antiretro\liral therapy. The natureof the treatment andthe needfor strict adherenceto the regimen must be discussedin detail with all patients. The possibleconsequencesof poor adherenceto the regimen (i.e., treatment failure, viral resistance, cross-resistanceto other drugs and thus, decreasedtreatment options) should be clearly and specifically discussed. The regimen should be specifically selectedto facilitate adherence.Care-givers
et al
of non-nucleoside
reverse
transcriptase
inhibitors
> 10%: rash. neutrooenia < l-IO%: GI: nausea, diarrhea. n transaminases other: fever, headache; 0.5%: Steven’s Johnson > 10%: rash, 2Zlf.K: nausea, vomiting. fatigue, lt transaminases
diarrhea.
(NNRTls).
syndrome headache,
and patients must recognize that the number of treatment options currently available is very limited. Proteaseinhibitor-containing regimens are fairly strict in terms of the dosing requirements. In contrast, NonNucleoside ReverseTranscriptaseInhibitor (NNRTI)basedregimens are lessdemanding. Preliminary data suggest that a triple nucleoside (NRTI) regimen may also be a viable and lessdemandingoption. No completed study, however, has yet compared the relative merits of starting therapy with two nucleosidesplus a potent protease inhibitor or two nucleosides plus a NNRTI or thee nucleosides.This is a critical issue, which will hopefully be addresseddefinitively in the next severalmonthsonce the resultsof studiesbecome available. TREATMENT-EXPERIENCED INDIVIDUALS
CD4tT Cell
When to change therapy
transcriptase /
&tease inhihitors work here
Nbn-nucleoside and nucleoside reversetranscriptase inhibitors work here Figure 1. Mechanisms of action of antiretroviral agent:.. HIV is a retrovirus. To reproduce. it uses the reverse transcriptase enzyme Lo convert RNA into DNA. DNA then enters the nucleus 3f the cell and makes many copies of the original virus. New viral particles are then modified, assembled and leave the cell able to Infect new cells. Nucleoside analogues cause the cell to produce incomplete DNA by incorporating themselves into the DNA of the virus ard thus stopping the replication process. Non-nucleoside rc,erse trdw scriptasc inhibitors bind directly to the reverse transcriplaie enLyme and prevent it from functioning. Protease inhibitors prevent nw progeny HIV particles from being assembled and releas~:d.
A numberof variables can impact the decisionof when to change treatment. Obviously, the specific reason(s) leading to a change of therapy will often place severe constraints on the available options. In general, patients developing toxicity to a given agent shouldbe advisedto changeto a secondagent which haslimited or non overlapping toxicity. Similarly, when clinical or virologic failure are the motivation for change, issues of cross-resistancewill become the critical determinants. The following provides a practical, though not necessarily all-encompassing, perspective on when and how to change treatment under different clinical circumstances. Modifying therapy - intolerance, adverse effects or drug interactions The developmentof intoleranceoften dictates an early change in the antiretroviral therapy regimen. Fortu-
Antiretrovird
nately, a number of agents are available which have only limited overlapping toxicity. Drug interactions can also dictate a change in therapy. This is particularly the case when chemotherapeutic agents are required for treatment of associated conditions. The known effect of protease inhibitors on cytochome P4.50 is responsible for a lengthy list of potential drug interactions that should be carefully reviewed before using these compounds. Drugs such as alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride. clorazepate, clozapine, diazepam, dihydroergotamine, encainide, ergotamine, flecainide, flurazepam, meperidine, midazolam, pimozide, piroxicam, propafenone. propoxyphene, quinidine, rifabutin, terfenadine, triazolam, and zolpidem are not to be taken with ritonavir. Although drug interactions have been best characterized in the context of ritonavir use, it is likely that this issue also plays a role with other potent protease inhibitors. It is important to emphasize that intolerance to agiven antiretroviral agent in the distant past, even if due to a well-documented adverse effect, does not necessarily preclude rechallenging with the same agent if clinically indicated. Obviously, this should always be done under controlled circumstances and in consultation with an experienced physician. Patients presenting a well-characterized intolerance or adverse effects to a single agent, in the context of sustained full suppression of viral replication. can be offered a direct switch of the offending agent. Under other circumstances, a change of regimen will be necessary. Metabolic disorders and body fat redistribution have now been recognized in substantial numbers of patients receiving long term treatment with protease inhibitors containing regimens 1251.A hypothesis has been put forward linking these to an underlying protease inhibitor-induced insulin resistance status. The ultimate clinical significance of these adverse effects has not yet been elucidated. Similarly, the best strategy to deal with these problems has not yet been defined. Modifying
therapy - due to treatment
failure
Prior to defining treatment failure it should be noted that short term variability is at least in the order of 3fold for plasma viral load (pVL) and about 30% for CD4 count. Furthermore, variability may be increased by intercurrent illnesses, vaccinations, or stimulants in general. On the other hand, variability decreases with repeated testing. It is therefore important to obtain duplicate measuretnents at baseline and prior to taking any active therapeutic steps. While treatment fail-
ther;lpy
67
ure has traditionally been defined in terms of the development of a new AIDS-defining illness, opportunistic infections, development of symptoms, or a decline in CD4+ counts, the current understanding of the pathophysiology of HIV disease mandates a change in antiretroviral therapy prior to clinical disease progression or immunological deterioration 133, 391. Within the context of this pVL-driven therapeutic strategy, treatment failure is best defined in quantitative terms. Currently, drug failure is defined mainly in virological terms (i.e., substantial and confirmed rebound of pVL in the absence of another likely reason). Once treatment failure has been confirmed, one should consider the following principles: - change to thee new drugs; - a\ oid using drugs likely to be cross-resistant to previously failed agents; - changing a single drug within a failing regimen is not acceptable; - always consider the downstream implications of a given change in therapy, (i.e., a change in therapy virtually always decreases future therapeutic options). The initial goal of therapy is to achieve sustained maximal suppression of viral replication; this implies the reduction of pVL to below the limit of quantitation of the most sensitive clinical assay available. From a technical standpoint, anything less than maximal suppression of viral replication represents virological failure. However, there is now ample evidence that partial suppression of viral replication is associated with substantial improvements in clinical outcomes. In addition, the number of non cross-resistant triple drug combinations that can be offered, given the number of drugs currently available, is probably limited to two and certainly not more than thee. Thus, if sustained maximal suppression of viral replication cannot be achieved, a given regimen should be continued as long as there is evidence of partial suppression of viral replication and that there is no reason to suspect that its continued use will compromise the ability to benefit from the next available regimen. If there is a viable alternative treatment available. a change to a new regimen will be warranted if there is rebound of viral replication to detectable levels (greater than 400 copies/ml) , or evidence of a declining CD4+ count. Under these circumstances, the decision of what to change to has typically been based on a thorough understanding of the past exposure to antiretroviral drugs and the possible cross resistance and/or synergy of the available agents. However, the issue of cross-resistance appears to be more critical when agents such as protease inhibitors
68
J.S.G. Montaner et al.
or non-nucleoside reverse transcriptase inhibitors are considered. Again, drug interactions can potentially place important constraints on the number of options
available. Table V outlines someselectedoptions for a change in therapy given the failure of a specific regimen. It should be emphasized that there are very limited data available regarding this issue at present. Thus, it isdesirable that changes in therapy be monitored with viral load immediately before and within the first 4-8 weeks of therapy so that the expected effect on viral load can be confirmed. It should also be emphasized that the best
strategy regardingwhen to changetherapy asa resull of treatment failure is not fully defined at present.Specifically the risk-benefit
ratio of a change in therapy, at dif-
ferent thresholdsof rebound viral replication, has not been established. At all times one must consider the implications of continuing therapy on the presenceof active viral replication, as this will allow continued evolution of the virus and therefore a higher level of crossresistance to related agents. On the other hand, changing therapy before it is strictly necessary may rapidly decrease the number of treatment options available ar a
time in which these are rather limited. In this context,
it is particularly important to appreciatethe fact that a clinical benefit hasbeendemonstratedeven when modestand transientvirologic effects were present.In other words, that a clinical benefit hasremainedevenbeyond the time when rebound viral replication first occurred. This apparent ‘dissociation’ betweenlaboratory markersand clinical benefit wasfirst apparentin clinical trals involving dual nucleoside therapy, such asDelta or ACTG 175 and more recently the CAESAR trial [93. Not surprisingly a similar and probably more dramatic ‘dissociation’ betweenviral rebound while on therapy, and persistent immunologic and clinical benefit has beenobservedin clinical practice when the more powerful triple drug therapy regimens have been used.
currently
available
It is therefore useful to separate virologic failure from treatment failure. Virologic failure occurs when a patient who has continuously adheredto the regimen and has had plasmaHIV RNA levels below the lower limit
of detection
of the assay (whatever
the limit of
sensitivity of the assay) presents with consistently detectable plasma HIV RNA. Virologic failure may also be identified in a patient with a plasmaviral load that increasessignificantly from a baselinethat may
Table V. FDA-approved antiretrovirals: dosage and potential tcxicity of protease inhibitors. Generic name hrund name@ (FDA-crpproved/
U.rual
adult
dosage
All approved Pls
Indinavir: IDV crixivan@ (1996)
Side
&em/toxicity
(food
requrrements)
fat redistribution (including ‘buffalo hump’, ‘protease paunch’) lipid abnormalities (e.g. hypertriglyceridemia) glucose intolerance/diabetes mellitus 800 mg y8h
GI: nausea, diarrhea, abdominal pain, benign hyperbilirubinemia (-10%) +/-jaundice, GU: crystalluria, flank pain, kidney
stones. Other: rash. Take with low fat/protein snack or on empty stomach;
RitDnavir: RTV norvir@ ( 1996)
600 mg bid dose escalation as follows: 300 mg bid x 3 da) s, 400 mg hid x 2-3 days. COO mg hid x
2-3 days, 600 mg hrd thereafter
store pills with desiccant
GI: nausea, vomiting, taste perversion, diarrhea, n transaminases (ALT, AST) neuromuscular. Circumoral and peripheral paresthesias, headache, muscle weakness, fi CPK. General aathenia refrigerate medication
Nelfinavir: NFV viracept” (1997)
750 mg tid
(possible new dosing: 1,250 mg hid)
< 10%: nausea, vomiting, flatulence, or CPK take with snack or light meal
Saquinavir-HGC: SQV-HGC invirase@(1995) Saquinavir-SGC: SQV-SCC fortovasem(1997)
400 mg PO hid (when used with ritonavir 400 mg PO hid) 1,200 mg qXh
GI: nausea, abdominal oral ulcers
> 10%: diarrhea
discomfort/pain,
asthenia,
fl transaminases
anorexia,
diarrhea,
CNS: headache, dizziness, asthenia neuromuscular and skeletal: numbness/tingling in limbs, muscle aches, muscle and bone pain hamatological: Neutropenia other: rash, pruritus if used with RTV, take with a fatty snack. Store saquinavir soft-gel in refrigerator
Antiretroviral
never have reached the lower limit of detection. The need for an urgent change in therapy would be substantially greater if continuation on the same regimen is felt to increase the likelihood of cross-resistance to other therapeutic alternatives. This is probably most important in patients who are taking protease inhibitor based regimens. In such an instance, one could retain Table
VI. 1998 Investigational
antiretrovirals:
Usual
Nucleoside Abacavir: expanded
FIG
analog reverse
transcriptase
IS92U89 access
inhibitors
transcriptase
CNS: headache, asthenia. insomnia GI: nausea allergic: potentially life-threatening anaphylaxis; if allergic reaction (usually fever, malaise, nausea f rash) develops. drug is discontinued; do not o-challenge (deaths reported) ‘,
inhibitors
Adefovir dipivoxil: bis-POM-PMEA prev,eon” investigational
120 (pass. 60) mg qd used in conjunction with L-carnitine
pmpa investigational
not yet determined (doses used in early trials with SIV-infected macaques have ranged from 30-75 mg/kg yd)
Non-nucleoside
500
reverse
transcriptase
inhibitors
(NNRTIa)
600 mg qd
MKC-442 investigational
not yet determined (doses used in early human trials have ranged from loo-350 mg bid) *development has been discontinued* --~--
Table
VII.
1998 Investigational
ABT-378 investigational
Other medications
antiretrovirals:
rash, dizziness, ‘hangover’ (j/l3 pregnant monkeys given efavirenz do not use in pregnant women)
dosages and potential
not yet determined (doses used in early human trials have ranged from 200-600 mg hid) used with RTV 50 mg qd-bid 1,200 mg hid
Amprenavir: 141 W94 = VX-478 investigational
nausea. diarrhea, headache. sinusitis lab: fi liver enzymes, CPK, creatinine
mg qd
Efavirenz: DMP-266 sustiva” expanded access
Loviride: LVD not available -
toxicity.
(NTRIs)
200 mg qd
analog reverse
the two nucleosides while switching from a single to a dual protease inhibitor containing combination. The issue is less clear if the patient is being treated with two nucleosides plus a non-nucleoside reverse transcriptase inhibitor (NNRTI). For the NNRTI’s, resistance tends to behave as more of an all or none phenomenon.
udrrlt dosup
300 mg hid
investigational
Nucleotide
dosages and potential
69
therapy
(possible
synergy
have had birth defects;
with AZT. dd1. SQV)
toxicity.
diarrhea
nausea and vomiting
(IO-IS%).
diarrhea
(S-IO%),
rash
(< 5%)
(not developed
Hydroxyurea: hydrea” available for rescue therapy
as antiretrovirals 500 mg hid
onlv
but shown to have adjutant
anti-HIV
effect)
ncutropenia (associated with blunted CD4+ responses direct effect of the drug on the bone marrow)
due to
70
J.S.G.
Montaner
Hydroxyurea agent has been used to treat leukemia and sickle cell disease for several decades. More recently, hydroxyurea has been shown to play a role in the management of HIV infection [3 1. 381. Its proposed mechanism of action is related to its known inhibition of ribonucleotide reductase, a cellular enzyme noi specific 1‘01 retroviruses. In vitro studies done earlier this decade have shown the ability ofhydroxyurea to decrease HIV activity when used in combination with ddI and possibly d4T, or 3TC. The fact that it does not work against HIV-specific enzymes minimizes the chance of resistance developing as a result of its use. Hydroxyurea is most commonly used at a dose of 500 nlg PO hid in combination with nucleosides (chiefly ddl, but also d4T and 3TC). Enhanced pVL suppression can be easily demonstrated with hydroxyurea as ;an adjuvant. However, hydroxyurea is known to have a suppressive effect on bone marrow and can cause not only ncutropenia but may also diminish the increase in CD,Jcells usually seen with pVL suppression The precise role of hydroxyurea within the current thrrapeutic strategy remains to be established in prospectively controlled clinical trials, many of which are currenrly underway. This
SIMPLIFICATION
OF THER.$PY
It has become clear over the last couple of’ years that the rate of success of triple drug therapy can be compromised by a variety of factors. Among them are adequacy of the treatment regimen. pre-existence of drug resistance, very advanced immune deficiency. and incomplete adherence. Of all of the above, rhe I,ltter has become one of the most frequent determinant: of treament failure in the clinical setting. The currently available regimens are often complex and associ:.ted wrth potential side effects. Beyond that. treatments often have a substantial impact on the patienl’s I fe-style. Restrictions regarding what patients should and should not eat and what medicines may or may not be used may sound trivial at first glance, but they after becotme insurmountable obstacles in the long term. It is for this reason that attempts have been initiated towards the development of simplified regimens. Amotlg them, combining AZT and 3TC in a single tablet ::an allow for the back bone of the nucleoside therapy to be Irovidcd by one tablet, taken twice daily. Also, recent data suggests that effectiveness may be at least preserved when nelfinavir is given as I.250 mg hid, rathrr than in its conventional rid regimen [241.
et al
Several drugs of proven antiviral efficacy are currently being evaluated for simplified once daily regimens.Among them are 3TC 300 mg qd, ddI400 mg qd and nevirapine 200 mg qd for 14 days increasing to 400 mg qd thereafter. Furthermore, several new drugs suchasadefovir, possibly PMPA andefavirenz arecurrently being developedfor once daily therapy. In addition, ABT-378, a new potent proteaseinhibitor, may be given as a qd regimen if combined with low dosesof ritonavir [291.TablesVI andVII describeinvestigational antiretroviral dosagesand potential toxicity. CONCLUSIONS The field of antiretroviral therapy continues to evolve at a very rapid pace. Currently, we are in a position to guide the initiation and optimization of antiretroviral therapy basedon serial plasma viral load determinations. Preliminary data strongly suggestthat plasma viral load driven antiretroviral therapy representsa significant improvement over treatment based on CD4+ decline, the developmentof symptoms.or the development of minor or major HIV-related diseases.With increasing experience in the use of plasma viral load determinations, it is likely that our recommendations will needto be revised. Furthermore. increasingavailability of newer andmorepotent antiretroviral regimens will continue to enhanceand simplify the number of therapeutic options available in the not too distant future. REFERENCES Arribas JR. Gonzalez-Garcia J. Ibanez C, Ruin B. Peiia JM, Esteban C. et al. Acute hepatitis in AIDS patients during ritonavir treatment [Abslract 4 I7 1. 5th Conference on Retroviruses and Opportunistic Infections: 1908. Bar] PA, Rizard CiP. Gallant S. Welbon C. Graziosi C. Chave JP, et al. Comhination lSY2/141 WY4 therapy in HIV-Iinfected antiretroviral naive subjects with CD4counts > 400 cells/p1 and viral load > S.000 copies/ml [ Abhlract 36.51. 5th Confcrencc on Retrovirusc\ and Opportunistic Infections; 1998. 3 Beach RS. Wohlfeilcr MB. SilvaA. IndinaviriNevirapine conbination therapy in advanced HIV- I infection [Abstract 42X]. 5th Conference on Rctroviruses and Opportumstic Infections: 199x. 4 Borleffs JC on behalf of the CHEESE Study Team. First comparative study of saquinavir soft gel capsulks versus indinavir as part of triple therapy regimen (CHEESE) [Abstract 387bl. 5th Confereke on R&ovik~es and Opportunistic Infections; I YYX. 5 Bouhamdan M. Duan LX. Pomerantr RJ. Inhibition of human immunodeticiency virus type A replication by expression of fusion protein, vpr-
Antiretroviral
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therapy
71
21 Hazelwood D, Koel JL. Nail CD, Marangos M, Smith R. Miles S, et al. Multi-drug resistant HIV-I isolates from patients with rising plasma viral burden during double or triple combination therapy in clinical practice [Abstract 4211. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 22 Hecht FM, Colfax G. Swanson M, Chesney JA. Adherence and effectiveness of protease inhibitors in clinical practice [Abstract 1511. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 23 Hertogs K, Mellors JW, Schel P, Van Cauwenberghe A. Larder B, Kemp S, et al. Patterns of cross-resistance among protease inhibitors in 4X3 clinical HIV-I isolates [Abstract 395].5th Conference on Retroviruses and Opportunistic Infections; 1998. 24 Johnson M for the European Viracept Clinical Trial Group. Comparison of BID and TID dosing of VIRACEPT@ (nelfinavir; NFV) in combination with stavudine (d4T) and lamivudine (3TC) [Abstract 373].5th Conference on Retroviruses and Opportunistic Infections: 199X. 25 Keruly JC. Chaisson RE, Moore RD. Diabetes and hyperglycemia in patients receiving protease inhibitors [Abstract 4 IS 1, 5th Conference on Retroviruses and Opportunistic Infections: 1998. 26 Kost R, Cao Y, Vesanen M, Talal A. Hurley A, Schluger R. et al. Combination therapy with abacavir (1592),141 W94. and AZT/3TC in subjects acutely and chonically infected with HIV [Abstract 3631. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 21 Kravcik S, Farnsworth A, Patick A, Duncan I, Hawley-Foss N. Anderson R. et al. Long-term follow-up of combination protease inhibitor therapy with neltinavirand saquinavir (soft gel) in HIV infection [Abstract 394-C]. 5th Conference on Retroviruaes and Opportunistic Infections; 1998. 2X Kuritzkes DR, Marschner IC, Johnson VA, Bassett RL, Eron JJ. Fischl MA, et al. A randomized. double-blind, placebo-controlled trial of lamivudine (3TC) in combination with zidovudine (ZDV), stavudine (d4T). or didanosine (dd1) in treatment nai‘vc patients IAbstract I I. 5th Conference on Retroviruaes and Opportunistic Infections; 199X. 2’) Lal R, Hsu A, Granneman GR. El-Shourbagv T. Johnson M. Lam W, et al. Multiple dose safety. tolerability and phamuLokinetics of ABT-378 in combination with ritonavir [Abstract 6471. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 30 Lawrence J, Schapiro J. Winters M. Montoya J, Zolopa A, Pesano R. et al. Salvage therapy with indinavir plus nevirapine in patients previously treated with two other protease inhibitors and multiple reverse iranscriptase inhibitors [Abstract 4221. Sth Conference on Retroviruses and Opportunistic Infections: 1998. 31 Lori F, Jessen H. Clerici M, Lieberman J, Lisziewicz J. Right S. et al. Consistent, sustained HIV suppression without rebound by hydroxyurea, dd1. and a protease inhibitor prevents loss of immunological functions [Abstract 6551. 5th Conference on Ketroviruses and Opportunistic Infections; I998. 32 Mellora J, Lederman M, Haas D. Horton J, Haubrich R. Stanrord J. et al. Antiretroviral effects of- therapy combining abaccavir ( 1592) with HIV protease inhibitors (Pis) [Abstract 41. 5th Conference on Retroviruses and Opportunistic Infections; I Y98. 33 Mellors JW, Munoz A. Giorgi JV, Margolick JB, Tassoni CJ. Gupta P. et al. Plasma viral load and CD4+ Ivmohocvtc.\ as pr&nostic markers of HIV- I infection. Ann In&m’Med 1097 ; I26 : 946.54. 34 Moorman A, Delaney K. Palella F. Ashman D and the HIV lOutpatient Study Group. Recent patterns of antiretroviral lherapy and clinical response in ambulatory HIV patients
72
35
36
37
3X
J.S.G. Montaner
lAbstract 1441. 5th Conference on Retroviruses zrd Opportunistic Infections; 1998. Opravil M, on behalf of the SPICE study team. Study of Protease Inhibitor Combination in Europe (SPICE): Saquinavir soft gelatin capsule and nelfinavir in HIV-infected individuals [Abstract 394-B]. 5th Conference on Retroviruses .md Oppz tunistic Infections; 1998. Raboud JM, Montaner JSG, Conway B, Rae S, Reiss P, Vella S. et al. Suppression of plasma viral below 20 copies/ml. is needed to achieve a long term antiretroviral response. AIDS (in press 1998). Rozenbaum W, Adda N, Wirbel E, Hadacek B, Schneider V. Costagliola D. Predictors and incidence of failure in 500 advanced stage HIV patients treated witt indinavit ]Abstract 4201. 5th Conference on Retroviruses ;nd Opp’Jrtunistic Infections; 1998. Rutschmann OT, Opmvil M. Iten A, Malinverni R, Vernazza P. Bucher H, et al. ddI + d4T +/- hydroxyurea for HIV-1 infec-
et al.
tion [Abstract 6561. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 39 Shaefer M, Shaker-Irwin L, Maude C, Williams V, Morales D. Thommes J, et al. Progression of disease in the Pacific Oaks Population Study (POPS) since the introduction of protease inhibitors and use of highly active antiretroviral therapy [Abstract 1921. 5th Conference on Retroviruses and Opportunistic Infections; 1998. 40 Sommadossi JP, Zhou XJ, Moore J, Havlir DV, Friedland G. Tiernev C. et al. Impairment of stavudine (d4T) ohospho_ . rylation in patients receiving a combination of zidovudine (ZDV) and d4T (ACTG 290) [Abstract 31. 5th Conference on Retroviruses and Opportunistic infections; 1998. 3 I Workman C, Mussen R. Sullivan J. Salvage therapy using six drugs in heavily pretreated patients [Abstract 4261. 5th Conference on Retroviruses and Opportunistic Infections; 1998.