1. What antiretroviral regimen do you now recommend for your HIV-
positive patients? How do you decide when to start antiretroviral therapy in
an individual patient? When you consider developing a new treatment
strategy for a patient, to what extent do you consider the patient's individual
needs, lifestyle and ability to comply?
Preferred Regimens
Most use two drugs (25 percent) or choose between two or three drugs (25
percent) based on the patient's condition. The three drug combination
includes a protease inhibitor. The most popular two drug combination is AZT
plus 3TC mentioned as a choice for first-line therapy by 67 percent of
participants. Reasons cited for this combination included tolerability (3TC),
CNS penetration (AZT) and the potential for prolonged sensitivity or
resensitization of the virus to AZT with the use of 3TC. AZT plus ddI is the
second most popular combination (33 percent), followed by d4T plus 3TC (25
percent).
As brand names and abbreviations for pharmaceuticals may vary worldwide,
the following table lists those used in survey responses.
| Generic Name | Brand Name | Abbreviations |
|---|
| acyclovir | Zovirax | ACV |
| azithromycin | Zithromax |
| clarithromycin | Biaxin, Klaricid |
| delavirdine | Rescriptor |
| didanosine | Videx | ddI |
| fluconazole | Diflucan |
| ganciclovir | Cytovene | DHPG |
| indinavir | Crixivan |
| ketoconazole | Nizoral |
| lamivudine | Epivir | 3TC |
| nevirapine | Viramune |
| rifabutin | Mycobutin |
| ritonavir | Norvir |
| saquinavir | Invirase |
| stavudine | Zerit | d4T |
trimethoprim/
sulfamethoxazole | Bactrim, Septra | TMP/SMX |
| zalcitabine | Hivid | ddC |
| zidovudine | Retrovir | AZT, ZDV |
Hardy: I recommend combination therapy for all patients -- initially with
ZDV/3TC, d4T/3TC or d4T/ddI. A protease inhibitor is added if a patient's
initial HIV RNA is greater than 100,000 and the patient is agreeable to triple-
drug therapy. (See accompanying article on HIV RNA viral load.)
Mayer: My clinical practice has changed over the past year to never start
antiretroviral therapy without a combination of drugs. The most common
combinations that I would start with in an antiretroviral-naive patient would
be AZT plus 3TC, or AZT plus ddI.
Katz: I start with AZT/3TC (AZT has best CNS penetration, and is a
reasonably effective drug if tolerated). The AZT/3TC combination data looked
better than that for AZT/ddC and while AZT/ddI may be comparable, ddI is
difficult to administer. The upcoming Glaxo-Wellcome combined dosing of
300 mg AZT plus 150 mg 3TC should make compliance even better. 3TC is
preferred from the onset also because of the reversal of AZT resistance and
the fact that this drug is clearly the best tolerated of the reverse transcriptase
inhibitors. In patients for whom compliance seems to be a huge issue, I might
start with d4T/3TC; also for patients who simply won't take AZT.
Volberding: I recommend two nucleosides as the "standard" platform, either
AZT/ddI, AZT/ddC or AZT/3TC. If the patient is intolerant of or refuses AZT
then I use d4T/ddI or d4T/3TC. I add a protease inhibitor to this platform if
HIV RNA is very high (greater than 100,000), the CD4 is very low (less than
100 or falling by more than 200 cells per year), the patient is symptomatic or if
the two nucleoside analogs do not drop HIV RNA by more than half a log.
Some institute three-drug combinations including a protease inhibitor at the
very initiation of antiretroviral therapy.
Johnson: I start AZT plus 3TC in my HIV-positive patients independent of
CD4 cell count. I start the AZT one month prior to the 3TC to make sure that
it is tolerated. I have been adding indinavir to AZT plus 3TC for just about
everyone, independent of CD4 cell count or viral load level.
Rhame: 3TC plus AZT plus ritonavir if early and the patient is willing to
accept the chance of side effects. Otherwise, especially if the patient is on many
other medications, 3TC plus AZT plus indinavir.
Giordano: For everyone with a viral burden greater than 10,000, AZT plus
3TC plus Crixivan or ritonavir.
Ong: AZT plus 3TC plus ritonavir in those with CD4 less than 500, a recent
decline in CD4 count or recent changes in clinical status.
When they begin, some continue to consider monotherapy an option which
is almost invariably ddI, cited as a first-line option by 19 percent of
participants.
Vella: Monotherapy with ddI, for instance, is a reasonable alternative for
patients who refuse a heavier regimen or show intolerance to AZT.
Yancey: Some patients are probably still appropriate for single-drug reverse
transcriptase inhibitor therapy (not AZT) or a combo within this class.
And those who stand out as particularly conservative, aggressive or
alternative on when to use antiretrovirals.
Sonnabend: There is little data to support a rational decision on antiretroviral
therapy. Since ACTG 175 and Delta are about the only source of evidence,
although unpublished, I can recommend ddI even alone for people with
under 400 CD4 cells whose status is declining (on the basis of 175). For those
who are stable above 300, I don't know what to recommend and discuss this.
Individuals who are stable can do very well without antiretroviral therapy.
Most of my patients who are stable are content to do without antiretroviral
therapy.
Bihari: The only antiretroviral regimen I use on a significant scale is AZT
plus 3TC. I recommend it in general to patients with less than 200 CD4 cells.
[This combination is particularly effective in] AZT-naive patients. Ninety
percent of my patients are AZT-naive because of my past reluctance to use
AZT monotherapy.
When to Begin
Most commonly, respondents use a combination of symptoms and surrogate
markers (CD4 and viral load) when deciding to begin antiretroviral therapy
(42 percent). However, the precise CD4/viral load values leading to initiating
treatment varied greatly. Some clinicians described algorithms (below).
Mayer: The types of criteria that I utilize in recommending initiation of
antiretroviral therapy include a pattern of consistent drop in CD4 count, a
CD4 count less than 500 cells/mm3, an HIV load detected by plasma bDNA or
a QC-PCR greater than 10,000 RNA equivalents per ml and/or constitutional
symptoms or thrush.
Jäger: The criteria considered before starting an antiretroviral therapy are
numerous and varied: CD4 count less than ca. 300 cells/ml for greater than
one month and/or bDNA greater than 50,000 copies/ml greater than one
month and/or the clinical impression of disease progression, e.g., recurrent
minor infections, weight loss, lymphadenopathy and/or the occurrence of an
OI.
Montaner: Therapy is begun if symptoms, a CD4 less than 500 or a viral load
greater than 10,000 copies/ml is/are present.
Vella: Antiretroviral therapy is initiated when CD4 cell count is at or below
500/mm3 or HIV RNA titer exceeds 5,000 copies/ml or symptoms are present,
irrespective of CD4 and HIV RNA values.
Hirsch: Decisions are made by the patient after discussion. Factors considered
are HIV RNA, CD4 cell count, clinical status, lifestyle, ability to comply and
cost, among others.
Volberding: All symptomatic HIV-positive; all patients with CD4 less than
500; all patients with CD4 greater than 500 and HIV RNA greater than 50,000;
all patients who, after discussion, wish to be treated.
Para: Start when the patient is ready and the CD4 is less than 500 if the viral
load is greater than 10,000 or when the CD4 is greater than 500 if the viral load
is greater than 100,000.
However, many begin their patients on therapy based predominately on CD4
counts (25 percent), but this may partially be due to the limited availability of
the viral load tests in certain areas.
Birnbaum: I usually recommend starting therapy below 500 CD4 count but
have given it to some patients felt to be in the very early stages of infection
(less than one year) with more than 500 CD4 cells. Much of this depends upon
the patients' interest and willingness to take drugs.
Rhame: If their CD4 is below 200, I press them hard to start. With CD4's
between 200 and 500, I press them gently to start. If their CD4 is above 500, I'll
start if they press me.
Fewer use viral load alone (17 percent) as a reason to begin therapy.
Hardy: HIV RNA levels greater than 5,000 copies/ml are associated with
decreased survival and increased risk of developing AIDS. I use viral load
measurements greater than 5,000 /ml as my starting point to initiate
antiretroviral therapy regardless of CD4 cell counts or percent.
Katz: Starting therapy: I get a viral load (bDNA) on every new patient --
anyone with over 100,000 gets two reverse transcriptase inhibitors
immediately, anyone with 10,000-100,000 gets told by me that if I were them, I
would start, but they might want to repeat/observe for a while. For under
10,000 I repeat in three to four months, but for the patient who absolutely
wants to be maximally aggressive at whatever T-cell/viral load, I would give
two drugs without hesitation at this time.
Patient Considerations
Essentially everyone considered the patient's lifestyle, wishes or compliance
when prescribing therapy.
Mayer: The most important thing for any patient to feel is that he or she has a
great number of choices and that no choice is to be considered permanent and
that all choices should be re-evaluated in light of new information. It is
essential for the patient to feel that he or she is in control and that the
medical providers are allies in their care. Our clinical encounters should be
times when they ask as many questions as possible and patients only elect to
begin or add treatments once they feel that they have enough information to
make an intelligent and informed choice.
Jäger: The patient's lifestyle and needs, but, above all, ability to comply, play a
major role in developing a treatment strategy; without the patient's
cooperation, even the best possible treatment is doomed to end in frustration
and failure.
Abrams: I usually prescribe antiretroviral therapy to patients who ask me for
it. They usually know what they want and ask for it specifically.
| Regimens Mentioned as First-line Therapy | Respondents |
|---|
| # | % |
| AZT/3TC | 24 | 67% |
| AZT/ddI | 12 | 33% |
| d4T/3TC | 9 | 25% |
| ddI monotherapy | 7 | 19% |
| AZT/ddC | 5 | 14% |
| ddI/d4T | 3 | 8% |
| d4T monotherapy | 1 | 3% |
| d4T/ddC | 1 | 3% |
| AZT/d4T | 1 | 3% |
Reverse trascriptase inhibitors
plus "protease inhibitor" | 4 | 11% |
| RTIs plus Crixivan | 4 | 11% |
| RTIs plus Crixivan or Norvir | 1 | 3% |
2. What factors would enter into a decision to switch or stop antiretroviral
therapy in an individual patient?
Toxicity and adverse events were mentioned most frequently as reasons to
stop or switch therapy (78 percent), followed by a combination of symptoms
and surrogate markers (64 percent). Patient's request was cited by 22 percent of
participants.
Mayer: Any subjective experiences that might be considered toxicities have to
be at the top of the list, including nausea, fatigue, weakness, headaches, etc.
Since we know that with some drugs the experiences may be highly transient
(e.g., such as when individuals start AZT), I may counsel the patient to see if
they can tolerate the symptoms over several days. Other symptoms may
resolve after a drug holiday and reinstitution of the treatment at a lower dose
level (e.g., sensory neuropathy with d4T), but often these symptomatic
toxicities necessitate changing treatment independent of clinical responses.
Other factors that might lead to changes in treatment would include a rapid
drop in CD4 count, a rapid increase in HIV load, the onset of new minor
(thrush) or major opportunistic infections and/or constitutional
symptomatology.
Johnson: I stop therapy based on an individual's compliance and tolerance of
a particular regimen. Most of my patients tolerate therapy across all HIV-1
disease stages. I have been switching therapy mainly based on symptoms
suggestive of viremia, although I will probably obtain a viral load test more
often in the future to decide if a person is failing from a serologic standpoint.
Jäger: Factors which would lead to a change or stop in antiretroviral therapy
include: side effects not tolerable and/or treatable (e.g., nausea, vomiting,
headaches, (poly-)neuropathy), WHO grade three or higher changes in
laboratory parameters (GOT/GPT, AP, anemia, CD4, viral load greater than at
baseline, etc.) and/or during an acute opportunistic infection. The antiviral
therapy is then re-started as soon as possible when the OI is stable.
Katz: Intolerance is an easy one -- if they can't take the drug, I switch. If
neuropathy occurs on a 'D-drug' [ddI, ddC, d4T], I stop completely (assume
they're on 3TC already, as most of my patients would be), push AZT to the
extent it can be. I have seen only a few patients (less than 2 percent) who are
intolerant of all reverse transcriptase inhibitors. For a patient who can take
only 3TC (e.g., AZT-induced headaches/nausea and 'D-induced' neuropathy)
I start a protease inhibitor as the second drug regardless of viral load/T-cells.
Viral load -- anytime it goes over 100,000, therapy must be switched. If it was
undetectable, however, and now is above 10,000, I will propose a switch.
Clinically -- let's not forget the patient with sustained low viral load and
tolerating meds well but who is developing new symptoms or T-calls falling
steadily (unlikely if viral load is low). I would propose adding a drug here,
probably a PI if already on two reverse transcriptase inhibitors.
Hardy: Poor compliance, especially on protease inhibitors. It is probably better
to be on no antiretroviral therapy rather than suboptimal dosing.
Youle: Toxicities which occur on rechallenge or are not amenable to
reasonable supportive therapies.
A number of doctors discontinue therapy in very late stage patients.
Carpenter: We make the decision to stop whenever side effects of
antiretroviral therapy exceed potential benefits of therapy. This is fairly
common in very advanced illness, when the need to treat CMV, MAI and to
prevent PCP is more important than the continuation of antiretroviral
therapy.
Cooper: I stop therapy when no further benefit is demonstrated, there's too
much toxicity or there's more benefit from prophylaxis [alone].
Jäger: Although it is difficult to decide, patients who are at the "point of no
return," i.e., show no positive response to medications, have several OIs
simultaneously and/or are, in general, very ill are no longer treated with
antiretroviral agents.
Some doctors consider discontinuation of therapy, when treatment reduces
viral load to a very low level, and stays there when treatment is stopped.
Cooper: I stop therapy if a patient becomes asymptomatic with viral load
below 10,000 off therapy.
Cohen: Some buzz is starting on using powerful regimens to get virus load to
undetectable for about one month and it [viral load] staying low even when
drugs are stopped.
3. Are you making use of HIV RNA viral load assays? If so, what absolute
levels or changes do you consider significant? How often do you recommend
these tests? How does the availability of viral load assays alter your treatment
strategy?
Eighty-three percent have access to viral load testing. With the
exception of one physician who believes there is little evidence which
supports "early intervention," all those who have access use viral load in
making treatment decisions. Those who have had access the longest appeared
to have more confidence in its use as a reliable indicator of when treatment
was necessary and/or of treatment response. This greater confidence in turn
yields more aggressive use of these assays. Many who cannot offer the test
cited payer constraints and managed care obstacles and would like broader
access to help in patient assessment and response to therapy.
Viral load is most commonly checked before initiating therapy, four to
eight weeks after initiating therapy and then every three or four months. Of
those who use viral load, approximately two-thirds offered their view on
what absolute levels or changes were considered significant and these were
quite varied. Six believed levels greater than 5,000 were significant; four
believed 10,000; one believed 50,000; three believed 100,000; one said no
absolute level was significant; one said that any detectable virus was
significant. In terms of changes, one believed that a change of 0.3 log was
significant; eight believed 0.5-0.6 log; two believed 1.0 log; one said no
absolute level of change was significant. Two respondents stated that the goal
of therapy was to keep viral load below detection; two said the goal was to
keep it below 5,000; four liked to keep it below 10,000.
Here are examples of viral load's impact on some specific strategies.
Mayer: I am starting to use HIV RNA viral load assays more frequently and
am tending to obtain a baseline value on each new patient that I see. I
consider an HIV RNA viral load level of greater than 10,000 copies/ml to be
significant and have tried to use antiretroviral therapy to keep the level
below that threshold. I do not use the viral load to the exclusion of other
important clinical markers. However, I would consider an increase in the
HIV load of a log to be of significance and to warrant re-evaluation of the
current antiretroviral regimen that the patient is taking.
Collier: I like to see HIV RNA that becomes undetectable. I am more
aggressive with treatment at higher CD4 counts if HIV RNA is high.
Bihari: I recommend this test every three months in all of my patients. I
consider a change of 0.5 log or more significant enough to influence
treatment decisions.
Rhame: I use the level for starting considerations to "adjust" the CD4; e.g.,
CD4 of 250 with load of 100,000 would adjust to CD4 200. For change, greater
than 0.5 log seems significant.
Standish: I consider a 0.3 log unit drop significant. I recommend them every
three months and I am using this test more frequently in patients with whom
I am doing informal patient-oriented single-subject studies of herbs.
Some physicians stressed the extreme importance of monitoring and treating
viral load. Many believe it has changed their approach to the treatment of
HIV.
Hardy: I've been making use of viral load assays for 20 months now and
recommend antiretroviral therapy for HIV seropositive persons with HIV
RNA greater than 5,000/ml. Persons with HIV do clinically better with
lowering their viral load, especially with dramatic decreases from greater than
50,000/ml to less than 500/ml. It's amazing and wonderful to see. A ray of
optimism is emerging.
Braun: Any amount of detectable virus is significant. The availability of viral
load along with the susceptibility assay [viral genotyping] heighten the
certainty of effectiveness of treatment.
Giordano: Check it six weeks after altering antivirals and every three months
when a satisfactory viral load is achieved. Treat the viral load!
Dieterich: I use viral load to make all treatment decisions, and [the goal is to]
keep it below 5,000 copies/ml.
Vella: We believe that viral load is the most reliable marker for disease
progression and recommend therapy when HIV RNA exceeds 5,000 (possibly
10,000) copies/ml of plasma. Patients with more than 30,000 copies are at high
risk of progression. To be considered as successful, antiretroviral treatment
should cause at least a 1 log decrease in viral load. However, not only the
magnitude is important, but also the durability of the response.
Katz: Over 100,000 necessitates beginning or changing therapy. Under 10,000
necessitates no change, but between 10,000 and 100,000 I feel the patient out
for how aggressive he/she wishes to be. I'm prescribing more drug with
higher T-cells than I would have in past.
Barriers to access continue to be a problem. This may change with the recent
U.S. FDA approval of the Roche Amplicor test.
Birnbaum: Viral load assays are not available to my patient population [Kings
County Hospital, Brooklyn] so I have not made a single treatment decision
based upon them. I look forward to the opportunity to use these tests.
Brosgart: A major problem is that managed care doesn't want to pay.
Johnson: I think it is expensive to get two baseline viral load tests, and I
sometimes can only justify getting a viral load test four weeks after initiation
of triple therapy.
Ong: We see Medicaid patients almost exclusively in an inner city
environment. HIV RNA viral load assays are not presently Medicaid
reimbursed.
Para: Without FDA approval and with lack of payment, I am not using RNA
to the fullest extent.
Jäger: In patients on treatment, we tend to test every six to eight weeks.
Financially it is difficult to justify testing more often, although being able to
document monthly changes would surely be beneficial.
But some practitioners raised a number of issues about the use of the test.
Stein: A change of 0.5 log [three-fold] is needed to be significant given the
test's and biologic variability. This assumes that the specimen was actually
handled correctly, that the plasma or serum is used consistently and that the
same assay is being compared. In follow-up, it is not as clear. It is most useful
when one is unclear whether therapy is working or not. [But viral load
monitoring] probably doesn't add a lot to the follow-up of asymptomatic and
CD4 stable patients.
Para: I don't feel comfortable about non-research handling and reliability of
the result. Research specimens are carefully processed and quality controlled.
Others are sent out. RNA is useful for prognosis and assessing response to
therapy but I am unsure what absolute values to use. You need a three- to
five-fold change in a single patient to believe it's a real change.
Cotton: I'm using viral load assays but so far my practice is far more 'art' than
science. I'm using the test to decide to switch or add therapies but, once again,
only in a qualitative way.
Sonnabend: I have no evidence that this [viral load] means anything in
patients above 100 CD4 cells. I don't know how to use this test for treatment
decisions but do so anyway in order to learn something. It is obviously
important as a prognostic indicator. I'm worried that now that viral load tests
are available, that the results will influence treatment decisions. There is no
evidence that's convincing that early intervention makes much difference.
So why should this [test] change that?
4. When do you recommend the use of protease inhibitors? What sort of
experience have you had with these drugs? (Please relate your overall
impression of their effectiveness and also patient tolerance and compliance
with dosing schedule, mentioning distinct characteristics of each particular
drug.)
The majority (66 percent) of physicians cited a combination of critical
CD4/viral load levels or changes as the reason to initiate protease inhibitor
treatment. Symptoms or patient request was cited by 8 percent, while only 8
percent always use protease inhibitors as first-line therapy. One participant
stated that he never uses protease inhibitors and another questioned the
clinical relevance of the increased CD4 count.
Approximately 50 percent of survey participants commented on
specific protease inhibitors. While indinavir and ritonavir were uniformly
considered effective, saquinavir was considered too weak or too poorly
bioavailable to be effective in its current form (85 percent). Indinavir and
saquinavir were almost universally considered well tolerated while 89
percent of comments on ritonavir noted its poor tolerability (mostly
gastrointestinal) or difficult drug interaction issues. Some expressed hope that
a slower dose escalation strategy over two weeks would reduce these side
effects but others noted that these GI adverse effects are worse than what was
seen in the clinical trials despite the slow dose escalation. Four physicians
noted the difficulty with indinavir access through Stadtlanders or problems
with the Merck Patient Assistance Program.
Overall, one might characterize the response to protease inhibitors as
tempered optimism. The increased CD4 counts and decline in viral loads
were viewed as encouraging but duration of response was questioned. Drug
interactions (particularly, ritonavir), side effects (particularly, gastrointestinal
problems with ritonavir) and compliance requirements (particularly,
coordinating meals with thrice daily indinavir) were frequently noted as
problems.
An example of aggressive protease inhibitor use
Giordano: [I use] protease inhibitors almost always and have extensive
experience. Tolerance: ritonavir is excellent after four weeks if prescribed
correctly (dose escalate over two weeks); indinavir and saquinavir are
excellent. Efficacy: saquinavir is not effective; ritonavir and indinavir are
effective. Advanced disease is reversible if protease inhibitors are used.
Most add protease inhibitors when they believe nucleosides alone are not
enough.
Cooper: [I use protease inhibitors in those] failing double nucleosides and
have extensive experience. These drugs are very effective and generally well
tolerated. Compliance is good if careful explanation is given to the patient.
Saquinavir is less potent and well tolerated; indinavir is potent and well
tolerated; ritonavir is potent and slightly less tolerated.
Jäger: We recommend their use as a monotherapy when other regimens are
not tolerable and/or effective or we combine them with other antiretrovirals
when those begin losing their effect as seen in rising bDNA levels and/or
falling CD4 counts.
Cotton: I am generally reserving protease inhibitors for patients with less
than 300 CD4 cells who have viral loads greater than 10,000 despite nucleoside
therapy (usually AZT/3TC).
Montaner: Given the issues of cost, toxicity and drug interactions, I reserve
them as second-line therapy.
Dieterich: I have vast experience with protease inhibitors and use them when
the patient's T-cells fall below 500 with a viral load greater than 20,000.
Saquinavir is not toxic but not effective. Norvir is effective but toxic. Crixivan
is the most effective and least toxic.
Some concerns
Bihari: I have chosen to recommend the avoidance of protease inhibitors
until the Roche/Abbott study of the saquinavir/ritonavir combination has
shown what doses of each are safe in combination.
Matula: [Use when] patients fail other combinations. There are good increases
in CD4 counts but I'm not sure how effective. One female patient went from
CD4 of 21 to 380 and still broke through her PCP prophylaxis.
Vella: Protease inhibitors appear to be highly effective. However, their use
has some drawbacks, especially when they are given to advanced patients,
who are likely to assume many other medications. [Drawbacks include] the
high number of capsules that must be swallowed and the side effects
(especially the gastrointestinal disturbances with ritonavir).
Mayer: I have to review the patient's medication list and discuss with him or
her their eating patterns, given the need to administer indinavir on an empty
stomach or with a very light meal. Because of the issue of drug compliance in
relation to meals, several patients have been started on ritonavir. I have had
complaints about "metal mouth" and gastrointestinal discomfort with both
ritonavir and indinavir so I really cannot say one drug is better tolerated than
the other.
Sonnabend: I only prescribe protease inhibitors for people with less than 100
CD4 cells who are symptomatic, as I have good evidence for benefit in this
population. Why waste them (with resistance developing) in healthy people
who may need them later? They are more toxic, particularly GI toxicity, than
generally presented, particularly ritonavir which also has the worst problem
with interactions with other drugs.
And some comments on specific agents
Saquinavir:
Most felt the drug to be safe, but not very effective. Respondents
were hopeful about the new formulation
Braun: Thirty percent to 60 percent of patients respond to saquinavir.
Collier: I rarely use saquinavir unless other protease inhibitors are
contraindicated.
Montaner: Saquinavir is the less desirable of them due to poor bioavailability.
Katzenstein: Awaiting for formulation with increased bioavailability.
Volberding: Saquinavir is easy to use, but there are few indications for the
current formulation due to poor levels. I'm watching the new formulation
closely. If higher levels, will we see more toxicity, drug interactions?
Indinavir:
Almost everyone is pleased with its efficacy and patient tolerance,
but there's some frustration with the Stadtlanders' distribution program.
Carpenter: I have had 20 months of experience with indinavir. Patient
compliance has been excellent!
Hardy: Efficacy is excellent, RNA declines 99 percent to 100 percent and it is
generally well tolerated. There is a rare increase in total bilirubin. I have seen
two patients with kidney stones, but patient acceptance is good.
Katz: Indinavir clearly has the best profile of ease of dosing and patient
acceptance presently. It's the cheapest by far of the three (30 percent price
advantage versus ritonavir).
Volberding: Indinavir is the current 'winner' in terms of toxicity/benefit
balances. Eight-hour dosing a real problem with compliance (especially the
need to avoid meals). Stadtlanders is a very cumbersome bureaucracy.
Johnson: My impression is that indinavir is well tolerated, although it has
been difficult to obtain this drug through the Merck Patient Assistance
Program.
Ong: Because of the difficulty in indinavir access, I have used ritonavir.
Rhame: It's a big hassle getting indinavir.
Yancey: Coordination with meals is difficult. Less indinavir is prescribed
secondary to the monopoly by Stadtlanders.
Ritonavir:
Almost everyone is impressed by the efficacy but most are
disturbed by the toxicity and drug interactions.
Saag: Ritonavir is OK if patients can tolerate it. There are more patients with
intolerance than we observed in the studies. I don't know why.
Collier: Tolerance to ritonavir has been a problem even with the initial
gradual dose escalation.
Ong: Ritonavir: nausea, vomiting and diarrhea can be problems. Hopefully,
the new starting dose regimen will be better tolerated.
Braun: Only 30 percent to 40 percent of patients tolerate ritonavir even with
an empowered patient tapering up over two weeks.
Katzenstein: Ritonavir is a great concept but a difficult drug over long term in
advanced patients because of interactions with other meds.
Starrett: Wasted patients need to eat so the indinavir schedule may not be
optimal. Patients who don't have regular schedules of medications would be
best with twice daily dosing of ritonavir.
| When to Start Protease Inhibitors | Respondents |
| # | % |
| Critical CD4 Level/Change | 12 | 33% |
| Critical Viral Load Level/Change | 12 | 33% |
| Always as First-Line Therapy | 3 | 8% |
| When Symptoms Appear | 3 | 8% |
| Patient Request | 3 | 8% |
| Never | 1 | 3% |
5. Do you prescribe or do many of your patients take on their own additional,
unapproved anti-HIV therapies (for example, acyclovir, hydroxyurea, N-
acetylcysteine, or vitamin supplementation)? How are they used and what is
your evaluation of their effectiveness?
With the exception of two physicians, participants do not, themselves,
actively prescribe alternative therapies. However, 72 percent have patients
who use alternative therapies. The consensus was that if alternatives did not
seem to have negative effects, physicians did not have a problem with
patients using them. Of those who mentioned alternative therapies, 42
percent mentioned acyclovir while 38 percent mentioned vitamins. But of
those who mentioned acyclovir only nine participants actively recommended
its use.
Abrams: Most of my patients take acyclovir with or without other antiviral
drugs. I believe HSV probably upregulates HIV and have thought it wise to
suppress it.
Katz: I still recommend it, especially in persons who have a history of herpes
and patients who can't tolerate many therapies and have low T-cells.
Mayer: If patients have problems with herpes simplex recurrences and the
costs of acyclovir isn't a disincentive that leads to underutilization of other
medications, I am comfortable based on the data from several studies that
suggest a survival benefit, with maintaining patients with CD4 counts less
than 100 on acyclovir 800 mg, five times at day. On the other hand, because
several other studies did not corroborate this survival benefit, and given the
drug's cost and concerns about compliance with polypharmacy, there are
many patients for whom I do not recommend acyclovir when their CD4
counts drop below 100 cells/mm3.
Sonnabend: I have always believed that acyclovir was potentially beneficial
since I have believed that herpes viruses are important factors.
Braun: We are switching all patients from higher doses to acyclovir 400 mg
twice daily.
Several physicians offered opinions on some alternative therapies.
Birnbaum: I have found that Chinese herbs when properly prescribed by a
Chinese herbalist have been very effective treatments, mostly for fatigue and
wasting. One patient used kombucha mushrooms to treat PML and had a
remission of signs and symptoms.
Giordano: NAC and acyclovir are not effective; hydroxyurea is effective but
use it only on study; vitamin supplementation is of unknown efficacy.
Cooper: Hydroxyurea: I'm not impressed with the results. NAC doesn't work.
Katz: Hydroxyurea: I wish more patients would glom onto this. I think it's
clearly worth a shot, but I have no one on it. I'm eager to see the studies. I
recommend vitamin/mineral supplementation for all patients at any T-cell
level (see Baum et al, Micronutrients and HIV Progression, J. AIDS, 1995). I
have nothing more than anecdotal experience that patients on
vitamin/mineral supplementation do better, but they are generally doing 42
other things simultaneously.
Sonnabend: NAC and antioxidants can't hurt.
Braun: S-7 flavor tea was used once and worsened the patient's renal status.
QoXing was used once and was poorly tolerated. Patients have abandoned
NAC. We encourage multivitamins but are neutral on Vitamin B12 and
antioxidants. With DHEA, we see no objective improvement but it's hard to
monitor. Thalidomide is excellent for ulcers and great for diarrhea with some
limited improvement in wasting.
Two physicians stood out as using alternative therapies as the foundation for
their anti-HIV therapy.
Bihari: I prescribe acyclovir 3,200 mg/day to all HIV-positive patients. I also
prescribe naltrexone 3 mg at bedtime to all patients regardless of CD4 level.
Naltrexone stops the CD4 decline in 80 percent of patients and in 90 percent of
those with more than 200 CD4 cells. I also recommend NAC 600 mg three
times daily and several antioxidants to all patients.
Standish: Now that viral load testing is readily available for many patients, I
am trying botanicals, homeopathics and hyperthermia. Thus far, nothing I've
tried has substantially reduced viral load, with the exception of high
dilutional growth factors and cytokines. All of my patients are using
alternative methods. Acupuncture is the most common and perhaps the
most useful. I have yet to see anything that produces dramatic improvements
of immune markers such as CD4. We are using a lot of DHEA too, if a
patient's serum levels are low or low normal. It seems to help overall energy.
We hope to be doing a small trial of DHEA soon. We are working hard at
Bastyr's clinic to keep the intestines healthy using acidophilus, glutamine,
NAC, UltraClear Sustain, beta carotene, Vitamin C, Vitamin E, quercitin.
Also we're using CoQ10 more and more.
Note:We need HIV-positive men and women to participate in the Bastyr
University Study of alternative medicine in HIV/AIDS to find out if any of
these alternative approaches are helping people. Please call 800-475-0135 to
enroll or find out more.
-- Leanna Standish, Bastyr University, Seattle
6. Do payer constraints influence your treatment decisions (for example,
Medicaid, ADAP or formularies)? If so, please explain.
Of total participants, 69 percent cited payer constraints influencing treatment
decisions. Of the seven physicians from outside the U.S., three had no
problem with payment: one from each of Italy, Germany and Australia. One
physician from Canada, one from France and two from the U.K. cited payer
constraints. Within the U.S., 72 percent cited payer constraints. Many cited
that Medicaid is far better than ADAP, where choices are much more limited;
however, Medicaid was often cited as the reason for not being able to use viral
load assays.
Examples of problems
Brosgart: Yes, yes. Many payers refuse off-label drug use. Managed care has
prior authorization and restricted formularies. ADAP has a long lag between
licensure and inclusion on its formulary. Managed care has fixed pharmacy
dollars but lots of new experimental drugs. The HIV specialist is being
squeezed by managed care. We need to effectively advocate to treat patients.
Often we're not considered primary care, as a way of keeping patients out of
health plans. Delivering comprehensive, coordinated high quality care costs
more up front but saves on big ticket items (hospitals, ER).
Volberding: We need to find a way to get HMOs to provide HIV centers of
excellence without fear of adverse selection.
Saag: Absolutely, I live in Alabama. Medicaid is inaccessible for most (need
less than $479 a month income; net worth less than $3,000). Ryan White: no
Title I; limited Title II/III. We spend hours per week applying for assistance.
Abrams: Medicaid usually pays. ADAP has just put 3TC on the formulary. No
protease inhibitors are yet on in California, but most of my patients utilize the
federal insurance program, not ADAP.
Birnbaum: Most of my patients are Medicaid covered. If they have Medicaid,
there's no problem prescribing these meds. If they are covered by ADAP only,
my treatment choices are limited to what ADAP covers. If they are uninsured,
I am limited to my hospital formulary of AZT plus ddI only plus a supply of a
few months worth of 3TC which was donated to my clinic.
Kessler: Yes, viral load is not paid for by public aid or Medicare.
Ong: We cannot use HIV RNA plasma levels.
Para: Yes, we don't get RNA on these [Medicaid, ADAP] patients unless they
are in trials. We cannot get protease inhibitors on ADAP.
Stein: Medicaid has, at present, better coverage than [New York] ADAP or the
VA for antivirals. HMOs can be a problem.
Katlama: We are very concerned about the long-term cost of treatments. I do
not use very expensive drugs which don't have optimal efficacy.
Even more difficult for alternative medicine
Standish: Yes, payer constraints severely and adversely influence what
treatments are possible for many of my patients. It is rare that third party
payers will reimburse for natural and alternative medicines. Some insurance
companies don't cover viral loads, or not as often as I think medically
necessary. In Washington State, alternative medicine is now being covered by
insurers, reluctantly and incompletely. Being part of the insurance game
presents even more constraints. We have a horrible system in the United
States.
Some good news
Katz: We have a very liberal formulary at Kaiser, and every HIV-approved
drug is on it, so this is not a consideration.
Cohen: [Massachusetts] ADAP covers all antivirals except indinavir (which
we get instead from Merck). The only other rare problem is that ADAP
doesn't cover unlimited fluconazole and acyclovir.
Jäger: Fortunately, the social medical system in Germany allows (nearly)
complete coverage of all necessary medication and/or therapy regimens.
Thus, all of the approved antiretroviral substances including protease
inhibitors can be prescribed, also in combination.
And in a word:
Rhame: Only when they won't pay.
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