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GMHC Treatment Issues
Flying by the Seat
Last March, the United States Food and Drug Administration
authorized the sale of two additional protease inhibitors, indinavir and
ritonavir. This makes for eight anti-HIV drugs currently on the U.S. market,
compared to only four as recently as last fall. Continuing this historic
expansion, nevirapine will shortly join the ranks (see June/July Treatment
Issues article, Nevirapine Surprise). On the heels of nevirapine are
two more protease inhibitors and five reverse transcriptase inhibitors in
advanced human testing. AIDS-related opportunistic conditions also have
seen significant developments. In particular, new agents have been proffered
over the past year for preventing CMV and MAC as well as for combating
AIDS-related weight loss.
Tests for viral load -- the Roche PCR version is newly approved in the U.S. (see June/July Treatment Issues article, Viral Load Comes of Age) -- may help make some sense of this therapeutic kaleidoscope. Unfortunately, research on the relation of HIV levels to disease has been inadequate. Viral load tests' potential for settling questions of overall therapeutic strategy and for guiding individuals' treatment decisions requires further delineation. Opinion differs in the meantime about the optimal starting point for pharmacological intervention, when to change therapy and which regimens have the best therapeutic indices and duration of effect.
When patients and doctors lack sufficient carefully collected study data, they can only rely on their own and others' clinical experience to guide them. In an effort to further disseminate that experience, we at Treatment Issues surveyed a group of prominent HIV specialists in North America, Europe and Australia. We recapitulate their answers in the pages that follow.
Our respondents have large AIDS practices conducted in diverse care settings -- public clinics, private practice, health maintenance organizations and university hospitals. Many work within the constraints of managed care, payer formularies, Medicaid and ADAP programs. The questions they answered were open-ended and intended to stimulate discussion of diverse treatment strategies.
Our goal was to uncover the range of approaches followed today by experts in the field rather than to systematically reflect the opinions of all physicians who treat HIV and AIDS. We therefore have included answers illustrating both dominant trends and contrarian views. Statements attributed to individuals may be paraphrased and are not necessarily the complete response to any given question. The tables do provide a quick overview of all the responses, but because of the survey's eclectic nature, we urge that readers carefully look at the individual responses rather than just peruse the summaries.
Associating Viral Load and Physical Health
The most striking observation to come from these respondents is the remark by several that they are seeing clinical improvement in patients (i.e., patients noticeably feel better) at the same time as these patients' HIV levels are dramatically reduced by the new treatments. Such observations complement a published report by a group of Australians -- among them was David Cooper, one of our survey participants -- on the partial restoration of 21 volunteers' immune function during an early ritonavir monotherapy trial (see Journal of Infectious Disease, February 1996; 173(2):321-9). Reducing the inflammatory response and cell killing that HIV infection provokes may have a number of immediate benefits in terms of a person's overall functioning.
The great hope that currently available combination regimens are potent enough to lead to at least limited recovery remains entirely speculative. It is notable that the latest word from the Australians describe the qualitative immune improvements they observed as "small and transient and occurr[ing] in a minority of subjects" (see June/July Treatment Issues article Throw Down Your Crutches and Walk).
Our respondents had divergent opinions as to how far viral load has to drop before their patients reach a safe zone. One result is a wide variety of practices concerning initial and subsequent anti-HIV therapy. Several of the less mainstream doctors remain so unconvinced by the present data that they continue to concentrate on aggressively preventing OIs rather than HIV. (This in itself could be a potent antiviral strategy because keeping the immune system relatively quiet reduces the number of activated cells vulnerable to HIV. Lending credibility to this approach is, among others, a recent article on the HIV-simulating effect of tetanus toxoid vaccination. See the New England Journal of Medicine, May 9, 1996, pages 1222-30.)
Responsibility for the confusion over viral load lies at least in part with the developers of viral load tests. The companies have not taken the lead in establishing the worth (as opposed to the accuracy) of their products. University and government researchers instead have been active in establishing guidelines for interpreting viral load tests results. This has turned out to be a slow process, with most of the available data arising from retrospective reviews of trials testing specific drugs. Even though Roche's PCR-based Amplicor test kit has been licensed in the U.S., trials that directly observe the usefulness of viral loads in treatment decisions are only now getting under way. The difficulties of creating ethical designs for such trials and recruiting volunteers for them will surely mount as viral load testing becomes more widely available. (See June/July Treatment Issues article, Viral Load Comes of Age, for an examination of the currently available viral tests and what is known of their uses.)
Holding Off on the Protease Inhibitors
With little to guide them, our respondents tend to be conservative about bringing out the heavy guns against HIV. They generally choose two nucleoside analogs as first-line therapy in patients with relatively low viral load and high CD4 counts. Protease inhibitors are added only when patients start to worsen or have exceptionally high viral loads to begin with. Still, the present strategies are a marked change from the recent past, when AZT monotherapy would no doubt have been most frequently mentioned as the preferred first line therapy for HIV, to be applied mainly when CD4 counts were clearly deficient and physical symptoms evident.
Several recent combination drug trials have affected this evolution in treatment strategies. Especially important were ACTG 175 (which tested AZT vs. ddI vs. AZT/ddI and AZT/ddC) and the AZT/3TC trials. AZT/3TC was by far the most commonly mentioned initial regimen. Not only does it have documented substantial and sustained antiviral activity in treatment-naive people, but also its side effect record seems less than that of other possible nucleoside analog pairings.
By comparison, only one doctor mentioned using the non-nucleoside reverse transcriptase inhibitor nevirapine, for which there has been little available data. This drug, currently available in the U.S. through an expanded access program, could be administered with protease inhibitors as an alternative to nucleoside analog regimens or combined with both types of agents to create extra powerful four-drug combinations. (But beware of nevirapine's potential to accelerate liver metabolism of protease inhibitors -- see June/July Treatment Issues article, Nevirapine Surprise.)
The reluctance to employ the protease inhibitors stems from fears of increased toxicity, drug interactions and the evolution of drug-resistant virus. Patient fatigue could be a big factor, too, in creating difficulties for managing and adjusting multiple drug combinations that must be taken without let-up over long periods of time. It was generally considered best to leave well enough alone when viral loads could be brought and kept down to low levels without the protease inhibitors.
Trials that further explore protease inhibitor use obviously are needed to optimize their use. Such trials would help decide when protease inhibitor therapy can be omitted, when it should be initiated and when it is perhaps no longer needed. And what about using two protease inhibitors concurrently? Another major effort should go to simplifying drug combinations as much as possible. Some two-drug combinations may be as good as combinations of three weaker or more toxic drugs, for example.
The thorniest questions concern the evolution of drug-resistant HIV: how do you detect it and what drugs can you switch to when it occurs? The amount of cross-resistance to the various protease inhibitors that HIV mutations can confer requires further exploration, as does the clinical significance of that resistance. Finally, some therapeutic strategies may delay the emergence of drug resistance better than others.
The question of how clinical research should proceed -- who should carry out what studies at this point -- is now the subject of a national working group sponsored by the Keystone Center. This broadly based committee, composed of representatives of the scientific and activist communities, the pharmaceutical industry, health insurers, and the government, will report its conclusions this August to Vice President Al Gore.
Eradicating HIV
Until the threat of resistance and cross-resistance is more fully mapped out, fears will persist of wasting drugs by using them unnecessarily: during the early asymptomatic period of HIV infection, the relatively intact immune system usually keeps viral loads low by itself. From now on all treatment studies will be faced with the fundamental question we need to know -- how much viral suppression is sufficient to keep HIV permanently in check?
There are glimmers of hope that the best combinations of presently available agents are indeed strong enough to suppress HIV over the long- term. Ironically, the best prospects for accomplishing this feat occur during the low HIV levels typical of early disease. The June conference "Can HIV Be Eradicated from an Infected Individual?" (summarized in June/July Treatment Issues article, Throw Down Your Crutches and Walk) was conducted by scientists who foresee using a protease inhibitor plus several other drugs to keep viral loads below currently detectable limits for indefinite lengths of time. The emergence of drug-resistant HIV might be blocked by the virus' inability to develop the large number of needed genetic alterations in the face of such forceful constraints on its replication. After some years, the HIV infection might even peter out as chronically infected cells die off without replacement by newly infected ones.
Our present ability to conquer HIV may turn out to be greatly limited still, but this goal cannot be altogether out of reach. After all, a few people already control their HIV infection without any treatment (and a tiny number seem to eliminate the virus entirely). AZT monotherapy increased the number of success stories somewhat. With the aid of effective therapies, the number of such durable resistors can only increase further. But this is all logical deduction. Reducing viral load below viral load assays' level of detection does not mean that HIV is absent from the body, just that the amount of virus has been reduced beyond a purely artificial threshold set by technology. There is no evidence that people whose viral load is undetectable cannot transmit HIV, for example. The data is also insufficient to say how long it takes for HIV to re-emerge despite continued treatment with potent drug combinations or how often this occurs. Certainly, no one on record has stopped treatment without witnessing a rebound in HIV.
Economic Constraints
These high hopes come at a time when health care delivery faces unprecedented financial pressures, and the new economic constraints can limit physicians' ability to try out the most advanced therapies without waiting for their acceptance by the medical authorities. In our survey, this obstacle arose most commonly in regard to use of viral load testing by U.S. doctors, whose patients could not obtain reimbursement from private and public health plans for what has been an unapproved and costly technique. The failure of state AIDS Drug Assistance Programs (ADAPs) in the U.S. to add newly approved drugs to their formularies in a timely fashion was another frequently mentioned impediment to accessing necessary therapy. More generally, the rise of managed care has restricted treatment options even for those covered by inclusive health plans (see June/July Treatment Issues article, Health Care Quality verus Economics in HIV).
Comprehensive care centers for HIV/AIDS were mentioned by several of our respondents as a way to bring together the expertise necessary to keep up with the rapidly evolving, increasingly complex standards of care. Since new standards can be vaguely determined and poorly backed up by experimental data, therapy is best practiced in a collegial setting. As always, open communication needs to exist within teams of specialists advising patients on the different conditions stemming from HIV infection. More urgent than ever is consultation between people in the same field.
But commitment to excellence weakens as economic pressures intensify. The following survey is one small attempt to bridge the gap between health care providers in this uncertain era.
Treating HIV and AIDS:
We sent surveys to 79 leading AIDS physicians in the U.S., Canada and
Europe; 36 (46 percent) responded. We are very grateful to all those who
participated in this rather cumbersome open-ended survey
A. Antiretroviral Therapy
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
As brand names and abbreviations for pharmaceuticals may vary worldwide,
the following table lists those used in survey responses.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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?
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.
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.
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.
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.
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.
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
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.
B. Opportunistic Infections
7. Do you recommend prophylaxis for CMV, MAC or fungal infections? If so, with what agent and in what patient population?
For opportunistic infection prophylaxis, the trends were very clear. Only 11 percent prescribe primary prophylaxis for fungal infections. Concerns about azole resistance were cited. Approximately 17 percent prescribe prophylaxis for CMV, most commonly at CD4 counts below 25. The negative CPCRA oral ganciclovir CMV prophylaxis study (see Treatment Issues, October 1995, page 10), the large number of pills, toxicity and cost were the most common reasons cited for not prescribing prophylactic oral ganciclovir.
Primary prophylaxis for MAC, conversely, was quite popular (83 percent). Of the 22 participants who cited their choice of therapy, 82 percent prescribe macrolides (clarithromycin or azithromycin). Recent data on macrolide prophylaxis was cited by many. A few physicians described a recent switch from rifabutin to macrolides and some cited difficulty in using rifabutin with the protease inhibitors as the reason for a macrolide preference. Of the 21 physicians who described when they start MAC prophylaxis, eleven initiated therapy at a CD4 count below 50, seven started below 100, and two started below 25.
Those who are most aggressive with prophylaxis are also the most conservative with antiretroviral therapy. One physician cited occupational risks for fungal infections.
Although MAC prophylaxis was common, there were some concerns.
Katz: Until recently, I have used rifabutin (since its 1992 approval). Then with the protease interactions, I started using clarithromycin. Now, it's all a big wash. More and more at Kaiser our infectious disease specialists are suggesting not using any and either getting blood cultures every three months or treating at the first MAC symptoms. It has become a reasonably treatable condition nowadays and patients generally prefer to have one less drug to take; so does the health care economy. The effect this [prophylaxis] will have on ultimate development of MAC and possibly cross-resistant clarithromycin-azithromycin strains remains to be seen. If we lose the ability to fight this infection with either of these two drugs, we're back in the mid- 80s--with four to five drugs, IVs and still not great results.
Johnson: I have not been routinely recommending prophylaxis for CMV, MAC or fungal infections. I am concerned that many of these agents may interrupt or alter levels of antiviral therapies. I have mainly focused on maximal antiretroviral suppression, rather than starting prophylaxis for these opportunistic infections. However, my thinking has changed based on the data from Dr. Diane Havlir and the California Collaborative Treatment Group. I will likely start azithromycin weekly to prevent MAC. I am also very aggressive about early initiation of clarithromycin and ethambutol for empiric treatment of MAC.
Brosgart: Yes, in those with CD4 less than 75. First choice is a macrolide (azithromycin is number 1; clarithromycin is number 2); second choice is rifabutin.
Saag: For CD4 less than 25, take two drugs: clarithromycin and ethambutol.
Bihari: If the CD4 cells are below 100, Biaxin 500 mg/day with ethambutol, 800
mg/day to prevent MAC.
CMV prophylaxis
Abrams: No, I agree with the CPCRA study.
Brosgart: All patients with CD4 less than 100 are seen by an ophthalmologist every three months. No oral ganciclovir prophylaxis: it's of limited benefit, too toxic and expensive.*
Mayer: Based on the CPCRA study of primary CMV prophylaxis, we do not routinely start empiric therapy with ganciclovir based on the CD4 count criterion. We hope that in the near future that quantitative CMV measurements in the plasma will enable us to predict which patients are most likely to progress with CMV retinitis.
Bihari: In those with CD4 cells below 150, start acyclovir, 4,800 mg/day to prevent CMV infections.
Fungal prophylaxis
Brosgart: Fungal prophylaxis only if severe, chronic, recurrent disease.
Bihari: In patients with CD4 cells below 200, Diflucan 100 mg/day to prevent cryptococcal meningitis.
Rhame: Fluconazole for CD4 less than 100--more anti-candida effort required [for female patients]. Prevention of histoplasmosis as a rationale for azole prophylaxis is not adequately appreciated.
Hardy: Only for those with CD4 less than 100 and chronic exposure to fungi, coccidiodomycosis (gardeners, construction).
8. Do you recommend TB prophylaxis for patients who are HIV-positive and anergic?
Only three participants answered this question affirmatively. Some of those who answered, no, explained that they reserved prophylaxis for those with high risk histories or a positive PPD (skin test for TB exposure).
Mayer: We definitely recommend TB prophylaxis of INH with Vitamin B-6 for one year for patients who are HIV-positive and anergic in our community, given our experience with several recent outbreaks.
Ong: Yes, for patients who receive directly observed preventive therapy in our drug treatment centers.
9. What treatments do you utilize to reverse weight loss and wasting (nutritional, human growth hormone, anabolic steroids, thalidomide or other anti-TNF compounds, etc.)?
The most common interventions for weight loss are anabolic steroids (72 percent) and nutritional counseling/supplementation (67 percent). Often mentioned were Megace (42 percent), Marinol (33 percent) and human growth hormone (19 percent).
Although these agents were used by many, views on their utility were anything but uniform.
Brosgart: Nutritional counseling; rule out hypogonodal and hypoadrenal. Deal with nausea and oral ulcers. Try to give most meds with meals. I love thalidomide. I like to put my patients in trials so we can learn more about treatment or preventing weight loss and wasting. Sometimes patients are just losing weight because they don't have food.
Cohen: New antivirals are clearly effective as an antiwasting treatment. I have seen big weight gains with ritonavir. A few patients have done thalidomide but had more side effects than benefits.
Mayer: Our first line of defense is enteral supplementation tailored to a regimen that patients can maximally tolerate. We also recommend that the patient engage in weight bearing exercise in order to maximally benefit with a positive anabolic reaction.
Bihari: In general, identifying a slowly developing OI that is causing weight loss and treating it is the most common approach. AZT plus 3TC reversed weight loss and wasting in patients more effectively than growth hormone, thalidomide, Trental or anabolic steroids.
Anabolic steroids, particularly testosterone, are the most common pharmaceutical interventions for wasting but physicians did not describe their effects in any great detail. Some mentioned oxandrolone, one mentioned decadurobolin.
Volberding: Anabolics are the easiest way to get some benefit.
Cohen: Intramuscular testosterone with or without decadurobolin in many (male) patients. I'm considering oxandrolone.
Human growth hormone's price was cited as a problem.
Volberding: HGH works, but it's way too expensive.
Brosgart: I rarely use rHGH; it's expensive and of limited benefit. It's a last resort.
Cohen: I don't use HGH. It's not clearly worth the price.
Mayer: In patients who have lost more than 5 percent of lean body weight, we
begin discussions about the possibility of utilizing human growth hormone,
which to date has impressed us as the most effective agent in reversing
Megace and Marinol
Volberding: Megace: poor side effects and all fat. Marinol: not too effective but some like it (many more prefer marijuana which is available in SF through a local buyers' club).
Brosgart: We use Megace and Marinol.
Cohen: I will use Marinol/Megace to improve appetite (as well as suggest
marijuana if helpful).
An alternative approach
Standish: We are beginning to try high dilutional insulin growth factor and Sea Cure protein supplements. I think early total parenteral nutrition [TPN] helps a lot. It's hard to get other doctors to see the wisdom of early TPN.
Preventing PCP Breakthrough
Assuming that PCP prophylaxis was universal, we did not specifically ask about it. However, Dr. Victoria Johnson, University of Alabama, offered an interesting perspective on preventing PCP breakthrough:
C. General
10. If you see significant numbers of women or children with HIV, can you comment on age or gender-related differences in treatment of the virus or opportunistic infections?
Unfortunately we received little or no responses about treating children. The vast majority of those with experience in treating women believed there was little significant difference. The need for diligent screening for vaginal infection (particularly candidiasis) and cervical cancer were emphasized. An increased incidence of oral/esophageal candidiasis and a decreased incidence of KS were noted. Two physicians believe that women present with more advanced disease.
Bihari: I see a lot of women, who represent 30 percent to 35 percent of my practice. Apart from the obvious differences (i.e., need for frequent PAP smears, alertness to and aggressive treatment for vaginal infections and pregnancy issues), I find no differences in the treatment of the virus or OIs.
Brosgart: Women are 25 percent of my population. There are few differences when adjusted for CD4. We often must weight-adjust meds.
Carpenter: I have not noticed gender-related differences in treatment of the virus. OI treatment is also similar, the only difference being the gender specificity of vulvovaginal candidiasis.
Johnson: Unfortunately, due to the demographics of HIV-1 infection in Alabama, I see a significant number of women (approximately 50 percent of my clinic). I think that these women tend to get diagnosed at a later disease stage, but that their complications are not terribly different from those of adult men. The women in my clinic do seem to have more difficulty with vaginal candidiasis during antibiotic therapy for other infections. They also tend to have unrecognized concomitant STDs such as human papillomavirus.
Mayer: With regard to the major opportunistic infections that men can develop, the women seem to develop them at a similar rate and do not have substantively different clinical patterns with these opportunistic infections, except for a slightly increased propensity toward mucosal candidial infection, resulting in a slightly higher annual rate of candidial esophagitis. The major clinical differences in HIV-infected women compared to men is that there is substantial gynecological morbidity that the women experience in the course of their HIV infection. With meticulous gynecological care, invasive cervical carcinoma is rare; however, atypical PAP smears are common and require careful follow-up with quarterly PAP smears and colposcopy when abnormalities persist. Prompt, but specific surgical procedures can help avert wider spread of localized cervical neoplasia.
Several of my colleagues have seen women with recurrent pelvic inflammatory disease. Traditional sexually transmitted diseases have been uncommon among the HIV-infected women that we followed, but recurrent candidial vaginitis, bacterial vaginosis and trichomoniasis may be common causes of clinical discomfort and require prompt diagnosis and treatment. Several of the women that we follow have recurrent sinusitis and pneumonia but the prevalence and incidence rates for these conditions have not been radically different from that of demographically similar men.
Saag: We have no data about menopause.
Cotton: I do think there are emerging issues in antiviral treatment of women in terms of how to treat women with plans for conception, etc.
Standish: Women are simply much sicker when I begin working with them. They also seem to tolerate less well anti-retrovirals, ganciclovir and MAI regimens.
Volberding: Women present a different array of social and financial issues.
A note about adolescents
Birnbaum: In general, it has been historically difficult to get adolescents to take antiretroviral medications. More recently, since the advent of widespread use of combination therapy many actually have started requesting to start on combination therapy and to use protease inhibitors. Many are reluctant to use OI prophylaxis but usually do so, at least for PCP, after they have been given the information to make an educated decision. As a general rule I try to prescribe medications that have once or twice a day dosing, as this tends to improve compliance.
11. Do you have any further observations from your practice that you would like to report (particularly findings that are not commonly discussed)?
Carpenter: A comprehensive care program in a single site is of critical importance, I think, with maintaining adequate long-term compliance with any regimen.
Johnson: Indeed, the majority of my patients have more problems related to wasting syndrome and ultimate demise than from opportunistic infections. I also think that IV amikacin is the drug of choice for MAC relapsed episodes and give a four-to-six week course on top of oral therapy for relapses. By giving this drug intravenously by home health nursing five days of the week for four to six weeks, I have been impressed that several patients have resumed excellent quality of life.
Finally, it is my impression that patients with CD4 less than 10 cells/mm3 can tolerate double and triple antiretroviral therapy well, despite prior observations about enhanced toxicity. I think that it is a myth that patients with advanced HIV-1 disease cannot benefit from antiviral therapy, which can reduce the frequency and severity of their opportunistic infections. Many of these patients have survived for years with excellent quality of life despite their advanced disease stage.
Bihari: My long-term patients very rarely develop OIs and 85 percent to 90 percent have long term stability of CD4s. The three major factors are: 1) low dose naltrexone; 2) aggressive OI prophylaxis as described in question seven; 3) the effectiveness of AZT plus 3TC in AZT-naive patients and the fact that 90 percent of my patients are AZT-naive because of my past reluctance to use AZT monotherapy.
Saag: Patients are living longer with new problems: fluconazole-resistant cryptococcus after two to three years of secondary prophylaxis and resistant CMV. There may be less HIV dementia. There is a significant change in demographics: more poor, more African Americans, more women, more heterosexuals (despite the Wall Street Journal!).
Para: I stress the importance of regular exercise in reducing symptoms.
Standish: We have done a little experimental work with high dilutional growth factors and cytokines. This seems like a promising area. GM-CSF 200C seems to elevate platelets in thrombocytopenic patients, for example. We need NIAID funding for this to go forward.
Weekly Fluconazole
Few of our survey respondents administered prophylaxis for fungal
infections of any sort, although several noted that vaginal yeast infections
("candidiasis" caused by the yeast species Candida albicans) were a special
problem for women with HIV. These specialists also noted that such women
seemed to have more oral and esophageal candidiasis than HIV-positive
A recently concluded trial conducted in women by the government-sponsored Community Programs for Clinical Research on AIDS (CPCRA) has found that 200 mg of fluconazole taken weekly can cut the risk of developing oral/throat or vaginal yeast infections by half. The effect on yeast in the esophagus could not be determined because of its low rate of occurrence during the study.
This placebo-controlled trial, known as CPCRA 010, enrolled 323 women with CD4 counts less than 350 (average CD4 count: 199). The median time on study medication was sixteen months for those receiving fluconazole and ten months for those on placebo.
Use of fluconazole to prevent fungal or yeast infections has been widely shunned because of the risk of developing drug-resistant microbes. Such resistance would render fluconazole useless for the valuable treatment role it now performs. In CPCRA 010, however, the incidence of fluconazole- resistant candidiasis was low and equal in both the fluconazole and placebo arms. But although weekly fluconazole reduced the frequency with which Candida albicans was isolated in vaginal secretions, there was increased isolation of closely related, though less pathogenic species of yeast.
The researchers concluded that weekly fluconazole could have a useful role in preventing recurrent mucosal candida infection in women. In the study, women with a recent history of repeated vaginal candidiasis had a significantly higher risk of new episodes. The women who had previously had candida in the mouth, pharynx or esophagus were at higher risk for another infection in those areas, as were women who had AIDS or used one of the standard preventive drugs for Pneumocystis carinii pneumonia. - Dave Gilden
Donald Abrams, Community Consortium, San Francisco, CA
Bernard Bihari, New York, NY
Jeff Birnbaum, Kings County Hospital, Brooklyn, NY
James Braun, New York, NY
Carol Brosgart, East Bay AIDS Center, Berkeley, CA
Charles Carpenter, Brown University/Miriam Hospital, Providence, RI
Cal Cohen, CRI/New England, Brookline, MA
Ann Collier, University of Washington, Seattle, Washington
David Cooper, National Centre in HIV, Sydney, Australia
Deborah Cotton, Massachusetts General Hospital, Boston, MA
Douglas Dieterich, New York University Medical Center, New York, NY
Brian Gazzard, Chelsea & Westminster Hospital, London, England
Michael Giordano, New York Hospital-Cornell Medical Center, NY, NY
W. David Hardy, UCLA School of Medicine, Los Angeles, CA
Martin Hirsch, Massachusetts General Hospital, Boston, MA
Hans Jäger, Munich, Germany
Victoria Johnson, University of Alabama, Birmingham, AL
Christine Katlama, Hôpital Pitié Salpétri?re, Paris, France
Mark Katz, Kaiser Permanente, Los Angeles, CA
David Katzenstein, Stanford University Medical Center, Stanford, CA
Harold Kessler, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL
George Matula, Kaiser Permanente, San Francisco, CA
Kenneth Mayer, Memorial Hospital of Rhode Island, Pawtucket, RI
Julio Montaner, St. Pauls Hospital, Vancouver, Canada
Kenneth Ong, Catholic Medical Center, Jamaica, NY
Michael Para, Ohio State ACTU, Columbus, OH
Frank Rhame, University of Minnesota, Minneapolis, MN
Michael Saag, University of Alabama, Birmingham, AL
Joseph Sonnabend, New York, NY
Leanna Standish, Bastyr University, Seattle, WA
Barbara Starrett, New York, NY
Daniel Stein, Albany Medical College, Albany, NY
Stephano Vella, Instituto Superiore Di Sanita
Paul Volberding, University of California, San Francisco, CA
Todd Yancey, New York, NY
Mike Youle, St. Stephen's Clinic (Kobler Center), London, England
Starting Treatment:
Charles Carpenter, Brown University/Miriam Hospital, Providence, RI
Naive Subjects:
Health Care Quality
by Gabriel Torres, M.D.
The cost of HIV care can be astronomical, particularly during the late
stages of AIDS. At the same time, the high cost of health insurance has forced
many individuals and employee groups into "managed care" programs such
as HMOs (health maintenance organizations) devoted to providing the
cheapest health care possible. Government financial support for indigent
programs like Medicaid is decreasing, too. Third-party payers are attempting
to increase cost-efficiency by such measures as emphasizing preventive care,
reducing duplication of services and avoiding expensive pharmaceuticals and
medical procedures. Capitation initiatives focus on cost containment by
limiting the annual amount of reimbursement for a given individual's
health care. Competition for the large patient pools often driven into the
managed care plans is a further factor in minimizing cost.
Occasionally, the highest quality of care may be the most cost-efficient. For example, prophylaxis with Bactrim (trimethoprim/sulfamethoxazole, or TMP/SMX), oral dapsone or aerosolized pentamidine can dramatically reduce the incidence of Pneumocystis carinii pneumonia (PCP) and is significantly less expensive than care of acute PCP. Several studies have shown that TMP/SMX is significantly more cost-effective than aerosolized pentamidine in patients at risk for PCP.1,2 In addition, if the signs and symptoms of PCP are identified early in the course of the infection, less costly and better tolerated oral regimens can be used for treatment.
Some managed care companies have developed working "models of care" that reduce costs through lessened utilization of acute care hospitals, emergency rooms, lung specialists, diagnostic procedures and intravenous therapies for PCP. One such model has been implemented by the Community Medical Alliance (CMA). This organization was prepaid by the Massachusetts Medicaid Program on a fully capitated basis to provide comprehensive services to a subset of the greater Boston AIDS population receiving Supplemental Security Income (SSI, a federal disability program). The CMA's model used physician/nurse practitioner teams to direct a contracted network of medical specialty, home health, personal care, private duty nursing, home infusion, day care, foster care, mental health, substance abuse, hospital, hospice care and skilled nursing facility providers.
A study was performed to evaluate the cost-effectiveness and quality of care that this model provided.3 The endpoints in the study were the incidence of PCP, general health outcome and location of care. (Due to episodes of illness or disability, over one-third of all medical visits were made in the home by one of the team members or providers in the network.)
An analysis looked at 113 enrollees with median CD4 counts of 61 who received over 81 patient-years of care. During this period, fourteen PCP cases occurred -- a rate of 17.2 per 100 patient-years. This rate is significantly less than that observed in the same population before enrollment in the program (58.7 per 100 patient-years) or the rate in a comparable New York City population (39.6 per 100 patient-years).4 Over half (57 percent) of the episodes were managed at home, three partially in the hospital and three totally in the hospital. There was just one death, for a total PCP mortality of 7.1 percent, which compares favorably with rates of 12 to 33 percent reported in the literature.
Review of patient medical records demonstrated that 73 percent of the patients had evidence of adequate PCP prophylaxis. The study's author, Robert J. Master, M.D., of the Boston University School of Public Health, inferred that compliance with PCP prophylaxis through the coordinated team approach had reduced the incidence of PCP. In addition, the author implied that the shift to home care was possible due to the early identification of the signs and symptoms of PCP. Timely diagnosis allowed for treatment at a stage when the infection was comparatively mild and treatable with oral antibiotics under the supervision of a nurse practitioner.
Although this model may be possible for such easily manageable infections as PCP, it is unclear whether it could work for other conditions such as disseminated MAC or CMV infections, wasting and diarrheal disorders and systemic lymphoma. These have rapidly become the leading causes of hospitalization of AIDS patients over the last several years.
MAC and CMV can be prevented to some degree through the use of drugs such as clarithromycin and oral ganciclovir, but those drugs are more costly and toxic than TMP/SMX or dapsone. They also have more drug-drug interactions that require intensive monitoring. The rates of infection that occur despite prophylaxis are higher, too. When infections do break through, they may require multi-drug regimens, intravenous infusions and more intense monitoring or nursing care during their acute treatment phase. Lymphomas usually require expensive diagnostic work-ups followed by radiation and combination chemotherapy. These regimens are costly in themselves and toxic. Their use necessitates extremely close monitoring, which usually is possible only in an acute care hospital.
Nevertheless, many of these treatments may be administered at home these days, as intravenous infusions administered through either peripherally inserted or central venous catheters. Establishing whether costs are reduced and quality of life improved in this new era will require further studies of nonhospital care models, including the use of allied health professionals such as nurse practitioners to coordinate care.
Physician and Hospital Experience
Additional studies suggest that other trends at some health care management organizations -- such as not reimbursing for certain procedures and limiting the choice of primary health care providers to doctors who have agreed with HMOs to charge less but who have little or no experience treating AIDS patients -- may decrease quality of care.
A recently published study has demonstrated that experience of primary care physicians in management of AIDS is significantly associated with survival of their patients. The study conducted at a health care maintenance organization in Seattle by Kitahata et al5 evaluated outcomes of 403 adult male patients diagnosed between 1984 and 1994 and cared for by 125 primary care physicians. The researchers rated physicians based on their experience caring for AIDS patients during their residency and the cumulative number of patients with AIDS that they had cared for in their practices.
The median survival of patients who had physicians with the least experience in managing AIDS was fourteen months, as compared to 26 months for the patients of physicians with the most experience. The authors controlled for CD4 count, severity of illness and year of diagnosis. They were still able to show a 43 percent reduction in the risk of death for patients in the hands of the most AIDS-experienced physicians as compared to those cared for by the least experienced physicians. CD4 monitoring was more frequent, and PCP prophylaxis and antiretroviral therapies more extensively utilized by those doctors with the longest AIDS track record.
Several studies have demonstrated that hospitals that have treated more AIDS-related PCP had a lower in-patient AIDS mortality rate.6,7 This may be due to earlier recognition of the disease, more aggressive diagnostic evaluations and appropriate treatment regimens in facilities with the most AIDS-experienced staff
Reimbursement and Outcome
Whatever practitioners' skill, problems obtaining reimbursement for medical procedures or treatments can undermine their ability to provide quality care. A recently published survey of 387 HIV/AIDS specialists8 found that 40 percent of all the drugs they prescribed were for indications that were not officially approved (mostly for treatment and prevention of opportunistic infections). Although such usage frequently reflected the accepted standard of care, half of the doctors responding reported that they had seen third-party payers deny reimbursement for "off-label" prescriptions. The authors concluded that when faced with such obstacles many patients will receive less effective, albeit covered, therapies or be hospitalized to gain access to the preferred therapy.
In another study, the survival for patients insured under Medicaid was lower than those who were privately insured.9 This seemed to be related to fewer diagnostic procedures such as bronchoscopies (used to diagnose PCP), which are reimbursed at a very low rate by Medicaid and thus less frequently used in people covered by this program. Medicaid patients with PCP in the study were 1.7 times more likely to die in the hospital, and only nine percent had bronchoscopy within two days of hospitalization compared to 32 percent of privately insured patients.
It remains to be seen how the health care experience of people with
HIV will be affected by the advent of intensive viral monitoring early in
disease and of high-priced but potent antiretroviral agents such as protease
inhibitors. This added cost may be offset by prevention or delay of
opportunistic infections and malignancies that require expensive clinical
management. For many people, access to these new measures may depend on
how the cost equation balances out.
Managed Care
by Gabriel Torres, M.D.
Managed care plans reimburse providers using a method called
capitation. Capitation pays providers on a fixed "fee-per-head" (per capita)
basis regardless of the types and amounts of services provided to any given
individual. This directly contrasts with the traditional "fee for service" system
in which providers are paid for each service delivered. Capitation means
doctors get the same amount of money for a person they never see as for a
very sick person for whom they provide many services.
The goal of managed care is to contain costs by coordinating care through a "gatekeeper," a general practitioner who decides on all referrals for diagnostic services, specialists, emergency care and hospitalizations. Gatekeepers often receive incentives from the plans for minimally serving patients; thus they minimize the number and types of referrals they make. Many plans have gatekeepers without appropriate HIV expertise but nonetheless refrain from referring patients to HIV or infectious disease specialists offering state-of-the art HIV care.
Capitation also provides incentives for early detection and preventive care to avoid higher costs for serious illness, but managed care plans often lack adequate outreach and culturally appropriate health education and HIV prevention services. In addition, many plans limit their drug formularies, nutritional services or range of therapies offered to include only the least costly option. Such restrictions may pose problems for HIV-positive patients, who may not receive the best treatment for their particular condition or stage of illness.
There are various sorts of managed care organizations, including two types of health maintenance organizations (HMOs): the traditional staff or group model and the independent practice association (IPA). The staff or group model HMO employs salaried doctors serving only plan members. IPAs are HMOs that contract with independent doctors and hospitals to provide care for their enrollees according to treatment protocols, per-case fees and review and approval rules set by the plan. In both cases, care is prepaid and members are covered only when using HMO-designated providers and hospitals.
Preferred provider organizations (PPOs) offer enrollees a network of "preferred" providers who deliver care according to set fee schedules. The managed care company may review individual providers' treatment decisions, but PPOs do not control decision making as closely as HMOs. They reimburse providers according to negotiated rates by the service rather than through captitated payments. PPO members may choose out-of-plan physicians but will be forced to pay higher out-of-pocket costs for doing so.
Employers more and more are choosing managed care plans to cut costs even though such plans have been reluctant to cover "high risk" groups such as people with HIV. HIV-positive beneficiaries should educate themselves on the services provided by each plan. Some features that are left out may be important in managing HIV infection, including mental health and substance abuse coverage. It is also advisable to ascertain which medications, nutritional supports and alternative treatments are in the plan's formulary, as some therapies may have been "carved out" from the program, and to determine the HIV expertise of the network or HMO physicians. A plan's complaint and grievance procedures also are important should needed services be denied.
Patients insured under the Medicaid or Medicare programs also are experiencing a growing shift toward mandatory managed care plans, although many state Medicaid programs have little experience providing HIV care under this new type of system. Small pilot programs have been initiated in California at the AIDS Health Care Foundation and in Baltimore at the Johns Hopkins University. These trial programs have assumed full responsibility for managing of HIV-positive patients insured under Medicaid.
In New York State, a planning process has begun to develop Special Needs Plans (SNPs), under the auspices of the New York State AIDS Institute. The SNPs would coordinate HIV care through regional networks of providers who work in unison and share the risk. These networks will ensure that all needed services, including hospitalization, outpatient care, substance abuse treatment, home care, emergency care, hospice care, case management, clinical trials and nutritional services, come under the umbrella of a lead or group of lead agencies who shoulder the financial risk. Pilot SNPs implemented next year are expected to have safeguards to avoid the pitfalls found in traditional HMOs.
Physician Training Threatened
The results of the Kitahata study imply that the continuing training of physicians devoted to HIV care is crucial to their optimal management of patients. Recent Congressional threats to the funding of the Education and Training Centers (ETCs), the federal program to train medical professionals in HIV care, may affect the ability of many providers to receive state-of-the-art medical information. ETC training can improve practice patterns and result in better health care outcomes for AIDS patients. On-going advocacy in Congress is needed to continue to support funding for the ETCs as a vehicle for keeping physicians current on HIV treatment.
Post-Exposure Prophylaxis
by Dave Gilden
The U.S. Public Health Service has issued some very tentative
recommendations on using antiviral agents as "post-exposure prophylaxis"
(PEP) to prevent HIV infection in health care workers exposed to the virus on
the job. (See the Morbidity and Mortality Weekly Report (MMWR), June 7,
1996, pages 468-72). The agency first classified HIV exposures by levels of risk
and then examined the value of using the various available medications at
the different risk levels. In deciding which drugs are appropriate, the PHS
follow a logic remarkably similar to that invoked by the doctors in our survey
when deciding on therapy for established HIV infection.
Level of risk was determined by two factors: the type of exposure and type of HIV-infected source material. The highest risk exposure concerned occasions when the worker's skin was punctured ("percutaneous" exposure, by a contaminated needle, say). The second highest risk was from mucous membrane exposure (for example, the mouth or eyes), and the lowest risk was when HIV containing material splashed on the skin.
The most risky source material was blood from an HIV-positive person, particularly if larger volumes of blood were involved or if the source person was experiencing either late-stage AIDS or initial HIV infection (blood from such people presumably has high HIV levels). Lower risk sources include other potentially infectious body fluids (such as semen, vaginal secretions and internal fluids, including amniotic fluid) while the source least likely to spread HIV was such fluids as urine and saliva. The highest risk scenario -- percutaneous exposure to HIV-tainted blood -- has an average 0.3 percent risk of HIV transmission.
The choice of preventive agent was first of all AZT, because this is the only drug for which there is any relevant data at all. One retrospective study indicated that it reduced the risk of occupational HIV transmission by 79 percent (see the MMWR, Dec. 22, 1995, pages 929-33). Then 3TC was added to the mix because trials in people with established HIV found that the AZT/3TC combination suppressed HIV more than AZT alone. Finally, the protease inhibitor indinavir (Crixivan) was considered. Indinavir was favored over both saquinavir and ritonavir because of the former's weak anti-HIV activity and the latter's greater side effects and interactions with other drugs.
But even indinavir was thought to have too many toxicities to be administered except in the highest risk situations or in cases in which AZT- resistant strains are likely. (Non-nucleoside reverse transcriptase inhibitors like nevirapine -- see page 25 -- were not considered at all. Nevirapine's propensity for causing skin rashes does pose problems for its use in this setting, though.) For moderate risk incidents, AZT/3TC should be "offered" -- rather than "recommended" -- to the individual. Indinavir is regarded as probably unjustified in these situations. For accidents carrying the least risk of transmission, nothing should be done.
PEP should commence within hours of HIV exposure. It will not reduce the chances of HIV transmission if initiated more than a day after exposure. Even if started late, though, PEP's capacity to reduce viral loads during primary HIV infection might improve an individual's long-term prognosis. In all cases, the PEP doses recommended are the same as for treating established HIV. The length of time treatment should be administered is unknown, but the PHS considers four weeks a safe bet for preventing HIV.
Viral Load Comes of Ageby Theo Smart
On June 3, the Food and Drug Administration (FDA) granted Roche
Molecular Systems license to market the Amplicor HIV-1 Monitor Test (this
company's HIV viral load or viral burden assay). Virtually simultaneously,
guidelines on how to use the viral load tests in clinical practice, developed by
a panel sponsored by the International AIDS Society (IAS), were published in
the journal Nature Medicine.1 The two events indicated that viral load -- the
quantity of free virus in plasma (fluid portion of blood) as measured by the
concentration of HIV RNA (genetic material) -- is now widely accepted by the
medical establishment as a marker of disease status. The IAS consensus
statement and the FDA approval together should increase the odds that
insurance companies, Medicaid and other third party reimbursers now will
pay for the test. When and how frequently people will be able to receive
reimbursement for viral load testing is unclear -- there was little resemblance
between the FDA and IAS views of how the test should be used, and it
remains to be seen which perspective will have greater influence.
According to its FDA-approved labeling, the Roche viral load test can be used to predict the risk of disease progression in people with HIV. The FDA also allowed mention on the label that the test has been used as an aid in assessing the activity of antiretroviral therapy, and in fact, that changes in viral load as measured by the test contributed to the approval of 3TC and the protease inhibitors. But the agency shied clear of endorsing the use of the test for patient monitoring by insisting on the following caveat: "the clinical significance of changes in HIV RNA measurements has not been fully established although several large studies that will more fully determine the role of comparative HIV RNA measurements in patient management are now in progress."
In contrast to the FDA, the IAS panel of experts believes that there are enough available data to use the test not only to determine the risk of disease progression, but to decide when to initiate therapy, whether a new treatment is having an effect and when to switch treatments because the current treatment is failing. Both the FDA and the IAS recommend that the viral load tests should be used in conjunction with other surrogate markers, in particular CD4 cell counts, which, the IAS panel said, remain, "the best predictor for the risk of developing an AIDS-related complication." High viral loads may predict rapid progression (see below) but it is the loss of CD4 cells that puts one in imminent danger of contracting PCP or another opportunistic infection.
One Virus, Three Ways to Count It
One of the FDA Blood Products Advisory Committee's chief stumbling blocks when reviewing Roche's application last March (see "FDA Panel Takes Up Viral Load" in the March Treatment Issues), was that many of the data supporting the use of viral load were generated using different assays (and blood samples processed several different ways).
The three available tests do indeed work differently:
The FDA was considering only the Roche viral load assay this spring, with Chiron's version now undergoing separate review. The IAS panel recommendations apply to all three viral load tests regardless of FDA status. While the tests are not standardized with each other, a number of studies have shown that they tally up very similar viral loads from the same plasma sample. Though the FDA's Blood Products Advisory Committee hesitated to extrapolate data generated by the bDNA or NASBA test to use of the Roche test, the IAS panel treated them as equivalent. "The IAS guidelines are guesswork by a bunch of people working with incomplete data, while the FDA was being more cautious," stated Robert Combs, M.D., a member of the IAS panel.
By necessity, the IAS group considered together data produced by all three tests. Yet there are slight variations between these tests, and, for reasons of consistency, the panel advised that people continue with the assay used to establish their initial value.
Vaccinations (against the flu, hepatitis, tetanus and pneumococcus) have been shown to cause a significant rise in viral load that can persist for weeks after the immunization. Intercurrent herpes outbreaks and opportunistic infections can boost viral loads even more. The IAS panel recommends that viral load should not be measured until one month after immunizations or acute illnesses, but some studies suggest that vaccination induced increases in viral load can persist for a longer period.
Each company's tests are subject to a certain amount of technical variability which, according to one study, may increase substantially for measurements at the lower limit of detection (see Treatment Issues, September 1995, pages 12-14). There also may be a degree of biologic variability unrelated to major infections or vaccinations. Together, these variations seldom exceed 0.5 log (a three-fold difference). To be on the safe side, Dr. Coombs, who is one of the leading experts on viral load, has said, "You always need two baselines [at least one confirmatory test] for making clinical decisions."
The FDA and the IAS panel agreed that data from several cohorts show viral load to be a good prognostic indicator. Treatment Issues has covered this application of viral load extensively in the past (see November, 1994, pages 4- 6, 10-11; December 1995, pages 1, 3-4; February 1996, pages 1, 12-16) In summary, the NIH, the Aaron Diamond Institute, researchers studying disease course in the MACS cohort and others have found that viral load several months after seroconversion, and at any timepoint thereafter, can be used to determine whether the individual will have a rapid, moderate or slow rate of disease progression.
There is a range of opinion on what precise figures to use for predicting disease outcome. The FDA cited data from trials ACTG 116A and 116B/117 (AZT vs. ddI studies), where the frequency of disease progression within five years exceeded 60 percent in patients with viral loads over 250,000 copies/ml. Progression was rare in those with fewer than 11,000 copies/ml unless they also had very low CD4 cells counts. This observation underscores the need to consider viral load in conjunction with CD4 count. The disadvantage of the two ACTG trials is they say little about the use of viral load for prognosis beyond five years.
The IAS guidelines also refer to recently published data (using the bDNA assay) from 180 patients from the MACS cohort with a follow-up period of up to 11.2 years. In his analysis, John Mellors, M.D., determined that time to progression within ten years in patients with more than 500 CD4 cells was greater than 70 percent if their viral load was above 10,200 copies/ml.2 But Dr. Mellors retrospectively tested frozen samples of heparinized blood. As noted above, heparinization reduces measurable viral load by more than one third, and the effect of long-term storage on further diminishing observed viral load is unclear.
Monitoring the Effect of Treatment
Pivotal studies testing AZT/3TC, ritonavir, and indinavir and NIH- sponsored studies ACTG 229 (testing saquinavir/ddC, saquinavir/AZT, and all three together), ACTG 175 (AZT, ddI, AZT/ddI and AZT/ddC), ACTG 116A, 116B/117 and VA 298 (early versus deferred AZT) all found that viral load tests indicate when a drug is having an antiviral effect. Even when the relatively impotent AZT is used, there is a very rapid drop in viral load within the first several days. This has been seen with every approved antiviral tested. Furthermore, rebounds in viral load back to baseline levels are correlated with loss of CD4 cells and clinical deterioration in a number of studies. Although mentioned in the Roche test's labeling, it is hard to understand why the FDA could not explicitly approve the use of the test to demonstrate whether a new drug is working. The proposition that antiretroviral therapies could have their effect by any mechanism other than anti-HIV activity seems straight out of Lewis Carroll.
If an antiretroviral drug does not reduce the level of HIV, why take it? The FDA has implied that it does not really intend to constrain frequent monitoring of viral load while on therapy. In the FDA's internal briefing paper ("Talk Paper") on the Roche test, the agency employs a broad definition of prognosis, noting that in ACTG 116B/117, a five-fold increase in viral load eight weeks after beginning therapy was "prognostic of progression." If this ACTG finding comes under the "prognosis" rubric, one might then be justified in checking viral load every other month while on therapy to make certain that it has not gone up.
To the FDA's credit, treatment should improve one's physical condition, not merely ameliorate a laboratory marker like viral load. Although therapeutically induced reductions in viral load are generally associated with increases in CD4 cell counts and, in some studies, with a reduction in opportunistic conditions and death, the data do not show that the greatest reductions in viral load consistently produce the greatest physical or CD4 cell improvements. For example, in ACTG 229, AZT/ddC effected the largest reduction of viral load, but AZT/saquinavir produced a better rise in CD4 cell counts. One factor could be the toxicity of the nucleoside analog ddC compared to the protease inhibitor saquinavir -- one-third of the volunteers on AZT/ddC had reduced CD4 counts even as their viral load went down, compared to one-tenth of those in the AZT/saquinavir arm. Dr. Coombs commented, "There might be other ways a protease inhibitor improves CD4 count. Viral load didn't explain all the treatment effect of the therapy."
The rate of CD4 decline after a rebound in viral load also appears related to the particular drugs being administered and not merely to the increase in viral load itself. Preservation of CD4 cell count gains have been reported in protease inhibitor studies even as viral load has returned to baseline.
In ACTG 175, the AZT/ddI and AZT/ddC arms reduced viral burden more than the ddI arm, but the volunteers on ddI alone did at least as well physically as those on the more potent combinations. At the advisory committee meeting in March, representatives of the FDA noted that such discrepancies made it difficult to establish algorithms to aid physicians employing viral load to manage individual patients. Such algorithms should be established by a number of ongoing or planned studies that are designed to show, regardless of the therapy used, that it is the reduction in viral load that slows disease progression. But it is unlikely that equally potent regimens will always have the same clinical effect since their differing toxicity can impair responses.
The guidelines from IAS panel (which do not mention many of the conflicting data) recommend a general algorithm based nearly as much upon theory as clinical data. The IAS panel believes that the goal of therapy should be to reduce viral load levels to below the limit of detection, or at least below 5,000 copies/ml. This desirable goal may not be achievable in all patients. There is a danger that while attempting to reach the 5,000 copy level, physicians will rapidly shift through their entire therapeutic arsenal and create HIV resistant to all available agents. Less dramatic reductions in viral burden may stabilize a patient and stretch out the available therapies so that they can be relied on when symptoms reflecting serious immune deficiency appear. But there are no data at present to support either the "hard and early" or the "soft and early" approach.
The odds are that there is less of a chance for HIV to become resistant to a drug when there is less of it replicating. Even reducing viral load to undetectable levels may not be enough to prevent eventual treatment failure, though. At the lower limit of detection for the present viral load tests (around 500 HIV RNA copies/ml), the virus may still be replicating in the blood, not to mention viral reservoirs in the lymph nodes, where HIV concentrations are much higher than in the blood, or in other organs including the brain that drugs may not reach well. As long as the virus can reproduce, there is a chance of drug resistance emerging.
Initiating Therapy
The most controversial aspect of the IAS viral load recommendations is the use of the test to decide when to initiate therapy. The panel concluded that practitioners should consider treatment of individuals with viral loads greater than 5,000 to 10,000 copies/ml and definitely should treat those with viral loads in excess of 30,000 to 50,000 because such individuals are supposed to be in immediate danger of progression.
The viral load ranges given indicate that the panel members could not settle on a single absolute value that predicted progression. But long-term prognosis is not the only factor to consider when initiating treatment -- especially when there is a potential to exhaust the available therapies and no clear evidence that treating low levels of viral load early in the course of disease has any effect on progression.
There is a wide range of opinion among clinicians in our survey regarding when to treat on the basis of viral load. Most respondents still rely on a combination of symptoms and lab tests to initiate treatment. They usually believe therapy should drive viral load down below at least 10,000 copies/ml to achieve disease stability.
Early intervention: David Ho, M.D., has written that the establishment of a viral load set-point after the initial acute phase of HIV infection provides a rationale for early intervention -- that if you can lower the viral load during this critical period, you may be able to effect a long-term delay in disease progression.3 One six-month study of AZT in early patients with primary HIV infection found that those who received treatment were less likely to develop "soft" clinical endpoints, such as thrush, than those who received no treatment.4 This is not resounding proof that treatment at this stage of disease will have any lasting impact, but Dr. Ho is conducting several studies with more potent antiviral regimens that should provide clearer evidence of benefit.
Other Factors in Treatment Decisions
The FDA approval of the Roche viral load test is a watershed event that will increase access to the tests in the U.S. But again, viral load is not the only factor to take into consideration when making treatment decisions. Some strains of the virus may be more dangerous than others, and there are suggestions that this may be the case for AZT-resistant strains. Conversely, if drug resistance one day breeds a less pathogenic virus, it might be missed if people are quickly shuffled to a different therapy just because their viral load is once again on the rise.
Dr. Coombs noted, "I think there is a host range in which patients contain the virus. There is no evidence of clinical benefit to driving the virus population very much lower." Everyone's immune system is different, though. Some people may be able to sustain higher viral loads without progressing or, alternatively, progress at much lower viral loads.
In ACTG 116A and 116B/117, disease progression continued in a
number of advanced patients with low viral loads and in patients whose viral
load was reduced to low levels in response to therapy. If viral load and CD4
cell counts both decline on therapy, is that treatment adequate? Clearly no.
Finally, starting therapy in asymptomatic patients with low viral loads who
are not prepared to comply with arduous therapy may be irresponsible or
downright dangerous since there is always the potential of exhausting
therapeutic options by breeding drug-resistant HIV. Given the dangers
involved, initiating and switching therapy are matters that must be carefully
weighed using all available pertinent information. Viral load is but one of a
constellation of tools to help people make those choices, but no single
surrogate marker can dictate all treatment decisions.
Azithromycin Approved
On June 17, the FDA approved marketing of the macrolide antibiotic
azithromycin (Zithromax) for preventing disseminated Mycobacterium
avium in persons with advanced HIV. Azithromycin's advantage is that it
need be taken only once weekly (two 600 mg tablets), compared to daily
administration of the other two MAC prophylaxes, rifabutin and
clarithromycin. In trials, azithromycin reduced the rate of MAC by half in
people with AIDS. Azithromycin's main disadvantage is its common
tendency to cause diarrhea and nausea. See Treatment Issues, April 1996,
pages 6-7, 10, for more information on azithromycin and MAC prevention.
Nevirapine Surpriseby Theo Smart
On June 7, in a rare unanimous vote, the Food and Drug
Administration's (FDA) Antiviral Advisory Committee recommended that
the agency grant accelerated approval to Boehringer Ingleheim's nevirapine
(Viramune(r)) for treating HIV-infected adults with evidence of decline. The
committee specified that nevirapine should be combined with nucleoside
analogs. On June 24, the FDA followed the committee's recommendation,
making nevirapine the ninth marketed anti-retroviral, and the first non-
nucleoside reverse transcriptase inhibitor. It will be on sale in July.
The ease with which approval occurred stands in stark contrast to the drug's tortured development. Although potent, the drug has attracted little interest from either physicians or people with HIV because of the rapid emergence of nevirapine-resistant HIV in people treated with the drug. Probably as a result, nevirapine showed only marginal benefit when combined with AZT or AZT/ddI in trials involving people with extensive prior AZT. Nevirapine also caused frequent skin rash (17 percent of patients) which on a few occasions became life-threatening.
The case for nevirapine at the committee hearing was buoyed unexpectedly by interim results from a new study following 151 treatment- naive patients who are receiving either AZT/ddI, AZT/nevirapine or AZT/ddI/nevirapine (see table). The patient population is much less advanced than in the earlier studies, with a mean CD4 count of 376 cells and a mean viral load of 4.41 log (25,704 copies per milliliter of plasma).
At the week 28 interim analysis, the AZT/ddI and AZT/ddI/nevirapine arms outperformed the AZT/nevirapine arm in both CD4 and viral load responses (see table). There was a trend toward greater viral load and CD4 cell responses in the triple combination. This combination also reduced viral load to undetectable levels (below 200 copies per ml) in a significantly larger percentage of patients than in the other arms. Moreover, the CD4 cell response at one year was sustained for the triple combination arm while CD4 cell counts had begun to fall in the other two arms.
A resistance analysis performed on four patients in the three-drug arm at week 28 found resistance to nevirapine in two who discontinued one of the nucleoside analogs for more than four weeks, while isolates from two patients who were compliant to all three medications remained sensitive to nevirapine. This suggests that the antiviral effect of nevirapine may be sustained if used consistently in a potent enough combination.
Further support for nevirapine came from John Sullivan, M.D., of the University of Massachusetts, Worcester, who reported on the activity of AZT/ddI/nevirapine in eight infants older than two months and with baseline viral loads ranging between 40,000 and 1,600,000. All except one child had sustained reductions in viral load and normalization of CD4 cell counts. Viral load became undetectable in two children with baseline viral loads close to 300,000 copies per ml. By the 168th day, these two had begun testing negative on HIV antibody tests. Such data indicate that the two infants may be eliminating the HIV in their bodies. Although spontaneous remission has been previously observed in infants, it is not an everyday occurrence.
The data in naive patients were so much better than the earlier experience with nevirapine that many advisory panel members wanted the drug's labeling to stress that nevirapine should not be added to an ongoing nucleoside analog regimen, but initiated in combination with drugs to which the patient has not yet been exposed. Some suggested that it should not be used with AZT alone except as a last resort, given that combination's poor performance.
The FDA approved combining nevirapine with nucleoside analogs in
adults but held off on protease inhibitors because nevirapine can accelerate
the CYP3A liver pathway that metabolizes these drugs, especially saquinavir.
Data released at the advisory hearing, though, revealed that nevirapine only
lowered saquinavir's blood levels by seventeen percent (not considered
significant) in the first eleven patients in a drug-interaction study. This bodes
well for the potential use of this drug in combination with indinavir, which
has the lowest rate of elimination by the liver. Complete data from
interaction studies with saquinavir and indinavir should be available in the
fall. Interaction data with ritonavir will take longer because of difficulty
coordinating the study with Abbott Laboratories, ritonavir's manufacturer.
*statistically significant for the triple combination arm compared to the other two arms
Throw Down Your Crutches
by Gregg Gonslaves
"Can HIV Be Eradicated From An Infected Individual?" was the brash
title of a conference held in Washington, D.C. on June 12 and 13. The new
journal Antiviral Therapy and the University of Amsterdam sponsored the
event, while Glaxo-Wellcome, Bristol-Myers Squibb and Gilead Sciences paid
for it. Douglas Richman, M.D., of the University of California San Diego and
Joep Lange, M.D., from the University of Amsterdam were the conference
organizers. "The meeting was convened to discuss the possibilities of the new
therapies eliminating the virus in infected people," Julio Montaner, M.D., of
the University of British Columbia, and a meeting participant, told The New
York Times (Saturday, June 15). As the conference began, though, Douglas
Richman warned that no one was claiming yet to have achieved that goal. Dr.
Richman did proclaim that with the suppression of viral replication in some
patients for up to two years, we had moved beyond the era of palliative
therapy for HIV infection.
The symposium gathered together about 75 scientists from academia and industry, with a high concentration of investigators affiliated with the AIDS Clinical Trials Group. Many of the researchers in attendance were people with a long history of presumptuous optimism about the power of antiretroviral therapy. There was scant representation of researchers and clinicians who have strong concerns about defining optimal use of the new generation of anti-HIV drugs, development of resistance and compliance with dosage schedules.
At its worst, the proceedings took place in an idealized world full of antiretroviral-naive patients who could reap the benefits of a "hit early and hit hard" strategy employing fresh triple combination regimens to which their HIV had not had the opportunity to develop resistance. Such patients were also assumed to all respond to therapy and stay on their drugs through whatever side effects and drug-drug interactions they encountered. At its best, the meeting triggered a thoughtful discussion concerning exactly what is happening in patients on the potent new combinations, of exactly how far the new therapies can take us and how much farther we have to go.
A lot of the conference consisted of a recapitulation of the results of studies presented in other forums, broad theoretical musings or a recitation of studies planned by NIH-sponsored trial networks or industry. But several key lectures marked considerable advances in the viral suppression debate.
The conference began with a presentation by Guiseppe Panteleo, of the Laboratory of Immunoregulation at the National Institute of Allergy and Infectious Diseases. Dr. Panteleo discussed the changes in distribution of virus during the acute and chronic phases of HIV infection and the implications for therapy. Using macaques acutely infected with Simian Immunodeficiency Virus, Dr. Panteleo described how SIV infiltrates the lymph nodes during the first week after transmission but by the second week is either cleared by the immune response or exhausts the initial supply of the activated CD4 cells it targets. By the end of the first month of infection, most of the SIV in the lymph nodes is composed of virions caught in the network of follicular dendritic cells (FDCs), where they remain highly concentrated and infectious.
The story is largely the same in humans. There are many individual cells expressing HIV in the lymph nodes during early infection, but after three months the viral population there consists mainly of FDC-associated virions. Dr. Panteleo then asked if peripheral control of HIV infection by antiretroviral therapy in the blood also indicated control of viral replication in the lymph nodes. Answering his own question, Dr. Panteleo said that even with complete suppression of virus in plasma there was still a large pool of virus trapped in the lymph nodes. Additionally, the decline in blood-borne free virus did not affect levels of proviral DNA (HIV genetic material integrated into the cell's chromosomes), from which he surmised the existence of a large pool of latently infected cells. Dr. Panteleo thought that it might be possible to achieve full or almost full clearance of virus in very early acute infection, but once the chronic phase of the disease has begun, eliminating HIV is not possible.
The next speaker at the meeting was John Coffin from the Tufts University School of Medicine, one of the grand old men of retrovirology. Building on work by David Ho, George Shaw and others, Dr. Coffin's presentation focused on viral population dynamics. After describing the steady-state achieved by HIV infection following primary infection, Dr. Coffin reminded those present of the astounding reproductive capacity of the virus: within a year HIV has gone through approximately 180 generations; within five to six years, it has gone through 1,000 generations. While the new potent therapies have stirred up a lot of hope, the evolutionary potential of the virus may just outrun our ability to control it. Indeed, in the HIV steady-state, Dr. Coffin calculates that there are already 1,000 cells with viral mutants resistant to any given triple combination regimen. Most of these mutants may have impaired function, but if one of them has a selective advantage over other HIV in the presence of therapy, it will be the basis for creating a new multi- drug resistant viral population.
Dr. Coffin outlined some of the additional barriers to eradicating the virus from infected individuals. In what would become one of the central themes of the meeting, Dr. Coffin expressed concerns about the population of latently infected or long-lived productively infected cells, which could easily reseed the body with HIV should therapy wipe out the active virus-producing cells and then be discontinued.
Probably the most remarkable presentation of the meeting was by Alan Perelson of the Los Alamos National Laboratory. Using data from a triple combination study of AZT/3TC and Agouron Pharmaceutical's protease inhibitor nelfinavir, Dr. Perelson has developed a complex mathematical model of two-phased viral decline under antiretroviral therapy. In the first phase, after initiation of three-drug therapy, there is a one- to two- log (90 to 99 percent) reduction in virus, which represents the clearance of activated HIV-producing CD4 T-cells and free virus. The second phase is much more drawn out (ten- to twenty-fold slower decay) and represents the clearance of either latently infected cells, in which HIV is not reproducing, or long-lived infected cells chronically emitting a low stream of new HIV (these latter cells probably are macrophages).
Dr. Perelson tried fitting the patient data to a mathematical model based on either latently infected or long-lived productively infected cells. He concluded that viral production by long-lived HIV-producing cells infected before initiation of therapy better explained the second phase of viral decline. Dr. Perelson then calculated the length of treatment required to eradicate HIV from long-lived infected cells. For patients in the AZT/3TC/nelfinavir study, the clearance of long-lived cells would take anywhere from a few months to approximately five years. Barring the appearance of drug resistance in the trial participants, the model brazenly implied that something close to eradication will be achieved after long-lived cells are cleared.
In one of the meeting's last lectures, Anthony Kelleher, M.D., from Center for Immunology at St. Vincent's Hospital in Syndey, Australia, discussed whether or not even the most suppressive antiretroviral therapy can rebuild immune function. Dr. Kelleher has observed that protease inhibitor therapy increases CD4 and CD8 T-cell numbers and restores immune cells' proliferative responses to various mitogens and recall antigens. But it cannot mend the holes in immune system response that open up as entire cell subsets disappear. According to Dr. Kelleher, the increase in CD4 and CD8 T-cell numbers during protease inhibitor therapy represents a peripheral expansion of pre-existing memory T-cells with no generation of the new na?ve T-cells needed to fight infections to which an individual has no previous exposure. Based on these findings, Dr. Kelleher recommended early and potent antiretroviral therapy in order to preserve the diversity of the immune response.
He also posed a warning to individuals with symptomatic disease or very low T-cell counts who have seen their CD4 counts bound upward on the new triple combination therapies. Any gaps in these people's immune repertoire are likely to remain despite the higher CD4 count, and withdrawal of prophylactic therapy for opportunistic infections is not a good idea.
The use of the new protease-containing triple combination regimens is in its infancy. Only time will tell if the dramatic reductions in viral load are buying people with HIV/AIDS simply a few months or years or are turning HIV disease into a chronic, manageable illness. "Can HIV Be Eradicated From An Infected Individual?" Maybe yes and maybe no. That was the answer from the two-day gathering.
Be Kind to Your Chemokinesby Dave Gilden
The rapidly increasing understanding of the way in which HIV gains
access to new cells may lead to new strategies for stopping the virus. Last
month saw the announcement of "fusin," a second receptor alongside the
long-known CD4 receptor to which HIV needs to bind when infecting cells
(see Treatment Issues article, Viral Entry Discovery Suggests New Treatments;
May 1996). Fusin turns out to be useful only to a restricted variety of
HIV strains, notably lab strains and the strains frequently appearing late in
disease, which are T-cell tropic (they especially bind to and infect CD4
lymphocytes in test tube cultures). In late June (at Treatment Issues' press
time), no less than five papers appeared in three journals (the June 20 edition
of Nature and the June 28 editions of Science and Cell) claiming that a related
receptor is the co-receptor for the so-called macrophage-tropic HIV strains
present earlier in the disease process. This new receptor is designated
chemokine receptor 5, or CC-CKR-5.
CC-CKR-5 normally binds to a class of intercellular messenger molecules called "b-chemokines." The major known function of chemokines is to attract immune cells to sites of infection, but several, RANTES, MIP-1a and MIP-1b, also interfere with HIV replication, according to recent discoveries made by Robert Gallo's lab at the National Cancer Institute (see Treatment Issues article, HIV Suppressors Found in Cells; January 1996). It turns out that CC-CKR-5 is a common receptor for all three of these chemokines. In the experiments described by the five articles, HIV was able to infect cells bearing both the CD4 and CC-CKR-5 receptors, but not just CD4. That infectability was practically eliminated in the joint presence of RANTES and the two MIPs. When only one of these chemokines was present, infectability was greatly reduced but not eliminated.
The simplest explanation seems to be that by binding to CC-CKR-5, the chemokines block HIV from joining with cell membranes and entering the cells. One research group, from the Aaron Diamond AIDS Research Center in New York, also looked at two "exposed but uninfected" individuals, i.e., persons who have remained HIV-negative despite a lifestyle that almost certainly exposed them to the virus. Lo and behold, CD4 cells from these two individuals were not only were exceptionally resistant to intrusion by HIV. They also produced abnormally high amounts of the RANTES and MIP-1a and b. The researchers have not yet determined whether this overexpression of chemokines or some genetic defect in CC-CKR-5 is at the root of the cells' resistance to HIV.
Should the chemokines prove to be the key to protecting cells from HIV, it is probably not a good idea to just inject large quantities of these molecules into patients' bloodstreams. High levels of the b-chemokines are associated with several autoimmune diseases. Still, it should be possible to develop benign drugs that bind to either part of CC-CKR-5 or, more likely, to the part of HIV's gp120 envelope protein that attaches itself to this receptor. As Treatment Issues reported last month when discussing fusin, such drugs might already exist among the various known compounds (some already under development as drugs) that block HIV's entry into new cells.
But there are limits to such an anti-CC-CKR-5 binding strategy: the cells
that the Aaron Diamond group isolated from the two exposed but uninfected
persons were susceptible to infection by HIV that depends on fusin rather
than CC-CKR-5. More generally in the experiments, the specific characteristics
of the envelope protein on different HIV strains affected the strains'
sensitivity to b-chemokines, and characteristics of different cell types also
seemed to have a major influence. Researchers at Harvard are proposing two
additional chemokine receptors, CKR-3 and CKR-2b, as alternatives to CC-
CKR-5 or fusin in certain cells. Whether or not this is confirmed, drugs that
might help some people might not help others or might only protect some
types of cells.
The Correct Amplicor Phone Number
Last month's Treatment Issues contained an article describing Roche Diagnostic System's 60-day introductory program that will provide two free baseline Amplicor viral load tests to anyone who applies. That program commenced June 17. Note, though, that due to a last minute change by Roche's long distance telephone company, the toll-fee phone number printed by Treatment Issues is wrong. The correct toll-free number is 1-888 TEST PCR. (Do not forget to dial the "1" first so as to access long-distance service. Several Manhattan residents who forgot this have complained that they ended up with an A&P supermarket and not Roche!)