Birth of a Paradigm
Panel Embraces Maximum Viral Suppression as Goal of Therapy; Drug Company Bonanza Creates Headaches for Third-Party Payers and AIDS Treatment Educators
Eleventh hour backstage skullduggery stymied by unified community
"And What Rough Beast, Its Hour Come Round at Last, Slouches Towards Bethesda to Be Born?"
(with apologies to W.B. Yeats)
In June the Federal government published draft Principles of HIV Therapy and Clinical Practice Guidelines for Treatment of HIV Infection, developed by two committees over the last eight months to provide guidance for physicians, people with HIV and third-party payers about how best to use new antiretroviral drugs and viral load tests. TAG's Mark Harrington was a member of the NIH Panel to Develop Principles of HIV Therapy and, along with TAG's Spencer Cox, the HHS Panel on Clinical Practices for Treatment of HIV Infection. He submitted this report.
Turning the treatment revolution of 1996 into new standard of care for 1997 was no picnic. After Vancouver, it was obvious that the previous Public Health Service (PHS) guidelines for treating HIV, published in 1993, were antiquated, dating from the era of AZT as first-line monotherapy, when there was still no clinical evidence of benefit for combination therapy, let alone of the dramatic impact protease-inhibitor containing regimens can have on prolonging health and life. Sophisticated, accurate viral load testing was experimental in 1993, but is now the basis for clinical management. While some self-appointed blue ribbon panels in 1996 promulgated interim treatment guidelines -- notably the International AIDS Society, USA (an oxymoronic cognomen) -- these were based more on expert guesswork than on a thorough review of the rapidly changing field.
With a sublimity only a dysfunctional government bureaucracy could have devised, two branches of the US Department of Health & Human Services (HHS) set up not one, but two panels to codify the new approach to anti-HIV therapy. Under the aegis of the Office of AIDS Research (OAR), the National Institutes of Health (NIH) set up the NIH Panel to Define Principles of Therapy of HIV Infection, chaired by Chuck Carpenter of Brown University, with OAR's Mark Feinberg as executive secretary. The NIH panel held hearings in November 1996 to update its members on the latest data, and subsequently developed a series of twelve principles of HIV therapy.
Simultaneously, the Office of HIV/AIDS Policy (OHAP) in HHS, administered by Eric Goosby, set up the Panel on Clinical Practices for Treatment of HIV Infection, co-chaired by John Bartlett of Johns Hopkins University and Anthony S. Fauci, director of the National Institute of Allergy & Infectious Diseases (NIAID). The HHS panel met in four contentious working sessions over four months to work out how best HIV should be treated in the era of viral load testing, protease inhibitor polytherapy, and "undetectability."
It took six months for the panel leaders to define their respective roles. Eventually, the bureaucrats worked out a stunningly simple solution: the NIH panel wrote principles of HIV therapy, which are expected to endure, and the HHS panel wrote clinical practice guidelines, which are expected to change as new studies finish, new drugs become available, and new information emerges about pathogenesis and treatment. Pulling would-be practice guidelines out of the principles document and vice versa was like pulling teeth.
It was not easy to be part of a process which will affect treatment decisions made by hundreds of thousands of people living with HIV. Along with fellow activists Cornelius Baker of NAPWA, David Barr (formerly at GMHC, now with the Forum for Collaborative HIV Research), Spencer Cox of TAG, Martin Delaney of Project Inform, and Sallie Perryman of the New York State AIDS Institute, I felt the crushing responsibility of getting it right in a rapidly changing field, curbing the excessive impulses of certain gun-happy virologists, and bringing a reality check to the proceedings. For there were many who wanted to add triple-combination therapy to the drinking water, or so it seemed. Concerns about adherence, convenience, cost, toxicity and hassle were relegated to a lower priority, and some researchers seemed unaware that, though the treatment options of 1997 are broader than they were before, they are still quite limited, and the risk of cross-resistance remains quite real. Data are still inadequate on when to start therapy, and what to start with. However, after six months of work, helped along by the emergence of new data from studies such as ACTG 320, and only after a last-minute effort to substitute bias for data by some prominent researchers, blocked by the community representatives, the HHS panel came to some strong conclusions.
When Should Therapy be Started?
This proved to be the most controversial part of the Guidelines. The April draft was based on risk thresholds derived from ACTG 175 and the Multicenter AIDS Cohort Study (MACS) study. In May, a group of ACTG investigators hijacked the draft and recommended starting therapy in about 97% of the HIV-infected population. The community representatives to the Panel responded by threatening to pull out, and later in May this controversy appeared to be resolved. The final Guidelines provide more information about the risk of progressing to AIDS at various CD4 and RNA levels and may assist doctors and people with HIV in making treatment decisions. A comparison of the April, May and June draft Guidelines appears in Table 1.
Table 1: Triple therapy into the drinking water
Consensus: April draft
|Asymptomatic infection and:|
|CD4 350, any HIV RNA level*||"Treat" (based on ACTG 175)|
|CD4 350-500, RNA >40,000||"Treat" (based on MACS study)|
|CD4 350-500, RNA||"Treat or observe"|
|CD4>500, RNA >120,000||"Treat"|
|CD4>500, RNA 40,000-120,000||"Treat or observe"|
|CD4>500, RNA||"Observe or treat"|
Coup: May draft
|Asymptomatic infection and:|
|CD4 350-500, undetectable HIV RNA||"Treat or observe"|
|CD4>500, HIV RNA >20,000-40,000||"Treat"|
|CD4>500, RNA||"Treat or observe"|
|CD4>500, HIV RNA undetectable||"Observe"|
'Conciliation': June draft
Asymptomatic infection and:
Any CD4 cell count, HIV RNA >20,000
CD4 350-500, HIV RNA
|"Treat or observe"|
CD4>500, HIV RNA
|"Observe or treat"|
CD4>500, HIV RNA >20,000
|"Treat or observe"|
|*All RNA values are given for RT-PCR; bDNA values are 50% lower (that is, half the above values are the approximate bDNA equivalents)|
To effectively guide clinical management, support appropriate access and reimbursement, and set the scientific agenda for future research, the Guidelines should at least attempt to be honest about what we know and what we don't. The April draft, which based when-to-start decisions on the MACS cohort and ACTG 175, was data-driven, scientifically credible, and defended physician-patient autonomy. The May draft subverted this autonomy, discarded MACS and ACTG 175, and set up the very real possibility of over-treating a healthy asymptomatic population including many who may not be ready for treatment, may not need it, may lack the requisite motivation, and may benefit from waiting.
A few ACTG investigators-despite having missed most Panel meetings-exerted overwhelming pressure behind the scenes to discard the April draft and adopt a more aggressive, less data-driven approach. It was ironic, to say the least, that the leadership of the world's largest AIDS trials network was so sure of when we should start therapy that they are not only unwilling to conduct studies to prove their belief (in spite of having been wrong many times before), but also appeared determined to foreclose the possibility that anyone could conduct studies to answer this question by moving it beyond the realm of research into the realm of certainty.
According to one researcher, the May draft would have placed 97% of the HIV-infected population on therapy-completely disregarding the difficulty of adherence to a life-long treatment regimen, the possibility of creating widespread cross-resistance, low risks of immediate progression, and the toxicity and cost of overly aggressive treatment guidelines. Drug companies are already doing a good job of scaring providers and patients into considering early therapy-perhaps too early. Is it the role of the Public Health Service to provide them with yet another, ostensibly objective, promotional tool?
Three very different prospects open up before HIV-infected individuals with access to treatment: eradication, lifelong suppression, or delayed progression to AIDS. If eradication of HIV infection proves possible, then all infected should start eradicative treatment regimens as soon as possible. However, eradication remains a chimera. [N.B. And the recent trebling of the estimated time to total body clearance of infectious viral particles (from 2.3-3.1 years to some 6 years) along with evidence of continual low-level viral replication even at "undetectable" viral loads severely clouds the prospect for eventual eradication of HIV.]
If chronic lifelong suppression of HIV proves possible, it becomes essential to determine whether in fact there is an immunological "point of no return," so people could start treatment before that point. It may be important to intervene as early as possible, or it may be just as good (and less expensive or toxic) to wait until some yet-to-be-defined trigger point to start therapy. Until we know more, the April Guidelines seemed a good place to start. Because we can be sure that better, more convenient, less toxic, and perhaps more potent regimens will be available in coming years, at least some people may gain from waiting.
If all maximally suppressive therapy can do is delay progression to AIDS, it is still critical to determine the best time to initiate therapy. If resistance is sure to develop to any regimen, no matter how potent, it is by no means clear that earlier is better, both for individuals on treatment and for the public health, where widespread transmission of resistant HIV may make the epidemic uncontrollable again.
In the May draft, physician-patient autonomy was side-lined by a strong bias towards initiating therapy in all infected individuals regardless of CD4 count or viral load. Luckily, the Panel co-chairs responded to the threatened walk-out by the community representatives and restored some semblance of rationality to the Guidelines by providing more detailed information about risks of progression, enabling people at all stages of HIV infection to make informed decisions about whether and when to start, while preserving the necessity for third-party reimbursement when someone decides to start treatment.
Who Should be Treated?
"In current practice there are two general approaches to initiating therapy in the asymptomatic patient: a more aggressive approach that would treat most patients early in the course of HIV infection due to the recognition that HIV disease is virtually always progressive; and a more cautious approach in which therapy may be delayed because the balance of the risk of clinically significant progression and other factors (long-term durability and toxicity of the drugs and the risk of developing resistance to them) are felt to weigh in favor of observation and delayed therapy. The aggressive approach is heavily based on the Principles of Therapy [see HHS text], particularly the Principle that one should begin treatment before the development of significant immunosuppression and one should treat to achieve 'undetectable' [quotes ours] viremia; thus, almost all patients."
For symptomatic HIV infection: "Treat."
For acute primary HIV infection: "While many experts would recommend treatment with maximally-suppressive antiretroviral therapy for an indefinite period of time, there is no evidence yet of clinical benefit or altered long-term disease progression."
For asymptomatic HIV infection, CD4 T cells <500 or HIV RNA >10,000 (bDNA) or >20,000 (RT-PCR): "Treatment should be offered. (Some experts would observe patients with CD4+ T cell counts between 350-500/mm3 and HIV RNA levels
For asymptomatic HIV infection, CD4 T cells >500 and HIV RNA: "Most experts would delay therapy and observe; however, some experts would treat."
For salvage therapy (anyone on suboptimal therapy or failing potent combination therapy): "Switch to another potent regimen to which the virus has not already become resistant (if this is feasible), recognizing that little or no clinical information is available for this population, and options will vary by treatment history."
Viral load risk thresholds for disease progression: The HHS Guidelines provide detailed information on the risk of progression to AIDS first presented by John Mellors at Vancouver, derived from follow-up on 1,604 HIV-infected men from the MACS whose blood was drawn in 1985, measured by bDNA in 1995. Their risk of progression over that decade was strongly correlated with their baseline viral load.
The MACS is the biggest, longest study to demonstrate that baseline viral load predicts the rate of progression, but the bDNA values given for the 1985 samples suffer from several distorting factors. The blood was stored at room temperature for several hours, and stored in heparinized tubes. Heparin degrades HIV RNA. Therefore, the Mellors 1985 numbers must be at least doubled to get a realistic picture of the risk of progression associated with a given bDNA viral load measurement taken today. Similarly, values given by bDNA must be doubled again to obtain an equivalent value for PCR. For example, a comparison of the risk of AIDS in several groups of men from the MACS shows the risk of developing AIDS within three, six and nine years using adjusted bDNA and RT-PCR values.
Progression rates by CD4 and viral load category
|bDNA (1997 values1||RT-PCRI||N||within 3 years||within 6 years||within 9 years|
What to Start With?
What are the optimal first-line therapeutic regimens? After ACTG 320 proved the [short-term] superiority of AZT+3TC+indinavir to AZT+3TC in an AZT-experienced population starting with fewer than 200 CD4 cells, the panel decided it was time to abandon partially-suppressive regimens such as double-nucleoside combinations.
After one year of treatment, such regimens render fewer than 10% of recipients "undetectable" (viral load Table 3).
Only one study, INCAS, has shown nevirapine-containing regimens can render over 50% of participants "undetectable" after one year, with AZT+ddI+nevirapine. An AZT+ddC+nevirapine study conducted by the Inter-Company Collaboration (ICC), however, found no such benefit. Unlike the protease inhibitors, nevirapine has yet to demonstrate clinical benefit.
Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as delavirdine are even less impressive virologically, while more powerful candidates such as DMP-266 are moving rapidly through the pipeline. There is no firm evidence that the current FDA-approved saquinavir formulation can render even 40% of treatment-naïve people "undetectable" when used with two nucleoside analogues, although virology results from the recently completed SV14604 in drug naïve patients (as well as the improved formulation of saquinavir) are eagerly awaited.
What to start with...
" Strong evidence of clinical benefit and sustained suppression of plasma viral load." Such a three-drug combination would combine one highly active protease inhibitor* (from column A, below) with a specified double nucleoside combo (as in column B):
|Column A||Column B|
|* indinavir||* AZT+ddI|
|* nelfinavir||* d4T+ddI|
|* ritonavir||* AZT+ddC|
"Less likely to provide sustained viral suppression; clinical benefit undetermined:"
|"Not generally recommended"|
"Clinical benefit demonstrated, but initial viral suppression not sustained in most patients:"
"Evidence against use, virologically undesirable:"
|1The protease inhibitor saquinavir is not included because the current formulation has poor bioavailability.|
2High level resistance to 3TC develops within 2-4 weeks in less suppressive regimens, so 3TC is best used in 3-drug combinations that include a highly active protease inhibitor and reduce viral load to <20-50copies/ml
3The only combination of 2 nucleosides and a non-nucleoside RTI that has been shown to suppress viremia to levels.
What drugs should be used in changing an antiretroviral regimen? [a.k.a. "Never-Never Land"]. A subgroup of the HHS Panel held discussions in March and April to discuss treatment options for this large and important group of people living with HIV. According to the CDC, 225,000 Americans are living with AIDS, and the number can be expected to grow as the death rate drops and people live longer on potent antiretroviral combinations. However, data on optimizing treatment in this population are scanty at best, and most of the recommendations were based on guesswork, or on small surrogate marker studies.
Suggested New Regimens for Patients Whose Antiretroviral Therapy Has Failed Them*
|Prior Regimen||Consider switching to|
|2 nucleosides + saquinavir||2 new nucleosides + nelfinavir, or 2 new nucleosides + ritonavir, or 2 new nucleosides + ritonavir+saquinavir, or 2 new nucleosides + nevirapine + indinavir|
|2 nucleosides + indinavir||2 new nucleosides + ritonavir+saquinavir, or [2 new nucleosides + nelfinavir+high-dose saquinavir**], or 2 new nucleosides + nevirapine + nelfinavir|
|2 nucleosides + ritonavir||2 new nucleosides + ritonavir+saquinavir, or [2 new nucleosides + nelfinavir+high-dose saquinavir**], or 2 new nucleosides + nevirapine + nelfinavir|
|2 nucleosides + nelfinavir||2 new nucleosides + ritonavir, or 2 new nucleosides + indinavir, or 2 new nucleosides + ritonavir+saquinavir, or 2 new nucleosides + nevirapine + indinavir 2 new nucleosides + nevirapine + ritonavir|
|2 nucleosides + nevirapine||2 new nucleosides + protease inhibitor|
|2 nucleosides||2 new nucleosides + protease inhibitor|
|1 nucleoside||2 new nucleosides + protease inhibitor, or 2 new nucleosides + nevirapine|
|* These suggested alternative regimens have not been proven to be clinically effective.|
**The combination of high-dose saquinavir (7,200 mg/day: 3,600 mg twice daily with meals) with twice daily nelfinavir (2,250 mg/day: 1,125 mg twice daily with meals) is not included in PHS Guidelines but has been effective in some patients.
Use of viral load testing for HIV management. Viral load testing is key to assessing a given HIV-infected individual's prognosis, rate of progression, and need for antiretroviral therapy. Higher viral load means more rapid disease progression. Countless studies presented at and after Vancouver demonstrate this, and other studies (ACTG 116B/117, ACTG 175, ACTG 320) demonstrate that treatment-induced viral load reductions reduce the risk of disease progression as well. Consequently, periodic viral load monitoring is critical in HIV management for 1) diagnosis of acute or chronic HIV infection, 2) assessing prognosis in chronic infection, and 3) making decisions to start or switch treatment.
Viral load should be: 1) tested before starting treatment, at one month and every three months after starting treatment, and be measured twice before switching, to reduce the risk of measurement error; and 2) taken in clinically stable individuals who have not had an intercurrent infection or recent immunization, which can cause transient spikes in viral load. It is important to stress that different viral load tests given different values. Few people know that the Chiron bDNA assay yields numbers about one half those given by the Roche RT-PCR kit, although both kits, used consistently, are equally predictive of prognosis and demonstrative of virological response to treatment. Therefore, it is important for people to always get their blood tested at the same lab, with the same kit.
Turning the new clinical practice guidelines into reality. However tortuous, writing the new treatment guidelines was the easy part. Turning them into reality will be another thing altogether. While a recent CDC study showed that last year-for the first time-the AIDS death rate fell by 12% nationwide, it fell by 50% in ACTG 320 (a federally sponsored study which compared adding the nucleoside analogue 3TC (a.k.a. lamivudine or Epivir) vs. adding 3TC plus the protease inhibitor indinavir (a.k.a. Crixivan) to the AZT monotherapy regimens of HIV-infected persons with CD4 cell counts Unequal access to state-of-the-art HIV care clearly reduces the impact of the new therapies on AIDS and death. AIDS deaths actually increased in 1996 among women and heterosexuals, barely dropped (by just 2% ) in African-Americans, and dropped less in Hispanics than among non-Hispanic, non-African-Americans. It dropped by just 8% in the south, whereas in New York City, endowed with a generous state AIDS Drug Assistance Program (ADAP) and major Ryan White AIDS care funding programs, it dropped by 30%. In places with province-wide health care, such as British Columbia, by contrast, the death rate dropped by 50% -- or just as much as in ACTG 320.
Making the new treatment regimens available to all will be an enormous undertaking. Advocacy groups will have to focus on systemic health care reform, defending Medicaid and Medicare from Federal budget cutters, expanding coverage of state ADAPs through Ryan White titles I and II, pressuring health insurance companies and HMOs to cover viral load testing and combination therapy regimens, and working to force drug companies to charge fair prices for their drugs. After all, the taxpayer subsidized some of their pivotal clinical trials, such as ACTG 229 for saquinavir and ACTG 320 for indinavir. And the accelerated approval process greatly reduced development costs.
Another enormous task will be the construction of professional treatment education programs within AIDS service providers and community-based organizations to educate clients and communities about the complicated new treatment strategies, and to assist people with HIV in making treatment decisions, maintaining adherence to complex regimens, and staying abreast of a field in rapid evolution. Perhaps new federal programs will be necessary to support broadened treatment education by community organizations in the era of potent polytherapy. TAG is working with other advocacy groups in the ADAP Working Group, the Patients' Coalition, and with organizations such as the AIDS Treatment Data Network (ATDN), Gay Men's Health Crisis (GMHC), the National Association of People with AIDS (NAPWA), the National Minority AIDS Council (NMAC), Project Inform, and the People with AIDS Coalition (PWAC) to ensure that all people with HIV get the information and support they need to make informed treatment decisions in the new era.
In general, the Panel completely ducked this question saying, in effect, "Here are the Mellors risk tables: you decide." While much of the rush to initiate triple combo therapy in asymptomatic HIV infection can be traced back to the original, jaw-dropping (and originally flawed) Mellors risk diagrams, the numbers seem much more reasonable once Mellors' mistakes are corrected (see Table 2). Still, most lecture circuit early therapy fanatics have not bothered to update their slide carousels, and as a result the misleading and irresponsibly alarmist progression curves are likely to enjoy a decay half-life longer than even integrated proviral HIV DNA. Indeed, Guiseppe Pantaleo's long-term non-progressors had a mean plasma RNA copy number of some 70,000 (New England Journal of Medicine, 1995; vol. 332: 209-16) -- although the standard deviation among the 15 LTNPs was similarly high (which in itself might prompt one to posit the now heretical proposition that perhaps all viral loads are not created equal...) Likewise, the treatment guidelines of the United Kingdom, published in the April 12 issue of The Lancet, (vol. 349: 1086-92) are using a viral load threshold of 100,000 copies and a T cell cut-off of 200-300 cells/mm3. (That's where the BHIVA cognoscenti (Gazzard, Moyle, Weber, Weiss et al.) believe irreversible immune system damage begins to occur.) Unfortunately, the critical question of who (and when) to treat is likely to remain an article of faith for some time.