- Maximal HIV Suppression becomes the Goal of Antiretroviral Therapy
- Unequal Access to Care Still Hinders Treatment Advances
Members of the Treatment Action Group (TAG), a non-profit AIDS research and treatment advocacy group in New York City, offered strong praise for new guidelines on AIDS therapy announced today in the Federal Register. The new guidelines, developed by a consensus panel of researchers, clinicians and AIDS advocates for the U.S. Public Health Service (PHS), offer instructions for using powerful drugs, known as protease inhibitors, and new tests of HIV levels in the blood to monitor and treat HIV-infected patients.
According to TAG’s President Barbara Hughes, “In the last two years, AIDS treatment has undergone a revolutionary transformation. People living with HIV can expect much longer, healthier lives than was the case even a short while ago. These guidelines will strengthen our struggle to ensure that HIV-infected individuals have access to the best current standard of care.”
Spencer Cox, Director of TAG’s Antiviral Project, and TAG Policy Director Mark Harrington served as members of the PHS task force which developed the guidelines.
According to Harrington, “The new PHS guidelines serve a threefold purpose: first, to provide guidance to physicians and people with HIV in making the best available treatment decisions, second, to strengthen the basis for third-party payment for combination antiretroviral therapy and viral load monitoring, and third, to lay out the research agenda to fill the gaps in our current knowledge about when to start antiretroviral therapy and how to manage patients who are no longer benefitting from current drugs.”
Cox added, “Past approaches to HIV treatment used inadequate therapy by giving patients just one or two drugs, which weren’t strong enough to maximally suppress HIV. As a result, most patients rapidly developed resistance to the treatments and their immune system damage continued to progress. Under the new model, potent triple combination therapies are applied to reduce HIV levels beneath the limit of detection of current viral load tests, slowing down or stopping immune system damage and delaying or preventing the emergence of drug resistance. The new guidelines also recognize that treatment must be tailored to one’s individual readiness to start therapy and stick with it, one’s viral load, immune status, and symptoms, and one’s treatment history.”
Gregg Gonsalves, TAG’s Director of Legislative Affairs, also noted that the new treatment guidelines would support efforts to increase government and private-sector funding for AIDS treatment. “These guidelines make clear the new consensus that HIV treatment needs to occur earlier in the course of disease and more aggressively than has previously been the case, and should include multiple antiretroviral drugs and regular laboratory monitoring. As publicly funded health care programs struggle to decide what should be covered, these guidelines will define the minimally acceptable standard of treatment.”
But Harrington cautioned that, “unequal access to health care hinders our ability to ensure that all HIV-infected people receive state-of-the-art AIDS treatment. AIDS deaths dropped last year by 12%, but we could do much better. Women, African-Americans, Latinos and Latinas, children and adolescents, and prisoners, among others, continue to be denied access to the best treatment for their HIV disease. AIDS advocates will struggle in the coming years to ensure that all HIV-infected Americans can access the HIV treatment they need to survive.”
The HHS Guidelines themselves are available on-line at the NIH AIDS Treatment Information Service, and are open for a thirty-day period of public comment. Written comments should be submitted to the HIV/AIDS Treatment Information Service, P.O. Box 6363, Rockville, Maryland, 20849-6303. Only written responses will be accepted. They are due by 21 July 1997. After reviewing the comments a final document will be published in the CDC’s Morbidity and Mortality Weekly Report (MMWR).
Additional information and commentary from TAG about the new HIV treatment guidelines can be accessed at https://www.treatmentactiongroup.org/tagline/1997/june/birth-paradigm.
The Treatment Action Group (TAG) is the nation’s first and only AIDS activist organization dedicated solely to the effort to find effective treatments for AIDS and its associated diseases, as well as a preventive vaccine. TAG supports the work of approximately fifty AIDS treatment activists, many of whom are living with HIV. TAG strives to ensure that all people living with HIV receive the treatment, care and information needed to save their lives.
PUBLIC HEALTH SERVICE
GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS
IN HIV-INFECTED ADULTS AND ADOLESCENTS
- These guidelines are important because they will enourage the systematic implementation of recent treatment breakthroughs.
Many private physicians in urban epicenters of the epidemic have already incorporated innovations such as viral load testing and protease inhibitor therapy into their treatment of patients. However, studies have repeatedly shown that treatment of patients who lack private insurance, or who are receiving treatment outside of urban epicenters, lags behind. These guidelines will help to ensure that all HIV-infected patients in the United States receive an acceptable level of treatment including protease inhibitors used in combination with older anti-HIV drugs, as well as regular monitoring of viral load.
- These guidelines differ from previous guidelines in several key factors.
First, they include technological breakthroughs, such as viral load testing. Second, they incorporate new drugs, such as HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Third, they make use of new research findings about how HIV causes disease. All of these factors have come together in the past few years to produce a revolution in AIDS treatment, which these guidelines reflect.
- These guidelines also recognize the importance of tailoring anti-HIV treatment to the individual patient, and offer physicians the flexibility of individualizing treatment.
Patients differ substantially, not only in biological categories, such as levels of viral load and CD4+ cell counts, but also in subjective categories that may affect treatment outcome, such as willingness and/or ability to adhere to difficult treatment regimens, and willingness to tolerate the sometimes substantial toxicities associated with anti-HIV therapy. These guidelines offer guidance for discussion between patients and physicians about the decision to initiate therapy, and recognize that that decision will not always be based solely on biological criteria.
- These guidelines are based on a variety of evidence.
Studies supporting recommendations range from large, well-controlled clinical trials evaluating the effects of treatment on rates of illness and death, to smaller studies evaluating the impact of therapy on “surrogate markers” of drug effects, such as CD4+ cell counts and viral load tests, to “expert opinion.” Each recommendation is graded, to provide readers with information about the evidential basis supporting the recommendation. This grading system allows physicians and patients to understand the arguments supporting the guidelines.
- These guidelines will offer AIDS advocates a powerful tool to argue for increased public spending on AIDS treatment.
As the publicly-funded AIDS Drug Assistance Programs (ADAPs) have struggled to keep up with expensive new therapies, new federal and state funding has often been necessary. In addition, current Medicaid eligibility for HIV-infected people is predicated on an AIDS diagnosis: by recommending treatment before symptomatic disease develops, these guidelines offer important support for Vice-President Gore’s recent proposal to expand Medicaid eligibility to include asymptomatic HIV-infected people. These guidelines will also help patients who are struggling to ensure coverage of expensive regimens by Health Maintenence Organizations (HMOs).
PUBLIC HEALTH SERVICE
GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS
IN HIV-INFECTED ADULTS AND ADOLESCENTS
After last summer’s International Conference on AIDS in 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, before studies which showed 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 — notably the International AIDS Society, USA — promulgated interim treatment guidelines these were based more on expert guesswork than on a thorough review of the rapidly changing field.
Two branches of the US Department of Health & Human Services (HHS) set up not one, but two separate 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 (see TAGLine, February 1997), and subsequently a series of twelve principles of HIV therapy were developed (see appendix I).
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). In four contentious working sessions, the HHS panel met 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: 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 be modified as new studies finish, new drugs become available, and new information emerges about pathogenesis and treatment.
When Should Therapy be Started?
The guidelines for starting antiretroviral therapy recognize that the prognoses of different patients can vary widely at different stages of HIV infection, as defined by viral load, CD4+ cell count and symptoms. Furthermore, patients will differ substantially in their willingness to tolerate side effects of treatment, to comply with difficult regimens, and to risk undefined long-term side effects.
Consequently, although most panel members believed that all patients with symptoms, substantial immune system deterioration and high viral load should be treated, there was no consensus as to when exactly in the course of disease progression treatment should be initiated. As data are not presently available to clearly indicate the best course of action, the guidelines leave a certain amount of flexibility for patients and physicians to discuss treatment options, and to make an individually responsive decision about beginning treatment.
Three very different prospects open out 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 those who are infected should start eradicative treatment regimens as soon as possible. However, eradication may remain elusive.
If chronic lifelong suppression of HIV proves possible, it becomes very important indeed to determine whether in fact there is an immunological “point of no return,” so people could start treatment before then. 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.
Because we can anticipate 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 before initiating treatment.
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 always better, both for individuals on treatment and for the public health, when widespread transmission of resistant HIV may make the epidemic uncontrollable again.
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. Strength of recommendation is based on readiness of patient for therapy and prognosis for disease-free survival as determined according to Table IV (see below).
For asymptomatic HIV infection, CD4 T cells >500 or HIV RNA <10,000 (bDNA) or <20,000 (RT-PCR): Most experts would delay therapy and observe; however, some experts would treat.
For symptomatic HIV infection: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 (see ACTG 333).
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 of the University of Pittsburgh in Vancouver, derived from follow-up on 1,604 HIV-infected men from the Multicenter AIDS Cohort Study (MACS) whose blood was drawn in 1985, measured by the Chiron branched chain (bDNA) HIV RNA test 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 viral load measurement taken today. Similarly, values given by bDNA must be doubled again if they are given for Hoffmann-LaRoche’s Amplicor reverse transcriptase polymerase chain reaction (RT-PCR) HIV RNA test. 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:
MACS Study: Progression Rates by CD4 and Viral Load Category
|% developing AIDS
|CD4 < 350
Thus, if a recent bDNA test showed CD4 under 350 and viral load over 60,000, one’s risk of progression over three years might be as high as 73%, and similarly for an RT-PCR result over 120,000. By contrast, none of the three MACS participants with low CD4s but undetectable (<500 bDNA) viral load progressed over nine years.
|% developing AIDS
|CD4 < 350-500
Higher viral load (over 20,000 by bDNA or 40,000 by RT-PCR) distinguishes a medium-risk (32% at three years) from a low risk (5% over three years) group in this group with medium CD4 counts.
|% developing AIDS
|CD4 > 500
People with over 500 CD4 cells whose bDNA is over 60,000, or PCR over 120,000, appear to have a 33% risk of progression over three years — the same as those with 350-500 CD4 cells and over 20,000 bDNA or 40,000 PCR HIV copies. For those with high CD4s and high viral loads, starting treatment might might be more strongly indicated than for those with low viral loads — especially as treatment options should improve over the next few years. Some asymptomatic persons with high CD4s and low to moderate viral load may do better by waiting.
What to Start With?
What are the optimal first-line therapeutic regimens? After ACTG (AIDS Clinical Trials Group) 320 proved the superiority of AZT/3TC/indinavir to AZT/3TC in an AZT-experienced population starting with under 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 <400 copies per milliliter), as compared with 65-85% on triple-drug therapy including at least one new nucleoside and a potent protease inhibitor.
Therefore, the new standard of care for anyone starting anti-HIV therapy should include a regimen designed to give a high likelihood that virus will become undetectable and stay that way for at least a year. This will minimize the chance of developing resistance, thereby prolonging immune function and delaying progression to AIDS.
AI Preferred: Strong evidence of clinical benefit and sustained suppression of plasma viral load. One highly active protease inhibitor and two nucleoside reverse transcriptase inhibitors (NRTIs) (one drug from column A and two from column B):
BII. Alternative: Less likely to provide sustained virus suppression; clinical benefit is undetermined:
- Two NRTIs + nevirapine, or
- Two NRTIs + saquinavir
Unlike the protease combinations, only one study, INCAS, has shown nevirapine-containing regimens can render over 50% of participants undetectable after one year, using AZT/ddI/nevirapine. An AZT/ddC/nevirapine study conducted by the Inter-Company Collaboration (ICC), however, found no such benefit. Other NNRTIs such as delavirdine are even less impressive virologically, while more potentially 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-naive people undetectable when used with two NRTIs. While Roche is preparing a new, more bioavailable soft-gel capsule formulation of saquinavir, this is not yet approved by the FDA.
CI. Not generally recommended. Clinical benefit demonstrated, but initial virus suppression is not sustained in most patients.
- Two NRTIs, as listed above.
DI. Not recommended. Evidence against use, virologically undesirable:
- All monotherapies
What drugs should be used in changing an antiretroviral regimens? 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 Who Have Failed Antiretroviral Therapy
|Consider switching to
|2 NRTIs + nelfinavir
|2 new NRTIs + Ritonavir, or indinavir, or saquinavir/ritonavir, or nevirapine/ritonavir, or nevirapine/indinavir
|2 NRTIs + ritonavir
|Saquinavir/ritonavir, or nelfinavir/nevirapine
|2 NRTIs + indinavir
|Nelfinavir, or ritonavir/saquinavir, or nevirapine/indinavir
|2 NRTIs + saquinavir
|Nelfinavir, or ritonavir, or ritonavir/saquinavir, or nevirapine/indinavir
|2 NRTIs + NVP
|2 new NRTIs + a PI
|2 new NRTIs + a PI
|1 NRTI 2 new NRTIs + a PI
|2 new NRTIs + nevirapine
* These suggested alternative regimens have not been proved to be clinically effective.
NRTI = nucleoside analogue RTI; NNRTI = non-nucleoside RTI; PI = protease inhibitor; RTI = reverse transcriptase inhibitor”
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, 175, 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 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. Viral load should be 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 an imperative and Herculean task.. While a recent CDC study showed that last year, for the first time, the AIDS death rate fell by 12% nationwide, it fell by fifty percent in the triple-combination patients from ACTG 320. Unequal access to state-of-the-art HIV care is clearly reflected in statistics on AIDS-related survival. 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. Mortality 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 the drug companies’ pivotal clinical trials, such as ACTG 229 for saquinavir and ACTG 320 for indinavir, and the accelerated approval process has greatly reduced the companies’ development costs.
Another enormous task will 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 strategy, 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 program 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 decisions in the new treatment era.
APPENDIX I: Summary of Twelve Principles of Therapy of HIV Infection
- Ongoing HIV replication leads to immune system damage and progression to AIDS. HIV infection is always harmful and true long-term survival free of clinically significant immune dysfunction is unusual.
- Plasma HIV RNA levels indicate the magnitude of HIV replication and its associated rate of CD4 T cell destruction, while CD4 T cell counts indicate the extend of HIV-induced immune damage already suffered. Regular, periodic measurement of plasma HIV RNA levels and CD4 T cell counts are necessary to determine the risk of disease progression in an HIV- infected individual and to determine when to initiate or modify antiretroviral treatment regimens.
- As rates of disease progression differ among individuals, treatment decisions should be individualized by level of risk indicated by plasma HIV RNA levels and CD4 T cell counts.
- The use of potent combination antiretroviral therapy to suppress HIV replication to below the levels of detection of sensitive plasma HIV RNA assays limits the potential for selection of antiretoviral-resistant HIV variants, the major factor limiting the ability of antiretroviral drugs to inhibit virus replication and delay disease progression. Therefore, maximum achievable suppression of HIV replication should be the goal of therapy.
- The most effective means to accomplish durable suppression of HIV replication is the simultaneous initiation of combinations of effective anti-HIV drugs with which the patient has not been previously treated and that are not cross-resistant with antiretroviral agents with which the patient has been treated previously.
- Combination antiretroviral therapy should be initiated and maintained using optimum schedules and dosages of each of the components of the treatment regimen.
- The available antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, any change in antiretroviral therapy always increases future therapeutic constraints.
- Women should receive optimal antiretroviral therapy regardless of pregnancy status.
- The same principles of antiretroviral therapy apply to both HIV-infected children and adults, although the treatment of HIV-infected children involves unique pharmacologic, virologic and immunologic considerations.
- Persons with acute primary HIV infections should be treated with combination antiretroviral therapy to suppress virus replication to levels below the limit of detection of sensitive plasma HIV RNA assays.
- Antiretroviral treatment of persons who have experienced occupational exposure to HIV should be encouraged.
- Until there are data to suggest otherwise, HIV-infected persons, even those with viral loads below detectable limits, should be considered infectious and should avoid sexual and drug-use behaviors that are associated with transmission or acquisition of HIV and other infectious pathogens.