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Being Alive
New Federal Guidelines For HIV Treatment Released For Comment
Walt Senterfitt
July 5, 1997
Being Alive 1997 Jul 5: 3

The U.S. Public Health Service on June 20 released a draft of new guidelines for treatment of hiv infection in adults, accompanied by a statement of principles for treatment that should help explain the guidelines, and also help clinicians adapt the guidelines as new drugs come on line. Each of these forty-page documents was prepared by a panel of experts and community representatives. There is now a 30-day period for public comment on the guidelines, before they are revised (if necessary) and printed as a special supplement to the Centers for Disease Control's weekly newsletter, MMWR (Morbidity and Mortality Weekly Reports).

Many of us will want to comment critically on one or another particular in these guidelines, but most community observers think they will be very helpful overall in ensuring more widespread access to the best treatments for hiv+ people. There are few surprises for those who get care from hiv specialists in an urban epicenter of the epidemic like Los Angeles. But for the tens of thousands in smaller cities and rural areas, in HMOs and overstressed public health systems, in prisons and shelters, the guidelines provide advocates strong ammunition with which to fight for state-of-the-art care as a basic right. They will also help all of us in making sure that so-called "third-party payers" (insurance companies, state and local governments, and the federal government itself, who foot the bill for medicines and medical monitoring) pay for all the drugs that are needed as well as viral load monitoring tests.

What's In Them An attractive aspect of these guidelines is that they offer flexibility for individual assessment and patient and physician choice, rather than a one-size-fits-all cookbook. The document recognizes that experts continue to disagree on some key points, such as exactly when in the course of infection to start therapy. In cases of disagreement, the panel presents its best consensus or dominant opinion but also clearly explains the difference of opinion and evidence for each viewpoint.

The consensus on what therapy is best, whenever it is started, is quite clear: a three drug regimen containing a potent protease inhibitor (meaning Crixivan, Viracept or Norvir but not Invirase alone) and one of the following recommended combinations of "nukes": AZT plus ddI, d4T plus ddI, AZT plus ddC, AZT plus 3TC, and d4T plus 3TC.

It cautions that for the two options containing 3TC, it is critically important that the combo as a whole suppress viral load to undetectable (less than 500 copies per ml) levels or else resistance to 3TC is likely to develop within a very short time, two to four weeks.

The following nuke combinations should not be used together in any cocktail: AZT plus d4T, ddC plus ddI, ddC plus d4T, and ddc plus 3TC. It also strongly recommends against any monotherapy (using only one antiviral of whatever type). Also listed as "not generally recommended" are combos of two nukes only.

As alternative regimens for those choosing not to start with the preferred formula, the guidelines recommend either Viramune (an NNRTI, nevirapine) or Invirase (a protease inhibitor, saquinavir) and one of the nuke combinations in the recommended list above.

Changing Therapy Once again recognizing that there are no hard and fast rules for everyone, the panel suggested the following criteria as reasons to seriously consider changing combos: less than a 10-fold (1.0 log) drop in viral load by 4 weeks after starting therapy; failure to suppress viral load to undetectable levels by 4-6 months after starting a therapy (unless levels were extremely high, like over a million, to start with); detectable viral load at least twice in a row after having once been undetectable on this combothis pattern suggests development of resistance; any significant increase, confirmed by repeating the test, defined as 3-fold (0.5 log) or greater, from the lowest viral load achieved by the combo one is on, and which is not explained by another infection, vaccination or change in type of viral load test or lab; persistently dropping T-cell count; or clinical deterioration, such as a new OI, appearance or re-appearance of wasting, etc.

When changing therapies, the panel underscored that, if at all possible, all three or least two of the drugs should be changed at the same time.

When To Start Treatment The panels agreed that anyone with symptomatic hiv infection should be treated, including any aids-defining illness, thrush or unexplained fever. They agreed that anyone who is without any symptoms (asymptomatic in medicalese) should be offered treatment if the CD4 or T-cell count is under 500 or if viral load is more than 10,000 (on the Chiron bDNA test) or more than 20,000 (on the Roche PCR test). The strength of this "offered" recommendation was advised to be calibrated by looking at the tables from the MACS data which shows the predicted time to full-blown aids for different baseline levels of T-cells taken together with viral loads.

[Note: This is the best characterized and longest-followed group of infected people, but is all male and virtually all white, so any gender or racial/ethnic differences would not be taken into account.] If asymptomatic and with more than 500 T-cells and with viral load less than 10,000 (bDNA) or 20,000 (RNA PCR), some experts would delay treatment and observe the person every 34 months and others would start treatment immediately.

The report also lists the potential risks as well as potential benefits of starting treatment early. It recommends occasions when viral load tests should be done and how often they should be repeated for different purposes. This is key, since there has been resistance in many jurisdictions and by many insurers to paying for adequate viral load monitoring.

Summary of the Principles of Therapy The "Principles" panel laid out a case for each of the following 11 points as basic principles to guide hiv treatment: 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 T-cell destruction, while T-cell counts indicate the extent of hiv-induced immune damage already suffered. Regular, periodic measurement of plasma hiv RNA levels and T-cell counts is 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 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 limit the potential for selection of resistant hiv variants, which has been the main reason previous antiretroviral monotherapies and two-drug combos did not work very well for very long in most people. Therefore, the goal of therapy should be undetectable viral loads.

The most effective means to accomplish lasting suppression of hiv replication is simultaneous (that means, not alternating or sequential) use of combinations of effective drugs which are new to the particular individual and are not cross-resistant to drugs the person has previously taken.

Each of the antiretroviral drugs in a combination regimen should always be used at optimum schedules and dosages.

The available antiretroviral drugs are limited in number and mechanism of action, and cross-resistance between specific drugs has been documented. Therefore, each change of regimen limits one's future options.

Women should receive optimal antiretroviral therapy regardless of pregnancy status.

The same principles of therapy apply to both hiv-infected children and adults, though the treatment of children involves unique virologic, pharmacologic and immunologic considerations.

Persons with acute primary hiv infection should be treated with combination therapy to suppress viral load to undetectable levels. hiv-infected persons, even those with viral loads below detectable limits, should be considered infectious to others and should be counseled to avoid sexual and drug-use behaviors that are associated with transmission or acquisition of hiv and other infectious pathogens.

How To Get the Documents and Comment The guidelines and statement of principles documents are both available on-line at the CDC National AIDS Clearing House (http://www.cdcnac.org) and at the NIH AIDS Treatment Information Service (http://www.hivatis.com). They are also available at Being Alive and no doubt at many other hiv resource centers in the area. Written comments (only) should be submitted before July 21 to hiv/aids Treatment Information Service, P.O. Box 6363, Rockville, MD 20849-6303.

www.aegis.org