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
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
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
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
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.