Scientific American, 7/98, John G. Bartlett, Richard D. Moore, page 64
Improving HIV Therapy
A vaccine would certainly be ideal for preventing infection by HIV and thus for
avoiding AIDS - the late stage of HIV infection, when immunity is severely impaired. Yet
the near-term prospects for a vaccine are poor, and people who contract the virus need
care. For the immediate future, then, many scientists are concentrating on improving
therapy.
Until only a few years ago, HIV infection was everyone's worst nightmare - it was almost
invariably a progressive, lethal disease that completely robbed its victims of dignity.
Most medical interventions focused on treating pneumonias and other serious
"opportunistic" infections that stemmed from immune failure, not on controlling
HIV itself.
Since late 1995, howeve5 several related advances have led to a profound shift in the
prospects for most patients who receive treatment today. Notably, scientists have gained a
much fuller understanding of how HIV behaves in the body and a 6etter sense of how to
shackle it. Two classes of potent drugs have joined the anti-HIV arsenal, and tests that
can directly monitor viral levels have been introduced, enabling physicians to assess a
therapy's effectiveness rapidly. Together these advances have made it possible to treat
HIV infection aggressively and to improve health and survival-at least in the industrial
nations, where the intensive therapy is now widely available.
Initially, the signs of a sea change were anecdotal: extraordinary but increasingly
frequent tales of people who were plucked from the brink of death to resume vigorous,
productive lives. More recently, statistics have borne out the anecdotes. between the
first half of 1996 and the first half of 1997, deaths from AIDS in the U.S. declined by 44
percent. In roughly the same period the frequency of HIV related hospitalizations and
major HIV complications dropped markedly as well.
Nevertheless, both scientific understanding and treatment remain far from perfect. For
instance, researchers do not know whether the impressive responses to therapy can be
sustained. Treatment is burdensome and costly, which puts it out of reach of certain
patients. In addition, some fraction of people who receive the best available care respond
poorly. For such reasons, the search continues for ways to make therapy more universally
effective and accessible.
The ultimate goal, of course, is a cure. Investigators are unsure whether that aim is
feasible. But many of us are cautiously optimistic that we are, at last, beginning to
accumulate the weaponry needed to manage HIV as a bearable, chronic disorder, somewhat
akin to diabetes or hypertension.
Recommendations for optimal therapy seek to halt viral replication indefinitely-something
inconceivable just three years ago. To meet this target, patients must usually take three
or even four carefully selected drugs twice or more a day, exactly as prescribed. These
general guidelines, and more specific recommendations, derive from current knowledge of
HIV's activity in untreated patients.
How HIV Harms
The virus spreads from one person to another usually through sexual intercourse, direct
exposure to contaminated blood, or transmission from a mother to her fetus or suckling
infant. In the body, HIV invades certain cells of the immune system-including CD4, or
helper, T lymphocytes-replicates inside them and spreads to other cells. (These
lymphocytes, named for the display of a molecule called CD4 on their surface, are central
players in immunity.)
At the start of an infection, hefty viral replication and the killing of CD4 T cells are
made manifest both by high levels of HIV in the blood and by a dramatic drop in CD4 T cell
concentrations from the normal level of at least 800 cells per cubic millimeter of blood.
About three weeks into this acute phase, many people display symptoms reminiscent of
mononucleosis, such as fever enlarged lymph nodes, rash, muscle aches and headaches. These
maladies resolve within another one to three weeks, as the immune system starts to gain
some control over the virus. That is, the CD4 T cell population responds in ways that spur
other immune cells-CD8, or cytotoxic, T lymphocytes-to increase their killing of infected,
virus-producing cells. The body also produces antibody molecules in an effort to contain
the virus; they bind to free HIV particles (outside cells) and assist in their removal.
Despite all this activity, the immune system rarely, if ever, fully eliminates the virus.
By about six months, the rate of viral replicätion reaches a lower, but relatively
steady, state that is reflected in the maintenance of viral levels at a kind of "set
point." This set point varies greatly from patient to patient and dictates the
subsequent rate of disease progression; on average, eight to 10 years pass before a major
HIV related complication develops. In this prolonged, chronic stage, patients feel good
and show few, if any, symptoms.
Their apparent good health continues because CD4 T cell levels remain high enough to
preserve defensive responses to other pathogens. But over time, CD4 T cell concentrations
gradually fall. When the level drops below 200 cells per cubic millimeter of blood, people
are said to have AIDS.
As levels dip under 100, the balance of power shifts away from the immune system. HIV
levels skyrocket, and microbes that the immune system would normally control begin to
proliferate extensively, giving rise to the potentially deadly opportunistic infections
that are the hallmarks of AIDS (such as Pneumocystis carinii pneumonia and toxoplasmosis).
Once such diseases appear, AIDS frequently becomes lethal within a year or two.
(Opportunistic infections sometimes occur before the CD4 T cell level falls under 200; in
that case, the appearance of the infections leads to a diagnosis of AIDS, regardless of
the CD4 T cell level.)
Although patients typically survive HIV infection for 10 or 11 years, the course can vary
enormously. Some die within a year after contracting the virus, whereas an estimated 4 to
7 percent maintain fully normal CD4 T cell counts for eight years or more and survive
beyond 20 years.
At the cellular level, scientists also know how HIV invades and destroys CD4 T
lymphocytes. The virus gains access to the interior of these cells (and certain other cell
types) by binding to CD4 itself and to another molecule, a "co-receptor," on the
cell surface. Such binding enables HIV to fuse with the cell membrane and to release its
contents into the cytoplasm. Those contents include various enzymes and two strands of RNA
that each carry the entire HIV genome: the genetic blueprint for making new HIV particles.
One of the enzymes, reverse transcriptase, copies the HIV RNA into double-strand DNA (a
property that qualifies HIV as a "retrovirus"). Then a second enzyme, integrase,
helps to splice the HIV DNA permanently into a chromosome in the host cell. When a T cell
that harbors this integrated DNA (or provirus) becomes activated against HIV or other
microbes, the cell replicates and also unwittingly begins to produce new copies of both
the viral genome and viral proteins. Now another HIV enzyme-a protease-cuts the new
protein molecules into forms that are packaged with the virus's RNA genome in new viral
particles. These particles bud from the cell and infect other cells. If enough particles
form, they can overwhelm and kill the cell that produced them.
Data's Message: Stop Viral Growth
All approved anti-HIV, or antiretroviral, drugs attempt to block viral replication
within cells by inhibiting either reverse transcriptase or the HIV protease. Two classes
inhibit reverse transcriptase and thus forestall genetic integration. Agents in one of
these classes, the nucleoside analogues, resemble the natural substances that become
building blocks of HIV DNA; when reverse transcriptase tries to add the drugs to a
developing strand of HIV DNA, the drugs prevent completion of the strand. This group
includes the first anti-HIV drug - zidovudine (AZT), which was introduced in 1987-and its
close chemical relatives. Nonnucleoside reverse transcriptase inhibitors, composed of
other kinds of substances, constitute the second class of antiretrovirals. A third class,
the protease inhibitors, blocks the active, catalytic site of the HIV protease, thereby
preventing it from cleaving newly made HIV proteins.
The basic course of untreated HIV infection has been known for a while, but recent work
has been filling in some missing pieces. It is these results that have convinced
physicians of the urgent need to halt viral replication as completely as possible.
At one time, for example, crude technology suggested that HIV actually infected few CD4 T
cells and replicated only weakly for a long time. This view implied that most of the lost
T cells disappeared via a mechanism other than wild HIV proliferation, which in turn meant
that drugs able to block viral reproduction might not interfere much with disease
progression until shortly before AIDS set in. Now it is clear that HIV replicates
prolifically from the start. HIV levels remain fairly stable for several years only
because the body responds for a time by manufacturing extraordinary numbers of CD4 T
cells.
In addition, investigators have learned that in untreated patients the strength of the
initial immune response (in the acute stage) apparently exerts a decisive influence on the
rate of progression to AIDS. Patients who display strong CD8 T cell activity, and who thus
achieve greater suppression of viral replication and a lower viral set point, progress
more slowly than do individuals who mount a weaker fight.
It also seems that strong immunological activity in the acute phase of infection helps to
preserve the body's later ability to manufacture the subset of CD4 T cells that
specifically react to HIV Once those cells are lost, they may not return, even if
subsequent treatment stops viral replication and gives the immune system a chance to shore
up its overall CD4 T cell numbers.
Finally, at any stage, viral levels correlate with prognosis. Many studies specifically
relating those levels to disease progression suggest that patients whose viral
concentrations fall into the undetectable realm and stay there are most likely to avoid
progression to AIDS.
In aggregate, such findings teach that the amount of virus in the system plays a major
role in determining a patient's fate. That is why therapy must aim to shut down viral
reproduction. For the vast majority of patients, whose immune systems cannot fight HIV
adequately unaided, aggressive drug therapy offers the best chance for long-term
well-being. It appears, however, that even patients who respond well to therapy (in whom
replication stops) will have to continue taking the medicines
for several years and perhaps indefinitely. The reason, as will be seen, has to do with
the presence in the body of HIV sequestering havens that are not eradicated by
antiretroviral therapy.
The Elements of Optimal Therapy
Theory and clinical trials indicate that the best way to achieve maximum
viral suppression is HAART: highly active antiretroviral therapy. At the moment, HAART
usually consists of triple therapy, including two nucleoside analogues and a protease
inhibitor (at a cost for the medicines of about $10,000 to $12,000 a year). For an
up-to-date list of recommended combinations, readers can consult "Guidelines for the
Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents," issued by the
U.S. Department of Health and Human Services (on the World Wide Web, see
http://www.hivatis.org/trtgdlns.html).
Doctors prescribe the combination of two nucleoside analogues and a protease inhibitor
most often because this configuration was the first shown to work well. Other kinds of
drug cocktails that incorporate newer drugs and may be more powerful or simpler to use are
being evaluated as first-line options as well. Among those are two protease inhibitors or
one protease inhibitor combined with a nonnucleoside reverse transcriptase inhibitor;
drugs in both those classes are more potent than zidovudine and other nucleoside
analogues. Physicians are also examining the value of combining four or more agents.
Multiple-drug regimens make sense for a couple of reasons. If one drug fails to block
viral replication, a second may pick up the slack. And if both of those attacks fail, the
third drug should provide extra insurance.
In addition, as Douglas D. Richman explains on the opposite page, HIV inevitably becomes
resistant, or unresponsive, to antiretrovirals that fail to suppress viral replication
completely. Because no single drug on the market can achieve such suppression on its own,
any agent given alone will eventually be rendered useless, sometimes within weeks.
Moreover, HIV strains that become resistant to one drug often become insensitive to other
drugs in the same class (a phenomenon known as cross-resistance), eliminating those drugs
as alternatives. The virus should have much more difficulty becoming resistant to
treatment if it is assaulted by a mix of compounds that together end viral replication
fully.
Given that viral levels in the blood correlate with time to AIDS and years of survival,
physicians monitor those levels as a window to a therapy's effectiveness. That way,
treatments unable to control the virus can be detected before immune failure results, in
time to take corrective measures.
Viral levels are assessed by viral-load assays, which count copies of HIV RNA in a
milliliter of plasma (the cell-free part of blood); the number of viral particles is half
the RNA count [see next page]. Current tests are sensitive to RNA concentrations of 500 or
more copies per milliliter and above. Assays now becoming available are sensitive to as
few as 50 copies per milliliter. Within eight weeks after therapy starts, viral levels
should drop by at least 10-fold. By six months from the initiation of treatment, levels
should be undetectable and remain so thereafter
In clinical trials the results of triple therapy have been phenomenal. For instance, in
patients who had CD4 T cell counts between 200 and 500 cells per cubic millimeter and had
not been treated before (and so were unlikely to harbor resistant virus), 75 to 85 percent
achieved viral loads below 500 RNA copies per milliliter within 24 to 100 weeks, and 60 to
75 percent of the patients achieved viral loads below 50 copies.
The "real life" experience has also been good but less so. Almost identical
results from clinics at San Francisco General Hospital and the Johns Hopkins Medical
Institutions reveal that approximately 50 percent of patients given triple-drug therapy
achieved the goal of viral loads below 500 copies per milliliter at six to 52 weeks after
the start of treatment.