AIDS TREATMENT UPDATE, Issue 30, June 1995
Keith Alcorn

WHAT HAPPENS AFTER INFECTION?

In the weeks immediately after infection with HIV the virus begins to reproduce unchecked in the body and very large quantities can found in the blood, semen and vaginal fluid. From two to six weeks after infection, the individual may develop flu-like symptoms, known as primary infection or seroconversion illness. This signals that an immune response has begun, as the immune system attempts to eliminate the HIV-infected cells by producing CD8 cells, or cytotoxic T-lymphocytes. This response is called the cell-mediated immune response. Antibodies against HIV begin to appear soon afterwards and the quantity of these antibodies will continue to increase for up to a year; this is known as the humoral immune response. Together, these two arms of the immune system are able dramatically to reduce the amount of HIV in the blood, at least in the short term.

In most viral infections that would be the end of the matter. Unfortunately, because of its preference for infecting lymphocytes, HIV is able to take up residence in the lymph nodes, which are storage points for lymphocytes rather like a bee-hive in their structure and organisation. Millions of unactivated lymphocytes sit in the lymph nodes waiting to be called to do their work in the immune response. HIV infiltrates itself into lymphocytes in the lymph tissue, infecting up to 25% of the cells, and each time the lymphocytes are activated, HIV is triggered to reproduce itself.

A number of doctors in Europe and America are keen to test the theory that very early use of anti-HIV drugs might prevent this large-scale 'seeding' of the lymph tissue with HIV, and dramatically reduce the severity of HIV infection.

Paul Griffiths, Professor of Virology at the Royal Free Hospital in London, is one of those who thinks that early treatment should be tested more thoroughly. "My view has long been that we should be learning from the basic principles of anti-viral chemotherapy, that early therapy is important for many viruses; it's beneficial for the ultimate disease state. When the cell-mediated immune response to HIV comes in, you get a very dramatic reduction in viral load, but ideally you need to give anti-viral treatment within the first six weeks of infection, before the immune system responds. I would propose quite extensive combination therapy - 3 or 4 drugs for six weeks in acute infection and then no more drug, just careful follow-up, to observe differences in disease progression."

TREATMENT RESULTS

Some researchers have treated HIV-infected people with anti-retrovirals during primary infection, on the assumption that the greater the reduction in viral load which takes place during primary infection, the longer it will take for HIV to damage the immune system.

One international study whose results have been presented at AIDS conferences enrolled newly-infected people with seroconversion illness and compared the effects of treatment with AZT versus no treatment. The AZT-treated group displayed a much stronger CD8 cell response than the placebo group after one year, although no data was reported on the CD8 response during the earliest stages of primary infection, which may be the time when a strong CD8 response is most crucial. Only 4% of the AZT-treated group experienced a fall in their CD4 count to below 350 after one year, compared with 32% of the placebo group. The importance of this is unclear, as trials like Concorde have shown that early AZT treatment usually produces a short-term increase in CD4 count, but that this does not necessarily mean that people will experience fewer symptoms or have a slower progression to AIDS. This study was too small and too short to look for such clinical benefits.

However, some scientists argue that AZT treatment during primary infection could hamper the immune system's own response to HIV, and ultimately speed up disease progression. In 1993 Australian researchers found that the production of CD8 cells was reduced in people treated during primary infection with AZT when compared to an untreated group. In addition, researchers at Hamburg's Institute of Tropical Medicine have reported that in the early stages of infection, anti-retrovirals may inhibit the proliferation of both CD4 and CD8 lymphocytes. CD8 cells are thought to be the most effective part of the immune system's attack on HIV, and to interfere with this immune response may lead to more rapid disease progression.

Professor Tony Pinching of St Bartholomew's Hospital stresses a need for caution in any approach to primary infection. "What remains uncertain is the role CD8 cells play in containing HIV infection - it's the sort of area where a wise man would tread cautiously. We're also uncertain about the role that antibodies play. In the light of all this evidence, the question remains whether the immune response needs to be greater or smaller" he says.

Agreeing with Professor Pinching, Professor Jonathan Weber of St Mary's Hospital stresses the difficulties of measuring the effects of very early treatment on disease progression, because most people with HIV can expect not to develop any symptoms for many years even if they don't take any anti-HIV treatments. Recipients of early treatment would need to monitored for a decade or more, during which time they might well use a range of other treatments. "If you had really effective treatments surely the earlier you treat the better, but it's going to be very hard indeed to demonstrate the effects."

WHAT ARE THE SYMPTOMS?

Whilst the idea of treatment in primary infection is very controversial, most doctors argue that nevertheless it makes sense to identify people who are HIV-positive as early as possible, so that they can be counselled about factors which may deplete their immune system and so that they can take advantage of any treatment advances as early as possible.

But how do people even know that they've been infected? Some people suspect that they've been infected after they have unsafe sex with a partner who is HIV-positive, but many people will not even know they've been at risk.

For some people, a flu-like illness is the sign that seroconversion is taking place. High fever, aches and pains, swollen glands and very sore throat are commonly reported symptoms around the time that antibodies to HIV appear, but these symptoms could also be due to many other infections. However, some people also report symptoms that are very specific to HIV seroconversion illness, including severe ulceration which may affect the mouth and throat, the genitals or the anus, or a red, raised rash on the trunk, palms and soles of the feet. Both symptoms are unusual; ulcers of such severity are very unusual unless aphthous mouth ulcers were already a problem, and a rash of the type described is not typical of other infections. Problems related to the nervous system may also emerge; sometimes individuals have reported paralysis or very severe headaches and disorientation, meningitis and temporary nerve damage (neuropathy) causing pain, weakness or tingling in the hands or feet.

Dr Stephen Jollis of the Royal Free Hospital is concerned because he believes that some doctors miss new cases of HIV infection due to ignorance of the distinctive symptoms. "Outside the well-established risk groups, a flu-like illness is unlikely to trigger the suspicion of HIV infection, for instance amongst pregnant women" he says. But Professor Weber argues that "identifying seroconverters is terribly difficult even if you know what to look for, because most people's symptoms are incredibly mild. When we really worked hard to find seroconverters at St Mary's we still only found two in the course of a year."

There is no clear information about what proportion of newly infected people develop seroconversion symptoms. One study found that less than half of the seroconverters in a Vancouver cohort of gay men reported any symptoms at all, and in most cases where symptoms were reported, they were relatively minor and could easily be mistaken for a mild flu-like illness.

Studies suggest that people who experience significant seroconversion symptoms may, on average, have a worse prognosis from people who have only mild or no symptoms during primary infection, but the evidence is limited.

REFERENCES

The study showing benefits from AZT during primary infection is:

Kinloch S et al. "Treatment of primary HIV-1 infection with zidovudine", Tenth Intl Conf on AIDS, Yokohama, abstract 002B, 1994.

The less optimistic Australian research is:

Tindall B et al. "Administration of zidovudine during primary HIV-1 infection may be associated with a less vigorous immune response", AIDS 7(1):127-128, 1993.

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