AIDS Treatment Update, No. 44, August 1996
Keith Alcorn

In the first few weeks of treatment, an effective combination of drugs can reduce virus levels in the blood by more than 2 logs (99%); in this phase, it is mainly the production of HIV from short-lived CD4 cells that is being blocked.

However, other infected cells with longer life-spans such as as clearly being sustained somewhere in the patient's body, and currently available treatments may need to be taken for much longer to flush out all virus from the body. Alternatively, total elimination of virus may prove to be impossible with anything short of total long-term suppression of replication, because of the 'reservoir' of infection in long-lived cells.

In another study among recently infected people, two participants had decreasing levels of antibodies to HIV after six months (which indicates that virus was no longer in contact with the immune system), and three had no evidence of HIV in their lymph nodes. People in this study were receiving just two drugs, AZT plus ddI, given within weeks of infection, which drove viral load in the blood to undetectable levels in eight of the twelve participants. Patients and doctor will discuss ceasing treatment 'soon' (We.B.532).

Another study enrolled people with longer-established HIV infection (their average CD4 count was 525) and treated them with the combination of ddI and hydroxyurea (discussed in AIDS Treatment Update issue 26). Six out of twenty participants who have been followed for at least one year had viral load below the level of detection in both their blood and their lymph nodes. One person has just come off treatment and will be reviewed on a regular basis to see if virus production resumes. However, another participant with undetectable viral load in the blood had a viral load of 260,000 in a lymph node, indicating that suppression of HIV in the blood is not necessarily accompanied by suppression in other parts of the body (Th.B.291).

It is unclear which HIV-infected people are likely to be the best candidates for elimination of HIV. Almost all the experiments which have been conducted so far have taken place in groups of people infected for less than six months who have never received drug treatment before. It is suggested that treatment within the first few months of infection has the best chance of success for three reasons: first, because individuals in the early stages of infection are less likely to have developed a wide variety of strains of HIV, some of which may prove to be resistant to anti-HIV drugs (see page 6); secondly, because it might prevent the lymph tissue from becoming infected; and thirdly, because people with very early stage infection are likely to have strong immune responses, and are less likely to have suffered immune damage that the body cannot repair.

Very few people with HIV are identified at or soon after the time at which they first become infected. But very promising results have also been seen from triple combinations among people with later disease. In fact, many researchers consider that the best results to date are those from the study of AZT, 3TC and indinavir that were first reported in Washington last January (see AIDS Treatment Update issue 39), and were updated in Vancouver (Th.B.931).

That study enrolled people with an average CD4 count of only 142 and a relatively high viral load of over 40,000, and they had taken AZT for an average of 31 months before starting the triple combination; 80% of participants had developed AZT-resistant HIV strains before they joined the trial. Nevertheless, the triple combination reduced viral load to undetectable levels (below 500 copies/ml) in between 80% and 90% of the participants, and the antiviral effects have now been sustained for almost a year (although no information on viral load in the lymph nodes have been presented from this study).

In other words, triple combinations may still be very effective for people with relatively advanced infection, including those who have already used anti-HIV drugs extensively.

Treating newly infected people

Dr Luc Perrin in Geneva treated 12 recently infected people with the combination of AZT plus ddI. After 24 weeks, eight out of twelve had viral load below 200 copies/ml (the level below which HIV becomes undetectable using the most widely used viral load test, Amplicor). Using a newly developed test that is more sensitive to very tiny amounts of HIV, five of these eight were shown to have viral load below 20 copies/ml. The researchers then used a different test (called a proviral DNA assay) which looks for HIV-infected cells, rather than HIV particles in the circulation, and found that four people had no detectable infected cells. Three of these four also had no detectable virus in a lymph node. By contrast, only one out of fifteen seroconverters treated with AZT monotherapy achieved undetectable viral load, and none of eighteen untreated seroconverters (We.B.532).

Dr Bradford Saget in San Francisco treated six people with a combination of AZT, ddI, ddC, 3TC and alpha interferon. All were symptomatic seroconverters who began treatment within weeks of showing signs of primary HIV infection. All six had reductions in viral load to below 10 copies/ml; the average reduction in viral load was 4.5 log. As long as patients stayed on the drugs, their viral load remained suppressed throughout the follow-up period, which was a minimum of 30 weeks and a maximum, to date, of 200 weeks. One person stopped treatment after 18 months of treatment, since his viral load had been below the level of detection for well over 6 months and a lymph node biopsy showed no signs of HIV. However, his viral load rebounded to 11,000, but was suppressed to 10 copies within a fortnight of resuming treatment (We.B.533).

Dr Martin Markowitz in New York treated 12 patients with AZT, 3TC and ritonavir. Their average time since exposure to HIV was anywhere between 65 and 125 days, and all had had a symptomatic seroconversion illness. Three dropped out of the study due to problems sticking to the multi-drug regimen or due to side-effects (the study initially used the unpalatable liquid form of ritonavir). All had viral load below the level of detection (fewer than 500 copies/ml) within three months of treatment, and it was impossible to grow HIV from samples of their blood. Their CD4 counts rose from an average of 450 to 750, and the balance between different types of immune cells (the CD4:CD8 ratio) normalised, and their levels of antibodies against HIV declined over time. The researchers will perform lymph node biopsies after participants have had undetectably low viral load for at least nine months, and will discuss stopping treatment if there is no evidence of active HIV production (Th.B.933).

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