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Treatment for Primary Infection




 

GMHC Treatment Issues 1995 Dec 1; 9(12): 1

Despite its theoretical appeal, there has long been little attempt to diagnose or treat HIV during primary HIV infection -- the acute stage of disease just after transmission. The weakness of available anti-HIV drugs and the lack of sensitivity of diagnostic assays led most researchers to abandon the field. Recent developments, though, have prompted prominent virologist David Ho, M.D., Ph.D., to argue that a more aggressive approach to treatment during primary infection may now offer significant clinical advantages.

"Recent scientific findings and therapeutic developments converge to favor an aggressive interventional strategy early in the course of HIV-1 infection," Dr. Ho wrote in a recent commentary.1 These developments include a better understanding of viral replication and viral variance during primary infection as well as late stage disease. The rate of replication during these periods may drive (or at least reflect) disease progression. The viral population in persons recently infected with HIV also turns out to be relatively homogeneous and less likely to quickly become resistant to therapy. Given the rate of viral replication and variation later in disease, drug resistance is almost unavoidable. Another significant development is the availability of much more potent antiretroviral drug regimens (including PMPA -- see page 3).

Dr. Ho, who directs the Aaron Diamond AIDS Research Center in New York, is currently working with his colleague Martin Markowitz, M.D., on two studies evaluating combination antiviral therapy with AZT, 3TC and a protease inhibitor (either indinavir or ritonavir) in people recently infected with HIV.

Primary Infection and HIV Setpoint Primary HIV infection usually passes unnoticed in most individuals. Symptoms, such as fevers, swollen glands, rashes and diarrhea, are frequently mistaken for the flu or the common cold. If a person undergoing primary infection does seek medical attention, HIV is rarely diagnosed unless there is good reason to suspect it (such as a known recent exposure).

During primary infection, viral load levels are extremely high, but this initial burst of viral replication is brought under control within several weeks by cytotoxic T-lymphocytes (CTLs). The CTLs can reduce virus levels by a thousand-fold or more, a greater reduction than any currently available treatment can accomplish.

Two recent studies suggest that the level at which an individual's viral load eventually plateaus (the HIV "setpoint") predicts the rate at which that person will progress to AIDS. If antiviral therapy can help to lower the viral load setpoint so that there is a more stable equilibrium with the immune system, it might slow disease progression.

The first study followed 62 men from the Multicenter AIDS Cohort Study (MACS) for at least four years, measuring their HIV RNA levels at seroconversion to HIV-positive on the standard ELISA test.2 Researchers reported that those developing AIDS within the course of the study had higher viral loads at seroconversion than those who did not progress to AIDS. A viral load measured at greater than 100,000 copies of HIV RNA (the HIV gene set) per milliliter of plasma at seroconversion was associated with more than a ten-fold increase in risk of progression to AIDS.

A second study of stored blood samples from 42 seroconverters found that the people who advanced to AIDS within four years had the highest setpoints as measured after seroconversion, those who progressed within four to nine years had lower setpoints, and those who did not develop AIDS within six to eleven years had the lowest setpoints.3 AZT Primary Infection Study Dr. Ho cites one study that indicates early AZT therapy does indeed offer limited clinical benefit. This European Australian Cooperative Study evaluated six months of AZT treatment (250 mg twice daily) versus placebo in 77 persons with primary HIV infection.4 During the mean follow-up of fifteen months, seven opportunistic infections occurred in patients on placebo, and only one in the group on AZT. These opportunistic infections were not AIDS-defining events, but conditions like thrush and herpes zoster that may predict future progression.

The rest of the data is hard to interpret because the two groups of patients were not perfectly matched at entry -- CD4 cells were higher and viral load was significantly lower in those on placebo. The patients on AZT nevertheless had a CD4 count at six months that was 130 points higher than those on placebo. This difference was not quite statistically significant, though, and the difference in CD4 cell count dwindled after treatment discontinuation. But at two years of follow-up, the AZT group still appeared to have at least a 50 point higher CD4 count on average.

As usual, HIV levels dropped in both groups after primary infection, when the anti-HIV immune response commenced. Because of the small size of the study and the fact that everyone had a fairly substantial drop in viral load, the difference between those on AZT and placebo was not statistically significant. However, AZT-treated people had a viral load reduction that was about 70 percent greater than those on placebo -- which is identical to the reduction that AZT can achieve later in disease. There was no rebound in viral load after treatment discontinuation.

Although the researchers found the 215 codon mutation that helps confer high-level resistance to AZT in six out of 58 patients at baseline (four in the AZT group and two in the placebo group), they could find no evidence of additional resistance emerging in response to the six months of AZT treatment, which lends support to Dr. Ho's contention that resistance may be slow to develop in response to treatment during primary infection. AZT resistance often occurs within less than four months in more advanced patients.5 AZT monotherapy has not fared so well in a number of other studies. An earlier Australian study noted a decrease in CD8 cells in seven people treated with AZT (one gram a day) for 56 days as compared to fifteen untreated historic controls, although there was no difference in post-treatment absolute CD4 cell counts.6 This was not a randomized study, and the doses of AZT used were higher and more toxic than the current recommended dose.

DATRI 002, a National Institute of Allergy and Infectious Diseases study of AZT monotherapy in primary infection, has had trouble finding acceptable volunteers.

New Studies Dr. Ho's final argument in favor of aggressive treatment during primary infection is that much more benefit can be expected from the more potent combination regimens becoming available. Accordingly, Dr. Markowitz's studies evaluate one year of treatment with AZT/3TC/protease inhibitor in people infected with HIV within the last three months. Participants can test positive for antibodies to HIV or can have a positive test for p24 antigen (HIV core protein). The main endpoint will be the change in viral load.

Screening has already begun for the first trial, an open label study of AZT, 3TC and ritonavir in twelve patients. The second study will begin within a month and randomizes 18 patients to receive either AZT/3TC/indinavir, AZT/3TC or indinavir monotherapy (in a 2:1:1 ratio). What happens in either study after the first year depends upon the responses seen in the volunteers. If viral load becomes undetectable, trial participants may elect to have lymph node biopsies to see whether the virus has been cleared from the germinal centers which can serve as a reservoir for the virus. For more information, call 212/725-0018.

Since neither study is placebo-controlled, it may be difficult to ascertain the extent to which treatment can supplement the anti-HIV immune response unless the treatment's effects are dramatic. Another potential pitfall is that treatment before seroconversion (while viral replication is extremely high) may have a different effect than treatment following seroconversion. Reducing replication before seroconversion (when the rates of replication are at the highest) may have a greater clinical effect.

Three drugs at once may represent a formidable challenge for the single strain of virus attacking a person during primary infection. There remains the possibility that HIV will acquire resistance to the therapy being administered. This may limit a patient's options for treatment in the future, when disease progression accelerates.

One last consideration: as virologists, Drs. Ho and Markowitz may naturally look to targeting HIV. But since it is the cell-mediated immune response that is primarily responsible for the initial massive reduction in viral load, it would make as much sense to evaluate therapies that can sustain or enhance this response. Appropriate immune modulators or cytokines such as IL-12 clearly should be tested in primary infection.

1 Ho, D. The New England Journal of Medicine. August 17, 1995; 333(7):450-1.

2 Mellors, JW et al. Annals of Internal Medicine. Apr 15 1995; 122(8):573-9.

3 Henrard, DR. Journal of the American Medical Association. Aug 16 1995; 274(7):554-8.

4 Kinloch De Lo�s, S et al. The New England Journal of Medicine. Aug 17 1995; 333(7):408-13.

5 Nelson R et al. Tenth International Conference on AIDS. Aug 7-12 1994; 10(1):104 (abstract no PA0033).

6 Tindall B et al. AIDS. Jan 1993; 7(1):128-9.



 


Copyright © 1995 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in December 1, 1995. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.