Bulletin of Experimental Treatments for AIDS, No. 26; September 1995
Harvey Bartnof, MD

The August 17, 1995 issue of The New England Journal of Medicine contains 2 research papers and an editorial that address the recurrent issue of the optimal time to start anti-HIV therapy. It is well established that AZT prolongs survival and decreases the rates of opportunistic infections among those with AIDS (advanced HIV disease). Starting AZT during the asymptomatic stage of HIV infection (when the CD4 cell count is high) is somewhat more controversial: disease progression is delayed and the CD4 cell count increases, but there is no apparent survival increase, according to the results of the Concorde Trial. (Other smaller studies at the same stage of HIV infection do show some survival benefit.) However, the issue of starting anti-HIV therapies at even earlier stages of HIV infection represents an even larger question.

Sabine Kinloch-de Loes, MD, and colleagues have reported on the significant clinical benefits of AZT therapy during and after the time people are first infected with HIV. Fifty to eighty percent (50-80%) of HIV positive individuals experience a flu-like illness after initial infection with HIV, during the seroconversion period. This is known as "primary" or "acute" HIV infection. Symptoms include fever, sore throat, swollen lymph glands and weakness. During acute infection, growth and production of HIV is at its peak, and the virus rapidly spreads throughout the body. During this time, the HIV viral burden reaches some of the highest levels that it will ever achieve during the entire HIV disease course. As the immune system responds with cellular and antibody defenses, almost all symptoms resolve; the HIV antibody test turns positive and HIV viremia decreases.

The multicenter, double-blind, placebo-controlled trial enrolled 77 people with primary HIV infection from Europe and Australia. Participants were randomly assigned to receive placebo (PBO) or AZT at a dose of 250 mg twice daily for a period of 6 months.

During the follow-up period of 15 months, minor opportunistic infections occurred in 8 people: oral candidiasis in 4, oral hairy leukoplakia in 2 and herpes zoster (shingles) in 2. Seven of the 8 infections occurred in the PBO group; only 1 infection occurred in the AZT group. This difference was statistically significant. The single infection in the AZT group was oral hairy leukoplakia, which occurred over 2 years after enrollment into the study.

The CD4 cell count changes were also different between the 2 groups, but only approached statistical significance. Among the AZT group, there was an average monthly increase of 8.9 CD4 cells/mm3, with an average 15-month increase of 137 cells/mm3. This is compared with the PBO group, which had an average monthly decrease of 12 CD4 cells/mm3. These CD4 cell increases due to AZT also can be compared with the Concorde Trial of asymptomatic HIV positives, wherein the CD4 cell count increase was only 25% of the increase observed in the current study.

The duration of symptoms associated with primary HIV infection was not significantly different between the AZT and PBO groups. There was a decrease in the viremia (HIV in the blood) in both groups, with a larger decrease in the AZT group; the difference was not statistically significant. Toxicity in the AZT group was not as severe as that which occurs among people with AIDS taking AZT. Nausea led to a temporary discontinuation of drug in 2 participants. A significantly low white blood cell count that occurred in 1 participant was likely due to AZT.

Paul Volberding, MD, of UCSF San Francisco General Hospital, is the lead author of the second study reported in the same issue of the New England Journal of Medicine. The article represents a published version of data presented at the X International Conference on AIDS in Yokohama, Japan, in August, 1994 (see BETA, September 1994, page 12, No clinical benefit for AZT with CD4 cell count over 500).

The study was a multicenter, double-blind trial that included asymptomatic HIV positive individuals with greater than 500 CD4 cells/mm3. A total of 1,650 participants were randomized to 1 of the following 3 groups: 500 mg AZT daily, 1,500 mg AZT daily and placebo (PBO). Two years after the trial started, it was modified so that open-label treatment ("deferred therapy") with 500 mg of AZT daily was offered to all participants after their CD4 cell counts dropped to less than 500 cells/mm3. End-points within the study included survival, time to development of AIDS, changes in CD4 cell counts and toxicity. Participants were followed for an average of 4.8 years, with a maximum follow-up of 6.5 years.

There were no significant differences in survival or in time to development of AIDS among the groups. The decrease in CD4 cell counts was slower among those in either of the AZT treatment groups, compared with those in the PBO group, which later became the deferred treatment group. Toxicities were uncommon, but occurred more frequently among the high-dose AZT group.

David Ho, MD, a leading AIDS researcher at the Aaron Diamond AIDS Research Center of the New York University School of Medicine, published an editorial in the same issue of the New England Journal of Medicine. His article focused on the findings of the 2 studies just discussed while relating other research data from recent literature. The editorial title is, "Time to Hit HIV, Early and Hard." In spite of the lack of efficacy shown in using AZT for asymptomatic individuals, as demonstrated in the Volberding article, Dr. Ho believes the Kinloch-de Loes article provides striking evidence in favor of starting anti-HIV therapy very early, at the time of primary infection. Dr. Ho outlines 3 factors recently reported in medical research.

First, HIV positive individuals newly infected with HIV harbor strains that show little variation. This contrasts with those who are chronically infected with a "diverse swarm of viruses." An HIV population that is relatively homogeneous is less likely to have genetic variants with drug resistance, and thereby is more likely to respond to therapy. Such facts would indicate that early treatment for HIV makes more sense than later treatment. This line of reasoning is similar to the general wisdom of treating early in any treatable infectious disease, Dr. Ho contends.

Second, Dr. Ho outlines recent research regarding rates and quantity of HIV growth throughout HIV infection and disease (see BETA Research Notes, June 1995, page 46-47). In vivo, HIV grows very rapidly, around-the-clock, for years. Half of all the HIV in blood plasma is cleared in less than 2 days. Approximately 1 billion HIV particles are produced daily in each HIV positive person. Over a period of 10 years of HIV infection, a total of 10 trillion HIV particles are produced in each individual, representing thousands of growth cycles. Given the known mutation rate of HIV, "every viable (survivable) mutation" combination will occur. Therefore, Dr. Ho contends, "monotherapy as we know it is doomed to fail, especially in the case of antiviral agents to which HIV-1 can become resistant." He continues, "The number of (HIV) virions produced during the typical 1-month duration of primary infection approximates the number produced in several subsequent years of asymptomatic infectio! n. Consequently, the effect of zid ovudine [AZT] therapy during the seroconversion period is expected to be greater than the effect of similar treatment for a year during the asymptomatic period. This concept provides a potential explanation for the apparent discrepancy between the results of Volberding et al, and those of Kinloch-de Loes et al."

Third, Dr. Ho also emphasizes that a higher viral burden after primary HIV-1 infection predicts a poorer long-term prognosis (see BETA Research Notes June 1995, pages 46-47). Therefore, "treatment at the time of seroconversion may lower the initial viral load -- and thereby improve the subsequent clinical course."

Dr. Ho concludes that the "maximal antiviral pressure" (with the optimal combination of anti-HIV drugs) should take place when HIV "is most homogeneous -- during the initial phase of infection." He cites historic medical lessons learned from treating tuberculosis and childhood leukemia. Each of these diseases showed resistance and relapse when only monotherapy was used. Today, combination drug regimens are standard when successfully curing either of these diseases, and treatment begins early in the disease course of both.

Another recently published article on the issue of early AZT treatment appears in the June 1, 1995 Annals of Internal Medicine. J. Ioannidis and colleagues performed a "meta-analysis" bringing together the results of 10 different published articles on the topic. The authors conclude that early AZT treatment improves the clinical picture at first, but that the beneficial effects decrease over time.

All of the 10 trials were randomized, double-blinded and placebo-controlled, and enrolled people who were HIV positive. No participants had received prior anti-HIV drugs, and none had CDC-defined AIDS illnesses at enrollment. With the use of any clinical endpoints, 9 of the 10 studies favored early treatment with AZT. Overall progression to AIDS or death was decreased by approximately one-half, although this observation was not statistically significant. When all the data were combined, a 40% decrease in any adverse clinical outcome was observed with early treatment. Those participants with no symptoms or with a CD4 cell count of less than 500 cells/mm3 showed the greatest benefits.

Bartnof HS. Research Notes. BETA: 68-69, March 1995; BETA: 12, September 1994.

Ho DD. Time to hit HIV, early and hard. New England Journal of Medicine 333(7):450-451. August 17, 1995.

Ioannidis JP and others. Early or deferred zidovudine therapy in HIV-infected patients without an AIDS-defining illness: a meta-analysis. Annals of Internal Medicine 122: 856-866, June 1, 1995.

Kinloch-de Loes S and others. A controlled trial of zidovudine in primary human immunodeficiency virus infection. New England Journal of Medicine 333(7):408-413. August 17, 1995.

Volberding PA and others. A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter. New England Journal of Medicine 333(7):401-407. August 17, 1995.

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