Can treatment during primary HIV infection lead to control of disease without drugs?

The US Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (1) recommend treating patients during primary HIV infection. The rationale for this recommendation is largely theoretical and is based on results from clinical studies involving a relatively small number of patients, cellular immune responses, and other laboratory markers. Indeed, many of the scientific findings that justify treating patients during PHI are recent and have yet to be validated in larger cohorts of patients. There are no answers to critical questions such as "How long should treatment last?" or "What combination of therapy should be used first?" Nonetheless, some of the data gathered to date on the effects of treatment during PHI are intriguing and indicate that such treatment may alter the nature of the patient's disease course, from shifting viral "set point" and decreasing the degree of viral "seeding" to potentially preserving some HIV-specific immune function.

These insights lend hope that the immune system has the ability to control HIV under the right circumstances. The challenge for biomedical research is to discover those circumstances and harness that information to realize a functional cure for HIV--a cure where the virus will not be eradicated per se, but rendered less pathogenic by immune control. This article reviews some of the findings thus far in the study of the treatment of PHI. Be forewarned that not all study protocols are directly comparable: some look at treating patients during acute disease (symptomatic PHI, i.e. before seroconversion), while others include those in early disease (recent seroconverters).

Why PHI? A look at the labs. In 1997, a group of researchers in Boston published a paper in Science that reported on the importance of HIV-specific CD4 T cell responses in the control of HIV viremia. (2) The researchers looked at the immune function of chronically infected individuals who were never on antiretroviral therapy but were able to control viral replication for extended periods of time and maintain relatively normal CD4 T cell counts. These individuals are sometimes known as long-term nonprogressors. The investigators found that the immune systems of such individuals exhibited a variety of strong HIV-specific proliferative responses (mediated by CD4 T cells), for instance to viral antigens like the p24 or gp160 epitopes. Also, there was a highly significant inverse correlation where the strongest p24-specific proliferative responses were in individuals with the lowest viral loads. The researchers then looked at these immune responses in 3 individuals diagnosed with PHI (specifically during symptomatic acute retroviral syndrome) who had begun combination antiretroviral therapy before seroconversion. The lowering of viral load in these patients was strongly correlated with p24-specific proliferative responses. Such responses had not been seen in chronically infected patients who started antiretroviral therapy, suggesting that the "early, aggressive treatment of primary [HIV] infection may facilitate the generation of these responses."

A more recent paper by this same group of researchers and colleagues in San Francisco and Seattle (3) found that although patients treated during PHI had less diverse viral populations, they also had weaker and narrower cytotoxic T lymphocyte (CTL) responses than patients treated with antiretroviral therapy soon after seroconversion. Longer exposure to viral antigen was associated with increased HIV-specific CTL responses. However, the PHI group did exhibit stronger T helper cell responses, which led the researchers to suggest that "individuals treated in early infection may benefit from [therapeutic] strategies aimed at enhancing virus-specific CTL responses, whereas individuals treated later in infection may benefit from strategies aimed at enhancing HIV-1-specific T helper cell functions as well as broadening CTL responses to combat increased viral diversity." Decreased CTL activity had also been observed in early-disease patients who had been treated from 45 to 90 days after symptomatic acute infection, according to a study published 2 years earlier by researchers from the Aaron Diamond AIDS Research Center (ADARC) in New York and colleagues. (4) Subsequently published work by ADARC and collaborators has shown that viremic episodes (due to nonadherence in therapy (5) or a lack of viral suppression while on therapy (6)) were associated with stronger neutralizing antibody responses (5) and HIV-specific CD8 T cell responses (6) among patients treated during acute or early infection, respectively.

In their earlier papers (3,4) both the ADARC and Boston groups recognized the importance of such observations for HIV-specific immunity: the immune system must have sufficient levels of viral antigen (specifically those epitopes that induce the strongest responses) to maintain better control of the virus. Two ways of doing this would be: 1) stopping antiviral therapy, allowing viral replication to increase, and 2) using a therapeutic vaccine that could help stimulate immunity.

Structured treatment interruptions: hit and miss. One way to stimulate HIV-specific immune responses might be to allow viral replication after a period of suppression with antiretroviral therapy. Exposure to sufficient titers of autologous virus has been the idea behind using structured treatment interruptions (STIs) in clinical research. The bad news is that the success of this strategy is highly dependent on an individual's immune characteristics and success has been inconsistent, if not elusive, especially in chronically infected patients. Currently, the only reason to interrupt treatment in chronically HIV-infected individuals would be because of side effects or toxicities, or because such treatment was initiated too early and is now in conflict with current treatment guidelines.

Both the ADARC and Boston researchers have implemented treatment interruptions in their study protocols involving patients treated during acute infection (within days of symptoms) or early infection (usually within several months of symptoms). The results have been both encouraging and perplexing.

In a research letter published in Nature, (7) the Boston researchers described the use of STIs in 8 individuals with acute or early HIV infection (2 of these individuals were ELISA positive). These individuals had been on suppressive antiretroviral therapy from just less than 1 year to as long as almost 3 years. Therapy was stopped and reinitiated when HIV RNA (viral load) levels exceeded 5000 copies/mL for 3 consecutive weeks or reached 50,000 copies/mL or greater at any one time. After the first treatment interruption, plasma viral load became detectable in these patients after a median of 17 days. However, viral load levels spontaneously dropped below 5000 copies/mL in 3 patients. These effects were durable over several months. The other 5 patients restarted therapy for a median of 16 weeks. A second interruption was initiated in these 5 patients and viral load rose to a lower peak than after the first STI, and then dropped to less than 5000 copies/mL. As in the other patients, the suppression of viral load lasted for several months. (Some patients voluntarily elected to restart therapy even though they did not meet the criteria to do so). The study data also showed enhanced HIV-specific CD4 and CD8 T cell activity in these patients. At the time of the paper's publication, 5 of these 8 individuals remained in control of viremia while off therapy for a mean of 2.7 years after initial infection.

At the 8th Conference on Retroviruses and Opportunistic Infections in early 2001, several presentations looked at STIs or treatment discontinuation in patients treated during acute or early infection. Bruce Walker, MD, from Boston presented a State of the Art Lecture (8) summarizing data on a total of 14 patients (data on the first 8 had been published earlier (7)) treated during acute infection. At that time, 7 out of 14 patients remained off therapy with viral loads less than 5000 copies/mL. Six patients were in their second or third STI. Only one patient was unable to control viremia, even after 4 STIs.

Researchers from Belgium presented an abstract showing sustained control of viremia for a median of 17 months in 4 out of 10 patients treated within 2 to 5 months after PHI. Three of these patients had viral loads less than 50 copies/mL and the fourth had experienced transient viremia before once again suppressing viral load to less than 500 copies/mL. This study involved treatment discontinuation (treatment duration ranged from 12 to 40 months), i.e. there were not multiple STIs.

Another abstract, submitted by ADARC researchers and colleagues in Spain, reported similar results in 2 out of 7 patients treated within 90 days of acute infection. (9) Additionally, the ADARC group reported on 14 patients treated after a mean of 60 days (range 7 to 120 days) after symptomatic PHI. (10) After a mean on 1145 days, antiretroviral therapy was stopped. Thirteen of these patients were able to spontaneously lower their plasma viral loads and exhibited measurable increases in HIV-specific immune responses. However, most viral load levels remained detectable, with only 2 patients maintaining viral loads less than 1000 copies/mL while off therapy.

Not all of the above studies use the same protocols, which may very well account for the differences in results. Some cohorts are treated soon after diagnosis with PHI (usually before seroconversion), while others are treated several months after acute symptoms and seroconversion. Also, the length of time on treatment varies. Obviously, such differences make cross comparisons of results quite difficult. Considering the relative newness of this line of research, future reports should help answer the growing number of questions regarding treatment during PHI.

Testing the water with therapeutic vaccines. Although several groups are initiating studies with vaccines aimed at generating improved immune responses to specific viral epitopes, little data has been published or presented yet. Some of the work that has been done so far involves a recombinant canarypox vaccine (vCP1452) carrying specific HIV genes (env, gag, nef, and pol) with recombinant gp 160. ADARC researchers have reported transient antibody responses to HIV antigens in patients treated within 90 days of PHI who were given vaccine (intramuscular injection) at 0, 30, 90, and 180 days. (11) Also, broad CD8 T cell responses to multiple HIV antigens were seen in a majority of patients. However, the ability of these patients to control viremia after stopping therapy was similar to nonimmunized individuals. (12) Certainly, more research in this area will elucidate how therapeutic vaccines might fit into this puzzle.

Summary. Initiating antiretroviral treatment during PHI, particularly in the acute phase (before seroconversion), appears to interrupt the natural history of HIV infection in the host. Although all the parameters of such an interruption are not understood, what remains clear is that a condition can be induced where the host is better able to control viremia in the absence of therapy. Structured treatment interruptions, therapeutic vaccines, and other novel mechanisms may further enhance HIV-specific immunity and viral suppression. The duration of such effects, their outcome on survival, and how they apply to chronic infection are not known. However, just as the study of long-term nonprogressors has provided valuable information about host-virus interactions, so too may the study of induced host control of viremia lead to improved therapeutic approaches and perhaps one day a functional cure.

REFERENCES

(1.) US Dept. of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. August 2001. http://www.hivatis.org/trtgdlns.html#Adult

(2.) Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997; 278:1447-1450.

(3.) Altfeld M, Rosenberg ES, Shankarappa R, et al. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med. 2001; 193(2):169-180.

(4.) Markowitz M, Vesanen M, Tenner-Racz K, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis. 1999;179:525-537.

(5.) Binley JM, Trkola A, Ketas T, et al. The effect of highly active antiretroviral therapy on binding and neutralizing antibody responses to human immunodeficiency virus type 1 infection. J Infect Dis. 2000;182:945-949.

(6.) Ortiz GM, Hu J, Goldwitz JA, et al. Residual viral replication during antiretroviral therapy boosts human immunodeficiency virus type 1-specific CD8+ T-cell responses in subjects treated early after infection. J Virol. 2002;76(1):411-415.

(7.) Rosenberg ES, Altfeld M, Pooh SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523-526.

(8.) Walker B. State of the Art Lecture and Summary. "Structured treatment interruption: novel strategy or oxymoron?" 8th Conference on Retroviruses and Opportunistic Injections, February 4-8,2001; Chicago. Session 37.

(9.) Miro JM, Tortajada C, Plana M, et al. HIV-1-specific T-cell responses and spontaneous control of viremia can be detected after the first cycle of structured treatment interruptions (STI) in patients receiving HAART since primary HIV-1 infection (PHI). 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001; Chicago. Abstract 359.

(10.) Markowitz M, Jin X, Ramratnam B, et al. Prolonged HAART initiated within 120 days of primary HIV-1 infection does not result in sustained control of HIV-1 after cessation of therapy. 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001; Chicago. Abstract 288.

(11.) Jin X, Ramanathan Jr. S, Barsoum G, et al. Safety and immunogenicity study of vCP1452/rgp160 therapeutic vaccines in patients treated with HAART over two years. 8th Conference on Retroviruses and Opportunistic Infections, February 4-8, 2001; Chicago. Abstract 21.

(12.) Walker B. Structured treatment interruption: some answers, more questions. Medscape Conference Coverage, based on selected sessions at the 8th Conference on Retroviruses and Opportunistic Infections. http://www.medscape.com/medscape/cno/2001/RETRO/Story.cfm?story_id=2053