Hitting HIV Early: A Swift Attack on the Virus is a Sound Strategy
The earliest days and weeks after exposure to HIV are critical for predicting the course of HIV infection, recent studies confirm.
Hope generated by these findings, however, is tempered by the rigors of long-term therapy and a public health system that does not stress the importance of identifying recent HIV infection.
University of Wisconsin researcher Todd Allen and his group have used a monkey model to demonstrate why (See Nature, Sept. 21, 2000).
Once HIV infection is established, special immune cells called cytotoxic ("cell-toxic") T lymphocytes (CTLs) are activated.
CTLs are killer cells equipped to recognize and destroy cells infected with a virus. Recognition takes place when an infected cell displays in receptors on its surface pieces of protein processed from the virus.
Infected CD4 cells display segments of an HIV regulatory protein called Tat. These segments consist of viral peptides that are eight to ten amino acids long. CTLs are proficient at recognizing Tat peptides and killing the infected cells.
Allen and his colleagues have shown that as the immune system develops its initial response, subtle mutations in the Tat peptide develop. Mutations of a single amino acid can cause CTLs to not recognize the Tat peptide. This subtle change enables HIV to escape detection by CTLs. When this happens, chronic HIV infection is established.
Why does Tat play such a significant role in facilitating the escape of HIV from the immune system? Harvard researchers Bruce Walker and Philip Goulder suggest two possible answers.
Since the Tat peptide is derived from a region of Tat with no defined function, mutations to it resulting from selective pressure from the immune system may not damage the protein or compromise the virus' viability. Or, Tat-specific CTLs may be more proficient at controlling HIV infection than CTL responses specific to other regulatory proteins.
Through changes in Tat, HIV overcomes the immune system's robust, early response to HIV and abiding infection is established. Knowing which peptides are expressed early in HIV infection could have important consequences for the development of an HIV vaccine.
Pierre-Alexandre Bart, a University of Lausanne researcher, and his group assessed the impact of highly active antiretroviral therapy (HAART) on the immunological and virological responses of infected adults at early stages of HIV infection (AIDS 2000, vol. 14, No. 13). In this study, "early infection" was determined using assessments of the immune system and viral activity, not the length of time a person was infected.
This study is important because most previous work on post-HAART immune reconstitution has focused on individuals at advanced stages of HIV infection or at the level of viral load in the blood compartment.
Bart and his colleagues looked at the impact of a regimen of abacavir (Ziagen, 300 mg/every 12 hours) and amprenavir (Agenerase, 1200 mg/every 12 hours) on 41 treatment-naive individuals with 400 or more CD4 cells/ml and a plasma viral load of greater than 5,000 copies/ml. This combination was chosen because earlier work suggested that treatment with abacavir was at least as effective as therapy with a combination of zidovudine (AZT) and lamivudine (3TC).
Glaxo Wellcome, the manufacturer of the drugs studied, and Fonds National Suisse, sponsored the research.
After 72 weeks of HAART, 34 of 41 subjects had completed the study. Four left because of adverse effects and three left for personal reasons.
Outcomes at week 72 included suppression of viral replication (-3.5 log10), and increases of CD4 counts in blood (mean increase of 240 CD4) and percentage in lymph nodes (54 percent).
These increases were equally distributed between naive (mean increase of 82) and memory (mean increase of 108) cells. Memory cells are a type of T lymphocytes that have been exposed to specific antigens. When they encounter the same antigen, they can reproduce dramatically. Naive cells are T lymphocytes that have not yet been exposed and primed to respond to a specific antigen.
Recovery of HIV-specific CD4 responses was observed in 40 percent of patients.
Although no physical changes associated with lipodystrophy were reported or observed, 25 percent and 50 percent of study subjects had levels of triglycerides or cholesterol above the cut-offs associated with cardiovascular disease.
This study demonstrates that initiation of HAART during the early stages of HIV infection is associated with durable viral suppression, increases of CD4 cells that approach normalization, and partial recovery of HIV-specific immune responses. In other words, just what the doctor ordered.
The Barcelona group headed by Montserrat Plana also has demonstrated the positive benefits of initiating HAART at the very early stages of HIV infection (AIDS 2000, Vol. 14, No. 13).
Plana and associates compared the effects of combinations of two and three drugs in patients in early chronic HIV infection. Entry criteria were based on immunological and virological markers: CD4 cells/ml of greater than 500 and a plasma viral load of greater than 10,000 copies/ml.
At twelve months, better results were observed in the triple-drug study arm. Subsets of CD4 and CD8 cells had almost completely normalized. The absolute number of naive and memory T lymphocytes increased. T cell function, largely maintained even before the start of therapy, was preserved.
Sound Too Good to Be True? Maybe
What these studies do not discuss are the potentially serious consequences associated with therapy that could extend over several decades. Issues like expense, adherence, short-term side effects and long-term toxicities significantly impact the feasibility of initiating treatment at the earliest stages of HIV infection. The immediate benefits of initiating therapy early need to be balanced against the long-term impact.
If treatment of early HIV infection can lead to the immune reconstitution illustrated above, does this mean that after assistance from HAART, the body is capable of producing an immune response powerful enough to control HIV? Achieving this balance is implicit in the desire to assess the potential benefits of structured treatment interruptions.
To test this notion, a team from Massachusetts General Hospital and Harvard Medical School supervised one or two treatment interruptions for eight patients with treated acute infection. Therapy was re-initiated if viral load exceeded 5,000 copies/ml for three consecutive weeks, or 50,000 copies/ml at one time.
Despite a return of viremia, all patients were able to achieve a steady state viral load of less than 5,000 copies/ml, and five of the eight remained off therapy with a viral load of less than 500 copies/ml for a median of 6.5 months. HIV-specific CD4 and CTL responses were also observed.
Although structured treatment interruptions may not be successful in chronic HIV infection, STI may have significant benefits in acute infection.
The control of viremia these individuals experienced suggests the potential efficacy of a "hit hard, very early" approach. More studies of structured treatment interruption following successful treatment of acute infection should be pursued.
If acute infection emerges as a critical moment in controlling HIV disease, a significant public health challenge may develop. A systemic approach to quickly and efficiently identify early HIV infection does not exist. Many health care providers miss the diagnosis of acute retroviral syndrome (ARS) in patients they treat, and public awareness about the symptoms of acute HIV infection is lacking.
On a more positive note, insights into HIV gleaned from its earliest stages usually spill over to all stages of disease. A vaccine directed against Tat could benefit both the uninfected and the infected by having preventative and therapeutic value as well. Knowledge about the best antiviral, an efficient immune system, will benefit people at all stages of HIV infection.
Lee Klosinski directs AIDS Project Los Angeles' Education Division. He can be reached at lklosinksi@APLA.org.
This article has been reprinted at The Body with the permission of AIDS Project Los Angeles (APLA).
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.