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Studies Reveal Early Impact of HIV Infection, Effects of Treatment

Studies Reveal Early Impact of HIV Infection, Effects of Treatment NEW STUDIES about events early in the course of infection with the human immunodeficiency virus (HIV) may have important implications in treating the infection, namely, when clinicians should institute aggressive anti-HIV therapy. Results of these studies and other findings, including information about the emergence of unusual adverse effects in patients treated with protease inhibitors and the earliest evidence about when HIV infection appeared in the human population, were among the discoveries reported at the Fifth Conference on Retroviruses and Opportunistic Infections held in Chicago, Ill, last month. How Crucial is Early Treatment? Initiating treatment with a potent combination of antiretroviral drugs as soon as possible after infection with HIV may be critical to preserving a key element of the immune system, said Bruce D. Walker, MD, of Massachusetts General Hospital, Charlestown. New studies described by Walker suggest that for most HIV-infected people, virus-specific helper T cells are eliminated very early in the course of infection, and without early intervention with antiretroviral drugs, the damage may be irreversible. However, studies of a handful of patients treated soon after they became infected suggest that early and aggressive treatment using potent anti-HIV drug combinations can preserve this crucial component of the immune response. Long-term "nonprogressors"—rare HIV-infected individuals who have lived for up to 2 decades without disease progression—are living evidence that somehow the virus can be successfully held in check by some mechanism besides antiviral drug therapy. Studies by Walker and others, comparing such individuals with HIV-positive patients experiencing progressive disease, have found that the body's ability to control viral load is correlated with a vigorous response by HIV-specific CD8 cytotoxic T lymphocytes (CTLs). This level of activity by CTLs, in turn, depends on a strong response by helper T cells, which secrete cytokines that activate the CTLs. While a robust anti-HIV helper T cell response is found in long-term nonprogressors, it is absent in people with progressive HIV infection. Just why these helper T cells are missing in action wasn't clear until Walker and coworkers measured levels of HIV-specific helper T cells in patients at different stages of the HIV disease. The reason: the virus preferentially infects these key cells, and many are eliminated during the early stages of infection, before seroconversion. Once banished, anti-HIV helper T–cell activity does not seem to recover. Research by Walker and colleagues involving 7 acutely infected patients suggests that HIV-specific helper T–cell activity can be preserved with aggressive antiviral therapy. All 7 individuals generated a strong response over a period of 6 weeks to 3 months of antiretroviral treatment, and "all continue to generate strong levels of helper-cell response," said Walker. Such a response isn't seen in chronically infected patients who are not long-term nonprogressors. These findings are likely to figure prominently in the intense debate concerning when to initiate anti-HIV drug therapy, notably so-called highly active antiretroviral therapy, or HAART. (HAART usually consists of drug combinations involving at least 1 protease inhibitor in combination with 2 other antiretroviral drugs.) While some clinicians advocate starting HAART as early as possible, others have recommended postponing such therapy for patients with early HIV disease and relatively low plasma levels of virus and high CD4 cell counts. The new evidence about the fate of helper T cells should add considerable weight to arguments favoring early treatment. "There appears to be a window of opportunity early on when one can generate these responses"—perhaps within the first 6 months after infection, said Walker. The immune responses of the 7 treated patients, who have been treated for up to 11 months so far, appear to be similar to those seen in long-term nonprogressors. It remains to be seen, however, whether the immune system will be able to keep the virus in check if drug therapy is discontinued. Latent HIV Another issue receiving much attention from acquired immune immunodeficiency syndrome (AIDS) researchers is the question of how to deal with reservoirs of latent HIV, particularly in long-lived resting memory CD4 T cells. While HIV kills most of the T cells it infects, some survive as resting memory cells. Because the biological function of these cells is to persist for years and provide immunologic memory, "they present a potential long-term reservoir of HIV," said Robert Siliciano, MD, of the Johns Hopkins University School of Medicine, Baltimore, Md. Studies of patients on antiviral therapy producing good HIV suppression have demonstrated that such patients have a low level but stable reservoir of latently infected resting memory T cells. Because the reservoir is established very early, during acute infection, even patients treated with highly potent antiviral drugs have some of these cells. The finding underscores the potential for a rebound of HIV infection if treatment is discontinued, even in patients who have a viral load that is too low to measure using standard assays. At last year's meetings, some AIDS researchers, including David D. Ho, MD, head of the Aaron Diamond AIDS Research Center at the Rockefeller University, New York, NY, raised the possibility that with drug treatment that prevented viral replication, patients could become virus free within 3 years after latently infected cells died off (JAMA. 1997;277:614-616). Ho now concedes that, given the half-life of memory cells of 3 to 5 months and assuming that drug treatment completely suppresses viral replication, extinguishing the last embers of infection in the resting memory T–cell population would take longer, 5 years at a minimum. "The worst case scenario is that it's going to be more than 20 years [of virus-suppressing drug treatment] before that pool will go away," he said. However, some investigators believe that it might be possible to activate the resting memory cells and hasten their rate of decay in the body. Ho plans to try such a strategy on patients with no detectable plasma levels of HIV using monoclonal antibodies targeting CD3 markers on the surface of memory cells. Another strategy, suggested by Anthony J. Fauci, MD, PhD, director and chief of the National Institute of Allergy and Infectious Diseases, Bethesda, Md, and his colleagues, involves the use of cytokines such as interleukin 2 to activate the latently infected cells, while preventing further viral replication with HAART. The approach is currently being tested at the National Institutes of Health Clinical Center, also in Bethesda. Odd Fat Deposits Linked to Therapy Along with good news of dramatic declines in AIDS deaths credited to therapeutic regimens featuring protease inhibitors were disconcerting reports of the emergence of an unusual adverse effect of the drugs: an abnormal distribution of body fat. These observations, coupled with studies linking protease inhibitors with possible abnormalities such as high levels of triglycerides and glucose, insulin resistance, and diabetes, raise concerns about possible effects of long-term use of the powerful new drugs. Several reports from investigators in the United States, Canada, and Australia noted that small numbers of patients taking the newer combination therapies developed prominent deposits of fat, usually without an associated weight gain, including a "buffalo hump" at the base of the neck, abdominal fat (dubbed "protease paunch"), or a round "moon" face. Others experienced lipodystrophy, characterized by a loss of subcutaneous fat in the face and limbs along with an accumulation of abdominal fat. Although the symptoms bring to mind physical findings in patients with Cushing syndrome, investigators have found no evidence that excessive levels of corticosteroids are responsible for the Cushing-like symptoms seen in patients taking protease inhibitors. These upsets in fat distribution seem to be occurring most often in HIV-infected patients taking protease inhibitors, including indinavir, ritonavir, saquinavir, and nelfinavir. But such disturbances apparently have also been seen in small numbers of patients taking other antiretroviral drugs. In a study by researchers at the National Institutes of Health, abdominal computed tomography scans of 10 patients who had developed distended abdomens and a sensation of fullness within 3 months of beginning treatment with indinavir revealed that the patients had accumulated excessive amounts of visceral fat (without overall weight gain). They also found that the patients had elevated serum cholesterol and triglyceride levels. "Our data suggest an association between the development of visceral obesity and hyperlipidemia," they noted. Another study by investigators at St Vincent's Hospital, Garvan Institute of Medical Research, and the National Center in HIV Epidemiology and Clinical Research in Sydney, Australia, found that on average, 64% of 116 HIV-infected patients taking protease inhibitors had a loss of fat from the face and limbs and accumulations of abdominal fat after an average duration of 10 months' treatment. Overall, these patients also developed elevated triglyceride and cholesterol levels and insulin resistance scores, compared with 32 HIV-infected patients who had never taken protease inhibitors and 47 healthy controls. While some investigators believe that the unusual patterns of fat deposition may reflect drug-related metabolic disturbances, abnormalities such as hyperlipidemia, hyperglycemia, insulin resistance, and diabetes are not consistently found in patients with the atypical fat wasting and deposits. Some researchers have hypothesized that patients who develop such abnormalities as a consequence of taking the drugs may have an inherited predisposition to do so. Clinical trials of extended duration and postmarketing surveillance may help clear up some unanswered questions about how often the problem occurs in patients taking protease inhibitors and its long-term implications, and whether the effect is reversible by altering the drug regimen, researchers noted. Something Old Countless laboratory freezers around the world are crammed with old serum samples collected for studies long ago completed. Now researchers have delved into one such freezer and identified the earliest confirmed case of HIV infection, found in blood drawn from an African man in 1959. The investigators looked for evidence of HIV in 1213 blood samples collected in Africa between 1959 and 1982, said Tuofu Zhu, MD, of the University of Washington, Seattle, who reported the findings. The study's findings also were published in the February 5 issue of Nature. One of those blood samples, originally gathered for a human genetics study, came from a Bantu man living in Leopoldville, Belgian Congo (now Kinshasa, Democratic Republic of Congo). Medical records indicated that he had sickle cell trait and glucose-6-phosphate-dehydrogenase deficiency (resulting from a common genetic variant in Africa which offers some protection against malaria), but nothing is known about his subsequent clinical course. Although the sample had deteriorated over the years, the researchers were able to isolate a total of 4 fragments from 2 viral genes—enough genetic material to clearly confirm the virus as HIV. The investigators then compared the genetic material from the 1959 virus with samples taken in the 1980s and 1990s to try to reconstruct how the virus has evolved over the decades. Genetic difference between related viruses can be used to estimate how much time has elapsed since the strains diverged from a common ancestor. "We realized if we could get the genetic sequence of an old virus, it would paint a pretty nice picture about HIV origin and evolution," said Dr David Ho, one of the report's authors. HIV mutates quickly, at a relatively constant rate, with about 1% of the virus's genetic material changing annually. Over the years, 10 distinct subtypes have emerged, designated A through J. Subtype B is the dominant subtype in North America and Europe, while subtype D predominates in Africa. Comparing the old virus with modern specimens, the investigators constructed a viral family tree. Their analysis indicates that the virus in the sample is an ancestor to B and D. The findings suggest that the virus first infected people in the 1940s or early 1950s, said Zhu, and that all the HIV subtypes evolved from 1 introduction of HIV into humans, rather than several independent cross-species jumps. "The diversification of HIV-1 in the past 40-50 years portends even greater viral heterogeneity in the coming decades, and underscores the need for continued surveillance," Zhu and collaborators wrote in the Nature paper. What factors spurred the initial spread of HIV-1 in central Africa remain unknown. Possibilities include the reuse of unsterilized needles in large-scale vaccination campaigns that began in Africa in the 1960s, although "social changes such as easier access to transportation, increasing population density, and more frequent sexual contacts may have been more important," the investigators noted. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Studies Reveal Early Impact of HIV Infection, Effects of Treatment

Stephenson, Joan
JAMA , Volume 279 (9) – Mar 4, 1998
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Publisher
American Medical Association
Copyright
Copyright © 1998 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.279.9.641
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Abstract

NEW STUDIES about events early in the course of infection with the human immunodeficiency virus (HIV) may have important implications in treating the infection, namely, when clinicians should institute aggressive anti-HIV therapy. Results of these studies and other findings, including information about the emergence of unusual adverse effects in patients treated with protease inhibitors and the earliest evidence about when HIV infection appeared in the human population, were among the discoveries reported at the Fifth Conference on Retroviruses and Opportunistic Infections held in Chicago, Ill, last month. How Crucial is Early Treatment? Initiating treatment with a potent combination of antiretroviral drugs as soon as possible after infection with HIV may be critical to preserving a key element of the immune system, said Bruce D. Walker, MD, of Massachusetts General Hospital, Charlestown. New studies described by Walker suggest that for most HIV-infected people, virus-specific helper T cells are eliminated very early in the course of infection, and without early intervention with antiretroviral drugs, the damage may be irreversible. However, studies of a handful of patients treated soon after they became infected suggest that early and aggressive treatment using potent anti-HIV drug combinations can preserve this crucial component of the immune response. Long-term "nonprogressors"—rare HIV-infected individuals who have lived for up to 2 decades without disease progression—are living evidence that somehow the virus can be successfully held in check by some mechanism besides antiviral drug therapy. Studies by Walker and others, comparing such individuals with HIV-positive patients experiencing progressive disease, have found that the body's ability to control viral load is correlated with a vigorous response by HIV-specific CD8 cytotoxic T lymphocytes (CTLs). This level of activity by CTLs, in turn, depends on a strong response by helper T cells, which secrete cytokines that activate the CTLs. While a robust anti-HIV helper T cell response is found in long-term nonprogressors, it is absent in people with progressive HIV infection. Just why these helper T cells are missing in action wasn't clear until Walker and coworkers measured levels of HIV-specific helper T cells in patients at different stages of the HIV disease. The reason: the virus preferentially infects these key cells, and many are eliminated during the early stages of infection, before seroconversion. Once banished, anti-HIV helper T–cell activity does not seem to recover. Research by Walker and colleagues involving 7 acutely infected patients suggests that HIV-specific helper T–cell activity can be preserved with aggressive antiviral therapy. All 7 individuals generated a strong response over a period of 6 weeks to 3 months of antiretroviral treatment, and "all continue to generate strong levels of helper-cell response," said Walker. Such a response isn't seen in chronically infected patients who are not long-term nonprogressors. These findings are likely to figure prominently in the intense debate concerning when to initiate anti-HIV drug therapy, notably so-called highly active antiretroviral therapy, or HAART. (HAART usually consists of drug combinations involving at least 1 protease inhibitor in combination with 2 other antiretroviral drugs.) While some clinicians advocate starting HAART as early as possible, others have recommended postponing such therapy for patients with early HIV disease and relatively low plasma levels of virus and high CD4 cell counts. The new evidence about the fate of helper T cells should add considerable weight to arguments favoring early treatment. "There appears to be a window of opportunity early on when one can generate these responses"—perhaps within the first 6 months after infection, said Walker. The immune responses of the 7 treated patients, who have been treated for up to 11 months so far, appear to be similar to those seen in long-term nonprogressors. It remains to be seen, however, whether the immune system will be able to keep the virus in check if drug therapy is discontinued. Latent HIV Another issue receiving much attention from acquired immune immunodeficiency syndrome (AIDS) researchers is the question of how to deal with reservoirs of latent HIV, particularly in long-lived resting memory CD4 T cells. While HIV kills most of the T cells it infects, some survive as resting memory cells. Because the biological function of these cells is to persist for years and provide immunologic memory, "they present a potential long-term reservoir of HIV," said Robert Siliciano, MD, of the Johns Hopkins University School of Medicine, Baltimore, Md. Studies of patients on antiviral therapy producing good HIV suppression have demonstrated that such patients have a low level but stable reservoir of latently infected resting memory T cells. Because the reservoir is established very early, during acute infection, even patients treated with highly potent antiviral drugs have some of these cells. The finding underscores the potential for a rebound of HIV infection if treatment is discontinued, even in patients who have a viral load that is too low to measure using standard assays. At last year's meetings, some AIDS researchers, including David D. Ho, MD, head of the Aaron Diamond AIDS Research Center at the Rockefeller University, New York, NY, raised the possibility that with drug treatment that prevented viral replication, patients could become virus free within 3 years after latently infected cells died off (JAMA. 1997;277:614-616). Ho now concedes that, given the half-life of memory cells of 3 to 5 months and assuming that drug treatment completely suppresses viral replication, extinguishing the last embers of infection in the resting memory T–cell population would take longer, 5 years at a minimum. "The worst case scenario is that it's going to be more than 20 years [of virus-suppressing drug treatment] before that pool will go away," he said. However, some investigators believe that it might be possible to activate the resting memory cells and hasten their rate of decay in the body. Ho plans to try such a strategy on patients with no detectable plasma levels of HIV using monoclonal antibodies targeting CD3 markers on the surface of memory cells. Another strategy, suggested by Anthony J. Fauci, MD, PhD, director and chief of the National Institute of Allergy and Infectious Diseases, Bethesda, Md, and his colleagues, involves the use of cytokines such as interleukin 2 to activate the latently infected cells, while preventing further viral replication with HAART. The approach is currently being tested at the National Institutes of Health Clinical Center, also in Bethesda. Odd Fat Deposits Linked to Therapy Along with good news of dramatic declines in AIDS deaths credited to therapeutic regimens featuring protease inhibitors were disconcerting reports of the emergence of an unusual adverse effect of the drugs: an abnormal distribution of body fat. These observations, coupled with studies linking protease inhibitors with possible abnormalities such as high levels of triglycerides and glucose, insulin resistance, and diabetes, raise concerns about possible effects of long-term use of the powerful new drugs. Several reports from investigators in the United States, Canada, and Australia noted that small numbers of patients taking the newer combination therapies developed prominent deposits of fat, usually without an associated weight gain, including a "buffalo hump" at the base of the neck, abdominal fat (dubbed "protease paunch"), or a round "moon" face. Others experienced lipodystrophy, characterized by a loss of subcutaneous fat in the face and limbs along with an accumulation of abdominal fat. Although the symptoms bring to mind physical findings in patients with Cushing syndrome, investigators have found no evidence that excessive levels of corticosteroids are responsible for the Cushing-like symptoms seen in patients taking protease inhibitors. These upsets in fat distribution seem to be occurring most often in HIV-infected patients taking protease inhibitors, including indinavir, ritonavir, saquinavir, and nelfinavir. But such disturbances apparently have also been seen in small numbers of patients taking other antiretroviral drugs. In a study by researchers at the National Institutes of Health, abdominal computed tomography scans of 10 patients who had developed distended abdomens and a sensation of fullness within 3 months of beginning treatment with indinavir revealed that the patients had accumulated excessive amounts of visceral fat (without overall weight gain). They also found that the patients had elevated serum cholesterol and triglyceride levels. "Our data suggest an association between the development of visceral obesity and hyperlipidemia," they noted. Another study by investigators at St Vincent's Hospital, Garvan Institute of Medical Research, and the National Center in HIV Epidemiology and Clinical Research in Sydney, Australia, found that on average, 64% of 116 HIV-infected patients taking protease inhibitors had a loss of fat from the face and limbs and accumulations of abdominal fat after an average duration of 10 months' treatment. Overall, these patients also developed elevated triglyceride and cholesterol levels and insulin resistance scores, compared with 32 HIV-infected patients who had never taken protease inhibitors and 47 healthy controls. While some investigators believe that the unusual patterns of fat deposition may reflect drug-related metabolic disturbances, abnormalities such as hyperlipidemia, hyperglycemia, insulin resistance, and diabetes are not consistently found in patients with the atypical fat wasting and deposits. Some researchers have hypothesized that patients who develop such abnormalities as a consequence of taking the drugs may have an inherited predisposition to do so. Clinical trials of extended duration and postmarketing surveillance may help clear up some unanswered questions about how often the problem occurs in patients taking protease inhibitors and its long-term implications, and whether the effect is reversible by altering the drug regimen, researchers noted. Something Old Countless laboratory freezers around the world are crammed with old serum samples collected for studies long ago completed. Now researchers have delved into one such freezer and identified the earliest confirmed case of HIV infection, found in blood drawn from an African man in 1959. The investigators looked for evidence of HIV in 1213 blood samples collected in Africa between 1959 and 1982, said Tuofu Zhu, MD, of the University of Washington, Seattle, who reported the findings. The study's findings also were published in the February 5 issue of Nature. One of those blood samples, originally gathered for a human genetics study, came from a Bantu man living in Leopoldville, Belgian Congo (now Kinshasa, Democratic Republic of Congo). Medical records indicated that he had sickle cell trait and glucose-6-phosphate-dehydrogenase deficiency (resulting from a common genetic variant in Africa which offers some protection against malaria), but nothing is known about his subsequent clinical course. Although the sample had deteriorated over the years, the researchers were able to isolate a total of 4 fragments from 2 viral genes—enough genetic material to clearly confirm the virus as HIV. The investigators then compared the genetic material from the 1959 virus with samples taken in the 1980s and 1990s to try to reconstruct how the virus has evolved over the decades. Genetic difference between related viruses can be used to estimate how much time has elapsed since the strains diverged from a common ancestor. "We realized if we could get the genetic sequence of an old virus, it would paint a pretty nice picture about HIV origin and evolution," said Dr David Ho, one of the report's authors. HIV mutates quickly, at a relatively constant rate, with about 1% of the virus's genetic material changing annually. Over the years, 10 distinct subtypes have emerged, designated A through J. Subtype B is the dominant subtype in North America and Europe, while subtype D predominates in Africa. Comparing the old virus with modern specimens, the investigators constructed a viral family tree. Their analysis indicates that the virus in the sample is an ancestor to B and D. The findings suggest that the virus first infected people in the 1940s or early 1950s, said Zhu, and that all the HIV subtypes evolved from 1 introduction of HIV into humans, rather than several independent cross-species jumps. "The diversification of HIV-1 in the past 40-50 years portends even greater viral heterogeneity in the coming decades, and underscores the need for continued surveillance," Zhu and collaborators wrote in the Nature paper. What factors spurred the initial spread of HIV-1 in central Africa remain unknown. Possibilities include the reuse of unsterilized needles in large-scale vaccination campaigns that began in Africa in the 1960s, although "social changes such as easier access to transportation, increasing population density, and more frequent sexual contacts may have been more important," the investigators noted.

Journal

JAMA – American Medical Association

Published: Mar 4, 1998

Keywords: hiv,hiv infections

There are no references for this article.