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Caution: should we be treating HIV infection early?
VIEWPOINT
Viewpoint
Caution: should we be treating HIV infection early? Jay A Levy The overriding conclusion of my clinical colleagues is that HIV infection should be treated as soon as possible and with as large an armamentarium as is available. For this reason, therapy with a three-drug combination is recommended and it appears we will soon be increasing this to a four or five drug regimen. This approach is similar to that used in cancer, but have we really succeeded going in this direction with malignancies? Moreover, with HIV infection, administration of these drugs has to be on a continual basis. No cancer patient takes three or four chemotherapeutic drugs for a lifetime. The need for continual therapy underlines the requirement for compliance and for acceptance of the toxicity that often occurs. If strict adherence to protocols is not followed, resistant viruses can readily emerge. Many untoward consequences can occur with the present regimens,1 including the “protease paunch” and myocardial infarction associated with high circulating lipid levels in the blood resulting from protease inhibitor administration.2,3 We must also be attentive to the potential detrimental interaction of anti-HIV drugs with other important ongoing treatments given to HIV-infected individuals for non-HIV-related disorders.4 With these concerns, are we then choosing the right direction by giving these drugs to all infected individuals who have evidence of virus in their blood? Would we not serve infected people better by reserving certain therapies and administering them at a time when their use is clearly required? I favour this latter approach. Certainly this issue merits further discussion and experimental evaluation. My concern is not about the therapies used during acute or primary infection. At that time, within days after the virus enters the body, a major benefit to the newly infected individual can be provided by lowering the viral load dramatically and perhaps even arresting the establishment of HIV infection. Antiviral therapy given before seroconversion seems to protect the cellular immune response to HIV.5 Conceivably, this type of host reaction occurs naturally in some individuals who have been exposed to the virus on many occasions but are not infected. In these high-risk uninfected people, the immune system has resolved the infection.6–9 My great concern lies in the administration of drugs to individuals who have been infected for several months to years. By that time, most estimates show that several hundred billion cells in the body can carry the virus, particularly in the lymphoid system,10 but also in tissues, such as the brain, intestine and testes.1 What is the current advice for treatment of these people? The published recommendation by national groups dealing with clinical care is the administration of three drugs when the viral RNA level in blood is over 5000 (some physicians now even administer them with any detectable viral load) and a CD4 cell-count below 500.11 The clinical state (if the Lancet 1998; 352: 982–83 University of California, School of Medicine, San Francisco, CA 94143, USA (J A Levy MD)
982
person is without symptoms) is not a major detriment: it is the numbers that appear to decide the therapeutic course. I take issue with that approach. A justification for early treatment is that if any virus replication takes place, mutations might develop, eventually leading to a drug-resistant virus. We should be aware that mutations occurring at a steady rate during HIV replication are random and would not select for viruses resistant to current drugs. Instead, it is the drugs themselves that encourage the emergence of these types of viruses. Under normal circumstances, no selective advantage against a non-resistant virus is introduced and it is more likely that a wild-type virus will dominate. Another reason given for early treatment is that any replication of HIV will lead to irreversible destruction of the immune system. The resulting damage would then prevent an infected individual from regaining control of the virus. What is overlooked by this assumption is that these drugs can be toxic1 and can be directly detrimental to a natural immune response to HIV, which is present in most individuals during the asymptomatic phase of infection.8 This effective antiviral immune response is characteristic of long-term survivors who have been infected for over 20 years, have no symptoms, and have not been on any therapy.1,8 These individuals have a strong cell-mediated (CD8 cell) anti-HIV immune response that maintains low viral loads and inhibition of the clinical sequellae of the infection.1,8 In some people on triple therapy, however, we have observed a decrease in this CD8-cell antiviral response (Stranford SA, Levy JA, unpublished observations). It appears that the current antiviral therapies, while reducing virus replication, do not bring about the results achieved by a natural host anti-HIV response. This immune response, observed in long-term survivors, maintains control of HIV replication without the need for antiviral treatment.1,5,8,12,13 In my view early treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime of the person. Any decision to stop the drugs could only be made if one had assurances that all infected cells had been eliminated (now an unlikely event) or that the immune system has recovered sufficiently to control HIV. What we have learned in the past year is not encouraging in this matter. Individuals who have elected to stop therapy even after 3 years not only experience the resumption of virus production, but the amount of viraemia observed (sometimes at 100 000 to 1 million RNA molecules/mL) is often higher than when these individuals began therapy These (Levy JA, unpublished observations).14,15 observations strongly suggest that the immune system has either been compromised by the drugs or “put to rest” by the therapy. Without exposure to a sufficient amount of viral antigens, the ability to recognise replicating HIV is lost. Thus, the host, off treatment, cannot respond effectively to a re-establishment of productive virus infection by the remaining cellular reservoirs of HIV.16 These infected cells, found in tissues throughout the body,
THE LANCET • Vol 352 • September 19, 1998
VIEWPOINT
are not directly affected by antiviral therapies that target only new infections but not those cells already infected.17,18 What is the solution? Physicians should carefully consider the time when drug therapy is begun for infected individuals who are past the acute infection phase. Until we have a good surrogate marker presaging irreversible damage to the immune system or a means of inducing an anti-HIV immune response, a delay in initiating therapy should be considered. The current therapeutic regimens should be reserved for those patients who have symptoms or whose CD4 cell-counts have dropped substantially. Let us consider the possibility of beginning treatment only after the CD4 cell-count falls below 400 and the viral loads have been above 30 000 on at least two occasions. These numbers, though arbitrary, are chosen because they are representative of what appears to be evidence of an early demise in the immune response, but one that can be reversed. For example, 30 000 viral RNA copies/mL of blood, or about 450 million total circulating virus particles in the plasma, would require about 450 000 infected cells—a small number compared to the billions of cells infected.10 (These estimates are calculated from 30⫻104 viral RNA copies multiplied by blood plasma volume [3⫻103 mL], divided by the number of copies in a virion [two], and considers the finding that productively infected cells produce about 1000 viral particles.19,20) Thus, at this point in the infection, treatment would be started when the immune system is still functioning because the large infected cellular reservoirs in the host are still being controlled in HIV production. Many of these infected cells may contain defective genomes, but our studies suggest that up to 50% of these latent cells in lymphoid tissue have competent virus capable of reinfection. CD8 cells appear to be responsible for keeping the virus suppressed.21 Administering drugs at this selected time seems the best strategy because the virus can be controlled and the immune system can recover, as measured by the eventual return of naive CD4 cells.22 Instead of subjecting infected people to antiviral therapy early, when it is not needed (the immune system is functioning), requires strict adherence, and can be harmful, a delay can provide an interval of several years in which immune cells can control the virus and selection of resistant mutants can be avoided. Moreover, drugs given at this later time will still permit a recovery of the immune system from a state that is not irreversibly damaged. Observations on treated AIDS patients with massive destruction of lymphoid tissues have shown reformation of germinal follicles (Feinberg M, unpublished observations). After extensive damage to the immune system from irradiation, patients show a recovery in the production of white blood cells.23 The return of immune function during antiviral therapy is reflected by immune responses to many pathogens, but unfortunately usually not HIV. Therefore, along with the use of antiviral drugs, we need to evaluate the concomitant administration of cytokines (such as IL-2) or other compounds that enhance immune reactions against HIV. Indeed, eventually, it might prove valuable to concurrently provide patients with antiviral drugs, immune restorative therapy, and appropriate immunisation procedures. By this approach, an effective immune response against HIV can be induced as well as against other pathogens. This direction could lead to the prolonged control of the virus from two directions: an activated immune system and antiviral drugs. In fact, with the immune system functioning, perhaps the drugs will eventually be
THE LANCET • Vol 352 • September 19, 1998
unnecessary. This approach seems important in light of the fact that current treatments appear to leave the patient in a naive immune state, like an uninfected individual, rather than someone prepared to control HIV infection. The ultimate objective, if not elimination of the virus, is to return all HIV-infected people to the state of long-term survivors who do not need treatment even after 20 years of infection. Their immune system is the dominant force controlling HIV and preventing its inevitable pathogenesis.8 I thank Donald Abrams, Frederick Hecht, Richard Chaisson, R Ellen Koenig, Alan Landay, and John Phair for helpful comments on the text.
References 1 2
3
4 5
6
7
8 9 10
11 12
13
14
15
16
17 18 19
20
21
22
23
Levy JA. HIV and the pathogenesis of AIDS. 2nd edn. Washington, DC: American Society of Microbiology, 1998. Miller KD, Jones E, Yanovski JA, Shankar R, Reuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351: 871–75. Gallet B, Pulik M, Genet P, Chedin P, Hiltgen M. Vascular complications associated with use of HIV protease inhibitors. Lancet 1998; 351: 1958–59. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. JAMA 1997; 277: 145–53. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1specific CD4+ T cell responses associated with control of viremia. Science 1997; 278: 1447–50. Stranford S, Skurnick J, Louria D, et al. HIV-exposed uninfected individuals appear to be protected by a CD8+ cell anti-HIV noncytotoxic response. Submitted. Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol 1995; 7: 448–55. Levy JA. HIV pathogenesis and long-term survival. AIDS 1993; 7: 1401–10. Shearer GM, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today 1996; 17: 21–24. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362: 359–62. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998. JAMA 1998; 280: 78–86. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995; 332: 201–08. Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998; 279: 2103–06. Angel JB, Kumar A, Parato K, et al. Improvement in cell-mediated function during potent anti-human immunodeficiency virus therapy with ritonavir plus saquinavir. J Infect Dis 1998; 177: 898–904. Montaner JSG, Harris M, Mo T, Harrigan PR. Rebound of plasma HIV viral load following prolonged suppression with combination therapy. AIDS 1998; 12: 1398–99. Tenner-Racz K, Stellbrink HJ, van Lunzen J, et al. The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of highly active antiretroviral therapy. J Clin Invest 1998; 187: 949–59. Levy JA. HIV research: a need to focus on the right target. Lancet 1995; 345: 1619–21. Levy JA. Surrogate markers in AIDS research. Is there truth in numbers? JAMA 1996; 276: 161–62. Dimitrov DS, Willey RL, Sato H, Chang L-J, Blumenthal R, Martin MA. Quantitation of human immunodeficiency virus type 1 infection kinetics. J Virol 1993; 67: 2182–90. Levy JA, Ramachandran B, Barker E, Guthrie J, Elbeik T. Plasma viral load, CD4+ cell counts, and HIV-1 production by cells. Science 1996; 271: 670–71. Blackbourn DJ, Mackewicz CE, Barker E, et al. Suppression of HIV replication by lymphoid tissue CD8+ cells correlates with the clinical state of HIV-infected individuals. Proc Natl Acad Sci USA 1996; 93: 13125–30. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112–16. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332: 143–49.
983
Viewpoint
Caution: should we be treating HIV infection early? Jay A Levy The overriding conclusion of my clinical colleagues is that HIV infection should be treated as soon as possible and with as large an armamentarium as is available. For this reason, therapy with a three-drug combination is recommended and it appears we will soon be increasing this to a four or five drug regimen. This approach is similar to that used in cancer, but have we really succeeded going in this direction with malignancies? Moreover, with HIV infection, administration of these drugs has to be on a continual basis. No cancer patient takes three or four chemotherapeutic drugs for a lifetime. The need for continual therapy underlines the requirement for compliance and for acceptance of the toxicity that often occurs. If strict adherence to protocols is not followed, resistant viruses can readily emerge. Many untoward consequences can occur with the present regimens,1 including the “protease paunch” and myocardial infarction associated with high circulating lipid levels in the blood resulting from protease inhibitor administration.2,3 We must also be attentive to the potential detrimental interaction of anti-HIV drugs with other important ongoing treatments given to HIV-infected individuals for non-HIV-related disorders.4 With these concerns, are we then choosing the right direction by giving these drugs to all infected individuals who have evidence of virus in their blood? Would we not serve infected people better by reserving certain therapies and administering them at a time when their use is clearly required? I favour this latter approach. Certainly this issue merits further discussion and experimental evaluation. My concern is not about the therapies used during acute or primary infection. At that time, within days after the virus enters the body, a major benefit to the newly infected individual can be provided by lowering the viral load dramatically and perhaps even arresting the establishment of HIV infection. Antiviral therapy given before seroconversion seems to protect the cellular immune response to HIV.5 Conceivably, this type of host reaction occurs naturally in some individuals who have been exposed to the virus on many occasions but are not infected. In these high-risk uninfected people, the immune system has resolved the infection.6–9 My great concern lies in the administration of drugs to individuals who have been infected for several months to years. By that time, most estimates show that several hundred billion cells in the body can carry the virus, particularly in the lymphoid system,10 but also in tissues, such as the brain, intestine and testes.1 What is the current advice for treatment of these people? The published recommendation by national groups dealing with clinical care is the administration of three drugs when the viral RNA level in blood is over 5000 (some physicians now even administer them with any detectable viral load) and a CD4 cell-count below 500.11 The clinical state (if the Lancet 1998; 352: 982–83 University of California, School of Medicine, San Francisco, CA 94143, USA (J A Levy MD)
982
person is without symptoms) is not a major detriment: it is the numbers that appear to decide the therapeutic course. I take issue with that approach. A justification for early treatment is that if any virus replication takes place, mutations might develop, eventually leading to a drug-resistant virus. We should be aware that mutations occurring at a steady rate during HIV replication are random and would not select for viruses resistant to current drugs. Instead, it is the drugs themselves that encourage the emergence of these types of viruses. Under normal circumstances, no selective advantage against a non-resistant virus is introduced and it is more likely that a wild-type virus will dominate. Another reason given for early treatment is that any replication of HIV will lead to irreversible destruction of the immune system. The resulting damage would then prevent an infected individual from regaining control of the virus. What is overlooked by this assumption is that these drugs can be toxic1 and can be directly detrimental to a natural immune response to HIV, which is present in most individuals during the asymptomatic phase of infection.8 This effective antiviral immune response is characteristic of long-term survivors who have been infected for over 20 years, have no symptoms, and have not been on any therapy.1,8 These individuals have a strong cell-mediated (CD8 cell) anti-HIV immune response that maintains low viral loads and inhibition of the clinical sequellae of the infection.1,8 In some people on triple therapy, however, we have observed a decrease in this CD8-cell antiviral response (Stranford SA, Levy JA, unpublished observations). It appears that the current antiviral therapies, while reducing virus replication, do not bring about the results achieved by a natural host anti-HIV response. This immune response, observed in long-term survivors, maintains control of HIV replication without the need for antiviral treatment.1,5,8,12,13 In my view early treatment with antiviral drugs starts the clock ticking too soon, limiting future options and making therapy a necessity for the lifetime of the person. Any decision to stop the drugs could only be made if one had assurances that all infected cells had been eliminated (now an unlikely event) or that the immune system has recovered sufficiently to control HIV. What we have learned in the past year is not encouraging in this matter. Individuals who have elected to stop therapy even after 3 years not only experience the resumption of virus production, but the amount of viraemia observed (sometimes at 100 000 to 1 million RNA molecules/mL) is often higher than when these individuals began therapy These (Levy JA, unpublished observations).14,15 observations strongly suggest that the immune system has either been compromised by the drugs or “put to rest” by the therapy. Without exposure to a sufficient amount of viral antigens, the ability to recognise replicating HIV is lost. Thus, the host, off treatment, cannot respond effectively to a re-establishment of productive virus infection by the remaining cellular reservoirs of HIV.16 These infected cells, found in tissues throughout the body,
THE LANCET • Vol 352 • September 19, 1998
VIEWPOINT
are not directly affected by antiviral therapies that target only new infections but not those cells already infected.17,18 What is the solution? Physicians should carefully consider the time when drug therapy is begun for infected individuals who are past the acute infection phase. Until we have a good surrogate marker presaging irreversible damage to the immune system or a means of inducing an anti-HIV immune response, a delay in initiating therapy should be considered. The current therapeutic regimens should be reserved for those patients who have symptoms or whose CD4 cell-counts have dropped substantially. Let us consider the possibility of beginning treatment only after the CD4 cell-count falls below 400 and the viral loads have been above 30 000 on at least two occasions. These numbers, though arbitrary, are chosen because they are representative of what appears to be evidence of an early demise in the immune response, but one that can be reversed. For example, 30 000 viral RNA copies/mL of blood, or about 450 million total circulating virus particles in the plasma, would require about 450 000 infected cells—a small number compared to the billions of cells infected.10 (These estimates are calculated from 30⫻104 viral RNA copies multiplied by blood plasma volume [3⫻103 mL], divided by the number of copies in a virion [two], and considers the finding that productively infected cells produce about 1000 viral particles.19,20) Thus, at this point in the infection, treatment would be started when the immune system is still functioning because the large infected cellular reservoirs in the host are still being controlled in HIV production. Many of these infected cells may contain defective genomes, but our studies suggest that up to 50% of these latent cells in lymphoid tissue have competent virus capable of reinfection. CD8 cells appear to be responsible for keeping the virus suppressed.21 Administering drugs at this selected time seems the best strategy because the virus can be controlled and the immune system can recover, as measured by the eventual return of naive CD4 cells.22 Instead of subjecting infected people to antiviral therapy early, when it is not needed (the immune system is functioning), requires strict adherence, and can be harmful, a delay can provide an interval of several years in which immune cells can control the virus and selection of resistant mutants can be avoided. Moreover, drugs given at this later time will still permit a recovery of the immune system from a state that is not irreversibly damaged. Observations on treated AIDS patients with massive destruction of lymphoid tissues have shown reformation of germinal follicles (Feinberg M, unpublished observations). After extensive damage to the immune system from irradiation, patients show a recovery in the production of white blood cells.23 The return of immune function during antiviral therapy is reflected by immune responses to many pathogens, but unfortunately usually not HIV. Therefore, along with the use of antiviral drugs, we need to evaluate the concomitant administration of cytokines (such as IL-2) or other compounds that enhance immune reactions against HIV. Indeed, eventually, it might prove valuable to concurrently provide patients with antiviral drugs, immune restorative therapy, and appropriate immunisation procedures. By this approach, an effective immune response against HIV can be induced as well as against other pathogens. This direction could lead to the prolonged control of the virus from two directions: an activated immune system and antiviral drugs. In fact, with the immune system functioning, perhaps the drugs will eventually be
THE LANCET • Vol 352 • September 19, 1998
unnecessary. This approach seems important in light of the fact that current treatments appear to leave the patient in a naive immune state, like an uninfected individual, rather than someone prepared to control HIV infection. The ultimate objective, if not elimination of the virus, is to return all HIV-infected people to the state of long-term survivors who do not need treatment even after 20 years of infection. Their immune system is the dominant force controlling HIV and preventing its inevitable pathogenesis.8 I thank Donald Abrams, Frederick Hecht, Richard Chaisson, R Ellen Koenig, Alan Landay, and John Phair for helpful comments on the text.
References 1 2
3
4 5
6
7
8 9 10
11 12
13
14
15
16
17 18 19
20
21
22
23
Levy JA. HIV and the pathogenesis of AIDS. 2nd edn. Washington, DC: American Society of Microbiology, 1998. Miller KD, Jones E, Yanovski JA, Shankar R, Reuerstein I, Falloon J. Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998; 351: 871–75. Gallet B, Pulik M, Genet P, Chedin P, Hiltgen M. Vascular complications associated with use of HIV protease inhibitors. Lancet 1998; 351: 1958–59. Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. JAMA 1997; 277: 145–53. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1specific CD4+ T cell responses associated with control of viremia. Science 1997; 278: 1447–50. Stranford S, Skurnick J, Louria D, et al. HIV-exposed uninfected individuals appear to be protected by a CD8+ cell anti-HIV noncytotoxic response. Submitted. Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol 1995; 7: 448–55. Levy JA. HIV pathogenesis and long-term survival. AIDS 1993; 7: 1401–10. Shearer GM, Clerici M. Protective immunity against HIV infection: has nature done the experiment for us? Immunol Today 1996; 17: 21–24. Embretson J, Zupancic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362: 359–62. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998. JAMA 1998; 280: 78–86. Cao Y, Qin L, Zhang L, Safrit J, Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995; 332: 201–08. Ogg GS, Jin X, Bonhoeffer S, et al. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 1998; 279: 2103–06. Angel JB, Kumar A, Parato K, et al. Improvement in cell-mediated function during potent anti-human immunodeficiency virus therapy with ritonavir plus saquinavir. J Infect Dis 1998; 177: 898–904. Montaner JSG, Harris M, Mo T, Harrigan PR. Rebound of plasma HIV viral load following prolonged suppression with combination therapy. AIDS 1998; 12: 1398–99. Tenner-Racz K, Stellbrink HJ, van Lunzen J, et al. The unenlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 T cell counts are sites for virus replication and CD4 T cell proliferation. The impact of highly active antiretroviral therapy. J Clin Invest 1998; 187: 949–59. Levy JA. HIV research: a need to focus on the right target. Lancet 1995; 345: 1619–21. Levy JA. Surrogate markers in AIDS research. Is there truth in numbers? JAMA 1996; 276: 161–62. Dimitrov DS, Willey RL, Sato H, Chang L-J, Blumenthal R, Martin MA. Quantitation of human immunodeficiency virus type 1 infection kinetics. J Virol 1993; 67: 2182–90. Levy JA, Ramachandran B, Barker E, Guthrie J, Elbeik T. Plasma viral load, CD4+ cell counts, and HIV-1 production by cells. Science 1996; 271: 670–71. Blackbourn DJ, Mackewicz CE, Barker E, et al. Suppression of HIV replication by lymphoid tissue CD8+ cells correlates with the clinical state of HIV-infected individuals. Proc Natl Acad Sci USA 1996; 93: 13125–30. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112–16. Mackall CL, Fleisher TA, Brown MR, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332: 143–49.
983