Highly active antiretroviral therapy
http://www.100md.com
《英国医生杂志》
Exhaustion of treatment options is a challenge that can be delayed
An HIV infected person can possibly live a normal lifespan today, provided she or he takes highly active antiretroviral therapy and takes it perfectly. As pointed out by Sabin et al in this issue,1 even though new drugs are available each year, a noteworthy proportion of people are at risk of exhausting their treatment options. This proportion is only an imperfect surrogate of the presence of mutations giving rise to resistance to antiretrovirals. For an increasing number of patients, identifying a new regimen that could lower the HIV viraemia, increase the CD4 cell count, and prevent clinical progression is somewhat complicated. Looking at reasons why a current regimen is no longer working may help to make the available options clearer.
Suboptimal adherence to treatment is the most common and crucial reason for failing an antiretroviral regimen. Taking treatment at the correct time, not missing doses or drug holidays, and respecting food restrictions is difficult. Currently treatment needs to be taken for life, and such treatment influences everyday life a lot. Even if adherence levels are nearly perfect the likelihood of developing resistance to drugs is high.2
Intolerance is another reason for failing a regimen.3 Side effects may be directly responsible for suboptimal adherence.4 However, using self reports for the assessment of symptoms and of the impact that symptoms have on quality of life is uncommon. Often doctors are unable to predict the frequency and intensity of adverse events,5 particularly when a regimen includes three or more different drugs.
So how and when can the rapid exhaustion of treatment options be prevented? This can be attempted at any time during the treatment and even before starting it. In recent years, difficulties in adherence, toxicity, and the consequent risk of drug resistance have induced HIV experts and clinicians to postpone the optimal time for starting highly active antiretroviral therapy.6 The fact that immune function can be restored even if treatment is started when the CD4 cell count is very low7 8 supports this conservative strategy. Currently healthcare providers try to delay treatment for as long as possible—until the risk of opportunistic infections is too high. An ongoing large international clinical trial (the SMART study) is attempting to identify the best time for starting highly active antiretroviral therapy (www.clinicaltrials.gov).
The first choice of regimen of highly active antiretroviral therapy is crucial.9 An appropriate sequencing of drugs preserves future options. The chance to have recourse to active drugs in case of failure of treatment needs to be preserved, and drugs that are likely to induce mutations across classes need to be avoided in the beginning. Meanwhile, we need to take the convenience of patients into account. This would mean few pills, few doses, absence of food restrictions, and few adverse events. After starting treatment, efforts for assessing and managing side effects should be supported.
We need to implement prolonged and multidimensional interventions for maintaining or increasing adherence to drugs. More use of therapeutic drug monitoring in treating HIV infected people may also help identify people at risk of drug failure earlier. After treatment failure, easy access to resistance testing and the availability of expert guidance have been shown to save some active therapeutic options.10
The optimal time to switch from a failing regimen is unknown. Patients with detectable but low levels of HIV viraemia do not have worse clinical or immunological outcomes than patients who maintain undetectable levels of viraemia, even in people who have received all three antiretroviral classes of drugs.11 12 When HIV changes and becomes resistant to some drugs, it sometimes loses its capacity to replicate. This is particularly true with protease inhibitors and with some nucleoside reverse transcriptase inhibitors that cause HIV to develop the M184V mutation. We need to find out if after treatment failure, delaying the change in treatment when HIV viraemia is below 10 000 copies/ml and the CD4 cell count remains stable over time may help to save therapeutic options without the risk of developing dangerous drug resistance.
Preventing the exhaustion of therapeutic options for HIV infected people is currently a major challenge for both providers and researchers because all these strategies need a large amount of resources. Finally, to maximise the opportunity for long term efficacy and tolerability, the selection of treatment would hinge on the patient's preferences. Even very potent compounds have a high probability of failure if patients do not find them convenient and if their quality of life is not preserved.
Rita Murri, consultant in infectious diseases
Department of Infectious Diseases, Catholic University of Rome, 8-00168, Rome, Italy (ritamurri@libero.it)
Papers p 695
Competing interests: None declared.
References
Sabin CA, Hill T, Lampe F, Matthias R, Baghani S, Gilson R, et al. Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study. BMJ 2005;330: 695-8.
Bangsberg DR, Porco TC, Kagay C, Charlebois ED, Deeks SG, Guzman D, et al. Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. J Infect Dis 2004;190: 162-5.
D'Arminio Monforte A, Cozzi Lepri A, Rezza G, Pezzotti P, Antinori A, Phillips AN et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. AIDS 2000;14: 499-507.
Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De Longis P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr 2001;28: 445-9.
Justice AC, Rabeneck L, Hays RD, Wu AW, Bozzette SA. Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. J Acquir Immune Defic Syndr 1999;21: 126-33.
Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. 29 October 2004. http://aidsinfo.nih.gov/guidelines/adult/AH_102904.pdf (accessed 10 March 2005).
Garcia F, De Lazzari E, Plana M, Castro P, Mestre G, Nomdedu M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr 2004;36: 702-13.
Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, Abrams DI, et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 2003;17: 1907-15.
Centers for Diseases Control. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Morb Mortal Wkly Rep MMWR 1998;47(RR-5):1-41.
Badri SM, Adeyemi OM, Max BE, Zagorski BM, Barker DE. How does expert advice impact genotypic resistance testing in clinical practice? Clin Infect Dis 2003;37: 708-13.
Raffanti SP, Fusco JS, Sherrill BH, Hansen NI, Justice AC, D'Aquila R, et al. Effect of persistent moderate viremia on disease progression during HIV therapy. J Acquir Immune Defic Syndr 2004;37: 1147-54.
The PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004;364: 51-62.
An HIV infected person can possibly live a normal lifespan today, provided she or he takes highly active antiretroviral therapy and takes it perfectly. As pointed out by Sabin et al in this issue,1 even though new drugs are available each year, a noteworthy proportion of people are at risk of exhausting their treatment options. This proportion is only an imperfect surrogate of the presence of mutations giving rise to resistance to antiretrovirals. For an increasing number of patients, identifying a new regimen that could lower the HIV viraemia, increase the CD4 cell count, and prevent clinical progression is somewhat complicated. Looking at reasons why a current regimen is no longer working may help to make the available options clearer.
Suboptimal adherence to treatment is the most common and crucial reason for failing an antiretroviral regimen. Taking treatment at the correct time, not missing doses or drug holidays, and respecting food restrictions is difficult. Currently treatment needs to be taken for life, and such treatment influences everyday life a lot. Even if adherence levels are nearly perfect the likelihood of developing resistance to drugs is high.2
Intolerance is another reason for failing a regimen.3 Side effects may be directly responsible for suboptimal adherence.4 However, using self reports for the assessment of symptoms and of the impact that symptoms have on quality of life is uncommon. Often doctors are unable to predict the frequency and intensity of adverse events,5 particularly when a regimen includes three or more different drugs.
So how and when can the rapid exhaustion of treatment options be prevented? This can be attempted at any time during the treatment and even before starting it. In recent years, difficulties in adherence, toxicity, and the consequent risk of drug resistance have induced HIV experts and clinicians to postpone the optimal time for starting highly active antiretroviral therapy.6 The fact that immune function can be restored even if treatment is started when the CD4 cell count is very low7 8 supports this conservative strategy. Currently healthcare providers try to delay treatment for as long as possible—until the risk of opportunistic infections is too high. An ongoing large international clinical trial (the SMART study) is attempting to identify the best time for starting highly active antiretroviral therapy (www.clinicaltrials.gov).
The first choice of regimen of highly active antiretroviral therapy is crucial.9 An appropriate sequencing of drugs preserves future options. The chance to have recourse to active drugs in case of failure of treatment needs to be preserved, and drugs that are likely to induce mutations across classes need to be avoided in the beginning. Meanwhile, we need to take the convenience of patients into account. This would mean few pills, few doses, absence of food restrictions, and few adverse events. After starting treatment, efforts for assessing and managing side effects should be supported.
We need to implement prolonged and multidimensional interventions for maintaining or increasing adherence to drugs. More use of therapeutic drug monitoring in treating HIV infected people may also help identify people at risk of drug failure earlier. After treatment failure, easy access to resistance testing and the availability of expert guidance have been shown to save some active therapeutic options.10
The optimal time to switch from a failing regimen is unknown. Patients with detectable but low levels of HIV viraemia do not have worse clinical or immunological outcomes than patients who maintain undetectable levels of viraemia, even in people who have received all three antiretroviral classes of drugs.11 12 When HIV changes and becomes resistant to some drugs, it sometimes loses its capacity to replicate. This is particularly true with protease inhibitors and with some nucleoside reverse transcriptase inhibitors that cause HIV to develop the M184V mutation. We need to find out if after treatment failure, delaying the change in treatment when HIV viraemia is below 10 000 copies/ml and the CD4 cell count remains stable over time may help to save therapeutic options without the risk of developing dangerous drug resistance.
Preventing the exhaustion of therapeutic options for HIV infected people is currently a major challenge for both providers and researchers because all these strategies need a large amount of resources. Finally, to maximise the opportunity for long term efficacy and tolerability, the selection of treatment would hinge on the patient's preferences. Even very potent compounds have a high probability of failure if patients do not find them convenient and if their quality of life is not preserved.
Rita Murri, consultant in infectious diseases
Department of Infectious Diseases, Catholic University of Rome, 8-00168, Rome, Italy (ritamurri@libero.it)
Papers p 695
Competing interests: None declared.
References
Sabin CA, Hill T, Lampe F, Matthias R, Baghani S, Gilson R, et al. Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study. BMJ 2005;330: 695-8.
Bangsberg DR, Porco TC, Kagay C, Charlebois ED, Deeks SG, Guzman D, et al. Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. J Infect Dis 2004;190: 162-5.
D'Arminio Monforte A, Cozzi Lepri A, Rezza G, Pezzotti P, Antinori A, Phillips AN et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. I.CO.N.A. Study Group. AIDS 2000;14: 499-507.
Ammassari A, Murri R, Pezzotti P, Trotta MP, Ravasio L, De Longis P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr 2001;28: 445-9.
Justice AC, Rabeneck L, Hays RD, Wu AW, Bozzette SA. Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. J Acquir Immune Defic Syndr 1999;21: 126-33.
Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. 29 October 2004. http://aidsinfo.nih.gov/guidelines/adult/AH_102904.pdf (accessed 10 March 2005).
Garcia F, De Lazzari E, Plana M, Castro P, Mestre G, Nomdedu M, et al. Long-term CD4+ T-cell response to highly active antiretroviral therapy according to baseline CD4+ T-cell count. J Acquir Immune Defic Syndr 2004;36: 702-13.
Hunt PW, Deeks SG, Rodriguez B, Valdez H, Shade SB, Abrams DI, et al. Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy. AIDS 2003;17: 1907-15.
Centers for Diseases Control. Report of the NIH panel to define principles of therapy of HIV infection and guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Morb Mortal Wkly Rep MMWR 1998;47(RR-5):1-41.
Badri SM, Adeyemi OM, Max BE, Zagorski BM, Barker DE. How does expert advice impact genotypic resistance testing in clinical practice? Clin Infect Dis 2003;37: 708-13.
Raffanti SP, Fusco JS, Sherrill BH, Hansen NI, Justice AC, D'Aquila R, et al. Effect of persistent moderate viremia on disease progression during HIV therapy. J Acquir Immune Defic Syndr 2004;37: 1147-54.
The PLATO Collaboration. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004;364: 51-62.