Treatment exhaustion of highly active antiretroviral therapy (HAART) a
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《英国医生杂志》
1 Department of Primary Care and Population Sciences, Royal Free and UC Medical School, London NW3 2PF, 2 MRC Clinical Trials Unit, London NW1 2DA, 3 Royal Free Centre for HIV Medicine, Royal Free Hospital, London NW3 2QG, 4 Centre for Sexual Health and HIV Research, Royal Free and UC Medical School, Mortimer Market Centre, London WC1E 6AU, 5 Lawson Unit, Department of HIV Medicine, Brighton and Sussex University Hospital Trust, Eastern Road, Brighton, BN2 5BE, 6 Department of GU Medicine and Communicable Diseases, St Mary's NHS Trust, London W2, 7 Guy's, King's and St Thomas' School of Medicine, London SE5 9RT, 8 Kobler Centre, Chelsea and Westminster Hospital, London SW10 9NH
Correspondence to: C A Sabin c.sabin@pcps.ucl.ac.uk
The UK Collaborative HIV Cohort (UK CHIC) is a collaboration of some of the largest HIV centres in the UK. The development and characteristics of the cohort have been described in detail elsewhere.5
Selection of patients
The criteria for inclusion of an individual in the UK CHIC study were that the patient was HIV positive, older than 16 years, and had attended one of the centres for care at any time after 1 January 1996. To date, data from existing clinical databases from six centres (Chelsea and Westminster NHS Trust, King's College Hospital, Mortimer Market Centre, St Mary's Hospital, Royal Free Hospital, and Brighton and Sussex University Hospitals, see bmj.com) have been merged. Data on demographics, AIDS events and deaths, antiretroviral treatment, and laboratory tests, were provided in a standardised format, including all information from the time of diagnosis. The analyses presented here are based on data collected over the period 2003-4.
Clinics provided data in a pseudo-anonymised form, using Soundex codes derived from surnames. We identified patients who had transferred between the centres in the study by matching on the basis of Soundex code and date of birth, and their records were linked.
Statistical methods
Patients were included in the cohort from 1 January 1996, their first attendance at one of the centres, or their 16th birthday, whichever occurred latest. We classified patients as under follow up in each year if the dates when they were first and last seen at any of the centres indicated that they were under follow up at that centre in that year. We present data for 1996-2002.
We defined individuals as being exposed to an antiretroviral drug if their treatment history included any use of that drug. We reported use of the following antiretroviral drugs: nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, zalcitabine, lodenosine, and abacavir), protease inhibitors (ritonavir, saquinavir (soft gel or hard gel formulation), indinavir, nelfinavir, amprenavir, or lopinavir), non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, delavirdine, and loviride), and a fusion inhibitor (enfuvirtide (T-20)). Use of two nucleotide reverse transcriptase inhibitors, adefovir and tenofovir, was limited over the study period; these drugs are included as nucleoside reverse transcriptase inhibitors in this analysis.
We used each patient's last available CD4 count and plasma HIV RNA burden in a year in the analysis of trends over time. We included patients only if they were under follow up and had a CD4 count or HIV RNA burden measured in that year. We did not consider patients who were lost to follow up as treatment failures.
We classified patients as having experienced virological failure to a regimen containing a protease inhibitor if two consecutive HIV RNA measurements had been above 500 copies/ml after at least six months' exposure to protease inhibitors. If patients had discontinued this class of drugs before the second HIV RNA measurement above 500 copies/ml we did not classify them as experiencing virological failure. We defined virological failure on a regimen that contained non-nucleoside reverse transcriptase inhibitors in a similar manner: we then classified patients as experiencing three class failure if they had experienced failure with regimens containing both protease inhibitors and non-nucleoside reverse transcriptase inhibitors (we assumed that failure had occurred with nucleoside reverse transcriptase inhibitors, as protease inhibitors or non-nucleoside reverse transcriptase inhibitors were rarely used without nucleoside reverse transcriptase inhibitors); we took the date of experiencing three class failure as the later of the dates of failure on a protease inhibitor and non-nucleoside reverse transcriptase inhibitors containing regimen. We considered CD4 count and HIV RNA trends separately in three groups: patients who had ever received antiretroviral therapy, patients who had been exposed to three or more classes of drugs, and patients who had experienced three class failure. We used the statistical package SAS, version 8, for all analyses.
Results
Although patients infected with HIV in the United Kingdom are becoming increasingly exposed to different antiretroviral treatments over time, immunological and virological profiles of these patients continue to improve at a population level. However, a small number of these individuals seem to be in danger of exhaustion of future treatment options.
As expected, an increasing proportion of individuals with HIV infection in the United Kingdom have been treated with antiretroviral therapy over time and, in line with this, their virological and immunological status has improved. Currently little evidence exists to indicate that a large proportion of patients are starting to experience therapeutic failure; this proportion has remained relatively stable since 2000. Even among patients who had experienced therapeutic failure with regimens containing all three classes of drugs, immunological and virological status has improved. We believe that these findings reflect the increasing number of new drugs that become available each year and the growing emphasis that is now placed on achieving good adherence, even in patients who have previously experienced problems when taking these drugs. However, the immunological and virological status of patients who have experienced three class failure remains relatively poor, showing that for a small number, treatment options are in danger of becoming exhausted.
Several new drugs from existing and new classes have recently been licensed.6-9 Other drugs in development may offer hopes of activity against existing resistant strains, or benefits in terms of reduced toxicity or a reduction in the number of pills that must be taken.10 However, past experience shows that preliminary reports of new drugs being associated with minimal cross resistance to other drugs are often followed by less positive findings.11 Whether the trends seen up to the end of 2002 in this current dataset have continued since will therefore be interesting to see.
Potential limitations
We have considered the impact of antiretroviral therapy on HIV infected individuals in the United Kingdom at a population level. Such trends should always be interpreted cautiously. In particular, increased CD4 counts over time may result from an increase in the number of newly diagnosed individuals with high CD4 counts attending the centres in the collaboration. However, results from the CD4 surveillance scheme in the United Kingdom12 and from individual cohorts in the collaboration13 14 indicate that this is not the case. A second concern is that as this is a dynamic cohort, patients may leave the cohort at any time as they move to centres that are not part of the collaboration. CD4 counts and HIV RNA values cannot be included in our analyses once patients leave the cohort, which may be a source of bias, particularly if those who were starting to experience therapeutic failure were more likely to drop out of the cohort. Although it is certainly true that some patients will have dropped out with therapeutic failure, many will have dropped out for unrelated reasons. The median last available CD4 count and HIV RNA measurement for those who dropped out of the cohort was above 200 cells/mm3 in 41% and < 2.7 log10 copies/ml in 32%, respectively, implying that many of these patients did not have therapeutic failure at their last visit. These proportions have remained relatively stable over time; we therefore do not believe that this will affect the trends seen.
One of the benefits of using data from a large multicentre study is that it is more representative of the UK epidemic than cohorts from single centres. However, although the dataset currently includes data on a third of all HIV infected individuals seen for care in the United Kingdom15 and patients in the cohort are broadly representative of HIV infected individuals in the UK,5 the cohort includes disproportionately more homosexual men and individuals of white ethnicity than are seen in the United Kingdom as a whole. Furthermore, as all centres actively participate in research studies (including clinical trials of new drugs), it is possible that exposure to novel treatments in these clinics may occur sooner than in other centres. Finally, discrepancies may still occur in histories of antiretroviral treatment if patients attend other centres either before or during the periods of follow up and treatment information from previous centres is incomplete. In this situation, our estimates of exposure to antiretroviral therapy may be underestimated.
Meaning of the study
We have identified two groups thought to be at high risk of treatment exhaustion: patients exposed to three or more drug classes and those who had experienced virological failure on regimens including both protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Not all treatment switches are made as a result of virological failure; individuals may also change treatments for convenience or to reduce toxicity. Thus, patients who have been exposed to three classes of drugs may not have experienced virological failure while receiving these drugs and may not necessarily show signs of treatment exhaustion. Patients who are known to have experienced virological failure while receiving these drugs, however, would be expected to have developed some resistance to their failing regimens, possibly leading to cross resistance to other drugs in the same class16 and placing these individuals at high risk of therapeutic failure. Although this group had higher HIV RNA measurements and lower CD4 counts than other treated individuals, virological failure is an imperfect surrogate for the presence of resistance mutations, and some of these patients may not have developed resistance to both protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Close links with the UK HIV Drug Resistance Database17 will allow us to deal with this question directly once the use of resistance testing has become routine in this group. Further follow up of clinical events in these patients will allow us to assess whether our definition of three class failure is a good indicator of subsequent poorer clinical outcome.
Our findings show that new drugs with low toxicity, which are not associated with cross resistance to existing drugs, will be needed for such patients.
What is already known on this topic
Highly active antiretroviral therapy (HAART) has had a dramatic impact on the health of individuals infected with HIV
For several reasons, however, many patients may not be able to tolerate their initial treatment regimen or may experience virological failure while receiving HAART
It may therefore be necessary to switch treatments on one or more occasions, raising the concern that some patients may exhaust all currently available treatment options
What this study adds
The immunological and virological status of infected patients generally improved
A small but growing proportion of these patients, however, seem to be in danger of exhaustion of current treatment options
The participating centres and collaborators are on bmj.com
The authors thank all the clinicians, data managers, and research nurses in participating clinical centres (see bmj.com) who have helped with the provision of data for this project.
Contributors: CAS contributed to the initial concept and design of the study, analysed and interpreted the data, and wrote the manuscript. She is guarantor. TH and RM provided the central coordination for the study, merged the datasets, and were involved with cleaning the datasets. FL provided input to the creation of datasets. ANP, RG, MAJ, MF, GS, PE, and BG contributed to the initial concept and design of the study, supervised the data collection, and provided input into the preparation of the manuscript. SB and MSY provided input into the preparation of the manuscript. All authors provided comments on the interpretation of the data and gave approval for the final version to be submitted for publication.
Funding: Medical Research Council, UK (grant G0000199).
Competing interest statement: Many of the authors have over the previous five years received reimbursement for attending symposiums, fees for speaking, membership of advisory boards, organising education or consultancy or funding for research from: Abbott (MY, SB, ANP, MAJ, RG, MF, GS), Boehringer Ingelheim (CAS, MY, ANP, MF, GS), Bristol Myers Squibb (BG, MY, SB, ANP, MAJ, MF, GS), Gilead Sciences (CAS, BG, MY, SB, ANP, RG, MF, GS), GlaxoSmithKline (CAS, FL, BG, SB, ANP, MF), Pfizer Pharmaceuticals (BG, MF), Roche (MY, SB, MAJ, RG, MF), Schering Plough (RG) and Tibotec (ANP). None of the authors hold any shares in any of the companies.
Ethical approval: Multicentre research ethics committee and local ethics committees.
References
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338: 853-860.
Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000;356: 291-296.
Phillips AN, Staszewski S, Lampe F, Youle MS, Klauke S, Bickel M, et al. Human immunodeficiency virus rebound after suppression to < 400 copies/mL during initial highly active antiretroviral therapy regimens, according to prior nucleoside experience and duration of suppression. J Infect Dis 2002;186: 1086-91.
Mocroft A, Phillips AN, Miller V, Gatell J, van Lunzen J, Parkin JM, et al. The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study. AIDS 2001;15: 201-209.
The UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: the UK Collaborative HIV Cohort (UK CHIC) study. HIV Med 2004;5: 115-24.
Lalezari J et al. Forty-eight week analysis of patients receiving T-20 as a component of multi-drug salvage therapy. 13th International Conference on AIDS, LBP116, Durban, 9-14 July 2000.
Squires K et al. Atazanavir (ATV) qd and efavirenz (EFV) qd with fixed-dose ZDV+3TC: comparison of antiviral efficacy and safety through wk 24 (AI424-034). 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, H-1076, 2002.
Colonno R, Rose R, Cianci C, Aldrovandi G, Parkin N, Friborg J. Emergence of atazanavir resistance and maintenance of susceptibility to other PIs is associated with an I50L substitution in HIV protease. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, 597, 2003.
Staszewski S, Gallant JE, Pozniak AL, Suleiman JMAH, DeJesus E, Lu B, Sayre J, et al. Efficacy and safety of tenofovir DF (TDF) versus stavudine (d4T) when used in combination with lamivudine and efavirenz in antiretroviral na?ve patients: 96-week preliminary interim results. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, 564b, 2003.
Gulick RM, Staszewski S. New drugs for HIV therapy. AIDS ( 2002);16(suppl 4): S135-S144.
Paulsen D, Liao Q, Fusco G, St. Clair M, Shaefer M, Ross L. Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV infection. AIDS Res Hum Retrovir 2002;18: 1011-9.
Chadborn T, Dingley S, Morgan D, Evans BG. CD4 cell counts in HIV-infected adults at HIV diagnosis in England and Wales, 1990 to 2001. O28. Presented at 9th Annual Conference of the British HIV Association (BHIVA), Manchester, England, 24-26 April 2003.
Easterbrook PJ, Yu LM, Goetghebeur E, Boag F, McLean K, Gazzard B. Ten-year trends in CD4 cell counts at HIV and AIDS diagnosis in a London HIV clinic. AIDS 2000;14: 561-71.
Barry SM, Lloyd-Owen SJ, Madge SJ, Cozzi-Lepri A, Evans AJ, Phillips AN, et al. The changing demographics of new HIV diagnoses at a London centre from 1994 to 2000. HIV Med 2002;3: 129-34.
Public Health Laboratory Service Communicable Disease Surveillance Centre, Institute of Child Health (London), Scottish Centre for Infection and Environmental Health. HIV and AIDS in the UK in 2001. London: Communicable Duisease Surveillance Centre, 2002.
Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Pat Care STDs 2004;18: 259-73.
The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS (in press).(Caroline A Sabin, professor of medical s)
Correspondence to: C A Sabin c.sabin@pcps.ucl.ac.uk
The UK Collaborative HIV Cohort (UK CHIC) is a collaboration of some of the largest HIV centres in the UK. The development and characteristics of the cohort have been described in detail elsewhere.5
Selection of patients
The criteria for inclusion of an individual in the UK CHIC study were that the patient was HIV positive, older than 16 years, and had attended one of the centres for care at any time after 1 January 1996. To date, data from existing clinical databases from six centres (Chelsea and Westminster NHS Trust, King's College Hospital, Mortimer Market Centre, St Mary's Hospital, Royal Free Hospital, and Brighton and Sussex University Hospitals, see bmj.com) have been merged. Data on demographics, AIDS events and deaths, antiretroviral treatment, and laboratory tests, were provided in a standardised format, including all information from the time of diagnosis. The analyses presented here are based on data collected over the period 2003-4.
Clinics provided data in a pseudo-anonymised form, using Soundex codes derived from surnames. We identified patients who had transferred between the centres in the study by matching on the basis of Soundex code and date of birth, and their records were linked.
Statistical methods
Patients were included in the cohort from 1 January 1996, their first attendance at one of the centres, or their 16th birthday, whichever occurred latest. We classified patients as under follow up in each year if the dates when they were first and last seen at any of the centres indicated that they were under follow up at that centre in that year. We present data for 1996-2002.
We defined individuals as being exposed to an antiretroviral drug if their treatment history included any use of that drug. We reported use of the following antiretroviral drugs: nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, zalcitabine, lodenosine, and abacavir), protease inhibitors (ritonavir, saquinavir (soft gel or hard gel formulation), indinavir, nelfinavir, amprenavir, or lopinavir), non-nucleoside reverse transcriptase inhibitors (efavirenz, nevirapine, delavirdine, and loviride), and a fusion inhibitor (enfuvirtide (T-20)). Use of two nucleotide reverse transcriptase inhibitors, adefovir and tenofovir, was limited over the study period; these drugs are included as nucleoside reverse transcriptase inhibitors in this analysis.
We used each patient's last available CD4 count and plasma HIV RNA burden in a year in the analysis of trends over time. We included patients only if they were under follow up and had a CD4 count or HIV RNA burden measured in that year. We did not consider patients who were lost to follow up as treatment failures.
We classified patients as having experienced virological failure to a regimen containing a protease inhibitor if two consecutive HIV RNA measurements had been above 500 copies/ml after at least six months' exposure to protease inhibitors. If patients had discontinued this class of drugs before the second HIV RNA measurement above 500 copies/ml we did not classify them as experiencing virological failure. We defined virological failure on a regimen that contained non-nucleoside reverse transcriptase inhibitors in a similar manner: we then classified patients as experiencing three class failure if they had experienced failure with regimens containing both protease inhibitors and non-nucleoside reverse transcriptase inhibitors (we assumed that failure had occurred with nucleoside reverse transcriptase inhibitors, as protease inhibitors or non-nucleoside reverse transcriptase inhibitors were rarely used without nucleoside reverse transcriptase inhibitors); we took the date of experiencing three class failure as the later of the dates of failure on a protease inhibitor and non-nucleoside reverse transcriptase inhibitors containing regimen. We considered CD4 count and HIV RNA trends separately in three groups: patients who had ever received antiretroviral therapy, patients who had been exposed to three or more classes of drugs, and patients who had experienced three class failure. We used the statistical package SAS, version 8, for all analyses.
Results
Although patients infected with HIV in the United Kingdom are becoming increasingly exposed to different antiretroviral treatments over time, immunological and virological profiles of these patients continue to improve at a population level. However, a small number of these individuals seem to be in danger of exhaustion of future treatment options.
As expected, an increasing proportion of individuals with HIV infection in the United Kingdom have been treated with antiretroviral therapy over time and, in line with this, their virological and immunological status has improved. Currently little evidence exists to indicate that a large proportion of patients are starting to experience therapeutic failure; this proportion has remained relatively stable since 2000. Even among patients who had experienced therapeutic failure with regimens containing all three classes of drugs, immunological and virological status has improved. We believe that these findings reflect the increasing number of new drugs that become available each year and the growing emphasis that is now placed on achieving good adherence, even in patients who have previously experienced problems when taking these drugs. However, the immunological and virological status of patients who have experienced three class failure remains relatively poor, showing that for a small number, treatment options are in danger of becoming exhausted.
Several new drugs from existing and new classes have recently been licensed.6-9 Other drugs in development may offer hopes of activity against existing resistant strains, or benefits in terms of reduced toxicity or a reduction in the number of pills that must be taken.10 However, past experience shows that preliminary reports of new drugs being associated with minimal cross resistance to other drugs are often followed by less positive findings.11 Whether the trends seen up to the end of 2002 in this current dataset have continued since will therefore be interesting to see.
Potential limitations
We have considered the impact of antiretroviral therapy on HIV infected individuals in the United Kingdom at a population level. Such trends should always be interpreted cautiously. In particular, increased CD4 counts over time may result from an increase in the number of newly diagnosed individuals with high CD4 counts attending the centres in the collaboration. However, results from the CD4 surveillance scheme in the United Kingdom12 and from individual cohorts in the collaboration13 14 indicate that this is not the case. A second concern is that as this is a dynamic cohort, patients may leave the cohort at any time as they move to centres that are not part of the collaboration. CD4 counts and HIV RNA values cannot be included in our analyses once patients leave the cohort, which may be a source of bias, particularly if those who were starting to experience therapeutic failure were more likely to drop out of the cohort. Although it is certainly true that some patients will have dropped out with therapeutic failure, many will have dropped out for unrelated reasons. The median last available CD4 count and HIV RNA measurement for those who dropped out of the cohort was above 200 cells/mm3 in 41% and < 2.7 log10 copies/ml in 32%, respectively, implying that many of these patients did not have therapeutic failure at their last visit. These proportions have remained relatively stable over time; we therefore do not believe that this will affect the trends seen.
One of the benefits of using data from a large multicentre study is that it is more representative of the UK epidemic than cohorts from single centres. However, although the dataset currently includes data on a third of all HIV infected individuals seen for care in the United Kingdom15 and patients in the cohort are broadly representative of HIV infected individuals in the UK,5 the cohort includes disproportionately more homosexual men and individuals of white ethnicity than are seen in the United Kingdom as a whole. Furthermore, as all centres actively participate in research studies (including clinical trials of new drugs), it is possible that exposure to novel treatments in these clinics may occur sooner than in other centres. Finally, discrepancies may still occur in histories of antiretroviral treatment if patients attend other centres either before or during the periods of follow up and treatment information from previous centres is incomplete. In this situation, our estimates of exposure to antiretroviral therapy may be underestimated.
Meaning of the study
We have identified two groups thought to be at high risk of treatment exhaustion: patients exposed to three or more drug classes and those who had experienced virological failure on regimens including both protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Not all treatment switches are made as a result of virological failure; individuals may also change treatments for convenience or to reduce toxicity. Thus, patients who have been exposed to three classes of drugs may not have experienced virological failure while receiving these drugs and may not necessarily show signs of treatment exhaustion. Patients who are known to have experienced virological failure while receiving these drugs, however, would be expected to have developed some resistance to their failing regimens, possibly leading to cross resistance to other drugs in the same class16 and placing these individuals at high risk of therapeutic failure. Although this group had higher HIV RNA measurements and lower CD4 counts than other treated individuals, virological failure is an imperfect surrogate for the presence of resistance mutations, and some of these patients may not have developed resistance to both protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Close links with the UK HIV Drug Resistance Database17 will allow us to deal with this question directly once the use of resistance testing has become routine in this group. Further follow up of clinical events in these patients will allow us to assess whether our definition of three class failure is a good indicator of subsequent poorer clinical outcome.
Our findings show that new drugs with low toxicity, which are not associated with cross resistance to existing drugs, will be needed for such patients.
What is already known on this topic
Highly active antiretroviral therapy (HAART) has had a dramatic impact on the health of individuals infected with HIV
For several reasons, however, many patients may not be able to tolerate their initial treatment regimen or may experience virological failure while receiving HAART
It may therefore be necessary to switch treatments on one or more occasions, raising the concern that some patients may exhaust all currently available treatment options
What this study adds
The immunological and virological status of infected patients generally improved
A small but growing proportion of these patients, however, seem to be in danger of exhaustion of current treatment options
The participating centres and collaborators are on bmj.com
The authors thank all the clinicians, data managers, and research nurses in participating clinical centres (see bmj.com) who have helped with the provision of data for this project.
Contributors: CAS contributed to the initial concept and design of the study, analysed and interpreted the data, and wrote the manuscript. She is guarantor. TH and RM provided the central coordination for the study, merged the datasets, and were involved with cleaning the datasets. FL provided input to the creation of datasets. ANP, RG, MAJ, MF, GS, PE, and BG contributed to the initial concept and design of the study, supervised the data collection, and provided input into the preparation of the manuscript. SB and MSY provided input into the preparation of the manuscript. All authors provided comments on the interpretation of the data and gave approval for the final version to be submitted for publication.
Funding: Medical Research Council, UK (grant G0000199).
Competing interest statement: Many of the authors have over the previous five years received reimbursement for attending symposiums, fees for speaking, membership of advisory boards, organising education or consultancy or funding for research from: Abbott (MY, SB, ANP, MAJ, RG, MF, GS), Boehringer Ingelheim (CAS, MY, ANP, MF, GS), Bristol Myers Squibb (BG, MY, SB, ANP, MAJ, MF, GS), Gilead Sciences (CAS, BG, MY, SB, ANP, RG, MF, GS), GlaxoSmithKline (CAS, FL, BG, SB, ANP, MF), Pfizer Pharmaceuticals (BG, MF), Roche (MY, SB, MAJ, RG, MF), Schering Plough (RG) and Tibotec (ANP). None of the authors hold any shares in any of the companies.
Ethical approval: Multicentre research ethics committee and local ethics committees.
References
Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998;338: 853-860.
Mocroft A, Katlama C, Johnson AM, Pradier C, Antunes F, Mulcahy F, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet 2000;356: 291-296.
Phillips AN, Staszewski S, Lampe F, Youle MS, Klauke S, Bickel M, et al. Human immunodeficiency virus rebound after suppression to < 400 copies/mL during initial highly active antiretroviral therapy regimens, according to prior nucleoside experience and duration of suppression. J Infect Dis 2002;186: 1086-91.
Mocroft A, Phillips AN, Miller V, Gatell J, van Lunzen J, Parkin JM, et al. The use of and response to second-line protease inhibitor regimens: results from the EuroSIDA study. AIDS 2001;15: 201-209.
The UK Collaborative HIV Cohort Steering Committee. The creation of a large UK-based multicentre cohort of HIV-infected individuals: the UK Collaborative HIV Cohort (UK CHIC) study. HIV Med 2004;5: 115-24.
Lalezari J et al. Forty-eight week analysis of patients receiving T-20 as a component of multi-drug salvage therapy. 13th International Conference on AIDS, LBP116, Durban, 9-14 July 2000.
Squires K et al. Atazanavir (ATV) qd and efavirenz (EFV) qd with fixed-dose ZDV+3TC: comparison of antiviral efficacy and safety through wk 24 (AI424-034). 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, H-1076, 2002.
Colonno R, Rose R, Cianci C, Aldrovandi G, Parkin N, Friborg J. Emergence of atazanavir resistance and maintenance of susceptibility to other PIs is associated with an I50L substitution in HIV protease. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, 597, 2003.
Staszewski S, Gallant JE, Pozniak AL, Suleiman JMAH, DeJesus E, Lu B, Sayre J, et al. Efficacy and safety of tenofovir DF (TDF) versus stavudine (d4T) when used in combination with lamivudine and efavirenz in antiretroviral na?ve patients: 96-week preliminary interim results. Tenth Conference on Retroviruses and Opportunistic Infections, Boston, 564b, 2003.
Gulick RM, Staszewski S. New drugs for HIV therapy. AIDS ( 2002);16(suppl 4): S135-S144.
Paulsen D, Liao Q, Fusco G, St. Clair M, Shaefer M, Ross L. Genotypic and phenotypic cross-resistance patterns to lopinavir and amprenavir in protease inhibitor-experienced patients with HIV infection. AIDS Res Hum Retrovir 2002;18: 1011-9.
Chadborn T, Dingley S, Morgan D, Evans BG. CD4 cell counts in HIV-infected adults at HIV diagnosis in England and Wales, 1990 to 2001. O28. Presented at 9th Annual Conference of the British HIV Association (BHIVA), Manchester, England, 24-26 April 2003.
Easterbrook PJ, Yu LM, Goetghebeur E, Boag F, McLean K, Gazzard B. Ten-year trends in CD4 cell counts at HIV and AIDS diagnosis in a London HIV clinic. AIDS 2000;14: 561-71.
Barry SM, Lloyd-Owen SJ, Madge SJ, Cozzi-Lepri A, Evans AJ, Phillips AN, et al. The changing demographics of new HIV diagnoses at a London centre from 1994 to 2000. HIV Med 2002;3: 129-34.
Public Health Laboratory Service Communicable Disease Surveillance Centre, Institute of Child Health (London), Scottish Centre for Infection and Environmental Health. HIV and AIDS in the UK in 2001. London: Communicable Duisease Surveillance Centre, 2002.
Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Pat Care STDs 2004;18: 259-73.
The UK Collaborative Group on HIV Drug Resistance and UK CHIC Study Group. Long term probability of detection of HIV-1 drug resistance after starting antiretroviral therapy in routine clinical practice. AIDS (in press).(Caroline A Sabin, professor of medical s)