BMJ  2005;330:695 (26 March), doi:10.1136/bmj.38369.669850.8F (published 4 March 2005)

Paper

Treatment exhaustion of highly active antiretroviral therapy (HAART) among individuals infected with HIV in the United Kingdom: multicentre cohort study

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 1NY, ⁷ Guy's, King's and St Thomas' School of Medicine, London SE5 9RT, ⁸ Kobler Centre, Chelsea and Westminster Hospital, London SW10 9NH

Abstract

Objectives To investigate whether there is evidence that an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 cell count that are consistent with exhaustion of available treatment options.

Design Multicentre cohort study.

Setting Six large HIV treatment centres in southeast England.

Participants All individuals seen for care between 1 January 1996 and 31 December 2002.

Main outcome measures Exposure to individual antiretroviral drugs and drug classes, CD4 count, plasma HIV RNA burden.

Results Information is available on 16 593 individuals (13 378 (80.6%) male patients, 10 340 (62.3%) infected via homosexual or bisexual sex, 4426 (26.7%) infected via heterosexual sex, median age 34 years). Overall, 10 207 of the 16 593 patients (61.5%) have been exposed to any antiretroviral therapy. This proportion increased from 41.2% of patients under follow up at the end of 1996 to 71.3% of those under follow up in 2002. The median CD4 count and HIV RNA burden of patients under follow up in each year changed from 270 cells/mm³ and 4.34 log₁₀ copies/ml in 1996 to 408 cells/mm³ and 1.89 log₁₀ copies/ml, respectively, in 2002. By 2002, 3060 (38%) of patients who had ever been treated with antiretroviral therapy had experienced all three main classes. Of these, around one quarter had evidence of "viral load failure" with all these three classes. Patients with three class failure were more likely to have an HIV RNA burden > 2.7 log₁₀ copies/ml and a CD4 count < 200 cells/mm³.

Conclusions The proportion of individuals with HIV infection in the United Kingdom who have been treated has increased gradually over time. A substantial proportion of these patients seem to be in danger of exhausting their options for antiretroviral treatment. New drugs with low toxicity, which are not associated with cross resistance to existing drugs, are urgently needed for such patients.

Introduction

Most HIV infected individuals starting highly active antiretroviral therapy (HAART) will experience good virological responses to treatment. However, imperfect adherence, tolerability problems, inadequate drug concentrations, and pre-existing or newly developed antiretroviral resistance may mean that in some patients, virological responses on their first treatment combination will fail within the first few years.¹ Compared with the initial treatment regimen, subsequent regimens are progressively less likely to produce a durable virological response.² Although new drugs are continually being developed, concern has therefore arisen that patients will ultimately exhaust all currently available options for treatment.

We describe levels of exposure to antiretroviral treatment and assess, at a population level, the relations between exposure to antiretroviral drugs and immunological and virological status in a large multicentre cohort of HIV infected patients from the United Kingdom. We investigate whether an increasing proportion of HIV infected patients is starting to experience increases in viral load and decreases in CD4 count, consistent with exhaustion of available treatment options.

Methods

The UK Collaborative HIV Cohort (UK CHIC) is a collaboration of some of the largest HIV centres in the UK.³

Selection of patients
The criteria for inclusion 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. Data from existing clinical databases from six centres have been merged (see bmj.com).

Clinics provided data in a pseudo-anonymised form which still allowed records to be linked when patients transferred between the centres in the study.

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 defined individuals as being exposed to an antiretroviral drug if their treatment history included any use of that drug. We reported use of nucleoside reverse transcriptase inhibitors, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and a fusion inhibitor, enfuvirtide (T-20; see bmj.com).

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 regimen containing a protease inhibitor and a non-nucleoside reverse transcriptase inhibitor.

Results

The database contains information on 16 593 individuals. Most (n = 13 378; 80.6%) were male, the predominant risk factor for HIV infection was homosexual or bisexual sex (10 340; 62.3%), with 4426 (26.7%) reporting a heterosexual risk. The median (interquartile range) age of the cohort at first study visit was 34 (29-39) years. Fifty six per cent (n = 9201) of the cohort were white, 2987 (18.0%) were of black African ethnicity, and 2101 (12.7%) were of other ethnicities (information on ethnicity is unknown for 13.9%). More than a quarter (4336; 26.1%) have developed AIDS, and 1255 (7.6%) have died.

The number of individuals under follow up in the cohort rose each year, from 7588 in 1996 to 11 200 in 2002. Changes in the number of individuals under follow up reflect the number of individuals attending one of the clinics for the first time in the year as well as the number of individuals who had previously been seen but were not seen at any of the cohort centres in that year.

Overall, 10 207 of the 16 593 patients (61.5%) had been exposed to any antiretroviral therapy, 10 176 (61.3%) to nucleoside reverse transcriptase inhibitors, 5657 (34.1%) to protease inhibitors, and 6857 (41.3%) to non-nucleoside reverse transcriptase inhibitors. Only 450 (2.7%) patients had been exposed to enfuvirtide. By the end of 2002, patients had been exposed to a median of four (range 0-16) different antiretroviral drugs. As expected, patterns of exposure changed over time (table 1).

View this table: [in this window] [in a new window]   Table 1 Exposure to different classes of antiretroviral drugs among individuals from the UK CHIC study

 

The median CD4 count of patients under follow up in each year rose steadily and the median HIV RNA burden fell (table 2).

View this table: [in this window] [in a new window]   Table 2 Overall trends in CD4 counts and HIV RNA levels over time among patients in the UK CHIC study

 

Among patients who had ever received antiretroviral treatment, the proportion with a CD4 count < 200 cells/mm³ and the proportion with an HIV RNA measurement > 2.7 log₁₀ copies/ml both fell between 1996 and 2002 (table 3). The number of patients exposed to all three main classes of drugs increased from 1% of those under follow up in 1996 to 27.3% of those under follow up in 2002. The proportions of these patients who showed signs of therapeutic failure in each year were similar to those seen in the overall treated population. Among patients exposed to three drug classes, the proportion experiencing three class failure increased until 2000 but remained relatively stable thereafter. Among patients in this group, the proportions with a CD4 count < 200 cells/mm³ or an HIV RNA measurement > 2.7 log₁₀ copies/ml were high but seemed to be falling over time.

View this table: [in this window] [in a new window]   Table 3 Trends in CD4 cell counts and HIV RNA levels over time among patients who had ever started antiretroviral therapy, patients with three class exposure, and patients who had previously experienced three class failure

 

Discussion

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.

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 this reflects the increasing number of new drugs that become available each year and the growing emphasis that is now placed on achieving good adherence. 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.

Although several new drugs from existing and new classes have recently been licensed 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.⁴

Potential limitations
Trends at a population level 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 Kingdom⁵ and from individual cohorts in the collaboration^{6 7} 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. This may lead to bias if those who were starting to experience therapeutic failure were more likely to drop out of the cohort. The median last available CD4 count and HIV RNA measurement for those who dropped out imply that many did not have therapeutic failure. These proportions have remained relatively stable over time; we therefore do not believe that this will affect the trends seen.

Although the cohort is broadly representative of HIV infected individuals in the UK,³ it 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, it is possible that exposure to novel treatments in these clinics may occur sooner than in other centres. Finally, treatment information from previous centres may be incomplete, so 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 class⁸ 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 Database⁹ 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.

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

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.

---

The participating centres and collaborators are on bmj.com

This is the abridged version of an article that was posted on bmj.com on 4 March 2005: http://bmj.com/cgi/doi/10.1136/bmj.38369.669850.8F

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: See bmj.com

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.

Editorial by Murri

References

1. 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.[CrossRef][Web of Science][Medline]
2. 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.[CrossRef][Web of Science][Medline]
3. 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.[Medline]
4. 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.[CrossRef][Medline]
5. 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. Abstract O28. Presented at 9th Annual Conference of the British HIV Association (BHIVA), Manchester, England, 24-26 April 2003.
6. 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.[CrossRef][Web of Science][Medline]
7. 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.[CrossRef][Medline]
8. Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Pat Care STDs 2004;18: 259-73.
9. 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).

(Accepted 14 January 2005)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Antiretroviral treatment of HIV infected adults

Steven G Deeks
BMJ 2006 332: 1489. [Extract] [Full Text] [PDF]

Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study

UK Group on Transmitted HIV Drug Resistance
BMJ 2005 331: 1368. [Abstract] [Full Text] [PDF]

HIV/AIDS demographics in US county and southeast England are similar

Stefan P Kruszewski
BMJ 2005 330: 1209-1210. [Extract] [Full Text]

HIV patients need new antiretroviral drugs
BMJ 2005 330: 0. [Full Text] [PDF]

Highly active antiretroviral therapy

Rita Murri
BMJ 2005 330: 681-682. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Grover, D., Copas, A., Green, H., Edwards, S. G., Dunn, D. T., Sabin, C., Phillips, A., Allen, E., Pillay, D., on behalf of the UK Collaborative Group on HIV Dru, (2008). What is the risk of mortality following diagnosis of multidrug-resistant HIV-1?. J Antimicrob Chemother 61: 705-713 [Abstract] [Full text]  
• Lampe, F. C., Smith, C. J., Madge, S., Kinloch-de Loes, S., Tyrer, M., Sabin, C. A., Chaloner, C., Youle, M., Johnson, M. A., Phillips, A. N. (2007). Success of Clinical Care for Human Immunodeficiency Virus Infection According to Demographic Group Among Sexually Infected Patients in a Routine Clinic Population, 1999 to 2004. Arch Intern Med 167: 692-700 [Abstract] [Full text]  
• Ogden, J., Esim, S., Grown, C. (2006). Expanding the care continuum for HIV/AIDS: bringing carers into focus.. Health Policy Plan 21: 333-342 [Abstract] [Full text]  
• Van Rompay, K. K. A., Singh, R. P., Heneine, W., Johnson, J. A., Montefiori, D. C., Bischofberger, N., Marthas, M. L. (2006). Structured treatment interruptions with tenofovir monotherapy for simian immunodeficiency virus-infected newborn macaques.. J. Virol. 80: 6399-6410 [Abstract] [Full text]  
• Deeks, S. G (2006). Antiretroviral treatment of HIV infected adults.. BMJ 332: 1489-1489 [Full text]  
• UK Group on Transmitted HIV Drug Resistance, (2005). Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study. BMJ 331: 1368- [Abstract] [Full text]  
• (2005). Options for HAART may be limited. Sex. Transm. Infect. 81: 337-337 [Full text]  
• Kruszewski, S. P (2005). HIV/AIDS demographics in US county and southeast England are similar. BMJ 330: 1209-1210 [Full text]  
• Murri, R. (2005). Highly active antiretroviral therapy. BMJ 330: 681-682 [Full text]  

Rapid Responses:

Read all Rapid Responses

HIV/AIDS Demographics Similar in Dauphin County, Pennsylvania USA

Stefan P. Kruszewski
bmj.com, 29 Mar 2005 [Full text]

Drug exhaustion of HIV treatment: are we the culprit?

Carlo Torti, et al.
bmj.com, 6 Jun 2005 [Full text]

Online poll

Find out more >>