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High rate of discontinuations of highly active antiretroviral therapy as a result of antiretroviral intolerance in clinical practice: missed opportunities for adherence support?

Park-Wyllie, Laura Y.a; Scalera, Alissaa; Tseng, Aliceb; Rourke, Seana

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aSt Michael's Hospital, Inner City Health, Toronto, Canada; and bUniversity Health Network, Immunodeficiency Clinic, Toronto, Canada.

Received: 6 December 2001; accepted: 13 December 2001.

In this brief report, we have reviewed the literature on the timing and reasons for the discontinuation of highly active antiretroviral therapy (HAART) in order to gain a better understanding of the patterns of antiretroviral use in patients initiating new antiretroviral regimens.

In a recent article in this journal, Mocroft et al. [1] retrospectively described reasons for the discontinuation of HAART in a clinic cohort of patients. Mocroft et al. [1] pointed out that viral suppression rates in excess of 90% have been achieved in patients in controlled trials. In contrast, viral suppression rates are often reported to be less than 50% in observational cohorts [2].

This discrepancy appears to parallel the discontinuation rates of observational cohorts of antiretroviral therapy and controlled clinical trials. Discontinuation rates have ranged from 4 to 43% [3–5] in clinical trials, but have been reported to be as high as 60% of patients in observational cohorts [6].

The peer-reviewed literature was searched using the terms: ‘antiretroviral therapy, highly active', ‘discontinuation', ‘modification', ‘reasons', ‘switch', ‘failure', and ‘intolerance'. In Table 1 we summarize the observational and surveillance studies describing the discontinuation or modification of HAART regimens in antiretroviral naive and experienced individuals. Ten studies were identified, which described participants starting HAART regimens between 1996 and 1999 with follow-up durations of 6–16 months (Table 1) [1,6–14]. In all but one study, patients were receiving their first HAART regimen [1,7–14].

Table 1
Table 1
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Overall, the discontinuation or modification rates of HAART regimens among the cohorts ranged from 8 to 59% (median 33%) [1,6–14]. A further examination of the reasons for discontinuing or modifying therapy in the subgroup of patients who did so revealed the main reasons to be antiretroviral toxicity/intolerance, which accounted for 20–78% of all discontinuations, followed by therapeutic failure, which accounted for 9–60% of all discontinuations [1,6–14]. For this review, the reasons of patient choice and poor adherence were combined with antiretroviral toxicity and intolerance, as has previously been done [1]. It is likely that these reasons are related and thus problematical to report independently. Antiretroviral toxicity or intolerance was cited as the predominant reason for treatment discontinuation or modification in eight out of 11 analyses. Treatment failure was the predominant reason in two out of 11 analyses [1,6,7,9,11–14]. In most cases, the discontinuation of antiretroviral drugs as a result of toxicity/intolerance was gastrointestinal related [6,7,9,10,14]. In general, discontinuations or modifications caused by antiretroviral toxicities or intolerances occurred within the first 3 months of initiation [1,9,10,12], whereas treatment failure led to the discontinuation or modification of HAART within 6–8 months [1,8,9,12].

Several factors were shown to be independently associated with a higher probability of treatment discontinuation or modification such as antiretroviral non-naivete, younger age, and four or more antiretroviral drugs with ritonavir [1,10].

In summary, the results of this review demonstrate that the most common reason for stopping antiretroviral therapy is drug toxicity or intolerance, and such discontinuations tend to occur earlier compared with terminations for treatment failure. As this review is based on data from 1996–1999, the relevance of some of these results are questionable given that many studies included subjects who were initiated on saquinavir hard-gel capsules, indinavir 8 hourly dosing, were using ritonavir at the full therapeutic dosage (e.g. 600 mg twice a day), or were using a liquid formulation of ritonavir. Other limitations revealed by this review include: the lack of detail from existing studies regarding precise discontinuation times and specific reasons for discontinuation at that time; the lack of detail describing what kind of adherence support (if any) was provided to the patients; and the already dated nature of the information as the studies only reported on data from before year 2000 (before the widespread use of boosted protease inhibitor regimens and protease-sparing regimens). Finally, antiretroviral adherence was not consistently assessed in these studies.

However, the studies clearly suggest a need to focus efforts on medication support, especially side-effect management after the initiation of therapy. In order to further our understanding of how to target medication support strategies for patients, more studies are required that study factors leading to the discontinuation of HAART regimens in patients also receiving salvage regimens, mega-HAART, protease inhibitor-sparing regimens, ritonavir-boosted regimens, newer formulations of agents (i.e. saquinavir soft-gel capsules, enteric-coated didanosine, ritonavir-sec capsules) and newer agents (i.e. amprenavir, lopinavir, tenofovir, T-20, etc). Further characterization of these factors will allow healthcare providers to develop more targeted support programmes, such as intensive side-effect counselling and management during the first few months of therapy. Studies are also needed to assess whether such targeted approaches may decrease drug discontinuation rates and improve outcomes.

Laura Y. Park-Wylliea

Alissa Scaleraa

Alice Tsengb

Sean Rourkea

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Acknowledgement

The authors would like to extend special thanks to Dr Ahmed Bayoumi for his comments in the writing of the manuscript and statistical support.

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References

1. Mocroft A, Youle M, Moore A. et al. Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre. AIDS 2001, 15: 185–194.

2. Deeks S, Loftus R, Cohen P, et al. Incidence and predictors of virologic failure to indinavir and or ritonavir in an urban health clinic. In:Program and Abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy. Toronto, Ontario, 28 September–1 October 1997 [Abstract LB-2].

3. Erb P, Battegay M, Zimmerli W. et al. Effect of antiretroviral therapy on viral load, CD4 cell count, and progression to acquired immunodeficiency syndrome in a community human immunodeficiency virus-infected cohort. Swiss HIV Cohort Study. Arch Intern Med 2000, 160: 1134–1140.

4. Wit FW, van Leeuwen R, Weverling GJ. et al. Outcome and predictors of failure of highly active antiretroviral therapy: one-year follow-up of a cohort of human immunodeficiency virus type 1-infected persons. J Infect Dis 1999, 179: 790–798.

5. Powderly WG, Saag MS, Chapman S, Yu G, Quart B, Clendeninn NJ. Predictors of optimal virological response to potent antiretroviral therapy. AIDS 1999, 13: 1873–1880.

6. Bini T, Testa L, Chiesa E. et al. Outcome of a second-line protease inhibitor-containing regimen in patients failing or intolerant of a first highly active antiretroviral therapy. J Acquired Immune Defic Syndr 2000, 24: 115–122.

7. Hansel A, Bucher HC, Nuesch R, Battegay M. Reasons for discontinuation of first highly active antiretroviral therapy in a cohort of proteinase inhibitor-naive HIV-infected patients. J Acquired Immune Defic Syndr 2001, 26: 191–197.

8. Manfredi R, Chiodo F. Switch of protease inhibitor-containing HAART in routine clinical practice: a four-year prospective observational study. Int J STD AIDS 2001, 12: 84–88.

9. Arminio Monforte A, Lepri AC, Rezza G. et al. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy (HAART) regimen in a cohort of antiretroviral naive patients. AIDS 2000, 14: 499–507.

10. Van Roon EN, Verzijl JM, Juttmann JR, Lenderink AW, Blans MJ, Egberts ACG. Incidence of discontinuation of highly active antiretroviral combination therapy (HAART) and its determinants. J Acquired Immune Defic Syndr 1999, 20: 290–294.

11. Bassetti S, Battegay M, Furrer H. et al. Why is highly active antiretroviral therapy (HAART) not prescribed or discontinued? J Acquired Immune Defic Syndr 1999, 21: 114–119.

12. Guardiola JM, Domingo P, Vazquez G. Switching HIV-1 protease inhibitor therapy: which? when? and why? Arch Intern Med 1999, 159: 194–195.

13. Ferrer E, Ezequiel C, Podzamczer D. et al. Analysis of the discontinuation of protease inhibitor therapy in routine clinical practice. Scand J Infect Dis 1999, 31: 495–499.

14. d'Arminio Monforte A, Testa L, Adorni F. et al. Clinical outcome and predictive factors of failure of highly active antiretroviral therapy in antiretroviral-experienced patients in advanced stages of HIV-1 infection. AIDS 1998, 12: 1631–1637.

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