1 Royal Free Centre for HIV Medicine and Department of Primary Care and Population Sciences, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill St, London NW3 2PF, UK; 2 Copenhagen HIV Program, Hvidovre Hospital, Copenhagen, Denmark
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Abstract |
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Keywords: HIV infection , treatments , outcomes
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Why should patients start HAART? |
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When should patients start HAART? |
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There have been a number of observational studies considering the risks and benefits of HAART according to the CD4 cell count when starting HAART (Table 1). The risk of developing new AIDS-defining diseases and/or death was increased in patients starting HAART at CD4 cell counts below 200 cells/mm3, but these studies have not been able to demonstrate a consistent significant benefit of starting HAART at CD4 cell counts above 350 cells/mm3. In order to minimize the risk of disease progression after starting HAART, it would seem important to start HAART before the CD4 cell count falls below 200 cells/mm3.
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Randomized trials are best suited to answer the question of the optimal time to start therapy. This would require large and lengthy trials, and there are none in progress at present. As an intermediate, one randomized trial is comparing two strategies of using HAART, the drug conservation and the viral suppression strategy. In the drug conservation strategy arm, HAART is used periodically to maintain the CD4 cell count above 200 cells/mm3 whereas in the virological suppression strategy arm, HAART is used at all time points in order to maximize suppression of HIV replication (http://www.smart-trial.org/). This trial will recruit 6000 patients and will be completed when 910 new AIDS events or deaths have occurred, currently estimated to be 2012.
It is important to emphasize that our understanding of the optimal approach to manage patients with HIV remains immature. Should resistance develop, this is an irreversible process because resistant strains will be archived in host DNA. New strategies for treatment, such as the drug conservation strategy discussed above, are currently being developed. In addition, short-term courses of interleukin-2 increase the CD4 cell count by 50150%, and the absolute increase in CD4 cells is associated with the CD4 cell count before starting HAART. If the ongoing Phase III trials demonstrate that the CD4 cells induced by interleukin-2 are clinically protective, this would be an argument to start HAART with a reasonable immune function.6
The drugs used are powerful antiretrovirals, but have a cost in terms of added toxicity. Chronic hyperlactaemia is a rare but potentially fatal toxicity with an incidence of around 1.3 per 1000 person-years exposure to nucleosides.7 There is an increased risk of hepatotoxicity,8 particularly among patients infected with hepatitis C, and an increased risk of cardiovascular events associated with longer exposure to HAART.9 Two observational studies have considered the risk of toxicities according to CD4 cell count before HAART (Table 1), with conflicting results. Future studies should ensure that events expected to occur in patients with severe immunodeficiency (such as HIV-related neuropathy) are separated from toxicities induced by the therapy provided to such patients.
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Response to HAART |
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There are several factors commonly reported to be associated with initial virological response to HAART. One of the most important factors related to virological response to HAART is prior treatment; treatment-experienced patients have a poorer response to HAART and are less likely to achieve a viral load of below the limit of detection.12 Treatment-experienced patients may have accumulated drug resistance, which may result in a poorer virological response. Adherence also plays a key role in virological response. Results from both clinical trials and observational studies report an increase in virological response amongst patients who are more adherent,13,14 although it is often difficult to capture accurate data on adherence. Estimates of adherence have used pill counts, electronic monitoring, records of prescription refills, drug-level monitoring and detailed questionnaires, all of which can be time-consuming and impractical within a busy clinic schedule. Failure to adhere to HAART results in low drug levels, which can rapidly lead to the selection of virus with decreased susceptibility. In addition, as different antiretrovirals within the same drug-class are cross-resistant, the number of potential regimens rapidly decreases for the non-adherent patient.
It takes longer for a patient with a high viral load when starting HAART to reduce their viral load to below the limit of detection; some studies also suggest that patients with a higher viral load when starting HAART are less likely to respond with a viral load below the limit of detection.12,15 The viral loads at weeks 4 and 8 after starting HAART are also related to virological outcome at 24 weeks after starting HAART.16 Assessing the reasons for a lack of early response to HAART and addressing problems can improve the longer-term response to therapy, however, it is not known if a change in treatment or intensification of the regimen will improve the clinical outcome. Other factors related to virological response include starting new nucleosides at the time of starting HAART and age.15,17 Among patients with previous nucleoside treatment, those that start HAART with two new nucleosides (i.e. nucleosides that the patient has never taken before) have a better response. The addition of new drugs may increase the genetic barrier of therapy, as the sequential initiation of antiretrovirals impairs drug efficacy because of the failure to overcome drug-resistant mutations. Older patients have been reported to have a better initial virological response to HAART, which may be a marker for greater maturity and reflect a more stable lifestyle, both of which may impact on adherence. Conversely, younger patients have been shown to have an improved immunological response,18 possibly due to preserved thymic function.
It is worth noting that response to HAART is a multifactorial process which depends on many factors in addition to those described above. The availability of emotional and practical support, relationship between the patient and clinical team, the skills and experience of the team treating the patient, presence of concomitant diseases and the possibility of drug interactions should also be taken into account.
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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