Important note: Information in this article was accurate in May 2006. The state of the art may have changed since the publication date.
Treatment Interruption in Children
Hopkins HIV Report 2006 May; 18(3):6
Deborah Persaud, M.D.
Johns Hopkins
Data from four large clinical trials in adults, most notably the SMART trial, on CD4 guided treatment interruption were prominently featured at the 13th CROI and were cogently summarized by Joel Gallant [HHR 2006; 18(2):1]. That the largest randomized study to date on treatment interruption in adults living in resource-rich settings (n=5472 patients in 33 countries) was stopped prematurely because of an increased risk of clinical disease progression or death will have a dramatic impact on the future of this treatment strategy in patients of all ages, including children and adolescents. Similarly, in the Trivican study (n=940), conducted in West Africa, the CD4-guided arm, in which therapy was resumed when the CD4 count fell below 250 cells/mm3, was discontinued because of the increased incidence of tuberculosis and serious bacterial infections with organisms resistant to the prophylaxis regimen (cotrimoxazole). This is likely to discourage the study of treatment interruption in resource-poor settings, where the cost-benefit ratio is likely to be greatest. Two studies on treatment interruption in children were reported at CROI this year. The first was PACTG 1015, a proof of concept trial in which 14 children who had maintained suppression of viral replication for more than one year underwent incremental increases in time off therapy, starting with a 3-day cycle that was increased by 2 days for each subsequent cycle [Borkowsky W, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 19]. The overall goal of the study was to evaluate whether this “gentle” approach of cycling on and off therapy induced HIV-specific immunity in children who had achieved prior control of virus replication with HAART. Levels of rebound viremia during successive cycles off therapy and the total duration of each STI cycle before treatment reinitiation were recorded. Peak levels of rebound viremia (4.4 log10 c/mL at cycle 7) were reported to decline to lower levels (3.9, 4, and 3.7 log10 at cycles 9, 12, 15 respectively) with successive increases in time off therapy; however, these differences were not statistically significant. Drug resistance mutations resulted in study discontinuation in 3 of the 14 subjects, and the median CD4 percentage dropped slightly for the group (40.5% vs 36.5%).
The occurrence of drug resistance mutations and a trend towards CD4 decline observed in this small study highlight the risk of this treatment strategy. However, these risks need to be balanced with the requirement for life-long therapy in children, many of whom are now surviving to their twenties. Importantly, a sequential increase in HIV-specific, interferon-γ producing cells was observed with this “gentle” cycling approach. Whether this increase in HIV-specific immunity provides clinical benefit is unclear, but demonstrates that HIV-infected children treated with effective HAART can mount HIV-specific immune responses to autologous virus, a finding that has relevance to the development of therapeutic vaccine strategies. Similar studies in HIV-1 infected adult patients have also shown no long term clinical benefit of cyclic treatment interruption strategies [Fisher M, et al., AIDS. 2003 Jan 24;17(2):195-9].
Data from a CD4-guided interruption study in children, the Botswana/Baylor Antiretroviral Assessment Trial (BANA 2), were also reported [Lowenthal E. et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 700]. BANA 2 is a prospective, randomized, comparative trial (n=600) of continuous versus intermittent lopinavir/ritonavir (LPV/r)-based HAART for HIV-infected infants and children in Botswana. In this trial, children who remain in CDC immunologic category 1 (CD4% ≥25%) for greater than 6 months while on HAART are allowed to discontinue their therapy until they experience progression to immunologic category 2 (15-24%) or 3 (<15%). A repeat interruption was allowed for children who experience immune reconstitution and remained in immunologic category 1 for at least 3 months. The majority of the children enrolled in the trial were immune category 2 (114/263 or 43%) or 3 (133/263 or 50%), and were symptomatic. Only 31% of the children (44 of 142 subjects) enrolled in the interruption arm reached criteria for treatment discontinuation possibly due to the low baseline CD4 counts at the initiation of therapy. Nearly half required resumption of therapy, but the longest duration off therapy was 14 months. Importantly, the majority (95%) of subjects achieved suppression of viral loads to <400 c/mL with treatment re-initiation.In this larger study of treatment interruption in children residing in a resource-limited setting, no increases in toxicity or disease progression were observed. Such studies are important for guiding policies on the time to start therapy in children. Given the high rates of disease progression in the first year of life for HIVinfected infants, a planned CD4-guided treatment interruption strategy for older children who start HAART from infancy may make early therapy feasible for infants living in resource-poor settings where early infant diagnosis is possible.
2006-05-10
HHR-2006-05-02
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