Project Inform - September, 1998

The recently updated pediatric treatment guidelines (Federal Guidelines Box) seem to agree with the more aggressive pediatricians. It suggests all approved therapies, including those approved for adults, can be used to treat children with HIV. Three-drug combinations including a protease inhibitor have been shown to be the most effective in reducing viral load (HIV RNA levels) and increasing CD4+ cell counts in children. However, more studies are needed to assess the appropriate dosing regimens, risk of side effects and long-term potency. Pediatricians, parents and their children should not be expected to figure out such matters for themselves.

Ritonavir

Preliminary results are available from studies looking at combinations of ritonavir with one or two nucleoside analogue reverse transcriptase inhibitors (NARTIs) in children with advanced disease who have previously taken anti-HIV therapy. These studies show that anti-HIV regimens including ritonavir can provide decreases in viral load and increases in CD4+ cell counts in the short-term, but it remains to be seen if long-term benefits can be maintained. There is little reason to believe, however, that the long-term outcome would be any different than in adult studies.

One retrospective study looked at ritonavir (350mg/m² twice daily; total daily dose 700mg/m²) with 1 or 2 NARTIs in 21 children with advanced HIV disease. The children had previously taken many of the available anti-HIV therapies. After 12 months of a ritonavir-containing regimen, children aged 1-5 had an increase of over 500 CD4+ cells and about a 1.3 log reduction in viral load. Children aged 6-12 had an increase of about 450 CD4+ cells and a viral load reduction of about 0.5 logs. Since most of the children had previously been on many NARTIs, it is not surprising they had only a modest reduction in HIV levels as ritonavir was probably the only active drug. It is now known that the optimal way to treat HIV disease, for both adults and children, is to combine at least two potent drugs which the person has not previously taken. (When comparing these results to adult studies, particularly in terms of CD4+ cell increase, remember that young children generally have much higher natural CD4+ counts than adults and tend to have larger numeric increases in response to therapy.)

A second retrospective study looked at ritonavir plus 2 NARTIs in 63 children with advanced disease who had not previously taken a protease inhibitor (median age 55 months). The doses of ritonavir ranged from 150mg/m² twice daily (total daily dose 300mg/m²) to 430mg/m² twice daily (total daily dose 860mg/m²). After 6 months of the study, the mean CD4+ count increased by 486 cells and viral load levels dropped by almost 1 log. Fifteen children had to discontinue ritonavir because of side effects, including vomiting and diarrhea.

A large US study (the Pediatric AIDS Clinical Trials Group study 338) compared two- and three-drug combination regimens in children who had previously been on anti-HIV therapies. The study showed that children who received d4T + ritonavir or AZT + 3TC + ritonavir did significantly better than those receiving AZT + 3TC alone. The study included 298 children at a median of 7.1 years of age with a median viral load of about 25,000 copies HIV RNA. Data at 12 weeks are presented in Table 1.

Table 1: Ritonavir Combinations in Children

RTV=ritonavir

It remains to be seen how long the antiviral response will last and if the combinations are safe and tolerable for the long-term. The results from this study are not unexpected. Previous studies in adults have all shown only limited antiviral activity of AZT + 3TC, especially in people who have been on previous NARTI therapies, and AZT + 3TC is not considered an optimal therapeutic regimen.

A final ritonavir study looked at the effects of simply adding ritonavir (350mg/m² twice daily (total daily dose 700mg/m²) to existing 2-drug regimens in 35 children (mean age 7.4 years). Prior to adding ritonavir, the mean viral load was 247,000 copies HIV RNA and the mean CD4+ cell count was 239. After 12 weeks, the mean viral load reduction was 1.1 logs, and 31% (11/35) of children reached levels below 400 copies HIV RNA. CD4+ cell counts increased by about 225. However, 42% of the children experienced side effects, including gastrointestinal problems (primarily diarrhea) and increased triglyceride levels. Again, the results here are not unexpected. Since the children had high viral loads (HIV RNA) prior to adding ritonavir, it can be safely assumed they were failing their 2-drug regimens and were likely to have developed resistance to those drugs. As a result, ritonavir was probably the only active drug in most of these regimens, resulting in only a modest antiviral response. It has been well established that when changing therapies, at least two new drugs should be added or changed in the regimen. The addition of a single drug is an ineffective way to suppress HIV and can lead to the rapid development of drug resistance. It is difficult to understand why an ethical review board would approve a study of this type, given the well-established recommendation to avoid simply adding a protease inhibitor onto a failing (or even stable) 2-drug regimen. This is another sad example of how pediatric research sometimes fails to learn from basic principles established in adult research.

Nelfinavir

Results from a small study comparing two different nelfinavir regimens (one combined with AZT + 3TC and the other with d4T + ddI) showed sustained viral load decreases after 6 months in both study groups, but surprisingly no lasting increases in CD4+ cell counts. Fourteen children who had received no prior anti-HIV therapy (median age 68 months) received one of the two three-drug combinations. The dose of nelfinavir was 20-30mg/kg three times daily (total daily dose of 60-90mg/kg). The median viral load decrease after 24 weeks was more than 2 logs, with 9 children below 500 copies HIV RNA. CD4+ cell counts increased from an average pre-study level of 650 cells (the range was 40-2,250 cells) to 925 after 12 weeks, but returned to pre-study levels after 24 weeks. The unusual lack of a sustained CD4+ cell response may be due to problems with adherence, study design, or perhaps just a function of the small number of children in the study. Overall, the regimens were well-tolerated, but there were difficulties in administering the doses to small children.

Saquinavir

Two studies provided new information on the use of the enhanced saquinavir soft gel capsules (saquinavir sgc, Fortovase^®) in children. While saquinavir is not yet approved for use in children, these studies show that combination therapy with saquinavir sgc may provide yet another option for HIV-infected kids. However, saquinivir is still only available as tablets and a liquid formulation needs to be developed to make the drug accessible to children who cannot swallow tablets.

The first study looked at saquinavir sgc (33mg/kg three times daily; total daily dose of about 100mg/kg) in combination with two NARTIs (at least one of which had never been used before) in 14 children aged 3-13 years, most of whom had been on previous anti-HIV therapies. The most common nucleoside combination used in this study was d4T + 3TC. At study entry, the average CD4+ cell count was 446 and viral load was about 40,000 copies HIV RNA. After 16 weeks of therapy, CD4+ counts increased by an average of 229 cells, and the average viral load decreased 2.1 logs, with 8 of 13 children below 400 copies HIV RNA. While the regimens were safe and well-tolerated, five had to add nelfinavir because they did not achieve adequate saquinavir levels to effectively stop HIV replication. In addition, as is true for most drugs, children clear saquinavir from their bodies more quickly than adults and thus may require even higher doses per kilogram body weight.

A second study showed that adding nelfinavir (30mg/kg three times daily) to a combination of saquinavir sgc (33mg/kg three times daily) plus 2 NARTIs can help maintain higher saquinavir drug levels. In adults, adding nelfinavir increased saquinavir levels by 392% without any increase in side effects. This study included 14 children aged 3-16 with average pre-study CD4+ counts of 587 cells and HIV RNA levels of 31,000 copies. After 16 weeks on therapy, there was an average viral load decrease of 1.8 logs and a CD4+ count increase of 109 cells. While this combination does appear to substantially increase the levels of saquinavir sgc, there seems to be little evidence that addition of nelfinavir results in any increased benefit in terms of viral load reductions and CD4+ cell increases. This parallels the adult experience and raises questions about whether the addition of a second protease inhibitor is worth the cost and inconvenience involved. It also raises the question of whether clinical outcomes can be predicted based on pharmacokinetic observations of drug blood levels. Overall, it would seem more important to trust well established outcome markers like viral load and CD4+ counts to assess the efficacy of a drug regimen.

Abacavir

Latest results from a study of the NARTI abacavir (formerly 1592, now also known as Ziagen^®) in combination with AZT and 3TC show that the drug is safe and more effective than AZT + 3TC alone. The study included 205 children (ages 90 days-12 years) who had previously received anti-HIV therapies and had CD4% less than 15, which is considered moderate to severe immunosuppression in children. Mean pre-study CD4+ cell counts were about 675 cells and the mean viral load level was about 40,000 copies HIV RNA. The children received either AZT + 3TC or a combination of AZT + 3TC + abacavir (8mg/kg twice daily) and had the option to switch to abacavir plus any two NARTIs if they had more than a 0.5 log increase in viral load after 8 weeks or had greater than 10,000 copies HIV RNA anytime after 16 weeks of the study. Preliminary results are shown in Table 2 below.

Side effects were similar in both treatment groups, except for two suspected allergic reactions to abacavir. The most common adverse events were nausea and vomiting, respiratory infections, fever and diarrhea. These rather lukewarm results may be due to the fact that the majority of children were shown to have developed resistance to the approved NARTIs which may also have resulted in resistance to abacavir.

Commentary

While these sometimes encouraging data suggest that children now have greater and more effective treatment options than ever before, it appears that children, like adults, will have to continue taking therapy for a lifetime. The side effects, drug interactions and taste problems of many drugs make it imperative that more effective, less toxic, and easier to use treatment options be developed for children. These issues also increase the difficulties and highlight the importance of adherence to these strict regimens. Helping families overcome barriers to adherence is an important goal for the treatment of children with HIV to allow these therapies to provide the most potent and longest-lasting response. While further studies of safety and effectiveness of anti-HIV therapies in children are critical, equally important are efforts to make drugs more palatable, establish appropriate dosing regimens and seek ways to help families and their children adhere to these regimens.

In addition, it seems that pediatric drug trials continue to repeat the mistakes of trials in adults. Too many children who bravely participate in trials are receiving sub-optimal combinations or are receiving single drugs in succession, both of which allow only moderate viral suppression and therefore increase the likelihood of developing drug resistance. Future trials need to be designed to treat children with the highest standard of care, a three-drug regimen with at least two potent drugs never used before.

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