Planned interruption of highly active antiretroviral therapy does not select drug resistance mutations in HIV-1-infected children

Tom Egwang
Published: 07 May 2008

Stopping highly active antiretroviral therapy (HAART) containing two non-nucleoside reverse transcriptase inhibitors (NNRTI) for 9 or 14 days in HIV-1-infected children with viral suppression did not increase the risk of drug resistance, according to the results of a prospective multicentre study published in the May 15th edition of Clinical Infectious Diseases.

Early studies in HIV-1-infected adults demonstrated that irregular interruption of HAART resulted in the loss of CD4 T cells, onset of drug resistance, and a rapid rebound of plasma viral load. A Cochrane Review concluded that structured treatment interruption was harmful in patients with advanced HIV disease.

By contrast, other studies have demonstrated that structured or planned treatment interruptions (PTI) limited viral load, maintained CD4 counts, and minimized drug resistance. Furthermore, treatment was successfully resumed in all patients with the same drugs used before the interruption.

Clinical studies in adult subjects also demonstrated that efavirenz plasma concentrations persisted for longer than 14 days after stopping therapy. Nevirapine plasma concentrations persisted for at least 21 days after delivery in women who received a single dose prophylactic treatment for the prevention of mother to child transmission of HIV (PMTCT). Both drugs belong to the NNRTI class of HAART.

NNRTI drugs like nevirapine and efavirenz have the longest plasma half-lives. Stopping an HAART triple combination containing NNRTIs therefore results in a temporary functional monotherapy due to the persistence of these drugs in the circulation. This raises the spectre of drug resistance during treatment interruption of NNRTIs.

This public health concern is underscored by clinical studies of nevirapine for PMTCT in HIV-1-infected women. Six months after treatment, nevirapine-exposed HIV-1-infected women were unable to suppress their viral load by comparison with their unexposed counterparts.

The problem is that at present there is little or no clinical experience with NNRTI treatment interruption in children. This is problematic, given the possibility that children may need to interrupt treatment in some circumstances.

In this regard, a multicentre team of investigators belonging to the Paediatric European Network for Treatment of AIDS (PENTA) are carrying out a randomized phase II trial (PENTA-11) to identify the optimum PTI strategy for a NNRTI-containing regimen which reduces the risk of drug resistance.

The study participants were children with viral loads < 50 copies/mL and CD4 cell percentages ≥ 30% (for children aged 2–6 years) or CD4 cell percentages ≥ 25% and CD4 cell counts ≥ 500 cells/mm3 (for children aged 7–15 years).

The children were randomised to either a planned treatment interruption or to continuous therapy. In the PTI arm, either (1) treatment with nevirapine or efavirenz was stopped, and treatment with the remaining drugs was continued for 7–14 days, or (2) nevirapine or efavirenz were replaced by a protease inhibitor, and all drugs were stopped after 7–14 days.

Blood samples were collected for the determination of plasma drug concentrations, measurement of viral load, and genetic drug resistance testing on day 0, day 7 (drug concentrations only), day 14, and day 28 after interruption of treatment with an NNRTI.

Treatment with an NNRTI was interrupted for 35 children (20 were receiving nevirapine, and 15 were receiving efavirenz). The median time from NNRTI cessation to stopping all drugs was 9 days (range, 6–15 days) for nevirapine and 14 days (range, 6–18 days) for efavirenz.

At 7 days, 1 (5%) of 19 and 4 (50%) of 8 children had detectable nevirapine and efavirenz concentrations, respectively; efavirenz remained detectable in 3 (25%) of 12 children at 14 days. At 14 days, viral load was ≥ 50 copies/mL in 6 of 16 children on PTI with nevirapine (range, 52–7000 copies/mL) and in 2 of 12 children on PTI with efavirenz (range, 120– 1600 copies/mL). Interestingly, no new NNRTI mutations were observed in viral isolates from children in the PTI arm.

In conclusion, in children with virological suppression who experienced PTI with an NNRTI-based HAART, treatment interruption for a median of 9 and 14 days for nevirapine and efavirenz, respectively, was not associated with the selection of NNRTI resistance mutations. There is need for additional studies like this in order to generate the paediatric data and clinical experience needed to inform on an optimal PTI strategy for HIV-infected children.


Cressey TR et al. Plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase inhibitors in HIV type 1–infected children. Clinical Infectious Diseases 46:1601–1608,2008.

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