Jittamala P, Puthanakit T, Chaiinseeard S. Predictors of virologic failure and genotypic resistance mutation patterns in Thai children receiving non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Pediatr Infect Dis J. 2009 Sep;28(9):826-30.
Most resource-limited countries use two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) as first-line HIV treatment. The regimen d4T/3TC/NVP had been used widely because it could be taken as a single pill and is inexpensive. This combination has not been recommended as first-line therapy in resource-rich countries for several years.(1) The World Health Organization (WHO) now recommends phasing out d4T because of toxicities and side effects.(2) There is also concern about development of drug resistance, particularly among children.(3, 4)
To determine patterns of virologic failure and drug resistance in HIV-infected children in Thailand treated with NNRTI-based regimens
Northern Thailand, Chiang Mai University Hospital and three provincial hospitals
Sub-study of a prospective longitudinal observational study
Two hundred two HIV-infected children <18 years of age who were antiretroviral naïve except for exposure during prevention of mother-to-child transmission (PMTCT) and who were started on an NNRTI-based regimen
Children were initiated on antiretroviral therapy (ART) from August 2002 to October 2006 and were followed every three months with a clinical assessment and every six months with tests of their CD4 cell counts and HIV RNA levels. Children were treated with split fixed-dosed combination tablets of d4T/3TC/NVP. Efavirenz (EFV)-based regimens used 3TC/d4T or 3TC/ZDV as the NRTI backbone. The choice of regimen was based on physician preference. Adherence was measured by pill count. Determinations of virologic, immunologic and clinical failure were made. Virologic failure was classified as HIV RNA >1000 copies/mL after 24 weeks of treatment. Incomplete suppression was classified as <1000 copies/mL but never achieving undetectable levels (<50 copies/mL); viral rebound was defined as >1000 copies/mL after having had undetectable levels. Genotypic resistance testing was performed on blood samples taken closest to the time of viral failure. Immunologic failure was classified as a CD4 cell count increase of <5% compared to baseline, or <50 cells/mL for children >5 years old. Clinical failure was defined by a change in Centers for Disease Control and Prevention (CDC) clinical category. The NRTI and NNRTI mutations were based on International AIDS Society-USA guidelines.
The median follow-up time was 200 weeks (interquartile range (IQR) 167-241), during which period four children died, none of whom had virologic failure. A total of 40 (20%) of 202 children met criteria for virologic failure, of whom 33 (83%) failed in the first year; 32 of these children had been on a nevirapine (NVP)-containing regimen. Having been on an NVP-regimen compared to being on EFV was the only factor independently predictive of failure (odds ratio (OR) 3.7, 95% confidence interval (CI): 1.5-9.4; P=0.006), controlling for age, gender, CD4 level, clinical category, and baseline plasma HIV RNA level. Poor adherence (<95%) was associated with viral failure in bivariate but not in multivariate analysis. At one year, five of the 33 children (15%) with viral failure also had immunologic failure; 32 of the 169 (19%) without viral failure had immunologic failure. None had clinical failure at the time of viral failure. The sensitivity, specificity, positive predictive value, and negative predictive value of immunologic failure were 15%, 81%, 16%, and 83%, respectively. Thirty-nine of 40 specimens were sent for genotypic resistance testing, 13 of which were collected 6 to 12 months after detection of virologic failure. The number that had any major mutations conferring drug resistance to NRTIs was 34/39 (89%) (mostly to 3TC), and 37/39 (97%) had a mutation conferring drug resistance to the NNRTI. Only three patients had multi-NRTI resistance mutations (≥3 TAMs or Q151M).
This study showed that 20% of children initiating an NNRTI-based treatment developed viral failure, mostly within the first year of therapy. Children on an NVP-based regimen were almost four times as likely to develop failure compared with those on an EFV-based regimen. Almost all children with failure had NNRTI and 3TC resistance, but very few had multi-NRTI resistance. Children exposed to NVP during PMTCT did not have higher rates of virologic failure compared with those who were not. Immunologic failure at 48 weeks was not sensitive enough to detect virologic failure; clinical failure was not at all sensitive.
This was a high quality study that provides important information on drug resistance among children. However, because 33% of specimens that were genotyped were collected 6 to 12 months after virologic failure, some mutations may have occurred while continuing the failing regimen.
This study shows that virologic failure among children who are treated with recommended WHO regimens occurs early and is poorly predicted by clinical symptoms or CD4 cell counts. Rates reported here (20%) are similar to those of other studies.(5) In resource-constrained settings, clinical symptoms are often used to determine the need to switch regimens; by that time, however, children already may have viral failure and multiple resistance mutations. Avoiding NVP and using EFV instead may result in better outcomes, less resistance, and greater effectiveness of second-line drugs. If viral failure is detected early, meaning there are few multi-NRTI mutations, recommended WHO second-line treatment probably will be useful.(4) Relying on immunologic or clinical failure without performing viral load and resistance testing, however, could result in poor response to these regimens. Affordable HIV RNA testing during the first year of therapy for children is important.
- Guidelines for the use of antiretroviral agents in pediatric HIV infection. US Department of Health and Human Services (DHHS). February 23, 2009.
- World Health Organization (WHO). Antiretroviral Therapy for HIV Infection in Infants and Children: Toward Universal Access. Recommendations for a Public Health Approach. Geneva, Switzerland: World Health Organization; 2006.
- Patel K, Hernan MA, Williams PL, et al. Long-term effectiveness of highly active antiretroviral therapy on the survival of children and adolescents with HIV infection: a 10-year follow-up study. Clin Infect Dis. 2008;46:507-15.
- Sungkanuparph S, Manosuthi W, Kiertiburanakul S, et al. Options for a second-line antiretroviral regimen for HIV type 1-infected patients whose initial regimen of a fixed-dose combination of stavudine, lamivudine, and nevirapine fails. Clin Infect Dis. 2007;44:447- 52.
- Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure among Uganda children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr. 2007;46:187-93.