HIV-positive children are at high risk of drug resistance, which is of particular concern in settings where antiretroviral options are limited. In this Review we explore resistance rates and patterns among children in developing countries in whom antiretroviral treatment has failed. We did a systematic search of online databases and conference abstracts and included studies reporting HIV-1 drug resistance after failure of first-line paediatric regimens in children (<18 years) in resource-poor regions (Latin America, Africa, and Asia). We retrieved 1312 citations, of which 30 studies reporting outcomes in 3241 children were eligible. Viruses with resistance-associated mutations were isolated from 90% (95% CI 88-93%) of children. The prevalence of mutations associated with nucleoside reverse transcriptase inhibitors was 80%, with non-nucleoside reverse transcriptase inhibitors was 88%, and with protease inhibitors was 54%. Methods to prevent treatment failure, including adequate paediatric formulations and affordable salvage treatment options are urgently needed.

/pdf/hiv-1-resistance-associated-mutations-after-failure-of-first-4kl4d3jant.pdf

HIV-1-resistance-associated mutations after failure of first-line antiretroviral treatment among children in resource-poor regions: a systematic review

Antiretroviral therapy (ART) improves growth and survival of HIV-infected individuals. We designed a retrospective cohort study to assess clinical factors associated with growth in HIV-infected children on ART in Uganda between July 2003 and March 2006. Height and weight measurements taken pre- and post-ART initiation for at least 6 months were age- and gender-standardized to CDC 2000 reference. We analyzed medical records of 749 children receiving ART. Descriptive and logistic regression analyses were conducted to identify covariates associated with risk of either stunting or being underweight. Longitudinal regression analysis with a mixed model using autoregressive covariance structure was used to compare change in height and weight before and after initiation of ART. The mean age of the study population at first visit was 7.5 years. Mean height-for-age, weight-for-age, and weight-for-height percentiles at first visit were 8.6, 7.7, and 7.9, respectively. At last visit mean height-for-age, weig...

Growth in HIV-infected children receiving antiretroviral therapy at a pediatric infectious diseases clinic in Uganda.

Background:Long-term (>12 months follow-up) virologic data of children receiving antiretroviral therapy (ART) in Sub-Saharan Africa are limited. Data from rural areas are especially scarce. The aim of this study was to evaluate the long-term virologic outcome of a pediatric cohort in rural South Afr

Long-term outcome of children receiving antiretroviral treatment in rural South Africa: substantial virologic failure on first-line treatment.

OBJECTIVE. Few studies have investigated the efficacy of antiretroviral therapy among HIV-infected children in resource-poor settings. This observational, retrospective analysis describes the clinical, immunologic, and virologic effects of highly active antiretroviral therapy in treatment-naive, HIV-infected children in Mombasa, Kenya. In keeping with a public health approach, all children were treated by using a simplified, nationally approved, triple-drug regimen. METHODS. Clinical data and stored plasma samples from 29 children who were followed prospectively between April 2003 and October 2004 were analyzed. All children received generic formulations of nevirapine, zidovudine, and lamivudine and were evaluated at baseline and at 3, 6, 9, 12, and 15 months. At each visit, weight and CD4 lymphocyte counts were measured and plasma samples were stored for analysis. HIV RNA load was determined retrospectively at baseline and 9 months after initiation of therapy. RESULTS. The mean age of the children was 8.5 years (range: 2–16 years). At baseline, the mean CD4 count (±SD) was 182.3 × 106 cells per μL (±145.6). On treatment, CD4 counts increased step-wise by a mean of 187 × 106 cells per μL at 3 months, 293 cells per μL at 6 months, 308 cells per μL at 9 months, 334 cells per μL at 12 months, and 363 cells per μL at 15 months. The mean plasma viral load decreased from a baseline level of 622 712 to 35369 copies per mL, and at 9 months was undetectable in 55% of the patients. Mean z scores for weight for age increased from a baseline of −1.61 to −1.12 at 12 months into therapy. CONCLUSIONS. A public health approach using 1 treatment regimen in generic form showed excellent efficacy among treatment-naive, HIV-infected children in a resource-limited country. Clinical and immunologic improvement occurred in all patients, but 9 months after the start of therapy, only 55% of the children had an undetectable viral load.

Efficacy of highly active antiretroviral therapy in HIV-1 infected children in Kenya

Early recognition of antiretroviral therapy (ART) failure in resource limited settings is a challenge given the limited laboratory facilities and trained personnel. This study aimed at describing the incidence, risk factors and the resistance associated mutations (RAMs) of first line treatment failure among HIV-1-infected children attending the Joint Clinical Research Centre (JCRC), Kampala, Uganda. A retrospective cohort of 701 children who had been initiated on ART between January 2004 and September 2009 at the JCRC was studied. Data of children aged 6 months up to 18 years who had been started on ART for at least 6 months was extracted from the clinic charts. The children who failed the first-line ART were taken as cases and those who did not fail as the controls. Data was analysed using STATA version10. Of 701 children, 240(34%) failed on first line ART (cases) and 461(66%) did not fail (controls). The overall median time (IQR) to first line ART failure was 26.4 (18.9 – 39.1) months. The factors associated with treatment failure were poor adherence [(OR = 10, 95 CI: 6.4 – 16.7) p < 0.001], exposure to single dose nevirapine (sdNVP) [(OR = 4.2, 95% CI:1.8-9.4), p = 0.005] and a NVP containing regimen [(OR = 2.2,95% CI:1.4-3.6), p < 0.001]. Of 109 genotypic resistance profiles analyzed, the commonest non nucleoside reverse transcriptase inhibitor (NNRTI) resistance associated mutations (RAM) were: K103N (59; 54%)), Y181C (36; 27%)) and G190A (26; 24%)) while the commonest nucleoside reverse transcriptase inhibitor (NRTI) RAM was the M184V (89; 81%). Thymidine analogue- mutations (TAMs) were detected in 20% of patients. One in three children on first-line ART are likely to develop virological treatment failure after the first 24 months of therapy. Poor adherence to ART, a NVP based first-line regimen, prior exposure to sdNVP were associated with treatment failure.

/pdf/incidence-and-risk-factors-for-first-line-anti-retroviral-io9cvgfn0f.pdf

Incidence and risk factors for first line anti retroviral treatment failure among Ugandan children attending an urban HIV clinic

OBJECTIVES: To evaluate the virological response and to describe the resistance profiles in the case of failure after 6 months of first-line highly active antiretroviral therapy (HAART) in HIV-1-infected children living in resource-limited settings. PATIENTS AND METHODS: Ninety-seven HIV-1-infected children who started two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (mainly zidovudine/lamivudine/nevirapine) in Mali were prospectively studied. Virological failure (VF) was defined as loss to follow-up death or HIV-1 RNA viral load (VL) of >400 copies/mL at 6 months. When VL was >50 copies/mL a genotypic resistance test was performed. RESULTS: Among the 97 children median age at antiretroviral initiation was 31 months and the majority were in WHO clinical (77.3%) and immunological (70.1%) stage III or IV. At month 6 44% of children had VL > 400 copies/mL (61% VF). Among the children with detectable VL 30/37 genotypic resistance tests were available 8 with wild-type viruses and 22 with resistance mutations (73%): 19 M184V/I 21 NNRTI mutations and only 3 thymidine analogue mutations (TAMs) (K70R D67N and L210W in three distinct viruses). At failure 6/8 children with wild-type viruses had a VL of 1000 copies/mL. CONCLUSIONS: Under NNRTI-based regimens early detection of VF could allow the reinforcement of adherence when VL was 1000 copies/mL. The low frequency of TAMs suggests that most NRTIs can be used in a second-line regimen after early failure.

Level of viral load and antiretroviral resistance after 6 months of non-nucleoside reverse transcriptase inhibitor first-line treatment in HIV-1-infected children in Mali

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Level of viral load and antiretroviral resistance after 6 months of non-nucleoside reverse transcriptase inhibitor first-line treatment in HIV-1-infected children in Mali