Resistance is common in paediatric patients failing ART in South Africa.

BACKGROUND: Minimal data exist on HIV drug resistance patterns and prevalence among paediatric patients failing ART in resource-limited settings. We assessed levels of HIV drug resistance in children with virological failure. METHODS: This cross-sectional study, performed from March 2017 to March 2019 in South Africa, enrolled HIV-positive children aged ≤19 years, receiving ART through public health facilities with recent evidence suggestive of virological failure (at least one viral load ≥1000 copies/mL), across 45 randomly selected high-volume clinics from all nine provinces. Resistance genotyping was performed using next-generation sequencing technologies. Descriptive analysis taking into account survey design was used to determine outcomes. RESULTS: Among 899 participants enrolled, the adjusted proportion of HIV drug resistance among children with virological failure was 87.5% (95% CI 83.0%-90.9%). Resistance to NNRTIs was detected in 77.4% (95% CI 72.5%-81.7%) of participants, and resistance to NRTIs in 69.5% (95% CI 62.9%-75.4%) of participants. Overall, resistance to PIs was detected in 7.7% (95% CI 4.4%-13.0%) of children. CONCLUSIONS: HIV drug resistance was highly prevalent in paediatric patients failing ART in South Africa, with 9 in 10 patients harbouring resistance to NNRTIs and/or NRTIs. PI-based regimens are predicted to be highly efficacious in achieving virological suppression amongst patients failing NNRTI-based regimens. Scaling up resistance testing amongst patients would facilitate access to second- and third-line regimens in South Africa.

Prevalence of HIV-1 drug resistance amongst newly diagnosed HIV-infected infants age 4-8 weeks, enrolled in three nationally representative PMTCT effectiveness surveys, South Africa: 2010, 2011-12 and 2012-13.

BACKGROUND: South Africa (SA) has expanded efforts to reduce mother-to-child transmission of HIV (MTCT) to less than 2% at six weeks after birth and to less than 5% at 18 months postpartum by 2016. Despite improved antiretroviral regimens and coverage between 2001 and 2016, there is little data on infant HIV drug resistance. This paper tracks the prevalence of HIV drug resistance patterns amongst HIV infected infants from three nationally representative studies that assessed the effectiveness of national programs to prevent MTCT (PMTCT). The first study was conducted in 2010 (under the dual therapy PMTCT policy), the second from 2011 to 12 (PMTCT Option A policy) and the third from 2012 to 13 (PMTCT Option A policy). From 2010 to 2013, infant non-nucleoside reverse transcriptase inhibitor (NNRTI) exposure increased from single dose to daily throughout breastfeeding; maternal nucleoside reverse transcriptase inhibitor (NRTI) and NNRTI exposure increased with initiation of NNRTI-and NRTI- containing triple antiretroviral therapy (ART) earlier in gestation and at higher CD4 cell counts. METHODS: Three nationally representative surveys were conducted in 2010, 2011-12 and 2012-13. During the surveys, mothers with known, unknown, or no exposure to antiretrovirals for PMTCT and their infants were included, and MTCT was measured. For this paper, infant dried blood spots (iDBS) from HIV PCR positive infants aged 4-8 weeks, with consent for additional iDBS testing, were analysed for HIV drug resistance at the National Institute of Communicable Diseases (NICD), SA, using an in-house assay validated by the Centers for Disease Control and Prevention (CDC). Total viral nucleic acid was extracted from 2 spots and amplified by nested PCR to generate a ~ 1 kb amplicon that was sequenced using Sanger sequencing technologies. Sequence assembly and editing was performed using RECall v3. RESULTS: Overall, HIV-1 drug resistance was detected in 51% (95% Confidence interval (CI) [45-58%]) of HIV PCR positive infants, 37% (95% CI [28-47%]) in 2010, 64% (95% CI [53-74%]) in 2011 and 63% (95% CI [47-77%]) in 2012 (p < 0.0001), particularly to the NNRTI drug class. Pooled analyses across all three surveys demonstrated that infants whose mothers received ART showed the highest prevalence of resistance (74%); 26% (21/82) of HIV PCR positive infants with no or undocumented antiretroviral drug (ARV) exposure harboured NNRTI resistance. CONCLUSIONS: These data demonstrate increasing NNRTI resistance amongst newly-diagnosed infants in a high HIV prevalence setting where maternal ART coverage increased across the years, starting earlier in gestation and at higher CD4 cell counts. This is worrying as lifelong maternal ART coverage for HIV positive pregnant and lactating women is increasing. Also of concern is that resistant virus was detected in HIV positive infants whose mothers were not exposed to ARVs, raising questions about circulating resistant virus. Numbers in this group were too small to assess trends over the three years.

Provincial and national prevalence estimates of transmitted HIV-1 drug resistance in South Africa measured using two WHO-recommended methods.

BACKGROUND: Sentinel surveillance of transmitted HIV drug resistance (TDR) among recently infected populations within a country was recommended by the World Health Organization from 2004 to 2015. METHODS: Serum specimens collected as part of the 2010, 2011 and 2012 National Antenatal Sentinel HIV Prevalence Surveys were used to estimate provincial and national TDR prevalence in South Africa. RESULTS: Moderate (5-15%) levels of transmitted non-nucleoside reverse transcriptase inhibitor (NNRTI) drug class resistance were detected in three of five provinces surveyed in 2010 and 2011 (Eastern Cape, Free State and KwaZulu-Natal). Inclusion of all nine of South Africa's provinces in the 2012 survey enabled calculation of a national TDR point prevalence estimate: TDR to the NNRTI drug class was 5.4% (95% CI 3.7, 7.8%), with K103N and V106M being the most frequently detected mutations. TDR estimates for the nucleoside reverse transcriptase inhibitor (NRTI) drug class were 1.1% (95% CI 0.5, 2.4%) and 0.6% (95% CI 0.1, 1.6%) for protease inhibitors (PI). CONCLUSIONS: These data provide national TDR estimates for South Africa in 2012 and indicate that levels of TDR were low to moderate for the NNRTI drug class and low for NRTIs and PIs in the population surveyed.

Walking and living independently with spina bifida: a 50-year prospective cohort study.

AIM: To describe trends in walking and living independently in a cohort of consecutive cases of spina bifida, followed-up over 50 years. METHOD: From 1972 to 2017, a cohort of 117 (born 1963-1971, 50 males, 67 females) survivors and/or carers was surveyed approximately every 5 years by clinical examination and/or postal questionnaire/telephone interview. The Office for National Statistics provided details of deaths. RESULTS: The follow-up in 2016 and 2017 was 99% (116/117). There were 37 survivors (17 males, 20 females) aged 46 to 53 years and 79 deaths (50y survival, 32%). The percentage of survivors who could walk more than 50m at the mean ages of 9 years, 18 years, 25 years, 30 years, 35 years, 40 years, 45 years, and 50 years was 51% (38/75), 50% (34/68), 33% (20/61), 30% (17/57), 30% (16/54), 30% (14/46), 31% (12/39), and 27% (10/37) respectively. However, the percentage living independently in the community after age 25 years increased over time: 23% (14/61); 37% (21/57); 41% (22/54); 39% (18/46); 56% (22/39); and 54% (20/37). Living independently at age 50 years was more common in survivors without a history of raised intracranial pressure or cerebrospinal fluid shunt revisions. INTERPRETATION: In this unselected cohort, mobility declined with age, possibly because of increasing obesity and deteriorating health. By contrast, partly because survival was better in those least disabled, the percentage living independently increased. WHAT THIS PAPER ADDS: By age 50 years, the percentage of patients who could walk more than 50m had declined to 27%. By age 50 years, the percentage living independently had doubled to over 50%. Survivors without a history of raised intracranial pressure or cerebrospinal fluid shunt revision are more likely to live independently.

CAMINAR Y VIVIR DE MANERA INDEPENDIENTE CUANDO SE TIENE UN DIAGNÓSTICO DE ESPINA BÍFIDA: UN ESTUDIO PROSPECTIVO DE COHORTE DE 50 AÑOS: OBJETIVO: Describir las tendencias para caminar y vivir de forma independiente en una cohorte de casos consecutivos de espina bífida, seguidos durante 50 años. MÉTODO: Desde 1.972 hasta 2.017, una cohorte de 117 (nacidos entre 1.963-1.971, 50 varones, 67 mujeres) sobrevivientes y/o cuidadores fueron encuestados aproximadamente cada 5 años mediante examen clínico y/o cuestionario postal/entrevista telefónica. La Oficina de Estadísticas Nacionales proporcionó detalles de las muertes. RESULTADOS: El seguimiento en 2.016 y 2.017 fue del 99% (116/117). Hubo 37 sobrevivientes (17 varones, 20 mujeres) de 46 a 53 años y 79 muertes (50 años de supervivencia, 32%). El porcentaje de sobrevivientes que pudieron caminar más de 50 metros en las edades medias de 9, 18, 25, 30, 35, 40, 45 y 50 años fue del 51% (38/75), 50% (34/68), 33% (20/61), 30% (17/57), 30% (16/54), 30% (14/46), 31% (12/39) y 27% (10/37) respectivamente. Sin embargo, el porcentaje de vida independiente en la comunidad después de los 25 años aumentó con el tiempo: 23% (14/61); 37% (21/57); 41% (22/54); 39% (18/46); 56% (22/39); y 54% (20/37). Vivir de forma independiente a los 50 años de edad fue más común en los sobrevivientes sin antecedentes de aumento de la presión intracraneal o revisiones de derivación del líquido cefalorraquídeo. INTERPRETACIÓN: En esta cohorte no seleccionada, la movilidad disminuyó con la edad, posiblemente debido al aumento de la obesidad y al deterioro de la salud. Por el contrario, en parte porque la supervivencia fue mejor en los individuos con menos desafíos fisicos, el porcentaje de vida independiente aumentó.

CAMINHANDO E VIVENDO COM INDEPENDÊNCIA TENDO ESPINHA BÍFIDA: UM ESTUDO DE COORTE PROSPECTIVO DE 50 ANOS: OBJETIVO: Descrever tendências no caminhar e viver com independência em uma coorte de casos consecutivos de espinha bífida, acompanhados por 50 anos. MÉTODO: De 1972 a 2017, uma coorte de 117 (nascidos 1963-1971, 50 do sexo masculino, 67 do sexo feminino) sobreviventes e/ou cuidadores foi avaliada aproximadamente a cada 5 anos por exame clínico e/ou entrevista por telefone ou correios. O Escritório de Estatística Nacional forneceu detalhes sobre óbitos. RESULTADOS: O acompanhamento em 2016 e 2017 foi 99% (116/117). Houve 37 sobreviventes (17 do sexo masculino, 20 do sexo feminino) com idades de 46 to 53 anos e 79 óbitos (sobrevivência em 50a, 32%). A porcentagem de sobreviventes que podiam andar mais de 50m nas idades médias de 9, 18, 25, 30, 35, 40, 45, e 50 foi 51% (38/75), 50% (34/68), 33% (20/61), 30% (17/57), 30% (16/54), 30% (14/46), 31% (12/39), and 27% (10/37) respectivamente. No entanto, a porcentagem vivendo independentemente na comunidade após a idade de 25 anos aumentou com o tempo: 23% (14/61); 37% (21/57); 41% (22/54); 39% (18/46); 56% (22/39); e 54% (20/37). Viver com independência na idade de 50 anos foi mais comum em sobreviventes sem história de aumento de pressão intra-craniana ou revisões da válvula de líquido cérebro-espinhal. INTERPRETAÇÃO: Nesta coorte não selecionada, a mobilidade diminuiu com a idade, possivelmente por causa do aumento da obesidade e deterioração das condições de saúde. Em contraste, em parte porque a sobrevivência foi melhor naqueles com menos incapacidades, a porcentagem dos que viviam com independência aumentou.

Rates of virological suppression and drug resistance in adult HIV-1-positive patients attending primary healthcare facilities in KwaZulu-Natal, South Africa.

BACKGROUND: KwaZulu-Natal (KZN) Province in South Africa has the highest HIV disease burden in the country, with an estimated population prevalence of 24.7%. A pilot sentinel surveillance project was undertaken in KZN to classify the proportion of adult patients failing first-line ART and to describe the patterns of drug resistance mutations (DRMs) in patients with virological failure (VF). METHODS: Cross-sectional surveillance of acquired HIV drug resistance was conducted in 15 sentinel ART clinics between August and November 2013. Two population groups were surveyed: on ART for 12-15 months (Cohort A) or 24-36 months (Cohort B). Plasma specimens with viral load ≥1000 copies/mL were defined as VF and genotyped for DRMs. RESULTS: A total of 1299 adults were included in the analysis. The prevalence of VF was 4.0% (95% CI 1.8-8.8) among 540 adults in Cohort A and 7.7% (95% CI 4.4-13.0) of 759 adults in Cohort B. Treatment with efavirenz was more likely to suppress viral load in Cohort A (P = 0.005). Independent predictors of VF for Cohort B included male gender, advanced WHO stage at ART initiation and treatment with stavudine or zidovudine compared with tenofovir. DRMs were detected in 89% of 123 specimens with VF, including M184I/V, K103N/S, K65N/R, V106A/M and Y181C. CONCLUSIONS: VF in adults in KZN was <8% up to 3 years post-ART initiation but was associated with a high frequency of DRMs. These data identify key groups for intensified adherence counselling and highlight the need to optimize first-line regimens to maintain viral suppression.

Rapid Detection of Common HIV-1 Drug Resistance Mutations by Use of High-Resolution Melting Analysis and Unlabeled Probes.

HIV rapidly accumulates resistance mutations following exposure to subtherapeutic concentrations of antiretroviral drugs that reduces treatment efficacy. High-resolution melting analysis (HRMA) has been used to successfully identify single nucleotide polymorphisms (SNPs) and to genotype viral and bacterial species. Here, we tested the ability of HRMA incorporating short unlabeled probes to accurately assign drug susceptibilities at the 103, 181, and 184 codons of the HIV-1 reverse transcriptase gene. The analytical sensitivities of the HRMA assays were 5% of mixed species for K103N and Y181C and 20% for M184V. When applied to 153 HIV-1 patient specimens previously genotyped by Sanger population sequencing, HRMA correctly assigned drug sensitivity or resistance profiles to 80% of the samples at codon 103 (K103K/N) (Cohen's kappa coefficient [κ] > 0.6; P < 0.05), 90% at 181 (Y181Y/C) (κ > 0.74, P < 0.05), and 80% at 184 (M184M/V) (κ > 0.62; P < 0.05). The frequency of incorrect genotypes was very low (≤1 to 2%) for each assay, which in most cases was due to the higher sensitivity of the HRMA assay. Specimens for which drug resistance profiles could not be assigned (9 to 20%) often had polymorphisms in probe binding regions. Thus, HRMA is a rapid, inexpensive, and sensitive method for the determination of drug sensitivities caused by major HIV-1 drug resistance mutations and, after further development to minimize the melting effects of nontargeted polymorphisms, may be suitable for surveillance purposes.

The use of dried blood spot specimens for HIV-1 drug resistance genotyping in young children initiating antiretroviral therapy.

Paired plasma and dried blood spots (DBS) from 232 South African HIV-infected children initiating antiretroviral therapy (ART) were genotyped for drug resistance mutations, most of who had prior exposure to ART for prevention-of-mother-to-child-transmission. Non-nucleoside reverse transcriptase inhibitor mutations were most commonly detected in both specimen types, particularly Y181C/I and K103N/S. Resistance interpretation concordance was achieved in 97% of pairs with seven children having mutations detected in DBS only. These results validate the preferential use of DBS specimens for HIVDR genotyping in this patient group.

Genetic Changes in HIV-1 Gag-Protease Associated with Protease Inhibitor-Based Therapy Failure in Pediatric Patients.

Studies have shown a low frequency of HIV-1 protease drug resistance mutations in patients failing protease inhibitor (PI)-based therapy. Recent studies have identified mutations in Gag as an alternate pathway for PI drug resistance in subtype B viruses. We therefore genotyped the Gag and protease genes from 20 HIV-1 subtype C-infected pediatric patients failing a PI-based regimen. Major protease resistance mutations (M46I, I54V, and V82A) were identified in eight (40%) patients, as well as Gag cleavage site (CS) mutations (at codons 373, 374, 378, 428, 431, 449, 451, and 453) in nine (45%) patients. Four of these Gag CS mutations occurred in the absence of major protease mutations at PI failure. In addition, amino acid changes were noted at Gag non-CS with some predicted to be under HLA/KIR immune-mediated pressure and/or drug selection pressure. Changes in Gag during PI failure therefore warrant further investigation of the Gag gene and its role in PI failure in HIV-1 subtype C infection.

Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis.

BACKGROUND: Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. METHODS AND FINDINGS: We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions­a proxy for recent infection­yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs­K101E, K103N, Y181C, and G190A­accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. CONCLUSIONS: Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

Neurological level at birth predicts survival to the mid-40s and urological deaths in open spina bifida: a complete prospective cohort study.

AIM: To conduct a 50-year complete, community-based, prospective cohort study to investigate long-term survival, causes of death, and influence of level of the lesion in treated open spina bifida. METHOD: The cohort comprised 117 consecutive cases whose backs were closed non-selectively at birth between 1963 and 1971 in Cambridge, UK. In 2013 we surveyed the survivors (n=39, 18 males, 21 females; mean age 46y, range 43-49y) by postal questionnaire and telephone interview. We compared outcomes in those born with a neurological deficit in terms of sensory and motor levels of L1 and above versus L2 and below. RESULTS: Two-thirds of the cohort (78/117) had died. Causes of death were cardiorespiratory (n=26), neurological (n=24), urological (n=22), or other (n=6). Only the urological deaths were related to level of the lesion: there were none in those with a sensory level of L2 or below (p<0.001). Birth findings also predicted survival: of the 57 infants with a neurological level of L1 or above, only 12% (n=7) survived compared with 55% (30/55) of the remainder (p<0.001). INTERPRETATION: The increased mortality in those born with an extensive neurological deficit was mainly due to urological deaths. Neurological level, particularly the sensory level, is the best predictor of long-term outcome and should be assessed routinely at birth.

Population-based surveillance of HIV drug resistance emerging on treatment and associated factors at sentinel antiretroviral therapy sites in Namibia.

OBJECTIVE: The World Health Organization (WHO) prospective surveys of acquired HIV drug resistance (HIVDR) evaluate HIVDR emerging after the first year of antiretroviral therapy (ART) and associated factors. METHODS: Consecutive ART starters in 2009 were enrolled at 3 sentinel sites in Namibia. Genotyping was performed at start and after 12 months in patients with HIV viral load (VL) >1000 copies per mL. HIVDR outcomes were: HIVDR prevention (VL ≤1000 copies/mL), possible HIVDR (VL >1000 copies/mL without detectable HIVDR or loss to follow-up or ART stop), and HIVDR (VL >1000 copies/mL with detectable HIVDR). Adherence was assessed using medication possession ratio (MPR). RESULTS: Of 394 starters, at 12 months, 80% were on first-line ART, 1% died, 4% transferred out, 1% stopped ART, <1% switched to second-line, and 15% were lost to follow-up. Among patients on first-line, 77% had VL testing, and 94% achieved VL ≤1000 copies per mL. At baseline, 7% had HIVDR. After 12 months, among patients with VL testing, 5% had HIVDR. A majority of patients failing therapy had high-level resistance to nonnucleoside reverse transcriptase inhibitors but none to protease inhibitors. All sites achieved the WHO target of ≥70% HIVDR prevention. Factors associated with not achieving HIVDR prevention were: baseline resistance to nonnucleoside reverse transcriptase inhibitors [odds ratio (OR) 3.0, P = 0.023], WHO stage 3 or 4 at baseline (OR 2.0, P = 0.012), and MPR <75% (OR 4.9, P = 0.021). CONCLUSIONS: Earlier ART initiation and removal of barriers to on-time drug pickups may help to prevent HIVDR. These data inform decisions at national and global levels on the effectiveness of first- and second-line regimens.

Concordance between allele-specific PCR and ultra-deep pyrosequencing for the detection of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations.

Recent advances in genotyping technologies have allowed for detection of HIV-1 drug resistance mutations present at low levels. The presence and percentage of Y181C and K103N drug-resistant variants in the blood of 105 subtype C HIV-infected infants who failed single-dose nevirapine prophylaxis for HIV transmission were compared using two highly sensitive genotyping methods, allele-specific PCR (AS-PCR) and ultra-deep pyrosequencing. Significant correlations in detection between both methods were found for both Y181C (correlation coefficients of 0.94 [95% CI 0.91-0.96]) and K103N (0.89 [95% CI 0.84-0.92]) mutations. The majority of discordant specimens (3/5 Y181C and 8/11 K103N) had wild-type variants when population sequencing was used, but mutant variants were detectable at very low levels (≤5%) with either assay. This difference is most likely due to stochastic variations in the appearance of mutant variants. Overall, both AS-PCR and ultra-deep pyrosequencing methods have proven to be sensitive and accurate, and may confidently be used where feasible.

Open spina bifida: birth findings predict long-term outcome.

OBJECTIVES: To investigate if lifestyle in spina bifida at age 40±3 years, relates to neurological deficit in infancy or cerebrospinal fluid shunt history. DESIGN: Prospective cohort study with 100% ascertainment. SETTING: Community. PARTICIPANTS: 117 consecutive cases of open spina bifida whose backs were closed non-selectively at birth. In 2007, all 46 (39%) survivors and/or carers were surveyed by postal questionnaires and telephone interviews. RESULTS: Of the 38 children with absent sensation only below the knee (sensory level below L3), 23 (61%) survived of whom 14 (61%) were community walkers and only 5 (22%) needed daily care. But in 42 babies with absent sensation up to the umbilicus (sensory level above T11) only seven (17%) survived, none could walk and five (71%) needed daily care. Survivors with no shunt revisions were more likely to walk, live independently and drive a car. CONCLUSION: Mobility and the need for care at 40 can be predicted from the neurological deficit.

HIV-1 drug resistance at antiretroviral treatment initiation in children previously exposed to single-dose nevirapine.

OBJECTIVE: To describe the prevalence of HIV-1 drug resistance mutations at the time of treatment initiation in a large cohort of HIV-infected children previously exposed to single-dose nevirapine (sdNVP) for prevention of transmission. DESIGN: Drug resistance mutations were measured pretreatment in 255 infants and young children under 2 years of age in South Africa exposed to sdNVP and initiating ritonavir-boosted lopinavir-based therapy. Those who achieved viral suppression were randomized to either continue the primary regimen or to switch to a nevirapine-based regimen. Pretreatment samples were tested using population sequencing and real time allele-specific PCR (AS-PCR) to detect Y181C and K103N minority variants. Those with confirmed viremia more than 1000 copies/ml by 52 weeks postrandomization in the switch group were defined as having viral failure. RESULTS: Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations, predominantly Y181C, were detected by either method in 62% of infants less than 6 months of age, in 39% of children 6-12 months of age, 22% 12-18 months, and 16% 18-24 months (P = <0.0001). NNRTI mutations detected by genotyping, but not K103N or Y181C mutations detected only by AS-PCR, were associated with viral failure in the switch group. CONCLUSION: The prevalence of mutations known to compromise primary NNRTI-based therapy is high in sdNVP-exposed children, supporting current guidelines recommending use of protease inhibitor-based regimens for young children. Standard genotyping is adequate to identify children who could benefit from switching to NNRTI-based therapy.

Expectation of life and unexpected death in open spina bifida: a 40-year complete, non-selective, longitudinal cohort study.

AIM: The aim of our study was to investigate survival and causes of death in a complete cohort of open spina bifida at the mean age of 40 years. METHOD: We conducted a community-based, prospective study of 117 consecutive infants (50 males, 67 females) with open spina bifida whose backs were closed non-selectively within 48 hours of birth between 1963 and 1971 at Addenbrooke's Hospital, Cambridge, UK. Of those who survived to age 1 year, 89% (82 out of 92) had a cerebrospinal fluid shunt. In 2007, all survivors were surveyed by postal questionnaire backed up by telephone interview. Details of deaths were obtained from the Office for National Statistics, medical records, and autopsy reports, and Kaplan-Meier survival curves were constructed. RESULTS: One in three of the cohort (40/117) died before the age of 5 years. A further 26% (31/117) died during the next 35 years, over 10 times the national average. Half the deaths (16/31) after the age of 5 were sudden and unexpected. All occurred in the community and were followed by a coroner's autopsy. The most frequent causes of these unexpected deaths were epilepsy, pulmonary embolus, acute hydrocephalus, and acute renal sepsis. The prognosis for survival was strikingly poor in those with the most extensive neurological deficit. Only 17% (7/42) of those born with a high sensory level (above T11) survived to the mean age of 40 years, compared with 61% (23/38) of those with a low sensory level (below L3; p=0.001). INTERPRETATION: Doctors and care planners need to be aware that, contrary to previous suggestions, there is continuing high mortality throughout adult life in individuals with open spina bifida, and many deaths are unexpected.

Lifestyle in adults aged 35 years who were born with open spina bifida: prospective cohort study.

BACKGROUND AND METHODS: From 1963 to 1971, 117 babies with open spina bifida were treated non-selectively from birth. In 2002 we reviewed all the survivors by postal questionnaire and telephone call. The aims were to find out how many were living independently in the community or were in open employment or drove a car. In addition to these achievements we recorded health, medication and admissions to hospital and asked how much daily help they needed. RESULTS: Ascertainment was 100%. There had been 63 deaths, mainly of the most severely affected. The mean age of the 54 survivors was 35 years. The outcome in terms of disability ranged from apparent normality to total dependency. It reflected both the neurological deficit, which had been recorded in infancy in terms of sensory level, and events in the CSF shunt history. Overall about 2 in 5 of the survivors lived independently in the community, 2 in 5 drove a car, 1 in 5 was in competitive employment and 1 in 5 could walk 50 metres. CONCLUSION: Although those who survived to age 35 years tended to be less disabled, 2 in 5 continued to need daily care.