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.

Pretreatment Human Immunodeficiency Virus (HIV) Drug Resistance Among Treatment-Naive Infants Newly Diagnosed With HIV in 2016 in Namibia: Results of a Nationally Representative Study.

Background: The World Health Organization (WHO) recommends routine surveillance of pretreatment human immunodeficiency virus (HIV) drug resistance (HIVDR) in children <18 months of age diagnosed with HIV through early infant diagnosis (EID). In 2016, 262 children <18 months of age were diagnosed with HIV in Namibia through EID. Levels of HIVDR in this population are unknown. Methods: In 2016, Namibia surveyed pretreatment HIVDR among children aged <18 months following WHO guidance. Reverse transcriptase, protease, and integrase regions of HIV-1 were genotyped from remnant dried blood spot specimens from all infants diagnosed with HIV in Namibia in 2016. HIVDR was predicted using the Stanford HIVdb algorithm. Results: Of 262 specimens genotyped, 198 HIV-1 protease and reverse transcriptase sequences and 118 HIV-1 integrase sequences were successfully amplified and analyzed. The prevalence of efavirenz/nevirapine (EFV/NVP), abacavir (ABC), zidovudine, lamivudine/emtricitabine (3TC/FTC), and tenofovir (TDF) resistance was 62.6%, 17.7%, 5.6%, 15.7%, and 10.1%, respectively. No integrase inhibitor resistance was detected. Conclusions: The high level of EFV/NVP resistance is unsurprising; however, levels of ABC and TDF resistance are among the highest observed to date in infants in sub-Saharan Africa. The absence of resistance to dolutegravir (DTG) is reassuring but underscores the need to further study the impact of ABC and 3TC/FTC resistance on pediatric protease inhibitor- and DTG-based regimens and accelerate access to other antiretroviral drugs. Results underscore the need for antiretroviral therapy optimization and prompt management of high viral loads in infants and pregnant and breastfeeding women.

Epidemiology of SARS-CoV-2 infection and SARS-CoV-2 positive hospital admissions among children in South Africa.

INTRODUCTION: We describe epidemiology and outcomes of confirmed SARS-CoV-2 infection and positive admissions among children <18 years in South Africa, an upper-middle income setting with high inequality. METHODS: Laboratory and hospital COVID-19 surveillance data, 28 January - 19 September 2020 was used. Testing rates were calculated as number of tested for SARS-CoV-2 divided by population at risk; test positivity rates were calculated as positive tests divided by total number of tests. In-hospital case fatality ratio (CFR) was calculated based on hospitalized positive admissions with outcome data who died in-hospital and whose death was judged SARS-CoV-2 related by attending physician. FINDINGS: 315 570 children aged <18 years were tested for SARS-CoV-2; representing 8.9% of all 3 548 738 tests and 1.6% of all children in the country. Of children tested, 46 137 (14.6%) were positive. Children made up 2.9% (n = 2007) of all SARS-CoV-2 positive admissions to sentinel hospitals. Among children, 47 died (2.6% case-fatality). In-hospital deaths were associated with male sex [adjusted odds ratio (aOR) 2.18 (95% confidence intervals [CI] 1.08-4.40)] vs female; age <1 year [aOR 4.11 (95% CI 1.08-15.54)], age 10-14 years [aOR 4.20 (95% CI1.07-16.44)], age 15-17 years [aOR 4.86 (95% 1.28-18.51)] vs age 1-4 years; admission to a public hospital [aOR 5.07(95% 2.01-12.76)] vs private hospital and ≥1 underlying conditions [aOR 12.09 (95% CI 4.19-34.89)] vs none. CONCLUSIONS: Children with underlying conditions were at greater risk of severe SARS-CoV-2 outcomes. Children > 10 years, those in certain provinces and those with underlying conditions should be considered for increased testing and vaccination.

Community-led cross-sectional study of social and employment circumstances, HIV and associated factors amongst female sex workers in South Africa: study protocol.

BACKGROUND: In South Africa, female sex workers (FSWs) are perceived to play a pivotal role in the country's HIV epidemic. Understanding their health status and risk factors for adverse health outcomes is foundational for developing evidence-based health care for this population. OBJECTIVE: Describe the methodology used to successfully implement a community-led study of social and employment circumstances, HIV and associated factors amongst FSWs in South Africa. METHOD: A community-centric, cross-sectional, survey of 3,005 adult FSWs was conducted (January-July 2019) on 12 Sex Work (SW) programme sites across nine provinces of South Africa. Sites had existing SW networks and support programmes providing peer education and HIV services. FSWs were involved in the study design, questionnaire development, and data collection. Questions included: demographic, sexual behaviour, HIV testing and treatment/PrEP history, and violence exposure. HIV rapid testing, viral load, CD4 count, HIV recency, and HIV drug resistance genotypic testing were undertaken. Partner organisations provided follow-up services. RESULTS: HIV Prevalence was 61.96%, the median length of selling sex was 6 years, and inconsistent condom use was reported by 81.6% of participants, 88.4% reported childhood trauma, 46.2% reported physical or sexual abuse by an intimate partner and 57.4% by a client. More than half of participants had depression and post-traumatic stress disorder (52.7% and 54.1%, respectively). CONCLUSION: This is the first national survey of HIV prevalence amongst FSWs in programmes in South Africa. The data highlight the vulnerability of this population to HIV, violence and mental ill health, suggesting the need for urgent law reform. Based on the unique methodology and the successful implementation alongside study partners, the outcomes will inform tailored interventions. Our rapid rate of enrolment, low rate of screening failure and low proportion of missing data showed the feasibility and importance of community-centric research with marginalised, highly vulnerable populations.

Estimating the contribution of key populations towards HIV transmission in South Africa.

INTRODUCTION: In generalized epidemic settings, there is insufficient understanding of how the unmet HIV prevention and treatment needs of key populations (KPs), such as female sex workers (FSWs) and men who have sex with men (MSM), contribute to HIV transmission. In such settings, it is typically assumed that HIV transmission is driven by the general population. We estimated the contribution of commercial sex, sex between men, and other heterosexual partnerships to HIV transmission in South Africa (SA). METHODS: We developed the "Key-Pop Model"; a dynamic transmission model of HIV among FSWs, their clients, MSM, and the broader population in SA. The model was parameterized and calibrated using demographic, behavioural and epidemiological data from national household surveys and KP surveys. We estimated the contribution of commercial sex, sex between men and sex among heterosexual partnerships of different sub-groups to HIV transmission over 2010 to 2019. We also estimated the efficiency (HIV infections averted per person-year of intervention) and prevented fraction (% IA) over 10-years from scaling-up ART (to 81% coverage) in different sub-populations from 2020. RESULTS: Sex between FSWs and their paying clients, and between clients with their non-paying partners contributed 6.9% (95% credibility interval 4.5% to 9.3%) and 41.9% (35.1% to 53.2%) of new HIV infections in SA over 2010 to 2019 respectively. Sex between low-risk groups contributed 59.7% (47.6% to 68.5%), sex between men contributed 5.3% (2.3% to 14.1%) and sex between MSM and their female partners contributed 3.7% (1.6% to 9.8%). Going forward, the largest population-level impact on HIV transmission can be achieved from scaling up ART to clients of FSWs (% IA = 18.2% (14.0% to 24.4%) or low-risk individuals (% IA = 20.6% (14.7 to 27.5) over 2020 to 2030), with ART scale-up among KPs being most efficient. CONCLUSIONS: Clients of FSWs play a fundamental role in HIV transmission in SA. Addressing the HIV prevention and treatment needs of KPs in generalized HIV epidemics is central to a comprehensive HIV response.

HIV drug resistance profile in South Africa: Findings and implications from the 2017 national HIV household survey.

BACKGROUND: HIV drug resistance (HIVDR) testing was included in the 2017 South African national HIV household survey. We describe the prevalence of HIVDR by drug class, age, sex and antiretroviral drugs (ARV) status. METHODS: Dried blood were spots tested for HIV, with Viral load (VL), exposure to ARVs and HIVDR testing among those HIV positive. HIVDR testing was conducted on samples with VL ≥1000 copies/ml using Next Generation Sequencing. Weighted percentages of HIVDR are reported. RESULTS: 697/1,105 (63%) of HIV positive samples were sequenced. HIVDR was detected in samples from 200 respondents (27.4% (95% confidence interval (CI) 22.8-32.6)). Among these 130 (18.9% (95% CI 14.8-23.8)), had resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) only, 63 (7.8% (95% CI 5.6-10.9)) resistance to NNRTIs and nucleoside reverse transcriptase inhibitors, and 3 (0.5% (95% CI 0.1-2.1)) resistance to protease inhibitors. Sixty-five (55.7% (95% CI 42.6-67.9) of ARV-positive samples had HIVDR compared to 112 (22.8% (95% CI 17.7-28.7)), in ARV-negative samples. HIVDR was found in 75.6% (95% CI 59.2-87.3), n = 27, samples from respondents who reported ARV use but tested ARV-negative, and in 15.3% (95% CI 6.3-32.8), n = 7, respondents who reported no ARV use and tested ARV-negative. There were no significant age and sex differences in HIVDR. CONCLUSION: 27% of virally unsuppressed respondents had HIVDR, increasing to 75% among those who had discontinued ARV. Our findings support strengthening first-line ARV regimens by including drugs with a higher resistance barrier and treatment adherence strategies, and close monitoring of HIVDR.

Multi-Laboratory Comparison of Next-Generation to Sanger-Based Sequencing for HIV-1 Drug Resistance Genotyping.

Next-generation sequencing (NGS) is increasingly used for HIV-1 drug resistance genotyping. NGS methods have the potential for a more sensitive detection of low-abundance variants (LAV) compared to standard Sanger sequencing (SS) methods. A standardized threshold for reporting LAV that generates data comparable to those derived from SS is needed to allow for the comparability of data from laboratories using NGS and SS. Ten HIV-1 specimens were tested in ten laboratories using Illumina MiSeq-based methods. The consensus sequences for each specimen using LAV thresholds of 5%, 10%, 15%, and 20% were compared to each other and to the consensus of the SS sequences (protease 4-99; reverse transcriptase 38-247). The concordance among laboratories' sequences at different thresholds was evaluated by pairwise sequence comparisons. NGS sequences generated using the 20% threshold were the most similar to the SS consensus (average 99.6% identity, range 96.1-100%), compared to 15% (99.4%, 88.5-100%), 10% (99.2%, 87.4-100%), or 5% (98.5%, 86.4-100%). The average sequence identity between laboratories using thresholds of 20%, 15%, 10%, and 5% was 99.1%, 98.7%, 98.3%, and 97.3%, respectively. Using the 20% threshold, we observed an excellent agreement between NGS and SS, but significant differences at lower thresholds. Understanding how variation in NGS methods influences sequence quality is essential for NGS-based HIV-1 drug resistance genotyping.

High levels of resistance to nucleoside/nucleotide reverse transcriptase inhibitors in newly diagnosed antiretroviral treatment-naive children in sub-Saharan Africa.

: Exposure of infants to antiretroviral drugs for prevention of mother-to-child transmission can induce resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). Data from nine national surveys of pretreatment drug resistance in children newly diagnosed with HIV show high levels of resistance to NRTIs included in first-line antiretroviral treatment (ART) regimens (dual abacavir-lamivudine/emtricitabine resistance). Additional research is needed to determine the impact of NRTI resistance on treatment response and optimize infant ART.

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study.

BACKGROUND: Understanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa. METHODS: We conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design. RESULTS: Overall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high-level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens. CONCLUSIONS: DRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression.

Low-Abundance Drug-Resistant HIV-1 Variants in Antiretroviral Drug-Naive Individuals: A Systematic Review of Detection Methods, Prevalence, and Clinical Impact.

BACKGROUND: The presence of high-abundance drug-resistant HIV-1 jeopardizes success of antiretroviral therapy (ART). Despite numerous investigations, the clinical impact of low-abundance drug-resistant HIV-1 variants (LA-DRVs) at levels <15%-25% of the virus population in antiretroviral (ARV) drug-naive individuals remains controversial. METHODS: We systematically reviewed 103 studies assessing prevalence, detection methods, technical and clinical detection cutoffs, and clinical significance of LA-DRVs in antiretroviral drug-naive adults. RESULTS: In total, 14 919 ARV drug-naive individuals were included. Prevalence of LA-DRVs (ie, proportion of individuals harboring LA-DRVs) was 0%-100%. Technical detection cutoffs showed a 4 log range (0.001%-10%); 42/103 (40.8%) studies investigating the impact of LA-DRVs on ART; 25 studies included only individuals on first-line nonnucleoside reverse transcriptase inhibitor-based ART regimens. Eleven of those 25 studies (44.0%) reported a significantly association between preexisting LA-DRVs and risk of virological failure whereas 14/25 (56.0%) did not. CONCLUSIONS: Comparability of the 103 studies is hampered by high heterogeneity of the studies' designs and use of different methods to detect LA-DRVs. Thus, evaluating clinical impact of LA-DRVs on first-line ART remains challenging. We, the WHO HIVResNet working group, defined central areas of future investigations to guide further efforts to implement ultrasensitive resistance testing in routine settings.

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.

HIV diagnostic challenges in breast-fed infants of mothers on antiretroviral therapy.

BACKGROUND: Prompt initiation of antiretroviral therapy (ART) for HIV-infected infants is strongly recommended but diagnostic confirmation is important as committing children to life-long ART carries serious health and social implications. METHODS: Two HIV-exposed infants in Johannesburg, South Africa were identified presenting with unusual trajectories of diagnostic nucleic acid amplification tests (NAAT) and viral load results. RESULTS: Case 1 had repeat indeterminate NAAT results during the first 3 weeks of life; repeat testing thereafter was negative with undetectable viral load including after daily nevirapine prophylaxis ended. ART was not initiated at this time. Case 2 had a single positive NAAT result at 1 month of age that prompted initiation of ART. Subsequent results were negative and ART was discontinued. Repeat negative NAAT with viral load below the limit of quantification or undetectable continued to be obtained. Shortly after and around weaning, positive NAAT results with high viral load (7.1 and 6.03 log10 copies/ml for Cases 1 and 2, respectively) were observed in both children. Both mothers were treated with tenofovir, emtricitabine and efavirenz during breastfeeding. Testing with ultrasensitive assays on early samples conclusively revealed HIV-1 proviral DNA in Case 1. Testing with ultrasensitive assays after the early period but prior to weaning did not detect HIV in either infant. CONCLUSION: We hypothesize that breast milk from the mothers of these two rare cases had HIV-specific or nonspecific factors that led to the undetectable results in already infected infants until breastfeeding ended. Our results raise the importance of repeat testing of HIV-exposed breast-fed infants after complete cessation of all breastfeeding.

Trends in Pretreatment HIV-1 Drug Resistance in Antiretroviral Therapy-naive Adults in South Africa, 2000-2016: A Pooled Sequence Analysis.

BACKGROUND: South Africa has the largest public antiretroviral therapy (ART) programme in the world. We assessed temporal trends in pretreatment HIV-1 drug resistance (PDR) in ART-naïve adults from South Africa. METHODS: We included datasets from studies conducted between 2000 and 2016, with HIV-1 pol sequences from more than ten ART-naïve adults. We analysed sequences for the presence of 101 drug resistance mutations. We pooled sequences by sampling year and performed a sequence-level analysis using a generalized linear mixed model, including the dataset as a random effect. FINDINGS: We identified 38 datasets, and retrieved 6880 HIV-1 pol sequences for analysis. The pooled annual prevalence of PDR remained below 5% until 2009, then increased to a peak of 11·9% (95% confidence interval (CI) 9·2-15·0) in 2015. The pooled annual prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR remained below 5% until 2011, then increased to 10.0% (95% CI 8.4-11.8) by 2014. Between 2000 and 2016, there was a 1.18-fold (95% CI 1.13-1.23) annual increase in NNRTI PDR (p < 0.001), and a 1.10-fold (95% CI 1.05-1.16) annual increase in nucleoside reverse-transcriptase inhibitor PDR (p = 0.001). INTERPRETATION: Increasing PDR in South Africa presents a threat to the efforts to end the HIV/AIDS epidemic. These findings support the recent decision to modify the standard first-line ART regimen, but also highlights the need for broader public health action to prevent the further emergence and transmission of drug-resistant HIV. SOURCE OF FUNDING: This research project was funded by the South African Medical Research Council (MRC) with funds from National Treasury under its Economic Competitiveness and Support Package. DISCLAIMER: The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of CDC.

Low Frequency of Protease Inhibitor Resistance Mutations and Insertions in HIV-1 Subtype C Protease Inhibitor-Naïve Sequences.

Human immunodeficiency virus-1 (HIV-1) protease sequences from 2,225 protease inhibitor (PI)-naïve HIV-1 subtype C-infected individuals collected over a 14-year period were analyzed for polymorphisms. Over 50% of sequences differed from an HIV-1 subtype B consensus sequence at 8 of the 99 amino acids at residues 12, 15, 19, 36, 41, 69, 89, and 93, but not in the functionally important regions. The frequency of primary resistance and accessory mutations occurred in <1% of the sequences. Of note, 11 sequences (0.5%) harbored amino acid insertions between residues 36 and 39, located in the elbow of the flap region. The insertions were found throughout the 13-year period. Occurrence of insertions in subtype C viruses is rare and viruses remain sensitive to currently used PIs (lopinavir/r, atazanavir/r, and darunavir/r). However, ongoing characterization of isolates is required to identify changes that may impact PI treatment since PIs are part of standard SA regimens.

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.

Moderate-to-High Levels of Pretreatment HIV Drug Resistance in KwaZulu-Natal Province, South Africa.

There is evidence of increasing levels of pretreatment HIV drug resistance (PDR) in Southern Africa. We used data from two large population-based HIV surveillance studies to estimate prevalence of PDR in KwaZulu-Natal, the province with the highest HIV prevalence in South Africa. Sanger sequencing was performed on samples obtained from a longitudinal HIV surveillance program (study A, 2013-2014) and the HIV Incidence Provincial Surveillance System (study B, 2014-2015). Sequences were included for adult HIV positive participants (age ≥15 years for study A, age 15-49 years for study B) with no documented prior exposure to antiretroviral therapy (ART). Overall and drug class-specific PDR was estimated using the World Health Organization 2009 surveillance drug resistance mutation (SDRM) list, and phylogenetic analysis was performed to establish evidence of drug resistance transmission linkage. A total of 1,845 sequences were analyzed (611 study A; 1,234 study B). An overall PDR prevalence of 9.2% [95% confidence interval (CI) 7.0-11.7] was observed for study A and 11.0% (95% CI 8.9-13.2) for study B. In study B, the prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR exceeded 10% for sequences collected in 2014 (10.2%, 95% CI 7.5-12.9). The most prevalent SDRMs were K103NS (7.5%), M184VI (2.4%), and V106AM (1.4%). There was no evidence of large transmission chains of drug-resistant virus. High level NNRTI PDR (>10%) suggests a need to modify the standard first-line ART regimen and to focus attention on improving the quality of HIV prevention, treatment, and care.

HIV-1 drug resistance before initiation or re-initiation of first-line antiretroviral therapy in low-income and middle-income countries: a systematic review and meta-regression analysis.

BACKGROUND: Pretreatment drug resistance in people initiating or re-initiating antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTIs) might compromise HIV control in low-income and middle-income countries (LMICs). We aimed to assess the scale of this problem and whether it is associated with the intiation or re-initiation of ART in people who have had previous exposure to antiretroviral drugs. METHODS: This study was a systematic review and meta-regression analysis. We assessed regional prevalence of pretreatment drug resistance and risk of pretreatment drug resistance in people initiating ART who reported previous ART exposure. We systematically screened publications and unpublished datasets for pretreatment drug-resistance data in individuals in LMICs initiating or re-initiating first-line ART from LMICs. We searched for studies in PubMed and Embase and conference abstracts and presentations from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Society Conference, and the International Drug Resistance Workshop for the period Jan 1, 2001, to Dec 31, 2016. To assess the prevalence of drug resistance within a specified region at any specific timepoint, we extracted study level data and pooled prevalence estimates within the region using an empty logistic regression model with a random effect at the study level. We used random effects meta-regression to relate sampling year to prevalence of pretreatment drug resistance within geographical regions. FINDINGS: We identified 358 datasets that contributed data to our analyses, representing 56 044 adults in 63 countries. Prevalence estimates of pretreatment NNRTI resistance in 2016 were 11·0% (7·5-15·9) in southern Africa, 10·1% (5·1-19·4) in eastern Africa, 7·2% (2·9-16·5) in western and central Africa, and 9·4% (6·6-13·2) in Latin America and the Caribbean. There were substantial increases in pretreatment NNRTI resistance per year in all regions. The yearly increases in the odds of pretreatment drug resistance were 23% (95% CI 16-29) in southern Africa, 17% (5-30) in eastern Africa, 17% (6-29) in western and central Africa, 11% (5-18) in Latin America and the Caribbean, and 11% (2-20) in Asia. Estimated increases in the absolute prevalence of pretreatment drug resistance between 2015 and 2016 ranged from 0·3% in Asia to 1·8% in southern Africa. INTERPRETATION: Pretreatment drug resistance is increasing at substantial rate in LMICs, especially in sub-Saharan Africa. In 2016, the prevalence of pretreatment NNRTI resistance was near WHO's 10% threshold for changing first-line ART in southern and eastern Africa and Latin America, underscoring the need for routine national HIV drug-resistance surveillance and review of national policies for first-line ART regimen composition. FUNDING: Bill & Melinda Gates Foundation and World Health Organization.

HIV-1 viraemia and drug resistance amongst female sex workers in Soweto, South Africa: A cross sectional study.

BACKGROUND: HIV drug resistance (HIVDR) poses a threat to future antiretroviral therapy success. Monitoring HIVDR patterns is of particular importance in populations such as sex workers (SWs), where documented HIV prevalence is between 34-89%, and in countries with limited therapeutic options. Currently in South Africa, there is a dearth in evidence and no ongoing surveillance of HIVDR amongst sex work populations. This study aims to describe the prevalence of HIVDR amongst a sample of female sex workers (FSWs) from Soweto, South Africa. METHODOLOGY: A cross-sectional, respondent driven sampling (RDS) recruitment methodology was used to enrol FSWs based in Soweto. Participants were tested for HIV and undertook a survey that included HIV knowledge and treatment status. Whole blood specimens were collected from HIV positive FSWs to measure for CD4 counts, viral load (VL) and perform HIVDR genotyping. Frequencies were determined for categorical variables and medians and interquartile ranges (IQR) for the continuous. RESULTS: Of the 508 enrolled participants, 55% (n = 280) were HIV positive and of median age 32 (IQR: 20-51) years. Among the HIV positive, 51.8% (132/269) were defined as virologically suppressed (VL < 400 copies/ml). Of the 119 individuals with unsuppressed viral loads who were successfully genotyped for resistance testing 37.8% (45/119) had detectable drug resistance. In this group, HIVDR mutations were found amongst 73.7% (14/19) of individuals on treatment, 27.4% (26/95) of individuals who were treatment naïve, and 100% (5/5) of defaulters. One phylogenetic cluster was found amongst treatment naïve FSWs. The K103N mutation was detected most commonly in 68.9% (31/45) individuals with HIVDR mutations, with 20/26 (76.9%) of treatment naïve FSW with detectable resistance having this mutation. The M184V mutation was found in both FSWs on treatment (12/14, 85.7%) and those defaulting (1/5, 20.0%). DISCUSSION: More than one third (45/119) of the genotyped sample had HIVDR, with resistance to the NNRTI class being the most common. Almost half of HIV positive FSWs had unsuppressed viral loads, increasing the likelihood for onward transmission of HIV. Disturbingly, more than 1:4 treatment naïve women with unsuppressed viral loads had HIVDR suggesting that possible sexual transmission of drug resistance is occurring in this high-risk population. Given the high burden of HIVDR in a population with a high background prevalence of HIV, it is imperative that routine monitoring of HIVDR be implemented. Understanding transmission dynamics of HIVDR in FSW and its impact on treatment success should be urgently elucidated.