Assessment of second-line antiretroviral regimens for HIV therapy in Africa.

BACKGROUND: The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit. METHODS: In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%). RESULTS: Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001). CONCLUSIONS: When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.)

Nucleoside reverse-transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomised, open-label, EARNEST trial.

BACKGROUND: Cross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV. METHODS: We did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12-16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039). FINDINGS: Baseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004). INTERPRETATION: Genotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs. FUNDING: European and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

A Prospective Evaluation of Xpert MTB/RIF Ultra for Childhood Pulmonary Tuberculosis in Uganda

BackgroundXpert MTB/RIF Ultra (Xpert Ultra) has improved the sensitivity to detect pulmonary tuberculosis (TB) in adults. However, there have been limited prospective evaluations of its diagnostic accuracy in children.MethodsWe enrolled children undergoing assessment for pulmonary TB in Kampala, Uganda, over a 12-month period. Children received a complete TB evaluation and were classified as Confirmed, Unconfirmed, or Unlikely TB. We calculated the sensitivity and specificity of Xpert Ultra among children with Confirmed vs Unlikely TB. We also determined the diagnostic accuracy with clinical, microbiological, and extended microbiological reference standards (MRSs).ResultsOf the 213 children included, 23 (10.8%) had Confirmed TB, 88 (41.3%) had Unconfirmed TB, and 102 (47.9%) had Unlikely TB. The median age was 3.9 years, 13% were HIV-positive, and 61.5% were underweight. Xpert Ultra sensitivity was 69.6% (95% confidence interval [CI]: 47.1-86.8) among children with Confirmed TB and decreased to 23.4% (95% CI: 15.9-32.4) with the clinical reference standard. Specificity was 100% (95% CI: 96.4-100) among children with Unlikely TB and decreased to 94.7% (95% CI: 90.5-97.4) with a MRS. Sensitivity was 52.9% (95% CI: 35.1-70.2) and specificity 95.5% (95% CI: 91.4-98.1) with the extended MRS. Of the 26 positive Xpert Ultra results, 6 (23.1%) were "Trace-positive," with most (5/6) occurring in children with Unconfirmed TB.ConclusionsXpert Ultra is a useful tool for diagnosing pulmonary TB in children, but there remains a need for more sensitive tests to detect culture-negative TB

HIV Drug Resistance Among Children Initiating First-Line Antiretroviral Treatment in Uganda

BACKGROUND There are limited data on primary human immunodeficiency virus drug resistance (HIVDR) in pediatric populations. This study aimed to assess the prevalence of primary HIVDR and associated risk factors among children initiating first-line antiretroviral therapy (ART) in Uganda. METHODS At three Ugandan clinics, children (ag

The socioeconomic burden of pediatric tuberculosis and role of child-sensitive social protection

BackgroundHouseholds of children with tuberculosis (TB) experience financial and social hardships, but TB-specific social protection initiatives primarily focus on adults.MethodsWe conducted a single-arm, pilot study of multi-component supportive benefits for children with pulmonary TB in Kampala, Uganda. At diagnosis, participants received in-kind coverage of direct medical costs, a cash transfer, and patient navigation. Caregivers were surveyed before diagnosis and 2&nbsp;months into TB treatment on social and financial challenges related to their child's illness, including estimated costs, loss of income and dissaving practices.ResultsWe included 368 children from 321 households. Pre-diagnosis, 80.1% of caregivers reported that their child's illness negatively impacted household finances, 44.1% of caregivers missed work, and 24% engaged in dissaving practices. Catastrophic costs (&gt; 20% annual income) were experienced by 18.4% (95% CI 13.7-24.0) of households. School disruption was common (25.6%), and 28% of caregivers were concerned their child was falling behind in development. Two months post-diagnosis, 12 households (4.8%) reported being negatively affected by their child's TB disease (difference -75.2%, 95% CI -81.2 to -69.2, p &lt; 0.001), with limited ongoing loss of income (1.6%) or dissavings practices (0.8%). Catastrophic costs occurred in one household (0.4%) at 2&nbsp;months post-diagnosis.ConclusionsHouseholds face financial and social challenges prior to a child's TB diagnosis, and child-sensitive social protection support may mitigate ongoing burden

Second-line HIV Treatment in Ugandan Children: Favorable Outcomes and No Protease Inhibitor Resistance

BACKGROUND: Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens. METHODS: Children ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml. RESULTS: 60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure. CONCLUSIONS: No PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART

The socioeconomic burden of pediatric tuberculosis and role of child-sensitive social protection

Abstract Background Households of children with tuberculosis (TB) experience financial and social hardships, but TB-specific social protection initiatives primarily focus on adults. Methods We conducted a single-arm, pilot study of multi-component supportive benefits for children with pulmonary TB in Kampala, Uganda. At diagnosis, participants received in-kind coverage of direct medical costs, a cash transfer, and patient navigation. Caregivers were surveyed before diagnosis and 2 months into TB treatment on social and financial challenges related to their child’s illness, including estimated costs, loss of income and dissaving practices. Results We included 368 children from 321 households. Pre-diagnosis, 80.1% of caregivers reported that their child’s illness negatively impacted household finances, 44.1% of caregivers missed work, and 24% engaged in dissaving practices. Catastrophic costs (> 20% annual income) were experienced by 18.4% (95% CI 13.7–24.0) of households. School disruption was common (25.6%), and 28% of caregivers were concerned their child was falling behind in development. Two months post-diagnosis, 12 households (4.8%) reported being negatively affected by their child’s TB disease (difference -75.2%, 95% CI -81.2 to -69.2, p < 0.001), with limited ongoing loss of income (1.6%) or dissavings practices (0.8%). Catastrophic costs occurred in one household (0.4%) at 2 months post-diagnosis. Conclusions Households face financial and social challenges prior to a child’s TB diagnosis, and child-sensitive social protection support may mitigate ongoing burden