Stability in care and risk of loss to follow-up among clients receiving community health worker-led differentiated HIV care: Results from a prospective cohort study in northern Tanzania.

BACKGROUND: HIV services in Tanzania are facility-based but facilities are often overcrowded. Differentiated care models (DCM) have been introduced into the National Guidelines. We piloted a Community Health Worker (CHW)-led HIV treatment club model (CHW-DCM) in an urban region, and assessed its effectiveness in comparison to the standard of care (SoC, facility-based model), in terms of stability in care, loss to follow-up (LTFU) and treatment adherence. METHODS: In two clinics in the Shinyanga region, clients established on ART (defined as stable clients by national guidelines as on first-line ART >6 months, undetectable viral load, no opportunistic infections or pregnancy, and good adherence) were offered CHW-DCM. This prospective cohort study included all stable clients who enrolled in CHW-DCM between July 2018 and March 2020 (CHW-DCM) and compared them to stable clients who remained in SoC during that period. Multivariable Cox regression models were used to analyse factors associated with continued stability in care and the risk of LTFU during 18 months of follow-up; treatment adherence was assessed by pill count and compared using Chi-square tests. RESULTS: Of 2472 stable clients, 24.5% received CHW-DCM and 75.5% SoC. CHW-DCM clients were slightly older (mean 42.8 vs. 37.9 years) and more likely to be female (36.2% vs. 32.2%). Treatment adherence was better among CHW-DCM than SoC: 96.6% versus 91.9% and 98.5% versus 92.2%, respectively (both p = 0.001). SoC clients were more likely to not remain stable over time than CHW-DCM (adjusted Hazard ratio [AHR] = 2.68; 95% CI: 1.86-3.90). There was no difference in LTFU (adjusted hazard ratio [AHR] = 1.54; 95%CI: 0.82-2.93). CONCLUSION: Clients attending CHW-DCM demonstrated better stability in care and treatment adherence than SoC, and the risk of LTFU was not increased. These findings demonstrate the potential of CHW in delivering community-based HIV services in the local Tanzanian context. These results could be used to extend this CHW-DCM model to similar settings.

Preparing healthcare facilities in sub-Saharan Africa for future outbreaks: insights from a multi-country digital self-assessment of COVID-19 preparedness.

BACKGROUND: Despite previous experience with epidemics, African healthcare systems were inadequately prepared and substantially impacted by the coronavirus disease 2019 (COVID-19) pandemic. Limited information about the level of COVID-19 preparedness of healthcare facilities in Africa hampers policy decision-making to fight future outbreaks in the region, while maintaining essential healthcare services running. METHODS: Between May-November 2020, we performed a survey study with SafeCare4Covid - a free digital self-assessment application - to evaluate the COVID-19 preparedness of healthcare facilities in Africa following World Health Organization guidelines. The tool assessed (i) COVID-19-related capabilities with 31 questions; and (ii) availability of essential medical supplies with a 23-supplies checklist. Tailored quality improvement plans were provided after assessments. Information about facilities' location, type, and ownership was also collected. RESULTS: Four hundred seventy-one facilities in 11 African countries completed the capability assessment; 412 also completed the supplies checklist. The average capability score on a scale of 0-100 (n=471) was 58.0 (interquartile range 40.0-76.0), and the average supplies score (n=412) was 61.6 (39.0-83.0). Both scores were significantly lower in rural (capability score, mean 53.6 [95%CI:50.3-57.0]/supplies score, 59.1 [55.5-62.8]) versus urban facilities (capability score, 65.2 [61.7-68.7]/supplies score, 70.7 [67.2-74.1]) (P<0.0001 for both comparisons). Likewise, lower scores were found for public versus private clinics, and for primary healthcare centres versus hospitals. Guidelines for triage and isolation, clinical management of COVID-19, staff mental support, and contact tracing forms were largely missing. Handwashing stations were partially equipped in 33% of facilities. The most missing medical supply was COVID-19 specimen collection material (71%), while 43% of facilities did not have N95/FFP2 respirators and 19% lacked medical masks. CONCLUSIONS: A large proportion of public and private African facilities providing basic healthcare in rural areas, lacked fundamental COVID-19-related capabilities and life-saving personal protective equipment. Decentralization of epidemic preparedness efforts in these settings is warranted to protect healthcare workers and patients alike in future epidemics. Digital tools are of great value to timely measure and improve epidemic preparedness of healthcare facilities, inform decision-making, create a more stakeholder-broad approach and increase health-system resilience for future disease outbreaks.

Exploring the mechanisms behind HIV drug resistance in sub-Saharan Africa: conceptual mapping of a complex adaptive system based on multi-disciplinary expert insights.

BACKGROUND: HIV drug resistance (HIVDR) continues to threaten the effectiveness of worldwide antiretroviral therapy (ART). Emergence and transmission of HIVDR are driven by several interconnected factors. Though much has been done to uncover factors influencing HIVDR, overall interconnectedness between these factors remains unclear and African policy makers encounter difficulties setting priorities combating HIVDR. By viewing HIVDR as a complex adaptive system, through the eyes of multi-disciplinary HIVDR experts, we aimed to make a first attempt to linking different influencing factors and gaining a deeper understanding of the complexity of the system. METHODS: We designed a detailed systems map of factors influencing HIVDR based on semi-structured interviews with 15 international HIVDR experts from or with experience in sub-Saharan Africa, from different disciplinary backgrounds and affiliated with different types of institutions. The resulting detailed system map was conceptualized into three main HIVDR feedback loops and further strengthened with literature evidence. RESULTS: Factors influencing HIVDR in sub-Saharan Africa and their interactions were sorted in five categories: biology, individual, social context, healthcare system and 'overarching'. We identified three causal loops cross-cutting these layers, which relate to three interconnected subsystems of mechanisms influencing HIVDR. The 'adherence motivation' subsystem concerns the interplay of factors influencing people living with HIV to alternate between adherence and non-adherence. The 'healthcare burden' subsystem is a reinforcing loop leading to an increase in HIVDR at local population level. The 'ART overreliance' subsystem is a balancing feedback loop leading to complacency among program managers when there is overreliance on ART with a perceived low risk to drug resistance. The three subsystems are interconnected at different levels. CONCLUSIONS: Interconnectedness of the three subsystems underlines the need to act on the entire system of factors surrounding HIVDR in sub-Saharan Africa in order to target interventions and to prevent unwanted effects on other parts of the system. The three theories that emerged while studying HIVDR as a complex adaptive system form a starting point for further qualitative and quantitative investigation.

Plasma Inflammatory Biomarkers Predict CD4+ T-cell Recovery and Viral Rebound in HIV-1 Infected Africans on Suppressive Antiretroviral Therapy.

This multicountry prospective study investigated whether persistent systemic inflammation, measured by 8 plasma biomarkers, in HIV-1-infected Africans during suppressive antiretroviral therapy (ART) (viral load <50 copies/mL), was associated with CD4+ T-cell recovery and viral rebound (>1000 copies/mL) during long-term treatment. On-ART sCD14 and C-reactive protein concentrations were inversely associated with subsequent CD4+ T-cell counts. Risk of viral rebound was increased for participants with higher on-ART CXCL10 concentrations and reduced for those with a greater sCD163 decline during the first year of ART. Persistent systemic inflammation predicted CD4+ T-cell recovery and viral rebound, warranting further mechanistic research in relation to clinical outcomes.

Distinct rates and patterns of spread of the major HIV-1 subtypes in Central and East Africa.

Since the ignition of the HIV-1 group M pandemic in the beginning of the 20th century, group M lineages have spread heterogeneously throughout the world. Subtype C spread rapidly through sub-Saharan Africa and is currently the dominant HIV lineage worldwide. Yet the epidemiological and evolutionary circumstances that contributed to its epidemiological expansion remain poorly understood. Here, we analyse 346 novel pol sequences from the DRC to compare the evolutionary dynamics of the main HIV-1 lineages, subtypes A1, C and D. Our results place the origins of subtype C in the 1950s in Mbuji-Mayi, the mining city of southern DRC, while subtypes A1 and D emerged in the capital city of Kinshasa, and subtypes H and J in the less accessible port city of Matadi. Following a 15-year period of local transmission in southern DRC, we find that subtype C spread at least three-fold faster than other subtypes circulating in Central and East Africa. In conclusion, our results shed light on the origins of HIV-1 main lineages and suggest that socio-historical rather than evolutionary factors may have determined the epidemiological fate of subtype C in sub-Saharan Africa.

Connected diagnostics to improve accurate diagnosis, treatment, and conditional payment of malaria services in Kenya.

BACKGROUND: In sub-Saharan Africa, the material and human capacity to diagnose patients reporting with fever to healthcare providers is largely insufficient. Febrile patients are typically treated presumptively with antimalarials and/or antibiotics. Such over-prescription can lead to drug resistance and involves unnecessary costs to the health system. International funding for malaria is currently not sufficient to control malaria. Transition to domestic funding is challenged by UHC efforts and recent COVID-19 outbreak. Herewith we present a digital approach to improve efficiencies in diagnosis and treatment of malaria in endemic Kisumu, Kenya: Connected Diagnostics. The objective of this study is to evaluate the feasibility, user experience and clinical performance of this approach in Kisumu. METHODS: Our intervention was performed Oct 2017-Dec 2018 across five private providers in Kisumu. Patients were enrolled on M-TIBA platform, diagnostic test results digitized, and only positive patients were digitally entitled to malaria treatment. Data on socio-demographics, healthcare transactions and medical outcomes were analysed using standard descriptive quantitative statistics. Provider perspectives were gathered by 19 semi-structured interviews. RESULTS: In total 11,689 febrile patients were digitally tested through five private providers. Malaria positivity ranged from 7.4 to 30.2% between providers, significantly more amongst the poor (p < 0.05). Prescription of antimalarials was substantially aberrant from National Guidelines, with 28% over-prescription (4.6-63.3% per provider) and prescription of branded versus generic antimalarials differing amongst facilities and correlating with the socioeconomic status of clients. Challenges were encountered transitioning from microscopy to RDT. CONCLUSION: We provide full proof-of-concept of innovative Connected Diagnostics to use digitized malaria diagnostics to earmark digital entitlements for correct malaria treatment of patients. This approach has large cost-saving and quality improvement potential.

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.

Plasma Biomarkers of Human Immunodeficiency Virus-Related Systemic Inflammation and Immune Activation in Sub-Saharan Africa Before and During Suppressive Antiretroviral Therapy.

We evaluated immune biomarker profiles in human immunodeficiency virus (HIV)-infected adults (n = 398) from 5 African countries. Although all biomarkers decreased after antiretroviral therapy (ART) initiation, levels of C-X-C chemokine ligand 10 (CXCL10), lipopolysaccharide-binding protein, C-reactive protein, soluble CD163, and soluble scavenger receptor CD14 were significantly higher during ART than in an HIV-uninfected reference group (n = 90), indicating persistent monocyte/macrophage activation, inflammation, and microbial translocation. Before ART initiation, high HIV viral load was associated with elevated CXCL10 and tuberculosis coinfection was associated with elevated soluble CD14. High pre-ART levels of each biomarker strongly predicted residual immune activation during ART. Chemokine (C-C motif) ligand 2, lipopolysaccharide-binding protein, C-reactive protein, and interleukin 6 were differentially expressed between countries. Further research is needed on the clinical implications of residual immune dysregulation.

Association between HIV-1 subtype and drug resistance in Nigerian infants.

Background: Many lines of evidence point to HIV-1 subtype-specific differences in the development of drug resistance mutations. While variation between subtype C and others has been extensively explored, there has been less emphasis on subtypes common to West Africa. We examined a previously described national survey of pretreatment drug resistance in HIV-1-infected Nigerian children aged <18 months, to explore the association between subtypes and patterns of resistance. Methods: Five hundred and forty-nine dried blood spots, from 15 early infant diagnostic facilities in Nigeria, were amplified and HIV-1 polymerase was sequenced. Four hundred and twenty-four were analysed for surveillance drug resistance mutations (SDRMs). Associations between subtype and SDRMs were evaluated by Fisher's exact test and logistic regression analysis, controlling for geographical region and exposure. Results: Using the sub-subtypes of HIV-1 G defined by Delatorre et al. (PLoS One 2014. 9: e98908) the most common subtypes were CRF02_AG (174, 41.0%), GWA-I (128, 30.2%), GWA-II (24, 5.7%), GCA (11, 2.6%), A (21, 5.0%) and CRF06_cpx (18, 4.2%). One hundred and ninety infants (44.8%) had ≥1 NNRTI mutation, 92 infants (21.7%) had ≥1 NRTI mutation and 6 infants (1.4%) had ≥1 PI mutation. By logistic regression, 67N was more common in GWA-II/GCA than CRF02_AG (OR 12.0, P = 0.006), as was 70R (OR 23.1, P = 0.007), 184I/V (OR 2.92, P = 0.020), the presence of ≥1 thymidine analogue mutation (TAM) (OR 3.87, P = 0.014), ≥1 type 2 TAM (OR 7.61, P = 0.001) and ≥1 NRTI mutation (OR 3.26, P = 0.005). Conclusions: This dataset reveals differences among SDRMs by subtype; in particular, between the GWA-II and GCA subclades, compared with CRF02_AG and GWA-I.

Using mobile transport vouchers to improve access to skilled delivery.

INTRODUCTION: Reducing maternal death remains a challenge in many low-income countries. Preventing maternal deaths depends significantly on the presence of a skilled birth attendant at child delivery. The main objective of this study was to find out whether use of mobile transport vouchers would result in an increased number of pregnant women choosing to deliver at a health facility rather than at home. METHOD: A total of 86 expectant mothers living in Samburu County (Kenya), all having access to a mobile phone with Safaricom mobile SIM card, were enrolled into the project. Mixed methods research design was used to generate quantitative data on the voucher transactions and qualitative data from telephone interviews on technical usability of the transport voucher. RESULTS: The study demonstrated that the mobile transport voucher was a major driver for pregnant women to access healthcare facilities for skilled delivery. Illiteracy and resource scarcity were the main challenges experienced during implementation. CONCLUSION: Mobile technology can be successfully used in remote rural settings in Africa for targeting funds and guiding individuals towards better health care. The combination of such technology with communication agents (community health volunteers, ambulance drivers) proved particularly effective.

Primary resistance to integrase strand transfer inhibitors in patients infected with diverse HIV-1 subtypes in sub-Saharan Africa.

Objectives: To investigate the prevalence and patterns of major and accessory resistance mutations associated with integrase strand transfer inhibitors (INSTIs), across diverse HIV-1 subtypes in sub-Saharan Africa. Methods: pol gene sequences were obtained using Illumina next-generation sequencing from 425 INSTI-naive HIV-infected adults from Kenya (21.2%), Nigeria (7.3%), South Africa (22.8%), Uganda (25.2%) and Zambia (23.5%). Drug resistance interpretation was based on the IAS 2017 mutation list and accessory mutations from Stanford HIVdb with resistance penalty scores of ≥10 to at least 1 INSTI. Resistance was further classified based on sensitivity thresholds of ≥20% (Sanger sequencing) and 1%-20% for low-frequency variants (next-generation sequencing). Results: Of 425 genotypes, 48.7% were subtype C, 28.5% A, 10.1% D, 2.8% G and 9.9% were recombinants. Major INSTI resistance mutations were detected only at <20% threshold, at a prevalence of 2.4% (2.5% in subtype A, 2.4% C, 0% D, 8.3% G and 2.4% in recombinants) and included T66A/I (0.7%), E92G (0.5%), Y143C/S (0.7%), S147G (0.2%) and Q148R (0.5%). Accessory mutations occurred at a prevalence of 15.1% at the ≥20% threshold (23.1% in subtype A, 8.7% C, 11.6% D, 25% G and 23.8% in recombinants), and included L74I/M (10.4%), Q95K (0.5%), T97A (4%), E157Q (0.7%) and G163R/K (0.7%). Conclusions: Major INSTI resistance mutations were rare and only occurred at low-level resistance detection thresholds. INSTI-based regimens are expected to be effective across the different major HIV-1 subtypes in the region.

Pretreatment HIV drug resistance results in virological failure and accumulation of additional resistance mutations in Ugandan children.

Background: Pretreatment HIV drug resistance (PDR) can impair virological response to ART, jeopardizing effective treatment for children. Methods: Children aged ≤12 years initiated first-line ART in Uganda during 2010-11. Baseline and 6 monthly viral load (VL) and genotypic resistance testing if VL >1000 copies/mL was done. The 2015 IAS-USA mutation list and Stanford algorithm were used to score drug resistance mutations (DRMs) and susceptibility. Virological failure (VF) was defined as two consecutive VLs >1000 copies/mL or death after 6 months of ART. Factors associated with failure and acquired drug resistance (ADR) were assessed in a logistic regression analysis. Results: Among 317 children enrolled, median age was 4.9 years and 91.5% received NNRTI-based regimens. PDR was detected in 47/278 (16.9%) children, of whom 22 (7.9%) had resistance against their first-line regimen and were therefore on a partially active regimen. After 24 months of follow-up, 92/287 (32.1%) had experienced VF. Children with PDR had a higher risk of VF (OR 15.25, P < 0.001) and ADR (OR 3.58, P = 0.01). Conclusions: Almost one-third of children experienced VF within 24 months of NNRTI-based first-line treatment. PDR was the strongest predictor of VF and ADR, and therefore presents a major threat in children. There is a need for ART regimens that maximize effectiveness of first-line therapy for long-term treatment success in the presence of PDR or incorporation of routine VL testing to detect VF and change treatment in time, in order to prevent clinical deterioration and accumulation of additional drug resistance. Children ≤3 years should be initiated on a PI-based regimen as per WHO guidelines.

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.

Protease Inhibitor Resistance in the First 3 Years of Second-Line Antiretroviral Therapy for HIV-1 in Sub-Saharan Africa.

BACKGROUND: As antiretroviral therapy (ART) programs in sub-Saharan Africa mature, increasing numbers of persons with human immunodeficiency virus (HIV) infection will experience treatment failure, and require second- or third-line ART. Data on second-line failure and development of protease inhibitor (PI) resistance in sub-Saharan Africa are scarce. METHODS: HIV-1-infected adults were included if they received >180 days of PI-based second-line ART. We assessed risk factors for having a detectable viral load (VL, ≥400 cps/mL) using Cox models. If VL was ≥1000 cps/mL, genotyping was performed. RESULTS: Of 227 included participants, 14.6%, 15.2% and 11.1% had VLs ≥400 cps/mL at 12, 24, and 36 months, respectively. Risk factors for a detectable VL were as follows: exposure to nonstandard nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based (hazard ratio, 7.10; 95% confidence interval, 3.40-14.83; P < .001) or PI-based (7.59; 3.02-19.07; P = .001) first-line regimen compared with zidovudine/lamivudine/NNRTI, PI resistance at switch (6.69; 2.49-17.98; P < .001), and suboptimal adherence (3.05; 1.71-5.42; P = .025). Among participants with VLs ≥1000 cps/mL, 22 of 32 (69%) harbored drug resistance mutation(s), and 7 of 32 (22%) harbored PI resistance. CONCLUSIONS: Although VL suppression rates were high, PI resistance was detected in 22% of participants with VLs ≥1000 cps/mL. To ensure long-term ART success, intensified support for adherence, VL and drug resistance testing, and third-line drugs will be necessary.

Suboptimal Viral Suppression Rates Among HIV-Infected Children in Low- and Middle-Income Countries: A Meta-analysis.

BACKGROUND: The 90-90-90 goal to achieve viral suppression in 90% of all human immunodeficiency virus (HIV)-infected people on antiretroviral treatment (ART) is especially challenging in children. Global estimates of viral suppression among children in low- and middle-income countries (LMICs) are lacking. METHODS: We searched for randomized controlled trials and observational studies and analyzed viral suppression rates among children started on ART during 3 time periods: early (2000-2005), intermediate (2006-2009), and current (2010 and later), using random effects meta-analysis. RESULTS: Seventy-two studies, reporting on 51 347 children (aged <18 years), were included. After 12 months on first-line ART, viral suppression was achieved by 64.7% (95% confidence interval [CI], 57.5-71.8) in the early, 74.2% (95% CI, 70.2-78.2) in the intermediate, and 72.7% (95% 62.6-82.8) in the current time period. Rates were similar after 6 and 24 months of ART. Using an intention-to-treat analysis, 42.7% (95% CI, 33.7-51.7) in the early, 45.7% (95% CI, 33.2-58.3) in the intermediate, and 62.5% (95% CI, 53.3-72.6) in the current period were suppressed. Long-term follow-up data were scarce. CONCLUSIONS: Viral suppression rates among children on ART in LMICs were low and considerably poorer than those previously found in adults in LMICs and children in high-income countries. Little progress has been made in improving viral suppression rates over the past years. Without increased efforts to improve pediatric HIV treatment, the 90-90-90 goal for children in LMIC will not be reached.

Prevalence and dynamics of the K65R drug resistance mutation in HIV-1-infected infants exposed to maternal therapy with lamivudine, zidovudine and either nevirapine or nelfinavir in breast milk.

BACKGROUND: K65R is a relatively rare drug resistance mutation (DRM) selected by the NRTIs tenofovir, didanosine, abacavir and stavudine and confers cross-resistance to all NRTIs except zidovudine. Selection by other NRTIs is uncommon. OBJECTIVES: In this study we investigated the frequency of emergence of the K65R mutation and factors associated with it in HIV-1-infected infants exposed to low doses of maternal lamivudine, zidovudine and either nevirapine or nelfinavir ingested through breast milk, using specimens collected from the Kisumu Breastfeeding Study. METHODS: Plasma specimens with viral load ≥1000 copies/mL collected from HIV-infected infants at 0-1, 2, 6, 14, 24 and 36 weeks of age and maternal samples at delivery were tested for HIV drug resistance using Sanger sequencing of the polymerase gene. Factors associated with K65R emergence were assessed using Fisher's exact test and the Wilcoxon rank-sum test. RESULTS: K65R was detected in samples from 6 of the 24 infants (25%) who acquired HIV-1 infection by the age of 6 months. K65R emerged in half of the infants by 6 weeks and in the rest by 14 weeks of age. None of the mothers at delivery or the infants with a positive genotype at first time of positivity had the K65R mutation. Infants with K65R had low baseline CD4 cell counts (P = 0.014), were more likely to have DRMs earlier (≤6 weeks versus ≥14 weeks, P = 0.007) and were more likely to have multiclass drug resistance (P = 0.035). M184V was the most common mutation associated with K65R emergence. K65R had reverted by 3 months after cessation of breastfeeding. CONCLUSIONS: A high rate of K65R emergence may suggest that ingesting low doses of lamivudine via breast milk could select for this mutation. The presence of this mutation may have a negative impact on future responses to NRTI-based ART. More in vitro studies are, however, needed to establish the molecular mechanism for this selection.

Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa.

OBJECTIVES: Limited availability of viral load (VL) monitoring in HIV treatment programmes in sub-Saharan Africa can delay switching to second-line ART, leading to the accumulation of drug resistance mutations (DRMs). The objective of this study was to evaluate the accumulation of resistance to reverse transcriptase inhibitors after continued virological failure on first-line ART, among adults and children in sub-Saharan Africa. METHODS: HIV-1-positive adults and children on an NNRTI-based first-line ART were included. Retrospective VL and, if VL ≥1000 copies/mL, pol genotypic testing was performed. Among participants with continued virological failure (≥2 VL ≥1000 copies/mL), drug resistance was evaluated. RESULTS: At first virological failure, DRM(s) were detected in 87% of participants: K103N (38.7%), G190A (21.8%), Y181C (20.2%), V106M (8.4%), K101E (8.4%), any E138 (7.6%) and V108I (7.6%) associated with NNRTIs, and M184V (69.7%), any thymidine analogue mutation (9.2%), K65R (5.9%) and K70R (5.0%) associated with NRTIs. New DRMs accumulated with an average rate of 1.45 (SD 2.07) DRM per year; 0.62 (SD 1.11) NNRTI DRMs and 0.84 (SD 1.38) NRTI DRMs per year, respectively. The predicted susceptibility declined significantly after continued virological failure for all reverse transcriptase inhibitors (all P < 0.001). Acquired drug resistance patterns were similar in adults and children. CONCLUSIONS: Patterns of drug resistance after virological failure on first-line ART are similar in adults and children in sub-Saharan Africa. Improved VL monitoring to prevent accumulation of mutations, and new drug classes to construct fully active regimens, are required.

Perspectives of frontline health workers on Ghana's National Health Insurance Scheme before and after community engagement interventions.

BACKGROUND: Barely a decade after introduction of Ghana's National Health Insurance Scheme (NHIS), significant successes have been recorded in universal access to basic healthcare services. However, sustainability of the scheme is increasingly threatened by concerns on quality of health service delivery in NHIS-accredited health facilities coupled with stakeholders' discontentment with the operational and administrative challenges confronting the NHIS. The study sought to ascertain whether or not Systematic Community Engagement (SCE) interventions have a significant effect on frontline health workers' perspectives on the NHIS and its impact on quality health service delivery. METHODS: The study is a randomized cluster trial involving clinical and non-clinical frontline health workers (n = 234) interviewed at baseline and follow-up in the Greater Accra and Western regions of Ghana. Individual respondents were chosen from within each intervention and control groupings. Difference-in-difference estimations and propensity score matching were performed to determine impact of SCE on staff perceptions of the NHIS. The main outcome measure of interest was staff perception of the NHIS based on eight (8) factor-analyzed quality service parameters. RESULTS: Staff interviewed in intervention facilities appeared to perceive the NHIS more positively in terms of its impact on "availability and quality of drugs (p < 0.05)" and "workload on health staff/infrastructure" than those interviewed in control facilities (p < 0.1). Delayed reimbursement of service providers remained a key concern to over 70 % of respondents in control and intervention health facilities. CONCLUSION: Community engagement in quality service assessment is a potential useful strategy towards empowering communities while promoting frontline health workers' interest, goodwill and active participation in Ghana's NHIS.

Long-term Virological Outcomes of First-Line Antiretroviral Therapy for HIV-1 in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

BACKGROUND: More than 11.7 million people are currently receiving antiretroviral therapy (ART) in low- and middle-income countries (LMICs), and focused efforts are needed to ensure high levels of adherence and to minimize treatment failure. Recently, international targets have emphasized the importance of long-term virological suppression as a key measure of program performance. METHODS: We systematically reviewed publications and conference abstracts published between January 2006 and May 2013 that reported virological outcomes among human immunodeficiency virus type 1 (HIV-1)-infected adults receiving first-line ART for up to 5 years in LMICs. Summary estimates of virological suppression after 6, 12, 24, 36, 48, and 60 months of ART were analyzed using random-effects meta-analysis. Intention-to-treat (ITT) analysis assumed all participants who were lost to follow-up, died, or stopped ART as having virological failure. RESULTS: Summary estimates of virological suppression remained >80% for up to 60 months of ART for all 184 included cohorts. ITT analysis yielded 74.7% (95% confidence interval [CI], 72.2-77.2) suppression after 6 months and 61.8% (95% CI, 44.0-79.7) suppression after 48 months on ART. Switches to second-line ART were reported scarcely. CONCLUSIONS: Among individuals retained on ART, virological suppression rates during the first 5 years of ART were high (>80%) and stable. Suppression rates in ITT analysis declined during 4 years.