Browsing by Subject "ART"

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    Open Access
    A comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa
    (BioMed Central, 2017-09-29) Huerga, Helena; Shiferie, Fisseha; Grebe, Eduard; Giuliani, Ruggero; Farhat, Jihane B; Van-Cutsem, Gilles; Cohen, Karen
    Background: Accurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods. Methods: Cross-sectional population-based survey in KwaZulu-Natal, South Africa. Individuals 15–59 years were eligible. Interviews included questions about ARV use. Rapid HIV testing was performed at the participants’ home. Blood specimens were collected for ARV detection, LAg-Avidity HIV incidence testing and viral load quantification in HIV-positive individuals. Multivariate logistic regression models were used to identify socio-demographic covariates associated with discordance between self-reported ART and ARV detection. Results: Of the 5649 individuals surveyed, 1423 were HIV-positive. Median age was 34 years and 76.3% were women. ART coverage was estimated at 51.4% (95%CI:48.5–54.3), 53.1% (95%CI:50.2–55.9) and 56.1% (95%CI:53.5–58.8) using self-reported ART, ARV detection and both methods combined (classified as ART exposed if ARV detected and/or ART reported) respectively. ART coverage estimates using the 3 methods were fairly similar within sex and age categories except in individuals aged 15–19 years: 33.3% (95%CI:23.3–45.2), 33.8% (95%CI:23.9–45.4%) and 44.3% (95%CI:39.3–46.7) using self-reported ART, ARV detection and both methods combined. Viral suppression below 1000cp/mL in individuals on ART was estimated at 89.8% (95%CI:87.3–91.9), 93.1% (95%CI:91.0–94.8) and 88.7% (95%CI:86.2–90.7) using self-reported ART, ARV detection and both methods combined respectively. HIV incidence was estimated at 1.4 (95%CI:0.8–2.0) new cases/100 person-years when employing no measure of ARV use, 1.1/100PY (95%CI:0.6–1.7) using self-reported ART, and 1.2/100PY (95%CI:0.7–1.7) using ARV detection. In multivariate analyses, individuals aged 15–19 years had a higher risk of discordance on measures of ARV exposure (aOR:9.4; 95%CI:3.9–22.8), while migrants had a lower risk (aOR:0.3; 95%CI:0.1–0.6). Conclusions: In KwaZulu-Natal, the method of identifying ARV use had little impact on estimates of ART coverage, viral suppression rate and HIV incidence. However, discordant results were more common in younger individuals. This may skew estimates of ART coverage and viral suppression, particularly in adolescent surveys.
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    A comparison of self-report and antiretroviral detection to inform estimates of antiretroviral therapy coverage, viral load suppression and HIV incidence in Kwazulu-Natal, South Africa
    (2017) Huerga, Helena; Shiferie, Fisseha; Grebe, Eduard; Giuliani, Ruggero; Farhat, Jihane Ben; Van Cutsem, Gilles; Cohen, Karen
    Accurately identifying individuals who are on antiretroviral therapy (ART) is important to determine ART coverage and proportion on ART who are virally suppressed. ART is also included in recent infection testing algorithms used to estimate incidence. We compared estimates of ART coverage, viral load suppression rates and HIV incidence using ART self-report and detection of antiretroviral (ARV) drugs and we identified factors associated with discordance between the methods.
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    Economic evaluation of models of prevention of mother-to-child transmission of HIV intervention for large scale implementation
    (2021) Cunnama, Lucy; Sinanovic, Edina; Myer, Benjamin
    Background: Huge successes have been seen in the prevention of mother-to-child transmission of HIV (PMTCT) towards its elimination. Now amidst a landscape of universal antiretroviral therapy (ART), focus has been placed on different models of care to support and retain mother-infant pairs in the vulnerable postpartum phase. Methods The aim was to establish economic evidence for scaling-up approaches and models of care for PMTCT particularly during the postpartum period in Southern Africa. The economic data were collected during three studies, Safe Generations (Eswatini), MCH-ART and PACER (South Africa), using mixed bottom-up and top-down methodology. Outcomes of these studies were used to estimate the cost-effectiveness using an incremental cost effectiveness ratio (ICER, calculated by the difference in cost divided by the difference in effects) of lifelong ART in comparison to Option A (the standard of care at the time) in Eswatini; and to estimate the annual costs, costeffectiveness and budget impact of three models of care (Model I: Routine Care - mothers in general ART and infants in well-baby clinics; Model II: Integrated Care - mothers-infant pairs in integrated care in midwife obstetric unit; and Model III: Community Care - mothers in community adherence clubs and infants in well-baby clinics) in South Africa, from the provider and patient's perspectives. Costs are presented in 2019 United States Dollars (US $). Results Lifelong ART can be considered cost-effective in Eswatini with an ICER of US $984 per mother retained in care to six months postpartum. In Cape Town, South Africa, Routine Care cost US $226 per mother-infant pair per annum; Integrated Care cost US $341; and Community Care cost US $254. Annual patient costs (direct and indirect costs) for Models I-III, were US $30-55, US $23-45 and US $76 per mother-infant pair respectively. Comparatively Community Care was the most cost-effective model with an ICER of US $97 per mother-infant pair retained and mother virally suppressed. Scaling-up Community Care nationally in South Africa would require US $5 720 096 more than Routine Care, 0.2% of the total health budget for 2020/21. Conclusions This work has generated novel empirical data in the form of new cost estimates and cost comparisons across different models of care. It has also provided a unique comparison of the different models of care using a cost-effectiveness analysis; and further a novel budget impact analysis of different approaches to rolling these strategies out. This data has helped to fill the gap in the evidence base for instance lifelong ART was implemented in Eswatini as a direct result of the Safe Generations study findings. Community Care was found to be cost-effective and if scaled up nationally in South Africa would only require a small increment of the total health budget. However, we recommend a mixture of models of care to cater for the needs and preferences of patients. Decision makers can use the empirical findings to help set realistic budgets in Southern Africa and explore ideal model implementation to support mother-infant pairs in the crucial postpartum phase.
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    Open Access
    ‘Feedback: Where data finally get thrilling’ – tools for facility managers to use data for improved health outcomes in the prevention of mother-to-child transmission of HIV and antiretroviral therapy
    (2013) Murphy, J; Mershon, C-H; Struthers, H; McIntyre, J
    Data use and data quality continue to be a challenge for government sector health facilities and districts across South Africa. Led by the National Department of Health, key stakeholders, such as the Anova Health Institute and district health management teams, are aligning efforts to address these gaps. Coverage and correct implementation of existing tools – including TIER.net, routine data collection forms and the South African District Health Information System – must be ensured. This conference report provides an overview of such tools and summarises suggestions for quality improvement, data use and systematic evaluation of data-related interventions.
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    Impact of immune reconstitution inflammatory syndrome on antiretroviral therapy adherence
    (2012) Nachega, Jean B; Morroni, Chelsea; Chaisson, Richard E; Goliath, Rene; Efron, Anne; Ram, Malathi; Maartens, Gary
    ObjectiveWe determined the impact of immune reconstitution inflammatory syndrome (IRIS) on antiretroviral therapy (ART) adherence in a cohort of 274 human immunodeficiency virus (HIV)-infected South African adults initiating ART.MethodsWe carried out a secondary analysis of data from a randomized controlled trial of partially supervised ART in Cape Town, South Africa. Monthly pill count adherence, viral suppression (HIV viral load < 50 c/mL), and IRIS events were documented. Poisson regression was used to identify variables associated with ART adherence below the median in the first 6 months of ART.ResultsWe enrolled 274 patients: 58% women, median age 34 years, median CD4 count 98 cells/μL, 46% World Health Organization clinical stage IV, and 40% on treatment for tuberculosis (TB). IRIS and TB-IRIS developed in 8.4% and 6.6% of patients, respectively. The median cumulative adherence at 6 months for those with an IRIS event vs no IRIS was 95.5% vs 98.2% (P = 0.04). Although not statistically significant, patients developing IRIS had a lower 6-month viral load suppression than those without IRIS (68% vs 80%, P = 0.32). ART adherence below the median of 98% was independently associated with alcohol abuse (relative risk [RR] 1.5; 95% confidence interval [CI] 1.2–1.9; P = 0.003) and IRIS events (RR 1.7; 95% CI 1.2–2.2; P = 0.001).ConclusionAlthough IRIS events were associated with slightly lower adherence rates, overall adherence to ART remained high in this study population. Concerns about IRIS should not deter clinicians from early ART initiation.
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    Impact of Unintended pregnancy on HIV viral load outcomes among postpartum women living with HIV in Cape Town, South Africa: clues from postpartum adherence clubs for antiretroviral therapy trial
    (2022) Mwalye, Pumulo Justine; Odayar, Jasantha; Brittain, Kirsty
    Introduction: Postpartum women living with HIV (WLWHIV) on antiretroviral therapy (ART) are at high risk of viraemia. We examined the association between unintended pregnancy and HIV viral load (VL) at 24 months postpartum in Cape Town, South Africa. Methods: Data are from a randomised trial that compared different ART delivery modalities for postpartum women aged at least 18 years who had initiated ART during their most recent pregnancy, had a VL<400 copies/ml in the previous three months, and had no comorbidities necessitating regular clinical follow-up. Pregnancy intentions regarding the most recent pregnancy were self-reported at enrolment into the study. VL was measured at 24 months postpartum, with elevated VL defined as VL≥1000 copies/ml. Chi-squared tests and logistic regression were used to examine predictors of unintended pregnancy. The impact of unintended pregnancy on elevated VL was examined using Poisson regression models. Results: Among 411 women included in the analysis (mean age: 28.7 years, 42% married/cohabiting, 75% with a parity≥2, and 86% with a VL<50 copies/ml), 57% reported that their most recent pregnancy was unintended. Compared to women aged 18-24 years, older women had a lower relative odds of unintended pregnancy [25-28 years, adjusted odds ratio (AOR): 0.34; 95% confidence interval (CI): 0.17-0.70; 29-34 years, AOR: 0.18; CI: 0.08-0.37; and ≥35 years, AOR: 0.35; CI: 0.14-0.89]. Additionally, unintended pregnancy was associated with being unmarried/not cohabiting (AOR: 4.44; CI: 2.78-7.09) and with higher parity (compared to parity=1: parity=2, AOR: 3.47; 95% CI: 1.86-6.50; and parity≥3, AOR: 6.38; 95% CI: 3.06-13.28). VL data at 24 months postpartum were available for 89% (366/411) of participants of whom 24% had elevated VL≥1000 copies/ml. Unintended pregnancy was associated with elevated VL in unadjusted analyses [risk ratio (RR): 1.54; CI: 1.03-2.28; p=0.032]. After adjustment for maternal factors and trial allocation, the association persisted despite not reaching statistical significance (adjusted risk ratio (aRR): 1.36; CI: 0.88-2.08; p=0.158). Conclusion: Among postpartum WLWHIV in South Africa, unintended pregnancy is prevalent and could be a risk factor for elevated VL. Reproductive health counselling and support during routine care visits may reduce unintended pregnancies and its effects.
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    Investigating the molecular pathogenesis of tuberculosis-associated immune reconstitution inflammatory syndrome
    (2025) Moseki, Raymond; Meintjes, Graeme; Wilkinson, Robert J.; Riou, Catherine; Lai, Rachel
    Thesis summary This thesis comprises a series of studies that adapted a reverse translational approach to investigate the mechanisms underlying the immunopathogenesis of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS). Paradoxical TB-IRIS is an aberrant immune response targeted against Mycobacterium tuberculosis or its residual antigens in patients with advanced human immunodeficiency virus (HIV) infection shortly after commencement of antiretroviral therapy (ART). TB-IRIS is characterized by hyperinflammation and tissue damage. Pulmonary and lymph node involvement are the most common clinical manifestations. The incidence of TB-IRIS can reach up to 54% in settings where both HIV and TB are endemic, such as the sub-Saharan-Africa region of the African continent. Approximately 25% of patients with paradoxical TB-IRIS will require hospitalization for syndromic management. The management and prevention of paradoxical TB-IRIS rely on the use of anti-inflammatories such as immunosuppressive corticosteroid intervention, which is associated with an increased risk of Kaposi sarcoma. Paradoxical TB-IRIS is potentially fatal, with cases of central nervous system (CNS) involvement having the highest fatalities (up to 56%). The underlying cause of paradoxical TB-IRIS is thought to arise from a dysregulated hyperinflammatory immune response during ART-mediated immune recovery, although the causal mechanisms and associated molecular pathways are incompletely defined. This knowledge gap compromises efforts to develop new diagnostic and prognostic modalities as well as safer and more efficacious therapeutic interventions. This served as the rationale for undertaking the studies reported in this thesis. Using clinical samples from the PredART intervention trial and the TB-ART observational study, this thesis investigated the cellular and molecular determinants of paradoxical TB-IRIS. Conventional scientific hypothesis-based approaches as well as unbiased hypothesis generating approaches were used, with major experimental approaches including ribonucleic acid (RNA) sequencing, flow cytometry and soluble analyte analyses. RNA extracted from whole blood of consenting participants from the Pred-ART intervention trial was sequenced to profile global gene expression. Cross-sectional and longitudinal analyses were performed to compare transcriptomic profiles in participants who developed paradoxical TB-IRIS to those who did not, at week 0, 2 and 12 on ART. Using pathway analysis, samples collected prior to the initiation of ART (week 0) in patients who later developed paradoxical TB-IRIS (cases) were characterized by the upregulation of transcripts encoding neutrophil-derived antimicrobial peptides and defensins and associated with hypoxemia compared to the TB-non-IRIS controls. These largely reflected biological processes involved in neutrophilic responses and adaptation to metabolic stress and dysfunction. Furthermore, pathways that were significantly downregulated in patients who later developed paradoxical TB-IRIS compared to those who did not, included chondroitin sulfate biosynthesis and interleukin (IL)-6. These finding suggest that paradoxical TB-IRIS is preceded by increased expression of antimicrobial peptides and the impairment of immune cellular function controlled by the extracellular matrix. Pathway analysis at week 2 on ART, which coincided with the median time of clinical manifestations in patients that developed paradoxical TB-IRIS, revealed the significant enrichment of neutrophil degranulation, interleukin (IL)-1 signalling, as well as type I and II interferon (IFN). Moreover, biological pathways that were significantly downregulated in cases as opposed to controls at week 2 on ART were largely overrepresented by epigenetic biological processes. These data suggested that neutrophil degranulation preceded and characterized the onset of paradoxical TB-IRIS. To validate these findings, we evaluated the associations between absolute neutrophil counts and neutrophil soluble markers, with paradoxical TB-IRIS at week 0 and week 2 on ART. No significant differences in absolute neutrophil counts were reported in participants who later developed paradoxical TB-IRIS compared to those who did not at week 0. However, azurocidin measured in plasma samples by enzyme-linked immunosorbent assay (ELISA) was significantly lower in samples from participants who later developed paradoxical TB-IRIS at week 0. This suggests that participants who are likely to develop paradoxical TB-IRIS might have impaired innate immune responses at week 0 compared to those who did not develop the syndrome. Absolute neutrophil counts were higher in cases compared to controls at week 2 on ART. Soluble neutrophil markers including human neutrophil peptide 1-3, myeloperoxidase, and neutrophil elastase were significantly higher in cases compared to controls at week 2 on ART. These data suggest that patients who develop paradoxical TB-IRIS have heightened neutrophil degranulation at the time of symptoms onset. Longitudinal perturbation of gene expression was investigated between week 0 and week 2 in people who developed paradoxical TB-IRIS and TB-non-IRIS controls, respectively. Among the top significantly upregulated biological pathways in samples of participants that developed paradoxical TB-IRIS were neutrophil degranulation, type I and II interferon signaling, IL-1 cytokine signalling, and pyroptosis. Biological pathways that were significantly downregulated in these patients included heme biosynthesis and oxygen-carbon dioxide gaseous exchange signalling metabolic dysfunction. In TB-non-IRIS controls, biological pathways that were significantly upregulated included epigenetic modulation of gene expression, collagen biosynthesis and extracellular cytoskeleton remodelling indicating anabolic processes that restore or maintain proper cellular functionality such as cellular signalling. Type I interferon signalling and immune responses to viral pathogens were among biological pathways that were significantly downregulated in people who did not develop paradoxical TB-IRIS at week 2 on ART compared to week 0, likely indicating decrease in antiviral responses as HIV viral load declined. The management and prevention of paradoxical TB-IRIS rely on the use of corticosteroids which is associated with an increased risk of Kaposi Sarcoma and herpes reactivations. Thus, there is a need to explore other anti-inflammatory but non-immunosuppressive drugs that can be repurposed for the management of IRIS-related pathologies. Gene expression data at week 2 on ART and previous published data indicated that aberrant inflammasome activation represent one of the molecular mechanisms that underpins the pathogenesis of paradoxical TB IRIS. We proposed that chemical inhibition of the inflammasome would result in a targeted reduction of inflammation. Two candidate drugs (anakinra and parthenolide) were evaluated and benchmarked against the standard of care (prednisolone) in an ex vivo mycobacterial cell stimulation model using patient samples. Both anakinra and parthenolide significantly reduced several markers of inflammation compared to prednisolone. However, parthenolide was the more potent in reducing cytokine production including IL-1 among others. These findings provide experimental evidence of in vitro use of novel anti-inflammatory agents. Anakinra has been approved for clinical use in inflammatory conditions such as rheumatoid arthritis and could potentially be repurposed for use in the context of paradoxical TB-IRIS. A hallmark of paradoxical TB-IRIS includes the partial reconstitution of Mtb-specific CD4 T cell responses within 3 months of initiating ART while on effective antituberculosis therapy. The phenotype and transcription factors of antigen-specific interferon-gamma producing (IFN+) CD4+ T cells and their potential involvement in the pathogenesis of paradoxical TB IRIS were characterized in an experimental mouse model of IRIS (by collaborators) as well as in human peripheral blood mononuclear cells (PBMC). In mice, antigen-specific CD4 T cells knocked out for Eomes showed significantly higher proportion of survival compared to wildtype mice. No significant differences in Eomes expression were observed in Mtb-300 specific, IFN+ CD4 T cells in PBMC from paradoxical TB-IRIS cases compared to controls at the onset of clinical symptoms. However, Eomes expression was higher in cases compared to controls in bulk CD4 T cells at week 2 on ART. HLA-DR expression was higher in cases compared to controls in Mtb300-specific IFN+ CD4 T cells at week 2 on ART. Additionally, Granzyme B producing, Mtb300-specific IFN+ CD4 T cells co-expressing Eomes and Tbet were significantly higher in cases compared to controls at week 2 on ART. These data indicate that HLA-DR expression on Mtb300-specific CD4 T cells producing IFN+ can potentially be developed as a diagnostic tool to identify individuals with paradoxical TB-IRIS. Collectively, these findings highlight the key contribution of neutrophils and Mtb-specific CD4 lymphocytes in the pathogenesis of paradoxical TB-IRIS. The gene expression findings suggest that the underlying mechanism involves interferon stimulated genes which trigger the secretion of proinflammatory cytokines and the aberrant activation of the inflammasome. Members of the IL-1 family of cytokines are secreted as catalytically inactive proenzymes that require the action of mature inflammasome for activation. IL-1a is the only exception since its proform and mature form are both fully functional. Active IL-1 family of cytokines are potent modulators of inflammation which is a defining feature in people who develop paradoxical TB-IRIS at the time of clinical symptom onset. In addition, the pathogenesis of paradoxical TB-IRIS appears to be mediated by the heightened degranulation of neutrophils which may cause acute inflammation and tissue damage.
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    A randomized comparison of health-related quality of life outcomes of dolutegravir versus efavirenz-based antiretroviral treatment initiated in the third trimester of pregnancy
    (2022-06-07) Ochanda, Perez N; Lamorde, Mohammed; Kintu, Kenneth; Wang, Duolao; Chen, Tao; Malaba, Thokozile; Myer, Landon; Waitt, Catriona; Reynolds, Helen; Khoo, Saye
    Introduction Evidence on health-related quality of life (HRQoL) outcomes is limited for new antiretroviral therapies (ART). Dolutegravir-based treatment is being rolled out as the preferred first-line treatment for HIV in many low- and middle-income countries. We compared HRQoL between treatment-naïve pregnant women randomized to dolutegravir- or efavirenz-based ART in a clinical trial in Uganda and South Africa. Methods We gathered HRQoL data from 203 pregnant women of mean age 28 years, randomized to either dolutegravir- or efavirenz-based ART. We used the medical outcomes study-HIV health survey at baseline, 24 and 48 weeks between years 2018 and 2019. Physical health summary (PHS) and mental health summary (MHS) scores were the primary study outcomes, while the 11 MOS-HIV subscales were secondary outcomes. We applied mixed model analysis to estimate differences within and between-treatment groups. Multivariate regression analysis was included to identify associations between primary outcomes and selected variables. Results At 24 weeks postpartum, HRQoL scores increased from baseline in both treatment arms: PHS (10.40, 95% CI 9.24, 11.55) and MHS (9.23, 95% CI 7.35, 11.10) for dolutegravir-based ART; PHS (10.24, 95% CI 9.10, 11.38) and MHS (7.54, 95% CI 5.66, 9.42) for efavirenz-based ART. Increased scores for all secondary outcomes were significant at p < 0.0001. At 48 weeks, improvements remained significant for primary outcomes within group comparison. Estimated difference in PHS were higher in the dolutegravir-based arm, while increases in MHS were more for women in the efavirenz-based armat 24 and 48 weeks. No significant differences were noted for corresponding PHS scores at these time points compared between groups. Differences between arms were observed in two secondary outcomes: role function (1.11, 95% CI 0.08, 2.13), p = 0.034 and physical function outcomes (2.97, 95% CI 1.20, 4.73), p = 0.001. In the multivariate analysis, internet access was associated with higher PHS scores while owning a bank account, using the internet and longer treatment duration were associated with an increase in MHS scores. Conclusion We found no important differences in HRQoL outcomes among HIV-positive women started on dolutegravir relative to efavirenz in late pregnancy. Increases in HRQoL in the first year after delivery provide additional support for the initiation of ART in HIV-positive women presenting late in pregnancy. Trial Registration Clinical Trial Number: NCT03249181
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    Treatment Failure and Adherence in Second- Line Patients
    (2012-10) Barnett, Whitney
    Results from an interview and photo-based research study looking at barriers and facilitators to adherence for second-line patients.
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    Why patients struggle with anti-retroviral treatment
    (2012-10) UCT Knowledge Co-op
    This is a Public Health project. The recent increase of anti-retroviral treatment (ART) in public clinics in South Africa means that many more people have access to treatment. If patients become resistant to the standard ART package they are put on an alternative second-line ART; if that fails, there is no further public treatment option to control the HI virus. Yet, literature addressing facilitators and barriers to treatment adherence faced by patients on second-line ART is scarce.