Accuracy of measures for antiretroviral adherence in people living with HIV.

BACKGROUND: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings. OBJECTIVES: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment. SEARCH METHODS: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity. DATA COLLECTION AND ANALYSIS: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis. MAIN RESULTS: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results. AUTHORS' CONCLUSIONS: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions.

IFN-γ ELISpot in Severe Cutaneous Adverse Reactions to First-Line Antituberculosis Drugs in an HIV Endemic Setting.

Severe cutaneous adverse reactions related to first-line antituberculosis drugs are associated with high mortality and long-term morbidity. Oral sequential drug challenge, as a form of drug provocation testing, helps to salvage therapy by identifying culprit drugs but is associated with risk and is costly. IFN-γ enzyme-linked immune absorbent spot (ELISpot), an adjunctive in vitro diagnostic tool, may help to guide risk-stratification approaches. To determine the diagnostic accuracy of IFN-γ ELISpot against full-dose sequential drug challenge, we analyzed samples collected prospectively at multiple time points in 32 patients with first-line antituberculosis drug‒associated severe cutaneous adverse reaction (81% HIV infected, 25 with drug reaction with eosinophilia and systemic symptoms, and 7 with Stevens‒Johnson syndrome/toxic epidermal necrolysis). Sensitivity of IFN-γ ELISpot was 33% (4 of 12), 13% (1 of 8), 11% (1 of 9), and 0% (0 of 4) for rifampicin, isoniazid, pyrazinamide, and ethambutol, respectively (positivity threshold ≥50 spot forming units/million cells). Specificity was 100% for all the four drugs. Rifampicin IFN-γ ELISpot sensitivity increased to 58% (7 of 12) if a threshold of 20 spot forming units was used and to 75% (3 of 4) when restricted to samples <12 weeks after acute severe cutaneous adverse reaction event; specificity remained 100% for both. IFN-γ ELISpot offers adequate risk stratification of rifampicin severe cutaneous adverse reaction using acute samples and lowered threshold for positivity. Given the low sensitivity of IFN-γ ELISpot for other first-line antituberculosis drugs, additional optimization is needed to improve risk-stratification potential.

The prevalence and spectrum of mucocutaneous disease in South African people living with HIV and accessing care at a district-level hospital.

BACKGROUND: Although the association between human immunodeficiency virus (HIV) and mucocutaneous diseases has been well studied within South African specialist centres, there is limited data from district-level hospitals. Available data may, therefore, fail to reflect the prevalence and full spectrum of dermatoses seen in people living with HIV (PLWH). OBJECTIVES: To determine the prevalence and spectrum of dermatoses seen in PLWH. METHOD: We conducted a cross-sectional, descriptive study of 970 PLWH (men and women, ≥ 18 years old) accessing care at Karl Bremer Hospital, a district-level hospital located in the Western Cape province, South Africa, between 01 September 2016 and 28 February 2017. RESULTS: The prevalence of mucocutaneous disease in this sample was 12.7% (95% confidence interval [CI] 0.11-0.15). Non-infectious dermatoses comprised 71.0% of the disorders. Pruritic papular eruption (20.0%) and seborrheic dermatitis (6.0%) were the most common non-infectious dermatoses. Tinea corporis (8.0%) and oral candidiasis (6.0%) were the most prevalent infectious dermatoses. There was no significant association between skin disease category (infectious or non-infectious dermatoses) and patient demographics (gender and ethnicity) or HIV-disease characteristics (CD4+ cell count, viral load and duration of antiretroviral therapy [ART]). CONCLUSION: This study provides valuable scientific data on the prevalence and spectrum of mucocutaneous disease in PLWH attending a South African district-level hospital. Prospective studies conducted in other district-level centres across the country are required to determine the lifetime prevalence and spectrum of dermatoses in PLWH in the ART era.

An Analysis of Biopsies for Suspected Skin Cancer at a Tertiary Care Dermatology Clinic in the Western Cape Province of South Africa.

BACKGROUND: Skin cancer is a growing health concern worldwide. It is the most common malignancy in South Africa and places a large burden on the public healthcare sector. There is a paucity of published scientific data on skin cancer in South Africa. OBJECTIVES: To report the findings of biopsies performed in patients with suspected skin cancer attending the Tygerberg Academic Hospital (TAH) Dermatology outpatient department (OPD) in the Western Cape Province of South Africa. Methodology: A retrospective chart review identified all patients who underwent a biopsy for a suspected skin cancer diagnosis between September 2015 and August 2016 at the TAH dermatology OPD. RESULTS: A total number of 696 biopsies from 390 participants were identified, of which 460 were histologically confirmed as malignant lesions. The proportion of clinically suspected skin cancers that were histologically confirmed as cancer was 68%. The most commonly occurring malignancies were basal cell carcinoma (BCC) (54.8%), squamous cell carcinoma (SCC) (18.9%), squamous cell carcinoma in-situ (SCCI) (8.0%), Kaposi's sarcoma (KS) (6.7%), malignant melanoma (MM) (6.1%), and keratoacanthoma (KA) (4.6%). The number needed to treat (NTT) for all cancers diagnosed and for MM was 1.5 and 4 respectively. BCC (89.3%) and KS (67.7%) was the most common skin cancer in the white and black population respectively. The ratio of BCC to SCC was 2.03. CONCLUSION: This study provides valuable scientific data on the accuracy of skin cancer diagnosis, distribution and patient demographics in the Western Cape Province of South Africa, on which further research can be based. The study highlights the burden of skin cancer on this specific population group and calls for standardised reporting methods and increased surveillance of skin cancers.

Rapid initiation of antiretroviral therapy for people living with HIV.

BACKGROUND: Despite antiretroviral therapy (ART) being widely available, HIV continues to cause substantial illness and premature death in low-and-middle-income countries. High rates of loss to follow-up after HIV diagnosis can delay people starting ART. Starting ART within seven days of HIV diagnosis (rapid ART initiation) could reduce loss to follow-up, improve virological suppression rates, and reduce mortality. OBJECTIVES: To assess the effects of interventions for rapid initiation of ART (defined as offering ART within seven days of HIV diagnosis) on treatment outcomes and mortality in people living with HIV. We also aimed to describe the characteristics of rapid ART interventions used in the included studies. SEARCH METHODS: We searched CENTRAL, the Cochrane Database of Systematic Reviews, MEDLINE, Embase, and four other databases up to 14 August 2018. There was no restriction on date, language, or publication status. We also searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform, and websites for unpublished literature, including conference abstracts. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared rapid ART versus standard care in people living with HIV. Children, adults, and adolescents from any setting were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of the studies identified in the search, assessed the risk of bias and extracted data. The primary outcomes were mortality and virological suppression at 12 months. We have presented all outcomes using risk ratios (RR), with 95% confidence intervals (CIs). Where appropriate, we pooled the results in meta-analysis. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included seven studies with 18,011 participants in the review. All studies were carried out in low- and middle-income countries in adults aged 18 years old or older. Only one study included pregnant women.In all the studies, the rapid ART intervention was offered as part of a package that included several cointerventions targeting individuals, health workers and health system processes delivered alongside rapid ART that aimed to facilitate uptake and adherence to ART.Comparing rapid ART with standard initiation probably results in greater viral suppression at 12 months (RR 1.18, 95% CI 1.10 to 1.27; 2719 participants, 4 studies; moderate-certainty evidence) and better ART uptake at 12 months (RR 1.09, 95% CI 1.06 to 1.12; 3713 participants, 4 studies; moderate-certainty evidence), and may improve retention in care at 12 months (RR 1.22, 95% CI 1.11 to 1.35; 5001 participants, 6 studies; low-certainty evidence). Rapid ART initiation was associated with a lower mortality estimate, however the CIs included no effect when compared to standard of care (RR 0.72, 95% CI 0.51 to 1.01; 5451 participants, 7 studies; very low-certainty evidence). It is uncertain whether rapid ART has an effect on modification of ART treatment regimens as data are lacking (RR 7.89, 95% CI 0.76 to 81.74; 977 participants, 2 studies; very low-certainty evidence). There was insufficient evidence to draw conclusions on the occurrence of adverse events. AUTHORS' CONCLUSIONS: RCTs that include initiation of ART within one week of diagnosis appear to improve outcomes across the HIV treatment cascade in low- and middle-income settings. The studies demonstrating these effects delivered rapid ART combined with several setting-specific cointerventions. This highlights the need for pragmatic research to identify feasible packages that assure the effects seen in the trials when delivered through complex health systems.

Maintaining relevance in HIV systematic reviews: an evaluation of Cochrane reviews.

BACKGROUND: Research turnover in the HIV field is rapid, and as a result, maintaining high-quality, up-to-date, and relevant systematic reviews is a challenge. One approach is to frequently update published reviews. METHODS: We evaluated the methods and relevance of all HIV systematic reviews and protocols published in the Cochrane Library over a 16-year period (2000-2016) to determine the need to update published reviews or complete of reviews in progress. RESULTS: Of 148 published reviews and protocols, 129 (87%) were identified as not for updating or progression to publication, mostly due to research questions which were either entirely outdated or addressed questions in an outdated manner (N = 89; 60%); this was anticipated for older reviews, but was found also to be the case for recent publications. Some research questions were also inadequately conceptualized, particularly when complex pragmatic trials or behavioral interventions were included. CONCLUSIONS: We suggest that authors clearly characterize interventions and synthesis approaches in their review protocols. In research fields, such as HIV, where questions change frequently, systematic reviews and protocols should be regularly re-evaluated to ensure relevance to current questions. This process of re-evaluation should be incorporated into the methods of living systematic reviews.