Gynaecologic and breast cancers in women living with HIV in South Africa: A record linkage study.

Breast and gynaecologic cancers account for approximately half of all cancers diagnosed amongst women in South Africa, many of whom also live with HIV. We aimed to determine the incidence of and risk factors for developing breast and gynaecologic cancers in women living with HIV (WLHIV) in South Africa. This is a longitudinal analysis of the South African HIV Cancer Match study including women aged ≥15 years with two or more HIV-related laboratory tests. We used Cox proportional hazard models to determine the association of Human Papilloma Virus (HPV)-related and hormone-related gynaecologic cancer with patient- and municipal-level characteristics. From 3 447 908 women and 10.5 million years of follow-up, we identified 11 384 incident and 7612 prevalent gynaecologic and breast cancers. The overall crude incidence rate was 108/1 00 000 person-years (pyears) (95% confidence interval [CI]: 106-110), with the highest incidence observed for cervical cancer (70/1 00 000 pyears; 95% CI: 68.5-71.7). Low CD4 cell counts and high HIV RNA viral loads increased the risk of cervical and other HPV-related cancers. Age was associated with both HPV-related and hormone-related cancers. Women accessing health facilities in high socioeconomic position (SEP) municipalities were more likely to be diagnosed with HPV-related cancers and breast cancer than women accessing care in low SEP municipalities. It is important to improve the immunologic status of WLHIV as part of cancer prevention strategies in WLHIV. Cancer prevention and early detection programmes should be tailored to the needs of women ageing with HIV. In addition, SEP disparities in cancer diagnostic services have to be addressed.

Identifying Potential Factors Associated with High HIV viral load in KwaZulu-Natal, South Africa using Multiple Correspondence Analysis and Random Forest Analysis.

BACKGROUND: Sustainable Human Immunodeficiency Virus (HIV) virological suppression is crucial to achieving the Joint United Nations Programme of HIV/AIDS (UNAIDS) 95-95-95 treatment targets to reduce the risk of onward HIV transmission. Exploratory data analysis is an integral part of statistical analysis which aids variable selection from complex survey data for further confirmatory analysis. METHODS: In this study, we divulge participants' epidemiological and biological factors with high HIV RNA viral load (HHVL) from an HIV Incidence Provincial Surveillance System (HIPSS) sequential cross-sectional survey between 2014 and 2015 KwaZulu-Natal, South Africa. Using multiple correspondence analysis (MCA) and random forest analysis (RFA), we analyzed the linkage between socio-demographic, behavioral, psycho-social, and biological factors associated with HHVL, defined as ≥400 copies per m/L. RESULTS: Out of 3956 in 2014 and 3868 in 2015, 50.1% and 41% of participants, respectively, had HHVL. MCA and RFA revealed that knowledge of HIV status, ART use, ARV dosage, current CD4 cell count, perceived risk of contracting HIV, number of lifetime HIV tests, number of lifetime sex partners, and ever diagnosed with TB were consistent potential factors identified to be associated with high HIV viral load in the 2014 and 2015 surveys. Based on MCA findings, diverse categories of variables identified with HHVL were, did not know HIV status, not on ART, on multiple dosages of ARV, with less likely perceived risk of contracting HIV and having two or more lifetime sexual partners. CONCLUSION: The high proportion of individuals with HHVL suggests that the UNAIDS 95-95-95 goal of HIV viral suppression is less likely to be achieved. Based on performance and visualization evaluation, MCA was selected as the best and essential exploration tool for identifying and understanding categorical variables' significant associations and interactions to enhance individual epidemiological understanding of high HIV viral load. When faced with complex survey data and challenges of variables selection in research, exploratory data analysis with robust graphical visualization and reliability that can reveal divers' structures should be considered.

Evaluation of a rapid antigen detection test (Panbio™ COVID-19 Ag Rapid Test Device) as a point-of-care diagnostic tool for COVID-19 in a pediatric emergency department.

We evaluated the Panbio™ COVID-19 Ag Rapid Test Device as a point-of-care diagnostic tool for COVID-19 in 357 patients at a pediatric emergency department. Thirty-four patients tested positive by reverse transcription polymerase chain reaction, of which 24 were positive by the antigen assay. The sensitivity and specificity of the assay were 70.5% and 100%, respectively.

Association of Immunosuppression and Human Immunodeficiency Virus (HIV) Viremia With Anal Cancer Risk in Persons Living With HIV in the United States and Canada.

BACKGROUND: People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. METHODS: We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. RESULTS: Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/µL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/µL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6). CONCLUSIONS: Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

Accuracy of quantitative HIV-1 RNA test methods at 1000 copies/mL and the potential impact of differences in assay calibration on therapy monitoring of patients.

The World Health Organization (WHO) recommends the clinical use of a human immunodeficiency virus 1 (HIV-1) viral load (VL) threshold level of 1000 copies (cp)/mL in patients on antiretroviral therapy (ART) to distinguish between viral control (VL < 1000 cp/mL) and viral failure or poor adherence (VL > 1000 cp/mL). The accuracy of five quantitative HIV-1 RNA assays at this level was compared by replicate testing (n = 24) of 1000 cp/mL samples prepared from the Viral Quality Control (VQC) HIV-1 subtype B standard, which is in use for validation of nucleic acid testing methods since 1995. Until 2004 the VL assays reported geometric mean (95% confidence interval [CI]) values ranging between 449 (188-1067) and 3162 (3057-2367) cp/mL when using the Siemens bDNA 3.0 assay as reference method for an assigned value of 1000 (962-1038) cp/mL. In 2018, the following values (95% CI) were found by 24 replicate tests in each of the VL assays on the 1000 cp/mL samples: Abbott RealTime 1084 (784-1572), BioMerieux EasyQ 1110 (533-2230), Roche CAP/CTM 1277 (892-1828), Hologic Aptima 1616 (1324-1973), and Cepheid GeneXpert 2502 (1713-3655) cp/mL. Calibration studies involving three consecutive WHO replacement standards showed a significant drift in the amount of RNA copies per International Unit overtime. Heat inactivation of HIV-1 standards was found to cause a destandardizing effect. Our study underlines the limitations in HIV-1 RNA assay calibration based on frequently replaced WHO international standards. It is therefore proposed that clinicians interpret the recommended 1000 cp/mL alert level in therapy monitoring with an inaccuracy range of 500 to 2000 cp/mL.

Early HIV infection is associated with reduced proportions of gamma delta T subsets as well as high creatinine and urea levels.

Renal dysfunctions are major predictors of co-morbidities and mortality in HIV-infected individuals. Unconventional T cells have been shown to regulate kidney functions. However, there is dearth of information on the effect of HIV-associated nephropathies on γδ and DN T cells. It is also not clear whether γδ T cell perturbations observed during the early stages of HIV infection occur before immune activation. In this study, we investigated the relationship between creatinine and urea on the number of unconventional T cells in HIV-infected individuals at the early and chronic stages of infection. Persons in the chronic stage of infection were divided into treatment naïve and exposed groups. Treatment exposed individuals were further subdivided into groups with undetectable and detectable HIV-1RNA in their blood. Creatinine and urea levels were significantly higher among persons in the early HIV infection compared with the other groups. Proportions of γδ T, γδ + CD8, γδ + CD16 cells were also significantly reduced in the early stage of HIV infection (P < .01). Markers of immune activation, CD4 + HLA-DR and CD8 + HLA-DR, were also significantly reduced during early HIV infection (P < .01). Taken together, our findings suggest that high levels of renal markers as well as reduced proportions of gamma delta T cells are associated with the early stages of HIV infection. This event likely occurs before systemic immune activation reaches peak levels. This study provides evidence for the need for early HIV infection diagnosis and treatment.

Field evaluation of GeneXpert® (Cepheid) HCV performance for RNA quantification in a genotype 1 and 6 predominant patient population in Cambodia.

GeneXpert® (Cepheid) is the only WHO prequalified platform for hepatitis C virus (HCV) nucleic acid amplification testing that is suitable for point-of-care use in resource-limited contexts. However, its application is constrained by the lack of evidence on genotype 6 (GT6) HCV. We evaluated its field performance among a patient population in Cambodia predominantly infected with GT6. Between August and September 2017, we tested plasma samples obtained from consenting patients at Médecins Sans Frontières' HCV clinic at Preah Kossamak Hospital for HCV viral load (VL) using GeneXpert® and compared its results to those obtained using COBAS® AmpliPrep/Cobas® TaqMan® HCV Quantitative Test, v2.0 (Roche) at the Institut Pasteur du Cambodge. Among 769 patients, 77% of the seropositive patients (n = 454/590) had detectable and quantifiable VL using Roche and 43% (n = 195/454) were GT6. The sensitivity and specificity of GeneXpert® against Roche were 100% (95% CI 99.2, 100.0) and 98.5% (95% CI 94.8, 99.8). The mean VL difference was -0.01 (95% CI -0.05, 0.02) log10  IU/mL for 454 samples quantifiable on Roche and -0.07 (95% CI -0.12, -0.02) log10  IU/mL for GT6 (n = 195). The limit of agreement (LOA) was -0.76 to 0.73 log10  IU/mL for all GTs and -0.76 to 0.62 log10 IU/mL for GT6. Twenty-nine GeneXpert® results were outside the LOA. Frequency of error and the median turnaround time (TAT) for GeneXpert® were 1% and 0 days (4 days using Roche). We demonstrated that the GeneXpert® HCV assay has good sensitivity, specificity, quantitative agreement, and TAT in a real-world, resource-limited clinical setting among GT6 HCV patients.

Study of Patterns and Markers of Human Immune Deficiency Virus -1 (HIV-1) Progression and Unemployment Rate among Patients from Alexandria, Egypt.

Middle East and North Africa (MENA) new HIV cases show the highest increase among all regions in the world. Even though Egypt has a low prevalence among the general population (< 0.02%), a national HIV epidemic occurs in certain population risk groups. The current study was conducted to asses clinical and immunological disease progression; following up viral load (VL) and detecting delta-32 CCR5 genotype polymorphism in selected cases, determining unemployment rate and identify predictors of employment for HIV-cases. A cross sectional design was adopted. HIV infected cases attending Alexandria Fever Hospital (AFH) for one year. Interview questionnaire and four CD+4 counts were done for all patients, HIV VL and delta-32 CCR5 polymorphism were done for selected cases. Sexual transmission and drug abuse are the most important risk factors. Infectious comorbidity increases the rate of HIV progression. CD4+ count at the end of the study; CD+4 (4), count was significantly higher than all other CD4+ readings among the whole cohort and among the treated group. Also, VL at the end of the study; VL(2), was significantly higher than VL(1) among the untreated group. Unemployment rate was 40%. Male gender and obtaining vocational training were significant predictors of employment. It can be concluded that having a family member living with HIV and drug abusers are high risk groups for HIV acquisition. Factors responsible for progression of HIV should be further investigated. Antiretroviral therapy is very effective in checking HIV replication rate, delaying the progression of HIV, reconstituting the immune response and should be available for all cases detected.

Increased Prevalence of Controlled Viremia and Decreased Rates of HIV Drug Resistance Among HIV-Positive People Who Use Illicit Drugs During a Community-wide Treatment-as-Prevention Initiative.

BACKGROUND: Although treatment-as prevention (TasP) is a new cornerstone of global human immunodeficiency virus (HIV)-AIDS strategies, its effect among HIV-positive people who use illicit drugs (PWUD) has yet to be evaluated. We sought to describe longitudinal trends in exposure to antiretroviral therapy (ART), plasma HIV-1 RNA viral load (VL) and HIV drug resistance during a community-wide TasP intervention. METHODS: We used data from the AIDS Care Cohort to Evaluate Exposure to Survival Services study, a prospective cohort of HIV-positive PWUD linked to HIV clinical monitoring records. We estimated longitudinal changes in the proportion of individuals with VL <50 copies/mL and rates of HIV drug resistance using generalized estimating equations (GEE) and extended Cox models. RESULTS: Between 1 January 2006 and 30 June 2014, 819 individuals were recruited and contributed 1 or more VL observation. During that time, the proportion of individuals with nondetectable VL increased from 28% to 63% (P < .001). In a multivariable GEE model, later year of observation was independently and positively associated with greater likelihood of nondetectable VL (adjusted odds ratio = 1.20 per year; P < .001). Although the proportion of individuals on ART increased, the incidence of HIV drug resistance declined (adjusted hazard ratio = 0.78 per year; P = .011). CONCLUSIONS: We observed significant improvements in several measures of exposure to ART and virologic status, including declines in HIV drug resistance, in this large long-running community-recruited cohort of HIV-seropositive illicit drug users during a community-wide ART expansion intervention. Our findings support continued efforts to scale up ART coverage among HIV-positive PWUD.

Factors associated with optimal pharmacy refill adherence for antiretroviral medications and plasma HIV RNA non-detectability among HIV-positive crack cocaine users: a prospective cohort study.

BACKGROUND: Crack cocaine use is known to contribute to poor adherence to antiretroviral medications; however, little is known about facilitators of or barriers to effective HIV treatment use among HIV-infected crack cocaine users. We sought to identify correlates of optimal pharmacy refill adherence for antiretroviral medications and plasma HIV RNA viral load (pVL) suppression among this population. METHODS: Data from a prospective cohort of HIV-positive people who use illicit drugs in Vancouver, Canada, were linked to comprehensive HIV clinical monitoring and pharmacy dispensation records. We used multivariable generalized linear mixed-effects modelling to longitudinally identify factors associated with ≥95 % adherence to pharmacy refills for antiretroviral medications and pVL <50 copies/mL among crack cocaine users exposed to highly-active antiretroviral therapy (HAART). RESULTS: Among 438 HAART-exposed crack cocaine users between 2005 and 2013, 240 (54.8 %) had ≥95 % pharmacy refill adherence in the previous 6 months at baseline. In multivariable analyses, homelessness (adjusted odds ratio [AOR]: 0.58), ≥daily crack cocaine smoking (AOR: 0.64), and ≥ daily heroin use (AOR: 0.43) were independently associated with optimal pharmacy refill adherence (all p < 0.05). The results for pVL non-detectability were consistent with those of medication adherence, except that longer history of HAART (AOR: 1.06), receiving a single tablet-per-day regimen (AOR: 3.02) and participation in opioid substitution therapies was independently associated with pVL non-detectability (AOR: 1.55) (all p < 0.05). CONCLUSIONS: Homelessness, and daily crack cocaine and/or heroin use were independently and negatively associated with optimal HAART-related outcomes. With the exception of opioid substitution therapies, no addiction treatment modalities assessed appeared to facilitate medication adherence or viral suppression. Evidence-based treatment options for crack cocaine use that also confer benefits to HAART need to be developed.

Patient Living with Human Immunodeficiency Virus and Depression with High HIV Viral Load Presenting for Evaluation of Root Caries.

A 26-year-old man living with HIV and depression presents with symptoms of tooth sensitivity. His laboratory studies are all within normal limits except for a high viral load. The patient does not require any special dental management protocol and should be treated like other patients, with his laboratory studies reviewed every 6 months to 1 year. HIV is now a chronic medical conditions, with most patients having stable disease if they are compliant with their medications. Universal infection control protocols should be followed for all patients regardless of their HIV status.

Treatment of Chronic Hepatitis C Infection with Sofosbuvir-Based Regimens in a Commercially Insured Patient Population.

BACKGROUND: The response to treatment with direct-acting antiviral agents in patients with chronic hepatitis C virus (HCV) is not well-characterized in the real-world setting. OBJECTIVE: To describe patients' response to 3 sofosbuvir-based treatment regimens among commercially insured patients with chronic HCV. METHODS: In this observational study, we identified patients with HCV who started sofosbuvir treatment with 1 of 3 sofosbuvir-based regimens between December 1, 2013, and April 30, 2014, in the HealthCore Integrated Research Database, a large managed care repository. All patients were aged ≥18 years and had ≥1 RNA viral load tests after starting treatment. Pharmacy and medical claims, laboratory results, and patient medical records were integrated for information on HCV genotype, treatment regimen, RNA viral load, and other clinical and demographic characteristics. The primary outcome was the response to HCV treatment during and after treatment completion, which was defined as an HCV RNA viral load of <25 IU/mL. The 3 HCV treatment regimens included sofosbuvir plus peginterferon alfa and ribavirin; sofosbuvir plus ribavirin; and sofosbuvir plus simeprevir, with or without ribavirin in patients with HCV genotypes 1 to 3. The secondary outcome was the number of patients who had a treatment response in the first 4, 6, and 8 weeks of therapy to determine whether a lack of early response to treatment is suggestive of a posttreatment lack of response. Relapse was defined as regression from response during treatment, with a detectable viral load of ≥25 IU/mL in the most recent test after treatment completion. RESULTS: Among 249 patients with ≥1 documented viral load tests after treatment initiation, 200 (80%) patients had ≥1 tests after the end of treatment. The posttreatment response rate for all 3 regimens was 88% (95% confidence interval, 84%-93%), ranging from 81% to 93%. In the largest category-patients with genotype 1 HCV (N = 130)-the response rate was between 83% and 92% across the 3 regimens. During treatment, 34% of the patients with any viral load test results by week 4 did not respond; however, 81% of those patients had a response after week 12. Of the patients who responded during treatment, 8% had relapsed disease after the end of treatment. CONCLUSION: The response rate to the sofosbuvir-based regimens included in this study was similar to those seen in published randomized clinical trials. Although 34% of the patients with any viral load test result by week 4 of treatment had viral loads of ≥25 IU/mL, persistent treatment was associated with response in the majority of those patients. This supports the effectiveness of sofosbuvir treatment and the need for treatment persistence. The rapid emergence of new treatments in this field presents exciting opportunities for additional research, and holds important clinical and economic implications for patients and their families, healthcare providers, and critically, for payers, who have to accommodate the new pricing models associated with these treatments.

Improvements in HIV treatment outcomes among indigenous and non-indigenous people who use illicit drugs in a Canadian setting.

INTRODUCTION: In many settings worldwide, members of indigenous groups experience a disproportionate burden of HIV. In Canada, there is an urgent need to improve HIV treatment outcomes for indigenous people living with HIV (IPLWH), to not only reduce HIV/AIDS-associated morbidity and mortality but also curb elevated rates of viral transmission. Thus, by comparing indigenous and non-indigenous participants in an ongoing longitudinal cohort of HIV-positive people who use illicit drugs, we sought to investigate longitudinal changes in three HIV treatment indicators for IPLWH who use illicit drugs during a community-wide treatment-as-prevention (TasP) initiative in British Columbia, Canada. METHODS: We used data from the ACCESS study, an ongoing observational prospective cohort of HIV-positive illicit drug users recruited from community settings in Vancouver, British Columbia. Cohort data are linked to comprehensive retrospective and prospective clinical records in a setting of no-cost HIV/AIDS treatment and care. We used multivariable generalized estimating equations (GEE) to evaluate longitudinal changes in the proportion of participants with exposure to antiretroviral therapy (ART) in the previous 180 days, optimal adherence to ART (i.e. ≥ 95% vs. < 95%) and non-detectable HIV-1 RNA viral load (VL <50 copies/mL plasma). RESULTS: Between 2005 and 2014, 845 individuals were recruited, including 326 (39%) self-reporting any indigenous ancestry, and contributed 6732 interviews and 13,495 VL measurements. Among indigenous participants, the proportion with recent ART increased from 51 to 94% and non-detectable VL from 23 to 65%. In multivariable models, later interview period was positively associated with recent ART (adjusted odds ratio (AOR) = 1.16 per interview period, 95% confidence interval (CI): 1.11 to 1.20) and non-detectable VL (AOR = 1.07, 95% CI: 1.04 to 1.10). In adjusted models comparing indigenous and non-indigenous participants, we did not observe differences between the two groups (all p>0.1). CONCLUSIONS: In this large and long-term study involving community-recruited HIV-positive illicit drug users, we observed a substantial and increasing proportion of indigenous participants reach several important thresholds in HIV care at rates indistinguishable from non-indigenous participants. The current findings highlight the important role of TasP on vulnerable populations in this setting and contribute to the evidence base supporting the immediate scale-up of ART to address HIV/AIDS-associated morbidity, mortality and viral transmission.

High-intensity cannabis use associated with lower plasma human immunodeficiency virus-1 RNA viral load among recently infected people who use injection drugs.

INTRODUCTION AND AIMS: Cannabis use is common among people who are living with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS). While there is growing pre-clinical evidence of the immunomodulatory and anti-viral effects of cannabinoids, their possible effects on HIV disease parameters in humans are largely unknown. Thus, we sought to investigate the possible effects of cannabis use on plasma HIV-1 RNA viral loads (pVLs) among recently seroconverted illicit drug users. DESIGN AND METHODS: We used data from two linked longitudinal observational cohorts of people who use injection drugs. Using multivariable linear mixed-effects modelling, we analysed the relationship between pVL and high-intensity cannabis use among participants who seroconverted following recruitment. RESULTS: Between May 1996 and March 2012, 88 individuals seroconverted after recruitment and were included in these analyses. Median pVL in the first 365 days among all seroconverters was 4.66 log10 c mL(-1) . In a multivariable model, at least daily cannabis use was associated with 0.51 log10 c mL(-1) lower pVL (ß = -0.51, standard error = 0.170, P value = 0.003). DISCUSSION AND CONCLUSIONS: Consistent with the findings from recent in vitro and in vivo studies, including one conducted among lentiviral-infected primates, we observed a strong association between cannabis use and lower pVL following seroconversion among illicit drug-using participants. Our findings support the further investigation of the immunomodulatory or antiviral effects of cannabinoids among individuals living with HIV/AIDS.

The effect of opportunistic illness on HIV RNA viral load and CD4+ T cell count among HIV-positive adults taking antiretroviral therapy.

INTRODUCTION: HIV RNA viral load (VL) has been shown to increase during opportunistic illnesses (OIs), suggesting active HIV replication in response to infection among patients not taking antiretroviral therapy (ART). We assessed the effects of OIs on HIV RNA VL and CD4+ T cell counts among patients on ART with initially suppressed VL. METHODS: Between 2003 and 2007, we enrolled and followed 1094 HIV-1-infected adults who initiated ART and had quarterly blood draws for VL and CD4+ T cell count. In VL/CD4+ T cell measurement intervals following undetectable VL, we compared the elevation in VL to detectable levels and CD4+ T cell count changes between intervals when participants had episodes of OIs and intervals when they did not have OIs. RESULTS: VL was more likely to be detectable if participants had OIs in the prior three months compared to when they did not (OR=4.0 (95% CI=1.9-8.6)). The CD4+ T cell counts declined 24.1 cells/µL per three months in intervals where the participants had OIs compared to an increase of 21.3 cells/µL per three months in intervals where they did not have OIs (adjusted difference in the rate of CD4+ T cell count change of 61.7 cells/µL per three months (95% CI=13.7-109.7), P value=0.012). The rate of CD4+ T cell count increase was 25.6 cells/µL per three months (95% CI=11.6-39.6) higher for females compared to males (p value=<0.001), 1.4 cells/µL per three months lower per one year increase in age (p value=0.046) and 4 cells/µL per three months lower per 10 cells/µL increase in the starting CD4+ T cell count value (p value=<0.001). CONCLUSION: Episodes of opportunistic infections among patients taking ART with undetectable VL were associated with elevation of HIV RNA VL to detectable levels and decline in CD4+ T cell counts. CLINICAL TRIAL NUMBER: NCT00119093.