Michael J. Vinikoor

Antiretroviral therapy initiated during acute HIV infection fails to prevent persistent T-cell activation.

Abstract:Initiation of antiretroviral therapy during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T-cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful antiretroviral therapy, and maintained viral suppression through 96 weeks. Pretherapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and although this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, P = 0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction.

Impact of Baseline Renal Function on Tenofovir-containing Antiretroviral Therapy Outcomes in Zambia

BACKGROUND Although tenofovir disoproxil fumarate (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. METHODS We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (estimated glomerular filtration rate [eGFR], 60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) according to the chronic kidney disease-epidemiology (CKD-EPI) formula. Differences in eGFR during ART were analyzed using linear mixed-effect models. The odds of developing moderate or severe eGFR decrease and mortality were assessed using logistic and competing risk regression, respectively. RESULTS We included 62 230 adults, of which 38 716 (62.2%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF than in the non-TDF group (1.9% vs 4.0%). Among patients with no or mild renal dysfunction, those receiving TDF were more likely to develop moderate (adjusted odds ratio, 3.11; 95% confidence interval, 2.52-3.87) or severe (2.43; 1.80-3.28) eGFR decrease, although the incidence in such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen, and mortality rates were similar in both treatment groups. CONCLUSIONS TDF use did not attenuate renal function recovery or increase the mortality rate in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

Effect of Baseline Renal Function on Tenofovir-Containing Antiretroviral Therapy Outcomes in Zambia

BACKGROUND Although tenofovir disoproxil fumarate (TDF) use has increased as part of first-line antiretroviral therapy (ART) across sub-Saharan Africa, renal outcomes among patients receiving TDF remain poorly understood. We assessed changes in renal function and mortality in patients starting TDF- or non-TDF-containing ART in Lusaka, Zambia. METHODS We included patients aged ≥16 years who started ART from 2007 onward, with documented baseline weight and serum creatinine. Renal dysfunction was categorized as mild (estimated glomerular filtration rate [eGFR], 60-89 mL/min), moderate (30-59 mL/min), or severe (<30 mL/min) according to the chronic kidney disease-epidemiology (CKD-EPI) formula. Differences in eGFR during ART were analyzed using linear mixed-effect models. The odds of developing moderate or severe eGFR decrease and mortality were assessed using logistic and competing risk regression, respectively. RESULTS We included 62 230 adults, of which 38 716 (62.2%) initiated a TDF-based regimen. The proportion with moderate or severe renal dysfunction at baseline was lower in the TDF than in the non-TDF group (1.9% vs 4.0%). Among patients with no or mild renal dysfunction, those receiving TDF were more likely to develop moderate (adjusted odds ratio, 3.11; 95% confidence interval, 2.52-3.87) or severe (2.43; 1.80-3.28) eGFR decrease, although the incidence in such episodes was low. Among patients with moderate or severe renal dysfunction at baseline, renal function improved independently of ART regimen, and mortality rates were similar in both treatment groups. CONCLUSIONS TDF use did not attenuate renal function recovery or increase the mortality rate in patients with renal dysfunction. Further studies are needed to determine the role of routine renal function monitoring before and during ART use in Africa.

Hepatitis B Infection, Viral Load and Resistance in HIV-Infected Patients in Mozambique and Zambia

Background Few data on the virological determinants of hepatitis B virus (HBV) infection are available from southern Africa. Methods We enrolled consecutive HIV-infected adult patients initiating antiretroviral therapy (ART) at two urban clinics in Zambia and four rural clinics in Northern Mozambique between May 2013 and August 2014. HBsAg screening was performed using the Determine® rapid test. Quantitative real-time PCR and HBV sequencing were performed in HBsAg-positive patients. Risk factors for HBV infection were evaluated using Chi-square and Mann-Whitney tests and associations between baseline characteristics and high level HBV replication explored in multivariable logistic regression. Results Seventy-eight of 1,032 participants in Mozambique (7.6%, 95% confidence interval [CI]: 6.1–9.3) and 90 of 797 in Zambia (11.3%, 95% CI: 9.3–13.4) were HBsAg-positive. HBsAg-positive individuals were less likely to be female compared to HBsAg-negative ones (52.3% vs. 66.1%, p<0.001). Among 156 (92.9%) HBsAg-positive patients with an available measurement, median HBV viral load was 13,645 IU/mL (interquartile range: 192–8,617,488 IU/mL) and 77 (49.4%) had high values (>20,000 UI/mL). HBsAg-positive individuals had higher levels of ALT and AST compared to HBsAg-negative ones (both p<0.001). In multivariable analyses, male sex (adjusted odds ratio: 2.59, 95% CI: 1.22–5.53) and CD4 cell count below 200/μl (2.58, 1.20–5.54) were associated with high HBV DNA. HBV genotypes A1 (58.8%) and E (38.2%) were most prevalent. Four patients had probable resistance to lamivudine and/or entecavir. Conclusion One half of HBsAg-positive patients demonstrated high HBV viremia, supporting the early initiation of tenofovir-containing ART in HIV/HBV-coinfected adults.

Hepatitis B viral load in dried blood spots: A validation study in Zambia

BACKGROUND Access to hepatitis B viral load (VL) testing is poor in sub-Saharan Africa (SSA) due to economic and logistical reasons. OBJECTIVES To demonstrate the feasibility of testing dried blood spots (DBS) for hepatitis B virus (HBV) VL in a laboratory in Lusaka, Zambia, and to compare HBV VLs between DBS and plasma samples. STUDY DESIGN Paired plasma and DBS samples from HIV-HBV co-infected Zambian adults were analyzed for HBV VL using the COBAS AmpliPrep/COBAS TaqMan HBV test (Version 2.0) and for HBV genotype by direct sequencing. We used Bland-Altman analysis to compare VLs between sample types and by genotype. Logistic regression analysis was conducted to assess the probability of an undetectable DBS result by plasma VL. RESULTS Among 68 participants, median age was 34 years, 61.8% were men, and median plasma HBV VL was 3.98logIU/ml (interquartile range, 2.04-5.95). Among sequenced viruses, 28 were genotype A1 and 27 were genotype E. Bland-Altman plots suggested strong agreement between DBS and plasma VLs. DBS VLs were on average 1.59logIU/ml lower than plasma with 95% limits of agreement of -2.40 to -0.83log IU/ml. At a plasma VL ≥2,000IU/ml, the probability of an undetectable DBS result was 1.8% (95% CI: 0.5-6.6). At plasma VL ≥20,000IU/ml this probability reduced to 0.2% (95% CI: 0.03-1.7). CONCLUSIONS In a Zambian laboratory, we observed strong agreement between DBS and plasma VLs and high sensitivity in DBS at plasma VL ≥2,000IU/ml. As HBV treatment expands, DBS could increase access to HBV VL testing and care in SSA settings.

Elevated AST‐to‐platelet ratio index is associated with increased all‐cause mortality among HIV‐infected adults in Zambia

We investigated the association between significant liver fibrosis, determined by AST‐to‐platelet ratio index (APRI), and all‐cause mortality among HIV‐infected patients prescribed antiretroviral therapy (ART) in Zambia.

Implementation of routine screening for chronic hepatitis B virus co-infection by HIV clinics in Lusaka, Zambia.

Dear Editor, In sub-Saharan Africa (SSA), approximately 3 million HIV-infected individuals have chronic hepatitis B virus (HBV) co-infection [1]. HIV–HBV-co-infected patients experience increased mortality, reduced immune recovery and increased risk of hepatotoxicity during antiretroviral therapy (ART) compared to those with HIV alone [2–4]. The World Health Organization (WHO) recommends HBV screening with a hepatitis B surface antigen (HBsAg) test for all HIV-infected individuals at the time of linkage to care and/or prior to ART initiation [5]. According to these guidelines, HIV–HBV patients with advanced liver disease should initiate ART regardless of CD4+ count. Despite its recommendation by the majority of national ART guidelines, HBV screening has not been widely implemented in most ART programmes in SSA; as a result, the epidemiology and outcomes of HIV–HBV co-infection remain poorly characterized in the region. In 2010, the Zambian Ministry of Health (MOH) [6] HIV treatment policy shifted from targeted HBsAg testing to routine baseline testing at enrolment. HBsAg-positive patients with ALT > 2.5 times normal were ART eligible regardless of CD4+ count and WHO stage. In this report, we describe HBV screening and initial treatment practices among public sector HIV clinics in Zambias capital city Lusaka during 2008–2012. In each calendar quarter (Q), we determined the proportion of newly enrolled patients who received an HBsAg test at baseline (defined as within 6 months of enrolment and prior to ART initiation) or during follow-up and compared these proportions over time using a Jonckheere–Terpstra test for trend. In the period after dissemination of the 2010 guidelines, using multivariable logistic regression, we identified factors associated with baseline testing including age, sex, WHO clinical stage, ALT, CD4+ count and facility volume, which we defined as the number of new patient enrolments per year. We also modelled patient demographic and clinical correlates of HBsAg positivity. We used Stata version 12 (Statacorp, College Station, TX, USA) for analysis. The ethics committees of the University of Zambia (Lusaka, Zambia) and the University of North Carolina at Chapel Hill (North Carolina, USA) approved the study. From 1 January 2008 to 31 December 2012, 60 060 HIV-infected patients enrolled across 15 treatment facilities in Lusaka district. There was a rapid and substantial increase in HBsAg testing following dissemination of the MOHs 2010 HIV treatment guidelines (Fig. 1). The overall percentage of patients tested increased from 1.0% in Q1 of 2008 to 46.8% in Q4 of 2012 (P for trend < 0.001). During this time, the percentage of HBsAg tests that occurred at baseline increased from 16.1% to 99.7% (P for trend < 0.001). Fig. 1 Rapid increase in the percent of HIV-infected individuals screened for hepatitis B surface antigen in Lusaka district following release of the Zambian Ministry of Health 2010 HIV guidelines. At the facility level, there was a wide variation in HBsAg testing in the 24 months following the guideline change, with only six of 15 facilities increasing testing rates (Fig. 1). Among the six facilities that increased baseline testing, by Q4 of 2012, nearly 80% of newly enrolled patients were HBsAg tested. The nine sites that did not increase HBsAg testing had similar patient volumes to those in the sites that increased testing. Among facilities that increased testing, during 2011–2012, adults [16+ years old; adjusted odds ratio (AOR) 6.09; 95% confidence interval (CI), 4.55–8.14] and males (AOR 1.13; 95% CI, 1.02–1.25) were more likely to be HBsAg tested, whereas patients with tuberculosis (AOR 0.60; 95% CI, 0.49–0.72) and/or WHO stage 3 or 4 (AOR 0.87; CI, 0.78–0.97) had reduced odds of testing. The percentage of positive HBsAg tests decreased (16.4% in 2008–2010 vs 11.8% in 2011–2012, P 40 U/L (AOR 2.35; 95% CI, 1.87–2.96) and CD4+ count <200 cells/mm3 (AOR 1.45; 95% CI, 1.18–1.78). HIV–HBV patients were more likely to be ART eligible (85.7% vs 72.4%, P < 0.001) and to initiate ART (76.0% vs 66.4%, P < 0.001) compared to those with HIV alone. Among HIV–HBV patients, only 5 (0.9%) became ART eligible on the basis of a positive HBsAg test and grade 2 or more ALT elevation. Regardless of HBV status, the majority of patients were prescribed a regimen containing two HBV-active drugs (92.0% in HIV alone vs 90.4% in HIV–HBV). This report highlights the importance of health policy dissemination and its monitoring in HIV treatment programmes in settings such as ours. In one of the first reports of public sector HBV screening in Africa, we observed rapid but variable increases in HBsAg testing across clinics in Lusaka following the MOHs revised testing policy. Among HBsAg-positive patients, approximately 10% did not receive recommended tenofovir disoproxil fumarate (TDF)-containing regimens. Implementation of routine HBV testing was associated with a reduction in the proportion of positive HBsAg tests because those tested prior to 2011 were a selected group that were likely sicker than other patients. HBsAg positivity in 2011–2012 (11.8%) is likely a good estimate of HBV co-infection prevalence in the programme and is similar to the 9.9% reported in one prior Zambian study [7] and 4.8–19.7% reported in South African studies [8,9]. In our programme, adult males were most likely to be screened; however, additional information is needed to identify groups that may lag behind in access to HBsAg testing. HBsAg testing at baseline did not substantially affect the decision to initiate ART as most HIV–HBV patients were ART eligible prior to HBsAg testing. In our programme, very few HIV–HBV patients with WHO stage 1 or 2 and high CD4+ counts had grade 2 ALT elevation. However, ALT is a poor surrogate for true liver disease, and better tests for liver disease staging are needed to fully understand the proportion of HIV–HBV patients who need ART. Regardless of HBsAg result, 90% of those on ART initiated a TDF-containing regimen, as TDF was a component of the preferred first-line ART regimen during the period of our analysis. In settings where TDF is not a predominant first-line drug, knowledge of HBsAg status would have a larger impact on ART regimen selection. In summary, monitoring the implementation of HBsAg testing is an important programme component that can optimize the care of HIV–HBV patients. New strategies in dissemination and implementation are critically needed, if we are to maximize the effectiveness of health programmes and close the gap between policy and practice.

Validation of Medicaid Claims-based Diagnosis of Myocardial Infarction Using an Hiv Clinical Cohort

Background:In nonexperimental comparative effectiveness research using health care databases, outcome measurements must be validated to evaluate and potentially adjust for misclassification bias. We aimed to validate claims-based myocardial infarction (MI) algorithms in a Medicaid population using an HIV clinical cohort as the gold standard. Methods:Medicaid administrative data were obtained for the years 2002–2008 and linked to the UNC CFAR HIV Clinical Cohort based on social security number, first name, and last name and MI were adjudicated. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. Results:There were 1063 individuals included in the study. Over a median observed time of 2.5 years, 17 had an MI. Specificity ranged from 0.979 to 0.993 with the highest specificity obtained using the ICD-9 code 410.xx in the primary or secondary position and a length of stay >3 days. Sensitivity of MI ascertainment varied from 0.588 to 0.824 depending on algorithm. Conclusions:Specificities of varying claims-based MI ascertainment criteria are high but small changes impact positive predictive value in a cohort with low incidence. Sensitivities vary based on ascertainment criteria. Type of algorithm used should be prioritized based on study question and maximization of specific validation parameters that will minimize bias while also considering precision.

Do all candidemic patients need an ophthalmic examination

Intraocular candidiasis is a potentially sight-threatening complication of candidemia. While the incidence of candidemia in North America has increased, the prevalence of intraocular candidiasis appears to be decreasing. In the USA and Europe, an ophthalmic examination is recommended for all candidemic patients to rule out intraocular involvement. However, improvements in management, clarification of the diagnosis, and trends in the epidemiology of intraocular candidiasis suggest that some candidemia patients might be safely managed without the recommended dilated ophthalmic examination.

Pediatric HIV-HBV Coinfection in Lusaka, Zambia: Prevalence and Short-Term Treatment Outcomes.

Hepatitis B virus (HBV) is endemic in Africa, where it may occur as an HIV coinfection. Data remain limited on HIV-HBV epidemiology in Africa, particularly in children. Using programmatic data from pediatric HIV clinics in Lusaka, Zambia during 2011-2014, we analyzed the prevalence of chronic HBV coinfection (defined as a single positive hepatitis B surface antigen [HBsAg] test) and its impact on immune recovery and liver enzyme elevation (LEE) during the first year of antiretroviral therapy. Among 411 children and adolescents, 10.4% (95% confidence interval, 7.6-14.1) had HIV-HBV. Coinfected patients were more likely to have World Health Organization stage 3/4, LEE and CD4 <14% at care entry (all p < 0.05). During treatment, CD4 increases and LEE incidence were similar by HBsAg status. HBsAg positivity decreased (11.8% vs. 6.6%; p = 0.24) following HBV vaccine introduction. These findings support screening pediatric HIV patients in Africa for HBV coinfection. Dedicated cohorts are needed to assess long-term outcomes of coinfection.