Cobas Ampliprep/Cobas TaqMan HIV-1 v2.0 Assay: Consequences at the Cohort Level

Background

High-sensitive real-time PCR assays are routinely used to monitor HIV-1 infected subjects. Inter-assay discrepancies have been described at the low viral load (VL) end, where clinical decisions regarding possible virological rebound are based.

Methods

A retrospective study was performed to analyze frequencies of viral blips after transition to the COBAS Ampliprep/COBAS TaqMan v2.0 HIV-1 assay (Taqman v2.0) in patients with prior undetectable VLs as measured with the Roche Cobas Ampliprep Amplicor HIV-1 Monitor Test, v1.5 (Amplicor) and was evaluated in comparison to a group of patients monitored with the Abbott Real-time HIV-1 assay (Abbott RT) during the same period of time.

Results

85 of 373 patients with VLs below the limit of quantification with Amplicor had VLs >50 copies/mL after transition to the TaqMan v2.0 assay. Among these 74.1% had VLs ranging from 50–499 copies/mL, 22.9% had VLs >500 copies/mL. From 22 patients with initial Taqman v2.0 based VLs exceeding 500 copies/mL, 6 patients had VLs <20 copies/mL after novel VL measurement on a next visit. In our control group with VL quantification using the Abbott RT assay, only 1 patient became detectable and showed a VL of <40 copies/mL after new measurement.

Conclusions

Transition to the Taqman v2.0 assay was accompanied by an increase of quantifiable HIV-1 VLs in patients with long term viral suppression under antiretroviral therapy that might be attributed to technical shortcomings of the Taqman v2.0 assay. A high test variability at the low VL end but also beyond was observed, making meaningful clinical interpretation of viral blips derived from different assays difficult.     

Residual Viremia Is Preceding Viral Blips and Persistent Low-Level Viremia in Treated HIV-1 Patients

Background

It has been suggested that low-level viremia or blips in HIV-infected patients on antiretroviral treatment are related to assay variation and/or increased sensitivity of new commercial assays. The 50-copy cut-off for virologic failure is, therefore, under debate.

Methods

Treated patients with low-level viremia (persistent viral loads (VL) of 50–1000 copies/mL, group A, N = 16) or a blip (single detectable VL, group B, N = 77) were compared to a control group (consistently suppressed viremia since start therapy (<50 copies/mL), N = 79). Residual viremia (detectable viral RNA <50 copies/ml) in the year preceding the first VL above 50 copies/mL (T0) was determined using Roche Cobas-Amplicor v1.5 or CAP-CTM v2.0. Subsequent virologic failure (2 consecutive VLs>500 or 1 VL>1000 copies/mL that was not followed by a VL<50 copies/mL; median follow up 34 months) was assessed.

Results

Significantly more patients in groups A and B had residual viremia in the year preceding T0 compared to controls (50% and 19% vs 3% respectively; p<0.001). Residual viremia was associated with development of low-level viremia or blips (OR 10.9 (95% CI 2.9–40.6)). Subsequent virologic failure was seen more often in group A (3/16) and B (2/77) than in the control group (0/79).

Conclusion

Residual viremia is associated with development of blips and low-level viremia. Virologic failure occurred more often in patients with low-level viremia. These results suggest that low-level viremia results from viral production/replication rather than only assay variation.     

Mode of Delivery among HIV-Infected Pregnant Women in Philadelphia, 2005-2013

Objective

Current guidelines call for HIV-infected women to deliver via scheduled Caesarean when the maternal HIV viral load (VL) is >1,000 copies/ml. We describe the mode of delivery among HIV-infected women and evaluate adherence to relevant recommendations.

Study Design

We performed a population-based surveillance analysis of HIV-infected pregnant women in Philadelphia from 2005 to 2013, comparing mode of delivery (vaginal, scheduled Caesarean, or emergent Caesarean) by VL during pregnancy, closest to the time of delivery (≤1,000 copies/ml versus an unknown VL or VL >1,000 copies/ml) and associated factors in multivariable analysis.

Results

Our cohort included 824 deliveries from 648 HIV-infected women, of whom 69.4% had a VL ≤1,000 copies/ml and 30.6% lacked a VL or had a VL >1,000 copies/ml during pregnancy, closest to the time of delivery. Mode of delivery varied by VL: 56.6% of births were vaginal, 30.1% scheduled Caesarean, and 13.3% emergent Caesarean when the VL was ≤1,000 copies/ml; when the VL was unknown or >1,000 copies/ml, 32.9% of births were vaginal, 49.9% scheduled Caesarean and 17.5% emergent Caesarean. In multivariable analyses, Hispanic women (adjusted odds ratio (AOR) 0.17, 95% Confidence Interval (CI) 0.04–0.76) and non-Hispanic black women (AOR 0.27, 95% CI 0.10–0.77) were less to likely to deliver via scheduled Caesarean compared to non-Hispanic white women. Women who delivered prior to 38 weeks’ gestation (AOR 0.37, 95% CI 0.18–0.76) were also less likely to deliver via scheduled Caesarean compared to women who delivered after 38 weeks’ gestation. An interaction term for race and gestational age at delivery was significant in multivariable analysis. Non-Hispanic black (AOR 0.06, 95% CI 0.01–0.36) and Hispanic women (AOR 0.03, 95% CI 0.00–0.59) were more likely to deliver prematurely and less likely to deliver via scheduled C-section compared to non-Hispanic white women. Having a previous Caesarean (AOR 27.77, 95% CI 8.94–86.18) increased the odds of scheduled Caesarean delivery.

Conclusions

Only half of deliveries for women with an unknown VL or VL >1,000 copies/ml occurred via scheduled Caesarean. Delivery prior to 38 weeks, particularly among minority women, resulted in a missed opportunity to receive a scheduled Caesarean. However, even when delivering at or after 38 weeks’ gestation, a significant proportion of women did not get a scheduled Caesarean when indicated, suggesting a need for focused public health interventions to increase the proportion of women achieving viral suppression during pregnancy and delivering via scheduled Caesarean when indicated.     

Virologic Response to Tipranavir-Ritonavir or Darunavir-Ritonavir Based Regimens in Antiretroviral Therapy Experienced HIV-1 Patients: A Meta-Analysis and Meta-Regression of Randomized Controlled Clinical Trials

Background

The development of tipranavir and darunavir, second generation non-peptidic HIV protease inhibitors, with marked improved resistance profiles, has opened a new perspective on the treatment of antiretroviral therapy (ART) experienced HIV patients with poor viral load control. The aim of this study was to determine the virologic response in ART experienced patients to tipranavir-ritonavir and darunavir-ritonavir based regimens.

Methods and Findings

A computer based literature search was conducted in the databases of HINARI (Health InterNetwork Access to Research Initiative), Medline and Cochrane library. Meta-analysis was performed by including randomized controlled studies that were conducted in ART experienced patients with plasma viral load above 1,000 copies HIV RNA/ml. The odds ratios and 95% confidence intervals (CI) for viral loads of <50 copies and <400 copies HIV RNA/ml at the end of the intervention were determined by the random effects model. Meta-regression, sensitivity analysis and funnel plots were done. The number of HIV-1 patients who were on either a tipranavir-ritonavir or darunavir-ritonavir based regimen and achieved viral load less than 50 copies HIV RNA/ml was significantly higher (overall OR = 3.4; 95% CI, 2.61– 4.52) than the number of HIV-1 patients who were on investigator selected boosted comparator HIV-1 protease inhibitors (CPIs-ritonavir). Similarly, the number of patients with viral load less than 400 copies HIV RNA/ml was significantly higher in either the tipranavir-ritonavir or darunavir-ritonavir based regimen treated group (overall OR = 3.0; 95% CI, 2.15 – 4.11). Meta-regression showed that the viral load reduction was independent of baseline viral load, baseline CD4 count and duration of tipranavir-ritonavir or darunavir-ritonavir based regimen.

Conclusions

Tipranavir and darunavir based regimens were more effective in patients who were ART experienced and had poor viral load control. Further studies are required to determine their consistent viral load suppression effect as the duration of treatment is more prolonged.     

Immuno-Virological Discordance and the Risk of Non-AIDS and AIDS Events in a Large Observational Cohort of HIV-Patients in Europe

Background

The impact of immunosuppression despite virological suppression (immuno-virological discordance, ID) on the risk of developing fatal and non-fatal AIDS/non-AIDS events is unclear and remains to be elucidated.

Methods

Patients in EuroSIDA starting at least 1 new antiretroviral drug with CD4<350 cells/µl and viral load (VL)>500 copies/mL were followed-up from the first day of VL< = 50 copies/ml until a new fatal/non-fatal non-AIDS/AIDS event. Considered non-AIDS events included non-AIDS malignancies, pancreatitis, severe liver disease with hepatic encephalopathy (>grade 3), cardio- and cerebrovascular events, and end-stage renal disease. Patients were classified over time according to whether current CD4 count was above (non-ID) or below (ID) baseline level. Relative rates (RR) of events were calculated for ID vs. non-ID using adjusted Poisson regression models.

Results

2,913 patients contributed 11,491 person-years for the analysis of non-AIDS. 241 pre-specified non-AIDS events (including 84 deaths) and 89 AIDS events (including 10 deaths) occurred. The RR of developing pre-specified non-AIDS events for ID vs. non-ID was 1.96 (95% CI 1.37–2.81, p<0.001) in unadjusted analysis and 1.43 (0.94–2.17, p = 0.095) after controlling for current CD4 count. ID was not associated with the risk of AIDS events (aRR 0.76, 95% CI 0.41–1.38, p = 0.361).

Conclusion

Compared to CD4 responders, patients with immuno-virological discordance may be at increased risk of developing non-AIDS events. Further studies are warranted to establish whether in patients with ID, strategies to directly modify CD4 count response may be needed besides the use of ART.     

Valganciclovir for Cytomegalovirus Prevention in Solid Organ Transplant Patients: An Evidence-Based Reassessment of Safety and Efficacy

Background

Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.

Methods

All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.

Findings

Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I² = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm³) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I² = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I² = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I² = 10%). For a neutropenia cut-off of <1,000/mm³, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I² = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I² = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.

Conclusions

Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.     

A Clinical Prediction Score in Addition to WHO Criteria for Anti-Retroviral Treatment Failure in Resource-Limited Settings - Experience from Lesotho

Objective

To assess the positive predictive value (PPV) of a clinical score for viral failure among patients fulfilling the WHO-criteria for anti-retroviral treatment (ART) failure in rural Lesotho.

Methods

Patients fulfilling clinical and/or immunological WHO failure-criteria were enrolled. The score includes the following predictors: Prior ART exposure (1 point), CD4-count below baseline (1), 25% and 50% drop from peak CD4-count (1 and 2), hemoglobin drop≥1 g/dL (1), CD4 count<100/µl after 12 months (1), new onset papular pruritic eruption (1), and adherence<95% (3). A nurse assessed the score the day blood was drawn for viral load (VL). Reported confidence intervals (CI) were calculated using Wilsons method.

Results

Among 1''131 patients on ART≥6 months, 134 (11.8%) had immunological and/or clinical failure, 104 (78%) had blood drawn (13 died, 10 lost to follow-up, 7 did not show up). From 92 (88%) a result could be obtained (2 samples hemolysed, 10 lost). Out of these 92 patients 47 (51%) had viral failure (≥5000 copies), 27 (29%) viral suppression (<40) and 18 (20%) intermediate viremia (40–4999). Overall, 20 (22%) had a score≥5. A score≥5 had a PPV of 100% to detect a VL>40 copies (95%CI: 84–100), and of 90% to detect a VL≥5000 copies (70–97). Within the score, adherence<95%, CD4-count<100/µl and papular pruritic eruption were the strongest single predictors. Among 47 patients failing, 8 (17%) died before or within 4 weeks after being switched. Overall mortality was 4 (20%) among those with score≥5 and 4 (5%) if score<5 (OR 4.3; 95%CI: 0.96–18.84, p = 0.057).

Conclusion

A score≥5 among patients fulfilling WHO-criteria had a PPV of 100% for a detectable VL and 90% for viral failure. In settings without regular access to VL-testing, this PPV may be considered high enough to switch this patient-group to second-line treatment without confirmatory VL-test.     

Pneumonia and Mortality Risk in Continuous Ambulatory Peritoneal Dialysis Patients with Diabetic Nephropathy

Background

Although clinical experience suggests that patients with diabetes mellitus are more susceptible to several types of infections, the overall scope of pneumonia in continuous ambulatory peritoneal dialysis (CAPD) patients with diabetic nephropathy (DN) has received little attention.

Methods

This was a prospective observational cohort study in CAPD patients in which prognostic risks of pneumonia were evaluated in DN and non-DN patients by Cox regression analysis. Hazard ratios of pneumonia events, all-cause and pneumonia-related mortality were calculated by Kaplan-Meier curves and the Cox proportional hazards model for DN versus non-DN patients.

Results

A total of 1148 patients (58.6% male, 48.34±15.78 years) had a median follow-up of 23.8 months and a maximum follow-up of 72.0 months. The pneumonia incidence rate of 62.3/1,000 patient-years in CAPD patients with DN was significantly higher than that of 28.5/1,000 patient-years in non-DN patients. On multivariate analysis, independent predictors of pneumonia occurrence in CAPD patients with DN were high body mass index (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.01–1.31; P = 0.037) and low serum albumin level (HR, 0.87; 95% CI, 0.78–0.98; P = 0.014). Older age (HR, 1.63; 95% CI, 1.35–1.96; P<0.001) was an independent risk factor for the presence of pneumonia in non-DN patients. CAPD patients with DN had higher pneumonia-related mortality (HR, 4.424; 95% CI, 1.871–10.461; P<0.001) and all-cause mortality (HR, 2.608; 95% CI, 1.890–3.599; P<0.001) hazards than their non-DN counterparts, even when extensive demographics, comorbidities, and lab adjustments were made.

Conclusions

The pneumonia and all-cause mortality risks were strikingly higher in CAPD patients with DN than in non-DN counterparts, which may warrant further investigation and therapeutic care intensification.     

Hepatitis C Viremia Is Associated with Cytomegalovirus IgG Antibody Levels in HIV-Infected Women

Background

Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.

Methods

Associations of HCV with CMV seropositivity and CMV IgG levels were studied in 635 HIV-infected women, 187 of whom were HCV-seropositive, with adjustment in multivariable models for age, race/ethnicity, and HIV disease characteristics. Eighty one percent of the women reported receipt of highly active antiretroviral therapy (HAART) prior to or at CMV testing.

Results

In adjusted models women with chronic HCV had higher CMV IgG levels than those without HCV RNA (β = 2.86, 95% CI:0.89 – 4.83; P = 0.004). The association of HCV RNA with CMV IgG differed by age (P _interaction = 0.0007), with a strong association observed among women in the low and middle age tertiles (≤45.3 years of age; β = 6.21, 95% CI:3.30 – 9.11, P<0.0001) but not among women in the high age tertile. CMV IgG levels were not associated with non-invasive measures of liver disease, APRI and FIB-4, or with HCV RNA level and adjustment for Epstein-Barr virus (EBV) IgG levels did not affect the association between HCV and CMV.

Conclusions

CMV IgG levels are higher in HCV/HIV co-infected women than in HIV mono-infected women. Further research on the association of HCV with CMV IgG is indicated because prior studies have found CMV IgG to be associated with morbidity and mortality in the general population and subclinical carotid artery disease in HIV-infected patients.     

Fluctuation of Serum Sodium and Its Impact on Short and Long-Term Mortality following Acute Pulmonary Embolism

Background

Baseline hyponatremia predicts acute mortality following pulmonary embolism (PE). The natural history of serum sodium levels after PE and the relevance to acute and long-term mortality after the PE is unknown.

Methods

Clinical details of all patients (n = 1023) admitted to a tertiary institution from 2000–2007 with acute PE were retrieved retrospectively. Serum sodium results from days 1, 3–4, 5–6, and 7 of admission were pre-specified and recorded. We excluded 250 patients without day-1 sodium or had <1 subsequent sodium assessment, leaving 773 patients as the studied cohort. There were 605 patients with normonatremia (sodium≥135 mmol/L throughout admission), 57 with corrected hyponatremia (day-1 sodium<135 mmol/L, then normalized), 54 with acquired hyponatremia and 57 with persistent hyponatremia. Patients’ outcomes were tracked from a state-wide death registry and analyses performed using multivariate-regression modelling.

Results

Mean (±standard deviation) day-1 sodium was 138.2±4.3 mmol/L. Total mortality (mean follow-up 3.6±2.5 years) was 38.8% (in-hospital mortality 3.2%). There was no survival difference between studied (n = 773) and excluded (n = 250) patients. Day-1 sodium (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.83–0.95, p = 0.001) predicted in-hospital death. Relative to normonatremia, corrected hyponatremia increased the risk of in-hospital death 3.6-fold (95% CI 1.20–10.9, p = 0.02) and persistent hyponatremia increased the risk 5.6-fold (95% CI 2.08–15.0, p = 0.001). Patients with either persisting or acquired hyponatremia had worse long-term survival than those who had corrected hyponatremia or had been normonatremic throughout (aHR 1.47, 95% CI 1.06–2.03, p = 0.02).

Conclusion

Sodium fluctuations after acute PE predict acute and long-term outcome. Factors mediating the correction of hyponatremia following acute PE warrant further investigation.     

Mortality Trends Observed in Population-Based Surveillance of an Urban Slum Settlement,Kibera, Kenya, 2007–2010

Background

We used population based infectious disease surveillance to characterize mortality rates in residents of an urban slum in Kenya.

Methods

We analyzed biweekly household visit data collected two weeks before death for 749 cases who died during January 1, 2007 to December 31, 2010. We also selected controls matched by age, gender and having a biweekly household visit within two weeks before death of the corresponding case and compared the symptoms reported.

Results

The overall mortality rate was 6.3 per 1,000 person years of observation (PYO) (females: 5.7; males: 6.8). Infant mortality rate was 50.2 per 1000 PYOs, and it was 15.1 per 1,000 PYOs for children <5 years old. Poisson regression indicates a significant decrease over time in overall mortality from (6.0 in 2007 to 4.0 in 2010 per 1000 PYOs; p<0.05) in persons ≥5 years old. This decrease was predominant in females (7.8 to 5.7 per 1000 PYOs; p<0.05). Two weeks before death, significantly higher prevalence for cough (OR = 4.7 [95% CI: 3.7–5.9]), fever (OR = 8.1 [95% CI: 6.1–10.7]), and diarrhea (OR = 9.1 [95% CI: 6.4–13.2]) were reported among participants who died (cases) when compared to participants who did not die (controls). Diarrhea followed by fever were independently associated with deaths (OR = 14.4 [95% CI: 7.1–29.2]), and (OR = 11.4 [95% CI: 6.7–19.4]) respectively.

Conclusions

Despite accessible health care, mortality rates are high among people living in this urban slum; infectious disease syndromes appear to be linked to a substantial proportion of deaths. Rapid urbanization poses an increasing challenge in national efforts to improve health outcomes, including reducing childhood mortality rates. Targeting impoverished people in urban slums with effective interventions such as water and sanitation interventions are needed to achieve national objectives for health.     

Mortality among Methadone Maintenance Clients in China: A Six-Year Cohort Study

Objective

To assess the overall mortality of methadone maintenance treatment (MMT) clients in China and its associated factors.

Methods

A total of 1,511 MMT clients, all of whom enrolled in China''s first eight MMT clinics between March and December 2004, were included in this cohort study and followed for approximately six years, until June 2010. Mortality and its predictors were examined using Cox proportional hazards regression models.

Results

A total of 154 deaths were observed within 5,391 person-years (PY) of follow-up for an all-cause mortality rate of 28.6 per 1,000 PY. The leading causes of death were drug overdose (33.8%), HIV/AIDS-unrelated disease (21.4%), and HIV/AIDS (16.9%). The all-cause mortality rate of clients engaged in MMT for one year or less was roughly three times that of clients who stayed in MMT for four years or more (14.0 vs. 4.6, p<0.0001), HIV-positive subjects was nearly four times mortality rate than that of HIV-negative individuals (28.1 vs.6.8, p<0.0001). ART-naive HIV-positive subjects had approximately two times higher mortality rate than those receiving ART (31.2 vs. 17.3, <0.0001). After adjusting for confounding variables, we found that being male (HR = 1.63, CI: 1.03–2.57, p = 0.0355) and being HIV-positive (HR = 5.16, CI: 3.70–7.10, p<0.0001) were both associated with higher risk of death whereas increased durations of methadone treatment were associated with a lower risk of death (HR = 0.26, CI: 0.18–0.38, p<0.0001 for two to three years, HR = 0.08, CI: 0.05–0.14, p<0.0001 for four or more years).

Conclusion

Overall mortality was high among MMT clients in China. Specific interventions aimed at decreasing mortality among MMT clients are needed. Our study supports the need for keeping client at MMT longer and for expanding ART coverage and suggests the potential benefits of integrated MMT and ART services for drug users in China.     

Frequency of HIV-1 viral load monitoring of patients initially successfully treated with combination antiretroviral therapy

Background

Although considered an essential tool for monitoring the effect of combination antiretroviral treatment (CART), HIV-1 RNA (viral load, VL) testing is greatly influenced by cost and availability of resources.

Objectives

To examine whether HIV infected patients who were initially successfully treated with CART have less frequent monitoring of VL over time and whether CART failure and other HIV-disease and sociodemographic characteristics are associated with less frequent VL testing.

Methods

The study included patients who started CART in the period 1999–2004, were older than 18 years, CART naive, had two consecutive viral load measurements of <400 copies/ml after 5 months of treatment and had continuous CART during the first 15 months. The time between two consecutive visits (days) was the outcome and associated factors were assessed using linear mixed models.

Results

We analyzed a total of 128 patients with 1683 visits through December 2009. CART failure was observed in 31 (24%) patients. When adjusted for the follow-up time, the mean interval between two consecutive VL tests taken in patients before CART failure (155.2 days) was almost identical to the interval taken in patients who did not fail CART (155.3 days). On multivariable analysis, we found that the adjusted estimated time between visits was 150.9 days before 2003 and 177.6 in 2008/2009. A longer time between visits was observed in seafarers compared to non-seafarers; the mean difference was 30.7 days (95% CI, 14.0 to 47.4; p<0.001); and in individuals who lived more than 160 kilometers from the HIV treatment center (mean difference, 16 days, p = 0.010).

Conclusions

Less frequent monitoring of VL became common in recent years and was not associated with failure. We identified seafarers as a population with special needs for CART monitoring and delivery.     

Predictors of Raised Viral Load during Antiretroviral Therapy in Patients with and without Prior Antiretroviral Use: A Cross-Sectional Study

Objectives

In Lagos, Nigeria, Médecins Sans Frontières (MSF) and the Ministry of Health (MoH) commenced free antiretroviral treatment (ART) in a hospital-based clinic. We performed a cross-sectional study to compare factors associated with raised viral load between patients with (“experienced”) and without (“naïve”) prior antiretroviral (ARV) exposure at commencement of ART at the clinic. We also examined factors influencing ARV adherence in experienced patients prior to clinic entry.

Methods

We included adult patients receiving ART from MSF who answered a questionnaire about previous antiretroviral use. Multivariate logistic regression was used to estimate odds ratios (OR) for raised viral load (≥1000 copies/mL).

Results

1246 (96%) patients answered: 1075 (86%) reported no, and 171 (14%) some, prior ARV exposure. ARV-naïve patients were more immunosuppressed at baseline: 65% vs 37% (p<0.001) had CD4<200; 17% vs 9% (p = 0.013) were WHO stage 4. Proportionately more experienced than naïve patients had raised viral loads (20% vs 9%, p<0.001) on ART in the MSF/MoH clinic. Raised viral load was associated with prior ARV experience (adjusted OR = 3.74, 95%CI 2.09–6.70, p<0.001) and complete interruption of current ART (adjusted OR = 3.71, 95%CI 2.06–6.68, p<0.001). Higher CD4 at time of VL and a higher self-rated score of recent adherence were associated with lower OR of a raised viral load. Among experienced patients who missed pills before joining MSF/MoH, most common reasons were because ARVS were not affordable (58%) or available (33%), with raised viral load associated with being unsure how to take them (OR = 3.16, 95%CI 1.10–9.12, p = 0.033).

Conclusions

Patients previously exposed to ARVs had increased OR of raised viral load. The cost and availability of ARVs were common reasons for missing ARVs before joining the MSF/MoH clinic, and inadequate patient knowledge was associated with raised viral load.     

Visceral Leishmaniasis Relapse in Southern Sudan (1999–2007): A Retrospective Study of Risk Factors and Trends

Background

Risk factors associated with L. donovani visceral leishmaniasis (VL; kala azar) relapse are poorly characterized.

Methods

We investigated patient characteristics and drug regimens associated with VL relapse using data from Médecins Sans Frontières - Holland (MSF) treatment centres in Southern Sudan. We used MSF operational data to investigate trends in VL relapse and associated risk factors.

Results

We obtained data for 8,800 primary VL and 621 relapse VL patients treated between 1999 and 2007. Records of previous treatment for 166 VL relapse patients (26.7%) were compared with 7,924 primary VL patients who had no record of subsequent relapse. Primary VL patients who relapsed had larger spleens on admission (Hackett grade ≥3 vs0, odds ratio (OR) for relapse = 3.62 (95% CI 1.08, 12.12)) and on discharge (Hackett grade ≥3 vs 0, OR = 5.50 (1.84, 16.49)). Age, sex, malnutrition, mobility, and complications of treatment were not associated with risk of relapse, nor was there any trend over time. Treatment with 17-day sodium stibogluconate/paromomycin (SSG/PM) combination therapy vs 30-day SSG monotherapy was associated with increased risk of relapse (OR = 2.08 (1.21, 3.58)) but reduced risk of death (OR = 0.27 (0.20, 0.37)), although these estimates are likely to be residually confounded. MSF operational data showed a crude upward trend in the proportion of VL relapse patients (annual percentage change (APC) = 11.4% (−3.4%, 28.5%)) and a downward trend in deaths (APC = −18.1% (−22.5%, −13.4%)).

Conclusions

Splenomegaly and 17-day SSG/PM vs 30-day SSG were associated with increased risk of VL relapse. The crude upward trend in VL relapses in Southern Sudan may be attributable to improved access to treatment and reduced mortality due to SSG/PM combination therapy.     

Effect of Genital Herpes on Cervicovaginal HIV Shedding in Women Co-Infected with HIV AND HSV-2 in Tanzania

Objectives

To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.

Design

Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.

Results

Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions (geometric means 1634 vs 3339 copies/ml, p = 0.03). In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (log₁₀ copies/mL) was closely associated with HIV PVL (β = 0.51 per log₁₀ copies/ml increase, 95%CI:0.41–0.60, p<0.001) and HSV shedding (β = 0.24 per log₁₀ copies/ml increase, 95% CI:0.16–0.32, p<0.001) but not the presence of herpetic lesions (β = −0.10, 95%CI:−0.28–0.08, p = 0.27).

Conclusions

HIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility.     

Levels of C-Reactive Protein Associated with High and Very High Cardiovascular Risk Are Prevalent in Patients with Rheumatoid Arthritis

Objective

C-reactive protein (CRP) levels>3 mg/L and>10 mg/L are associated with high and very high cardiovascular risk, respectively, in the general population. Because rheumatoid arthritis (RA) confers excess cardiovascular mortality, we determined the prevalence of these CRP levels among RA patients stratified on the basis of their RA disease activity.

Methods

We evaluated physician and patient global assessments of disease activity, tender and swollen 28 joint counts, erythrocyte sedimentation rate (ESR), and CRP measured in a single clinic visit for 151 RA patients. Disease activity was calculated using the Clinical Disease Activity Index (CDAI) and the Disease Activity Score 28 Joints (DAS28-ESR and DAS28-CRP).

Results

Median CRP level was 5.3 mg/L. 68% of patients had CRP>3 mg/L, and 25% had CRP>10 mg/L. Of those with 0–1 swollen joints (n = 56), or 0–1 tender joints (n = 81), 64% and 67%, respectively, had CRP>3 mg/L, and 23% and 20%, respectively, had CRP>10 mg/L. Of those with remission or mildly active disease by CDAI (n = 58), DAS28-ESR (n = 39), or DAS28-CRP (n = 70), 49–66% had CRP>3 mg/L, and 10–14% had CRP>10 mg/L. Of patients with moderate disease activity by CDAI (n = 51), DAS28-ESR (n = 78), or DAS28-CRP (n = 66), 67–73% had CRP>3 mg/L, and 25–33% had CRP>10 mg/L.

Conclusion

Even among RA patients whose disease is judged to be controlled by joint counts or standardized disease scores, a substantial proportion have CRP levels that are associated high or very high risk for future cardiovascular events in the general population.     

Long-Term Survival in HIV Positive Patients with up to 15 Years of Antiretroviral Therapy

Background

Life expectancy has increased for newly diagnosed HIV patients since the inception of combination antiretroviral treatment (cART), but there remains a need to better understand the characteristics of long-term survival in HIV-positive patients. We examined long-term survival in HIV-positive patients receiving cART in the Australian HIV Observational Database (AHOD), to describe changes in mortality compared to the general population and to develop longer-term survival models.

Methods

Data were examined from 2,675 HIV-positive participants in AHOD who started cART. Standardised mortality ratios (SMR) were calculated by age, sex and calendar year across prognostic characteristics using Australian Bureau of Statistics national data as reference. SMRs were examined by years of duration of cART by CD4 and similarly by viral load. Survival was analysed using Cox-proportional hazards and parametric survival models.

Results

The overall SMR for all-cause mortality was 3.5 (95% CI: 3.0–4.0). SMRs by CD4 count were 8.6 (95% CI: 7.2–10.2) for CD4<350 cells/µl; 2.1 (95% CI: 1.5–2.9) for CD4 = 350–499 cells/µl; and 1.5 (95% CI: 1.1–2.0) for CD4≥500 cells/µl. SMRs for patients with CD4 counts <350 cells/µL were much higher than for patients with higher CD4 counts across all durations of cART. SMRs for patients with viral loads greater than 400 copies/ml were much higher across all durations of cART. Multivariate models demonstrated improved survival associated with increased recent CD4, reduced recent viral load, younger patients, absence of HBVsAg-positive ever, year of HIV diagnosis and incidence of ADI. Parametric models showed a fairly constant mortality risk by year of cART up to 15 years of treatment.

Conclusion

Observed mortality remained fairly constant by duration of cART and was modelled accurately by accepted prognostic factors. These rates did not vary much by duration of treatment. Changes in mortality with age were similar to those in the Australian general population.     

Low Serum 25-Hydroxyvitamin D Concentrations Are Associated with Increased Risk for Melanoma and Unfavourable Prognosis

Background

Low vitamin D status (serum 25(OH)D concentration) is associated with increased incidence and unfavourable outcome of various types of cancer. However, there are limited data on influence of serum 25(OH)D on risk and prognosis of malignant melanoma.

Methods

Basal serum 25(OH)D concentrations were retrospectively analyzed in a cohort of melanoma patients (n = 324) and healthy controls (n = 141). We tested the hypothesis that serum 25(OH)D concentrations are predictive of melanoma risk, thickness of primary melanomas, and overall survival (OS).

Results

Median serum 25(OH)D concentrations were significantly lower (p = 0.004) in melanoma patients (median = 13.6 ng/ml) as compared to controls (median = 15.6 ng/ml). Primary tumors of patients with low serum 25(OH)D concentrations (<10 ng/ml) had significantly (p = 0.006) greater Breslow thickness (median: 1.9 mm) as compared to patients with higher levels (>20 ng/ml; median: 1.00 mm). Patients with 25(OH)D serum concentrations in the lowest quartile had inferior overall survival (median: 80 months) comparing with the highest quartile (median: 195 months; p = 0.049).

Conclusions

Our data support the concept that serum 25(OH)D concentrations are associated with risk and prognosis of melanoma. Whether normalizing serum 25(OH)D concentrations in these patients improves outcomes will require testing in future clinical trials.