CD4 Cell Count Trends after Commencement of Antiretroviral Therapy among HIV-Infected Patients in Tigray,Northern Ethiopia: A Retrospective Cross-Sectional Study

Background

The rate and extent of CD4 cell recovery varies widely among HIV-infected patients with different baseline CD4 cell count strata. The objective of the study was to assess trends in CD4 cell counts in HIV-infected patients after initiation of antiretroviral therapy in Tigray, Northern Ethiopia.

Methods

A retrospective cross-sectional study was conducted by reviewing medical records of HIV patients who received antiretroviral treatment at twenty health centers in Tigray region during 2008–2012. Multi-stage cluster sampling technique was employed to collect data, and the data were analyzed using SPSS version 20.0 software.

Results

The median change from baseline to the most recent CD4 cell count was +292 cells/μl. By 5 years, the overall median (inter-quartile range, IQR) CD4 cell count was 444(263-557) cells/μl while the median (IQR) CD4 cell count was 342(246-580) cells/μl among patients with baseline CD4 cell counts ≤200 cells/μl, 500(241-557) cells/μl among those with baseline CD4 cell counts of 201–350 cells/μl, and 652(537-767) cells/μl among those with baseline CD4 cell counts >350 cells/μl. Higher baseline CD4 cell counts and being male were independently associated with the risk of immunological non-response at 12 months. Furthermore, it was also investigated that these factors were significant predictors of subsequent CD4 cell recovery.

Conclusions

Patients with higher baseline CD4 cell stratum returned to normal CD4 Cell counts though they had an increased risk of immunological non-response at 12 months compared to those with the least baseline CD4 cell stratum. The findings suggest that consideration be given to initiation of HAART at a CD4 cell count >350 cells/μl to achieve better immune recovery, and to HIV-infected male patients to improve their health seeking behavior.     

Hierarchy Low CD4+/CD8+ T-Cell Counts and IFN-γ Responses in HIV-1+ Individuals Correlate with Active TB and/or M.tb Co-Infection

Objective

Detailed studies of correlation between HIV-M.tb co-infection and hierarchy declines of CD8+/CD4+ T-cell counts and IFN-γ responses have not been done. We conducted case-control studies to address this issue.

Methods

164 HIV-1-infected individuals comprised of HIV-1⁺ATB, HIV-1⁺LTB and HIV-1⁺TB^- groups were evaluated. Immune phenotyping and complete blood count (CBC) were employed to measure CD4+ and CD8+ T-cell counts; T.SPOT.TB and intracellular cytokine staining (ICS) were utilized to detect ESAT6, CFP10 or PPD-specific IFN-γ responses.

Results

There were significant differences in median CD4+ T-cell counts between HIV-1⁺ATB (164/μL), HIV-1⁺LTB (447/μL) and HIV-1⁺TB^- (329/μL) groups. Hierarchy low CD4+ T-cell counts (<200/μL, 200-500/μL, >500/μL) were correlated significantly with active TB but not M.tb co-infection. Interestingly, hierarchy low CD8+ T-cell counts were not only associated significantly with active TB but also with M.tb co-infection (P<0.001). Immunologically, HIV-1⁺ATB group showed significantly lower numbers of ESAT-6-/CFP-10-specific IFN-γ+ T cells than HIV-1⁺LTB group. Consistently, PPD-specific IFN-γ+CD4+/CD8+ T effector cells in HIV-1⁺ATB group were significantly lower than those in HIV-1⁺LTB group (P<0.001).

Conclusions

Hierarchy low CD8+ T-cell counts and effector function in HIV-1-infected individuals are correlated with both M.tb co-infection and active TB. Hierarchy low CD4+ T-cell counts and Th1 effector function in HIV-1+ individuals are associated with increased frequencies of active TB, but not M.tb co-infection.     

Plasma Levels of Neopterin and C-Reactive Protein (CRP) in Tuberculosis (TB) with and without HIV Coinfection in Relation to CD4 Cell Count

Background

While the risk of TB is elevated in HIV-positive subjects with low CD4 cell counts, TB may in itself be associated with CD4 lymphocytopenia. We investigated markers of immune activation (neopterin) and inflammation (CRP) in TB patients with and without HIV coinfection and their association with CD4 cell levels, and determined their predictive capacity as alternative markers of advanced immunosuppression.

Methods

Participants selected from a cohort of adults with TB at Ethiopian health centers (195 HIV+/TB+, 170 HIV-/TB+) and 31 controls were tested for plasma levels of neopterin and CRP. Baseline levels of neopterin and CRP were correlated to CD4 cell count before and after anti-TB treatment (ATT). The performance to predict CD4 cell strata for both markers were investigated using receiver operating curves.

Results

Levels of both biomarkers were elevated in TB patients (neopterin: HIV+/TB+ 54 nmol/l, HIV-/TB+ 23 nmol/l, controls 3.8 nmol/l; CRP: HIV+/TB+ 36 μg/ml, HIV-/TB+ 33 μg/ml, controls 0.5 μg/ml). Neopterin levels were inversely correlated (-0.53, p<0.001) to CD4 cell count, whereas this correlation was weaker for CRP (-0.25, p<0.001). Neither of the markers had adequate predictive value for identification of subjects with CD4 cell count <100 cells/mm³ (area under the curve [AUC] 0.64 for neopterin, AUC 0.59 for CRP).

Conclusion

Neopterin levels were high in adults with TB, both with and without HIV coinfection, with inverse correlation to CD4 cell count. This suggests that immune activation may be involved in TB-related CD4 lymphocytopenia. However, neither neopterin nor CRP showed promise as alternative tests for immunosuppression in patients coinfected with HIV and TB.     

Protective Effect of HLA-B*5701 and HLA-C -35 Genetic Variants in HIV-Positive Caucasians from Northern Poland

Aim of the Study

Association of two HLA class I variants with HIV-1 pretreatment viremia, CD4+ T cell count at the care-entry and CD4+ T cell nadir.

Methods

414 HIV-positive Caucasians (30% women) aged 19-73 years were genotyped for HLA-C -35 (rs9264942) and HLA-B*5701 variants. HIV-1 viral load, as well as CD4+ T cell count at care-entry and nadir, were compared across alleles, genotypes and haplotypes.

Results

HLA-C -35 C/C genotype was found in 17.6% patients, C/T genotype in 48.1%, and T/T genotype in 34.3% patients. HLA-B*5701 variant was present in 5.8% of studied population. HIV plasma viremia in the group with C allele was significantly lower (p=0.0002) compared to T/T group [mean:4.66 log (SD:1.03) vs. 5.07 (SD:0.85) log HIV-RNA copies/ml, respectively], while CD4+ T cell count at baseline was notably higher among C allele carriers compared to T/T homozygotes [median: 318 (IQR:127-537) cells/μl vs. median: 203 (IQR:55-410) cells/μl, respectively] (p=0.0007). Moreover, CD4+ T cell nadir among patients with C allele [median: 205 (IQR:83.5-390) cells/μl] was significantly higher compared to T/T group [median: 133 (IQR:46-328) cells/μl] (p=0.006). Among cases with HLA-B*5701 allele, significantly lower pretreatment viremia and higher baseline CD4+ T cell count were found (mean: 4.08 [SD: 1.2] vs. mean: 4.84 [SD:0.97] log HIV-RNA copies/ml, p=0.003 and 431 vs. 270 cells/μl, p=0.04, respectively) compared to HLA-B*5701 negative individuals. The lowest viremia (mean: 3.85 log [SD:1.3]) HIV-RNA copies/ml and the highest baseline and nadir CD4+ T cell [median: 476 (IQR:304-682) vs. median: 361 (IQR: 205-574) cells/μl, respectively) were found in individuals with HLA-B*5701(+)/HLA-C –35 C/C haplotype.

Conclusions

HLA-C -35 C and HLA-B*5701 allele exert a favorable effect on the immunological (higher baseline and nadir CD4+ T cell count) and virologic (lower pretreatment HIV viral load) variables. This protective effect is additive for the compound HLA-B*5701(+)/HLA-C -35 C/C haplotype.     

Long-Term CD4+ Cell Count in Response to Combination Antiretroviral Therapy

Objective

There is a continuous debate on how to adequately evaluate long-term CD4+ cell count in response to combination antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected individuals. Our study evaluated the long-term CD4+ cell count response (up to ten years) after initiation of ART and described the differences in the CD4+ cell count response stratified by pretreatment CD4+ cell count, and other socio-demographic, behavioral, and clinical factors.

Methods

The study population included patients starting ART in the clinical cohorts of Rio de Janeiro, Brazil, and Baltimore, United States. Inverse probability of censoring weighting was used to estimate mean annual CD4+ cell counts while adjusting for choice of initial ART regimen, ART discontinuation and losses-to-follow-up.

Results

From 1997 to 2011, 3116 individuals started ART; preferred initial regimen was NNRTI-based (63%). The median follow-up time was 5 years, 10% of the individuals had nine or more years of follow-up. Observed CD4+ cell counts increased throughout the ten years of follow-up. Weighted results, in contrast, increased up to year four and plateaued thereafter with 50% of the population reaching CD4+ cell counts of 449/μL or more. Out of all stratification variables considered, only individuals with pre-treatment CD4+ cell counts ≥350/μL showed increasing CD4+ cell counts over time with 76% surpassing the CD4+ cell count >500/μL threshold at year ten.

Conclusion

The present study corroborates the growing body of knowledge advocating early start of ART by showing that only patients who start ART early fully recover to normal CD4+ cell counts.     

Comparative Yield of Different Diagnostic Tests for Tuberculosis among People Living with HIV in Western Kenya

Background

Diagnosis followed by effective treatment of tuberculosis (TB) reduces transmission and saves lives in persons living with HIV (PLHIV). Sputum smear microscopy is widely used for diagnosis, despite limited sensitivity in PLHIV. Evidence is needed to determine the optimal diagnostic approach for these patients.

Methods

From May 2011 through June 2012, we recruited PLHIV from 15 HIV treatment centers in western Kenya. We collected up to three sputum specimens for Ziehl-Neelsen (ZN) and fluorescence microscopy (FM), GeneXpert MTB/RIF (Xpert), and culture, regardless of symptoms. We calculated the incremental yield of each test, stratifying results by CD4 cell count and specimen type; data were analyzed to account for complex sampling.

Results

From 778 enrolled patients, we identified 88 (11.3%) laboratory-confirmed TB cases. Of the 74 cases who submitted 2 specimens for microscopy and Xpert testing, ZN microscopy identified 25 (33.6%); Xpert identified those plus an additional 18 (incremental yield = 24.4%). Xpert testing of spot specimens identified 48 (57.0%) of 84 cases; whereas Xpert testing of morning specimens identified 50 (66.0%) of 76 cases. Two Xpert tests detected 22/24 (92.0%) TB cases with CD4 counts <100 cells/μL and 30/45 (67.0%) of cases with CD4 counts ≥100 cells/μl.

Conclusions

In PLHIV, Xpert substantially increased diagnostic yield compared to smear microscopy and had the highest yield when used to test morning specimens and specimens from PLHIV with CD4 count <100 cells/μL. TB programs unable to replace smear microscopy with Xpert for all symptomatic PLHIV should consider targeted replacement and using morning specimens.     

Use of Pentamidine As Secondary Prophylaxis to Prevent Visceral Leishmaniasis Relapse in HIV Infected Patients,the First Twelve Months of a Prospective Cohort Study

Background

Visceral leishmaniasis (VL) has become an important opportunistic infection in persons with HIV-infection in VL-endemic areas. The co-infection leads to profound immunosuppression and high rate of annual VL recurrence. This study assessed the effectiveness, safety and feasibility of monthly pentamidine infusions to prevent recurrence of VL in HIV co-infected patients.

Methods

A single-arm, open-label trial was conducted at two leishmaniasis treatment centers in northwest Ethiopia. HIV-infected patients with a VL episode were included after parasitological cure. Monthly infusions of 4mg/kg pentamidine-isethionate diluted in normal-saline were started for 12months. All received antiretroviral therapy (ART). Time-to-relapse or death was the primary end point.

Results

Seventy-four patients were included. The probability of relapse-free survival at 6months and at 12 months was 79% and 71% respectively. Renal failure, a possible drug-related serious adverse event, occurred in two patients with severe pneumonia. Forty-one patients completed the regimen taking at least 11 of the 12 doses. Main reasons to discontinue were: 15 relapsed, five died and seven became lost to follow-up. More patients failed among those with a CD4+cell count ≤ 50cells/μl, 5/7 (71.4%) than those with counts above 200 cells/μl, 2/12 (16.7%), (p = 0.005).

Conclusion

Pentamidine secondary prophylaxis led to a 29% failure rate within one year, much lower than reported in historical controls (50%-100%). Patients with low CD4+cell counts are at increased risk of relapse despite effective initial VL treatment, ART and secondary prophylaxis. VL should be detected and treated early enough in patients with HIV infection before profound immune deficiency installs.     

A Clinical Algorithm to Identify HIV Patients at High Risk for Incident Active Tuberculosis: A Prospective 5-Year Cohort Study

Background

Predicting the risk of tuberculosis (TB) in people living with HIV (PLHIV) using a single test is currently not possible. We aimed to develop and validate a clinical algorithm, using baseline CD4 cell counts, HIV viral load (pVL), and interferon-gamma release assay (IGRA), to identify PLHIV who are at high risk for incident active TB in low-to-moderate TB burden settings where highly active antiretroviral therapy (HAART) is routinely provided.

Materials and Methods

A prospective, 5-year, cohort study of adult PLHIV was conducted from 2006 to 2012 in two hospitals in Taiwan. HAART was initiated based on contemporary guidelines (CD4 count < = 350/μL). Cox regression was used to identify the predictors of active TB and to construct the algorithm. The validation cohorts included 1455 HIV-infected individuals from previous published studies. Area under the receiver operating characteristic (ROC) curve was calculated.

Results

Seventeen of 772 participants developed active TB during a median follow-up period of 5.21 years. Baseline CD4 < 350/μL or pVL ≥ 100,000/mL was a predictor of active TB (adjusted HR 4.87, 95% CI 1.49–15.90, P = 0.009). A positive baseline IGRA predicted TB in patients with baseline CD4 ≥ 350/μL and pVL < 100,000/mL (adjusted HR 6.09, 95% CI 1.52–24.40, P = 0.01). Compared with an IGRA-alone strategy, the algorithm improved the sensitivity from 37.5% to 76.5%, the negative predictive value from 98.5% to 99.2%. Compared with an untargeted strategy, the algorithm spared 468 (60.6%) from unnecessary TB preventive treatment. Area under the ROC curve was 0.692 (95% CI: 0.587–0.798) for the study cohort and 0.792 (95% CI: 0.776–0.808) and 0.766 in the 2 validation cohorts.

Conclusions

A validated algorithm incorporating the baseline CD4 cell count, HIV viral load, and IGRA status can be used to guide targeted TB preventive treatment in PLHIV in low-to-moderate TB burden settings where HAART is routinely provided to all PLHIV. The implementation of this algorithm will avoid unnecessary exposure of low-risk patients to drug toxicity and simultaneously, reduce the burden of universal treatment on the healthcare system.     

Field Evaluation of a Point-of-Care CD4 Analyzer for Monitoring HIV Patients in the Interior of the Amazon Region,Brazil

Objective

To evaluate the accuracy of the PIMA point-of-care CD4 analyzer (PIMA) under field conditions in comparison to the current CD4 count system (FACSCalibur), and to evaluate the operational suitability and acceptability of health professionals (HP) and HIV-patients in using the PIMA in health clinics in the Amazon Region.

Methods

CD4 counts were measured onsite by the PIMA using fingerprick blood and in the reference laboratory by both the PIMA and FACSCalibur using venous blood. We used the Bland–Altman method to estimate the mean bias, and calculated the sensitivity and specificity at <200 and <500 cell/μL thresholds. Patients (n = 404) and HP (n = 7) were interviewed on the acceptability and operational suitability of the PIMA.

Results

Using fingerprick blood (n = 337), the PIMA showed a concordance correlation coefficient (Rc) of 0.81, mean difference of -111.9 cell/μL, 93.1%/98.5% sensitivity, and 89.2%/56.7% specificity at <200 and <500 cell/μL thresholds, respectively. Venous blood (n = 340) showed an Rc of 0.89, mean difference of -83.4 cell/μL, 98.3%/97.5% sensitivity, and 93.9%/66.0% specificity at <200 and <500 cell/μL thresholds, respectively. The capillary PIMA was well accepted and found operationally appropriate by patients and HP.

Conclusions

The agreement between both instruments was poor and the PIMA underestimated CD4 cell counts, which was more pronounced at CD4 counts ≥500 cell/μl. The PIMA’s performance with fingerprick blood was less reliable than its performance with venous blood. In Brazil, where antiretroviral treatment is initiated regardless of CD4 counts, the PIMA’s systematic bias towards CD4 underestimation may limit its role for monitoring HIV-patients.     

Estimated Costs for Delivery of HIV Antiretroviral Therapy to Individuals with CD4+ T-Cell Counts >350 cells/uL in Rural Uganda

Background

Evidence favoring earlier HIV ART initiation at high CD4+ T-cell counts (CD4>350/uL) has grown, and guidelines now recommend earlier HIV treatment. However, the cost of providing ART to individuals with CD4>350 in Sub-Saharan Africa has not been well estimated. This remains a major barrier to optimal global cost projections for accelerating the scale-up of ART. Our objective was to compute costs of ART delivery to high CD4+count individuals in a typical rural Ugandan health center-based HIV clinic, and use these data to construct scenarios of efficient ART scale-up.

Methods

Within a clinical study evaluating streamlined ART delivery to 197 individuals with CD4+ cell counts >350 cells/uL (EARLI Study: {"type":"clinical-trial","attrs":{"text":"NCT01479634","term_id":"NCT01479634"}}NCT01479634) in Mbarara, Uganda, we performed a micro-costing analysis of administrative records, ART prices, and time-and-motion analysis of staff work patterns. We computed observed per-person-per-year (ppy) costs, and constructed models estimating costs under several increasingly efficient ART scale-up scenarios using local salaries, lowest drug prices, optimized patient loads, and inclusion of viral load (VL) testing.

Findings

Among 197 individuals enrolled in the EARLI Study, median pre-ART CD4+ cell count was 569/uL (IQR 451–716). Observed ART delivery cost was $628 ppy at steady state. Models using local salaries and only core laboratory tests estimated costs of $529/$445 ppy (+/-VL testing, respectively). Models with lower salaries, lowest ART prices, and optimized healthcare worker schedules reduced costs by $100–200 ppy. Costs in a maximally efficient scale-up model were $320/$236 ppy (+/- VL testing). This included $39 for personnel, $106 for ART, $130/$46 for laboratory tests, and $46 for administrative/other costs. A key limitation of this study is its derivation and extrapolation of costs from one large rural treatment program of high CD4+ count individuals.

Conclusions

In a Ugandan HIV clinic, ART delivery costs—including VL testing—for individuals with CD4>350 were similar to estimates from high-efficiency programs. In higher efficiency scale-up models, costs were substantially lower. These favorable costs may be achieved because high CD4+ count patients are often asymptomatic, facilitating more efficient streamlined ART delivery. Our work provides a framework for calculating costs of efficient ART scale-up models using accessible data from specific programs and regions.     

CD4 Enumeration Technologies: A Systematic Review of Test Performance for Determining Eligibility for Antiretroviral Therapy

Background

Measurement of CD4⁺ T-lymphocytes (CD4) is a crucial parameter in the management of HIV patients, particularly in determining eligibility to initiate antiretroviral treatment (ART). A number of technologies exist for CD4 enumeration, with considerable variation in cost, complexity, and operational requirements. We conducted a systematic review of the performance of technologies for CD4 enumeration.

Methods and Findings

Studies were identified by searching electronic databases MEDLINE and EMBASE using a pre-defined search strategy. Data on test accuracy and precision included bias and limits of agreement with a reference standard, and misclassification probabilities around CD4 thresholds of 200 and 350 cells/μl over a clinically relevant range. The secondary outcome measure was test imprecision, expressed as % coefficient of variation. Thirty-two studies evaluating 15 CD4 technologies were included, of which less than half presented data on bias and misclassification compared to the same reference technology. At CD4 counts <350 cells/μl, bias ranged from -35.2 to +13.1 cells/μl while at counts >350 cells/μl, bias ranged from -70.7 to +47 cells/μl, compared to the BD FACSCount as a reference technology. Misclassification around the threshold of 350 cells/μl ranged from 1-29% for upward classification, resulting in under-treatment, and 7-68% for downward classification resulting in overtreatment. Less than half of these studies reported within laboratory precision or reproducibility of the CD4 values obtained.

Conclusions

A wide range of bias and percent misclassification around treatment thresholds were reported on the CD4 enumeration technologies included in this review, with few studies reporting assay precision. The lack of standardised methodology on test evaluation, including the use of different reference standards, is a barrier to assessing relative assay performance and could hinder the introduction of new point-of-care assays in countries where they are most needed.     

Effect of Nadir CD4+ T Cell Count on Clinical Measures of Periodontal Disease in HIV+ Adults before and during Immune Reconstitution on HAART

Background

The contribution of HIV-infection to periodontal disease (PD) is poorly understood.  We proposed that immunological markers would be associated with improved clinical measures of PD.

Methods

We performed a longitudinal cohort study of HIV-infected adults who had started highly active antiretroviral therapy (HAART) <2 years. PD was characterized clinically as the percent of teeth with ≥1 site with periodontal probing depth (PPD) ≥5.0mm, recession (REC) >0mm, clinical attachment level (CAL) ≥4.0mm, and bleeding on probing (BOP) at ≥4 sites/tooth and microbiologically as specific periodontopathogen concentration. Linear mixed-effects models were used to assess the associations between immune function and PD.

Results

Forty (40) subjects with median 2.7 months on HAART and median nadir CD4+ T-cell count of 212 cells/μl completed a median 3 visits. Over 24 months, CD4+ T-cell count increased by a mean 173 cells/µl (p<0.001) and HIV RNA decreased by 0.5 log₁₀ copies/ml (p<0.001); concurrently, PPD, CAL and BOP decreased by a mean 11.7%, 12.1%, and 14.7% respectively (all p<0.001). Lower nadir CD4+ T-cell count was associated with worse baseline REC (-6.72%; p=0.04) and CAL (9.06%; p<0.001). Further, lower nadir CD4+ T-cell count was associated with a greater relative longitudinal improvement in PPD in subjects with higher baseline levels of Porphyromonas gingivalis (p=0.027), and BOP in subjects with higher baseline levels of Porphyromonas gingivalis or Treponema denticola (p=0.001 and p=0.006 respectively). Longitudinal changes from baseline in CD4+ T-cell count and level of HIV RNA were not independently associated with longitudinal changes in any clinical markers of PD.

Conclusion

Degree of immunosuppression was associated with baseline gingival recession. After HAART initiation, measures of active PD improved most in those with lower nadir CD4+ T-cell counts and higher baseline levels of specific periodontopathogens. Nadir CD4+ T-cell count differentially influences periodontal disease both before and after HAART in HIV-infected adults.     

Advanced HIV Disease at Enrolment in HIV Care: Trends and Associated Factors over a Ten Year Period in Cambodia

Background

Early HIV diagnosis and enrolment in care is needed to achieve early antiretroviral treatment (ART) initiation. Studies on HIV disease stage at enrolment in care from Asian countries are limited. We evaluated trends in and factors associated with late HIV disease presentation over a ten-year period in the largest ART center in Cambodia.

Methods

We conducted a retrospective analysis of program data including all ARV-naïve adults (> 18 years old) enrolling into HIV care from March 2003-December 2013 in a non-governmental hospital in Phnom Penh, Cambodia. We calculated the proportion presenting with advanced stage HIV disease (WHO clinical stage IV or CD4 cell count <100 cells/μL) and the probability of ART initiation by six months after enrolment. Factors associated with late presentation were determined using multivariate logistic regression.

Results

From 2003–2013, a total of 5642 HIV-infected patients enrolled in HIV care. The proportion of late presenters decreased from 67% in 2003 to 44% in 2009 and 41% in 2013; a temporary increase to 52% occurred in 2011 coinciding with logistical/budgetary constraints at the national program level. Median CD4 counts increased from 32 cells/μL (IQR 11–127) in 2003 to 239 cells/μL (IQR 63–291) in 2013. Older age and male sex were associated with late presentation across the ten-year period. The probability of ART initiation by six months after enrolment increased from 22.6% in 2003–2006 to 79.9% in 2011–2013.

Conclusion

Although a gradual improvement was observed over time, a large proportion of patients still enroll late, particularly older or male patients. Interventions to achieve early HIV testing and efficient linkage to care are warranted.     

Routine Eye Screening by an Ophthalmologist Is Clinically Useful for HIV-1-Infected Patients with CD4 Count Less than 200 /μL

Objective

To investigate whether routine eye screening by an ophthalmologist in patients with HIV-1 infection is clinically useful.

Methods

A single-center, retrospective study in Tokyo, Japan. HIV-1-infected patients aged over 17 years who visited our clinic for the first time between January 2004 and December 2013 and underwent full ophthalmologic examination were enrolled. At our clinic, ophthalmologic examination, including dilated retinal examination by indirect ophthalmoscopy was routinely conducted by ophthalmologists on the first visit. The prevalence of ophthalmologic diseases and associated factors including the existence of ocular symptoms were analyzed.

Results

Of the 1,515 study patients, cytomegalovirus retinitis (CMV-R) was diagnosed in 24 (2%) patients, HIV retinopathy (HIV-R) in 127 (8%), cataract in 31 (2%), ocular syphilis in 4 (0.3%), and uveitis with unknown cause in 8 (0.5%). Other ocular diseases were diagnosed in 14 patients. The CD4 count was <200 /μL in all CMV-R cases and 87% of HIV-R. The prevalence of any ocular diseases, CMV-R, and HIV-R in patients with CD4 <200 /μL were 22%, 3%, and 15%, respectively, whereas for those with CD4 ≥200 /μL were 5%, 0%, and 2%, respectively. No ocular symptoms were reported by 71% of CMV-R cases and 82% of patients with any ocular diseases.

Conclusions

Routine ophthalmologic screening is recommended for HIV-1-infected patients with CD4 <200 /μL in resource-rich settings based on the high prevalence of ocular diseases within this CD4 count category and because most patients with ocular diseases, including those with CMV-R, were free of ocular symptoms.     

Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

Background

Successful combination antiretroviral therapy (cART) increases levels of CD4+ T-cells, however this increase may not accurately reflect long-term immune recovery since T-cell dysregulation and loss of T-cell homeostasis often persist. We therefore assessed the impact of a decade of effective cART on immune regulation, T-cell homeostasis, and overall T-cell phenotype.

Methods

We conducted a retrospective study of 288 HIV+ cART-naïve patients initiating therapy. We identified 86 individuals who received cART for at least a decade, of which 44 consistently maintained undetectable plasma HIV-RNA levels throughout therapy. At baseline, participants were classified into three groups according to pre-treatment CD4+ T-cell counts: Group I (CD4<200 cells/mm³); Group II (CD4: 200–350 cells/mm³); Group III (CD4>350 cells/mm³). Outcomes of interest were: (1) CD4+ T-cell count restoration (CD4>532 cells/mm³); (2) normalization of CD4:CD8 T-cell ratio (1.2–3.3); (3) maintenance of CD3+ T-cell homeostasis (CD3: 65%–85% of peripheral lymphocytes); (4) normalization of the complete T-cell phenotype (TCP).

Results

Despite a decade of sustained successful cART, complete T-cell phenotype normalization only occurred in 16% of patients, most of whom had initiated therapy at high CD4+ T-cell counts (>350 cells/mm³). The TCP parameter that was the least restored among patients was the CD4:CD8 T-cell ratio.

Conclusions

Failure to normalize the complete T-cell phenotype was most apparent in patients who initiated cART with a CD4+ T-cell count <200 cells/mm³. The impact of this impaired T-cell phenotype on life-long immune function and potential comorbidities remains to be elucidated.     

Morbidity and Mortality According to Latest CD4+ Cell Count among HIV Positive Individuals in South Africa Who Enrolled in Project Phidisa

Background

Short-term morbidity and mortality rates for HIV positive soldiers in the South African National Defence Force (SANDF) would inform decisions about deployment and HIV disease management. Risks were determined according to the latest CD4+ cell count and use of antiretroviral therapy (ART) for HIV positive individuals in the SANDF and their dependents.

Methods and Findings

A total of 7,114 participants were enrolled and followed for mortality over a median of 4.7 years (IQR: 1.9, 7.1 years). For a planned subset (5,976), progression of disease (POD) and grade 4, potentially life-threatening events were also ascertained. CD4+ count and viral load were measured every 3 to 6 months. Poisson regression was used to compare event rates by latest CD4+ count (<50, 50–99, 100–199, 200–349, 350–499, 500+) with a focus on upper three strata, and to estimate relative risks (RRs) (ART/no ART). Median entry CD4+ was 207 cells/mm³. During follow-up over 70% were prescribed ART. Over follow-up 1,226 participants died; rates ranged from 57.6 (< 50 cells) to 0.8 (500+ cells) per 100 person years (py). Compared to those with latest CD4+ 200–349 (2.2/100py), death rates were significantly lower (p<0.001), as expected, for those with 350–499 (0.9/100py) and with 500+ cells (0.8/100py). The composite outcome of death, POD or grade 4 events occurred in 2,302 participants (4,045 events); rates were similar in higher CD4+ count strata (9.4 for 350–499 and 7.9 for 500+ cells) and lower than those with counts 200–349 cells (13.5) (p<0.001). For those with latest CD4+ 350+ cells, 63% of the composite outcomes (680 of 1,074) were grade 4 events.

Conclusion

Rates of morbidity and mortality are lowest among those with CD4+ count of 350 or higher and rates do not differ for those with counts of 350–499 versus 500+ cells. Grade 4 events are the predominant morbidity for participants with CD4+ counts of 350+ cells.     

Use of Surveillance Data on HIV Diagnoses with HIV-Related Symptoms to Estimate the Number of People Living with Undiagnosed HIV in Need of Antiretroviral Therapy

Background

It is important to have methods available to estimate the number of people who have undiagnosed HIV and are in need of antiretroviral therapy (ART).

Methods

The method uses the concept that a predictable level of occurrence of AIDS or other HIV-related clinical symptoms which lead to presentation for care, and hence diagnosis of HIV, arises in undiagnosed people with a given CD4 count. The method requires surveillance data on numbers of new HIV diagnoses with HIV-related symptoms, and the CD4 count at diagnosis. The CD4 count-specific rate at which HIV-related symptoms develop are estimated from cohort data. 95% confidence intervals can be constructed using a simple simulation method.

Results

For example, if there were 13 HIV diagnoses with HIV-related symptoms made in one year with CD4 count at diagnosis between 150–199 cells/mm³, then since the CD4 count-specific rate of HIV-related symptoms is estimated as 0.216 per person-year, the estimated number of person years lived in people with undiagnosed HIV with CD4 count 150–199 cells/mm3 is 13/0.216 = 60 (95% confidence interval: 29–100), which is considered an estimate of the number of people living with undiagnosed HIV in this CD4 count stratum.

Conclusions

The method is straightforward to implement within a short period once a surveillance system of all new HIV diagnoses, collecting data on HIV-related symptoms at diagnosis, is in place and is most suitable for estimating the number of undiagnosed people with CD4 count <200 cells/mm3 due to the low rate of developing HIV-related symptoms at higher CD4 counts. A potential source of bias is under-diagnosis and under-reporting of diagnoses with HIV-related symptoms. Although this method has limitations as with all approaches, it is important for prompting increased efforts to identify undiagnosed people, particularly those with low CD4 count, and for informing levels of unmet need for ART.     

Blunted Response to Combination Antiretroviral Therapy in HIV Elite Controllers: An International HIV Controller Collaboration

Objective

HIV “elite controllers” (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs).

Methods

ECs were defined as patients with at least ≥5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently-diagnosed (<1 year) ART-naïve HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models.

Results

After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63/month), followed by +0.19/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm³, the estimated mean CD4 T-cell gain during the first 12 months was 139/mm³ in VIRs and 80/mm³ in ECs (p = 0.048).

Conclusions

cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients.     

Effects of Prednisolone on Disease Progression in Antiretroviral-Untreated HIV Infection: A 2-Year Randomized,Double-Blind Placebo-Controlled Clinical Trial

Background

HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients.

Methods

Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948). Inclusion criteria were a CD4 count above 300 cells/μl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/μl.

Results

No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/μl compared to -37.42 ± 10.77 cells/μl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men.

Conclusions

This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01299948","term_id":"NCT01299948"}}NCT01299948     

Trends in CD4 Count Testing,Retention in Pre-ART Care,and ART Initiation Rates over the First Decade of Expansion of HIV Services in Haiti

Background

High attrition during the period from HIV testing to antiretroviral therapy (ART) initiation is widely reported. Though treatment guidelines have changed to broaden ART eligibility and services have been widely expanded over the past decade, data on the temporal trends in pre-ART outcomes are limited; such data would be useful to guide future policy decisions.

Methods

We evaluated temporal trends and predictors of retention for each step from HIV testing to ART initiation over the past decade at the GHESKIO clinic in Port-au-Prince Haiti. The 24,925 patients >17 years of age who received a positive HIV test at GHESKIO from March 1, 2003 to February 28, 2013 were included. Patients were followed until they remained in pre-ART care for one year or initiated ART.

Results

24,925 patients (61% female, median age 35 years) were included, and 15,008 (60%) had blood drawn for CD4 count within 12 months of HIV testing; the trend increased over time from 36% in Year 1 to 78% in Year 10 (p<0.0001). Excluding transfers, the proportion of patients who were retained in pre-ART care or initiated ART within the first year after HIV testing was 84%, 82%, 64%, and 64%, for CD4 count strata ≤200, 201 to 350, 351 to 500, and >500 cells/mm³, respectively. The trend increased over time for each CD4 strata, and in Year 10, 94%, 95%, 79%, and 74% were retained in pre-ART care or initiated ART for each CD4 strata. Predictors of pre-ART attrition included male gender, low income, and low educational status. Older age and tuberculosis (TB) at HIV testing were associated with retention in care.

Conclusions

The proportion of patients completing assessments for ART eligibility, remaining in pre-ART care, and initiating ART have increased over the last decade across all CD4 count strata, particularly among patients with CD4 count ≤350 cells/mm³. However, additional retention efforts are needed for patients with higher CD4 counts.