Incidence and predictors of immune reconstitution inflammatory syndrome in a rural area of Mozambique

Background

There is limited data on the epidemiology of Immune Reconstitution Inflammatory Syndrome (IRIS) in rural sub-Saharan Africa. A prospective observational cohort study was conducted to assess the incidence, clinical characteristics, outcome and predictors of IRIS in rural Mozambique.

Methods

One hundred and thirty-six consecutive antiretroviral treatment (ART)-naïve HIV-1-infected patients initiating ART at the Manhiça district hospital were prospectively followed for development of IRIS over 16 months. Survival analysis by Cox regression was performed to identify pre-ART predictors of IRIS development.

Results

Thirty-six patients developed IRIS [26.5%, incidence rate 3.1 cases/100 persons-month of ART (95% CI 2.2–4.3)]. Median time to IRIS onset was 62 days from ART initiation (IQR 35.5–93.5). Twenty-five cases (69.4%) were “unmasking”, 10 (27.8%) were “paradoxical”, and 1 (2.8%) developed a paradoxical worsening followed by the unmasking of another condition. Systemic OI (OI-IRIS) accounted for 47% (17/36) of IRIS cases, predominantly of KS (8 cases) and TB (6 cases) IRIS. Mucocutaneous IRIS manifestations (MC-IRIS) accounted for 53% (19/36) of IRIS events, mostly tinea (9 cases) and herpes simplex infection (3 cases). Multivariate analysis identified two independent predictors of IRIS development: pre-ART CD4 count <50 cells/µl (HR 2.3, 95% CI 1.19–4.44, p = 0.01) and body mass index (BMI) <18.5 (HR 2.15, 95% CI 1.07–4.3, p = 0.03). The pre-cART proportion of activated T-cells, as well as the immunologic and virologic response to ART were not associated with IRIS development. All patients continued on ART, 7 (19.4%) required hospitalization and there were 3 deaths (8.3%) attributable to IRIS.

Conclusions

IRIS is common in patients initiating ART in rural Mozambique. Pre-ART CD4 counts and BMI can easily be assessed at ART initiation in rural sub-Saharan Africa to identify patients at high risk of IRIS, for whom close supervision is warranted.     

Long Term 5-Year Survival of Persons with Cryptococcal Meningitis or Asymptomatic Subclinical Antigenemia in Uganda

Data presented previously as an abstract at the 2011 CUGH Global Health Conference in Montreal, Canada on 15 Nov 2011. The long-term survival of HIV-infected persons with symptomatic cryptococcal meningitis and asymptomatic, subclinical cryptococcal antigenemia (CRAG+) is unknown. We prospectively enrolled 25 asymptomatic, antiretroviral therapy (ART)-naïve CRAG+ Ugandans with CD4<100 cells/mcL who received pre-emptive fluconazole treatment (CRAG+ cohort) and 189 ART-naïve Ugandans with symptomatic cryptococcal meningitis treated with amphotericin (CM cohort). The 10-week survival was 84% (95%CI: 70–98%) in the CRAG+ cohort and 57% (95%CI: 50%–64%) in the CM cohort. The CRAG+ cohort had improved five-year survival of 76% (95%CI: 59%–93%) compared to 42% (95%CI: 35%–50%) in the CM cohort (P = 0.001). The two cohorts had similar immunosuppression pre-ART with median CD4 counts of 15 vs. 21 CD4/mcL in the CRAG+ and CM cohorts, respectively (P = 0.45). Despite substantial early mortality, subsequent 5-year survival of persons surviving 6-months was excellent (>88%), demonstrating that long term survival is possible in resource-limited settings. Pre-ART CRAG screening with preemptive fluconazole treatment and improved CM treatment(s) are needed to reduce AIDS-attributable mortality due to cryptococcosis which remains 20–25% in sub-Saharan Africa.     

Patients present earlier and survival has improved, but pre-ART attrition is high in a six-year HIV cohort data from Ethiopia

Background

Previous studies showed higher early mortality rates among patients treated with antiretroviral drugs in settings with limited resources. One of the reasons was late presentation of patients to care. With improved access to HIV services, we expect improvements in disease stage at presentation. Our objective was to assess the effect of improved availability of HIV services on patient presentation to care and subsequent pre-ART and on-ART outcomes.

Methodology and Principal Findings

At Arba Minch Hospital in Ethiopia, we reviewed baseline characteristics and outcomes of 2191 adult HIV patients. Nearly a half were in WHO stage III at presentation. About two-thirds of the patients (1428) started ART. Patients enrolled in the early phase (OR = 4.03, 95% CI 3.07–5.27), men (OR = 1.78, 95%CI 1.47–2.16), and those aged 45 years and above (OR = 2.04, 95%CI 1.48–2.82) were at higher risk of being in advanced clinical stage at presentation. The pre-treatment mortality rate was 13.1 per 100 PYO, ranging from 1.4 in the rapid scale-up phase to 25.9 per 100 PYO in the early phase. A quarter of the patients were lost to follow-up before starting treatment. Being in less advanced stage (HR = 1.9, 95% CI = 1.6, 2.2), being in the recent cohort (HR = 2.0, 95% CI = 1.6, 2.6), and rural residence (HR = 1.8, 95% CI = 1.5, 2.2) were independent predictors of pre-ART loss to follow-up. Of those who started ART, 13.4% were lost to follow-up and 15.4% died. The survival improved during the study. Patients with advanced disease, men and older people had higher death rates.

Conclusions and Significance

Patients started to present at earlier stages of their illness and death has decreased among adult HIV patients visiting Arba Minch Hospital. However, many patients were lost from pre-treatment follow-up. Early treatment start contributed to improved survival. Both pre-ART and on-ART patient retention mechanisms should be strengthened.     

Population-level reduction in adult mortality after extension of free anti-retroviral therapy provision into rural areas in northern Malawi

Background

Four studies from sub-Saharan Africa have found a substantial population-level effect of ART provision on adult mortality. It is important to see if the impact changes with time since the start of treatment scale-up, and as treatment moves to smaller clinics.

Methods and Findings

During 2002-4 a demographic surveillance site (DSS) was established in Karonga district, northern Malawi. Information on births and deaths is collected monthly, with verbal autopsies conducted for all deaths; migrations are updated annually. We analysed mortality trends by comparing three time periods: pre-ART roll-out in the district (August 2002–June 2005), ART period 1 (July 2005–September 2006) when ART was available only in a town 70 km away, and ART period 2 (October 2006–September 2008), when ART was available at a clinic within the DSS area. HIV prevalence and ART uptake were estimated from a sero-survey conducted in 2007/2008. The all-cause mortality rate among 15–59 year olds was 10.2 per 1000 person-years in the pre-ART period (288 deaths/28285 person-years). It fell by 16% in ART period 1 and by 32% in ART period 2 (95% CI 18%–43%), compared with the pre-ART period. The AIDS mortality rate fell from 6.4 to 4.6 to 2.7 per 1000 person-years in the pre-ART period, period 1 and period 2 respectively (rate ratio for period 2 = 0.43, 95% CI 0.33–0.56). There was little change in non-AIDS mortality. Treatment coverage among individuals eligible to start ART was around 70% in 2008.

Conclusions

ART can have a dramatic effect on mortality in a resource-constrained setting in Africa, at least in the early years of treatment provision. Our findings support the decentralised delivery of ART from peripheral health centres with unsophisticated facilities. Continued funding to maintain and further scale-up treatment provision will bring large benefits in terms of saving lives.     

Adherence to antiretroviral treatment and correlation with risk of hospitalization among commercially insured HIV patients in the United States

Purpose

A lower daily pill burden may improve adherence to antiretroviral treatment (ART) and clinical outcomes in patients with human immunodeficiency virus (HIV). This study assessed differences in adherence using the number of pills taken per day, and evaluated how adherence correlated with hospitalization.

Methodology

Commercially insured patients in the LifeLink database with an HIV diagnosis (International Classification of Diseases, 9th Revision, Clinical Modification code 042.xx) between 6/1/2006 and 12/31/2008 and receipt of a complete ART regimen were selected for inclusion. Patients were grouped according to their daily pill count and remained on ART for at least 60 days. Outcomes included adherence and rates of hospitalization. Adherence was measured as the proportion of days between the start and end of the regimen in which the patient maintained supply of all initiated ART components. Logistic regressions assessed the relationship between pills per day, adherence, and hospitalization, controlling for demographics, comorbidities, and ART-naïve (vs. experienced) status.

Results

7,073 patients met the study inclusion criteria, and 33.4%, 5.8%, and 60.8% received an ART regimen comprising one, two, or three or more pills per day, respectively. Regression analysis showed patients receiving a single pill per day were significantly more likely to reach a 95% adherence threshold versus patients receiving three or more pills per day (odds ratio [OR] = 1.59; P<0.001). Regardless of the number of pills received per day, patients were over 40% less likely to have a hospitalization if they were adherent to therapy (OR = 0.57; P<0.001). Patients receiving a single pill per day were 24% less likely to have a hospitalization versus patients receiving three or more pills per day (OR = 0.76; P = 0.003).

Conclusions

ART consisting of a single pill per day was associated with significantly better adherence and lower risk of hospitalization in patients with HIV compared to patients receiving three or more pills per day.     

Presentation and outcome of tuberculous meningitis in a high HIV prevalence setting

Background

Mycobacterium tuberculosis is a common, devastating cause of meningitis in HIV-infected persons. Due to international rollout programs, access to antiretroviral therapy (ART) is increasing globally. Starting patients with HIV-associated tuberculous meningitis (TBM) on ART during tuberculosis (TB) treatment may increase survival in these patients. We undertook this study to describe causes of meningitis at a secondary-level hospital in a high HIV/TB co-infection setting and to determine predictors of mortality in patients with TBM.

Methods

A retrospective review of cerebrospinal fluid findings and clinical records over a six-month period (March 2009–August 2009). Definite, probable and possible TBM were diagnosed according to published case definitions.

Results

TBM was diagnosed in 120/211 patients (57%) with meningitis. In 106 HIV-infected patients with TBM, six-month all-cause mortality was lower in those who received antiretroviral therapy (ART) during TB treatment; hazard ratio = 0.30 (95% CI = 0.08–0.82). Factors associated with inpatient mortality in HIV-infected patients were 1) low CD4⁺ count at presentation; adjusted odds ratio (AOR) = 1.4 (95% confidence interval [CI] = 1.03–1.96) per 50 cells/µL drop in CD4⁺ count and, 2) higher British Medical Research Council TBM disease grade (2 or 3 versus 1); AOR = 4.8 (95% CI = 1.45–15.87).

Interpretation

Starting ART prior to or during TB treatment may be associated with lower mortality in patients with HIV-associated TBM. Advanced HIV and worse stage of TBM disease predict in-hospital mortality in patients presenting with TBM.     

Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease

Background

Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART.

Methods

Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels.

Results

Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9–6.7) for hsCRP, 2.6 (95%CI 1.4–4.9) for D-dimer, and 3.8 (95% CI: 1.8–7.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001).

Conclusions

Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted.

Trial Registration

Parent Study: ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00342355","term_id":"NCT00342355"}}NCT00342355     

Integrating prevention of mother-to-child HIV transmission programs to improve uptake: a systematic review

Background

We performed a systematic review to assess the effect of integrated perinatal prevention of mother-to-child transmission of HIV interventions compared to non- or partially integrated services on the uptake in low- and middle-income countries.

Methods

We searched for experimental, quasi-experimental and controlled observational studies in any language from 21 databases and grey literature sources.

Results

Out of 28 654 citations retrieved, five studies met our inclusion criteria. A cluster randomized controlled trial reported higher probability of nevirapine uptake at the labor wards implementing HIV testing and structured nevirapine adherence assessment (RRR 1.37, bootstrapped 95% CI, 1.04–1.77). A stepped wedge design study showed marked improvement in antiretroviral therapy (ART) enrolment (44.4% versus 25.3%, p<0.001) and initiation (32.9% versus 14.4%, p<0.001) in integrated care, but the median gestational age of ART initiation (27.1 versus 27.7 weeks, p = 0.4), ART duration (10.8 versus 10.0 weeks, p = 0.3) or 90 days ART retention (87.8% versus 91.3%, p = 0.3) did not differ significantly. A cohort study reported no significant difference either in the ART coverage (55% versus 48% versus 47%, p = 0.29) or eight weeks of ART duration before the delivery (50% versus 42% versus 52%; p = 0.96) between integrated, proximal and distal partially integrated care. Two before and after studies assessed the impact of integration on HIV testing uptake in antenatal care. The first study reported that significantly more women received information on PMTCT (92% versus 77%, p<0.001), were tested (76% versus 62%, p<0.001) and learned their HIV status (66% versus 55%, p<0.001) after integration. The second study also reported significant increase in HIV testing uptake after integration (98.8% versus 52.6%, p<0.001).

Conclusion

Limited, non-generalizable evidence supports the effectiveness of integrated PMTCT programs. More research measuring coverage and other relevant outcomes is urgently needed to inform the design of services delivering PMTCT programs.     

Treatment outcomes and cost-effectiveness of shifting management of stable ART patients to nurses in South Africa: an observational cohort

Background

To address human resource and infrastructure shortages, resource-constrained countries are being encouraged to shift HIV care to lesser trained care providers and lower level health care facilities. This study evaluated the cost-effectiveness of down-referring stable antiretroviral therapy (ART) patients from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health care facility in Johannesburg, South Africa.

Methods and Findings

Criteria for down-referral were stable ART (≥11 mo), undetectable viral load within the previous 10 mo, CD4>200 cells/mm³, <5% weight loss over the last three visits, and no opportunistic infections. All patients down-referred from the treatment-initiation site to the down-referral site between 1 February 2008 and 1 January 2009 were compared to a matched sample of patients eligible for down-referral but not down-referred. Outcomes were assigned based on vital and health status 12 mo after down-referral eligibility and the average cost per outcome estimated from patient medical record data.The down-referral site (n = 712) experienced less death and loss to follow up than the treatment-initiation site (n = 2,136) (1.7% versus 6.2%, relative risk = 0.27, 95% CI 0.15–0.49). The average cost per patient-year for those in care and responding at 12 mo was US$492 for down-referred patients and US$551 for patients remaining at the treatment-initiation site (p<0.0001), a savings of 11%. Down-referral was the cost-effective strategy for eligible patients.

Conclusions

Twelve-month outcomes of stable ART patients who are down-referred to a primary health clinic are as good as, or better than, the outcomes of similar patients who are maintained at a hospital-based ART clinic. The cost of treatment with down-referral is lower across all outcomes and would save 11% for patients who remain in care and respond to treatment. These results suggest that this strategy would increase treatment capacity and conserve resources without compromising patient outcomes. Please see later in the article for the Editors'' Summary     

Antiretroviral treatment for HIV in rural Uganda: two-year treatment outcomes of a prospective health centre/community-based and hospital-based cohort

Background

In sub-Saharan Africa, a shortage of trained health professionals and limited geographical access to health facilities present major barriers to the expansion of antiretroviral therapy (ART). We tested the utility of a health centre (HC)/community-based approach in the provision of ART to persons living with HIV in a rural area in western Uganda.

Methods

The HIV treatment outcomes of the HC/community-based ART program were evaluated and compared with those of an ART program at a best-practice regional hospital. The HC/community-based cohort comprised 185 treatment-naïve patients enrolled in 2006. The hospital cohort comprised of 200 patients enrolled in the same time period. The HC/community-based program involved weekly home visits to patients by community volunteers who were trained to deliver antiretroviral drugs to monitor and support adherence to treatment, and to identify and report adverse reactions and other clinical symptoms. Treatment supporters in the homes also had the responsibility to remind patients to take their drugs regularly. ART treatment outcomes were measured by HIV-1 RNA viral load (VL) after two years of treatment. Adherence was determined through weekly pill counts.

Results

Successful ART treatment outcomes in the HC/community-based cohort were equivalent to those in the hospital-based cohort after two years of treatment in on-treatment analysis (VL≤400 copies/mL, 93.0% vs. 87.3%, p = 0.12), and in intention-to-treat analysis (VL≤400 copies/mL, 64.9% and 62.0%, p = 0.560). In multivariate analysis patients in the HC/community-based cohort were more likely to have virologic suppression compared to hospital-based patients (adjusted OR = 2.47, 95% CI 1.01–6.04).

Conclusion

Acceptable rates of virologic suppression were achieved using existing rural clinic and community resources in a HC/community-based ART program run by clinical officers and supported by lay volunteers and treatment supporters. The results were equivalent to those of a hospital-based ART program run primarily by doctors.     

Risk factors associated with increased mortality among HIV infected children initiating antiretroviral therapy (ART) in South Africa

Objective

To identify demographic and clinical risk factors associated with mortality after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency (HIV) infected children in KwaZulu-Natal, South Africa.

Methods

We performed a retrospective cohort study of 537 children initiating antiretroviral therapy at McCord Hospital in KwaZulu-Natal, South Africa. Data were extracted from electronic medical records and risk factors associated with mortality were assessed using Cox regression analysis.

Results

Overall there were 47 deaths from the cohort of 537 children initiating ART with over 991 child-years of follow-up (median 22 months on ART), yielding a mortality rate of 4.7 deaths per 100 child years on ART. Univariate analysis indicated that mortality was significantly associated with lower weight-for-age Z-score (p<0.0001), chronic diarrhea (p = 0.0002), lower hemoglobin (p = 0.002), age <3 years (p = 0.003), and CD4% <10% (p = 0.005). The final multivariable Cox proportional hazards mortality model found age less than 3 years (p = 0.004), CD4 <10% (p = 0.01), chronic diarrhea (p = 0.03), weight-for-age Z-score (<0.0001) and female gender as a covariate varying with time (p = 0.03) all significantly associated with mortality.

Conclusion

In addition to recognized risk factors such as young age and advanced immunosuppression, we found female gender to be significantly associated with mortality in this pediatric ART cohort. Future studies are needed to determine whether intrinsic biologic differences or socio-cultural factors place female children with HIV at increased risk of death following initiation of ART.     

Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa

Objective

To identify baseline demographic and clinical risk factors associated with poor CD4 and weight response after initiation of antiretroviral therapy (ART) in a cohort of human immunodeficiency virus (HIV)-infected children in KwaZulu-Natal, South Africa.

Methods

We performed a retrospective cohort study of 674 children initiating antiretroviral therapy at McCord and St. Mary''s hospitals in KwaZulu-Natal, South Africa, from August 2003 to December 2008.We extracted data from paper charts and electronic medical records to assess risk factors associated with CD4 and weight response using logistic regression.

Results

From the initial cohort of 901 children <10 years old initiating ART between August 2003 and December 2008, we analyzed 674 children with complete baseline data. Viral suppression rates (<400 copies/ml) were 84% after six months of therapy and 88% after 12 months of therapy. Seventy-three percent of children achieved CD4 recovery after six months and 89% after 12 months. Weight-for-age Z-score (WAZ) improvements were seen in 58% of children after six months of ART and 64% after 12 months. After six months of ART, lower baseline hemoglobin (p = 0.037), presence of chronic diarrhea (p = 0.007), and virologic failure (p = 0.046) were all associated with poor CD4 recovery by multivariate logistic regression. After 12 months of ART, poor CD4 recovery was associated with higher baseline CD4% (p = 0.005), chronic diarrhea (p = 0.02), and virologic failure (p<0.001). Age less than 3 years at ART initiation (p = 0.0003), higher baseline CD4% (p<0.001), and higher baseline WAZ (p<0.001) were all associated with poor WAZ improvements after 6 months by multivariate logistic regression.

Conclusion

The presence of chronic diarrhea at baseline, independent of nutritional status and viral response, predicts poor CD4 recovery. Age at initiation of ART is an important factor in early WAZ response to ART, while viral suppression strongly predicts CD4 recovery but not WAZ improvement.     

Association between the interleukin-6 promoter polymorphism -174G/C and serum lipoprotein(a) concentrations in humans

Background

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism −174G/C is associated with baseline serum Lp(a) concentrations.

Methodology/Principal Findings

We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (n = 510), and the ones with Lp(a) <60 mg/dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95% CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95% CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations.

Conclusions/Significance

The IL-6 single nucleotide polymorphism −174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established.     

Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review

Background

Improving the outcomes of HIV/AIDS treatment programs in resource-limited settings requires successful linkage of patients testing positive for HIV to pre–antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa.

Methods and Findings

We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%–88%); Stage 2, 46% (31%–95%); and Stage 3, 68% (14%–84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations.

Conclusions

Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported. Please see later in the article for the Editors'' Summary     

Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection

Objectives

The magnitude of HIV viral rebound following ART cessation has consequences for clinical outcome and onward transmission. We compared plasma viral load (pVL) rebound after stopping ART initiated in primary (PHI) and chronic HIV infection (CHI).

Design

Two populations with protocol-indicated ART cessation from SPARTAC (PHI, n = 182) and SMART (CHI, n = 1450) trials.

Methods

Time for pVL to reach pre-ART levels after stopping ART was assessed in PHI using survival analysis. Differences in pVL between PHI and CHI populations 4 weeks after stopping ART were examined using linear and logistic regression. Differences in pVL slopes up to 48 weeks were examined using linear mixed models and viral burden was estimated through a time-averaged area-under-pVL curve. CHI participants were categorised by nadir CD4 at ART stop.

Results

Of 171 PHI participants, 71 (41.5%) rebounded to pre-ART pVL levels, at a median of 50 (95% CI 48–51) weeks after stopping ART. Four weeks after stopping treatment, although the proportion with pVL≥400 copies/ml was similar (78% PHI versus 79% CHI), levels were 0.45 (95% CI 0.26–0.64) log₁₀ copies/ml lower for PHI versus CHI, and remained lower up to 48 weeks. Lower CD4 nadir in CHI was associated with higher pVL after ART stop. Rebound for CHI participants with CD4 nadir >500 cells/mm³ was comparable to that experienced by PHI participants.

Conclusions

Stopping ART initiated in PHI and CHI was associated with viral rebound to levels conferring increased transmission risk, although the level of rebound was significantly lower and sustained in PHI compared to CHI.     

Gender difference in 2-year mortality and immunological response to ART in an HIV-infected Chinese population, 2006-2008

Background

Since it was initiated in 2002, the China Free Antiretroviral Treatment (ART) Program has been progressing from an emergency response to a standardized treatment and care system. As of December 31, 2009, a total of 81,880 patients in 31 provinces, autonomous regions, and special municipalities received free ART. Gender differences, however, in mortality and immunological response to ART in this cohort have never been described.

Objective

To understand whether women and men who enrolled in the China National Free ART Program responded equally well to the treatment.

Methods

A retrospective analysis of the national free ART databases from June 2006–December 2008 was performed. HIV-infected subjects who were 18 years or older, ART naïve at baseline, and on a 3TC regimen enrolled in the program from June 1 to December 31, 2006, were included in this study, then followed up to 2 years.

Results

Among 3457 enrolled subjects who met the inclusion criteria, 59.2% were male and 40.8% female. The majority of the subjects were 19–44 years old (77%) and married (72%). Over the full 24 months of follow-up, the mortality rate was 19.0% in males and 11.4% in females (p = 0.0014). Males on therapy for 3–24 months were more likely to die than females (HR = 1.46, 95% CI: 1.04–2.06, p = 0.0307) after adjusting for baseline characteristics. Compared to men, women had higher CD4+ counts over time after initiating ART (p<0.0001).

Conclusions

Our study showed that women had an overall lower mortality and higher CD4+ counts than men in response to ART treatment, which may be attributed to adherence, biological factors, social, cultural and economic reasons. Further study is needed to explore these factors that might contribute to the gender differences in mortality and immunological response to ART.     

Renal Function Declines More in Tenofovir- than Abacavir-Based Antiretroviral Therapy in Low-Body Weight Treatment-Na?ve Patients with HIV Infection

Objective

To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection.

Design

We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART.

Methods

The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model.

Results

The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152–2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339–3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494–5.139; p = 0.001) (61–68 kg: adjusted HR = 1.908; 95%CI, 0.764–4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318–3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003).

Conclusion

The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.     

Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome in a Randomized Study of Early vs. Deferred ART during an Opportunistic Infection

Background

Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI).

Methodology/Principal Findings

A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher''s exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher''s exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS.

Implications

In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00055120","term_id":"NCT00055120"}}NCT00055120     

Validation of a new test for Schistosoma haematobium based on detection of Dra1 DNA fragments in urine: evaluation through latent class analysis

Background

Diagnosis of urogenital schistosomiasis in chronically infected adults is challenging but important, especially because long term infection of the bladder and urinary tract can have dire consequences. We evaluated three tests for viable infection: detection of parasite specific DNA Dra1 fragments, haematuria and presence of parasite eggs for sensitivity (Se) and specificity (Sp).

Methods

Over 400 urine specimens collected from adult volunteers in an endemic area in Western Nigeria were assessed for haematuria then filtered in the field, the filter papers dried and later examined for eggs and DNA. The results were stratified according to sex and age and subjected to Latent Class analysis.

Conclusions

Presence of Dra1 in males (Se = 100%; Sp = 100%) exceeded haematuria (Se = 87.6%: Sp = 34.7%) and detection of eggs (Se = 70.1%; Sp = 100%). In females presence of Dra1 was Se = 100%: Sp = 100%, exceeding haematuria (Se = 86.7%: Sp = 77.0%) and eggs (Se = 70.1%; Sp = 100%). Dra1 became undetectable 2 weeks after praziquantel treatment. We conclude detection of Dra1 fragment is a definitive test for the presence of Schistosoma haematobium infection.