Antiretroviral Treatment at Ethiopian Health Centers

In 2017,for the first time, more than half of all people living with HIV (PLHIV) had access to antiretroviral treatment (ART). This expansion of ART has in part been achieved through decentralization of HIV care in resource-limited settings. There, many PLHIV now receive care at ART clinics integrated within the primary health care system. At these clinics, non-physician clinicians are responsible for all aspects of care. Concomitant tuberculosis (TB) is common among PLHIV in many high-burden countries. Therefore, clinicians at these clinics must be able to diagnose and treat concomitant TB in parallell with ART in order to achieve satisfactory outcome of care. Failing ART results in high mortality and risk of drug resistance development that can be detrimental both for the individual and for the community at large. The first three papers in this thesis explores aspects of ART outcome among patients receiving care at Ethiopian public health centers. In particular, the impact of concomitant TB on ART outcome is investigated. For this purpose, 812 ART-naïve adults eligible to start ART (CD4 count <350 cells/mm3 or WHO stage 4) were prospectively recruited and followed for up to four years after ART initiation. At study inclusion, all participants were investigated for concomitant TB by active case-finding. We found that concomitant TB, present in nearly 1/5 study participants, did not negatively impact short-term virological suppression (paper I), risk of short-term mortality (paper II), or long-term virological, clinical, or immunological outcome of ART (paper III). However, we did find men to have an increased risk of poor virological outcome of ART both in short- and long-term, and that they had an increased risk of becoming lost to follow-up. Additionally, subjects with malnutrition had an elevated risk of mortality both soon after study enrollment, and during the long-term follow-up. Furthermore, these individuals had high risk of poor long-term virological outcome of ART. In the fourth paper, a clinical algorithm for targeted viral load testing was constructed. Through the use of three simple criteria (current CD4 count, mid-upper arm circumference, and adherence to ART) subjects with high risk of virological failure 12 months after ART initiation could be identified. If the performance is validated, this algorithm could be used to guide virological monitoring of ART more efficiently in areas where viral load resources are limited. In conclusion, we found that most PLHIV – regardless of concomitant TB – have good outcome of ART at Ethiopian public health centers during up to four years of follow-up. These findings demonstrate the feasibility of health center-based ART in settings where concomitant TB is common. In addition, we identified factors associated with poor outcome of care. If these individuals are identified in time, outcome of care might be improved and drug resistance development prevented. Finally, we constructed an algorithm for targeted viral load testing

Screening for cryptococcal antigenemia using the lateral flow assay in antiretroviral therapy-naïve HIV-positive adults at an Ethiopian hospital clinic.

Since treatment for latent cryptococcal infection (CI) before starting antiretroviral therapy (ART) reduces mortality in HIV-infected subjects, screening for cryptococcal antigen (CrAg) in blood is recommended for individuals with CD4 cell counts < 100 cells/µL in regions with high CI prevalence. We assessed CrAg screening using the lateral flow assay in HIV-infected adults eligible for ART in central Ethiopia

Long-term Outcome of Antiretroviral Treatment in Patients With and Without Concomitant Tuberculosis Receiving Health Center-Based Care-Results From a Prospective Cohort Study

Background: In order to increase treatment coverage, antiretroviral treatment (ART) is provided through primary health care in low-income high-burden countries, where tuberculosis (TB) co-infection is common. We investigated the long-term outcome of health center-based ART, with regard to concomitant TB.Methods: ART-naïve adults were included in a prospective cohort at Ethiopian health centers and followed for up to 4 years after starting ART. All participants were investigated for active TB at inclusion. The primary study outcomes were the impact of concomitant TB on all-cause mortality, loss to follow-up (LTFU), and lack of virological suppression (VS). Kaplan-Meier survival estimates and Cox proportional hazards models with multivariate adjustments were used.Results: In total, 141/729 (19%) subjects had concomitant TB, 85% with bacteriological confirmation (median CD4 count TB, 169 cells/mm3; IQR, 99-265; non-TB, 194 cells/mm3; IQR, 122-275). During follow-up (median, 2.5 years), 60 (8%) died and 58 (8%) were LTFU. After ≥6 months of ART, 131/630 (21%) had lack of VS. Concomitant TB did not influence the rates of death, LTFU, or VS. Male gender and malnutrition were associated with higher risk of adverse outcomes. Regardless of TB co-infection status, even after 3 years of ART, two-thirds of participants had CD4 counts below 500 cells/mm3.Conclusions: Concomitant TB did not impact treatment outcomes in adults investigated for active TB before starting ART at Ethiopian health centers. However, one-third of patients had unsatisfactory long-term treatment outcomes and immunologic recovery was slow, illustrating the need for new interventions to optimize ART programs

The risk of cancer among persons with a history of injecting drug use in Sweden - a cohort study based on participants in a needle exchange program.

Abstract Background. Injecting drug use (IDU) may lead to exposure to a range of carcinogenic agents. We investigated the risk and distribution of cancers among individuals with a history of IDU in Sweden. Material and Methods. The cancer incidence in a cohort of longitudinally followed participants in a needle exchange program (NEP), recruited between 1987 and 2007, was compared to that in the Swedish general population, matching for age group and gender. Baseline demographic and drug use data were collected and longitudinal testing of serological markers for HIV, hepatitis B and C virus was performed during NEP participation. Standardized incidence ratios (SIR) for types of cancer found in the study cohort were calculated, using data from the Swedish National Cancer Registry for reference. Results. The mean follow-up time for the 3255 participants was 11.8 years, constituting 38 419 person years at risk. The mean age at end of follow-up was 42.7 years, and 75% of participants were men. Seventy-eight cases of cancer were observed (SIR 1.1 [95% CI = 0.9-1.4]). The SIR was significantly increased for five cancer types among men; primary liver, laryngeal, lung, oropharyngeal and non-melanoma skin cancer (respective SIR 12.8 [95% CI = 4.2-30.0], 9.2 [95% CI = 1.9-26.8], 3.2 [95% CI = 1.5-6.1], 7.3 [95% CI = 1.5-21.2], and 3.5 [95% CI = 1.1-8.2]), and for cancers of endocrine organs among women (5.3 [95% CI = 1.7-12.4]). Conclusion. Although the standardized overall cancer incidence in this relatively young IDU cohort was similar to that in the general population, the risk of specific types of cancer was significantly increased, suggesting that IDU confers elevated risks for certain malignancies. These findings prompt further studies to investigate causative factors and suggest the need for surveillance among persons with a history of IDU

Retention in care among HIV-positive patients initiating second-line antiretroviral therapy: a retrospective study from an Ethiopian public hospital clinic.

Access to second-line antiretroviral therapy (ART) for HIV-positive patients remains limited in sub-Saharan Africa. Furthermore, outcomes of second-line ART may be compromised by mortality and loss to follow-up (LTFU)

Brief Report : Interferon-γ-Inducible Protein 10-A Potential Marker for Targeted Viral Load Monitoring of Antiretroviral Treatment?

BACKGROUND: The use of surrogate markers for targeting viral load (VL) testing could be an alternative to universal VL testing during antiretroviral treatment (ART) and would allow for more effective resource allocation. We investigated the correlation between levels of HIV RNA and interferon-γ-inducible protein 10 (IP-10) in Ethiopian adults at 12 months after ART initiation. In addition, we specifically investigated differences in IP-10 levels between patients with and without virological suppression.SETTING: Cohort of HIV-positive adults receiving ART at Ethiopian health centers.METHODS: Using a nested case-control design, individuals without virological suppression (HIV RNA ≥ 150 copies/mL) at 12 months after ART initiation were gender-matched with virologically suppressed controls (1:2 ratio). IP-10 levels were correlated with HIV RNA, and the distribution of IP-10 was compared for 3 VL strata: <150 copies/mL (VL < 150), 150-999 copies/mL (VL150-999), and ≥1000 copies/mL (VL ≥ 1000).RESULTS: At 12 months after ART initiation, the following VL distribution was found among 192 individuals (50% women): VL < 150, 122/192 (63.5%); VL150-999, 23/192 (12.0%); and VL ≥ 1000 47/192 (24.5%). IP-10 and HIV RNA levels were positively correlated (r = 0.481; P < 0.0001). Median IP-10 levels for the VL strata were VL < 150: 159 pg/mL [interquartile range (IQR) 121-246], VL150-999: 174 pg/mL (IQR 131-276), and VL ≥ 1000: 343 pg/mL (IQR 190-529), respectively. These differences were statistically significant for VL ≥ 1000 versus VL < 150 (adjusted P < 0.001) and VL150-999 (adjusted P = 0.004), respectively.CONCLUSIONS: IP-10 and HIV RNA levels during ART showed significant correlations, with significantly higher IP-10 concentration in ART recipients with VL ≥ 1000 copies/mL compared to those with suppressed or undetectable VL

Development of an algorithm for determination of the likelihood of virological failure in HIV-positive adults receiving antiretroviral therapy in decentralized care

Background: Early identification of virological failure (VF) limits occurrence and spread of drug-resistant viruses in patients receiving antiretroviral treatment (ART). Viral load (VL) monitoring is therefore recommended, but capacities to comply with this are insufficient in many low-income countries. Clinical algorithms might identify persons at higher likelihood of VF to allocate VL resources. Objectives: We aimed to construct a VF algorithm (the Viral Load Testing Criteria; VLTC) and compare its performance to the 2013 WHO treatment failure criteria. Methods: Subjects with VL results available 1 year after ART start (n = 494) were identified from a cohort of ART-naïve adults (n = 812), prospectively recruited and followed 2011-2015 at Ethiopian health centres. VF was defined as VL≥1000 copies/mL. Variables recorded at the time of sampling, with potential association with VF, were used to construct the algorithm based on multivariate logistic regression. Results: Fifty-seven individuals (12%) had VF, which was independently associated with CD4 count <350 cells/mm3, previous ART interruption, and short mid-upper arm circumference (<24cm and <23cm, for men and women, respectively). These variables were included in the VLTC. In derivation, the VLTC identified 52/57 with VF; sensitivity 91%, specificity 43%, positive predictive value (PPV) 17%, negative predictive value (NPV) 97%. In comparison, the WHO criteria identified 38/57 with VF (sensitivity 67%, specificity 74%, PPV 25%, NPV 94%). Conclusions: The VLTC identified subjects at greater likelihood of VF, with higher sensitivity and NPV than the WHO criteria. If external validation confirms this performance, these criteria could be used to allocate limited VL resources. Due to its limited specificity, it cannot be used to determine treatment failure in the absence of a confirmatory viral load

Performance of Galectin-9 for Identification of HIV Viremia in Adults Receiving Antiretroviral Therapy in a Resource-Limited Setting

Background: Targeted viral load (VL) testing has been proposed for antiretroviral treatment (ART) monitoring in resource-limited settings. In this study, we have investigated the performance of the host biomarker galectin-9 (Gal-9), alone and in combination with interferon-γ-inducible protein 10 (IP-10), in identifying individuals at increased likelihood of viremia during ART.Setting:Cohort of HIV-positive adults receiving ART at Ethiopian health centers.Methods:We included participants with detectable viremia (VL ≥150 copies/mL) 12 months after starting ART and sex-matched nonviremic controls. Performance to identify individuals with VL ≥1000 copies/mL was determined for Gal-9 and the Gal-9/IP-10 combination, respectively, using receiver operating characteristic (ROC) analysis.Results:Among 191 participants (50.3% women), 46 (24.1%) had VL ≥1000 copies/mL, 23 (12.0%) had 150-999 copies/mL, and 122 (63.9%) had <150 copies/mL. Gal-9 and VL were positively correlated (rs= 0.451, P < 0.001). Sensitivity and specificity for Gal-9 to identify individuals with VL ≥1000 copies/mL were 91.3% (95% CI: 79.2-97.6) and 54.5% (95% CI: 46.0-62.8), respectively. The area under the ROC curve for Gal-9 was 0.810 (95% CI: 0.745-0.875), which was similar to that of the combination of Gal-9 and IP-10 [0.849 (95% CI: 0.792-0.905)]. Assuming 10% prevalence of VL ≥1000 copies/mL, using Gal-9 for targeted VL testing instead of universal VL testing would reduce the number of VL tests from 10 to 5 to identify 1 viremic individual, with misclassification of 1 in 10 viremic individuals.Conclusions:Gal-9 is a potential screening marker for targeted VL monitoring in ART recipients. Further studies are needed to determine optimal threshold levels

Validation of the Viral Load Testing Criteria – an algorithm for targeted viral load testing in HIV-positive adults receiving antiretroviral therapy

Objectives: Restricted capacity for viral load (VL) testing is a major obstacle for antiretroviral therapy (ART) programmes in high-burden regions. Algorithms for targeted VL testing could help allocate laboratory resources rationally. We validated the performance of the Viral Load Testing Criteria (VLTC), an algorithm with satisfactory performance in derivation (sensitivity 91%, specificity 43%). Methods: HIV-positive adults who had been receiving first-line ART for ≥12 months at three Ethiopian public ART clinics were included. Healthcare providers collected data on variables of the VLTC: current CD4 count, mid-upper arm circumference (MUAC) and self-reported treatment interruption. VL testing was performed in parallel. Performance of the algorithm for identification of patients with VL ≥ 1000 copies/ml was evaluated. Results: Of 562 patients (female 62%, median ART duration 92 months), 33 (6%) had VL ≥ 1000 copies/ml. Sensitivity for the VLTC was 85% (95% CI, 68–95), specificity 60% (95% CI, 55–64), positive predictive value 12% (95% CI, 10–14) and negative predictive value 98% (95% CI, 97–99). Use of the algorithm would reduce the number of VL tests required by 57%. Misclassification occurred in 5/33 (15%) of subjects with VL ≥ 1000 copies/ml. Conclusion: In validation, the VLTC performed similarly well as derivation. Use of the VLTC may be considered for targeted VL testing for ART monitoring in high-burden regions