The shift in tuberculosis timing among people living with HIV in the course of antiretroviral therapy scale-up in Malawi.

INTRODUCTION: Although the use of antiretroviral therapy (ART) reduces HIV-associated tuberculosis (TB), patients living with HIV receiving ART remain at a higher risk of developing TB compared to those without HIV. We investigated the incidence of TB and the proportion of HIV-associated TB cases among patients living with HIV who are receiving ART. METHODS: The study used TB registration and ART programme data collected between 2008 and 2017 from an integrated, public clinic in urban Lilongwe, Malawi. ART initiation was based on either WHO clinical staging or CD4 cell count. The CD4 thresholds for ART initiation eligibility was initially 250 cells/µL then changed to 350 cells/µL in 2011, 500 cells/µL in 2014 and to universal treatment upon diagnosis from 2016. Using TB registration data, we calculated the proportion of TB/HIV patients who were already on ART when they registered for TB treatment by year of TB registration. ART registration data were used to examine TB incidence by calendar year of ART follow-up and by time on ART. RESULTS: The overall proportion of TB/patients living with HIV who started TB treatment while on ART increased from 21% in 2008 to 81% in 2017 but numbers remained relatively constant at 500 TB cases annually. The overall incidence rate of TB among patients on ART was 1.35/100 person-years (95% CI 1.28 to 1.42). The incidence of TB by time on ART decreased from 6.4/100 person-years in the first three months of ART to 0.4/100 person-years after eight years on ART. TB incidence was highest in the first month on ART. The annual rate of TB among patients on ART rapidly decreased each calendar year and stabilized at 1% after 2013. Although the risk of developing TB decreased with year of ART initiation in univariable analysis, there was no significant association after adjusting for sex, age and reason for ART eligibility. CONCLUSIONS: The decline in TB incidence over calendar years suggests protective effects of early ART initiation. The high TB incidence within the first month of ART highlights the need for more sensitive tools such as X-ray and GeneXpert to identify patients living with HIV who have clinical and subclinical TB disease at ART initiation.

Characteristics and outcomes of older HIV-infected patients receiving antiretroviral therapy in Malawi: A retrospective observation cohort study.

OBJECTIVE: To estimate patients enrolling on antiretroviral therapy (ART) over time; describe trends in baseline characteristics; and compare immunological response, loss to follow-up (LTFU), and mortality by three age groups (25-39, 40-49 and ≥50 years). DESIGN: A retrospective observation cohort study. METHODS: This study used routine ART data from two public clinics in Lilongwe, Malawi. All HIV-infected individuals, except pregnant or breastfeeding women, aged ≥ 25 years at ART initiation between 2006 and 2015 were included. Poisson regression models estimated risk of mortality, stratified by age groups. RESULTS: Of 37,378 ART patients, 3,406 were ≥ 50 years old. Patients aged ≥ 50 years initiated ART with more advanced WHO clinical stage and lower CD4 cell count than their younger counterparts. Older patients had a significantly slower immunological response to ART in the first 18 months on ART compared to patients aged 25-39 years (p = 0.04). Overall mortality rates were 2.3 (95% confidence Interval (CI) 2.2-2.4), 2.9 (95% CI 2.7-3.2) and 4.6 (95% CI 4.2-5.1) per 100 person-years in patients aged 25-39 years, 40-49 years and 50 years and older, respectively. Overall LTFU rates were 6.3 (95% CI 6.1-6.5), 4.5 (95% CI 4.2-4.7), and 5.6 (95% CI 5.1-6.1) per 100 person years among increasing age cohorts. The proportion of patients aged ≥ 50 years and newly enrolling into ART care remained stable at 9% while the proportion of active ART patients aged ≥50 years increased from 10% in 2006 to 15% in 2015. CONCLUSION: Older people had slower immunological response and higher mortality. Malawi appears to be undergoing a demographic shift in people living with HIV. Increased consideration of long-term ART-related problems, drug-drug interactions and age-related non-communicable diseases is warranted.

Implementation and Operational Research: Early Tracing of Children Lost to Follow-Up From Antiretroviral Treatment: True Outcomes and Future Risks.

BACKGROUND: Loss to follow-up (LTFU) challenges the success of antiretroviral therapy (ART) scale-up among pediatric patients. Little is known about children who drop out of care. We aim to analyze risk factors for LTFU among children on ART, find their true outcomes through tracing, and investigate their final outcomes after resuming ART. METHODS: This is a descriptive, retrospective, cohort study of children on ART between April 2006 and December 2010 in 2 clinics in urban Malawi. Routine data from an electronic data system were used and matched with information obtained through routine tracing procedures. RESULTS: Of 985 children (1999 child-years) on ART, 251 were LTFU: 12.6/100 child-years. At ART initiation, wasting [adjusted hazard ratio (AHR) 1.58 and 95% confidence interval (CI): 1.02 to 2.44] was independently associated with higher risk of LTFU. Of 201 LTFU children traced, 79% were found: 11% died, 25% stopped, 26% transferred-out, and 37% were still on ART. Median time between last visit and first tracing was 84 days (interquartile range: 64-101 days). Tracing reduced risk of LTFU by 38% (AHR 0.62 and 95% CI: 0.42 to 0.91) and decreased LTFU from 23.2% to 8.5%. Additional outcomes of stop, death, and transfer-out increased 4.4-fold, 1.8-fold, and 1.3-fold, respectively. Traced children with gaps in ART intake who resumed ART had higher risk of stopping (AHR 4.92 and 95% CI: 1.67 to 14.5) and transfer out (AHR 2.70 and 95% CI: 1.75 to 4.17) as final outcome. CONCLUSIONS: Early tracing substantially reduces LTFU; approximately one-third presumed LTFU was found to be still on ART. Children with wasting at initiation and those traced and found to have irregular ART intake require targeted interventions.

Timing of antiretroviral therapy and regimen for HIV-infected patients with tuberculosis: the effect of revised HIV guidelines in Malawi.

BACKGROUND: In July 2011, the Malawi national HIV program implemented the integrated antiretroviral therapy (ART) and prevention of mother-to-child transmission (PMTCT) guidelines. Among the principle goals of the guidelines were increasing ART uptake among TB/HIV co-infected patients and treating TB/HIV patients with a different drug regimen. We, therefore, assessed the effects of the new guidelines on ART uptake, the factors associated with ART uptake and the frequency of ARV-related adverse events in TB/HIV co-infected patients. METHODS: This was an observational cohort study using routine program data. All ART-naïve adult TB/HIV co-infected patients starting TB treatment over the six months preceding and following implementation of 2011 integrated ART/PMTCT guidelines were included. RESULTS: A total of 685 adult TB/HIV co-infected patients were registered in the study; 377 (55%) before and 308 (45%) after the implementation of the new guidelines. ART uptake increased from 70% (240/308) before implementation of the new guidelines to 78% (262/377) after the inception of the new guidelines (P=0.013). The proportion of TB patients initiating ART within two weeks of starting TB treatment increased from 30% before implementation of the new guidelines to 46% after implementation of the new guidelines (p <0.001). The median time from the start of TB treatment to ART initiation dropped from 16 days (IQR 14-31) before the new guidelines to 14 days (IQR 9-20; p = 0.004) after implementing the new guidelines. Factors associated with ART uptake were enrolment in HIV care before starting TB treatment and being a retreatment TB patient. The overall frequency of ARV-related adverse events was higher in patients on d4T/3TC/NVP (35%) than those on TDF/3TC/EFV (25%) but not significantly different (P=0.052). CONCLUSION: Implementation of the 2011 Malawi Integrated ART/PMTCT guidelines was associated with an overall increase in ART uptake among TB/HIV patients and with an increase in the number of patients initiating ART within two weeks of starting their TB treatment. However, the reduction in time between initiating TB treatment and starting ART was small suggesting that further measures must be implemented to facilitate ART uptake. Early enrolment in HIV care provides opportunities for timely ART initiation among TB patients.

Comparison of treatment outcomes of new smear-positive pulmonary tuberculosis patients by HIV and antiretroviral status in a TB/HIV clinic, Malawi.

BACKGROUND: Smear-positive pulmonary TB is the most infectious form of TB. Previous studies on the effect of HIV and antiretroviral therapy on TB treatment outcomes among these highly infectious patients demonstrated conflicting results, reducing understanding of important issues. METHODS: All adult smear-positive pulmonary TB patients diagnosed between 2008 and 2010 in Malawi's largest public, integrated TB/HIV clinic were included in the study to assess treatment outcomes by HIV and antiretroviral therapy status using logistic regression. RESULTS: Of 2,361 new smear-positive pulmonary TB patients, 86% had successful treatment outcome (were cured or completed treatment), 5% died, 6% were lost to follow-up, 1% failed treatment, and 2% transferred-out. Overall HIV prevalence was 56%. After adjusting for gender, age and TB registration year, treatment success was higher among HIV-negative than HIV-positive patients (adjusted odds ratio 1.49; 95% CI: 1.14-1.94). Of 1,275 HIV-infected pulmonary TB patients, 492 (38%) received antiretroviral therapy during the study. Pulmonary TB patients on antiretroviral therapy were more likely to have successful treatment outcomes than those not on ART (adjusted odds ratio : 1.83; 95% CI: 1.29-2.60). CONCLUSION: HIV co-infection was associated with poor TB treatment outcomes. Despite high HIV prevalence and the integrated TB/HIV setting, only a minority of patients started antiretroviral therapy. Intensified patient education and provider training on the benefits of antiretroviral therapy could increase antiretroviral therapy uptake and improve TB treatment success among these most infectious patients.

Managing HIV-infected children in a low-resource, public clinic: a comparison of nurse vs. clinical officer practices in ART refill, calculation of adherence and subsequent appointments.

BACKGROUND: In Malawi, as in other sub-Saharan African countries, nurses manage patients of all ages on antiretroviral treatment(ART). Nurse management of children is rarely studied.We compare ART prescribing between nurses and clinical officers during routine clinic visits at an urban, public clinic to inform policy in paediatric ART management. METHODS: Caregivers of children on first-line ART provided information about visit dates, pill counts, ART dosage and formulation to a nurse and, subsequently, to a clinical officer. Nurses and clinical officers independently calculated adherence, dosage based on body weight, and set next appointment date. Clinical officers, but not nurses, accessed an electronic data system that made the calculations for them based on information from prior visits, actual and expected pill consumption, and standard drug supplies. Nurses calculated with pen and paper. For numerical variables, Bland-Altman graphs plot differences of each nurse clinical officer pair against the mean, show the 95% limits of agreement (LoA), and also show the mean difference across all reviews. Kappa statistics assess agreement for categorical variables. RESULTS: A total of 704 matched nurse clinical officer reviews of 367 children attending the ART clinics between March and July 2010 were analyzed. Eight nurses and 18 clinical officers were involved; two nurses and five clinical officers managed 100 visits or more. Overall, there was a good agreement between the two cadres. Differences between nurses and clinical officers were within narrow LoA and mean differences showed little deviation from zero, indicating little skewing towards one cadre. LoA of adherence and morning and evening ART dosages varied from -24% to 24%, -0.4 to 0.4 and -0.41 to 0.40 tablets,respectively, with mean differences (95% CI) of 0.003 (-0.9, 0.91), -0.005 (-0.02, 0.01) and -0.009 (-0.02, 0.01). Next appointment calculations differed more between cadres with LoA from -40 to 42 days [mean difference: 0.96 days (95%CI:-0.6 to 2.5)], but agreement in the ART formulation prescribed was very good (kappa 0.93). CONCLUSIONS: Nurses' ART prescribing practices and calculations of adherence and next appointments are similar to clinical officers, although clinical officers used an electronic system. Our findings support the decision of Malawi's health officials to utilize nurses to manage paediatric ART patients.

Ensuring HIV-infected pregnant women start antiretroviral treatment: an operational cohort study from Lilongwe, Malawi.

OBJECTIVES: HIV-infected women identified through antenatal care (ANC) often fail to access antiretroviral treatment (ART), leaving them and their infants at risk for declining health or HIV transmission. We describe results of measures to improve uptake of ART among eligible pregnant women. METHODS: Between October 2006 and December 2009, interventions implemented at ANC and ART facilities in urban Lilongwe aimed to better link services for women with CD4 counts <250/µl. A monitoring system followed women referred for ART to examine trends and improve practices in referral completion, on-time ART initiation and ART retention. RESULTS: Six hundred and twelve women were ART eligible: 604 (99%) received their CD4 result, 344 (56%) reached the clinic, 286 (47%) started ART while pregnant and 261 (43%) were either alive on ART or transferred out after 6 months. Between 2006 and 2009, the median (IQR) time between CD4 blood draw and ART initiation fell from 41 days (17, 349) to 15 days (7,42) (P = 0.183); the proportion of eligible individuals starting ART while pregnant and retained for 6 months improved from 17% to 65% (P < 0.001). Delays generally shortened within the continuum of care from 2006 to 2009; however, time from CD4 blood draw to ART referral increased from 7 to 14 days. CONCLUSIONS: Referrals between facilities and delays through CD4 count measurements create bottlenecks in patient care. Retention improved over time, but delays within the linkage process remained. ART initiation at ANC plus use of point-of-care CD4 tests may further enhance ART uptake.

Re-treatment tuberculosis cases categorised as "other": are they properly managed?

BACKGROUND: Although the World Health Organization (WHO) provides information on the number of TB patients categorised as "other", there is limited information on treatment regimens or treatment outcomes for "other". Such information is important, as inappropriate treatment can lead to patients remaining infectious and becoming a potential source of drug resistance. Therefore, using a cohort of TB patients from a large registration centre in Lilongwe, Malawi, our study determined the proportion of all TB re-treatment patients who were registered as "other", and described their characteristics and treatment outcomes. METHODS: This retrospective observational study used routine program data to determine the proportion of all TB re-treatment patients who were registered as "other" and describe their characteristics and treatment outcomes between January 2006 and December 2008. RESULTS: 1,384 (12%) of 11,663 TB cases were registered as re-treatment cases. Of these, 898 (65%) were categorised as "other": 707 (79%) had sputum smear-negative pulmonary TB and 191 (21%) had extra pulmonary TB. Compared to the smear-positive relapse, re-treatment after default (RAD) and failure cases, smear-negative "other" cases were older than 34 years and less likely to have their HIV status ascertained. Among those with known HIV status, "other" TB cases were more likely to be HIV positive. Of TB patients categorised as "other", 462 (51%) were managed on the first-line regimen with a treatment success rate of 63%. CONCLUSION: A large proportion of re-treatment patients were categorised as "other". Many of these patients were HIV-infected and over half were treated with a first-line regimen, contrary to national guidelines. Treatment success was low. More attention to recording, diagnosis and management of these patients is warranted as incorrect treatment regimen and poor outcomes could lead to the development of drug resistant forms of TB.