Six months survival and risk factors for attrition for patients detected with cryptococcal antigenemia through screening in Malawi.

MAIN OBJECTIVE: A cohort of adult Malawian people living with HIV (PLHIV) testing positive for cryptococcal antigenemia was observed and followed to determine the outcomes and risk factors for attrition. METHODS CONCEPT: Eligible PLHIV were enrolled at 5 health facilities in Malawi, representing different levels of health care. ART naïve patients, ART defaulters returning to care, and patients with suspected or confirmed ART treatment failure with CD4 <200 cells/µL or clinical stage 3 or 4 were enrolled and received CrAg tests on whole blood specimens from August 2018 to August 2019. Hospitalized PLHIV were enrolled and tested for CrAg from January 2019 to August 2019, regardless of CD4 or clinical stage. Patients with cryptococcal antigenemia were managed per Malawian clinical guidelines and were followed up for six months. Survival and risk factors for attrition at six months were assessed. RESULTS: A total of 2146 patients were screened and 112 (5.2%) had cryptococcal antigenemia. Prevalence ranged from 3.8% (Mzuzu Central Hospital) to 25.8% (Jenda Rural Hospital). Of the 112 patients with antigenemia, 33 (29.5%) were diagnosed with concurrent CM at the time of enrollment. Six-month crude survival of all patients with antigenemia (regardless of CM status) ranged from 52.3% (assuming lost-to-follow-up (LTFU) patients died) to 64.9% (if LTFU survived). Patients who were diagnosed with concurrent CM by CSF test had poor survival (27.3-39.4%). Patients with antigenemia who were not diagnosed with concurrent CM had 71.4% (if LTFU died)- 89.8% (if LTFU survived) survival at six months. In adjusted analyses, patients with cryptococcal antigenemia detected after admission to inpatient care (aHR: 2.56, 1.07-6.15) and patients with concurrent CM at the time of positive antigenemia result (aHR: 2.48, 1.04-5.92) had significantly higher hazard of attrition at six months. CONCLUSIONS: Overall, our findings indicate a need for routine access to CrAg screening and pre-emptive fluconazole treatment as a way to detect cryptococcal antigenemia and prevent CM in outpatient and inpatient settings. Rapid access to diagnosis and treatment for cryptococcal meningitis (CM) with gold-standard antifungals is needed to improve survival of patients with advanced HIV in Malawi.

Isoniazid-associated pellagra during mass scale-up of tuberculosis preventive therapy: a case-control study.

BACKGROUND: Pellagra is caused by niacin (vitamin B3) deficiency and patients with pellagra present with a characteristic rash. Isoniazid disrupts intracellular niacin synthesis and might induce niacin deficiency. In 2017, Malawi scaled up continuous isoniazid preventive treatment (IPT) for tuberculosis prevention among people living with HIV. In addition, an under-diversified diet based on subsistence maize, as is commonly the case in Malawi, is a risk factor for pellagra. We aimed to investigate whether large-scale isoniazid exposure in Malawi contributed to the cumulative risk for pellagra in a nutritionally vulnerable population. METHODS: We did a matched case-control study to evaluate the association between daily, continuous isoniazid exposure and pellagra. We matched sequentially enrolled patients with pellagra each with four control participants by sex and age from referral dermatology centres in three IPT scale-up districts in Malawi (Lilongwe, Blantyre, and Zomba) to evaluate isoniazid as a risk for pellagra using multivariable conditional logistic regression. We established a community clinic referral system surrounding the dermatology clinic in each district to enhance case-finding and included all patients with pellagra, regardless of referral status. The primary outcome was dermatologist-diagnosed pellagra. We calculated the interval between isoniazid initiation and rash onset and assessed 30-day clinical outcomes after multi-B vitamin treatment containing 300 mg nicotinamide daily. FINDINGS: Between Feb 5 and Aug 9, 2019, we enrolled 197 patients with pellagra and 781 matched controls. Isoniazid exposure was associated with an increased risk of pellagra (adjusted odds ratio 42·6 [95% CI 13·3-136·6]). Significant covariates included HIV infection, referral status, food insecurity, underweight, excess alcohol consumption, and, among women, lactation. The median time from isoniazid initiation to rash onset was shorter during the season of food scarcity (5 months [IQR 3-7]) compared with the harvest season (9 months [8-11]; hazard ratio 7·2 [95% CI 3·2-16·2], log-rank p<0·0001). Those with isoniazid-associated pellagra who discontinued isoniazid and adhered to multi-B vitamin treatment showed 30-day clinical improvement. INTERPRETATION: Continuous IPT scale-up and the annual period of food scarcity both increased the risk of pellagra in Malawi. Use of shorter rifamycin-based regimens for tuberculosis prevention and food fortification in populations with undernutrition might reduce this risk. Niacin-containing multi-B vitamin co-administration with isoniazid as pellagra prevention is worth exploring further. FUNDING: This study was supported by the President's Emergency Plan for AIDS Relief through the US Centers for Disease Control and Prevention under project 7173.

Liberia adherence and loss-to-follow-up in HIV and AIDS care and treatment: A retrospective cohort of adolescents and adults from 2016-2019.

Antiretroviral therapy (ART) is a lifesaving intervention for people living with HIV infection, reducing morbidity and mortality; it is likewise essential to reducing transmission. The "Treat all" strategy recommended by the World Health Organization has dramatically increased ART eligibility and improved access. However, retaining patients on ART has been a major challenge for many national programs in low- and middle-income settings, despite actionable local policies and ambitious targets. To estimate retention of patients along the HIV care cascade in Liberia, and identify factors associated with loss-to-follow-up (LTFU), death, and suboptimal treatment adherence, we conducted a nationwide retrospective cohort study utilizing facility and patient-level records. Patients aged ≥15 years, from 28 facilities who were first registered in HIV care from January 2016 -December 2017 were included. We used Cox proportional hazard models to explore associations between demographic and clinical factors and the outcomes of LTFU and death, and a multinomial logistic regression model to investigate factors associated with suboptimal treatment adherence. Among the 4185 records assessed, 27.4% (n = 1145) were males and the median age of the cohort was 37 (IQR: 30-45) years. At 24 months of follow-up, 41.8% (n = 1751) of patients were LTFU, 6.6% (n = 278) died, 0.5% (n = 21) stopped treatment, 3% (n = 127) transferred to another facility and 47.9% (n = 2008) were retained in care and treatment. The incidence of LTFU was 46.0 (95% CI: 40.8-51.6) per 100 person-years. Relative to patients at WHO clinical stage I at first treatment visit, patients at WHO clinical stage III [adjusted hazard ratio (aHR) 1.59, 95%CI: 1.21-2.09; p <0.001] or IV (aHR 2.41, 95%CI: 1.51-3.84; p <0.001) had increased risk of LTFU; whereas at registration, age category 35-44 (aHR 0.65, 95%CI: 0.44-0.98, p = 0.038) and 45 years and older (aHR 0.60, 95%CI: 0.39-0.93, p = 0.021) had a decreased risk. For death, patients assessed with WHO clinical stage II (aHR 2.35, 95%CI: 1.53-3.61, p<0.001), III (aHR 2.55, 95%CI: 1.75-3.71, p<0.001), and IV (aHR 4.21, 95%CI: 2.57-6.89, p<0.001) had an increased risk, while non-pregnant females (aHR 0.68, 95%CI: 0.51-0.92, p = 0.011) and pregnant females (aHR 0.42, 95%CI: 0.20-0.90, p = 0.026) had a decreased risk when compared to males. Suboptimal adherence was strongly associated with the experience of drug side effects-average adherence [adjusted odds ratio (aOR) 1.45, 95% CI: 1.06-1.99, p = 0.02) and poor adherence (aOR 1.75, 95%CI: 1.11-2.76, p = 0.016), and attending rural facility decreased the odds of average adherence (aOR 0.01, 95%CI: 0.01-0.03, p<0.001) and poor adherence (aOR 0.001, 95%CI: 0.0004-0.003, p<0.001). Loss-to-follow-up and poor adherence remain major challenges to achieving viral suppression targets in Liberia. Over two-fifths of patients engaged with the national HIV program are being lost to follow-up within 2 years of beginning care and treatment. WHO clinical stage III and IV were associated with LTFU while WHO clinical stage II, III and IV were associated with death. Suboptimal adherence was further associated with experience of drug side effects. Active support and close monitoring of patients who have signs of clinical progression and/or drug side effects could improve patient outcomes.

Early-phase scale-up of isoniazid preventive therapy for people living with HIV in two districts in Malawi (2017).

BACKGROUND: Isoniazid preventive therapy (IPT) against tuberculosis (TB) is a life-saving intervention for people living with HIV (PLHIV). In September 2017, Malawi began programmatic scale-up of IPT to eligible PLHIV in five districts with high HIV and TB burden. We measured the frequency and timeliness of early-phase IPT implementation to inform quality-improvement processes. METHODS AND FINDINGS: We applied a two-stage cluster design with systematic, probability-proportional-to-size sampling of six U.S. Centers for Disease Control and Prevention (CDC)-affiliated antiretroviral therapy (ART) centers operating in the urban areas of Lilongwe and Blantyre, Malawi (November 2017). ART clinic patient volume determined cluster size. Within each cluster, we sequentially sampled approximately 50 PLHIV newly enrolled in ART care. We described a quality-of-care cascade for intensive TB case finding (ICF) and IPT in PLHIV. PLHIV newly enrolled in ART care were eligibility-screened for hepatitis and peripheral neuropathy, as well as for TB disease using a standardized four-symptom screening tool. Among eligible PLHIV, the overall weighted IPT initiation rate was 70% (95% CI: 46%-86%). Weighted IPT initiation among persons aged <15 years (30% [95% CI: 12%-55%]) was significantly lower than among persons aged ≥15 years (72% [95% CI: 47%-89%]; Rao-Scott chi-square P = 0.03). HIV-positive children aged <5 years had a weighted initiation rate of only 13% (95% CI: 1%-79%). For pregnant women, the weighted initiation rate was 67% (95% CI: 32%-90%), similar to non-pregnant women aged ≥15 years (72% [95% CI: 49%-87%]). Lastly, 95% (95% CI: 92%-97%) of eligible PLHIV started ART within one week of HIV diagnosis, and 92% (95% CI: 73%-98%) of patients receiving IPT began on the same day as ART. CONCLUSIONS: Early-phase IPT uptake among adults at ART centers in Malawi was high. Child uptake needed improvement. National programs could adapt this framework to evaluate their ICF-IPT care cascades.

Screening for HIV Among Patients at Tuberculosis Clinics - Results from Population-Based HIV Impact Assessment Surveys, Malawi, Zambia, and Zimbabwe, 2015-2016.

The World Health Organization and national guidelines recommend HIV testing and counseling at tuberculosis (TB) clinics for all patients, regardless of TB diagnosis (1). Population-based HIV Impact Assessment (PHIA) survey data for 2015-2016 in Malawi, Zambia, and Zimbabwe were analyzed to assess HIV screening at TB clinics among persons who had positive HIV test results in the survey. The analysis was stratified by history of TB diagnosis* (presumptive versus confirmed†), awareness§ of HIV-positive status, antiretroviral therapy (ART)¶ status, and viral load suppression among HIV-positive adults, by history of TB clinic visit. The percentage of adults who reported having ever visited a TB clinic ranged from 4.7% to 9.7%. Among all TB clinic attendees, the percentage who reported that they had received HIV testing during a TB clinic visit ranged from 48.0% to 62.1% across the three countries. Among adults who received a positive HIV test result during PHIA and who did not receive a test for HIV at a previous TB clinic visit, 29.4% (Malawi), 21.9% (Zambia), and 16.2% (Zimbabwe) reported that they did not know their HIV status at the time of the TB clinic visit. These findings represent missed opportunities for HIV screening and linkage to HIV care. In all three countries, viral load suppression rates were significantly higher among those who reported ever visiting a TB clinic than among those who had not (p<0.001). National programs could strengthen HIV screening at TB clinics and leverage them as entry points into the HIV diagnosis and treatment cascade (i.e., testing, initiation of treatment, and viral load suppression).

Protocol for a Case-Control Study to Investigate the Association of Pellagra With Isoniazid Exposure During Tuberculosis Preventive Treatment Scale-Up in Malawi.

Background: Pellagra is caused by niacin (vitamin B3) deficiency and manifested by a distinctive dermatitis. Isoniazid is critical for treating tuberculosis globally and is a component of most regimens to prevent tuberculosis. Isoniazid may contribute to pellagra by disrupting intracellular niacin synthesis. In 2017, Malawian clinicians recognized a high incidence of pellagra-like rashes after scale-up of isoniazid preventive treatment (IPT) to people living with HIV (PLHIV). This increase in pellagra incidence among PLHIV coincided with a seasonal period of sustained food insecurity in the region, which obscured epidemiological interpretations. Although isoniazid has been implicated as a secondary cause of pellagra for decades, no hypothesis-driven epidemiological study has assessed this relationship in a population exposed to isoniazid. We developed this case-control protocol to assess the association between large-scale isoniazid distribution and pellagra in Malawi. Methods: We measure the relative odds of having pellagra among isoniazid-exposed people compared to those without exposure while controlling for other pellagra risk factors. Secondary aims include measuring time from isoniazid initiation to onset of dermatitis, comparing niacin metabolites 1-methylnicotinamide (1-MN), and l-methyl-2-pyridone-5-carboxamide (2-PYR) in urine as a proxy for total body niacin status among subpopulations, and describing clinical outcomes after 30-days multi-B vitamin (containing 300 mg nicotinamide daily) therapy and isoniazid cessation (if exposed). We aim to enroll 197 participants with pellagra and 788 age- and sex-matched controls (1:4 ratio) presenting at three dermatology clinics. Four randomly selected community clinics within 3-25 km of designated dermatology clinics will refer persons with pellagra-like symptoms to one of the study enrollment sites for diagnosis. Trained study dermatologists will conduct a detailed exposure questionnaire and perform anthropometric measurements. A subset of enrollees will provide a casual urine specimen for niacin metabolites quantification and/or point-of-care isoniazid detection to confirm whether participants recently ingested isoniazid. We will use conditional logistic regression, matching age and sex, to estimate odds ratios for the primary study aim. Discussion: The results of this study will inform the programmatic scale-up of isoniazid-containing regimens to prevent tuberculosis.

Evaluation of 6-Month Versus Continuous Isoniazid Preventive Therapy for Mycobacterium tuberculosis in Adults Living With HIV/AIDS in Malawi.

BACKGROUND: To assist the Malawi Ministry of Health to evaluate 2 competing strategies for scale-up of isoniazid preventive therapy (IPT) among HIV-positive adults receiving antiretroviral therapy. SETTING: Malawi. METHODS: We used a multidistrict, compartmental model of the Malawi tuberculosis (TB)/HIV epidemic to compare the anticipated health impacts of 6-month versus continuous IPT programs over a 12-year horizon while respecting a US$10.8 million constraint on drug costs in the first 3 years. RESULTS: The 6-month IPT program could be implemented nationwide, whereas the continuous IPT alternative could be introduced in 14 (of the 27) districts. By the end of year 12, the continuous IPT strategy was predicted to avert more TB cases than the 6-month alternative, although not statistically significant (2368 additional cases averted; 95% projection interval [PI], -1459 to 5023). The 6-month strategy required fewer person-years of IPT to avert a case of TB or death than the continuous strategy. For both programs, the mean reductions in TB incidence among people living with HIV by year 12 were expected to be <10%, and the cumulative numbers of IPT-related hepatotoxicity to exceed the number of all-cause deaths averted in the first 3 years. CONCLUSIONS: With the given budgetary constraint, the nationwide implementation of 6-month IPT would be more efficient and yield comparable health benefits than implementing a continuous IPT program in fewer districts. The anticipated health effects associated with both IPT strategies suggested that a combination of different TB intervention strategies would likely be required to yield a greater impact on TB control in settings such as Malawi, where antiretroviral therapycoverage is relatively high.

The missed potential of CD4 and viral load testing to improve clinical outcomes for people living with HIV in lower-resource settings.

In a Policy Forum, Peter Ehrenkranz and colleagues discuss the contribution of CD4 and viral load testing to outcomes for people with HIV in low- and middle-income countries.

Feasibility and cost analysis of programmatic implementation of Microscopic-Observation Drug Susceptibility (MODS) assay in Nigeria.

Objectives: Detection of Multi-drug resistant tuberculosis in Nigeria still remains a challenge. We evaluated the feasibility of programmatic implementation of the Microscopic-Observation Drug Susceptibility (MODS) assay, a rapid culture and drug susceptibility testing technique for drug susceptibility testing in a low resource setting. Method: In a novel laboratory setting in Nigeria, we obtained data from the market on the cost of materials necessary for MODS assay. Three routinely collected sputum specimens from 160 tuberculosis suspects were evaluated by smear microscopy while only the early morning specimen was used for MODS culture. Results: MODS assay detected M. tuberculosis in 97.7% (42/43) of smear positive and 6.0% (7/117) of smear negative TB suspects. There was a statistically significant advantage of a single MODS culture over 3 smear microscopies (P=0.019). The modal time from culture of specimen to detection of M. tuberculosis and availability of drug susceptibility result for MODS was 7days with a mean of 8.4 days (Range= 5-13 days). Culture and susceptibility result was available in 18.4% (9/49) of patients within 5days of culture. Turnaround time for smear microscopy in the centers was 3 days. Cost of processing one specimen by MODS assay in the study was USD2.65. Multi-Drug resistant tuberculosis (MDR-TB) was detected in 4.1% (2/49) while Isoniazid mono-resistance was detected in 2.0% (1/49) of the culture positive cases. All the drug resistant isolates were from re-treatment cases with a statistically significant association (P=0.005). Conclusion: The MODS technique is simple, and its implementation in this novel setting was feasible. MODS can be scaled up to meet the demand for MDR-TB confirmation in XpertMTB/Rif deployed sites in Nigeria.

Debunking the myths perpetuating low implementation of isoniazid preventive therapy amongst human immunodeficiency virus-infected persons.

Isoniazid preventive therapy (IPT) is the administration of isoniazid (INH) to people with latent tuberculosis (TB) infection (LTBI) to prevent progression to active TB disease. Despite being life-saving for human immunodeficiency virus (HIV)-infected persons who do not have active TB, IPT is poorly implemented globally due to misconceptions shared by healthcare providers and policy makers. However, amongst HIV-infected patients especially those living in resource-limited settings with a high burden of TB, available evidence speaks for IPT: Among HIV-infected persons, active TB- the major contraindication to IPT, can be excluded with symptom screening; chest X-ray and tuberculin skin testing are unreliable and often lead to logistic delays resulting in increased numbers of people with LTBI progressing to active TB; the use of IPT has not been found to increase the risk of the development of INH mono-resistance; IPT is cost-effective and cheaper than the cost of treating cases of active TB that would develop without IPT; ART and IPT have an additive effect on the prevention of TB, and both are safe and beneficial even in children. In order to sustain the recorded gains from ART scale-up and to further reduce TB-related morbidity and mortality, more efforts are needed to scale-up IPT implementation globally.

Reducing mother-to-child transmission of HIV: findings from an early infant diagnosis program in south-south region of Nigeria.

BACKGROUND: Early diagnosis of HIV in infants provides a critical opportunity to strengthen follow-up of HIV-exposed children and assure early access to antiretroviral (ARV) treatment for infected children. This study describes findings from an Early Infant Diagnosis (EID) program and the effectiveness of a prevention of mother-to-child transmission (PMTCT) intervention in six health facilities in Cross-River and Akwa-Ibom states, south-south Nigeria. METHODS: This was a retrospective study. Records of 702 perinatally exposed babies aged six weeks to 18 months who had a DNA PCR test between November 2007 and July 2009 were reviewed. Details of the ARV regimen received to prevent mother-to-child transmission (MTCT), breastfeeding choices, HIV test results, turn around time (TAT) for results and post test ART enrolment status of the babies were analysed. RESULTS: Two-thirds of mother-baby pairs received ARVs and 560 (80%) babies had ever been breastfed. Transmission rates for mother-baby pairs who received ARVs for PMTCT was 4.8% (CI 1.3, 8.3) at zero to six weeks of age compared to 19.5% (CI 3.0, 35.5) when neither baby nor mother received an intervention. Regardless of intervention, the transmission rates for babies aged six weeks to six months who had mixed feeding was 25.6% (CI 29.5, 47.1) whereas the transmission rates for those who were exclusively breastfed was 11.8% (CI 5.4, 18.1). Vertical transmission of HIV was eight times (AOR 7.8, CI: 4.52-13.19) more likely in the sub-group of mother-baby pairs who did not receive ARVS compared with mother-baby pairs that did receive ARVs. The median TAT for test results was 47 days (IQR: 35-58). A follow-up of 125 HIV positive babies found that 31 (25%) were enrolled into a paediatric ART program, nine (7%) were known to have died before the return of their DNA PCR results, and 85 (67%) could not be traced and were presumed to be lost-to-follow-up. CONCLUSION: Reduction of MTCT of HIV is possible with effective PMTCT interventions, including improved access to ARVs for PMTCT and appropriate infant feeding practices. Loss to follow up of HIV exposed infants is a challenge and requires strategies to enhance retention.