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).

Cervical Cancer Screening Positivity Among Women Living With HIV in CDC-PEPFAR Programs 2018-2022.

BACKGROUND: The US President's Emergency Plan for AIDS Relief aims to address the higher risk of cervical cancer among women living with HIV by offering high-quality screening services in the highest burden regions of the world. METHODS: We analyzed the US President's Emergency Plan for AIDS Relief Monitoring, Evaluation, and Reporting data from Centers for Disease Control and Prevention-supported sites in 13 countries in sub-Saharan Africa for women living with HIV aged older than 15 years who accessed cervical cancer screening services (mostly visual inspection, with ablative or excisional treatment offered for precancerous lesions), April 2018-March 2022. We calculated the positivity by age, country, and clinical visit type (first lifetime screen or routine rescreening). We fitted negative binomial random coefficient models of log-linear trends in time to estimate the probabilities of testing positive and any temporal trends in positivity. RESULTS: Among the 2.8 million completed cancer screens, 5.4% identified precancerous lesions, and 0.8% were positive for suspected invasive cervical cancers (6.1% overall). The positivity rates declined over the study period among those women screening for cervical cancer for the first time and among those women presenting to antiretroviral therapy clinics for routine rescreening. CONCLUSIONS: These positivity rates are lower than expectations set by the published literature. Further research is needed to determine whether these lower rates are attributable to the high level of consistent antiretroviral therapy use among these populations, and systematic program monitoring and quality assurance activities are essential to ensure women living with HIV have access to the highest possible quality prevention services.

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.

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.

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.

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.

Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial.

HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index-partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner's infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART.