Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa.

BACKGROUND: Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. METHODS: We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. RESULTS: Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P<0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56-1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51-0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. CONCLUSION: We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

"If it weren't for my traditional healer, I would be dead": Engaging traditional healers to support people living with HIV in rural Mozambique.

Across rural sub-Saharan Africa, people living with HIV (PLHIV) commonly seek out treatment from traditional healers. We report on the clinical outcomes of a community health worker intervention adapted for traditional healers with insight into our results from qualitative interviews. We employed a pre-post intervention study design and used sequential mixed methods to assess the impact of a traditional healer support worker intervention in Zambézia province, Mozambique. After receiving a positive test result, 276 participants who were newly enrolled in HIV treatment and were interested in receiving home-based support from a traditional healer were recruited into the study. Those who enrolled from February 2016 to August 2016 received standard of care services, while those who enrolled from June 2017 to May 2018 received support from a traditional healer. We conducted interviews among healers and participants to gain insight into fidelity of study activities, barriers to support, and program improvement. Medication possession ratio at home (based on pharmacy pick-up dates) was not significantly different between pre- and post-intervention participants (0.80 in the pre-intervention group compared to 0.79 in the post-intervention group; p = 0.96). Participants reported receiving educational and psychosocial support from healers. Healers adapted their support protocol to initiate directly observed therapy among participants with poor adherence. Traditional healers can provide community-based psychosocial support, education, directly observed therapy, and disclosure assistance for PLHIV. Multiple factors may hinder patients' desire and ability to remain adherent to treatment, including poverty, confusion about medication side effects, and frustration with wait times at the health facility.

Healer-led vs. clinician-led training to improve personal protective equipment use among traditional healers in South Africa: a randomized controlled trial protocol.

There are estimated two million traditional healers in sub-Saharan Africa (SSA), with more than 10% (200,000) working in South Africa. Traditional healers in SSA are frequently exposed to bloodborne pathogens through the widespread practice of traditional 'injections', in which the healers perform dozens of subcutaneous incisions to rub herbs directly into the bloodied tissue with their hands. Healers who report exposure to patient blood have a 2.2-fold higher risk of being HIV-positive than those who do not report exposure. We propose a randomized controlled trial (61 healers in the intervention group and 61 healers in the control group) in Mpumalanga Province. Healers will receive personal protective equipment (PPE) education and training, general HIV prevention education, and three educational outreach visits at the healer's place of practice to provide advice and support for PPE use and disposal. Healers in the control arm will be trained by health care providers, while participants in the intervention arm will receive training and outreach from a team of healers who were early adopters of PPE. We will evaluate intervention implementation using data from surveys, observation, and educational assessments. Implementation outcomes of interest include acceptability and feasibility of PPE use during clinical encounters and fidelity of PPE use during treatments that involve blood exposure. We will test our two intervention strategies to identify an optimal strategy for PPE education in a region with high HIV prevalence.

Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study.

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.

Integrated prevention of mother-to-child HIV transmission services, antiretroviral therapy initiation, and maternal and infant retention in care in rural north-central Nigeria: a cluster-randomised controlled trial.

BACKGROUND: Antiretroviral therapy (ART) and retention in care are essential for the prevention of mother-to-child HIV transmission (PMTCT). We aimed to assess the effect of a family-focused, integrated PMTCT care package. METHODS: In this parallel, cluster-randomised controlled trial, we pair-matched 12 primary and secondary level health-care facilities located in rural north-central Nigeria. Clinic pairs were randomly assigned to intervention or standard of care (control) by computer-generated sequence. HIV-infected women (and their infants) presenting for antenatal care or delivery were included if they had unknown HIV status at presentation (there was no age limit for the study, but the youngest participant was 16 years old); history of antiretroviral prophylaxis or treatment, but not receiving these at presentation; or known HIV status but had never received treatment. Standard of care included health information, opt-out HIV testing, infant feeding counselling, referral for CD4 cell counts and treatment, home-based services, antiretroviral prophylaxis, and early infant diagnosis. The intervention package added task shifting, point-of-care CD4 testing, integrated mother and infant service provision, and male partner and community engagement. The primary outcomes were the proportion of eligible women who initiated ART and the proportion of women and their infants retained in care at 6 weeks and 12 weeks post partum (assessed by generalised linear mixed effects model with random effects for matched clinic pairs). The trial is registered with ClinicalTrials.gov, number NCT01805752. FINDINGS: Between April 1, 2013, and March 31, 2014, we enrolled 369 eligible women (172 intervention, 197 control), similar across groups for marital status, duration of HIV diagnosis, and distance to facility. Median CD4 count was 424 cells per µL (IQR 268-606) in the intervention group and 314 cells per µL (245-406) in the control group (p<0·0001). Of the 369 women included in the study, 363 (98%) had WHO clinical stage 1 disease, 364 (99%) had high functional status, and 353 (96%) delivered vaginally. Mothers in the intervention group were more likely to initiate ART (166 [97%] vs 77 [39%]; adjusted relative risk 3·3, 95% CI 1·4-7·8). Mother and infant pairs in the intervention group were more likely to be retained in care at 6 weeks (125 [83%] of 150 vs 15 [9%] of 170; adjusted relative risk 9·1, 5·2-15·9) and 12 weeks (112 [75%] of 150 vs 11 [7%] of 168 pairs; 10·3, 5·4-19·7) post partum. INTERPRETATION: This integrated, family-focused PMTCT service package improved maternal ART initiation and mother and infant retention in care. An effective approach to improve the quality of PMTCT service delivery will positively affect global goals for the elimination of mother-to-child HIV transmission. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development and US National Institutes of Health.

Substance Use and Adherence Among People Living with HIV/AIDS Receiving cART in Latin America.

This cross-sectional study describes substance use prevalence and its association with combination antiretroviral therapy (cART) adherence among 3343 individuals receiving care at HIV clinics in Argentina, Brazil, Chile, Honduras, Mexico, and Peru. A rapid screening tool evaluated self-reported 7-day recall of alcohol, marijuana, cocaine, heroin, and methamphetamine use, and missed cART doses. Overall, 29.3 % individuals reported having ≥1 alcoholic drinks, 5.0 % reported any illicit drug use and 17.0 % reported missed cART doses. In the logistic regression model, compared to no substance use, alcohol use [adjusted odds ratio (AOR) = 2.46, 95 % confidence interval (CI): 1.99-3.05], illicit drug use (AOR = 3.57, 95 % CI: 2.02-6.30), and using both alcohol and illicit drugs (AOR = 4.98, 95 % CI: 3.19-7.79) were associated with missed cART doses. The associations between substance use and likelihood of missing cART doses point to the need of targeting alcohol and illicit drug use to improve adherence among people living with HIV in Latin America.

HIV and cancer: a comparative retrospective study of Brazilian and U.S. clinical cohorts.

BACKGROUND: With successful antiretroviral therapy, non-communicable diseases, including malignancies, are increasingly contributing to morbidity and mortality among HIV-infected persons. The epidemiology of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) in HIV-infected populations in Brazil has not been well described. It is not known if cancer trends in HIV-infected populations in Brazil are similar to those of other countries where antiretroviral therapy is also widely available. METHODS: We performed a retrospective analysis of clinical cohorts at Instituto Nacional de Infectologia Evandro Chagas (INI) in Rio de Janeiro and Vanderbilt Comprehensive Care Clinic (VCCC) in Nashville from 1998 to 2010. We used Poisson regression and standardized incidence ratios (SIRs) to examine incidence trends. Clinical and demographic predictors of ADCs and NADCs were examined using Cox proportional hazards models. RESULTS: This study included 2,925 patients at INI and 3,927 patients at VCCC. There were 57 ADCs at INI (65% Kaposi sarcoma), 47 at VCCC (40% Kaposi sarcoma), 45 NADCs at INI, and 82 at VCCC. From 1998 to 2004, incidence of ADCs remained statistically unchanged at both sites. From 2005 to 2010, ADC incidence decreased in both cohorts (INI incidence rate ratio per year = 0.74, p < 0.01; VCCC = 0.75, p < 0.01). Overall Kaposi sarcoma incidence was greater at INI than VCCC (3.0 vs. 1.2 cases per 1,000 person-years, p < 0.01). Incidence of NADCs remained constant throughout the study period (overall INI incidence 3.6 per 1,000 person-years and VCCC incidence 5.3 per 1,000 person-years). Compared to general populations, overall risk of NADCs was increased at both sites (INI SIR = 1.4 [95% CI 1.1-1.9] and VCCC SIR = 1.3 [1.0-1.7]). After non-melanoma skin cancers, the most frequent NADCs were anal cancer at INI (n = 7) and lung cancer at VCCC (n = 11). In multivariate models, risk of ADC was associated with male sex and immunosuppression. Risk of NADC was associated with increased age. CONCLUSIONS: In both cohorts, ADCs have decreased over time, though incidence of KS was higher at INI than VCCC. Rates of NADCs remained constant over time at both sites.

Active cocaine use is associated with lack of HIV-1 virologic suppression independent of nonadherence to antiretroviral therapy: use of a rapid screening tool during routine clinic visits.

Clarifying the relationship between illicit drug use and HIV-1 virologic suppression requires characterization of both illicit drug use activity and adherence to antiretroviral therapy (ART). We developed a rapid clinical questionnaire to assess prior 7-day illicit drug use and ART adherence in a cross-sectional study among 1777 HIV-infected persons in care. Of these, 76% were male, 35% were African-American, and 8% reported injection drug use as their probable route of HIV-1 infection. Questionnaire-reported frequencies of cocaine and marijuana use within the previous 7 days were 3.3% and 12.1%, respectively. Over three quarters (77.8%) of participants were on ART, of whom 69.7% had HIV-1 virologic suppression (HIV-1 RNA<48 copies/mL). Univariate analyses revealed that compared to no use, cocaine and marijuana use were both associated with missed ART doses (P<0.01). Multivariable logistic regression analysis adjusting for nonadherence demonstrated that cocaine use was independently associated with failing to achieve virologic suppression (adjusted odds ratio (aOR): 0.46; 95% confidence interval (95% CI): 0.22-0.98) but marijuana use was not (aOR: 1.08; 95% CI: 0.72-1.62). This result strengthens the evidence of a direct effect of cocaine on virologic control, independent of nonadherence to ART.

HIV/AIDS-related attitudes and practices among traditional healers in Zambézia Province, Mozambique.

OBJECTIVES: To document HIV knowledge, treatment practices, and the willingness of traditional healers to engage with the health system in Zambézia Province, Mozambique. SETTINGS/LOCATION: Traditional healers offer culturally acceptable services and are more numerous in Mozambique than are allopathic providers. Late presentation of human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) is reported among persons who have first sought care from traditional healers. DESIGN: One hundred and thirty-nine (139) traditional healers were interviewed in their native languages (Chuabo or Lomwe) in Zambézia Province. Furthermore, 24 traditional healers were observed during patient encounters. Healers answered a semistructured questionnaire regarding their knowledge of HIV/AIDS, general treatment practices, attitudes toward the allopathic health system, and their beliefs in their abilities to cure AIDS. RESULTS: Traditional healers were older and had less formal education than the general population. Razor cutting in order to rub herbs into blooded skin was observed, and healers reported razor cutting as a routine practice. Healers stated that they did not refer HIV patients to clinics for two principal reasons: (1) patient symptoms/signs of HIV were unrecognized, and (2) practitioners believed they could treat the illness effectively themselves. Traditional healers were far more likely to believe in a spiritual than an infectious origin of HIV disease. Prior HIV/AIDS training was not associated with better knowledge or referral practices, though 81% of healers were interested in engaging allopathic providers. CONCLUSIONS: It was found that the HIV-related practices of traditional healers probably increase risk for both HIV-infected and uninfected persons through delayed care and reuse of razors. Mozambican traditional healers attribute HIV pathogenesis to spiritual, not infectious, etiologies. Healers who had received prior HIV training were no more knowledgeable, nor did they have better practices. The willingness expressed by 4 in 5 healers to engage local formal health providers in HIV/AIDS care suggests a productive way forward, though educational efforts must be effective and income concerns considered.

Nutrition and inflammation serum biomarkers are associated with 12-week mortality among malnourished adults initiating antiretroviral therapy in Zambia.

BACKGROUND: A low body mass index (BMI) at antiretroviral therapy (ART) initiation is a strong predictor of mortality among HIV-infected adults in resource-constrained settings. The relationship between nutrition and inflammation-related serum biomarkers and early treatment outcomes (e.g., less than 90 days) in this population is not well described. METHODS: An observational cohort of 142 HIV-infected adults in Lusaka, Zambia, with BMI under 16 kg/m2 or CD4+ lymphocyte counts of less than 50 cells/mm3, or both, was followed prospectively during the first 12 weeks of ART. Baseline and serial post-treatment phosphate, albumin, ferritin and highly sensitive C-reactive protein (hsCRP) serum levels were measured. The primary outcome was mortality. RESULTS: Lower baseline phosphate and albumin serum levels, and higher ferritin and hsCRP, were significantly associated with mortality prior to 12 weeks (p<0.05 for all comparisons), independent of known risk factors for early ART-associated mortality in sub-Saharan Africa. The time-dependent interval change in albumin was associated with mortality after adjusting for the baseline value (AHR 0.62 [0.43, 0.89] per 5 g/L increase), but changes in the other biomarkers were not. CONCLUSIONS: The predictive value of serum biomarkers for early mortality in a cohort of adults with malnutrition and advanced HIV in a resource-constrained setting was primarily driven by pre-treatment values, rather than post-ART changes. Interventions to promote earlier HIV diagnosis and treatment, address nutritional deficiencies, and identify the etiologies of increased systemic inflammation may improve ART outcomes in this vulnerable population.