Validating Five Questions of Antiretroviral Nonadherence in a Public-Sector Treatment Program in Rural South Africa

Simple questions are the most commonly used measures of antiretroviral treatment (ART) adherence in sub-Saharan Africa (SSA), but rarely validated. We administered five adherence questions in a public-sector primary care clinic in rural South Africa: 7-day recall of missed doses, 7-day recall of late doses, a six-level Likert item, a 30-day visual analogue scale of the proportion of doses missed, and recall of the time when an ART dose was last missed. We estimated question sensitivity and specificity in detecting immunologic (or virologic) failure assessed within 45 days of the adherence question date. Of 165 individuals, 7% had immunologic failure; 137 individuals had viral loads with 9% failure detected. The Likert item performed best for immunologic failure with sensitivity/specificity of 100%/5% (when defining nonadherence as self-reported adherence less than -excellent-), 42%/55% (less than -very good-), and 25%/95% (less than -good-). The remaining questions had sensitivities <=17%, even when the least strict cutoffs defined nonadherence. When we stratified the analysis by gender, age, or education, question performance was not substantially better in any of the subsamples in comparison to the total sample. Five commonly used adherence questions performed poorly in identifying patients with treatment failure in a public-sector ART program in SSA. Valid adherence measurement instruments are urgently required to identify patients needing treatment support and those most at risk of treatment failure. Available estimates of ART adherence in SSA are mostly based on studies using adherence questions. It is thus unlikely that our understanding of ART adherence in the region is correct.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90502/1/apc-2E2010-2E0257.pd

Blood culture utilization and epidemiology of antimicrobial-resistant bloodstream infections before and during the COVID-19 pandemic in the Indonesian national referral hospital.

BACKGROUND: There is a paucity of data regarding blood culture utilization and antimicrobial-resistant (AMR) infections in low and middle-income countries (LMICs). In addition, there has been a concern for increasing AMR infections among COVID-19 cases in LMICs. Here, we investigated epidemiology of AMR bloodstream infections (BSI) before and during the COVID-19 pandemic in the Indonesian national referral hospital. METHODS: We evaluated blood culture utilization rate, and proportion and incidence rate of AMR-BSI caused by WHO-defined priority bacteria using routine hospital databases from 2019 to 2020. A patient was classified as a COVID-19 case if their SARS-CoV-2 RT-PCR result was positive. The proportion of resistance was defined as the ratio of the number of patients having a positive blood culture for a WHO global priority resistant pathogen per the total number of patients having a positive blood culture for the given pathogen. Poisson regression models were used to assess changes in rate over time. RESULTS: Of 60,228 in-hospital patients, 8,175 had at least one blood culture taken (total 17,819 blood cultures), giving a blood culture utilization rate of 30.6 per 1,000 patient-days. A total of 1,311 patients were COVID-19 cases. Blood culture utilization rate had been increasing before and during the COVID-19 pandemic (both p  0.10). Incidence rate of hospital-origin AMR-BSI increased from 130.1 cases per 100,000 patient-days in 2019 to 165.5 in 2020 (incidence rate ratio 1.016 per month, 95%CI:1.016-1.017, p < 0.001), and was not associated with COVID-19 (p = 0.96). CONCLUSIONS: In our setting, AMR-BSI incidence and etiology were similar between COVID-19 and non-COVID-19 cases. Incidence rates of hospital-origin AMR-BSI increased in 2020, which was likely due to increased blood culture utilization. We recommend increasing blood culture utilization and generating AMR surveillance reports in LMICs to inform local health care providers and policy makers

Diagnostic and antibiotic use practices among COVID-19 and non-COVID-19 patients in the Indonesian National Referral Hospital.

BACKGROUND: Little is known about diagnostic and antibiotic use practices in low and middle-income countries (LMICs) before and during COVID-19 pandemic. This information is crucial for monitoring and evaluation of diagnostic and antimicrobial stewardships in healthcare facilities. METHODS: We linked and analyzed routine databases of hospital admission, microbiology laboratory and drug dispensing of Indonesian National Referral Hospital from 2019 to 2020. Patients were classified as COVID-19 cases if their SARS-CoV-2 RT-PCR result were positive. Blood culture (BC) practices and time to discontinuation of parenteral antibiotics among inpatients who received a parenteral antibiotic for at least four consecutive days were used to assess diagnostic and antibiotic use practices, respectively. Fine and Grey subdistribution hazard model was used. RESULTS: Of 1,311 COVID-19 and 58,917 non-COVID-19 inpatients, 333 (25.4%) and 18,837 (32.0%) received a parenteral antibiotic for at least four consecutive days. Proportion of patients having BC taken within ±1 calendar day of parenteral antibiotics being started was higher in COVID-19 than in non-COVID-19 patients (21.0% [70/333] vs. 18.7% [3,529/18,837]; p<0.001). Cumulative incidence of having a BC taken within 28 days was higher in COVID-19 than in non-COVID-19 patients (44.7% [149/333] vs. 33.2% [6,254/18,837]; adjusted subdistribution-hazard ratio [aSHR] 1.71, 95% confidence interval [CI] 1.47-1.99, p<0.001). The median time to discontinuation of parenteral antibiotics was longer in COVID-19 than in non-COVID-19 patients (13 days vs. 8 days; aSHR 0.73, 95%Cl 0.65-0.83, p<0.001). CONCLUSIONS: Routine electronic data could be used to inform diagnostic and antibiotic use practices in LMICs. In Indonesia, the proportion of timely blood culture is low in both COVID-19 and non-COVID-19 patients, and duration of parenteral antibiotics is longer in COVID-19 patients. Improving diagnostic and antimicrobial stewardship is critically needed

Nitroheterocyclic drugs cure experimental <i>Trypanosoma cruzi</i> infections more effectively in the chronic stage than in the acute stage

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies

Modeling dynamic interactions between pre-exposure prophylaxis interventions & treatment programs: predicting HIV transmission & resistance

Clinical trials have recently demonstrated the effectiveness of Pre-Exposure Prophylaxis (PrEP) in preventing HIV infection. Consequently, PrEP may soon be used for epidemic control. We model the dynamic interactions that will occur between treatment programs and potential PrEP interventions in resource-constrained countries. We determine the consequences for HIV transmission and drug resistance. We use response hypersurface modeling to predict the effect of PrEP on decreasing transmission as a function of effectiveness, adherence and coverage. We predict PrEP will increase need for second-line therapies (SLT) for treatment-naïve individuals, but could significantly decrease need for SLT for treatment-experienced individuals. If the rollout of PrEP is carefully planned it could increase the sustainability of treatment programs. If not, need for SLT could increase and the sustainability of treatment programs could be compromised. Our results show the optimal strategy for rolling out PrEP in resource-constrained countries is to begin around the “worst” treatment programs

Results of Antiretroviral Treatment Interruption and Intensification in Advanced Multi-Drug Resistant HIV Infection from the OPTIMA Trial

BACKGROUND: Guidance is needed on best medical management for advanced HIV disease with multidrug resistance (MDR) and limited retreatment options. We assessed two novel antiretroviral (ARV) treatment approaches in this setting. METHODS AND FINDINGS: We conducted a 2×2 factorial randomized open label controlled trial in patients with a CD4 count≤300 cells/µl who had ARV treatment (ART) failure requiring retreatment, to two options (a) re-treatment with either standard (≤4 ARVs) or intensive (≥5 ARVs) ART and b) either treatment starting immediately or after a 12-week monitored ART interruption. Primary outcome was time to developing a first AIDS-defining event (ADE) or death from any cause. Analysis was by intention to treat. From 2001 to 2006, 368 patients were randomized. At baseline, mean age was 48 years, 2% were women, median CD4 count was 106/µl, mean viral load was 4.74 log(10) copies/ml, and 59% had a prior AIDS diagnosis. Median follow-up was 4.0 years in 1249 person-years of observation. There were no statistically significant differences in the primary composite outcome of ADE or death between re-treatment options of standard versus intensive ART (hazard ratio 1.17; CI 0.86-1.59), or between immediate retreatment initiation versus interruption before re-treatment (hazard ratio 0.93; CI 0.68-1.30), or in the rate of non-HIV associated serious adverse events between re-treatment options. CONCLUSIONS: We did not observe clinical benefit or harm assessed by the primary outcome in this largest and longest trial exploring both ART interruption and intensification in advanced MDR HIV infection with poor retreatment options. TRIAL REGISTRATION: Clinicaltrials.gov NCT00050089

HIV Disclosure, Condom Use, and Awareness of HIV Infection Among HIV-Positive, Heterosexual Drug Injectors in St. Petersburg, Russian Federation

We examined the prevalence of HIV disclosure to sexual partners by HIV-positive drug injectors (IDUs) in St. Petersburg, Russia and compared the magnitude and direction of associations of condom use with awareness of one’s HIV infection and disclosure to partners. Among 157 HIV-infected participants, awareness of infection at time of last intercourse was associated with condom use with partners perceived to be HIV-negative (aOR 6.68, 95% CI 1.60–27.88). Among the 70 participants aware of their infection prior to enrolment, disclosure to potentially uninfected sexual partners was independently and negatively associated with condom use (aOR 0.13, 95% CI 0.02–0.66). Disclosure was independently associated with having injected ≥9 years (aOR 6.04, 95% CI 1.53–23.77) and partnership with another IDU (aOR 3.61, 95% CI 1.44–9.06) or HIV-seropositive (aOR 45.12, 95% CI 2.79–730.46). Scaling up HIV testing services and interventions that increase the likelihood of individuals receiving their test results is recommended

Surveillance of Transmitted Antiretroviral Drug Resistance among HIV-1 Infected Women Attending Antenatal Clinics in Chitungwiza, Zimbabwe

The rapid scale-up of highly active antiretroviral therapy (HAART) and use of single dose Nevirapine (SD NVP) for prevention of mother-to-child transmission (pMTCT) have raised fears about the emergence of resistance to the first line antiretroviral drug regimens. A cross-sectional study was conducted to determine the prevalence of primary drug resistance (PDR) in a cohort of young (<25 yrs) HAART-naïve HIV pregnant women attending antenatal clinics in Chitungwiza, Zimbabwe. Whole blood was collected in EDTA for CD4 counts, viral load, serological estimation of duration of infection using the BED Calypte assay and genotyping for drug resistance. Four hundred and seventy-one women, mean age 21 years; SD: 2.1 were enrolled into the study between 2006 and 2007. Their median CD4 count was 371cells/µL; IQR: 255–511 cells/µL. Two hundred and thirty-six samples were genotyped for drug resistance. Based on the BED assay, 27% were recently infected (RI) whilst 73% had long-term infection (LTI). Median CD4 count was higher (p<0.05) in RI than in women with LTI. Only 2 women had drug resistance mutations; protease I85V and reverse transcriptase Y181C. Prevalence of PDR in Chitungwiza, 4 years after commencement of the national ART program remained below WHO threshold limit (5%). Frequency of recent infection BED testing is consistent with high HIV acquisition during pregnancy. With the scale-up of long-term ART programs, maintenance of proper prescribing practices, continuous monitoring of patients and reinforcement of adherence may prevent the acquisition and transmission of PDR

Minor Protease Inhibitor Mutations at Baseline Do Not Increase the Risk for a Virological Failure in HIV-1 Subtype B Infected Patients

BACKGROUND: Minor protease inhibitor (PI) mutations often exist as polymorphisms in HIV-1 sequences from treatment-naïve patients. Previous studies showed that their presence impairs the antiretroviral treatment (ART) response. Evaluating these findings in a larger cohort is essential. METHODS: To study the impact of minor PI mutations on time to viral suppression and time to virological failure, we included patients from the Swiss HIV Cohort Study infected with HIV-1 subtype B who started first-line ART with a PI and two nucleoside reverse transcriptase inhibitors. Cox regression models were performed to compare the outcomes among patients with 0 and ≥ 1 minor PI mutation. Models were adjusted for baseline HIV-1 RNA, CD4 cell count, sex, transmission category, age, ethnicity, year of ART start, the presence of nucleoside reverse transcriptase inhibitor mutations, and stratified for the administered PIs. RESULTS: We included 1199 patients of whom 944 (78.7%) received a boosted PI. Minor PI mutations associated with the administered PI were common: 41.7%, 16.1%, 4.7% and 1.9% had 1, 2, 3 or ≥ 4 mutations, respectively. The time to viral suppression was similar between patients with 0 (reference) and ≥ 1 minor PI mutation (multivariable hazard ratio (HR): 1.1 [95% confidence interval (CI): 1.0-1.3], P = .196). The time to virological failure was also similar (multivariable HR:.9 [95% CI:.5-1.6], P = .765). In addition, the impact of each single minor PI mutation was analyzed separately: none was significantly associated with the treatment outcome. CONCLUSIONS: The presence of minor PI mutations at baseline has no effect on the therapy outcome in HIV infected individuals

High-levels of acquired drug resistance in adult patients failing first-line antiretroviral therapy in a rural HIV treatment programme in KwaZulu-Natal, South Africa.

OBJECTIVE: To determine the frequency and patterns of acquired antiretroviral drug resistance in a rural primary health care programme in South Africa. DESIGN: Cross-sectional study nested within HIV treatment programme. METHODS: Adult (≥ 18 years) HIV-infected individuals initially treated with a first-line stavudine- or zidovudine-based antiretroviral therapy (ART) regimen and with evidence of virological failure (one viral load >1000 copies/ml) were enrolled from 17 rural primary health care clinics. Genotypic resistance testing was performed using the in-house SATuRN/Life Technologies system. Sequences were analysed and genotypic susceptibility scores (GSS) for standard second-line regimens were calculated using the Stanford HIVDB 6.0.5 algorithms. RESULTS: A total of 222 adults were successfully genotyped for HIV drug resistance between December 2010 and March 2012. The most common regimens at time of genotype were stavudine, lamivudine and efavirenz (51%); and stavudine, lamivudine and nevirapine (24%). Median duration of ART was 42 months (interquartile range (IQR) 32-53) and median duration of antiretroviral failure was 27 months (IQR 17-40). One hundred and ninety one (86%) had at least one drug resistance mutation. For 34 individuals (15%), the GSS for the standard second-line regimen was <2, suggesting a significantly compromised regimen. In univariate analysis, individuals with a prior nucleoside reverse-transcriptase inhibitor (NRTI) substitution were more likely to have a GSS <2 than those on the same NRTIs throughout (odds ratio (OR) 5.70, 95% confidence interval (CI) 2.60-12.49). CONCLUSIONS: There are high levels of drug resistance in adults with failure of first-line antiretroviral therapy in this rural primary health care programme. Standard second-line regimens could potentially have had reduced efficacy in about one in seven adults involved