The Suboptimal Pediatric HIV Viral Load Cascade: Multidistrict Cohort Study Among Children Taking Antiretroviral Therapy in Lesotho, Southern Africa.

BACKGROUND: Children living with HIV and taking antiretroviral therapy (ART) are a priority group for routine viral load (VL) monitoring. As per Lesotho guidelines, a VL ≥1000 copies/mL ("unsuppressed") should trigger adherence counseling and a follow-up VL; 2 consecutive unsuppressed VLs ("virologic failure") qualify for switching to second-line ART, with some exceptions. Here, we describe the pediatric VL cascade in Lesotho. METHODS: In a prospective open cohort study comprising routine VL results from 22 clinics in Lesotho, we assessed outcomes along the VL cascade for children who had at least 1 VL test from January 2016 through June 2020. Data were censored on February 10, 2021. RESULTS: In total, 1215 children received 5443 VL tests. The median age was 10 years (interquartile range 7-13) and 627/1215 (52%) were female; 362/1215 (30%) had at least 1 unsuppressed VL. A follow-up VL was available for 325/362 (90%), although only for 159/362 (44%) within 6 months of the first unsuppressed VL. Of those with a follow-up VL, 172/329 (53%) had virologic failure and 123/329 (37%) qualified for switching to second-line ART. Of these, 55/123 (45%) were ever switched, although only 9/123 (7%) were switched within 12 weeks of the follow-up VL. Delays were more pronounced in rural facilities. Overall, 100/362 (28%) children with an unsuppressed VL received a timely follow-up VL and, if required, a timely regimen switch. CONCLUSIONS: Despite access to VL monitoring, clinical management was suboptimal. HIV programs should prioritize timely clinical action to maximize the benefits of VL monitoring.

First Extended-Release Injectable Drug Therapy for HIV.

Cabenuva-an injectable formulation of cabotegravir and rilpivirine and the first injectable complete therapy for adults with HIV-1-is now approved.It is administered once a month as two intramuscular injections following a month of treatment with the oral forms of these drugs.

Identifying appropriate candidates for long-acting antiretroviral therapy: findings from a survey of health care providers in the ATLAS-2M trial.

INTRODUCTION: Recent results from Phase 3 clinical trials with cabotegravir (CAB) and rilpivirine (RPV) long-acting (LA) have shown that a monthly regimen is non-inferior to daily oral antiretroviral therapy (ART). Additional insights are necessary to prepare for LA ART roll-out, including identifying the appropriate patients. METHODS: Within the ATLAS-2M trial, an online survey was administered to 329 health care providers (HCPs) in 13 countries. Multivariate logistic regression was conducted to identify factors associated with providers considering a greater proportion of patients as appropriate LA ART candidates. RESULTS: Forty-seven percent of HCPs believed that "some" patients (25-50%) would be appropriate while nearly one-quarter of HCPs (23%) felt that "many" patients (more than 50%) would be appropriate candidates for LA ART. Providers in the African region had a greater odds of identifying a greater proportion of their patients as appropriate candidates (AOR 8.97; p < 0.001) vs. other regions. Nurses/physician assistants and research staff/pharmacists had a higher odds of perceiving a greater proportion of their patients as appropriate candidates vs. physicians, respectively (AOR 3.42 p < 0.001; AOR 2.48; p = 0.19). Providers who had experience transitioning patients from LA to oral ART had a higher odds of reporting that more of their patients would be appropriate candidates (AOR 1.64; p = 0.008) vs. those without experience. CONCLUSION: A significant proportion of providers reported that many of their patients would be appropriate candidates for LA ART. To optimize roll-out after regulatory approval, it is important to support providers with tools to help identify patients who would most benefit from this option.

Antiretroviral Stewardship: A Review of Published Outcomes with Recommendations for Program Implementation.

Persons living with HIV (PLWHs) are at high risk for medication errors when hospitalized, but antiretroviral medications are not often evaluated by antimicrobial stewardship programs (ASPs) because they are not specifically discussed in the standards of practice. However, antiretroviral (ARV) stewardship programs (ARVSPs) have been shown to decrease medication error rates and improve other outcomes. The goal of this article is to review published literature on ARVSPs and provide guidance on key aspects of ARVSPs. A MEDLINE search using the term "antiretroviral stewardship" was conducted. Original research articles evaluating ARVSPs in hospitalized, adult PLWHs were included. Six original research articles evaluating unique inpatient ARVSPs met inclusion criteria. All 6 studies evaluating medication errors as the primary outcome found a significant reduction in errors in the postimplementation phase. Based on current standards for ASPs, we propose core elements for ARVSPs. Future organizational guidelines for antimicrobial stewardship should include official recommendations for ARV medications.

A simple tool to evaluate the antiretroviral therapy programme in primary health care setting of Lesotho.

AIM: An evaluative tool for the antiretroviral therapy programme was developed for use in the primary health care setting of Lesotho. BACKGROUND: Information on processes followed in the development of standardized and acceptable evaluative tools is not always available to practicing nurses. METHODS: Behaviours affecting the antiretroviral therapy (ART) programme were contextualized using the conceptual model for social programmes and Intervention Wheel framework. A convergent parallel mixed-methods design was used to describe perceptions and explore experiences of nurses and patients. The Instrument Development Construct Validation process was used to develop an evaluative tool that was pre-tested on 17 respondents. Results were analysed using SPSS (23), and internal consistency using Cronbach's alpha coefficient was .768. RESULTS: The tool collects information on staffing patterns, services offered, patients seen, time spent seeking services, consultation time, Antiretroviral (ARV) availability, staff adequacy, staff competency, equipment adequacy, service efficiency, activity documentation, patient satisfaction, job satisfaction, monitoring and evaluation. CONCLUSIONS: The evaluative tool permits identification of factors affecting delivery of the ART programme, hence assisting nurses to improve services provided. IMPLICATIONS FOR NURSING MANAGEMENT: This method can be used to develop evaluative tools to assess implementation of public health services and inform successes, challenges and recognize improvement approaches.

Development and Validation of Surveillance-Based Algorithms to Estimate Hepatitis C Treatment and Cure in New York City.

CONTEXT: Treatment options for chronic hepatitis C virus (HCV) have improved in recent years. The burden of HCV in New York City (NYC) is high. Measuring treatment and cure among NYC residents with HCV infection will allow the NYC Department of Health and Mental Hygiene (DOHMH) to appropriately plan interventions, allocate resources, and identify disparities to combat the hepatitis C epidemic in NYC. OBJECTIVE: To validate algorithms designed to estimate treatment and cure of HCV using RNA test results reported through routine surveillance. DESIGN: Investigation by NYC DOHMH to determine the true treatment and cure status of HCV-infected individuals using chart review and HCV test data. Treatment and cure status as determined by investigation are compared with the status determined by the algorithms. SETTING: New York City health care facilities. PARTICIPANTS: A total of 250 individuals with HCV reported to the New York City Department of Health and Mental Hygiene (NYC DOHMH) prior to March 2016 randomly selected from 15 health care facilities. MAIN OUTCOME MEASURES: The sensitivity and specificity of the algorithms. RESULTS: Of 235 individuals successfully investigated, 161 (69%) initiated treatment and 96 (41%) achieved cure since the beginning of 2014. The treatment algorithm had a sensitivity of 93.2% (95% confidence interval [CI], 89.2%-97.1%) and a specificity of 83.8% (95% CI, 75.3%-92.2%). The cure algorithm had a sensitivity of 93.8% (95% CI, 88.9%-98.6%) and a specificity of 89.4% (95% CI, 83.5%-95.4%). Applying the algorithms to 68 088 individuals with HCV reported to DOHMH between July 1, 2014, and December 31, 2016, 28 392 (41.7%) received treatment and 16 921 (24.9%) were cured. CONCLUSIONS: The algorithms developed by DOHMH are able to accurately identify HCV treatment and cure using only routinely reported surveillance data. Such algorithms can be used to measure treatment and cure jurisdiction-wide and will be vital for monitoring and addressing HCV. NYC DOHMH will apply these algorithms to surveillance data to monitor treatment and cure rates at city-wide and programmatic levels, and use the algorithms to measure progress towards defined treatment and cure targets for the city.

Quality of antiretroviral and opportunistic infection medications dispensed from developing countries and Internet pharmacies.

WHAT IS KNOWN AND OBJECTIVE: Generic manufacturers help decrease the cost of antiretroviral (ARV) and antimicrobial medications which are used to treat opportunistic infections (OIs) in developing countries. Concerns have been expressed about potential quality issues with such medications as a result of the identification of numerous counterfeit medications in developing countries. However, few studies have assessed the quality of these medications using the United States Pharmacopeia (USP) compendial standards. The goal of this study was to assess the quality of ARV and OI medications obtained from various sources, including South Africa, United States, China, Ethiopia, Thailand, Laos, Mexico, Nigeria and five Internet pharmacies. METHODS: Zidovudine, lamivudine, efavirenz, nevirapine, isoniazid and sulfamethoxazole/trimethoprim tablets/capsules were obtained from eight countries and five Internet pharmacies. The tablets/capsules were separated into distinct samples, based on the drug's active ingredient, manufacturer and drug control number. Each distinct sample was analysed for drug content, dissolution, content uniformity and breaking force using USP 32-National Formulary 27 (USP 32-NF 27) compendial methods and compared to the USP standards. RESULTS AND DISCUSSION: A total of 2027 tablets/capsules were obtained with 88 distinct samples identified. All samples met the USP 32-NF 27 standards for drug content with a range of 92.7-108.6%. Six of the 88 samples failed the dissolution test by 1.5-8.3% below the standard range. Ninety-eight per cent of all 88 samples met the USP criteria for content uniformity based on weight variation. One sample of isoniazid was found to have a low breaking force of 2.8 kiloponds. The results of this study show that there were no problems with the samples of ARV and OI medications tested for drug quality from the specified locations. As there are many studies and reports that discuss the poor quality of generic medications with only a few assessing drug quality, the implications of this study's results are to: (i) help better understand patient outcomes; (ii) help patients gain access to beneficial medications for HIV and OIs; and (iii) ensure an overall increase in access to medications where needed. WHAT IS NEW AND CONCLUSION: This study is one of the largest to date concerning medication type and sample size for the assessment of ARV and OI medications using drug content as a measure of quality. The samples were obtained from more diverse geographical locations compared to previous studies and, for the first time, included Internet pharmacies. In addition to drug content, this study evaluated a more complete quality profile including dissolution, content uniformity and breaking force. This study showed that drug quality should be assessed consistently in order to better identify counterfeit medications compared to current assessments and that there should be uniform guidelines for how to assess quality.

Cost-effectiveness analysis along the continuum of HIV care: how can we optimize the effect of HIV treatment as prevention programs?

The cascade of HIV care has been proposed as a useful tool to monitor health system performance across the key stages of HIV care delivery to reduce morbidity, mortality, and HIV transmission, the focal points of HIV Treatment as Prevention campaigns. Interventions to improve the cascade at its various stages may vary substantially in their ability to deliver health value per amount expended. In order to meet global antiretroviral treatment access targets, there is an urgent need to maximize the value of health spending by prioritizing cost-effective interventions. We executed a literature review on economic evaluations of interventions to improve specific stages of the cascade of HIV care. In total, 33 articles met the criteria for inclusion in the review, 22 (67 %) of which were published within the last 5 years. Nonetheless, substantial gaps in our knowledge remain, particularly for interventions to improve linkage and retention in HIV care in developed and developing-world settings and generalized and concentrated epidemics. We make the case here that the attention of scientists and policymakers needs to turn to the development, implementation, and rigorous evaluation of interventions to improve the various stages of the cascade of HIV care.

Quality of antiretroviral therapy in public health facilities in Nigeria and perceptions of end users.

AIM: This paper describes perceptions of the end users on quality of antiretroviral therapy (ART) in public health facilities in Nigeria. BACKGROUND: Health care services in Nigeria face challenges of meeting end users' requirements and expectations for quality ART service provision. METHOD: A qualitative design was followed. Unstructured focus group discussions were conducted with end users (n = 64) in six locations across the six geopolitical zones of Nigeria. RESULTS: The findings indicate that end users were satisfied with uninterrupted antiretroviral drug supplies, courtesy treatment, volunteerism of support group members and quality counselling services. CONCLUSION: End users expect effective collaboration between healthcare providers and support group members, to enhance the quality of life of people living with HIV. IMPLICATIONS FOR NURSING MANAGEMENT: A best practice guideline for the provision of end user focused ART service provision was developed for nurse managers.

A quantitative basis for antiretroviral therapy for HIV-1 infection.

Highly active antiretroviral therapy (HAART) has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.

The relationship of CCR5 antagonists to CD4+ T-cell gain: a meta-regression of recent clinical trials in treatment-experienced HIV-infected patients.

PURPOSE: Lower CD4+ T-cell counts are related to increased morbidity and mortality despite virologic suppression. CCR5 antagonists are associated with robust CD4+ T-cell responses. We examined the relationship of CCR5 antagonists to CD4+ T-cell gains. DESIGN: Meta-regression of recent phase 2-3 trials evaluating new antiretroviral agents in treatment-experienced subjects. METHODS: We analyzed the relationship of CCR5 antagonists to CD4+ T-cell count increase 24 weeks after initiating the new regimen using a linear model with generalized estimating equations controlling for differing rates of virologic suppression. Each treatment group was treated as a data point weighted by sample size. RESULTS: We included 46 treatment groups from 17 trials (11 groups from 5 trials used CCR5 antagonists). Controlling for average baseline HIV-1 RNA and proportion of subjects achieving HIV-1 RNA <50 copies/mL, use of a CCR5 antagonist was associated with an additional significant CD4+ T-cell gain of +30/µL (95% CI, 19-42) at 24 weeks compared to treatment groups not using a CCR5 antagonist. CONCLUSIONS: Use of a CCR5 antagonist was associated with an enhanced CD4+ T-cell count response independent of virologic suppression. This observation supports further evaluation of CCR5 antagonists in patients with discordant immunologic and virologic responses to ART.

Exploring the impact of target cell heterogeneity on HIV loads in a within-host model.

HIV can be transmitted from blood plasma or semen of an infected male. Viral loads in blood plasma are routinely measured, but the same is not true of semen. Even before drug treatment, viral loads have been shown to be different in the two body compartments (blood and genital tract), and this heterogeneity may be exacerbated by treatments using those antiretroviral drugs which have different efficacies in the two compartments. In addition to this heterogeneity, and despite highly effective drugs (in the blood) low-level viral replication is commonly reported for HIV patients as are differences in drug resistant mutation patterns in the two compartments. In this paper we investigate the effect of target cell heterogeneity between compartments on HIV viral loads using a within-host model that includes wildtype and drug resistant strains of HIV. We find that modelling target cell heterogeneity in the blood and male genital tract gives different viral loads in the two compartments prior to treatment and allows low-level viral loads to persist during therapy even if drug penetration is good. The model also allows coexistence of the two viral strains (in the absence of a mutation mechanism) with different dominance patterns in each body compartment. Our results suggest that monitoring of blood plasma viral strains may not give an accurate picture of the strains of HIV being transmitted between individuals and that continued research into the nature of HIV target cells in the male genital tract would be beneficial.

Three-year outcome data of second-line antiretroviral therapy in Ugandan adults: good virological response but high rate of toxicity.

OBJECTIVE: To evaluate the safety and virological response to lopinavir/ritonavir containing second-line therapy after failing a first line nonnucleoside reverse transcriptase inhibitor (NNRTI) based regimen. DESIGN: Prospective 36 months cohort study of patients switched to zidovudine/stavudine plus didanosine plus lopinavir/ritonavir capsules as second-line regimen. METHODOLOGY: Structured interview, medical examination, and laboratory assessment performed every 6 months. RESULTS: We enrolled 40 patients; 1 died and 3 were lost to follow-up. Median CD4+ count at baseline was 108 cell/microL, median log viral load was 4.8 copies/mL. Sixteen (40%) patients had baseline genotypic resistant test, 14 (87%) had lamivudine resistance mutations, and all had NNRTIs resistance mutations. At month 36, 82% of the patients achieved viral suppression (<400 copies/ mL) and the median increase in CD4+ count was 214 cell/microL, (interquartile range: 128-295). Twenty-five patients (62%) experienced at least one adverse event. CONCLUSIONS: Our study confirms lopinavir/ ritonavir-based second-line regimen but with a high rate of toxicities.

Human papillomavirus (HPV) genotypes and HPV16 variants in human immunodeficiency virus-positive Italian women.

Human immunodeficiency virus (HIV)-positive women have high rates of cervical squamous intraepithelial lesions (SIL) and concurrent human papillomavirus (HPV) infections with a variety of genotypes whose oncogenic risk is poorly documented. The prevalence and persistence of HPV genotypes and HPV16 variants were analysed in 112 HIV-positive and 115 HIV-negative Italian women. HIV-positive women were more likely than HIV-negative women to be infected by HPV at the initial examination (39.3 vs 13.9 %, P<0.001) and to have a higher period prevalence of HPV infection over a 3-year follow-up (43.8 % vs 17.4 %, P<0.001), regardless of CD4+ cell counts and anti-retroviral therapy. 'High-risk' and 'probable high-risk' HPVs (types 16, 18, 31, 33, 35, 45, 52, 58 and 66), among the 20 different viral genotypes identified, were predominant in HIV-positive (33.9 %) compared with HIV-negative (13.9 %) women. Among HIV-infected women, with normal cytology as well as with SIL of any grade, the most common genotypes were HPV16 followed by HPV81, -58, -72, -33 and -62. HPV16 isolates from 18 HIV-positive and eight HIV-negative women were classified into variant lineages based on sequencing analysis of E6 and E7 genes and the long control region. Whilst the HPV16 G350 European variant was prevalent in both HIV-positive (10.7 %) and -negative women (3.5 %), HPV16 African 2 variant was only detected in HIV-positive women (3.6 %), suggesting different sexual mixing behaviours. The increased prevalence of uncommon viral genotypes and HPV16 variants in HIV-positive Italian women underscores the need to target a wide range of HPV types in cervical screening of high-risk women.

Problems associated with substandard and counterfeit drugs in developing countries: a review article on global implications of counterfeit drugs in the era of antiretroviral (ARVs) drugs in a free market economy.

OBJECTIVES: To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs. METHODS: Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper. RESULTS: When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients. Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more harm than good to people's health and it is unethical to give such drugs to people. Of course, in any market, some corruption and fraud always exist, but there are few commercial markets where fraud can have such drastic impact on global health and welfare. It is essential, therefore, that a multi-faceted approach be used to control this problem which affects the international community and continuously threatens the health of millions of people especially in developing countries. CONCLUSION: Developing countries should try their best at all costs establish good laboratories for monitoring or checking for quality control for all pharmaceuticals locally manufactured and those imported (entering) or donated to countries to make sure that they meet the set or established international or national standards. Short of that countries will be wasting a lot of money using forex which has been borrowed in a form a loans procuring and distributing to its people sub-standard medications which will do more harm than good to its indigenous people and this is unethical per se to give people drugs not meeting required set international standards.