A higher proportion of the MOCT subset refilled antiretroviral therapy , with fewer deaths in the MOCT subset at 6 months  and a decreased likelihood of developing the composite outcome of death/failure to achieve viral suppression at 6 months . This study demonstrates preliminary intervention uptake and improvement in short-term outcomes for an urban cohort of PLWH, TB, and substance use enrolled in a multi-feature mHealth intervention, a novel strategy for the context.In Irkutsk, Siberia, there is a high prevalence of HIV and tuberculosis (TB) coinfection. Mobile health  strategies have shown promise for increasing linkage to and engagement in care for people living with HIV (PLWH) in other contexts. We evaluated outcomes for a cohort of PLWH, TB, and substance use in Irkutsk after participation in a multi-feature mHealth intervention called MOCT. Sixty patients were enrolled during hospitalization for TB. We evaluated participant app usage, linkage to HIV care postdischarge, perception of self-efficacy related to HIV care, and HIV-related clinical outcomes at 6 months. We also performed an exploratory analysis to compare a subset of 49 patients with a pre-intervention cohort matched for age and gender. Participants demonstrated engagement with app features examined at 6 months. The majority linked to HIV care by 6 months (83%). Self-scoring of confidence in ability to communicate with HIV providers improved from baseline  to 6 months (10, Clinical Trial Registration Number: NCT03819374. TB accounts for a third of HIV-associated deaths globally.8 In Siberia, TB incidence estimates are 1.6 times higher than the national rate.3 Within Siberia, Irkutsk is the federal jurisdiction with the highest HIV/TB coinfection prevalence.9 In Irkutsk, disengagement with HIV care is a primary driver of HIV/TB morbidity and mortality, which makes early ART initiation a high priority for coinfected patients, and inpatient TB hospitalization serves as a critical opportunity for engagement11Within the Russian Federation (RF), the HIV epidemic is still growing despite gains made to slow infections.12–15 mHealth strategies trialed in other HIV/TB-prevalent contexts to improve ART initiation and retention in care for patients with TB have employed single-feature mobile phone interventions. These have yet to demonstrate an improvement in these outcomes and, to our knowledge, they have not been designed for the Russian context.17 Our group has previously developed a smartphone-based intervention called PositiveLinks for a rural population of people living with HIV (PLWH) in the United States. PositiveLinks implementation was associated with improvement in several clinical outcomes.12 We hypothesized that, given relative smartphone familiarity and similar barriers of geographic remoteness existing in Irkutsk, a culturally tailored mHealth platform could improve linkage to HIV care for patients with comorbid TB and a history of substance use. We aimed to evaluate patient usage of the mHealth intervention, linkage to HIV care, and self-efficacy relative to HIV care in the 6 months after enrollment in the intervention. We also compared clinical outcomes for a subset of this study's cohort with those of a cohort of PLWH with a history of using substances that were hospitalized for inpatient TB therapy immediately before intervention implementation.Mobile health  strategies to improve linkage to and retention in HIV care and optimize adherence to ART have shown promise in diverse settings.Patients hospitalized at the Irkutsk Regional Tuberculosis Referral Hospital  were consecutively enrolled from April 2018 to November 2019 in the mHealth intervention (“MOCT”—Russian for “bridge”). Follow-up TB care was delivered at the TB Referral Hospital or affiliated TB clinics, and follow-up HIV care at the Irkutsk Regional AIDS Centre (AIDS Centre). Inclusion criteria included adults 18–64 years of age, with HIV status confirmed by chart review or laboratory testing, a history of using substances upon recruitment (confirmed by chart review or self-report), and primarily residing in Irkutsk city at the time of recruitment. Patients unable or unwilling to use a smartphone or cognitively unable to give informed consent were excluded. Written informed consent was obtained for all participants based on a protocol approved by the institutional review boards at the Scientific Centre for Family Health and Human Reproduction Problems (RF) and the University of Virginia (USA). This study used a single-arm prospective design with standardized assessments at baseline, 2 months, and 6 months.12 After translation and management of logistical considerations for implementation within Irkutsk, including server management, security, and privacy, we elicited TB Referral Hospital and AIDS Centre provider and patient feedback using unstructured interviews regarding platform design and functionality, usability, and acceptability. The MOCT platform provides several features as described in The MOCT smartphone app was adapted from PositiveLinks, an app originally developed using a theory-based iterative user-centered process.3) and HIV viral load , and ART refills obtained from AIDS Centre pharmacy records were collected within 90 days before the baseline time point and within 90 days before or after the 6-month time point.Baseline characteristics were collected upon enrollment using structured patient interviews and chart review. Data for laboratory values including CD4 count .Data relating to patient linkage (or re-linkage) to HIV care and self-efficacy relative to HIV care was collected at baseline, 2-, and 6-month assessments. A patient was considered “linked to care” at the 2- or 6-month time point if he or she reported attending at least one AIDS Centre appointment by that assessment. Loss to follow-up was defined as no patient registration information available in the AIDS Centre electronic medical record system after enrollment. Patient self-efficacy relative to retention in HIV care was evaluated using an adapted and translated 14-item retention-in-care assessment toolThe same study inclusion criteria were applied to the pre-intervention cohort, including documentation of presumed ability to give informed consent. Baseline characteristics were collected by chart review. Time points for the pre-intervention cohort were defined relative to the date of discharge from the TB Referral Hospital. A post hoc exploratory analysis was performed to compare 6-month outcomes for a subset of participants in the MOCT intervention with a historical (pre-intervention) cohort of PLWH with a history of substance use who were hospitalized at the TB Referral Hospital in the year before the start of enrollment. No other significant practice changes were identified in the pre-intervention and MOCT intervention time periods. Exploratory variables of interest for comparison between cohorts by 6 months included viral suppression and death  obtained by chart review, as well as dispenses of at least one refill of ART obtained by pharmacy monitoring.Baseline characteristics, linkage to care, and app feature usage were analyzed using descriptive statistics. A subset of patients in the pre-intervention and MOCT cohorts were matched using random 1:1 matching with a tolerance of 5 years for age and exact matching for gender. A total of 49 matches were obtained from a pool of 50 patients with sufficient data on chart review during the pre-intervention period to meet study inclusion criteria. The Wilcoxon signed-rank test was used to compare continuous variables for the MOCT cohort between baseline and 6 months , and between the matched pre-intervention and MOCT cohorts at baseline . McNemar's test was used to compare dichotomous variables for the MOCT cohort between time points , and between matched cohorts at baseline  and at 6 months . Binomial logistic regression was performed to examine the association between the composite outcome of death/failure to achieve viral suppression at 6 months with covariates, including exposure to the MOCT intervention. Analyses were performed with IBM SPSS Statistics for Mac, Version 26.0 .Sixty patients were enrolled in the intervention. Majority were male (60%) with a mean age of 38 years . Chart rp = 0.18). However, there was a significant difference in the proportion of active users for the community message board  and daily queries  between those time points. No security breaches of the portal occurred.Aggregate cohort usage of each app feature examined is summarized . By 6 moSurvey responses were missing for 10 patients at 6 months due to loss to follow-up (7), death (2), and no-show to 6-month assessment but ongoing AIDS Centre follow-up (1). Six of the seven patients lost to follow-up eventually re-established or linked to care after the end of the study assessment period. At 2 months, 40 patients reported linkage to care, or attending at least one visit since their baseline assessment. Thirty-six patients reported attending at least one additional visit by their 6-month assessment. Ten patients reported attending at least one visit for the first time at the 6-month assessment, for a total of 50 patients linked to care by 6 months (83%).N = 50 surveys with responses available) compared with baseline demonstrated that patients' median scoring of confidence in their ability to regularly “contact the clinic if I have questions about my medications” improved (p = 0.004). The median score on patient confidence in setting health goals was high at baseline with a wider spread in responses at 6 months.Analysis of retention-in-care scale scores at 6 months  compared with baseline .Laboratory data were missing for 10 patients at 6 months as noted earlier. The median CD4 count improved at 6 months [274 ] [184 (65–335), N = 49). The cohorts demonstrated similar baseline characteristics after matching (p = 0.02). The monitored dispense rate for ART at 6 months for the MOCT subset  was higher than the rate observed for the pre-intervention cohort .Exploratory analysis was performed for a subset of patients in the MOCT cohort matched to the pre-intervention cohort . Whereas a baseline VL >200 was also independently associated with an increased likelihood for developing the composite outcome , associations with the other covariates were not statistically significant.Binomial logistic regression evaluated the effects of covariates on the likelihood that patients develop the composite outcome of death/unable to achieve viral suppression at 6 months . ExposurThis study is the first, to our knowledge, to evaluate a multi-feature mHealth strategy among HIV/TB coinfected patients in the RF with substance use and otherwise at high risk of disengagement. The MOCT app was usable based on preliminary analysis, and participants demonstrated improved linkage to and engagement with HIV care as well as improved 6-month clinical outcomes relative to pre-intervention controls.20 Notably, although the number of active users remained relatively constant across the 6 months for the direct messaging feature, there was a significant early drop in the number of active users of the community message board and a more gradual drop in active users of daily queries over 6 months. Reasons for this drop in usage will be explored in further evaluation of app usability and acceptability.The cohort continued to use the MOCT app after enrollment. Although retention-in-care scale scores at baseline and 6 months indicated high confidence for patients on all measures, there was a significant increase in confidence related to ability to regularly reach out to providers at the clinic with questions about medications, a feature directly supported by the MOCT app. Messaging activity was highest within the first and third months after enrollment, with consistent use at 6 months. Messaging can enhance patient–provider rapport, and has been shown to be important for maintaining retention in care.21 In contrast to mobile phone interventions delivered as stand-alone strategies, the multi-feature MOCT app was intentionally embedded in a health systems integration effort for coordination between the TB Referral Hospital and the AIDS Centre through weekly meetings of institution representatives, shared access to laboratory values, medication refill data, and appointment scheduling. The significantly improved mean CD4 count and rates of viral suppression at 6 months were likely the effect of enhanced adherence in patients already on ART before enrollment as well as an increase in ART coverage for patients who were not previously prescribed ART. Examination of these outcomes at the 6-month time point limits the ability to detect maximal viral suppression, as the most commonly used ART regimens in this study are associated with longer time to suppression relative to the integrase inhibitors now in more common use in the RF.Good rates of patient linkage to HIV care were observed by 6 months. The intervention provided patients with the opportunity to engage with app features while hospitalized at the TB Referral Hospital and after discharge, when patients needed to coordinate their HIV and TB care independently. A recent systematic review described the heterogeneity of studies of SMS-based mHealth interventions for improving linkage and retention in care for PLWH in low- and middle-income countries and demonstrated in many settings a lack of clear benefit.22 and mortality typically occurs early during the anti-TB treatment course for coinfected patients not on ART.23 We observed higher rates of ART refills for the MOCT cohort by 6 months, and the cause of death at 6 months showed the majority were attributed to HIV in the pre-intervention cohort, whereas the single death in the MOCT subset was not related to HIV or TB.Exploratory analysis of the matched cohorts revealed a relative reduction in 6-month mortality in the MOCT cohort. There was also a statistically significant decrease in the likelihood for development of the composite outcome at 6 months for the MOCT cohort when controlling for other covariates related to severity of TB and HIV at baseline. We were unable to control for ongoing substance use patterns as these were not measured in the pre-intervention cohort. Early ART initiation followed by ongoing adherence is associated with reduced mortality in patients with HIV/TB coinfection,Limitations exist for this study. Loss to follow-up resulted in missing 6-month data on linkage to care and self-efficacy. The loss of these participants may introduce attrition bias, inflating the proportion of favorable survey responses obtained for retention-in-care scale scoring at 6 months. It also excludes laboratory values for patients unlikely to be virally suppressed at 6 months. Direct translation of several retention-in-care scale items during initial testing proved incomprehensible in Russian and required modification, which may have had unintended consequences on how patients ultimately responded to the scale. Twenty-five participants were provided a smartphone, and all were provided data plans, which may have motivated some patients to demonstrate app usage during ongoing assessments, but usage was not stated as a requirement to keep the phone. Deploying the platform through a smartphone may also limit the generalizability of findings if smartphones remain out of reach for PLWH and TB in other high-burden regions.The comparison between a pre- and MOCT-intervention cohort was not randomized to the intervention/standard of care or matched by baseline disease characteristics. Instead, we had to adjust for those characteristics by building them into our regression analysis. The comparative analysis was performed for two relatively small sample populations selected from a regional referral hospital specializing in the care of people with advanced disease and there may have been a higher underlying propensity for patients to encounter HIV/TB treatment failure that was not directly accounted for in our analysis. An additional residual confounder that may contribute to the observed improvement in outcomes for the MOCT cohort includes higher frequency of provider-initiated contact with patients associated with conducting study activities. The matching process also introduces some potential bias. The majority of the MOCT cohort participants excluded from exploratory comparison (9/11) were female; however, rates of 6-month mortality (1 death) and viral suppression  were not substantially different from those observed for the MOCT subset after matching.In conclusion, the MOCT app intervention employed a multi-feature mHealth strategy that is novel for the treatment of HIV in this context. There was sustained engagement in HIV care for a majority of the enrolled cohort by 6 months. Further work will study the scalability of the MOCT intervention after further iteration, including how the app may specifically enhance integration of care for PLWH/TB, and whether similarly positive outcomes are found if applied to PLWH without TB, or those already in the outpatient setting.


To describe antiretroviral treatment regimens prescribed and their compliance with the Clinical Protocol and Therapy Guidelines of the Ministry of Health for the management of HIV infection. Observational and descriptive study. Secondary data of the state of Paraná (Brazil) on drugs, treatment regimens, lines of treatment and number of individuals on treatment, from January to June 2018, were accessed at the Antiretroviral Agents Logistic Control System. Combinations of antiretroviral drugs (treatment regimens) were compared according to the current Clinical Protocol and Therapy Guidelines and non-compliances were classified and quantified. In Paraná, 35,127 individuals with HIV were treated with 253 different treatment regimens. Of the prescribed regimens, 19.1% were first-line, 27.4% second-line and 48.5% third-line. Among non-compliances, the most prevalent were absence of association of protease inhibitors and ritonavir (42.8%), low efficacy triple therapy (36.9%), double therapy (26.1%), monotherapy (20.3%), and triple therapy of nucleoside analog reverse transcriptase inhibitors (17.1%). Most individuals receiving HIV treatment in the state of Paraná are on treatment regimens established in the current Clinical Protocol and Therapy Guidelines, which contributes to successful therapy. However, associations not provided by the current Clinical Protocol and Therapy Guidelines were identified in the initial treatment lines, which could lead to ineffectiveness, virologic failure and viral resistance. The infection caused by the human immunodeficiency virus (HIV) is a major issue for community health in Brazil and worldwide, due to morbidity and mortality, and the consequent impact on public health policies.Sistema Único de Saúde ).   Studies have shown that this HIV infection control-oriented public policy contributed significantly to the reduction in mortality and hospitalizations due to HIV/AIDS in Brazil.  , 4 In 1996, federal law 9.313 was enacted and guaranteed access to antiretroviral therapy through the Unified Health System  and non-nucleoside reverse-transcriptase inhibitors (NNRTI), which prevent replication of viral RNA inside TCD4+ cells; protease inhibitors (PI), which block the enzyme that breaks viral proteins synthetized in host cells; integrase inhibitors (INI), which inhibit the enzyme that integrates viral RNA to the DNA of host cells; fusion inhibitors (FI), which prevent the fusion of the viral membrane to the human cell membrane; and CCR5 inhibitors, which inhibit membrane proteins that bind to the HIV and prevent the infection in host cells.Protocolo Clínico e Diretrizes Terapêuticas ) of the Ministry of Health, aimed to manage HIV infection, guides the choice of prescriptions through treatment regimens comprised by combinations of more than one antiretroviral drug, organized in different lines of therapy. Treatment success attained by treatment regimens provides reduction in the number of viral copies, increase in the number of TCD4+ lymphocytes and consequent restoration of immunity.  The Clinical Protocol and Therapy Guidelines  through the Paraná Medication Center (CEMEPAR - Centro de Medicamentos do Paraná ), of the Paraná State Department of Health (SESA-PR - Secretaria de Estado da Saúde do Paraná ).Observational and descriptive study. Secondary data, referring to the period between January and June 2018 were accessed on the Antiretroviral Drug Logistic Control System  dispensed, per lines of treatment regimens, and per number of users were attained.Information was computed and then classified according to compliance or non-compliance with the Ministry of Health PCDT to manage HIV infection (PCDT 2017). Non-compliances were identified and stratified into the following categories: monotherapy, double therapy not allowed in the PCDT in effect, low-efficiency triple therapy, non-association PI + ritonavir, double PI, three NRTI, therapeutic duplicity, and possible genotyping-guided treatment regimens.Universidade Federal do Paraná and of the Paraná State Health Department (SESA-PR), under CAAE: 82936318.3.3001.5225 and opinion 2.674.606.The study was approved by the Ethics Committee of In the period from January to June 2018, 235 different treatment regimens prescribed to 35,127 individuals living with HIV/AIDS in Paraná were identified. Of the 21 antiretroviral drugs standardized by SUS, 18 were prescribed at least once   .The most prevalent drugs were lamivudine, tenofovir, efavirenz and dolutegravir, usually prescribed to patients as first line therapy, followed by ritonavir, a potentiator, and atazanavir and darunavir, predominantly prescribed for second and third lines of antiretroviral therapy, respectively. Some drugs, such as enfuvirtide and maraviroc, were used exclusively in third line therapy.First line therapy encompassed 61.3% of users registered, for whom 19.1% of treatment regimens were prescribed. Second line therapy encompassed 27.4% of regimens identified, treating 30.2% of users. Third line corresponded to 48.5% of treatment regimens identified, which were prescribed to only 8.3% of all users registered in Paraná during the study period. The line of therapy of 5.0% of treatment regimens indicated for 0.2% of users was not defined   .Of the total 253 treatment regimens identified, 46.2% (n=117) were not envisaged by the PCDT in effect. The regimens covered 2.4% of antiretroviral users in the state. The 64% of prescriptions not foreseen in the PCDT presented only one non-compliance, 34% had two, and 2.0% had three non-compliances.Of the non-compliances identified, 20.5% occurred in first line treatment regimens, 29.9% in second line, and 39.3% in third line, making second line the most prevalent non-compliance.Non-compliances identified in the antiretroviral regimens in Paraná, after comparing with the most recent PCDT, are described and quantified in Of total non-compliances, the most frequent regimen was double therapy not allowed by the PCDT (23.8%), followed by non-association of PI and ritonavir (19.7%), and the association of three NRTI (17.0%).Of total individuals on regimens non-compliant with the PCDT, the non- association PI with ritonavir, low efficiency triple therapy, and double therapy not allowed in the PCDT were the scenarios in which there were more users .  Since the SUS made antiretrovirals available, new drugs and treatment regimens have been developed to control HIV infection. This occurs because antiretroviral therapy does not eliminate the virus from the body, and patients have to remain under treatment throughout their lives. There are many difficulties related to therapy in this scenario, such as problems with compliance, adverse reactions, drug interactions, and resistance of HIV to medication. For this reason, treatment protocols and guidelines are reviewed regularly, anticipating new antiretroviral pharmaceuticals and more effective treatment regimens, and are the major references for efficacious treatment of HIV/AIDS.  The current PCDT recommends associating three antiretroviral drugs, two NRTI drugs and one of another class . The initial treatment recommended is lamivudine + tenofovir + dolutegravir, mainly when there are no related comorbidities or restrictions (for example: tuberculosis or pregnancy).  but remains as the component of initial treatment for patients with satisfactory results and good tolerance to the drug.   It is also indicated preferably as the initial regimen for child-bearing age women.   Efavirenz has been gradually replaced by dolutegravir, the most recent antiretroviral added by the SUS.   The change is recommended, due to higher viral suppression, less likely resistance, higher recovery of the immune system, single daily dose, and few adverse reactions attributed to dolutegravir.  - 13 In the current study, lamivudine and tenofovir, prescribed as first line HIV therapy, were the most prevalent drugs in the treatment regimens assessed in Paraná. Efavirenz, that ranks next, is associated with neuropsychiatric reactions,  , 15 Ritonavir, although ranking with an expressive percentage of regimens of Paraná, should not be considered as a single drug, given it is only a pharmacokinetic potentiator.   Darunavir was the most prevalent drug in third line therapy, and comprises the salvage choice after multiple treatment failures. Its indication will likely be authorized after analysis by the HIV Technical Committee.  In Paraná, some drugs have stood out in second and third line therapies for HIV infection treatment. Atazanavir is a priority drug for cases of first line therapy failures, possibly because it has the advantage of being the only PI used as a daily single dose, allowing better treatment compliance.  The prevalence of use of enfuvirtide and maraviroc was low in Paraná, because their use is restricted to third line therapy and genotype-guided cases. Moreover, dispensing of these drugs also depends on approval by the HIV Technical Committee of the state.  As expected, first line therapy encompasses most of the population on therapy in Paraná, albeit it has the shortest list of prescribed regimens. The scenario is the contrary for third line therapy, given there are few users for many regimens prescribed. This result is expected, given first line regimens are well defined in the PCDT and prescribed for naïve patients. However, third line regimens are indicated for patients already on antiretrovirals after successive adjustments due to treatment failures, viral resistance and genotyping. Consequently, they are generally specific to each individual, impacting on the diversity of regimens prescribed and on possible non-compliances with PCDT.The classification of non-compliances identified in relation to the protocol revealed that almost half (46.2%) of antiretroviral regimens identified in the study were not included in the PCDT, but they were prescribed only for 2.26% of individuals on antiretroviral therapy in Paraná.   However, some non-compliances found are strictly forbidden by the PCDT in effect, and can cause treatment failure and viral resistance.   For example, monotherapy is characterized by using only one drug to treat HIV and is strongly contraindicated in the current antiretroviral therapy.   Still, it was present in the treatment of 161 users in the State of Paraná. It is important to underscore that in the present study, the association PI/r was considered monotherapy. Such monotherapy may be efficacious in the suppression of viral copies, but favors the development of resistant mutations.  The only exception to the monotherapy included in the PCDT is to prevent mother-child transmission of HIV, recommending zidovudine as monotherapy, indicated for pregnant women during labor.   However, there is no specific identification of pregnant patients on the SICLOM database. As SICLOM does not allow confirming if all monotherapies with zidovudine were prescribed to pregnant women, the indications of the drug as monotherapy were included in non-compliances, and represent a possible limitation of the study.The PCDT does not provide all treatment options, and it is the role of prescribing professionals to indicate the most appropriate treatment whenever required, taking into account the previous use of antiretrovirals, HIV mutations (genotype resistance) and effectiveness for patients.  Double therapy was present in 26.1% of non-compliances and is not described on PCDT, because it is described as a regimen of low genetic barrier to viral resistance mutations.   Regimens that did not associate ritonavir and PI are not accepted by the PCDT.   Ritonavir acts by inhibiting isoenzymes of cytochrome P450 3A4, decreasing the metabolism of the other associated PI, and pharmacokinetically maximizing the action of the second antiretroviral of the same class.  The PCDT suggests triple regimens for first and second lines. However, some triple regimens may be characterized as of low efficacy, since they are not effective to decrease viral load.   and currently is no longer recommended.  The combination of two PI + ritonavir was not frequently prevalent in the study. However, it has been previously allowed in cases of ample resistance to PI,   However, the triple NRTI association was indicated for 136 individuals whose treatment had some type of non-conformity. In the past, this was a treatment option for individuals coinfected with tuberculosis.   Other studies have correlated triple NRTI with more likely viral mutation and consequent virus resistance.  , 18 The triple NRTI association therapy regimen is also not indicated and may lead to viral resistance.   related to increase in adverse reactions, without increasing efficacy.  Therapeutic duplicity is characterized by double dose of the same drug at the same time, and is considered as a type of medication error   As they are customized regimens, they are highly specific . There were 17% of these regimens identified as not included in the current PCDT.The PCDT does not define third line regimens, as they are guided by genotyping. Third line regimens can contain several classes, including the most recent, CCR5 inhibitors and IF, according to the infecting viral strain of each individual.  The progression of antiretroviral therapies made available by the SUS is evident. Efforts concentrated on integral care to people living with HIV in Brazil have had positive results, given access to correct antiretroviral medications, in correct dosages and with satisfactory compliance, had a positive impact on the quality of life of the population and reduced transmission of the virus.Clinical protocols guide the choice of prescribers, but they are not sufficiently comprehensive to describe the entire plurality of required treatment regimens. Regardless, indication must be careful because some choices of drugs may lead to viral resistance and treatment failure.  , 23 Considering that treatment protocols and guidelines are developed based on successful experiences of clinical studies, people living with HIV/AIDS currently on treatment with antiretroviral drugs in Paraná are estimated to have at their disposal drugs capable of providing them with treatment success, especially if allied to satisfactory compliance   and appropriate outpatient follow-up.  The virologic success of antiretroviral therapy in Paraná was realized while the study was still ongoing, and endorses the low viral replication observed for patients on treatment.This study contributes to acknowledge antiretroviral drugs and regimens used to control HIV infection in Paraná. Similar studies have been conducted.In the state of Paraná, during the period of the present study, treatment regimens recommended by the Clinical Protocol and Treatment Guidelines prevailed, and were prescribed for almost all patients undergoing treatment with antiretrovirals in the state. Some non-compliances identified are strictly forbidden by the Clinical Protocol and Treatment Guidelines in effect, because they may lead to treatment failure and viral resistance.The fact that most non-compliances occurred for first and second line therapies draws attention. This is damaging to treatment success, as it increases the risk for requiring early changes in regimens to more harmful options to patients’ quality of life, and more expensive choices to the health system.   A infecção causada pelo vírus da imunodeficiência humana (HIV) constitui importante problema de saúde coletiva no Brasil e no mundo, em razão da morbimortalidade e do consequente impacto nas políticas públicas de saúde.  Estudos demonstram que esta política pública voltada ao controle da infecção pelo HIV contribuiu significativamente para a redução da mortalidade e dos internamentos por HIV/AIDS no Brasil.  , 4 Em 1996, foi promulgada a lei federal 9.313, a qual garantiu o acesso à terapia antirretroviral por meio do Sistema Único de Saúde (SUS).  Atualmente, o SUS disponibiliza 21 medicamentos para o controle da infecção pelo HIV, distribuídos em seis classes farmacológicas distintas: inibidores da transcriptase reversa análogos de nucleosídeos (ITRN) e inibidores da transcriptase reversa não análogos de nucleosídeos (ITRNN), que atuam impedindo a replicação do RNA viral dentro das células TCD4+; inibidores da protease (IP), que agem impedindo a enzima que fragmenta as proteínas virais sintetizadas na célula hospedeira; inibidores da integrase (INI), que atuam inibindo a enzima que integra o RNA viral no DNA da célula hospedeira; inibidor de fusão (IF), que impede a fusão da membrana viral com a membrana celular humana; e inibidor da CCR5, que inibe a proteína de membrana, que se liga ao HIV e não permite a infecção na célula hospedeira.  O Protocolo Clínico e Diretrizes Terapêuticas (PCDT) do Ministério da Saúde para manejo da infecção pelo HIV norteia a escolha de prescrições por meio de esquemas terapêuticos, constituídos por combinações de mais de um fármaco antirretroviral, dispostos em diferentes linhas de tratamento. O sucesso terapêutico alcançado pelos esquemas terapêuticos proporciona a redução do número de cópias virais, o aumento do número de linfócitos TCD4+ e a consequente restauração da imunidade.  , 7 A primeira linha de tratamento consiste no esquema terapêutico prescrito logo após o diagnóstico. Caso não haja sucesso na supressão viral e restauração da imunidade, a segunda linha deve ser prescrita, e assim por diante. As falhas no tratamento podem ocorrer devido às reações adversas aos medicamentos, esquemas pouco efetivos, má adesão e resistência viral transmitida. Nestas circunstâncias, os esquemas de antirretrovirais são modificados, podendo, em situações mais críticas, resultar em esquemas personalizados, guiados por genotipagem, não previstos no PCDT.Assim, torna-se importante identificar os fármacos em uso e suas associações, bem como a conformidade com o PCDT, de forma a contribuir com o uso racional dos antirretrovirais e o controle da infecção.Descrever os fármacos e esquemas terapêuticos antirretrovirais prescritos e sua conformidade com o Protocolo Clínico e Diretrizes Terapêuticas.Trata-se de estudo observacional e descritivo. Os dados secundários, referentes ao período de janeiro a junho de 2018, foram acessados via Sistema de Controle Logístico de Medicamentos Antirretrovirais (SICLOM) por intermédio do Centro de Medicamentos do Paraná (CEMEPAR), da Secretaria de Estado da Saúde do Paraná (SESA-PR).Foram obtidos dados sobre as dispensações de antirretrovirais no estado do Paraná, estratificados por esquemas terapêuticos (combinação de diferentes antirretrovirais) dispensados, por linhas de tratamento a que pertencem estes esquemas e pelo número de usuários.As informações foram tabuladas e, posteriormente, classificadas de acordo com a conformidade ou não em relação ao PCDT do Ministério da Saúde para manejo da infecção pelo HIV (PCDT 2017). As inconformidades foram identificadas e estratificadas nas seguintes categorias: monoterapia, terapia dupla não permitida no PCDT vigente, terapia tripla de baixa eficiência, não associação IP + ritonavir, duplo IP, três ITRN, duplicidade de tratamento e esquemas terapêuticos possivelmente guiados por genotipagem.Esta pesquisa foi aprovada pelo Comitê de Ética da Universidade Federal do Paraná e da Secretaria de Estado da Saúde do Paraná (SESA-PR) sob o número CAAE: 82936318.3.3001.5225 e parecer: 2.674.606.No período de janeiro a junho de 2018, foram identificados 235 esquemas terapêuticos distintos prescritos para 35.127 pessoas vivendo com HIV/AIDS no Paraná. Dos 21 fármacos antirretrovirais padronizados pelo SUS, 18 deles foram prescritos ao menos uma vez   .Os fármacos mais prevalentes foram lamivudina, tenofovir, efavirenz e dolutegravir, comumente prescritos para pacientes em primeira linha de tratamento, seguidos pelo ritonavir, um potencializador, e atazanavir e dorunavir, predominantemente prescritos para a segunda e terceira linhas da terapia antirretroviral, respectivamente. Alguns fármacos, como enfuvirtida e maraviroque, foram exclusivamente utilizados na terceira linha de tratamento.A primeira linha de tratamento abrangeu 61,3% dos usuários cadastrados, para os quais foram prescritos 19,1% dos esquemas terapêuticos. A segunda linha de tratamento abrangeu 27,4% dos esquemas identificados, que trataram 30,2% dos usuários. A terceira linha respondeu por 48,5% dos esquemas terapêuticos identificados, os quais foram prescritos para apenas 8,3% de todos os usuários cadastrados no Paraná no período deste estudo. Não foi definida a linha de tratamento de 5,0% dos esquemas terapêuticos, os quais foram indicados para 0,2% dos usuários   .Do total de 253 esquemas terapêuticos identificados, 46,2% (n=117) não eram contemplados no PCDT vigente. Estes esquemas tiveram alcance de 2,4% de usuários de antirretrovirais no estado. Os 64% destas prescrições não previstas no PCDT apresentaram apenas uma inconformidade, 34% apresentaram duas e 2,0% apresentaram três inconformidades.Das inconformidades identificadas, 20,5% ocorreram nos esquemas de primeira linha de tratamento, 29,9% na segunda linha e 39,3% na terceira linha, configurando a segunda linha como a mais prevalente.As inconformidades identificadas nos esquemas de antirretrovirais do Paraná, após comparação com o PCDT mais recente, estão descritas e quantificadas na Do total de inconformidades, a mais frequente nos esquemas é a terapia dupla não permitida em PCDT , seguida da não associação IP com o ritonavir  e da associação com três ITRN .Do total de indivíduos em uso de esquemas em desacordo com a PCDT, a não associação do IP com o ritonavir, a terapia tripla de baixa eficiência e a terapia dupla não permitida em PCDT foram as condições com mais usuários .  Desde a disponibilização de antirretrovirais pelo SUS, novos fármacos e esquemas terapêuticos foram desenvolvidos para o controle da infecção pelo HIV. Isto ocorre porque a terapia antirretroviral não elimina o vírus do organismo, e os pacientes devem permanecer em tratamento ao longo da vida. Neste contexto, existem muitas dificuldades relacionadas à terapia, como problemas na adesão, reações adversas, interações medicamentosas, e resistência do HIV à medicação. Por esta razão, os protocolos e diretrizes terapêuticas são periodicamente revisados, prevendo novos fármacos antirretrovirais e esquemas terapêuticos mais efetivos, tornando-se as maiores referências para o tratamento eficaz do HIV/AIDS.  O PCDT atual recomenda associar três fármacos antirretrovirais, dois fármacos ITRN e um de outra classe . A terapia inicial recomendada é lamivudina + tenofovir + dolutegravir, sobretudo quando não há comorbidades ou restrições relacionadas (por exemplo: tuberculose ou gestação).  porém permanece como componente de esquema inicial para pacientes com resultados satisfatórios e boa tolerância a este fármaco.  Também é indicado preferencialmente como esquema inicial para mulheres com possibilidade de engravidar.  O efavirenz tem sido gradativamente substituído pelo dolutegravir, o mais recente antirretroviral incorporado no SUS.  Esta troca é recomendada, devido à maior supressão viral, menor probabilidade de resistência, maior recuperação do sistema imune, dose única diária e poucas reações adversas atribuídas ao dolutegravir.  - 13 No atual estudo, a lamividina e o tenofovir, prescritos para a primeira linha de tratamento do HIV, foram os fármacos mais prevalentes nos esquemas terapêuticos avaliados no Paraná. O efavirenz, que surge na sequência, é relacionado a reações neuropsiquiátricas,  , 15 O ritonavir, embora apareça com expressiva percentagem nos esquemas do Paraná, deve ser desconsiderado como fármaco isolado, por ser apenas um potencializador farmacocinético.  O dorunavir foi o fármaco mais prevalente na terceira linha e compõe a escolha de resgate após múltiplas falhas de terapia. Sua indicação deve ser autorizada após análise da Câmara Técnica de HIV.  No Paraná, alguns fármacos ganharam destaque em esquemas de segunda e terceira linhas de tratamento da infecção pelo HIV. O atazanavir se apresenta como fármaco prioritário para casos de falhas na primeira linha de tratamento, possivelmente por apresentar a vantagem de ser o único IP utilizado em dose única diária, permitindo melhor adesão à terapia.  As prevalências de uso da enfuvirtida e do maraviroque foi baixa no Paraná, pois seus usos são restritos à terceira linha de tratamento e em casos guiados por genotipagem. Além disso, a dispensação destes fármacos também é condicionada à aprovação da câmara técnica de HIV do estado.  Como esperado, a primeira linha de tratamento abrange a maior parte da população em terapia no Paraná, porém contempla menor lista de esquemas prescritos. A situação se inverte na terceira linha de tratamento, pois existem poucos usuários para muitos esquemas prescritos. Este resultado é esperado, uma vez que os esquemas de primeira linha são bem definidos no PCDT e prescritos para pacientes sem uso prévio de antirretrovirais. Entretanto, os esquemas de terceira linha são indicados para pacientes já em uso de antirretrovirais, após sucessivos ajustes motivados por falhas na terapia, resistência viral e genotipagem. Consequentemente, costumam ser específicos para cada indivíduo, impactando na diversidade de esquemas prescritos e nas possíveis inconformidades com o PCDT.Na classificação das inconformidades identificadas em relação ao protocolo, obteve-se que praticamente metade  dos esquemas de antirretrovirais identificados no estudo não estão previstos no PCDT, porém estes foram prescritos para somente 2,26% das pessoas em tratamento com antirretrovirais no Paraná.  Entretanto, algumas inconformidades encontradas são expressamente proibidas pelo PCDT vigente, podendo ocasionar falha de tratamento e resistência viral.  Por exemplo, a monoterapia é caracterizada como a utilização de apenas um fármaco no tratamento de HIV e é fortemente contraindicada na terapia antirretroviral atual.  Mesmo assim, esteve presente no tratamento de 161 usuários do estado. Importante ressaltar que, neste estudo, a associação IP/r foi considerada monoterapia. Tal monoterapia pode ser eficaz na supressão das cópias virais, porém favorece o desenvolvimento de mutações de resistência.  A única exceção à monoterapia prevista no PCDT é para a prevenção da transmissão vertical do HIV, que recomenda o uso da zidovudina como monoterapia, indicada para gestantes em trabalho de parto.  Entretanto, na base de dados do SICLOM, não há identificação específica para pacientes gestantes. Por não permitir confirmar se todas as monoterapias com zidovudina foram prescritas para gestantes, as indicações deste fármaco como monoterapia foram incluídas nas inconformidades, caracterizando-se como possível limitação do estudo.O PCDT não prevê todas as opções de tratamento, cabendo ao profissional prescritor indicar o tratamento não previsto mais adequado quando necessário, considerando o histórico de usos prévios de antirretrovirais, mutações do HIV (resistência genotípica) e efetividade nos pacientes.  A terapia dupla esteve presente em 26,1% das inconformidades e não é indicada no PCDT, pois é descrita como esquema de baixa barreira genética para mutações de resistência viral.  Os esquemas que não apresentavam a associação do ritonavir ao IP não são aceitos pelo PCDT.  O ritonavir age inibindo a isoenzimas do citocromo P450 3A4, diminuindo o metabolismo do outro fármaco IP associado, potencializando, de maneira farmacocinética, a ação do segundo antirretroviral da mesma classe.  O PCDT sugere esquemas triplos para primeira e segunda linhas. Porém, alguns esquemas triplos podem ser caracterizados como de baixa eficácia, por não serem efetivos para diminuir a carga viral.  não sendo mais recomendada na atualidade.  A combinação de dois IP + ritonavir foi pouco prevalente no estudo. Entretanto, já foi previamente permitida em casos de resistência ampla a IP,  Entretanto, a associação tripla de ITRN foi indicada para 136 pessoas cujo tratamento apresentou alguma inconformidade. No passado, esta foi uma opção de tratamento de pessoas coinfectadas com tuberculose.  Outros estudos correlacionaram o triplo ITRN com maior probabilidade de mutação viral e consequente resistência do vírus.  , 18 A associação tripla de ITRN no esquema terapêutico também não é indicada e pode levar à resistência viral.  relacionado ao aumento de reações adversas, sem aumento da eficácia.  A duplicidade terapêutica é caracterizada pela utilização de dose duplicada de um mesmo fármaco ao mesmo tempo, sendo considerado um tipo de erro na medicação  Por serem esquemas personalizados, apresentaram grande especificidade (em média duas pessoas por esquema). Nesta condição, foram identificados 17% dos esquemas não previsto no PCDT vigente.O PCDT não define esquemas de terceira linha, pois são guiados por genotipagem. Os esquemas de terceira linha podem conter várias classes, incluindo as mais recentes, inibidor da CCR5 e o IF, conforme a cepa viral infectante em cada indivíduo.  A evolução das terapias antirretrovirais disponibilizadas pelo SUS é evidente. Os esforços concentrados no cuidado integral à pessoa vivendo com HIV no Brasil apresenta resultado positivo, pois o acesso ao medicamento antirretroviral correto, na dose correta e com boa adesão, impacta positivamente na qualidade de vida da população e reduz a transmissão do vírus.Os protocolos clínicos norteiam a escolha dos prescritores, porém não são amplos o suficiente para descrever toda a pluralidade de esquemas terapêuticos necessários. Apesar disto, é necessário ter cautela na indicação, pois algumas condutas na escolha medicamentosa podem acarretar em resistência viral e falha na terapia.  , 23 Considerando que os protocolos e diretrizes terapêuticas são elaborados a partir de estudos clínicos e experiências bem-sucedidas, estima-se que as pessoas vivendo com HIV/AIDS atualmente em tratamento com antirretrovirais no Paraná têm à disposição fármacos capazes de lhes proporcionar sucesso terapêutico, sobretudo se aliados à adesão  e ao bom acompanhamento ambulatorial.  Esta constatação tem ocorrido em estudo ainda em andamento sobre o sucesso virológico da terapia antirretroviral no Paraná e confirma a baixa replicação viral nos pacientes em tratamento.Este estudo contribui com o conhecimento dos fármacos antirretrovirais e esquemas em uso para controle da infecção pelo HIV no Paraná. Estudos semelhantes foram conduzidos previamente.No estado do Paraná, no período considerado neste estudo, predominaram os esquemas terapêuticos previstos no Protocolo Clínico e Diretrizes Terapêuticas, os quais foram prescritos para quase todos os pacientes em tratamento com antirretrovirais no estado. Algumas inconformidades identificadas são expressamente proibidas pelo Protocolo Clínico e Diretrizes Terapêuticas vigente, pois podem ocasionar falha de tratamento e resistência viral.Chama atenção o fato de que a maioria das inconformidades ocorre nas duas primeiras linhas de tratamento. Isto é negativo para o sucesso terapêutico, pois eleva os riscos de necessidade de troca precoce de esquemas para opções mais danosas para a qualidade de vida do paciente, bem como mais onerosas para o sistema de saúde.


Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi.We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019.PDR testing was successful in 197 of 200 samples. The overall NNRTI- PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI- PDR was 11.2% (22/197). The most common mutation was K103N , followed by Y181C . In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI- PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up.The prevalence of NNRTI- PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa. The global availability of antiretroviral therapy (ART) has resulted in a great reduction of new HIV infections, HIV related morbidity, and mortality , 2. HowePretreatment drug resistance (PDR) is defined by the WHO as resistance that is detected among people either newly initiating or reinitiating first-line ART . In prevMalawi has set up an effective HIV treatment program. According to the Malawian Ministry of Health quarterly reports, as of September 2018, out of the total one million PLHIV in Malawi, around 94% knew their status, 80% were on ART, and 89% of those on ART were virally suppressed .The Lighthouse Clinic is the largest provider of HIV counselling, treatment and care in Lilongwe, Malawi . We commThe study was conducted at one of the Lighthouse clinics on the campus of the Kamuzu Central Hospital in Lilongwe, Malawi. The Lighthouse is a large, specialized center for HIV treatment and care in the central region of Malawi, and mainly serves an urban population of lower socio-economic status. Access to testing and counselling as well as treatment and care is free of charge at the point of delivery .The present study is a subgroup analysis of participants in the LighTen study, which enrolled 1432 ART-naïve adults aged 18 years or older. 200 consecutively enrolled patients were selected at random for PDR testing during the recruitment process in 2014 and 2015. We drew baseline serum samples prior to treatment initiation, stored them at minus 80° C, and later analyzed them for the presence of HIV-1 drug resistance mutations.All LighTen enrollees received first-line ART according to Malawian treatment guidelines, which at the time of enrolment consisted of lamivudine (3TC), tenofovir disoproxil fumarate (TDF) and efavirenz (EFV). Decisions on treatment regimen and potential switches were not informed by the results of drug resistance testing. Participants were seen regularly during routine follow-up visits as scheduled in the Malawian national treatment guidelines and according to clinical needs. Treatment outcomes were analyzed at the end of 2019.All participants had baseline evaluation beyond the standards of the Malawian HIV treatment program, including full blood count, liver and renal function tests, CD4 cell count, and HIV viral load testing .Nucleic acid extraction from 500 µL of serum was performed using the DNA and viral NA large volume kit  for the automated MagNA Pure 96 system . The protease and reverse transcriptase regions were amplified for resistance analysis as described by Lübke et al. , and theOutcome variables were: viral load 6 months after treatment initiation, last viral load, and treatment outcome at the time of assessment. Treatment outcomes were categorized as either: alive and on treatment at the Lighthouse clinic, transferred out to another treatment facility, stopped ART, died, changed ART regimen, withdrawn from the study, or defaulted. The status “defaulted” was assigned to patients who had not been in contact with the clinic 60 days after a missed follow-up appointment. Drug resistance mutations conferring at least low-level resistance according to the Stanford HIVdb  were couWe compared the group included in drug resistance testing to the cohort not included in resistance testing at baseline using Chi square, Student’s Test and Kruskall-Wallis test as appropriate for the type of variable and the respective distribution. The significance level was set at 0.05.The LighTen study protocol was approved by the Ethics Committee of the National Health Research Committee of the Ministry of Health, Malawi and the ethics committees of the Universities of Heidelberg and Cologne, Germany.Overall, LighTen enrolled 1432 participants, of whom 200 were included in the HIV-1 resistance testing group. HIVDR testing was successful in 197 of 200 samples. All analyzed HIV-1 isolates were of subtype C.Baseline characteristics of the HIVDR testing group differed from the total LighTen cohort, with a higher proportion of WHO stage 1 (65% vs 43%) and a lower proportion of WHO stage 3 (9.6% vs 34.7%) in the HIVDR testing group. The HIVDR testing group had a higher median viral load. The groups also differed significantly regarding the treatment outcome “Alive and on ART” . The prevalence of mutations conferring intermediate or high level resistance to first-line ART was 11.2% (22/197). The most common PDR was K103N , followed by Y181C . In one case, we detected an additional NRTI drug resistance mutation (M184V)  in the HIVDR testing group.The results of HIVDR testing could not influence the choice of treatment, as testing was performed retrospectively from stored samples. Among the 12 patients with K103N and/or V106M mutations , only four were alive and on ART at the end of follow-up. Remarkably, two of these four patients were still on first-line treatment and virally suppressed. Our findings are in line with the multi-centre cohort study by Hamers et al., which found an odds ratio of 2.13 for virological failure in patients with PDR to at least one prescribed drug [Our results echo other data from the region. In a cohort of Malawians living with HIV, Rutstein et al. reported the same proportion of 11% NNRTI-PDR among 46 acutely infected persons in Malawi, with a similar distribution of different sub-types of mutations .According to recent data from the Malawian population-based HIV impact assessment consortium, the overall level of viral suppression in Malawi is 89%, with considerable variation between different regions in Malawi  For the Our observations add to the body of HIV-1 drug resistance data from Southern Africa and are in line with other reports from the region , 16. TheThe prevalence of NNRTI-PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance . The stu


In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety. In the cART approach, a cocktail of anti-AIDS drugs target functions that are essential to the life cycle of human immunodeficiency virus (HIV) , which ceatments ,12. Histeatments ,14. To aeatments ,16,17. Reatments , and IN eatments ,20,21. Teatments ,25,26,27eatments ,15. Histeatments ,29. New eatments ,37,38,39eatments ,41. Etraeatments ,43,44. Np < 0.01) [p < 0.0001) [ETR and RPV a are par < 0.01) . The ECH 0.0001) ,51,52. A 0.0001) ,50,52,60+ T-cell count (<200 cells/µL), the virologic failure rate was significantly higher when compared to EFV patients [A somewhat higher virologic failure rate was seen with RPV treatment than with EFV, but statistical significance was not established ,50,52,60patients ,54,61, apatients ,63. In tpatients . The virpatients ,65.Dual therapies have begun to replace other cARTs as a maintenance strategy for improving adherence and safety. A number of dual therapies that combine ETR or RPV with an INSTI are currently available or under investigation. These include ETR/RAL ,74, RPV/Four observational studies have reported efficacy for ETR/RAL therapies administered to HIV patients who were previously on other cARTs, but the criteria for efficacy differed with each study. A retrospective study in Paris, France with 18 patients defined efficacy as a plasma HIV load <200 copies/mL and saw 83.3% efficacy after 12 months of the ETR/RAL treatment . In a prThe Phase IIb LATTE trial in Canada and the United States compared the efficacy and safety of RPV/CAB to that of a traditional triple-drug therapy cART consisting of EFV and two NRTIs. The study began with a head-to-head comparison between CAB and EFV for 24 weeks. During this “induction therapy” period, the 243 patients, all on two NRTIs, were randomized between 600 mg EFV and CAB at doses of 10 mg, 30 mg, or 60 mg. By week 24, approximately 86% of each of the CAB groups and 74% of EFV patients had achieved the virologic suppression endpoint of <50 viral RNA copies/mL. At week 24 onward, virologically suppressed patients in the CAB groups stopped taking the NRTIs and received 25 mg RPV in addition to their randomly assigned CAB dose, while virologically suppressed EFV patients continued with their triple therapy regimen. At week 48, 82% of the RPV/CAB patients and 71% of the EFV/NRTs patients were virologically suppressed. At week 96, 76% of the RPV/CAB patients and 63% of the EFV/NRTs patients were still virologically suppressed. The AEs were lower in the RPV/CAB groups (51%) than the EFV/NRTs group (68%). There were six (3%) AE-related withdrawals from the study in the RPV/CAB groups and nine (15%) in the EFV/NRTs group . The resRPV/DTG was the first dual therapy regimen to be approved by the FDA for the maintenance treatment of virologically suppressed patients with HIV-1 . The effThese results were supported by three observational studies in which virologic suppression (<50 copies/mL) was maintained in patients who switched from conventional cARTs to RPV/DTG therapy. A prospective study observed the same proportion of virologic suppression (91.4%) at week 48 and baseline for 35 patients who had switched from other cARTs to RPV/DTG, with no difference in safety profile . In a stp = 0.03), with similar safety outcomes [n = 822), the SINGLE study , and the FLAMINGO study . While SPRING-2 and SINGLE were double-blinded studies, FLAMINGO was an open-label study. In all three studies, more DTG patients achieved the primary endpoint (<50 plasma HIV-1 RNA copies/mL) than the patients on the active control, a result that was significant in both the SINGLE and FLAMINGO trials [A number of analyses have compared DTG to RAL, EFV/tenofovir disoproxil fumarate/emtricitabine, or the PI combination of darunavir/ritonavir. A 48-week, Phase III, randomized, double-blinded, active-controlled study (SAILING) with 715 patients in virologic failure (≥400 plasma HIV-1 RNA copies/mL) favored DTG over RAL in the percent of patients achieving an endpoint of <50 HIV-1 RNA copies/mL  for 24 weeks after successfully switching from ETR/RAL to RPV/DTG to reduce pill burden and avoid the toxicity of previous treatments . MotivatLong-term cARTs face a variety of safety challenges from associated comorbidities ,33,39,89p = 0.006) for suicidal ideation, attempt, or completion. However, three of the four studies were open-label, and the studies did not share a standardized questionnaire on suicidal tendency [A recent review  stated ttendency . A “Multtendency . These sp < 0.0001) [p = 0.011) in the ETR group (6.3%) than the EFV group (21.5%) [Notwithstanding questions about the magnitude of the suicidal risk that is associated with EFV, a reduction in frequency of neuropsychiatric comorbidities is likely upon switching to RPV or ETR. Substituting RPV for EFV significantly lowered the incidence of neurological AEs for treatment-naïve HIV-1 patients in the ECHO/THRIVE trials ( 0.0001) ,94. In a 0.0001)  reported (21.5%) .p = 0.01) and among older patients (>60 years versus younger age) was 2.86  [Questions have also been raised regarding DTG association with neurological comorbidities. In a Netherlands-based cohort study, a 13.7% DTG intolerance rate was observed among 556 patients, especially if they also were administered abacavir. Comorbidities in these patients included neuropsychiatric  and gastrointestinal AEs . A retro= 0.003) . However= 0.003)  of data = 0.003) .Overall, the safety of ETR, RPV, RAL, and DTG have compared favorably to other antiretroviral agents. Categories of better safety include lipid metabolism, glycemia, and bone health. Low liver toxicity that is similar to placebo has been seen for ETR, and RPV liver toxicity is low and comparable to that of EFV . Some clp < 0.0001), triglycerides , and low-density lipoprotein (LDL)-cholesterol , although high-density lipoprotein (HDL)-cholesterol was also higher . The EFV group saw more Grade 3–4 increases in total cholesterol, LDL-cholesterol, and triglycerides  than the ETR group  [p < 0.001), in serum triglycerides , and in glycemia  [ETR has been associated with a safer profile than EFV and other antiretroviral therapeutic agents. In the double-blinded “SENSE” trial, 157 treatment-naïve patients were randomized between ETR and EFV, while on a background NRTI regimen . At week 48, compared to the ETR group, the EFV patients saw significantly larger elevations in total cholesterol  . In a 48p = 0.02), reductions of 15.61% in total cholesterol/HDL ratio (p = 0.001), a 6.96% increase in HDL cholesterol (p = 0.02), and a 7.06% drop in glycemia (p = 0.05), as well as improvements in the glomerular filtration rate. All of the patients switching off of EFV regimens saw neuropsychiatric improvements [p = 0.01) and triglycerides  at week 48 [An analysis of the FDA Adverse Event Reporting System found a higher incidence of myopathy and rhabdomyolysis events for RAL than EFV, ETR, nevirapine, ATV, or darunavir . Howeverovements . In anot week 48 . An obse week 48 .p < 0.001) in fasting total cholesterol (−19 mg/dL), LDL cholesterol (−12 mg/dL), and triglycerides (−27 mg/dL) when compared to baseline, but little change in the total cholesterol/HDL ratio [A number of investigations observed a safer lipid metabolism profile with RPV, compared to other NNRTIs. A retrospective, multicenter, cohort study (“ANRS CO3 Aquitaine Cohort 2012–2014”) reported that 304 patients switching from various cARTs to a RPV/emtricitabine/tenofovir disoproxil fumarate regimen saw significant six-month improvements  reduction from baseline in the estimated glomerular filtration rate (eGFR) of −11 mL/min./1.73 m2. This was not a controlled study [There has been some debate regarding whether DTG and RPV therapies may be associated with partial impairment of renal function. The above-cited ANRS CO3 Aquitaine Cohort 2012–2014 study observed a significant  and lumbar spine bone (p = 0.039), while the bone remodeling biomarkers decreased, including bone-specific alkaline phosphatase (p < 0.001), procollagen type 1 N-propeptide (p < 0.001), and type 1 collagen cross-linked C-telopeptide (p < 0.019) [p = 0.04), as well as significant improvements in total cholesterol, LDL, and glycemia [The current data support the view that bone mineral density, lipid metabolism, and glycemia are healthier with RPV/DTG than conventional cARTs. The SWORD-1 and SWORD-2 trials observed improved bone health in patients who switched from conventional cARTs to RPV/DTG. When compared to cART patients, the mineral density of RPV/DTG patients increased significantly more in total hip bone (< 0.019) . An obseglycemia .p = 0.035) and patients’ perception of complexity (p = 0.015), leading to a significant increase in adherence from 65% to 81.3% (p = 0.002) [Non-adherence to treatment remains a problem for HIV-infected patients ,108, but= 0.002) . Switchi= 0.002) ,111,112.= 0.002) , compare= 0.002) ,58,100. = 0.002) .p < 0.001), 1.61 for ETR , and 1.35 for RAL . Using EFV as a reference, the adjusted hazard ratio for discontinuation among treatment-naïve patients was 0.33 for RPV  and 1.47 for RAL . Thus, patients on RPV-containing treatments discontinued therapy less often than those on ETR or EFV [A study  with 254R or EFV , which iR or EFV .p = 0.004) upon switching to RPV/DTG for 48 weeks [Switching from conventional triple-therapies to a safe and effective dual therapy might further improve treatment adherence. An observational study following 30 patients who switched from conventional cARTs to various dual therapies reported that adherence increased from 86.79% before switching to 96.27% , but stap < 0.0001) linear correlation between reported adherence and the six-month virologic failure rate, defined as a viral load >500 HIV RNA copies/mL. Using this definition, the virologic failure rate was 2.4% for >95% adherence, 4.3% for 86–95% adherence, 12.2% for 76–85% adherence, and 17.4% for ≤75% adherence [p = 0.0011 for both). Put differently, poorly or moderately adherent patients were approximately 2–3 times more likely to develop drug resistance than patients with excellent (≥95%) adherence. Patients in these studies presented HIV with resistance mutations to NRTIs and NNRTIs, including ETR [Non-adherence to treatment leads to a rebound of viremia and the emergence of viral drug-resistance mutations. A 2005 study in Italy with 543 subjects found a significant  with 27 subjects selected for the resistance analysis population observed emergent RPV resistance that was more frequent than EFV resistance at week 48. The head-to-head comparison between an RPV treatment group and an EFV treatment group, both with a background treatment of emtricitabine/tenofovir disoproxil fumarate, saw resistance mutation rates that depended on the baseline viral load. For baseline viremia ≤ 100,000 HIV RNA copies/mL, 1.9% of RPV patients developed resistant isolates, compared to 0.8% of EFV patients (p = 0.45). For viremia >100,000 copies/mL, the resistance frequency was 9.0% in the RPV group and 0.7% in the EFV group (p = 0.001). The comparison between the two groups should be interpreted with caution due to the small sample sizes (20 RPV patients versus seven EFV patients) [Resistance to RPV might develop more rapidly than EFV. A Phase IIIb, randomized, open-label study  . Among satients) .Cross-resistance between NNRTIs has been reported in various studies, and NNRTI-treatment-experienced patients are more likely than treatment-naïve patients to carry HIV variants resistant to ETR and RPV. Among patients that were previously treated with NVP or EFV, mutations conferring resistance to RPV may be more common than mutations conferring resistance to ETR . In a ThMutations that result in resistance to ETR and RPV have been observed in HIV isolates from both adults ,124,125 Doravirine (DOR), a once/daily NNRTI that the FDA approved in 2018, reference  is reporAlthough seen less frequently than NNRTI-resistance mutations, INSTI-binding site mutations that confer resistance have included H51Y, T66A/I/K, V72I, L74I/L/M, E92G/Q, Q95R, T97A, G140A/C/S, E138A/K/T, Y143C/H/R/S, Q146R, Q148H/K/N/R, V151I, S147G, S153F, N155H/S, E157Q/K, G163K/R, D232N, and R263K  131,138,145. CurSome INSTI-resistance mutations associated with virologic failure  have been shown by in vitro assays to impair IN activity substantially in the absence of inhibitor. The accumulation of additional mutations can compensate for impaired fitness of some viral variants. The G140S + Q148H double mutant can rescue IN activity that is impaired in the solitary G140S and Q148H mutants ,146,152.+ T-cells and macrophages. Mutations resistant to RAL or EVG (FC ranging from 4.3 to > 100) that were highly susceptible to DTG (FC ranging from 1.0 to 2.0) included T97A + Y143C/R, N155H, G140S, and Q148H  at the catalytic site of IN, while simultaneously binding a halogenated aromatic ring in a pocket that is natively occupied by a 3’-terminal deoxyadenosine of the reverse-transcribed viral DNA [In typical INSTIs, a triad of coplanar oxygen and/or nitrogen atoms provide lone pair electrons that chelate two divalent cations . ThETR and RPV have had a major impact in the fight against AIDS. They have been effective in patients harboring HIV variants that are resistant to earlier generation NNRTIs and have been safer to use. Their high potencies have led to substantially lower dosages or pill burdens and improved adherence, which potentially slow the rate of emergence of new resistant viral variants. They have a higher genetic barrier to emergent resistance than some earlier generation NNRTIs, often requiring combinations of mutations for resistance breakthrough to occur.+ T-cell count show a significantly higher propensity for virologic failure than EFV patients. Although virologic breakthrough appears to be more common with RPV than ETR, RPV has a better safety profile and a lower pill burden. These DAPY-class NNRTIs may be favored for maintenance therapy in patients who have already achieved viral suppression with a previous therapy.On the other hand, resistant combinations of mutations have emerged, and RPV patients may develop resistance more often than EFV subjects. NNRTI-resistant viral variants infecting treatment-experienced patients are more likely to develop resistance to ETR and RPV than those of treatment-naïve patients. Patients that switched to RPV-containing therapies who have a high viral load or low CD4Treatments that combine RPV or ETR with INSTIs such as RAL, CAB, or DTG hold promise. Resistance mutations are still rare with INSTIs. DTG shows a relatively high genetic barrier to resistance. INSTI-resistance mutations tend to be more susceptible to DTG than RAL, CAB, or EVG . These I


Adolescents living with HIV (ALHIV) are challenged to adhere to antiretroviral therapy (ART) and achieve and maintain virologic suppression. Group-based adherence support interventions, such as adherence clubs, have been shown to improve long-term adherence in ART patients. The teen club intervention was introduced in 2010 in Namibia to improve treatment outcomes for ALHIV by providing adherence support in a peer-group environment. Adolescents who have completed the full HIV disclosure process can voluntarily join the teen clubs. The current study compared treatment outcomes of ALHIV receiving ART at a specialized paediatric HIV clinic between 1 July 2015 and 30 June 2017 in Windhoek, Namibia.  A retrospective cohort analysis was conducted on routine patient data extracted from the electronic Patient Monitoring System, individual Patient Care Booklets, and teen club attendance registers. A sample of 385 adolescents were analysed: 78 in teen clubs and 307 in standard care. Virologic suppression was determined at 6, 12, and 18 months from study start date, and compared by model of care, age, sex, disclosure status, and ART regimen. Comparisons between adolescents in teen clubs and those receiving standard care were performed using the chi-square test, and risk ratios were calculated to analyze differences in ART adherence and virologic suppression. p = 0.277) at 3 months. Virologic suppression over the 2-year observation period was 87% (68% fully suppressed <40 copies/ml and 19% suppressed between 40–999 copies/ml), with no difference between teen club members and those in standard care. However, there were statistically significant differences in virologic suppression levels between the younger (10–14 years) adolescents and older (15–19 years) adolescents at 6 months (p = 0.015) and at 12 months (p = 0.021) and between adolescents on first-line and second-line ART regimen at 6 months (p = 0.012), 12 months (p = 0.004), and 18 months (p = 0.005).  The average clinician-measured ART adherence was 89% good, 6% fair, and 5% poor amongst all adolescents, with no difference between teen club members and adolescents in standard care ( The teen club model delivering psychosocial support only did not improve adherence and virologic suppression levels for adolescents in a specialized paediatric ART clinic, neither were they inferior to standard care. Considering the limitations of this study, teen clubs may still hold potential for improving adherence and virologic suppression levels for older adolescents, and more robust research on adherence interventions for adolescents with higher methodological quality is required. Due to the successes in prevention of mother-to-child transmission (PMTCT) programs worldwide and advances in paediatric HIV treatment, children with HIV are surviving to reach adolescence . The WorPoor ART adherence increases the risk of viral drug resistance, limits treatment efficacy, leading to disease progression, and reduces future therapeutic options as well as increasing the risk of transmission due to unsuppressed viral replication . AlthougNamibia has adopted the Joint United Nations Programme on HIV and AIDS' (UNAIDS) fast track goals to achieve HIV epidemic control by 2030. The fast track goals are aimed at ensuring that 95% of PLHIV are identified; 95% of those identified are effectively linked and retained on ART; and 95% of these achieve virologic suppression . AdolescAccording to WHO, a maintained viral load of <1000 ribonucleic acid (RNA) copies per ml of plasma is considered evident of virologic suppression . Accordip < 0.01) [A teen club intervention was established in 2010 at a paediatric HIV clinic, in Windhoek, to address unique needs of adolescents on HIV treatment . The tee < 0.01) . EvaluatTo date, the effectiveness of the teen clubs on adolescents' ART adherence has not been formally evaluated in Namibia. This paper reports on the effects of the teen club intervention against standard care on ART adherence and virologic suppression amongst adolescents at the clinic. A retrospective cohort study was conducted using medical records of HIV positive adolescents between ages of 10 and 19 years receiving ART at a hospital-based paediatric HIV clinic in Windhoek, Namibia. The paediatric ART clinic is a specialized HIV clinic with dedicated staff for paediatric HIV management, which includes a physician, nurses, counsellors, and other support staff. The study population was stratified into two groups of adolescents attending the teen club and adolescents who were receiving standard care. Routine clinical records of the study population from 1 July 2015 to 30 June 2017 were reviewed. All adolescents between the ages of 10 and 19 years attending the clinic between 1 July 2015 and 30 June 2017 as their initial enrolment site were eligible for inclusion in the study. There were no changes in the treatment guidelines or clinical intervention during the study period.The study sample was all inclusive of the study population. The calculated minimum total sample size using Epi-Info was 272 participants, with 46 from the teen club stratum (exposed) and 226 in the standard care stratum (unexposed). Parameters used to calculate sample size include a power of 80%, an assumed 20% difference between the two groups, with a 95% confidence interval, and an unexposed/exposed ratio of 5.ePMS) by data clerks. Patient data was extracted from the electronic database into an Excel spreadsheet. Teen club members sign in at every teen club meeting. The teen club register was reviewed to match adolescents on the ePMS and the teen club members using the unique ART numbers allocated as unique patient identifiers.Patient demographics and visit details are completed routinely by healthcare workers into individual Patient Care Booklets (PCBs) during clinic visits. Patient information is then entered into an electronic Patient Monitoring System , we also analysed documented adherence at 3 monthly intervals from study start date and overall retention in care (attending clinic visits) at 24 months from study start date, which has been reported elsewhere [Adherence to ART was assessed through patient self-reports and pill counts conducted by clinicians during the 24-month study period. Clinicians ask the patients about the number of missed doses per month and conduct a physical pill-count. Virologic suppression has been used in several ART adherence studies as the standard biomarker of adherence levels and evidence shows that it is a reliable predictor of good adherence . Once vilsewhere .p < 0.05. If the sample size was very small in any cell (<5), Fisher's exact test was used as an alternative to the chi-square test. Relative risk was also calculated for comparison of ART adherence and virologic suppression levels between teen club members and adolescents in standard care. Calculation of relative risk was conducted using the Poisson regression with the glm command in Stata. Multivariate modeling was also performed to determine the relative risk adjusting for age and sex, disclosure, and type of ART regimen.The dataset in Excel was exported to Stata for the data analysis, and the analysis was done using the Stata statistical software, release 16, College Station, TX, StataCorp LLC. The data analysis included univariate analyses to describe demographic variables such as sex and age distribution; clinical variables such as model of care, disclosure status, period on ART, and type of regimen; and virologic suppression and adherence measured by clinicians. Bivariate analysis was performed using the chi-square test to determine the significance of associations between ART adherence and virologic suppression and selected demographic and clinical variables. Cut-off for significance of associations was set at This study was approved by the Namibian Biomedical Research Ethics Committee and Research Management Committee based at the Ministry of Health and Social Services (Ref: 18/3/3 FM) and the University of the Western Cape Biomedical Research Ethics Committee (Ref: BM17/8/14).ePMS for the two-year period. Records of adolescents who were transferred in from other facilities, who had incorrectly entered demographic information, and who are with missing files/PCBs were excluded from the final study sample. A total 385 adolescents were eligible, 78 of them being in the teen club. The average age amongst adolescents included in the study was 14 years and 51% were aged 10–14 years whilst 49% were aged 15–19 years. However, as presented in p = 0.015), and the same is true for the female adolescents enrolled in the teen club compared to standard care . The average measured ART adherence by the clinicians during clinical visits was 89% good (≥95%), 6% fair (85–94%), and 5% poor (<85%) amongst all the adolescents over the 2 years.A total of 482 adolescents aged between 10 and 19 years attended the paediatric ART clinic during the 2-year study period. All records of the adolescents were extracted from the p = 0.031) (All the adolescents in the teen club had their HIV status disclosed to them (a requirement for enrolment in the club), compared to 94% of adolescents in standard care (= 0.031) . The medViral load suppression amongst the adolescents who were included in the study at the Paediatric ART clinic was on average at 87% (68% fully suppressed and 19% suppressed) and 13% not suppressed for the 2-year study period. Full suppression is defined as a viral load <40 copies/ml or Target not Detected (TND), whilst individuals with a viral load between 40 and 999 copies/ml are categorized as suppressed. p = 0.927), 12 months (p = 0.324), and 18 months (p = 0.506). Compared to the primary findings, our study found no significant differences in the sensitivity analysis on viral load suppression rates between teen club members and adolescents in standard care by age groups at 6 months (p = 0.819) and 12 months (p = 0.427).At 18 months, the adjusted relative risk for all variables showed no significant differences. After controlling for age, sex, disclosure status, and type of ART regimen, the model of care did not significantly influence viral load suppression at 6 months  facility where you may not have dedicated specialized staff to manage paediatric HIV patients. The 2015 Namibia Preliminary Report for Adolescents Assessment reported viral load suppression rates of 74% and 70% among adolescent girls and boys, respectively, and 73% and 63% among 10–14 year and 15-19 year olds, respectively .Another study in South Africa showed that there were better viral suppression levels in an adolescent-friendly HIV clinic (91%) compared to those in a standard paediatric clinic (80%) . HoweverOur results suggest that the teen club intervention model implemented at the specialized paediatric HIV clinic may not offer adequate additional benefits to the club members on viral suppression, which may depend on other factors besides levels of adherence to treatment. Several reports have also showed reduced viral suppression levels amongst older adolescents and considering that most of the teen club members in our study were older adolescents, age could have influenced viral suppression levels among club members. The results showed that the teen club consists of twice as many older adolescents compared to younger adolescents and that the teen club had a higher proportion of older adolescents as compared to the standard care arm.There was a significant difference in viral load suppression levels between older and younger adolescents, with the older adolescents having less chance of viral load suppression compared to younger adolescents, although this difference was minimal and reduced after adjusting for sex, disclosure, and ART regimen. Similar results have been described in other studies in Africa, with Evans et al. reporting that older adolescents were more likely to be unsuppressed as compared to their younger counterparts at 6 months in a study conducted in adolescents and young adults in Mpumalanga  . The assOverall, the standard of care at the specialized paediatric HIV clinic was already high with high viral load suppression rates than reported elsewhere in Namibia. Indeed, as reported elsewhere many HIV programs in low- and middle-income countries may not have very strong standard of care models for adolescents to achieve similar treatment outcomes as the specialized paediatric clinic, as such the results may not be generalizable. Therefore, more research on the impact of group-based interventions such as teen clubs in settings where there are no specialized services is needed.The teen club model delivering psychosocial support only did not improve adherence and virologic suppression levels for adolescents in a specialized paediatric ART clinic, neither were they inferior to standard care. Considering the limitations of this study, teen clubs may still hold potential for improving adherence and virologic suppression levels for older adolescents, and more robust research on adherence interventions for adolescents with higher methodological quality is required.The use of a retrospective cohort study design meant that we had to rely on the accuracy of the record keeping by the healthcare workers. Reliance on routinely collected data meant that we could not control the exposures and outcomes of interest and could not account for unmeasured factors due to the limitations of routinely collected variables. The amount of missing data and files could have potentially influenced the findings of the results. The inequivalence in sample sizes between the comparison groups (teen club members vs. adolescents in standard care) could also potentially result in a type II error. Another limitation is the lack of detailed contents of each teen club session but just an overall description of topics discussed in general. This information could put some of the results into context and facilitate discussions into modifying the intervention where necessary. The dose effect was also not thoroughly investigated, as a single attendance to the teen club was considered as exposure to the intervention.


Passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 appears a promising strategy for eliciting long-term HIV-1 remission. When administered concomitantly with the cessation of antiretroviral therapy (ART) to patients with established viremic control, bNAb therapy is expected to prolong remission. Surprisingly, in clinical trials on chronic HIV-1 patients, the bNAb VRC01 failed to prolong remission substantially. Identifying the cause of this failure is important for improving VRC01-based therapies and unraveling potential vulnerabilities of other bNAbs. In the trials, viremia resurged rapidly in most patients despite suppressive VRC01 concentrations in circulation, suggesting that VRC01 resistance was the likely cause of failure. ART swiftly halts viral replication, precluding the development of resistance during ART. If resistance were to emerge post ART, virological breakthrough would have taken longer than without VRC01 therapy. We hypothesized therefore that VRC01-resistant strains must have been formed before ART initiation, survived ART in latently infected cells, and been activated during VRC01 therapy, causing treatment failure. Current assays preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation, and viral dynamics with multiple-dose VRC01 pharmacokinetics. The model predicted that single but not higher VRC01-resistant mutants would pre-exist in the latent reservoir. We constructed a virtual patient population that parsimoniously recapitulated inter-patient variations. Model predictions with this population quantitatively captured data of VRC01 failure from clinical trials, presenting strong evidence supporting the hypothesis. We attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly when VRC01 was at trough levels. Pre-existing resistant proviruses in the latent reservoir may similarly compromise other bNAbs. Our study provides a framework for designing bNAb-based therapeutic protocols that would avert such failure and maximize HIV-1 remission. Antiretroviral therapy (ART) can control but not eradicate HIV-1. Stopping ART leads to rapid viral resurgence and progressive disease. ART is therefore administered lifelong. Tremendous efforts are ongoing to devise strategies that will enable stopping ART and yet prevent viral resurgence. One such strategy involves the administration of broadly neutralizing antibodies (bNAbs) of HIV-1 at the time of stopping ART. This strategy is expected to delay if not prevent viral resurgence. Surprisingly, treatment with VRC01, a potent bNAb, resulted in hardly any improvement in viral remission. In this study, we elucidate the cause of this failure. We hypothesized that VRC01-resistant strains may pre-exist in latently infected cells, which are unaffected by ART. They can thus outlast ART and get reactivated, triggering VRC01 failure. We built a detailed mathematical model based on this hypothesis and showed that it quantitatively captured observations of VRC01 failure in clinical trials on chronic HIV-1 patients. Our study thus identifies a potential vulnerability of bNAbs, namely, bNAb-resistant strains pre-existing in latently infected cells. Our model offers a framework for predicting bNAb-based treatment protocols that would preclude failure due to pre-existing resistance and maximally prolong remission. Antiretroviral therapy (ART) for HIV-1 infection rapidly suppresses viremia to undetectable levels and curtails disease progression but is unable to eradicate the virus . The rebOne strategy that holds promise is to administer broadly neutralizing antibodies (bNAbs) of HIV-1 for a short period post-ART, i.e., during an analytical treatment interruption (ATI) ,14. bNAbin vivo /ln[W(t)/W(0)]+δt], where W(t)/W(0) is the fold expansion of wild type virus at time t; H(t)/H(0) is the fold change of the mutant-to-wild type ratio at time t; and δ is the death rate of infected cells. Rewriting this equation as Y = sX, where Y = ln[H(t)/H(0)] and X = ln[W(t)/W(0)]+δt, we estimate s by fits (lines) to corresponding data (symbols) [Y vs. X for three mutants: (A) R456W, (B) G458D, (C) N279K-N280D-R456W-G458D. The best-fit estimates (95%CI) of s are -0.568  for R456W; -0.5091  for G458D; and -0.5672  for N279K-N280D-R456W-G458D. The relative replicative fitness of the respective strains are obtained as ζ = (1+s).We applied a previous formalism  to analysymbols)  of Y vs.(TIF)Click here for additional data file.S2 FigPredictions of stochastic simulations (Eqs. S1-S11), showing (A) time-evolution of the latent cell pool, (B) distribution of the waiting time for the reactivation from latency, (C) time-evolution of activated or productively infected cells, and (D) distribution of the waiting time for the first productively infected cell carrying a VRC01-resistant strain (bar graph). (In (A) and (C), the different lines represent different stochastic realizations.) Variation of the latter distribution is shown with (E) initial latent cell pool size (cells), (F) VRC01 efficacy, and (G) viral production rate (virions/cell/day). In (D)-(G), the corresponding probability density function calculated using the deterministic formalism (Eqs. S12-S17) is shown as solid lines. (H) Expected waiting time, τm, for the formation of a productively infected cell carrying a VRC01-resistant provirus, calculated using the deterministic formalism as a function of the initial latent pool size for the VRC01 efficacy indicated, which is the efficacy against the wild-type averaged over the dosing interval.(TIF)Click here for additional data file.S3 Fig(A)(B)L0 (cells) from the different distributions indicated. The red line in (B) is data from the A5340 trial.Model predictions similar to those in (TIF)Click here for additional data file.S4 FigIC50 (μg/mL) indicated. The red line in (B) is data from the A5340 trial.Model predictions similar to those in (A) (TIF)Click here for additional data file.S5 FigIC50 (instead of p) in each virtual patient drawn from a log-normal distribution ) (Inset). The red line in (B) is data from the A5340 trial.Model predictions similar to those in (A) (TIF)Click here for additional data file.S6 Figη1, has been varied accordingly. The initial total antibody concentration (A1+A2) has been varied while keeping the ratioA1/A2 fixed, with the maximum (A1+A2) (in μg/mL) corresponding to the 40 mg/kg dosage of VRC01 , which (TIF)Click here for additional data file.