Viral Load Rebound Research Articles

Associations of menopausal age with virological outcomes and engagement in care among women living with HIV in the UK

Background: Women ageing with HIV undergo sex-specific changes. There is limited evidence available with regards to how the menopause impacts HIV outcomes. Objective: To investigate whether menopausal age is associated with engagement-in-care (EIC), viral load (VL) suppression and rebound among women living with HIV. Methods: Women were grouped by age (<40, 40–50, >50 years), corresponding to pre-, peri- and post-menopausal stages. EIC, HIV VL suppression (VL < 50 copies/mL) within 12 months of antiretroviral therapy initiation and VL rebound (two consecutive VL > 50 copies/mL) after VL suppression were compared across age groups using logistic/Cox proportional hazards regression. Associations were compared to those seen in heterosexual men. Results: Six thousand four hundred and fifty-five (6455) eligible women (median age 36 [interquartile range: 29–42], 64.4% black African, 19.1% white) contributed 44,226 person-years (PYRS) of follow-up; 29,846, 10,980 and 3,399 PYRS in those aged <40, 40–50 and >50, respectively. Women were engaged-in-care for 79.5% of follow-up time, 3,344 (78.0%) experienced VL suppression and 739 (22.1%) VL rebound. After adjustment, women aged >50 years had lower EIC than those aged <40. Women aged 40–50 were more likely to have VL suppression and were less likely to experience VL rebound than those aged <40 years. Trends in heterosexual men were similar for EIC but with no evidence of a higher VL suppression rate in those aged 40–50 years (p int. 0< .0001) and a stronger protective association between older age and VL rebound (p int. 0< .0001). Conclusion: Our findings warrant further research into the potential impact of the menopause to support women and clinicians through HIV care.

Outcomes of patients on second‐ and third‐line ART enrolled in ART adherence clubs in Maputo, Mozambique

ObjectivesAdherence clubs (AC) offer patient‐centred access to antiretroviral therapy (ART) while reducing the burden on health facilities. AC were implemented in a health centre in Mozambique specialising in patients with a history of HIV treatment failure. We explored the impact of AC on retention in care and VL suppression of these patients.MethodsWe performed a retrospective analysis of patients enrolled in AC receiving second‐ or third‐line ART. The Kaplan–Meier estimates were used to analyse retention in care in health facility, retention in AC and viral load (VL) suppression (VL < 1000 copies/mL). Predictors of attrition and VL rebound (VL ≥ 1000 copies/mL) were assessed using multivariable proportional hazards regression.ResultsThe analysed cohort contained 699 patients, median age 40 years [IQR: 35–47], 428 (61%) female and 97% second‐line ART. Overall, 9 (1.3%) patients died, and 10 (1.4%) were lost to follow‐up. Retention in care at months 12 and 24 was 98.9% (95% CI: 98.2–99.7) and 96.4% (95% CI: 94.6–98.2), respectively. Concurrently, 85.8% (95% CI: 83.1–88.2) and 80.9% (95% CI: 77.8–84.1) of patients maintained VL suppression. No association between predictors and all‐cause attrition or VL rebound was detected. Among 90 patients attending AC and simultaneously having VL rebound, 64 (71.1%) achieved VL resuppression, 10 (11.1%) did not resuppress, and 14 (15.6%) had no subsequent VL result.ConclusionImplementation of AC in Mozambique was successful and demonstrated that patients with a history of HIV treatment failure can be successfully retained in care and have high VL suppression rate when enrolled in AC. Expansion of the AC model in Mozambique could improve overall retention in care and VL suppression while reducing workload in health facilities.

Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018–2019 season and detection of variant influenza a viruses with polymerase acidic subunit substitutions

We conducted a prospective, multicenter, non-randomized observational study to assess the duration of fever and symptoms of influenza A/H1N1pdm09 and A/H3N2 infected children < 19 years old treated with either baloxavir or oseltamivir. Additionally, these symptoms were investigated in association with pre- and post-baloxavir treatment-emergent polymerase acidic unit (PA) variants as compared to non-substituted viruses. Following receipt of informed consent, baloxavir was administered to 102 influenza A patients, and oseltamivir to 52 patients during the 2018–2019 influenza season in Japan. The average age was higher in the baloxavir treatment group compared to the oseltamivir treatment group (10.6 ± 2.7 versus 6.9 ± 2.9 years old, p < 0.01). The duration of fever and symptoms in baloxavir-treated A/H1N1pdm09 and A/H3N2-infected children did not differ from those in oseltamivir-treated groups (median 22.0, 11.8, 23.0, and 21.0 h, and median 114.5, 121.0, 123.0, and 122.0 h, respectively). One (1.2%) of 83 A/H3N2 patients possessed a PA/I38T substituted virus prior to treatment. The frequency of PA variants in post-treatment samples obtained 2–11 days after beginning of baloxavir was 12.5% (4/32) for A/H1N1pdm09 and 14.1% (9/64) for A/H3N2 when the total number of cases was used as the denominator, however, were 57.1% (4/7) and 33.3% (9/27) when PCR-positive cases at the time of second sampling was used as the denominator. The most frequent PA substitution was I38T (9), with E23K (1), I38K (1), I38M (1), and PA/I38S (1) also observed. The duration of fever and overall symptoms did not differ significantly following baloxavir treatment in individuals with PA variant viruses, non-substituted virus, or in those that were PCR negative at the second sampling (median 20, 24 and 11 h, and median 121, 115 and 121 h, respectively). Rebound of viral RNA load was observed in 13.5% (2/13) of PA variants but it was not associated with recurrence of fever and symptoms. Hence, prolonged fever or symptoms were not observed in children treated with baloxavir following emergence of PA variants, however, further studies are needed to evaluate the clinical impact of PA variants.

Comparison of empirical and dynamic models for HIV viral load rebound after treatment interruption.

To compare empirical and mechanistic modeling approaches for describing HIV-1 RNA viral load trajectories after antiretroviral treatment interruption and for identifying factors that predict features of viral rebound process. We apply and compare two modeling approaches in analysis of data from 346 participants in six AIDS Clinical Trial Group studies. From each separate analysis, we identify predictors for viral set points and delay in rebound. Our empirical model postulates a parametric functional form whose parameters represent different features of the viral rebound process, such as rate of rise and viral load set point. The viral dynamics model augments standard HIV dynamics models-a class of mathematical models based on differential equations describing biological mechanisms-by including reactivation of latently infected cells and adaptive immune response. We use Monolix, which makes use of a Stochastic Approximation of the Expectation-Maximization algorithm, to fit non-linear mixed effects models incorporating observations that were below the assay limit of quantification. Among the 346 participants, the median age at treatment interruption was 42. Ninety-three percent of participants were male and sixty-five percent, white non-Hispanic. Both models provided a reasonable fit to the data and can accommodate atypical viral load trajectories. The median set points obtained from two approaches were similar: 4.44 log10 copies/mL from the empirical model and 4.59 log10 copies/mL from the viral dynamics model. Both models revealed that higher nadir CD4 cell counts and ART initiation during acute/recent phase were associated with lower viral set points and identified receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based pre-ATI regimen as a predictor for a delay in rebound. Although based on different sets of assumptions, both models lead to similar conclusions regarding features of viral rebound process.

A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection

Objective and DesignA randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI). MethodsFifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI. ResultsFifteen participants on ART (median: 178 weeks: range 79–295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation. ConclusionsAdministration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.

Incidences and factors associated with viral suppression or rebound among HIV patients on combination antiretroviral therapy from three counties in Kenya

BackgroundLimited data are available on the incidence and factors associated with viral rebound following viral suppression among HIV-infected individuals taking antiretroviral therapy (ART) in Kenya. Furthermore, the durability of viral suppression among HIV individuals taking ART is unknown. Information on incidence rates and factors associated with HIV viral load rebound and the durability of viral suppression (undetectable HIV copies in plasma) among HIV-infected individuals taking ART, will help improve the long-term management of HIV-infected individuals and explore approaches to long-term HIV remission or complete cure. ObjectivesThe objectives of this study were to investigate the incidence rates of viral rebound following viral suppression, factors associated with viral rebound, and the durability of viral suppression among HIV-infected individuals on ART from Kilifi, Meru, and Nakuru counties in Kenya. MethodsThis was a retrospective study involving 600 HIV-infected individuals taking combination ART (cART) and enrolled in comprehensive care centers (CCCs) at Malindi Sub-county Hospital, Nakuru Level 5 Hospital, and Meru Level 5 Hospital in Kenya. The medical files were inspected and medical history records abstracted for the selected participants. Participant laboratory data including HIV viral loads, types and history of ART, and treatment history of any opportunistic infections were abstracted using an abstraction checklist. Participants were grouped into those who achieved HIV viral suppression, with viral loads lower than the detection limit (LDL) (viral suppression), and those who experienced one or more detectable viral load measurements >40 copies/ml following the initial LDL (viral rebound). Durable viral suppression was defined as all viral load values at LDL over the 2-year period (2017–2019). Univariate and multivariate Poisson regression analyses were performed to assess the rates of viral rebound, as well as to investigate factors associated with it. ResultsOut of 549 HIV-positive patients, 324/549 (59%) achieved HIV viral suppression (Meru 159/194 (82%), Nakuru 21/178 (12%), and Malindi 144/177 (81%)). The overall viral rebound rate was 41%, with site-specific viral rebound of 88.2%, 18.6%, and 18.0% in Nakuru, Malindi, and Meru, respectively. There was an overall rate of first viral rebound of 3.9 (95% confidence interval (CI) 6.9–14.4), 0.7 (95% CI 0.5–1.0), and 0.89 (95% CI 0.64–1.24) per 100 person-months in Nakuru, Malindi, and Meru, respectively. Good ART adherence (p = 0.0002), widow status (p = 0.0062), and World Health Organization (WHO) stage I (p = 0.0002) were associated with viral suppression, while poor ART adherence (p < 0.0001), WHO stage II (p = 0.0024), and duration on ART of 36 months (p = 0.0350) were associated with viral rebound. ConclusionsThe rate of viral suppression in patients on cART in the CCCs fell short of the WHO target. However, the study provides proof of evidence of undetectable viral load levels for more than 2 years, a sign that the United Nation’s 2030 objective of controlling the risk of HIV transmission could be achieved.

A flexible nonlinear mixed effects model for HIV viral load rebound after treatment interruption.

Characterization of HIV viral rebound after the discontinuation of antiretroviral therapy is central to HIV cure research. We propose a parametric nonlinear mixed effects model for the viral rebound trajectory, which often has a rapid rise to a peak value followed by a decrease to a viral load set point. We choose a flexible functional form that captures the shapes of viral rebound trajectories and can also provide biological insights regarding the rebound process. Each parameter can incorporate a random effect to allow for variation in parameters across individuals. Key features of viral rebound trajectories such as viral set points are represented by the parameters in the model, which facilitates assessment of intervention effects and identification of important pretreatment interruption predictors for these features. We employ a stochastic expectation-maximization (StEM) algorithm to incorporate HIV-1 RNA values that are below the lower limit of assay quantification. We evaluate the performance of our model in simulation studies and apply the proposed model to longitudinal HIV-1 viral load data from five AIDS Clinical Trials Group treatment interruption studies.

Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix.

Therapeutic vaccinations aim to re-educate human immunodeficiency virus (HIV)-1-specific immune responses to achieve durable control of HIV-1 replication in virally suppressed infected individuals after antiretroviral therapy (ART) is interrupted. In a double blinded, placebo-controlled phase IIa multicenter study, we investigated the safety and immunogenicity of intranodal administration of the HIVACAT T cell Immunogen (HTI)-TriMix vaccine. It consists of naked mRNA based on cytotoxic T lymphocyte (CTL) targets of subdominant and conserved HIV-1 regions (HTI), in combination with mRNAs encoding constitutively active TLR4, the ligand for CD40 and CD70 as adjuvants (TriMix). We recruited HIV-1-infected individuals under stable ART. Study-arms HTI-TriMix, TriMix or Water for Injection were assigned in an 8:3:3 ratio. Participants received three vaccinations at weeks 0, 2, and 4 in an inguinal lymph node. Two weeks after the last vaccination, immunogenicity was evaluated using ELISpot assay. ART was interrupted at week 6 to study the effect of the vaccine on viral rebound. The vaccine was considered safe and well tolerated. Eighteen percent (n = 37) of the AEs were considered definitely related to the study product (grade 1 or 2). Three SAEs occurred: two were unrelated to the study product, and one was possibly related to ART interruption (ATI). ELISpot assays to detect T cell responses using peptides covering the HTI sequence showed no significant differences in immunogenicity between groups. There were no significant differences in viral load rebound dynamics after ATI between groups. The vaccine was safe and well tolerated. We were not able to demonstrate immunogenic effects of the vaccine.

Receipt of opioid agonist treatment halves the risk of HIV-1 RNA viral load rebound through improved ART adherence for HIV-infected women who use illicit drugs

BackgroundWomen living with HIV who use illicit drugs may be particularly vulnerable to HIV-1 RNA viral load (VL) rebound. MethodsWe used longitudinal data from 2006 to 2017 to evaluate the impact of sociodemographic, behavioral, social-structural, and clinical factors on the hazard of viral rebound for women enrolled in the ACCESS study, a prospective cohort with systematic VL monitoring. Women were included if they achieved VL suppression (<50 copies/mL) following antiretroviral therapy (ART) initiation and had more than one study interview. Sociodemographic as well as substance use, social-structural, addiction treatment, and HIV clinical factors were evaluated as predictors of viral rebound (VL > 1000 copies/mL). Cox regressions using a recurrent events framework, time-varying covariates, robust standard errors, and a frailty component were used. ResultsOf the 185 women included, 62 (34%) experienced at least one viral rebound event over an 11-year period, accumulating a total of 87 viral rebound events. In adjusted analysis, stimulant use more than doubled the hazard of viral rebound (adjusted hazard ratio [AHR]: 2.35, 95% confidence interval [CI]: 1.07–5.14) while the only factor protective against viral rebound was receipt of opioid agonist treatment (OAT) in the past six months (AHR: 0.46, 95% CI: 0.26–0.81). After adjusting for ART adherence in the past six months, the effect of OAT was attenuated (AHR: 0.57, 95% CI: 0.32–1.02). ConclusionsEfforts to improve access to and retention within OAT programs and decrease stimulant use may improve rates of viral suppression for HIV-positive women who use illicit drugs.

First-line antiretroviral treatment and virological response among HIV adult patients at an accredited HIV care center, Cameroon

BackgroundViral load (VL) monitoring in the clinical follow-up of HIV patients to detect treatment failure is not routinely offered in Cameroon. The study was designed to characterize virological response on antiretroviral treatment (ART) among adults living with HIV and to identify predictors of virological failure (VF).MethodsBetween November 2014 and January 2016, a prospective, population-based cohort study was conducted among HIV-positive adults under first-line treatment and monitored at the Accredited HIV Care Center (AHCC) of Laquintinie Hospital of Douala. Clinical and biological data at the initiation of ART were collected from patients’ medical records. HIV VL at 12 and 24 months after the patient started treatment on ART were performed using quantitative real-time PCR protocol with the generic HIV Roche TaqMan assay. Descriptive and logistic regression analysis were performed in Stata SE11 version in data analysis.ResultsOverall 150 (45.5%) of 330 adults living with HIV were tested with at least one VL, and of these patients, 51 (34.0%) were tested with two VL during the followed-up. The VF was observed in 13 of 51 (25.5%) patients and among them, 8 (61.5%) switched to second-line ART regimens. Thirty-five (68.6%) of the 51 patients had an undetectable VL at the first VL measurement, and seven (13.7%) patients subsequently developed viral load rebound (VLR) on tritherapy. Using a multivariate analysis, the risk of VF was seven times higher in HIV adults who did not respect the medication hours (OR = 7.38, 95%CI = 1.56–34.90, p = 0.012) and eleven times higher in patients with none or primary school education (OR = 11.38, 95% CI = 2.41–53.76, p = 0.002).ConclusionLow education level and poor adherence are the main risk factors for VF. Strengthening therapeutic failure prevention strategies and routine VL surveillance would allow early detection of VF and contribute in achieving the third goal of UNAIDS which recommends “90–90-90” targets for People Living with HIV in resource-limited settings.

Cost-Effectiveness Analysis of Lopinavir/Ritonavir Monotherapy Versus Standard Combination Antiretroviral Therapy in HIV-1 Infected Patients with Viral Suppression in France (ANRS 140 DREAM).

BackgroundProtease inhibitor monotherapy is a simplified treatment strategy for virally suppressed HIV-positive patients that has the potential for cost savings, as fewer drugs are used than with combination therapy. However, evidence for its economic value is limited.ObjectivesWe assessed the cost-effectiveness of lopinavir/ritonavir monotherapy followed by treatment intensification in case of viral load rebound versus combination antiretroviral therapy (cART) with efavirenz/emtricitabine/tenofovir in HIV-1 infected patients with viral suppression in the ANRS 140 DREAM trial.MethodsDREAM was conducted in 36 French Hospitals between 2009 and 2013. For each treatment strategy, we estimated the unadjusted and multivariate-adjusted mean costs (in €, year 2010 values) and quality-adjusted life-years (QALYs) per patient, as well as incremental costs and QALYs per patient. We then assessed uncertainty using the cost-effectiveness acceptability curve, scenario analyses and cost-effectiveness price-threshold (CEPT) analysis.ResultsIn the base-case analysis considering 2009–2013 antiretroviral drug (ARV) prices, adjusted incremental costs and QALYs were − €3296 (95% confidence interval [CI] − 5202 to − 1391) and 0.006 (95% CI − 0.021 to 0.033), respectively, over 2 years, suggesting that monotherapy was cost-effective with a probability of 100% at various cost-effectiveness thresholds. In scenario analyses considering 2018 ARV prices, monotherapy remained cost-effective but with a lower probability (94% vs. 100% in the base-case analysis). The current price of cART would have to decrease by 34% to be cost-effective with a probability of 95%.ConclusionMonotherapy appears to be cost-effective compared with cART for virologically suppressed HIV-positive patients in France. CEPT analysis is a useful tool to identify the preferred strategy to adopt given that ARV prices change rapidly.Trial registrationClinicaltrials.gov identifier: NCT00946595.Electronic supplementary materialThe online version of this article (10.1007/s41669-019-0130-7) contains supplementary material, which is available to authorized users.

Substance use patterns and HIV-1 RNA viral load rebound among HIV-positive illicit drug users in a Canadian setting.

Active illicit drug use can present a barrier to the medical management of HIV infection by complicating adherence to antiretroviral therapy (ART). Plasma HIV-1 RNA viral load (VL) rebound, defined as a period of detectable HIV VL following ART and VL suppression, can lead to the generation of viral resistance and potential treatment failure. We sought to investigate the contribution of substance use patterns on rates of VL rebound. We used data from the ACCESS study, a long-running community-recruited prospective cohort of HIV-positive people who use illicit drugs in Vancouver, Canada, a setting of universal no-cost HIV treatment. We analysed time to VL rebound (that is, two consecutive observations ≥1,000 copies/ml) after ART initiation and sustained viral suppression (that is, two consecutive observations <50 copies/ml) using extended Cox regression models with a recurrent events framework. Between May 1996 and November 2013, 564 ART-exposed participants achieved at least one instance of VL suppression and contributed 1,893.8 person-years of observation. Over follow-up, 198 (35.1%) participants experienced ≥ one instance of VL rebound. In adjusted analyses, VL rebound was associated with younger age (adjusted hazard ratio [AHR] =0.97, 95% CI: 0.95, 0.98), heroin injection (≥ daily versus < daily, AHR =1.52, 95% CI: 1.01, 2.30), crack use (≥ daily versus < daily, AHR = 1.73, 95% CI: 1.08, 1.92) and heavy alcohol use (≥ four versus < four drinks/day, AHR =1.97, 95% CI: 1.17, 3.31). The present study suggests that in addition to heavy alcohol use, high-intensity illicit drug use, particularly ≥ daily heroin injection and ≥ daily crack smoking are risk factors for VL rebound. In addition to the impact of high-intensity drug use on health-care engagement and ART adherence, some evidence exists on the direct impact of psychoactive substances on ART metabolism and the natural progression of HIV disease. At-risk individuals should be provided additional supports to preserve virological control and maintain the benefits of ART.

HIV viral suppression and longevity among a cohort of children initiating antiretroviral therapy in Eastern Cape, South Africa.

IntroductionThere are limited data on viral suppression (VS) in children with HIV receiving antiretroviral therapy (ART) in routine care in low‐resource settings. We examined VS in a cohort of children initiating ART in routine HIV care in Eastern Cape Province, South Africa.MethodsThe Pediatric Enhanced Surveillance Study enrolled HIV‐infected ART eligibility children zero to twelve years at five health facilities from 2012 to 2014. All children received routine HIV care and treatment services and attended quarterly study visits for up to 24 months. Time to VS among those starting treatment was measured from ART start date to first viral load (VL) result <1000 and VL <50 copies/mL using competing risk estimators (death as competing risk). Multivariable sub‐distributional hazards models examined characteristics associated with VS and VL rebound following suppression among those with a VL >30 days after the VS date.ResultsOf 397 children enrolled, 349 (87.9%) started ART: 118 (33.8%) children age <12 months, 122 (35.0%) one to five years and 109 (31.2%) six to twelve years. At study enrolment, median weight‐for‐age z‐score (WAZ) was −1.7 (interquartile range (IQR):−3.1 to −0.4) and median log VL was 5.6 (IQR: 5.0 to 6.2). Cumulative incidence of VS <1000 copies/mL at six, twelve and twenty‐four months was 57.6% (95% CI 52.1 to 62.7), 78.7% (95% CI 73.7 to 82.9) and 84.0% (95% CI 78.9 to 87.9); for VS <50 copies/mL: 40.3% (95% CI 35.0 to 45.5), 63.9% (95% CI 58.2 to 69.0) and 72.9% (95% CI 66.9 to 78.0). At 12 months only 46.6% (95% CI 36.6 to 56.0) of children <12 months had achieved VS <50 copies/mL compared to 76.9% (95% CI 67.9 to 83.7) of children six to twelve years (p < 0.001). In multivariable models, children with VL >1 million copies/mL at ART initiation were half as likely to achieve VS <50 copies/mL (adjusted sub‐distributional hazards 0.50; 95% CI 0.36 to 0.71). Among children achieving VS <50 copies/mL, 37 (19.7%) had VL 50 to 1000 copies/mL and 31 (16.5%) had a VL >1000 copies/mL. Children <12 months had twofold increased risk of VL rebound to VL >1000 copies/mL (adjusted relative risk 2.03, 95% CI: 1.10 to 3.74) compared with six to twelve year olds.ConclusionsWe found suboptimal VS among South African children initiating treatment and high proportions experiencing VL rebound, particularly among younger children. Greater efforts are needed to ensure that all children achieve optimal outcomes.

Determinants of viral load rebound on HIV/AIDS patients receiving antiretroviral therapy: results from South Africa

BackgroundAntiretroviral therapy (ART) has become the standard of care for patients with HIV infection in South Africa and has led to the reduction in AIDS related morbidity and mortality. In developing countries, the nucleosides reverse transcriptase inhibitors (NRTIs) class are widely used because of their low production costs. However patients treated with NRTIs develop varying degree of toxicity after long-term therapy. For this study patients are administered with a triple therapy of two NRTIs and one non-nucleoside reverse transcriptase inhibitor (NNRTI).MethodIn this study the progression of HIV in vivo is divided into some viral load states and a continuous time-homogeneous model is fitted to assess the effects of covariates namely gender, age, CD4 baseline, viral load baseline, lactic acidosis, peripheral neuropathy, non-adherence and resistance to treatment on transition intensities between the states. Effects of different drug combinations on transition intensities are also assessed.ResultsThe results show no gender differences on transition intensities. The likelihood ratio test shows that the continuous time Markov model for the effects of the covariates including combination give a significantly better fit to the observed data. From almost all states, rates of viral suppression were higher than rates of viral rebound except for patients in state 2 (viral load between 50 and 10,000 copies/mL) where rates of viral rebound to state 3 (viral load between 10,000 and 100,000 copies/mL) were higher than rates of viral suppression to undetectable levels. For this transition, confidence intervals were very small. This was quite notable for patients who were administered with AZT-3TC-LPV/r and FTC-TDF-EFV. Although patients on d4T-3TC-EFV also had higher rates of viral rebound from state 2 than suppression, the difference was not significant.ConclusionFrom these findings, we can conclude that administering of any HIV drug regimen is better when based on the viral load level of an HIV+ patient. Before initiation of treatment, patients should be well equipped on how antiretroviral drugs operate including possibilities of toxicity in order to reduce chances of non-adherence to treatment. There should also be a good relationship between patient and health-care-giver to ensure proper adherence to treatment. Uptake of therapy by young patients should be closely monitored by adopting pill counting every time they come for review.

Viral diversity is an obligate consideration in CRISPR/Cas9 designs for targeting the HIV reservoir

BackgroundRNA-guided CRISPR/Cas9 systems can be designed to mutate or excise the integrated HIV genome from latently infected cells and have therefore been proposed as a curative approach for HIV. However, most studies to date have focused on molecular clones with ideal target site recognition and do not account for target site variability observed within and between patients. For clinical success and broad applicability, guide RNA (gRNA) selection must account for circulating strain diversity and incorporate the within-host diversity of HIV.ResultsWe identified a set of gRNAs targeting HIV LTR, gag, and pol using publicly available sequences for these genes and ranked gRNAs according to global conservation across HIV-1 group M and within subtypes A–C. By considering paired and triplet combinations of gRNAs, we found triplet sets of target sites such that at least one of the gRNAs in the set was present in over 98% of all globally available sequences. We then selected 59 gRNAs from our list of highly conserved LTR target sites and evaluated in vitro activity using a loss-of-function LTR-GFP fusion reporter. We achieved efficient GFP knockdown with multiple gRNAs and found clustering of highly active gRNA target sites near the middle of the LTR. Using published deep-sequence data from HIV-infected patients, we found that globally conserved sites also had greater within-host target conservation. Lastly, we developed a mathematical model based on varying distributions of within-host HIV sequence diversity and enzyme efficacy. We used the model to estimate the number of doses required to deplete the latent reservoir and achieve functional cure thresholds. Our modeling results highlight the importance of within-host target site conservation. While increased doses may overcome low target cleavage efficiency, inadequate targeting of rare strains is predicted to lead to rebound upon cART cessation even with many doses.ConclusionsTarget site selection must account for global and within host viral genetic diversity. Globally conserved target sites are good starting points for design, but multiplexing is essential for depleting quasispecies and preventing viral load rebound upon therapy cessation.

Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection.

Antiretroviral therapy (ART) during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption (ATI). We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following ATI, indicating that additional strategies are required to control or eradicate HIV.

Human Immunodeficiency Virus Viral Load Rebound Near Delivery in Previously Suppressed, Combination Antiretroviral Therapy–treated Pregnant Women

(Obstet Gynecol. 2017;130(3):497–501) The administration of intrapartum intravenous (IV) zidovudine in combination with antenatal and neonatal zidovudine was the first antiretroviral regimen recommended for pregnant women by all guidelines. However, with the advent of antenatal combination antiretroviral therapy (CART), as well as the finding that women with an HIV viral load &lt;1000 copies mL at delivery who receive IV zidovudine may carry an increased risk of vertical transmission compared with controls, guidelines have since changed.

Next generation sequencing of HIV-1 protease in the PIVOT trial of protease inhibitor monotherapy

BackgroundThe PIVOT trial examined whether patients with suppressed viral load on combination antiretroviral therapy could be safely switched long-term to ritonavir-boosted protease inhibitor (PI) monotherapy. The main trial publication reported that only one of 296 patients allocated to PI monotherapy experienced a loss of drug options due to protease mutations (identified by local Sanger sequencing resistance tests) likely selected by study drug. ObjectivesTo assess if we had missed low frequency mutations, using a more sensitive methodology. Study designWe performed next generation sequencing (NGS) on all available frozen plasma samples with VL >1000 copies/ml from patients who were randomised to PI monotherapy. Assays were performed at Public Health England laboratories using a previously described method.Median coverage depth was 76,000 and the threshold for detection of minority variants was 2%. Drug susceptibility was predicted using the Stanford HIVdb algorithm. Results17 of 26 potential samples, all from different patients, were identified and successfully tested. The median viral load was 6780 copies/ml and the median time since randomisation was 43 weeks. NGS revealed previously unidentified minority variant protease mutations (G73D, I54T, L89V) in three samples, at frequencies ranging between 2% and 10%. None of these mutations predicted intermediate or high level resistance, the trial primary outcome. DiscussionThis report adds to the body of evidence that ritonavir-boosted PI monotherapy, when used as a switch strategy with prompt detection of viral load rebound and early re-introduction of combination therapy, rarely leads to the development of clinically important protease resistance mutations.

Virological response and resistance among HIV-infected children receiving long-term antiretroviral therapy without virological monitoring in Uganda and Zimbabwe: Observational analyses within the randomised ARROW trial.

BackgroundAlthough WHO recommends viral load (VL) monitoring for those on antiretroviral therapy (ART), availability in low-income countries remains limited. We investigated long-term VL and resistance in HIV-infected children managed without real-time VL monitoring.Methods and findingsIn the ARROW factorial trial, 1,206 children initiating ART in Uganda and Zimbabwe between 15 March 2007 and 18 November 2008, aged a median 6 years old, with median CD4% of 12%, were randomised to monitoring with or without 12-weekly CD4 counts and to receive 2 nucleoside reverse transcriptase inhibitors (2NRTI, mainly abacavir+lamivudine) with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or 3 NRTIs as long-term ART. All children had VL assayed retrospectively after a median of 4 years on ART; those with >1,000 copies/ml were genotyped. Three hundred and sixteen children had VL and genotypes assayed longitudinally (at least every 24 weeks). Overall, 67 (6%) switched to second-line ART and 54 (4%) died. In children randomised to WHO-recommended 2NRTI+NNRTI long-term ART, 308/378 (81%) monitored with CD4 counts versus 297/375 (79%) without had VL <1,000 copies/ml at 4 years (difference = +2.3% [95% CI −3.4% to +8.0%]; P = 0.43), with no evidence of differences in intermediate/high-level resistance to 11 drugs. Among children with longitudinal VLs, only 5% of child-time post–week 24 was spent with persistent low-level viraemia (80–5,000 copies/ml) and 10% with VL rebound ≥5,000 copies/ml. No child resuppressed <80 copies/ml after confirmed VL rebound ≥5,000 copies/ml. A median of 1.0 (IQR 0.0,1.5) additional NRTI mutation accumulated over 2 years’ rebound. Nineteen out of 48 (40%) VLs 1,000–5,000 copies/ml were immediately followed by resuppression <1,000 copies/ml, but only 17/155 (11%) VLs ≥5,000 copies/ml resuppressed (P < 0.0001). Main study limitations are that analyses were exploratory and treatment initiation used 2006 criteria, without pre-ART genotypes.ConclusionsIn this study, children receiving first-line ART in sub-Saharan Africa without real-time VL monitoring had good virological and resistance outcomes over 4 years, regardless of CD4 monitoring strategy. Many children with detectable low-level viraemia spontaneously resuppressed, highlighting the importance of confirming virological failure before switching to second-line therapy. Children experiencing rebound ≥5,000 copies/ml were much less likely to resuppress, but NRTI resistance increased only slowly. These results are relevant to the increasing numbers of HIV-infected children receiving first-line ART in sub-Saharan Africa with limited access to virological monitoring.Trial registrationISRCTN Registry, ISRCTN24791884

Human Immunodeficiency Virus Viral Load Rebound Near Delivery in Previously Suppressed, Combination Antiretroviral Therapy-Treated Pregnant Women.

To assess the stability of human immunodeficiency virus (HIV) viral load suppression within 1 month before birth in pregnant women receiving antenatal combination antiretroviral therapy (CART). This is a retrospective cohort study of a Canadian provincial perinatal HIV database from 1997 to 2015. Inclusion criteria were live birth and CART received for at least 4 weeks. Viral load rebound, defined as viral load greater than 50 copies/mL (or greater than 400 copies/mL for 1997-1998) and measured within 1 month before delivery, was identified in women who had at least one previous undetectable viral load during pregnancy. Logistic regressions were conducted to identify the risk factors for viral load rebound. Among the 470 women in the database, 318 met inclusion criteria. Viral load rebound was experienced by 19 women (6.0%, 95% CI 3.7-9.3%) with a mean log10 viral load near delivery of 2.71 copies/mL (=513 copies/mL). Six (32%) had a viral load above 1,000 copies/mL. The rebound was detected within 1 day before delivery in 50% of the women. Aboriginal ethnicity, cocaine use, and hepatitis C virus polymerase chain reaction positivity were significantly associated with viral load rebound. There were no HIV vertical transmissions. Even women attending for HIV care and achieving viral suppression in pregnancy can experience viral load rebound predelivery.