Protease Inhibitor-based Antiretroviral Therapy Research Articles

Updates in the Management of HIV During Pregnancy.

Human immunodeficiency virus in pregnant people remains a significant public health issue worldwide. The rate of perinatal transmission is 15% to 40% but can be decreased to less than 1% with appropriate antenatal management. Previous recommendations included a protease inhibitor-based antiretroviral therapy, infant prophylaxis, performance of cesarean section for uncontrolled viremia, and the use of formula for infant feeding. However, recent updates include first line of integrase inhibitor-based regimens and supporting parental choices for safe lactation. In this review, we summarize and provide updated recommendations for the care of people living with human immunodeficiency virus during pregnancy.

Sexual dysfunction among Nigerian women living with HIV infection.

Sexual dysfunction in women with HIV is a necessary but understudied aspect of HIV complications in women living with HIV. This study reports the prevalence, pattern, and risk factors for sexual dysfunction in women living with HIV in southwest Nigeria. A validated Female Sexual Function Index was used to determine sexual dysfunction in a cross-sectional study design involving 2926 adult women living with HIV in a large, publicly funded tertiary HIV treatment centre in Lagos, Nigeria. A score of less than 26.5 indicated sexual dysfunction. Multivariate logistic regression analysis was performed to identify risk factors for sexual dysfunction. P<0.05 was considered statistically significant at a 95% confidence interval (CI). The prevalence of sexual dysfunction was 71.4%. The types of dysfunctions detected included disorder of desire (76.8%), sexual arousal (66.0%), orgasm (50.0%), pain (47.2%), lubrication (47.2%), and satisfaction (38.8%). Multivariate analysis showed that menopause (aOR: 2.0; 1.4-4.1), PHQ score of 10 and above (aOR: 2.3; 1.7-3.2), co-morbid medical conditions (aOR: 1.8; 1.4-2.7), use of protease inhibitor-based antiretroviral therapy (aOR: 1.3; 1.2-2.1) and non-disclosure of HIV status (aOR: 0.7; 0.6-0.8) were factors associated with sexual dysfunction. Sexual dysfunction is common among Nigerian women living with HIV. Menopause, use of protease inhibitor-based regimens, PHQ score of at least 10, co-morbid medical condition, and non-disclosure of HIV status were associated with sexual dysfunction. National HIV programmes, in addition to incorporating screening and management of sexual dysfunction in the guidelines, should sensitise and train health workers on the detection and treatment of sexual dysfunction.

Metabolomic profiling of preterm birth in pregnant women living with HIV

BackgroundPreterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive.ObjectivesMetabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens.MethodsThis pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23–35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth.ResultsClassification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context.ConclusionThis study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Prevalence and Factors Associated With Delayed Puberty Among Adolescents on Boosted Protease Inhibitor-based Second-line Antiretroviral Therapy: A Cross-sectional Study at a Pediatric Infectious Diseases Clinic in Uganda.

Delayed puberty is a recognized phenomenon among children living with HIV type 1 infection but has not been widely reported among adolescents on second-line or newer treatments in high burden settings. The study aimed to determine the prevalence of, and factors associated with delayed puberty among adolescents on boosted protease inhibitor-based second-line antiretroviral therapy (ART) in Uganda. Between December 2017 and May 2018, we conducted a cross-sectional study among adolescents living with HIV (ALWHIV) 10-19 years of age on atazanavir- and lopinavir-based regimens at the Paediatric Infectious Diseases Clinic, Kampala. Participants were on ART for at least 3 months and had a recent viral load. Sociodemographics, clinical measurements: body mass index for age Z score, height for age Z score, Tanner staging were collected. ART history was extracted from medical records. The outcome was delayed puberty defined as absence of signs of breast development in a girl 13 years of age or a testicular volume of less than 4 mL in a boy 14 years of age by Tanner staging, or an age for Tanner staging which was at least 2 standard deviations above the expected mean. Among 230 perinatally infected ALWHIV participants, 14.7 ± 3.1 years of age were included, 54.9% were female, 5.2% were wasted and the median duration on ART was 9.5 years (interquartile range 7.3-11.7). The prevalence of delayed puberty was 8.7% (10.4% females, 6.7% males). Overall mean age estimates at different Tanner stages by sex were significantly higher than reference populations. Age at ART initiation (adjusted odds ratio 1.37, 95% confidence interval: 1.06-1.77) and body mass index for age Z score (adjusted odds ratio: 7.63, 95% confidence interval: 1.80-32.38) were associated with delayed puberty. Timely initiation of ART and nutritional monitoring could optimize body weight and consequently, normal puberty for ALWHIV. Longitudinal studies could establish biological diagnoses and guide treatment of delayed puberty in this population.

Realizing the Promise of Dolutegravir in Effectively Treating Children and Adolescents Living With HIV in Real-world Settings in 6 Countries in Eastern and Southern Africa.

Despite encouraging results from clinical trials and in high-income countries, large-scale data on the effectiveness and safety of dolutegravir (DTG) in children and adolescents living with HIV (CALHIV) are lacking in low- and middle-income countries (LMICs). Retrospective analysis was performed among CALHIV 0-19 years old and weighing greater than or equal to 20 kg who received DTG from 2017 to 2020 at sites in Botswana, Eswatini, Lesotho, Malawi, Tanzania and Uganda to determine effectiveness, safety and predictors of viral load suppression (VLS) among CALHIV using DTG, including through single drug substitutions (SDS). Among 9419 CALHIV using DTG, 7898 had a documented post-DTG VL, and VLS post-DTG was 93.4% (7378/7898). VLS for antiretroviral therapy (ART) initiations was 92.4% (246/263), and VLS was maintained for the ART-experienced [92.9% (7026/7560) pre- vs. 93.5% (7071/7560) post-DTG; P = 0.14). Among previously unsuppressed, 79.8% (426/534) achieved VLS with DTG. Only 5 patients reported a Grade 3 or 4 adverse event (0.057 per 100 patient-years) requiring DTG discontinuation. History of protease inhibitor-based ART [odds ratio (OR) = 1.53; 95% confidence interval (CI): 1.16-2.03], care in Tanzania (OR = 5.45; 95% CI: 3.41-8.70), and being 15-19 years old (OR = 1.31; 95% CI: 1.03-1.65) were associated with gain of VLS post-DTG. Predictors of VLS on DTG included VLS before DTG (OR = 3.87; 95% CI: 3.03-4.95) and using the once-daily, single tab tenofovir-lamivudine-DTG regimen (OR = 1.78; 95% CI: 1.43-2.22). SDS maintained VLS [95.9% (2032/2120) pre- vs. 95.0% (2014/2120) post-SDS with DTG; P = 0.19], and 83.0% (73/88) of unsuppressed gained VLS using SDS with DTG. We found DTG to be highly effective and safe within our cohort of CALHIV in LMICs. These findings can empower clinicians to prescribe DTG confidently to eligible CALHIV.

Аdverse events underlying antiretroviral therapy in children with HIV infection

Introduction. Human immunodeficiency virus infection can alter properties of blood vessels in children and increase the risk of development of cardiovascular diseases in the future. Today the actual contribution of the effects of both HIV infection and antiretroviral therapy into such changes remains unknown. Objective. We seek to assess adverse events, including metabolic disorders (dyslipidemias), underlying antiretroviral therapy, and to determine the relation between metabolic disorders and intima injury in children receiving antiretroviral therapy (ART).Materials and methods. The adverse events were investigated within the framework of a prospective and retrospective study. The study included evaluation of biochemical parameters in relation to the therapeutic regimen; calculation of atherogenic index of plasma; and determination of incidence of dyslipidemia in children. In addition to standard tests, children on ART were evaluated for insulin resistance (using HOMA-IR) and submitted to diagnostic imaging including Doppler ultrasonography of brachiocephalic arteries and veins.Results. Children on protease inhibitor-based ART have higher total cholesterol, LDL and triglyceride levels in comparison to both children on NNRTI-based ART and children who do not receive ART. LDL levels in children on long-term ART remained within the tolerance range and were clearly higher than those in children who did not receive ART. Carotid IMT was higher in children on NNRTI-based ART in comparison to those who received protease inhibitor-based therapy; and the correlation analysis conducted revealed positive correlation between the age and carotid IMT: The later ART was prescribed, the greater IMT was, which most likely was attributable to HIV effects.Conclusion. Prescription of antiretroviral therapy at an older age results in changes in the intima-media complex, which may give evidence to vasoprotective effects of the therapy. Since HIV is directly involved in causing injury to the intima, it is advisable to start managing HIV infection in children as soon as they are diagnosed with the infection; and children to whom ART is prescribed at an older age and who develop dyslipidemia should be additionally evaluated by medical imaging with Doppler ultrasonography with carotid IMT measurement.

Once-daily dolutegravir-based antiretroviral therapy in infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the randomised ODYSSEY trial

Young children living with HIV have few treatment options. We aimed to assess the efficacy and safety of dolutegravir-based antiretroviral therapy (ART) in children weighing between 3 kg and less than 14 kg. ODYSSEY is an open-label, randomised, non-inferiority trial (10% margin) comparing dolutegravir-based ART with standard of care and comprises two cohorts (children weighing ≥14 kg and <14 kg). Children weighing less than 14 kg starting first-line or second-line ART were enrolled in seven HIV treatment centres in South Africa, Uganda, and Zimbabwe. Randomisation, which was computer generated by the trial statistician, was stratified by first-line or second-line ART and three weight bands. Dispersible 5 mg dolutegravir was dosed according to WHO weight bands. The primary outcome was the Kaplan-Meier estimated proportion of children with virological or clinical failure by 96 weeks, defined as: confirmed viral load of at least 400 copies per mL after week 36; absence of virological suppression by 24 weeks followed by a switch to second-line or third-line ART; all-cause death; or a new or recurrent WHO stage 4 or severe WHO stage 3 event. The primary outcome was assessed by intention to treat in all randomly assigned participants. A primary Bayesian analysis of the difference in the proportion of children meeting the primary outcome between treatment groups incorporated evidence from the higher weight cohort (≥14 kg) in a prior distribution. A frequentist analysis was also done of the lower weight cohort (<14 kg) alone. Safety analyses are presented for all randomly assigned children in this study (<14 kg cohort). ODYSSEY is registered with ClinicalTrials.gov, NCT02259127. Between July 5, 2018, and Aug 26, 2019, 85 children weighing less than 14 kg were randomly assigned to receive dolutegravir (n=42) or standard of care (n=43; 32 [74%] receiving protease inhibitor-based ART). Median age was 1·4 years (IQR 0·6-2·0) and median weight 8·1 kg (5·4-10·0). 72 (85%) children started first-line ART and 13 (15%) started second-line ART. Median follow-up was 124 weeks (112-137). By 96 weeks, treatment failure occurred in 12 children in the dolutegravir group (Kaplan-Meier estimated proportion 31%) versus 21 (48%) in the standard-of-care group. The Bayesian estimated difference in treatment failure (dolutegravir minus standard of care) was -10% (95% CI -19% to -2%; p=0·020), demonstrating superiority of dolutegravir. The frequentist estimated difference was -18% (-36% to 2%; p=0·057). 15 serious adverse events were reported in 11 (26%) children in the dolutegravir group, including two deaths, and 19 were reported in 11 (26%) children in the standard-of-care group, including four deaths (hazard ratio [HR] 1·08 [95% CI 0·47-2·49]; p=0·86). 36 adverse events of grade 3 or higher were reported in 19 (45%) children in the dolutegravir group, versus 34 events in 21 (49%) children in the standard-of-care group (HR 0·93 [0·50-1·74]; p=0·83). No events were considered related to dolutegravir. Dolutegravir-based ART was superior to standard of care (mainly protease inhibitor-based) with a lower risk of treatment failure in infants and young children, providing support for global dispersible dolutegravir roll-out for younger children and allowing alignment of adult and paediatric treatment. Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.

A Study of Potential drug-drug interactions in HIV positive individuals with Co-morbidities

The high prevalence of comorbid conditions, both communicable and non-communicable, in HIV patients dictate the need for prescription of additional medications which makes way for the possibility of a particular medication altering the intensity of the pharmacotherapeutic effect of a concomitantly administered medication, a potential drug-drug interaction (PDDI), which can lead to the precipitation of adverse effects and even treatment failure. In this retrospective observational study, data was collected from medical records of adult HIV positive patients on antiretroviral therapy (ART) with comorbidities who visited the hospital between January, 2015 and June, 2017. Using the University of Liverpool drug-interaction database, the identified interactions were classified into three categories. The category of PDDI requiring monitoring, dose adjustment or adjustment of time of dosing was taken and evaluated for the type of interaction, risk and prevalence. Time of onset and severity was determined using Micromedex drug-interaction database. Data analysis was done using descriptive statistics and binomial logistic regression was used for risk estimation. In this study, a total of 244 people were enrolled. A total of 711 PDDIs were identified. By analysing risk ratio, patients with more than 5 concomitant medications, protease inhibitor-based ART regimen, duration of illness (≥6 years), cardiovascular disease and presence of coinfections were at a higher risk of development of PDDIs. Pharmacokinetic PDDIs (87.2%) were higher in comparison to pharmacodynamic PDDIs (12.8%). Awareness among prescribers of this silent but important occurrence will help in recognition, prevention and management of PDDI which might otherwise complicate the therapeutic outcome.

Adverse perinatal outcomes associated with protease inhibitor-based antiretroviral therapy in pregnant women living with HIV: A systematic review and meta-analysis

SummaryBackgroundThe World Health Organization recommends protease inhibitor (PI)-based antiretroviral therapy (ART) as second-line and third-line regimens in pregnant women living with HIV (WLHIV). US, European, and UK guidelines include PI-based ART as first-line regimens, but advise against the use of lopinavir/ritonavir (LPV/r)-based ART, citing an increased risk of preterm birth (PTB). We aimed to assess the risk of adverse perinatal outcomes in WLHIV receiving PI-ART and the comparative risks associated with different PI-ART regimens.MethodsWe conducted a systematic literature review by searching PubMed, CINAHL, Global Health, and EMBASE for studies published between Jan 1, 1980, and April 20, 2020. Two investigators independently selected studies and extracted data from studies reporting on the association of pregnant WLHIV receiving PI-ART with 11 perinatal outcomes: PTB, very PTB (VPTB), spontaneous PTB (sPTB), low birth weight (LBW), very LBW (VLBW), term LBW, preterm LBW, small for gestational age (SGA), very SGA (VSGA), stillbirth, and neonatal death. Pairwise random-effects meta-analyses examined the risk of each adverse perinatal outcome in WLHIV receiving PI-ART compared to non-PI-based ART (non-PI-ART), and comparisons of different PI-ART regimens. Quality assessments of studies were performed, subgroup and sensitivity analyses were conducted based on country income status and study quality, heterogeneity assessed, and the effect of adjustment for confounding factors assessed. The protocol is registered with PROSPERO, CRD42021248987.FindingsOf 94,594 studies identified, 34 cohort studies including 57,546 women met the inclusion criteria. Random-effects meta-analyses showed that PI-ART was associated with a significantly increased risk of SGA (Relative Risk [RR] 1.24, 95% CI 1.08–1.43; I2=66.7%) and VSGA (RR 1.40, 1.09–1.81; I2=0.0%), but not PTB (RR 1.09, 0.95–1.24; I2=68.3%), VPTB (RR 1.30, 0.78–2.18; I2=43.0%), sPTB (RR 1.91, 0.61–5.99; I2=95.7%), LBW (RR 1.04, 0.85–1.27; I2=63.9%), VLBW (RR 0.72, 0.37–1.43; I2=37.9%), term LBW (RR 0.94, 0.30–3.02; I2=0.0%), stillbirth (RR 1.04, 0.60–1.79; I2=0.0%), and neonatal death (RR 1.82, 0.97–3.40; I2=0.0%), compared to non-PI-ART. We found no significant differences in perinatal outcomes between ART regimens containing LPV/r, atazanavir/ritonavir (ATV/r), and darunavir/ritonavir (DRV/r), which are the most commonly used PIs.InterpretationPI-ART is associated with an increased risk of SGA and VSGA, but not PTB or other perinatal outcomes. No significant differences in perinatal outcomes were found between LPV/r, ATV/r, and DRV/r. These findings should inform clinical guidelines, and further efforts should be made to improve perinatal outcomes among pregnant WLHIV.FundingNone.

Protease inhibitor-based antiretroviral therapy in pregnancy: effects on hormones, placenta, and decidua.

The use of antiretroviral therapy (ART) in pregnancy is important for maternal health, and has been successful in reducing vertical transmission rates to almost zero in those taking effective ART regimens with good adherence. However, there are reports of higher rates of low birthweight and preterm births in women with HIV, which can be further exacerbated by ART usage in pregnancy. Protease inhibitors, and ritonavir-boosted lopinavir in particular, might directly contribute to placental and uteroplacental pathology in part by altering plasma concentrations of the essential steroid hormones of pregnancy, progesterone and oestradiol. In this Review, we collate the increasing evidence of dysregulated maternal endocrinology, reproductive physiology, and placental compromise associated with protease inhibitors. Based on findings of placental and decidual effects, we recommend that ritonavir-boosted lopinavir should be avoided in pregnancy, in line with US and European guidelines. Long-term follow-up of children exposed to protease inhibitors in utero is also recommended.

A natural history of efavirenz drug-induced liver injury.

Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, has been a component of first-line antiretroviral therapy (ART) in the South African HIV/AIDS programme since 2004. It is extensively used in ART programmes in other low- and middle-income countries. The natural history of the previously recognised EFV drug-induced liver injury (DILI) is not known. To define and establish a causality assessment for EFV DILI and document its natural history by detailing a patient cohort. All relevant features characterising the patterns of clinical and histological injury, the duration of clinical and biochemical recovery and the associated mortality rate were documented. Factors associated with specific histological patterns of liver injury were analysed. Patients were prospectively included after meeting causality and inclusion criteria for EFV DILI. Clinical, demographic and liver histological features (where possible) were documented from the time of presentation and throughout follow-up. Prednisone at 0.25 - 0.5mg/kg was initiated at the discretion of the treating hepatologist. Fifty patients were prospectively included in the analysis. The median age was 34 (interquartile range (IQR) 29 - 39) years, males being older than females (p=0.014). Most (92%) were female, and 86% were of black African ethnicity. The median duration of ART at presentation was 6 months, with half of the women having initiated ART during pregnancy, at a median gestation of 24 (IQR 11 - 36) weeks. The median CD4 nadir at ART treatment initiation was 517 cells/µL, with no significant difference in CD4 nadir between those who were pregnant and those who were not (p=0.6). The median RUCAM (Roussel Uclaf Causality Assessment Method) score was 7, and among the 75% of patients who had liver biopsies, three histological patterns were identified: submassive necrosis (60%), nonspecific hepatitis (35%), and mixed cholestatic hepatitis (5%). On multivariate analysis, predictors for the development of submassive necrosis included younger age (&lt;30 years; p=0.045), ART initiation in pregnancy (p=0.02), and a baseline CD4 count &gt;350 cells/µL (p=0.018). For the nonspecific hepatitis group, pregnancy was also an associated factor (p=0.04). The mortality rate was 14%, with a median time from admission to death of 15days. The median (IQR) time to initial hospital discharge was a lengthy 33 (24 - 52) days. Biochemical recovery was prolonged, necessitating a follow-up period of more than a year at an outpatient specialist clinic, with 86% of patients initiating a protease inhibitor-based ART regimen successfully. EFV DILI is a severe drug complication of ART with appreciable mortality and significant inpatient morbidity, requiring prolonged hospitalisation and follow-up.

HIV-1 drug resistance in adults and adolescents on protease inhibitor-based antiretroviral therapy in KwaZulu-Natal Province, South Africa

In low-middle-income countries, increasing levels of HIV drug resistance (HIVDR) on second-line protease inhibitor (PI)-based regimens are a cause for concern given the limited drug options for third-line antiretroviral therapy (ART). We conducted a retrospective analysis of routine HIV-1 genotyping laboratory data from KwaZulu-Natal, South Africa, to describe the frequency and patterns of HIVDR mutations and their consequent impact on standardised third-line regimens. This was a cross-sectional analysis of all HIV-1 genotypic resistance tests conducted by the National Health Laboratory Service in KwaZulu-Natal (January 2015 to December 2016) for adults and adolescents (age ≥10 years) on second-line PI-based ART with virological failure. We assigned a third-line regimen to each record based on a national treatment algorithm and calculated the genotypic susceptibility score (GSS) for that regimen. Of 348 samples analysed, 287 (82.5%) had at least one drug resistance mutation (DRM) and 114 (32.8%) had at least one major PI DRM. Major PI resistance was associated with longer duration on second-line ART (aOR per 6-months=1.11, 95% CI 1.04-1.19) and older age (aOR=1.03, 95% CI 1.01-1.05). Of 112 patients requiring third-line ART, 12 (10.7%) had a GSS of <2 for the algorithm-assigned third-line regimen. One-third of people failing second-line ART had significant PI DRMs. A subgroup of these individuals had extensive HIVDR, where the predicted activity of third-line ART was suboptimal, highlighting the need for continuous evaluation of outcomes on third-line regimens and close monitoring for emergent HIV-1 integrase inhibitor resistance.

Antiretroviral hair levels, self-reported adherence, and virologic failure in second-line regimen patients in resource-limited settings.

To evaluate associations between hair antiretroviral hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes. Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line protease inhibitor-based antiretroviral therapy (ART) but were susceptible to at least one nucleoside reverse transcriptase inhibitor (NRTI) and their protease inhibitor, and continued taking their protease inhibitor-based regimen. Antiretroviral hair concentrations in participants taking two NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography--tandem-mass-spectrometry assays. Participants' self-reported percentage of doses taken in the previous month; virologic failure was confirmed HIV-1 RNA at least 1000 copies/ml at week 24 or 48. From 181 participants with hair samples (61% women, median age: 39 years; CD4+ cell count: 167 cells/μl; HIV-1 RNA: 18 648 copies/ml), 91 (50%) experienced virologic failure at either visit. At 24 weeks, median hair concentrations were 2.95 [interquartile range (IQR) 0.49-4.60] ng/mg for atazanavir, 2.64 (IQR 0.73--7.16) for lopinavir, and 0.44 (IQR 0.11--0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with virologic failure, the hazard ratio (95% CI) for ATV, LPV, and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27), respectively. Protease inhibitor hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of second-line treatment failure in need of interventions.

Incidence and predictors of early loss to follow up among patients initiated on protease inhibitor-based second-line antiretroviral therapy in southwestern Uganda

BackgroundGood adherence to antiretroviral therapy (ART) and retention in care are essential for the effectiveness of an HIV care program. With the current increase in numbers of people living with HIV taking second-line ART in sub-Saharan Africa, there is a need to establish their treatment outcomes and the rate of loss to follow up. In this study, we determined the incidence and predictors of loss to follow up among patients taking second-line ART at an experienced HIV treatment center in southwestern Uganda.MethodsThis was a retrospective review of an electronic database at Mbarara Regional Referral Hospital HIV clinic in southwestern Uganda. Second-line ART included at least two of the nucleoside reverse transcriptase inhibitors and a boosted protease inhibitor. Loss to follow-up was defined as failure to return to the health facility for care or treatment refill for 180 days or more from the previous visit. After excluding children less than 15 years, we pooled data that included socio-demographic, clinical, and laboratory data for patients who started second-line ART between 2002 and 2017. Multiple imputation was done for variables with missing data. Variables that had a p < 0.05 in unadjusted bivariate analyses were included in a multivariate binomial regression model using a stepwise backward selection procedure to describe the factors that independently predicted loss to follow-up.ResultsBetween 2002 and 2017, 1121 patients had been initiated on second-line ART. We included data from 924 participants and of these, 518 (56.1%) were female, the mean age (SD) was 38.4 (± 10.5) years, and 433 (52.4%) had a CD4 count less than 100 cells/µl at the start of second-line ART. The incidence of loss to follow-up was 26.7 per 100 person-years. Male gender (Adjusted risk ratio (ARR) = 1.8, 95% CI 1.5–2.0) p < 0.001 and anemia ARR 1.4, 95% CI 1.1–1.6) p < 0.001 were strongly associated with loss to follow up.ConclusionsThere is a high incidence of loss to follow up among patients taking protease-inhibitor based second-line ART at a tertiary HIV center in southwestern Uganda. There is a need to routinely measure hemoglobin during clinic reviews, and establish mechanisms to retain males initiated on second-line ART in care. The association of anemia and loss to follow up needs to be investigated.

Impact of Protease Inhibitor-Based Antiretroviral Therapy on Tacrolimus Intrapatient Variability in HIV-Positive Kidney Transplant Recipients

BackgroundHuman immunodeficiency virus (HIV)-positive kidney transplant (KT) recipients have been shown to experience higher rejection rates due in part to drug-drug interactions between antiretroviral therapy (ART) and immunosuppression regimens. High tacrolimus (FK) intrapatient variability (IPV) is associated with inferior outcomes in KT. The purpose of this study was to determine the impact of protease inhibitor (PI)-based ART on FK IPV and graft outcomes. MethodsWe performed a single-center review of HIV-positive KT recipients from 2007 to 2017. Percentage coefficient of variation (%CV = (σ/μ) × 100; σ, median; μ, standard deviation) was calculated for FK IPV. FK IPV at 6 and 12 months, graft function, and immune outcomes in PI-based vs non-PI-based KT recipients were compared. ResultsA total of 23 HIV-positive KT patients were identified, of whom 10 were maintained on PI-based ART. Median IPV for the entire cohort at 6 and 12 months was 35.8% and 41%, respectively. Patients on PI-based regimens were proportionally more likely to experience high IPV at both time points. Median FK IPV was numerically higher at 6 months (37.3% vs 26.8%, P = .11) and significantly higher at 12 months (57.8% vs 30.9%, P = .01) for patients on PI-based regimens. Lastly, inferior graft function was observed in PI-based patients. ConclusionOur data suggest that PI-based ART is associated with a higher degree of FK IPV, which may contribute to worsening graft function. Larger studies are warranted to determine the impact of PI-based ART on FK IPV and graft outcomes in this population.

HIV-positive deceased donor-to-HIV-positive recipient kidney transplantation: The HOPE must go on.

Nowadays, HIV infection is a chronic disease, this is due to the efficacy of antiretroviral therapy (ART) in the control of viral replication. The prevalence of chronic kidney disease (CKD) among those well-controlled HIV positive (HIV+) patients is higher than in the general population and kidney transplantation has been established as the best therapeutic option for HIV+ patients with end-stage renal disease. However, this population has lower access to transplantation.

Leveraging routine viral load testing to integrate diabetes screening among patients on antiretroviral therapy in Malawi.

BackgroundPeople living with HIV are at an increased risk of diabetes mellitus due to HIV infection and exposure to antiretroviral therapy (ART). Despite this, integrated diabetes screening has not been implemented commonly in African HIV clinics. Our objective was to explore the feasibility of integrating diabetes screening into existing routine HIV viral load (VL) monitoring and to determine a group of HIV patients that benefit from a targeted screening for diabetes.MethodsA mixed methods study was conducted from January to July 2018 among patients on ART aged≥18 y and healthcare workers at an urban HIV clinic in Zomba Central Hospital, Malawi. Patients who were due for routine VL monitoring underwent a finger-prick for simultaneous point-of-care glucose measurement and dried blood spot sampling for a VL test. Diabetes was diagnosed according to WHO criteria. We collected demographic and medical history information using an interviewer-administered questionnaire and electronic medical records. We conducted focus group discussions among healthcare workers about their experience and perceptions regarding the integrated diabetes screening program.ResultsOf patients undergoing routine VL monitoring, 1316 of 1385 (95%) had simultaneous screening for diabetes during the study period. The median age was 44 y (IQR: 38–53); 61% were female; 28% overweight or obese; and median ART duration was 83 mo (IQR: 48–115). At baseline, median CD4 count was 199 cells/mm3 (IQR: 102–277) and 50% were in WHO clinical stages I or II; 45% were previously exposed to stavudine and 88% were virologically suppressed (<1000 copies/mL). Diabetes prevalence was 31/1316 (2.4%). Diabetes diagnosis was associated with age ≥40 y (adjusted OR [aOR] 7.44; 95% CI: 1.74 to 31.80), being overweight and/or obese (aOR 2.46; 95% CI: 1.13 to 5.38) and being on a protease inhibitor-based ART regimen (aOR 5.78; 95% CI: 2.30 to 14.50). Healthcare workers appreciated integrated diabetes screening but also reported challenges including increased waiting time, additional workload and inadequate communication of results to patients.ConclusionsIntegrating diabetes screening with routine VL monitoring (every 2 y) seems feasible and was valued by healthcare workers. The additional cost of adding diabetes screening into VL clinics requires further study and could benefit from a targeted approach prioritizing patients aged ≥40 y, being overweight/obese and on protease inhibitor-based regimens.

Evaluation of the management of pretreatment HIV drug resistance by oligonucleotide ligation assay: a randomised controlled trial

Although experts have recommended testing for pretreatment drug resistance (PDR) before antiretroviral therapy (ART) initiation, there is little evidence to support its implementation. We aimed to establish whether an inexpensive point mutation assay can improve virological suppression by identifying PDR to guide drug selection for ART in a lower-middle income country. Investigators did an open-label, randomised controlled trial at three HIV treatment sites in Kenya: two in Nairobi and one in rural Maseno. Individuals (aged ≥2 years) were eligible to participate if they were confirmed HIV-seropositive, qualified for first-line ART, planned to reside in the area for more than 1 year, and provided informed consent. We randomly assigned participants (1:1) to either PDR testing by oligonucleotide ligation assay (OLA) to guide selection of ART or to standard of care, which did not include OLA testing. The OLA-guided therapy group had pre-ART peripheral blood mononuclear cells evaluated for drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) at codons Lys103Asn, Tyr181Cys, Gly190Ala, and to lamivudine at Met184Val, and when at least one drug-resistant codon was detected in a participant's pre-ART specimen, clinicians were directed to prescribe protease inhibitor-based second-line ART. Those without detected resistance and those who were randomised to standard of care received NNRTI-based first-line ART. The primary outcome was plasma HIV-1 RNA of at least 400 copies per mL at 4, 8, or 12 months after ART initiation, which defined virological failure, assessed in all participants who received treatment (data were censored for those lost-to-follow-up or who died). The study has been completed and is registered with ClinicalTrials.gov, NCT01898754. We screened 1198 participants between May 28, 2013, and Nov 4, 2014, of whom 991 (83%) were enrolled (492 received OLA and 495 received standard of care; four did not begin treatment). 93 participants (prevalence 9·4%) had PDR (95% CI 7·7-11·4). 34 (8·5%) of 400 participants in the OLA group had virological failure at month 12 of ART (95% CI 6·0-11·7) compared with 39 (9·7%) of 402 (7·0-13·0) in the standard-of-care group (log-rank p=0·26). Among participants with PDR, virological failure was lower in the OLA-guided therapy group than in the standard-of-care group: five (14%) of 35 compared with 13 (50%) of 26; p=0·0020). Among those prescribed NNRTI-based ART, participants given efavirenz were less likely to have virological failure than were those receiving nevirapine (odds ratio 0·37, 95% CI 0·22-0·62; p<0·0001). The OLA-guided therapy group had 39 serious non-lethal adverse events and 34 deaths. The standard-of-care group had 34 severe adverse events and 43 deaths, differences that were not significant. Adverse events judged to potentially be due to ART were few and similar between groups, with 17 (16%) in the OLA-guided therapy group and 16 (16%) in the standard-of-care group (p=0·90). Our finding that OLA testing for PDR reduced virological failure in only those with specific PDR mutations suggests that PDR poses less of a risk for virological failure than that predicted by past prevalence estimates, and that the value of PDR testing to reduce virological failure should be assessed for antiretroviral treatment regimens. US National Institutes of Health.

Abstract # 3251 You sleep, but your heart is not in it - the importance of nocturnal autonomic signalling

Although experts have recommended testing for pretreatment drug resistance (PDR) before antiretroviral therapy (ART) initiation, there is little evidence to support its implementation. We aimed to establish whether an inexpensive point mutation assay can improve virological suppression by identifying PDR to guide drug selection for ART in a lower-middle income country.Investigators did an open-label, randomised controlled trial at three HIV treatment sites in Kenya: two in Nairobi and one in rural Maseno. Individuals (aged ≥2 years) were eligible to participate if they were confirmed HIV-seropositive, qualified for first-line ART, planned to reside in the area for more than 1 year, and provided informed consent. We randomly assigned participants (1:1) to either PDR testing by oligonucleotide ligation assay (OLA) to guide selection of ART or to standard of care, which did not include OLA testing. The OLA-guided therapy group had pre-ART peripheral blood mononuclear cells evaluated for drug resistance to non-nucleoside reverse transcriptase inhibitor (NNRTI) at codons Lys103Asn, Tyr181Cys, Gly190Ala, and to lamivudine at Met184Val, and when at least one drug-resistant codon was detected in a participant's pre-ART specimen, clinicians were directed to prescribe protease inhibitor-based second-line ART. Those without detected resistance and those who were randomised to standard of care received NNRTI-based first-line ART. The primary outcome was plasma HIV-1 RNA of at least 400 copies per mL at 4, 8, or 12 months after ART initiation, which defined virological failure, assessed in all participants who received treatment (data were censored for those lost-to-follow-up or who died). The study has been completed and is registered with ClinicalTrials.gov, NCT01898754.We screened 1198 participants between May 28, 2013, and Nov 4, 2014, of whom 991 (83%) were enrolled (492 received OLA and 495 received standard of care; four did not begin treatment). 93 participants (prevalence 9·4%) had PDR (95% CI 7·7–11·4). 34 (8·5%) of 400 participants in the OLA group had virological failure at month 12 of ART (95% CI 6·0–11·7) compared with 39 (9·7%) of 402 (7·0–13·0) in the standard-of-care group (log-rank p=0·26). Among participants with PDR, virological failure was lower in the OLA-guided therapy group than in the standard-of-care group: five (14%) of 35 compared with 13 (50%) of 26; p=0·0020). Among those prescribed NNRTI-based ART, participants given efavirenz were less likely to have virological failure than were those receiving nevirapine (odds ratio 0·37, 95% CI 0·22–0·62; p<0·0001). The OLA-guided therapy group had 39 serious non-lethal adverse events and 34 deaths. The standard-of-care group had 34 severe adverse events and 43 deaths, differences that were not significant. Adverse events judged to potentially be due to ART were few and similar between groups, with 17 (16%) in the OLA-guided therapy group and 16 (16%) in the standard-of-care group (p=0·90).Our finding that OLA testing for PDR reduced virological failure in only those with specific PDR mutations suggests that PDR poses less of a risk for virological failure than that predicted by past prevalence estimates, and that the value of PDR testing to reduce virological failure should be assessed for antiretroviral treatment regimens.US National Institutes of Health.

Third-line antiretroviral therapy in low-income and middle-income countries (ACTG A5288): a prospective strategy study

Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure. A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov, number NCT01641367. From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60-68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]). Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance. National Institutes of Health.