The objective of this study in MSM living with HIV was to determine the incidence of HSIL and ASCC, related factors, and the response to treatment.Data were gathered in 405 consecutive HIV-infected MSM (May 2010-December 2018) at baseline and annually on: sexual behavior, anal cytology, and HPV PCR and/or high-resolution anoscopy results. They could choose mucosectomy with electric scalpel (from May 2010) or self-administration of 5% imiquimod 3 times weekly for 16 weeks (from November 2013). A multivariate logistic regression model was developed for ≥HSIL-related factors using a step-wise approach to select variables, with a significance level of 0.05 for entry and 0.10 for exit, applying the Hosmer-Lemeshow test to assess the goodness of fit.The study included 405 patients with a mean age of 36.2 years; 56.7% had bachelor´s degree, and 52.8% were smokers. They had a mean of 1 (IQR 1–7) sexual partner in the previous 12 months, median time since HIV diagnosis of 2 years, and mean CD4 nadir of 367.9 cells/uL; 86.7% were receiving ART, the mean CD4 level was 689.6 cells/uL, mean CD4/CD8 ratio was 0.77, and 85.9% of patients were undetectable. Incidence rates were 30.86/1,000 patient-years for ≥high squamous intraepithelial lesion (HSIL) and 81.22/100,000 for anal squamous cell carcinoma (ASCC). The ≥HSIL incidence significantly decreased from 42.9% (9/21) in 2010 to 4.1% (10/254) in 2018 (p = 0.034). ≥HSIL risk factors were infection with HPV 11 , HPV 16 , HPV 18 , HPV 53 ; HPV 61 ; HPV 68 ; low CD4 nadir  and history of AIDS . Among HSIL-positive patients, the response rate was higher after imiquimod than after surgical excision  and there were fewer re-treatments  and adverse events ; none developed ASCC.HSIL screening and treatment programs reduce the incidence of HSIL, which is related to chronic HPV infection and poor immunological status. Self-administration of 5% imiquimod as first-line treatment of HSIL is more effective than surgery in HIV+ MSM. Anal squamous-cell carcinoma (ASCC) is frequent among individuals living with HIV (HIV+) and associated with a high mortality rate  and withASCC has been associated with persistent infection by high-risk oncogenic HPV (HR-HPV) genotypes . InteracIt remains controversial whether the treatment of high-grade anal intraepithelial lesions (HSILs) prevents the subsequent development of ASCC , and no In this study of consecutive HIV+ MSM undergoing a screening/treatment program at our hospital, we previously reported that oncogenic genotype clearance in anal mucosa was associated with the length of ART but did not affect the incidence of HSILs or ASCC. In the present article, data from the same population  were anaThis longitudinal observational  prospective study was conducted in a population of 405 adult HIV+ MSM patients with no history of ASCC, who were consecutively enrolled between May 2010 and December 2018 in a screening and follow-up program for dysplasic anal mucosa lesions. This population and the methodology applied were previously reported  in a preGonorrhoeae, Mycoplasma spp, Chlamydia spp, Ureaplasma spp) and oral-anal-urethral exudate culture (Gonorrhoeae) studies in symptomatic patients or infected partners. In addition, two anal canal mucosa samples were taken at baseline for HPV detection and genotyping by qualitative PCR and for cytology study using the “thin-layer” technique (Processor Thin Prep 2000 (Hologic), and HRA was performed at 4–12 weeks taking samples of apparently normal mucosa and areas with Lugol-negative aceto-white lesions using an endoscopic retrograde cholangiopancreatography catheter. HRA results were obtained from 100% of patients, and findings of at least one follow-up anoscopy were available for 97.3% (394/405). HRA was performed by an infectious disease specialist specifically trained for one year by an expert in this technique from the Department of Digestive Disease of our hospital.In brief, data were gathered at baseline (V0), 4–12 weeks, and subsequent follow-ups  on clinical-epidemiological and analytical variables and on the results of PCR  were examined with cytology, HPV PCR, and anoscopy, whereas those with HSIL underwent electrosurgical mucosal resection (from May 2010) or self-administration of 5% imiquimod 3 times/week for 16 weeks (from November 2013), followed by another anoscopy. Surgery was the sole option from May 2010 until the introduction of imiquimod in 2013; since then, all patients have been offered imiquimod as first treatment option. If the imiquimod treatment failed, patients were offered extension of the course up to 18 weeks, a new 16-week cycle of imiquimod, or surgery. Between May 2012 and May 2014, quadrivalent HPV vaccine was received by patients with no HPV 16 or 18 infection and no presence or history of HSIL+-compatible lesions. Cytology results were categorized according to the Bethesda classification .Abnormal cytology: Cytology findings of ASCUS, LSIL, or HSIL.Histology with≥HSILs: Histology findings from HSIL to ASCC.Therapeutic failure: HSIL persistence after treatment.Post-treatment HSIL recurrence: Re-appearance of previously treated lesion with normal post-treatment anoscopy.Response to treatment: Disappearance of lesion in follow-up anoscopy after treatment with surgery or imiquimod.Self-administration of 5% imiquimod. On Mondays, Wednesdays and Fridays, patients used a preloaded single-use insulin syringe (after cleaning drug remains from its surface) to apply imiquimod inside the anal canal, 3 cm from the anal verge, while in left lateral decubitus position, preferably before sleeping. Before starting this therapy, the patient received detailed instructions on the procedure from the attending physician and nurse.SPSS 21.0 was used for data analyses. The descriptive statistics and tests used for bivariate analyses were previously reported in detail . In the In the multivariate analysis, the presence of ≥HSILs was related to infection with HPV genotypes 11 , 16 , 18 , 53 , 61  and 68 , low CD4 nadir , and history of AIDS . The remaining results obtained are exhibited in After excluding 11 patients who did not undergo two or more anoscopies, treatment outcomes were analyzed in a sample of 394 (87.2%) MSM, with a median follow-up of 36 months (IQR: 12–69), 1.215 patients-year. Mucosectomy was performed in 47 patients with HSIL, with a median follow-up of 60 months (IQR: 46–73 months) and median disease-free period of 48 months (IQR: 28–60 months).versus 96.8% to imiquimod (31/32) (p = 0.009) as evaluated by post-treatment HRA. A median of one surgical intervention was performed (IQR:1–1), with 31 patients undergoing one, 9 needing two, and 1 needing four interventions. Recurrence was recorded in 7 patients (15.2%), and repeat excision of the same lesion in 11 (23.4%). All surgical patients reported adverse effects, with a median duration of 15 days post-surgery (IQR: 7–21 days), including bleeding with defecation in 32 (68%), pain requiring anti-analgesics in 39 (82.9%), rectal incontinence in 1 (2.1%), and transient anal stenosis in 3 (6.4%) versus 1 in the imiquimod group . Among the 43 patients with follow-up HPV PCR results, clearance of oncogenic VPH genotypes was observed in 19 (44.2%).Forty-one (87.2%) of these patients received surgery alone, five (10.6%) received surgery plus self-administered imiquimod, due to failure of surgery in two cases and recurrence in three, and one patient underwent successful surgery after the failure of imiquimod treatment. Surgical margins were disease-free in 35 patients (76.9%) after first surgery. The response rate was 73.3% to surgery as first-line treatment (33/45) Thirty-seven patients with HSIL self-administered 5% imiquimod three times/week; the treatment lasted 16 weeks in 97.3% of these patients and 18 weeks in 2.7%. It was first-line treatment in 32 patients (86.4%) and administered after previous surgery in 5 (13.5%); all patients showed a complete response, except for one case of failure caused by intolerance to imiquimod. Only one patient (2.7%) needed retreatment of the same lesion, whereas 11 (23.4%) of the surgical group required repeat surgery (p = 0.02). The median number of affected quadrants was 1 (IQR: 1–2). Mean follow-up was 48 months (IQR: 35–57 months) and mean disease-free period 36 months (IQR: 12–48). Imiquimod was discontinued in one patient (2.7%) for adverse effects  attributed to non-compliance with the treatment protocol. Among the 35 (94.6%) patients treated with imiquimod for whom follow-up HPV PCR results were available, clearance of oncogenic VPH genotypes was observed in 10 (28.6%) (p = 0.065). No patient treated with surgery or imiquimod progressed to ASCC.vs. 4.1% (10/245) p = 0.034), between 2010 and 2013 (42.9% (9/21) vs. 13.8% (22/159), p = 0.003), and between 2013 and 2016 (13.8% (22/159) vs. 4.8% (13/273), p = 0.0001), followed by a stabilization between 2016 and 2018 (4.8% (13/273) vs. 4.1% (10/245), p = 0.617). Four deaths were recorded during the follow-up: one patient with hepatic cirrhosis secondary to chronic HCV infection in 2012, one with Burkitt lymphoma in 2013, one with small-cell lung cancer in 2014, and one with metastatic ASCC in 2015. Further data on outcomes were previously reported in detail [We found significant reductions in ≥HSIL cases between 2010 and 2018 (42.9% (9/21) Since the first HIV epidemic, the incidence of ASCC has increased in seropositive patients, mainly in MSM with AIDS . After tIn this prospective study of HIV+ MSM undergoing a screening/treatment program for anal mucosa dysplasic lesions, the presence of ≥high-grade anal intraepithelial lesions were related to infection by HPV genotypes 11 16, 18, 53, 61 and 68, a low CD4 nadir and a history of AIDS. This finding of a relationship between HSIL-positivity and poor immunological status is consistent with previous observations that prolonged antiretroviral treatment –23 and aversus placebo (n = 25) in the anal canal three times/week for 4 months found a significant association (P = 0.003) between imiquimod and a positive outcome [versus 6.25 mg dose of imiquimod, with no difference in CD4, HIV viral load, or serostatus [Self-administration of 5% imiquimod was a highly effective therapeutic strategy against HSIL in this series of HIV+MSM. Most of them did not need to repeat the topical treatment, whereas around a quarter of the patients undergoing excision required another intervention. Furthermore, the therapeutic failure rate and dropout for adverse effects were lower in the imiquimod group than in the surgery group. Various studies have supported the efficacy of imiquimod to treat HSIL in HIV+ patients , 28, 29. outcome . In addiFurther advantages of 5% imiquimod in comparison to ablative therapies include its self-administration and its usefulness in cases of extensive disease. The surgical option was also effective in a large proportion of our patients, although some needed retreatment due to recurrence or incomplete excision. No cases of permanent stenosis or fecal incontinence were observed in the surgical group; however, surgery is not currently recommended due to its adverse effects, especially in patients with large lesions .Limitations of this single-center study include its observational design, comparing the real-life clinical effectiveness of imiquimod and surgery rather than their efficacy . In addition, it only included HIV+MSM, and these data cannot be extrapolated to other types of patient. Finally, 11 of the 405 enrolled patients did not undergo two or more anoscopies and were therefore lost to the follow-up. However, its strengths include the prospective design and long follow-up period, which was a mean of 36 months. In fact, the present cohort of HIV+ patients is one of the few published to date that was created to measure predetermined objectives.In conclusion, HSIL screening and treatment programs reduce the incidence of this precursor of ASCC. Chronic mixed HPV infection and a history of poor immunological status are associated with the presence of HSILs. Self-administration of 5% imiquimod is more effective than surgery as first-line treatment of anal HSIL in HIV+MSM patients, with a lower recurrence rate and fewer adverse effects.S1 File(SAV)Click here for additional data file.


The impacts of genetic polymorphisms on drug resistance mutations (DRMs) among various HIV-1 subtypes have long been debated. In this study, we aimed to analyze the natural polymorphisms and acquired DRM profile in HIV-1 CRF01_AE-infected patients in a large first-line antiretroviral therapy (ART) cohort in northeastern China.The natural polymorphisms of CRF01_AE were analyzed in 2034 patients from a long-term ART cohort in northeastern China. The polymorphisms in 105 treatment failure (TF) patients were compared with those in 1148 treatment success (TS) patients. The acquired DRM profile of 42 patients who experienced TF with tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) treatment was analyzed by comparing the mutations at TF time point to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, Wilcoxon test and CorMut package were used to analyze the mutation rates and co-variation. Deep sequencing was used to analyze the evolutionary dynamics of co-variation.Before ART, there were significantly more natural polymorphisms of 31 sites on reverse transcriptase (RT) in CRF01_AE than subtype B HIV-1 , including five known drug resistance-associated sites . However, only the polymorphism at site 75 was associated with TF . The mutation rate at 14 sites increased significantly at TF time point compared to baseline, with the most common DRMs comprising G190S/C, K65R, K101E/N/Q, M184 V/I, and V179D/I/A/T/E, ranging from 66.7 to 45.2%. Moreover, two unknown mutations (V75 L and L228R) increased by 19.0 and 11.9% respectively, and they were under positive selection  and were associated with several other DRMs . Deep sequencing of longitudinal plasma samples showed that L228R occurred simultaneously or followed the appearance of Y181C.The high levels of natural polymorphisms in CRF01_AE had little impact on treatment outcomes. The findings regarding potential new CRF01_AE-specific minor DRMs indicate the need for more studies on the drug resistance phenotype of CRF01_AE. At the end of 2017, there were approximately 36.9 million people living with HIV, 59% of whom were receiving antiretroviral therapy (ART) . A studyMost drug resistance genotype data are derived from subtype B HIV-1, which is responsible for about 12% of infections worldwide and is mainly epidemic in North America and Europe . HoweverCRF01_AE is the first reported circulating recombinant form (CRF) of HIV-1 and one of the most influential CRFs in the world , accountThe DRM characteristics of CRF01_AE have been reported in several cross-sectional studies. However, most of these population-based studies assessed the prevalence of transmitted or acquired DRMs among populations –21 or coIn this study, we analyzed the natural polymorphisms of CRF01_AE from a large ART cohort in northeastern China and compared the polymorphisms between patients who experienced TF and those who experienced treatment success (TS). The acquired DRM profile was determined using self-control analyses that involved comparing baseline data to data collected at TF time point. Moreover, the potential role of unknown mutations was explored through co-variation analysis and next-generation sequencing (NGS).pol sequences (HXB2: 2253–3269) obtained by Sanger sequencing based on HIV drug resistance genotyping assays [2Two thousand and thirty-four HIV-1 CRF01_AE-infected patients were selected from a long-term ART cohort (follow-up every 3 to 6 months) at the First Affiliated Hospital, China Medical University in Shenyang between January 2002 and December 2017. Partial HIV-1 g assays  for eachs HXB2: 23–3269 obpol sequences of 2034 CRF01_AE-infected patients at baseline were aligned with reference sequences downloaded from the Los Alamos HIV database (https://www.hiv.lanl.gov/) using the ClustalW tool in Mega v7.0 software, and then were manually edited. The models package in Mega v7.0 was used to determine the best nucleotide substitution model for this dataset. The reference sequences included twelve CRF01_AE strains from Africa and Thailand sampled between 1990 to 2001 and the representative sequences from seven major CRF01_AE lineages in China previously reported [For phylogenetic analysis, the reported . FastTrereported .pol sequences of 42 TF patients at both baseline and TF using Mega v7.0. Bootstrap resampling (1000 datasets) of multiple alignments was performed to test the statistical robustness of the trees with the GTR + G + I nucleotide substitution model. A bootstrap value > 70 was identified as a cluster [A maximum-likelihood tree was reconstructed with the  cluster .https://hivdb.stanford.edu/) and interpreted using the Stanford HIVdb algorithm .DRMs were identified using the Stanford University HIV Drug Resistance Database  analyzed at each site . The mutation rates were also compared between 1148 TS patients and 105 TF patients. The HIV-1 strain HXB2 was used as the reference standard. The sites with a different amino acid (compared to the corresponding site in HXB2), and with a prevalence > 1%, were defined as natural polymorphism sites.The mutation rates of amino acids at sites 1 to 240 of reverse transcriptase (RT) region of the The CorMut package  v1.25.0 pol gene was then amplified by two rounds of nested polymerase chain reaction (PCR) using a KOD-Plus-Neo kit  with the following outer and inner primers, respectively: MAW26/RT-21n (5′-GTATTTCTGCATTAAGTCTTTTGATGG-3′), 3-3F (5′-ACAGTACTAGATGTGGGAGATGC-3′)/3-3R (5′-TATATCATTGACAGTCCAGCT GTC-3′). The reaction conditions are shown in Additional file 3.Longitudinal plasma samples between baseline and TF from four cases with Y181C and L228R mutations were selected. Viral RNA was extracted from the plasma samples using a QIAamp Viral RNA Mini Kit  according to the manufacturer’s protocol and reverse transcribed using a Transcriptor First Strand cDNA Synthesis Kit  with the specific primer Rev2–1 (5′-TCCTGCCATRGRAGATGCCTAA-3′). A 453-bp fragment (HXB2: 2868–3320) in the RT region of the The PCR products were purified with Agencourt AMPure XP beads  and then quantified using a Qubit 3.0 Fluorometer . The fragment length was accurately evaluated using an Agilent 2100 Bioanalyzer . Subsequently, the purified PCR products were adjusted to 2.5 ng/μl and indexed with an adaptor using a TruSeq Nano DNA LT library preparation kit  according to the manufacturer’s protocol. The indexed DNA libraries were analyzed using the Agilent 2100 Bioanalyzer and accurately quantified using a Roche LightCycler® 480 (LC480) Real-Time PCR system  and normalized to 10 nM, then pooled, denatured, and diluted to 15 pM, and finally mixed with 50% PHIX Control Libraries  to create a final volume of 600 μl.http://qiime.org/) in Windows operating system. According to the data quality assessment using FASTQC v0.11.7 software, paired-ended sequences were trimmed by 10–15 bp and truncated to 280–285 bp, and the other parameters were set to the default values. The data were denoised and dereplicated using dada2 plugin v2018.4.0 [Deep sequencing was performed using an Illumina MiSeq System . Oracle VM Virtual Box-5.2.22 software was used to build a virtual environment for running QIIME 2 Core-2018.4  treatment-naïve CRF01_AE-infected patients had transmitted DRMs, with the common DRMs comprising K103 N, G190S, K101E, T215S, K65R, and K219Q. In addition to above DRMs, natural polymorphisms of amino acids with a prevalence > 1% were detected at 53  sites in RT, of which nine sites  were known drug resistance-associated sites. Moreover, 31 sites  in CRF01_AE had higher mutation rates than subtype B HIV-1 strains in the Stanford HIV Drug Resistance Database  . Fifty-one and forty-four natural polymorphism sites in lineages 4 and 5 were detected, respectively, with differences in 35 sites between the two lineages . Both lineages had 26 polymorphism sites with higher mutation rates than in subtype B HIV-1globally , including two known drug resistance-associated sites (sites 179 and 238)  sequences of lineage 4 and 1522 (74.8%) sequences of lineage 5  patients experienced TF. We found 13 sites with differences between TF and TS patients , comprising the polymorphisms at sites 75 and 189, which were only found in TF patients, and the polymorphisms at sites 4, 5, 8, 21, 32, 49, 105, 165, 169, 171, and 204, which were only found in the TS patients. The mutation rate of site 75 in TF patients was significantly higher than in TS patients  . The sequences of the baseline and TF time point from each patient of the 42 TF patients clustered with bootstrap value higher than 85 in the phylogenetic tree . Moreover, a new mutation (L228R) was detected at site 228, a non-DRM site in the Stanford HIVdb algorithm, which increased from 0% at baseline to 11.9% at TF time point . We speculated that both V75 L and L228R might be potential new DRMs in CRF01_AE.Forty-two CRF01_AE-infected patients with TDF/3TC/EFV TF were selected according to the flow chart presented in Additional file Y181C-G190S = 22.86, LOD = infinity). V75 L was correlated with known DRMs G190S , K65R , and M184 V . L228R was correlated with known DRMs G190S  and K65R , and strongly correlated with Y181C   and two potential new DRMs (V75 L and L228R) were demonstrated to be under positive selection pressure . Twenty-eight links were detected among these mutations   were detected, which is even higher than the number of polymorphism sites in CRF01_AE strains mainly from Southeast Asia in a global study on non-B HIV-1 over 10 years ago , 32, andCRF01_AE , suggestCRF01_AE .In this study, the polymorphisms at five known drug resistance-associated sites  were polymorphic accessory mutations or other mutations that did not independently decrease drug sensitivity. None of them were associated with TF. Only V75 L, a low-frequency mutation, was associated with virologic failure, implying that most polymorphisms in CRF01_AE seldom lead to TF. A study on a London cohort in the United Kingdom found that different baseline polymorphisms, including V90I, A98S, and K103R, were associated with virologic failure , but theAt present, two NRTIs plus an integrase strand transfer inhibitor (INSTI) are recommended as a first-line ART regimen for adults in developed countries while, in developing countries like China, two NRTIs plus an NNRTI are still recommended as a first-line ART regimen. In this study, we evaluated the DRM profile of CRF01_AE after TDF/3TC/EFV TF. The most common acquired DRMs among CRF01_AE were K65R, M184 V, G190S/C, Y181C, and K103R, all of which are also common among subtype B and other subtypes. Despite some differences in the mutation type and rate, we cannot confirm that the differences were caused by the various subtypes , 37.More importantly, we detected two mutations with significant increases but without annotation in the Stanford HIVdb algorithm, V75 L and L228R. Site 75 is a drug resistance-associated site but no explanation for V75 L is provided in the Stanford HIVdb algorithm. The V75 L mutation has been reported to provide a selective advantage by allowing escape from the host immune responses  and it iThis study had several limitations. First, due to the high success rate of ART in this cohort, only a small number of TF patients could be included in the acquired DRM analysis. Second, the impact of the L228R mutation with or without Y181C needs further validation using virus growth competition and drug resistance phenotype assays. Nevertheless, this study provided more evidence of polymorphisms and DRMs in the non-B HIV-1 strain CRF01_AE.In summary, the high levels of polymorphisms in CRF01_AE had little impact on treatment outcomes, but some unknown mutations associated with TF might be minor DRMs. The results of this study indicate the need for more studies on drug resistance in non-B HIV-1, especially phenotypic studies to strengthen the drug resistance genotype interpretation, and to improve ART efficacy and minimize the transmission of drug-resistant strains.Additional file 1:Figure S1. Flow chart of selection and analysis.Additional file 2: Demographic and clinical characteristics of participants in this study.Additional file3: Reaction conditions of cDNA synthesis and amplification of the target fragment.Additional file 4: Figure S2. Phylogenetic analysis of the CRF01_AE HIV-1 pol sequences.Additional file 5:Figure S3. Phylogenetic analysis of the 42 TF CRF01_AE-infected patients.


Syphilis has been associated with an increase in HIV RNA and a temporary decline in CD4 T cell counts in people living with HIV who are not receiving antiretroviral treatment (ART), and may be associated with a transient HIV RNA rebound in those who are receiving ART. Our case is the first to highlight the risk of a multidrug-resistant HIV viral rebound during the course of early syphilis even if antiretroviral drug concentrations are within the therapeutic range.This 50-year-old HIV-1-positive male patient with concomitant early syphilis presented with an HIV RNA rebound (8908 copies/mL) during a scheduled visit to our clinic. He was receiving a stable ART regimen consisting of darunavir/cobicistat plus dolutegravir, and had a 15-year history of viral suppression. Good short-term drug adherence could be inferred as liquid chromatography tandem mass spectrometry showed that his trough antiretroviral drug concentrations were within the therapeutic range: darunavir 2353 ng/mL (minimum effective concentration > 500 ng/mL) and dolutegravir 986 ng/mL (minimum effective concentration > 100 ng/mL). A plasma RNA genotype resistance test revealed wild-type virus in the integrase region and protease region (PR), but extensive resistance in the reverse transcriptase (RT) region . Phylogenetic analysis of next-generation sequences , the PR and RT sequences from plasma HIV RNA and pro-viral DNA extracted from peripheral blood mononuclear cells during the viral rebound, and a Sanger sequence obtained during a previous virological failure suggested clonal viral expression because the previous PR resistance mutations had been lost or had not been archived in pro-viral DNA.This case shows that early syphilis may cause an HIV RNA rebound in patients under stable virological control with the potential of transmitting an extensively drug-resistant virus. There has recently been an increase in the incidence of sexually transmitted diseases (STDs) among men who have sex with men (MSM), whether they are people living with HIV/AIDS (PLWHAs) or the recipients of pre-exposure prophylaxis (PrEP) , 2. SyphWe here describe the case of an HIV-infected MSM with early syphilis experiencing a viral rebound and showing extensive resistance in the reverse transcriptase (RT) region. This is the first case to highlight the risk of an HIV multidrug-resistant viral rebound during early syphilis even when antiretroviral drug concentrations are within the therapeutic range.During a scheduled visit in September 2018, a 50-year-old MSM with early syphilis infection, who had tested positive for clade B HIV-1 in December 1991 and had subsequently been regularly followed up at our centre, was found to be affected by an HIV RNA rebound (8908 copies/mL). Figure At the time of the viral rebound, the patient’s syphilis was considered to be in an early stage as a rapid plasma reagin (RPR) test within 12 months of the index event was negative after treatment with benzathine penicillin for primary syphilis infection (RPR titre down from 1:32 to < 1:1 in March 2015), but the titre had increased to 1:4 in December 2017. Moreover, the patient reported that he had had multiple condomless, insertive/receptive anal intercourses in the previous months.After being purified by means of solid-phase extraction, the plasma sample used to quantify his HIV RNA viral load (handled on ice and stored at − 20 °C) was used to determine trough antiretroviral drug concentrations by means of liquid chromatography tandem mass spectrometry. The results indicated good short-term adherence to the prescribed ART as the trough concentrations were within the therapeutic range . Furthermore, all of the previous assessments of the trough concentrations of both drugs  had always shown levels within the therapeutic range, which provides indirect evidence of long-term treatment compliance.Viral rebound was assessed by means of genotype resistance tests . The test of plasma RNA showed wild-type virus in the PR and integrase region, but extensive resistances in the RT region , and the test of plasma DNA showed the same resistance profile. In order to investigate the presence of minor viral variants, next-generation sequencing analysis (NGS) of the same samples  revealed the presence of PR variants in < 1.0% of the viral population in the plasma RNA sample (DNA data are not available because of a failure in the amplification process). Phylogenetic analyses of Sanger PR and RT sequences obtained from plasma HIV RNA and pro-viral DNA extracted from peripheral blood mononuclear cells during the viral rebound, and a sequence obtained from the same patient during a previous VF in 2002 revealed close correlations, especially between the RNA and DNA samples simultaneously collected in 2018  is increasing among MSM worldwide , 2, and Conversely, Grewal et al. did not observe an increased risk of VF in a Canadian cohort of PLWHA MSM with acute syphilis who were receiving effective ART: the overall incidence of VF was 3.5/100 person-years  and, as there was no statistically significant association with acute syphilis, the authors concluded that ART may still reduce the risk of transmitting HIV to sexual partners . HoweverOur phylogenetic analysis reasonably excluded the possibility that the mutations observed during our patient’s viral rebound were due to HIV super-infection , 14, butAt the time of the viral rebound, our patent had trough concentrations of antiretrovirals within the therapeutic range. As therapeutic drug monitoring (TDM) can only provide evidence of short-term compliance to treatment, we cannot exclude the possibility that he may not have been compliant in the weeks before the event. However, he was regularly followed up at our clinic and all of the previous TDM assessments (made at least twice a year) also showed therapeutic drug concentrations, thus indirectly suggesting long-term adherence.Our case suggests that early syphilis can cause an albeit time-limited rebound of HIV viremia in patients with self reported good adherence to ART and antiretroviral trough concentrations within the therapeutic range. The HIV RNA levels reached during the rebound are consistent with a high rate of HIV transmission , and the


Although the association between human immunodeficiency virus (HIV) and mucocutaneous diseases has been well studied within South African specialist centres, there is limited data from district-level hospitals. Available data may, therefore, fail to reflect the prevalence and full spectrum of dermatoses seen in people living with HIV (PLWH).To determine the prevalence and spectrum of dermatoses seen in PLWH.We conducted a cross-sectional, descriptive study of 970 PLWH  accessing care at Karl Bremer Hospital, a district-level hospital located in the Western Cape province, South Africa, between 01 September 2016 and 28 February 2017.The prevalence of mucocutaneous disease in this sample was 12.7% . Non-infectious dermatoses comprised 71.0% of the disorders. Pruritic papular eruption (20.0%) and seborrheic dermatitis (6.0%) were the most common non-infectious dermatoses. Tinea corporis (8.0%) and oral candidiasis (6.0%) were the most prevalent infectious dermatoses. There was no significant association between skin disease category (infectious or non-infectious dermatoses) and patient demographics (gender and ethnicity) or HIV-disease characteristics .This study provides valuable scientific data on the prevalence and spectrum of mucocutaneous disease in PLWH attending a South African district-level hospital. Prospective studies conducted in other district-level centres across the country are required to determine the lifetime prevalence and spectrum of dermatoses in PLWH in the ART era. Skin diseases are common and well described in the HIV-positive population and may affect up to 90% of individuals during the course of their illness.5 Several of the HIV-associated dermatoses have declined during the ART era, but certain drug reactions and inflammatory skin conditions have increased.6 Management of PLWH in the ART era includes addressing common non-infectious dermatoses in addition to rare opportunistic infections and infection-associated malignancies.5Antiretroviral therapy (ART) has altered the natural progression of HIV infection, leading to immune reconstitution through the suppression of viral replication and the recovery of the CD4+ cell count. As a result of ART, PLWH are living longer and healthier lives with a near-normal life expectancy.7 South African studies performed before the roll-out of ART described the cutaneous manifestations of HIV.10 Following the launch of ART, studies placed more emphasis on severe cutaneous adverse drug reactions and dermatoses that occur in the setting of tuberculosis (TB) co-infection.12 Although the existing body of literature provides valuable insights into dermatoses more likely to occur at advanced stages of immunosuppression, it does not sufficiently describe the full spectrum and prevalence of all mucocutaneous diseases occurring in PLWH. This is because most prior studies were performed at specialist and tertiary-level hospitals, and there is limited data available from district-level hospitals.Of the 7.2 million PLWH residing in South Africa, an estimated 61% were accessing ART in 2017.13 Furthermore, most PLWH are cared for at primary and district-level healthcare facilities where they may present with common skin diseases that can be diagnosed and treated at the primary healthcare level. Overall, data from studies performed at tertiary referral centres could overestimate certain dermatoses and fail to represent the full spectrum of dermatoses seen in the majority of PLWH attending non-specialist centres.This limitation may have biased current knowledge and understanding regarding the spectrum and prevalence of dermatoses amongst PLWH. For example, studies performed at tertiary referral centres are more likely to include dermatoses that warrant inpatient management, such as inflammatory dermatoses, erythroderma and severe cutaneous drug reactions.This oversight may have important implications for the prescribed standard of care for PLWH at a district level. Therefore, to ensure that appropriate prevention and treatment strategies are implemented, there is a need to fully describe cutaneous diseases being treated at this level. Therefore, this study aimed to determine the prevalence and spectrum of HIV-related skin diseases at a South African primary healthcare facility. We additionally aimed to assess any possible associations between patient characteristics and dermatoses.This descriptive and cross-sectional study was conducted at the adult HIV clinic at Karl Bremer Hospital (KBH), Cape Town, South Africa, between 01 September 2016 and 28 February 2017.Karl Bremer Hospital is a publicly funded district-level hospital. It serves a heterogeneous patient population of low- to middle-income status. The HIV clinic is a division of the outpatient department and is operated by a nurse, two counsellors and a medical officer. Patients who require specialist dermatology care are referred to Tygerberg Hospital, which is a tertiary hospital in the vicinity.10 Herpes zoster was the most common cutaneous manifestation (19%) and opportunistic fungal infections were reported to be least prevalent conditions (3%). Using OpenEpi software (www.openepi.com), an expected prevalence of 10%, a 2% level of precision and a confidence interval (CI) of 95%, we calculated the required sample size to be 864. We considered this number to be sufficient to describe the spectrum of skin diseases in patients attending the HIV clinic with a high level of precision. During the 6-month study period, 970 patients were screened, of which 123 had skin disease and thus they were invited to participate in the study. The final sample comprised 100 patients who provided informed consent.All PLWH  seeking routine care at the HIV clinic at KBH were eligible to participate in the study. We included patients receiving ART and those awaiting ART commencement. We estimated an appropriate sample size using data provided in a previous study that reported the prevalence of cutaneous manifestations of HIV at a tertiary dermatology outpatient centre in KwaZulu-Natal (before the roll-out of ART).µL or ≥ 200 cells/µL), viral load (recorded as undetectable or detectable) and ART regimen (type and duration). Antiretroviral therapy was defined as a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir-boosted protease inhibitor (PI).A data collection sheet was completed by the medical officer (author S.C.) working at the HIV clinic for all participants who signed informed consent. Data recorded included demographics, body mass index (BMI), recent (within the preceding 6 months) CD4+ cell count , whilst nominal variables were summarised as counts and percentages. Pearson’s chi-square test was used to assess the possible association between skin disease category and patient demographics (gender and ethnicity) or HIV disease characteristics . Data were analysed using STATA  and statistical significance was set at Ethical approval was obtained from the Health Research Ethics Committee of Stellenbosch University (N16/05/071). The study was also approved by the management of Karl Bremer Hospital. Participation was voluntary and all participants provided written informed consent to take part in the study. All data were anonymised to ensure the privacy and confidentiality of participants’ personal information and each participant was assigned a unique identifier.N = 100 patients who provided informed consent) are summarised in µL (69%) and were on ART (74%). Of those participants on ART (n = 74), most  were on an NNRTI-based regimen, whilst nine (12.2%) participants were on a PI-based regimen. Most patients  had been on ART for more than a year. One-third of the sample (35%) had a normal weight (BMI 18.5–24), 24% were overweight (BMI 25–30) and 14% were obese (BMI > 30). Very few patients (7%) were classified as being underweight (BMI < 18.5). We were unable to calculate the BMI for 20 patients because of missing weight or height statistics in patient folders.We observed mucocutaneous disease in 123 patients out of a total of 970 who were screened, which is equivalent to a prevalence of 12.7% (95% CI 0.11–0.15). The demographic and clinical characteristics of the sample , followed by viral  and bacterial infections . Fungal infections included oral candidiasis (n = 6), pityriasis versicolor (n = 4), intertriginous candidiasis (n = 1) and a spectrum of dermatophytosis (n = 17), namely, tinea corporis (n = 8), onychomycosis (n = 5) (n = 3) and tinea faciei (n = 1). Overall, tinea corporis (8.0%) and oral candidiasis (6.0%) were the most prevalent of all infectious conditions. Bacterial infections included ecthyma (n = 3), folliculitis (n = 2), cellulitis (n = 1), impetigo (n = 1) and secondary syphilis (n = 1), whilst viral infections included condylomata acuminata (n = 4), herpes zoster (n = 2), molluscum contagiosum (n = 2), orolabial herpes simplex (n = 2), anogenital herpes simplex (n = 1), generalised verrucosis (n = 1), oral hairy leukoplakia (n = 1) and viral exanthem (n = 1).Infectious dermatoses affected half of the participants in the sample. Fungal infections were the most prevalent ( (n = 5) , tinea pn = 50) and included pruritic papular eruption (PPE) (n = 20) (n = 6), angular cheilitis (n = 4), atopic dermatitis (n = 4), contact dermatitis (n = 4), insect bite reaction  (n = 4), dermatitis not otherwise specified (n = 3), chronic paronychia (n = 2), eosinophilic folliculitis (n = 2) and acne vulgaris (n = 1). Neoplastic conditions (n = 5) included actinic keratosis (n = 1), anal squamous cell carcinoma in situ (n = 1), basal cell carcinoma (n = 1) (n = 1) and seborrheic keratosis (n = 1). Drug-related dermatoses (n = 2) included steroid-induced rosacea (n = 1) and zidovudine-induced mucocutaneous hyperpigmentation (n = 1). Other dermatoses (n = 14) included post-inflammatory hyperpigmentation (n = 4), xerosis (n = 4), keloids (n = 3), vitiligo (n = 2) and palmoplantar keratoderma (n = 1).Non-infectious dermatoses affected 71.0% of the sample. Of the non-infectious dermatoses, inflammatory dermatoses were the most common ((n = 20) , seborrh (n = 1) , cutaneop = 0.36; ethnicity, p = 0.31; BMI, p = 0.61) or HIV disease characteristics .Pearson’s chi-square test showed no significant association between skin disease category (infectious and non-infectious diseases) and patient demographics  and had a CD4+ cell count above 200 (69%) at the time of the study.Kore et al. found that the proportion of HIV-infected patients having dermatoses increased with immunological worsening and that the average number of skin disorders per patient was significantly higher in patients with a CD4+ cell count less than 200 cells/9 However, studies in the ART era have persistently shown the spectrum of skin diseases shift from infectious to non-infectious dermatoses.22Non-infectious dermatoses were the most common group of mucocutaneous manifestations in our study. Inflammatory dermatoses were the predominant non-infectious dermatoses. Inflammatory dermatoses in the setting of HIV tend to be chronic, atypical and difficult to treat and, therefore, frequently warrant referral to specialist centres where the prevalence might be overestimated. This could explain why inflammatory dermatoses related to HIV  were the most common dermatologic cause of admission in a South African study performed in the pre-ART era.24 Two Ugandan studies have suggested that PPE may be related to an exaggerated immunological reaction to arthropod bites.25 The prevalence of PPE in our study may be attributed to its chronicity, its association with increased levels of immunosuppression (one-third of our study population had a CD4+ cell count below 200) and poor socio-economic conditions, which predispose patients to arthropod bites.21In our study, the increased prevalence of inflammatory dermatoses was mainly attributed to PPE (20%) and seborrheic dermatitis (6%). The reported prevalence of PPE in the literature ranges from 11% to 46%.26 Studies from China, India and the United States of America performed in the ART era have reported low prevalence rates of seborrheic dermatitis at 1.21%, 1.8% and 10.6%, respectively.27 Likewise, the prevalence of seborrheic dermatitis in our study is similar to that of the HIV-negative population and may be attributed to the influence of ART.Seborrheic dermatitis (6%) was the second most common inflammatory dermatosis in our study. The prevalence of seborrheic dermatitis has been reported to be 40% in HIV-positive patients and as high as 80% in acquired immunodeficiency syndrome (AIDS) patients in comparison with 3% in the HIV-negative population.28 Basal cell carcinoma and squamous cell carcinoma comprise the keratinocyte carcinomas and are the most common malignancies worldwide in both the general population and PLWH.29 The spectrum of neoplastic conditions observed in this study comprised benign epidermal neoplasms and keratinocyte carcinomas. Condylomata acuminata were observed in four patients, one of whom had concomitant anal squamous cell carcinoma in situ. Anal cancer (a human papillomavirus-related cancer) has been associated with the duration of both immunodeficiency and viral replication.29 As a result of increased life expectancy, cancer-specific screening programmes in HIV-infected patients should be extended to include non-AIDS-defining cancers such as anal cancer and keratinocyte cancer.Neoplastic conditions were recorded in 5% of the study population. Since the introduction of ART, the incidence of AIDS-defining cancers  has decreased, whereas the relative frequency of non-AIDS-defining cancers has increased.18 A study performed in a tertiary hospital in Cape Town, South Africa, found that most severe skin reactions resulting in admission occurred during the first 2 months after combination ART initiation. Nevirapine and pregnancy are also known to be strongly associated with severe skin reactions.13 Most of the participants receiving ART had been on treatment for more than 1 year and all those receiving an NNRTI-based regimen were taking efavirenz and not nevirapine. This could explain the absence of severe cutaneous adverse drug reactions in our study. None of the female participants was pregnant at the time of the current study. Lastly, patients presenting with severe skin reactions mostly necessitate inpatient management and referral to tertiary institutions and may not present directly to a district-level health facility.Drug-related dermatoses were observed in 2% of our study population and included steroid-induced rosacea and zidovudine (AZT)-induced mucocutaneous hyperpigmentation. In this study, no patients presented with severe cutaneous adverse drug reactions such as Steven–Johnson syndrome, toxic epidermal necrolysis or drug hypersensitivity syndrome. International studies in the ART era have reported a prevalence of drug eruptions between 10% and 17%.30 Dermatophytosis was recorded in 17% of our patients, which is in line with other studies performed in the ART era reporting a prevalence between 11.9% and 17.6%.21Infectious dermatoses were observed in half of our study population and were encountered less frequently than non-infectious dermatoses. Tinea corporis (8%) and oral candidiasis (6%) were the two most common conditions in the infectious dermatoses group. Dermatophytosis  is common in the setting of HIV and tends to occur as an early manifestation of immunosuppression at higher CD4+ cell counts.15 Kore et al. and Han et al. demonstrated a significant decline in candidiasis in their study population after the initiation of ART (20.8% vs. 11.5% and 64.04% vs. 16.6%).20 The majority of participants in our study were on ART and had a CD4+ count above 200. These factors, together with an increased awareness and early treatment of oral candidiasis, could likely explain its low prevalence.Although oral candidiasis was one of the most common dermatoses recorded in our study, its prevalence is low compared with previous studies. The incidence of candidiasis has been shown to increase with a CD4+ cell count below 200.10 In general, PLWH in the ART era are increasingly older and have a near-normal life expectancy.31 Our findings are similar to those in a recent study performed at a specialised TB hospital in the Western Cape, which reported a mean age of 37 years in patients co-infected with TB and HIV.12 Historically, ART eligibility criteria in South Africa allowed for pregnant women to be initiated on ART at higher CD4+ cell counts compared with the general adult HIV-positive population.32 The routine surveillance of HIV during antenatal care may explain the increased proportion of females in this study as maternal services form an important referral pathway for ART services.The mean age of our study participants was 40 years, which is approximately 6 years older than that previously recorded in South African studies evaluating cutaneous manifestations of HIV in the pre-ART era.Our study has some limitations. Firstly, we emphasise that the accurate diagnoses of dermatoses can be challenging in HIV-positive patients because of the atypical presentation of skin disorders. Secondly, because of the cross-sectional nature of the study, the true prevalence of skin conditions in this study population may be underestimated. Long-term follow-up studies, as opposed to cross-sectional studies, are required to understand the true lifetime prevalence and spectrum of dermatoses in HIV-positive patients in the ART era. Thirdly, there could be an underestimation of dermatoses because none of the patients were examined by a dermatologist. Having a dermatologist see the patients primarily or using clinical photographs to verify the diagnosis of all skin conditions would have provided a more accurate presentation of dermatoses. Fourthly, our findings could be limited by self-report bias. Patients may be reluctant to mention minor skin complaints that do not interfere with daily functioning or cause cosmetic concern to avoid unnecessary time spent at the clinic.This study provides valuable scientific data on the prevalence and spectrum of mucocutaneous disease seen in PLWH attending a district-level hospital in South Africa. These findings could guide the development of training opportunities for primary healthcare workers to better manage the most prevalent HIV-associated dermatoses. This, in turn, may help to decentralise health services and improve the quality of care at primary and district levels. More studies performed outside tertiary-level hospitals are needed to provide insights into the true spectrum and prevalence of dermatoses affecting PLWH in the ART era.


The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS).Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014–2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen).We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients  changed due to virological failure.EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads. Treatment adherence is crucial for the effectiveness of antiretroviral therapy (ART) among HIV-infected patients. Adherence could be impaired with antiretroviral regimens that entail multiple pills or more than once-daily dosing ; this is®) and elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine  have been extensively used for the treatment of HIV-infected adults [The fixed-dose combinations elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine /emtricitabine plus darunavir 800 mg (EVG/COB/TFV/FTC + DRV) and analyse its effectiveness and tolerability in the multicentre Cohort of the Spanish HIV/AIDS Research Network (CoRIS). The specific objectives of the study were: (1) to describe the patients initiating EVG/COB/TFV/FTC + DRV and the reasons for starting this regimen, (2) to describe the toxicity of this regimen among patients who stopped it due to adverse events, and (3) to describe the effectiveness of EVG/COB/TFV/FTC + DRV in terms of viral suppression and change in CD4 count at 24 and 48 weeks after starting this regimen.Patients were selected from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS), which has been described in detail elsewhere , 13. CoRWe included all treatment-experienced patients who started treatment with EVG/COB/TFV/FTC + DRV from January 2014 to November 2018 and who had more than 24 weeks of follow-up. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide.We collected information on the following variables: age, sex, mode of HIV transmission , country of origin , CD4 count and viral load at the start of EVG/COB/TFV/FTC + DRV and at 24 and 48 weeks after starting this regimen (± 12 weeks), reasons for stopping the previous treatment and EVG/COB/TFV/FTC + DRV  and regimen to which it was switched, previous antiretroviral regimens, number of pills and doses per day with the previous antiretroviral regimen, and time since the start of the first ART.Descriptive analyses were carried out using frequency tables for categorical variables and median and interquartile range (IQR) for continuous variables. For the analysis of treatment effectiveness, the primary endpoint was the proportion of patients with virological response, defined as viral load < 50 copies/ml at 24 and 48 weeks after starting EVG/COB/TFV/FTC + DRV. Since the threshold of 200 copies/ml is used in several guidelines to define virologic failure , 15, we Statistical analyses were performed in Stata software . All patients signed informed consent forms. The study was approved by the Ethics Committee of Instituto de Salud Carlos III (Madrid).During the study period, 39 patients from 11 centres switched their ART to the regimen EVG/COB/TFV/FTC + DRV. Patients’ demographic and clinical characteristics are shown in Table At baseline, 10 (25.6%) patients were virologically suppressed and 29 (74.4%) patients had detectable viral load. The most frequent reasons for changing to this regimen were virological failure and treatment simplification (Table The patients received EVG/COB/TFV/FTC + DRV for a median of 391 IQR: 205 to 514) days. Outcomes at 24 and 48 weeks are shown in Table 05 to 514Among virologically suppressed patients at baseline, 85.7% and 80.0% of the patients achieved viral load < 50 copies/ml at 24 and 48 weeks, respectively. However, among patients with detectable baseline viral load, only 42.3% and 40.9% achieved these endpoints, respectively. The percentages of patients achieving viral load < 200/ml at 24 and 48 weeks were higher for both groups and reached 100% among the patients who were virologically suppressed at baseline.The number of patients who changed their treatment during the first 24 and 48 weeks, stratified by baseline viral load, is shown in Table This study has analysed the largest cohort published to date showing results from “real-world” clinical practice with the regimen EVG/COB/TFV/FTC + DRV. In our study, EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with baseline undetectable viral load as a simplification strategy, allowing a once-daily, two-pill regimen with three antiretroviral drug classes. However, effectiveness was low in patients with baseline detectable viral loads.There is only one open-label clinical trial that assessed the efficacy of this regimen, which analysed 135 treatment-experienced, virologically suppressed patients who were randomized to continue their previous ART or change to EVG/COB/TAF/FTC + DRV. The study found that this combination had high efficacy (96.6%) and was noninferior to maintaining the previous ART at 24 weeks and superior at 48 weeks . HoweverRegarding real-world data, the evidence for the effectiveness of this regimen is very limited: only three cohort studies have been published analysing EVG/COB/TDF/FTC + DRV, all from single centres, involving a very low number of patients, and analysing different endpoints. The effectiveness was high in the three studies: Naccarato et al. evaluated 21 treatment-experienced patients  who received EVG/COB/TDF/FTC + DRV: at week 48, 14 67%) patients had undetectable viral load, 1 had virologic failure (> 40 copies/ml) and 6 had stopped the treatment or had no viral load data . Harris 7% patienIn our study, the effectiveness of EVG/COB/TFV/FTC + DRV was high in patients who were virologically suppressed at baseline: 85.7% and 80.0% of the patients had viral loads < 50 copies at 24 and 48 weeks, respectively, and 100% of the patients had viral loads < 200 copies/ml at 24 and 48 weeks. These results are comparable to the studies mentioned above. However, the effectiveness was much lower for patients who had detectable viral loads at baseline. These results suggest that this regimen has high effectiveness as a switch strategy for virologically suppressed patients, but it should not be used in patients with virological failure if other alternatives exist. Overall, the treatment was well tolerated in both groups, as none of the patients discontinued their treatment due to toxicity. The treatment also allowed to decrease the pill burden in 43.6% of the patients and the number of doses per day in 28.2%.For the combination EVG/COB/TFV/FTC + DRV, our patients were receiving tenofovir either as alafenamide or as disoproxil fumarate. Also, as EVG/COB/TAF/FTC was commercialized in Spain in May 2016, many patients who were receiving EVG/COB/TDF/FTC changed their treatment to EVG/COB/TAF/FTC in order to minimize the risk of renal and bone toxicity, as did 8 of our patients. Given that the treatment with EVG/COB/TAF/FTC has shown non-inferiority compared to EVG/COB/TDF/FTC in clinical trials , 4, we hOur study has the limitation of low sample size. Also, since CoRIS does not routinely record resistance testing in pre-treated patients, we could not describe accumulated resistance mutations or those arising after failure with this regimen. Another limitation is that we cannot give information on patients’ adherence as CoRIS does not routinely record this variable. However, this is the largest cohort published to date analysing this treatment regimen, with a reasonable follow-up time, and it gives information from routine clinical practice for a combination that could be potentially useful for treatment simplification and has very little published evidence. Our strengths include the use of a multicentre cohort with rigorous quality control and which has clinical and demographic characteristics that are similar to the ones from the general population reported by the National HIV Surveillance System .The combination EVG/COB/TFV/FTC + DRV is an effective, well tolerated strategy for treatment simplification in virologically suppressed patients. This treatment is not suitable, however, for treatment-experienced individuals with detectable viral loads, given the low efficacy in this group of patients.


The Treat‐All policy – antiretroviral therapy (ART) initiation irrespective of CD4 cell criteria – increases access to treatment. Many ART programmes, however, reported increasing attrition and viral failure during treatment expansion, questioning the programmatic feasibility of Treat‐All in resource‐limited settings. We aimed to describe and compare programmatic outcomes between Treat‐All and standard of care (SOC) in the public sectors of Eswatini.3 treatment eligibility thresholds. Kaplan‐Meier estimates were used to describe crude programmatic outcomes. Multivariate flexible parametric survival models were built to assess associations of time from ART initiation with the composite unfavourable outcome of all‐cause attrition and viral failure.This is a prospective cohort study of ≥16‐year‐old HIV‐positive patients initiated on first‐line ART under Treat‐All and SOC in 18 health facilities of the Shiselweni region, from October 2014 to March 2016. SOC followed the CD4 350 and 500 cells/mm3 compared with 292 (IQR 161 to 430) (p < 0.001) under SOC. Although crude programme retention at 36 months tended to be lower under Treat‐All (71%) than SOC (75%) (p = 0.002), it was similar in covariate‐adjusted analysis . The hazard of viral suppression was higher for Treat‐All , while the hazard of viral failure was comparable . Among patients with advanced HIV disease (n = 1080), those under Treat‐All  had a similar risk of an composite unfavourable outcome to SOC. Factors increasing the risk of the composite unfavourable outcome under both interventions were aged 16 to 24 years, being unmarried, anaemia, ART initiation on the same day as HIV care enrolment and CD4 ≤ 100 cells/mm3. Under Treat‐All only, the risk of the unfavourable outcome was higher for pregnant women, WHO III/IV clinical stage and elevated creatinine.Of the 3170 patients, 1888 (59.6%) initiated ART under Treat‐All at a median CD4 cell count of 329 (IQR 168 to 488) cells/mmCompared to SOC, Treat‐All resulted in comparable retention, improved viral suppression and comparable composite outcomes of retention without viral failure. ART initiation and follow‐up care were performed by nurses in primary care clinics and supported by onsite medical doctors in secondary care outpatient departments. Patients usually had a baseline CD4 cell count and laboratory test , creatinine). The CD4 result was not a requirement for ART initiation under Treat‐All. Routine viral load (VL) monitoring was available . We chose this end point because the vital status was not actively ascertained in both interventions. LTFU was defined as six months without a clinic visit measured from the last clinic visit. Follow‐up time was censored at database closure (31 October 2017) or date of transfer out of the facility. Then we describe VL testing uptake (the probability of receiving at least one VL test) and viral suppression, defined as the proportion of VLs < 1000 copies/mL among patients with a first VL measurement recorded. Finally, viral failure was compared, defined as two consecutive VLs ≥ 1000 copies/mL measured at least five months after ART initiation and performed ≥1.5 months apart or treatment switching to a protease inhibitor based regimen with two new drugs in the absence of documented viral failure. All viral load outcomes were measured from five months after ART initiation.3 and/or WHO III/IV clinical staging.Third, Treat‐All aims to retain patients on virally suppressed ART to improve patient level outcomes and reduce transmission of HIV. Accordingly, we established a composite primary endpoint of death, LTFU and viral failure. To assess whether the unfavourable outcome was more likely to occur in the Treat‐All zone, we compared the interventions directly, first for the entire cohort and then restricted to patients presenting with advanced HIV disease defined as CD4 < 200 cells/mmFinally, we conducted separate analyses of the composite primary endpoint for both models of care to assess possible varying patterns of associations with Treat‐All and SOC during the implementation of different treatment guidelines.All data were collected by trained data clerks from individual‐level clinic records and paper registers, and entered into EpiData software. VL and TB data were complemented with data from separate electronic databases used for routine programme monitoring.2.4Baseline characteristics and crude programmatic outcomes were described with frequencies and proportions, and compared using the Pearson's chi‐squared test for categorical variables and Wilcoxon's rank‐sum test for continuous variables. Kaplan‐Meier estimates were used to describe retention, VL testing uptake and viral failure.Variables for inclusion in multivariate analyses were selected a priori based on clinical relevance and literature review. We used multiple imputation by chained equations 2.5This study was approved by the Scientific and Ethics Committee of Eswatini, the Research Ethics Committees of MSF and the University of Cape Town, South Africa. Informed written consent was obtained before ART initiation from patients in Treat‐All who were ineligible for ART according to the national SOC.33.13.1.1p < 0.001). The difference was highest for non‐pregnant adults in period‐1 when SOC applied the CD4 ≤ 350 treatment eligibility threshold .Figure 3.1.23 and WHO clinical stage I/II  patients presented with advanced HIV disease, of whom 620 (57.8%) were under Treat‐All. Distribution of baseline factors is presented in Table II Table .3.2The frequency of the outcomes is presented in Figure 3.2.1p < 0.001), younger patients (16 to 24 years) (p < 0.001) and those with low CD4 cell count (≤100 cells/mm3) (p = 0.005) tended to have had lower retention     Figure . Overall3.2.2p = 0.555) . In multivariate analysis, the hazard of viral suppression was higher for Treat‐all  than SOC (model not shown) . The cumulative 3‐year hazard of viral failure was 4% under Treat‐All and 3% under SOC (p = 0.690)  , time to first VL test was similarly low and delayed in both health zones at 6  and 36 months   Table  and for 2, haemoglobin ≤9 g/dL, creatinine ≥121 µmol/L and being unmarried. The hazard was higher for the entire cohort only for the CD4 strata ≤200 cells/mm3 (vs. CD4 201 to 350), WHO clinical stage III/IV (vs. WHO stage I), age 16 to 24 years (vs. 25 to 49 years) and shorter time since HIV care enrolment. The hazard of the unfavourable outcome varied over time for TB, with lower hazard during the first nine months after ART initiation and similar hazard thereafter   and lower for the later implementation period . Under Treat‐All only, the hazard was higher for pregnant women , WHO staging III/IV  (vs. WHO stage I) and elevated creatinine ≥121 µmol/L .Under SOC only, the hazard was higher for low BMI < 18.5 kg/mIn supplementary analysis, including health facility as a co‐variate instead of primary versus secondary care level, two primary care facilities under Treat‐All and one primary care facility under SOC showed an increased hazard of an unfavourable outcome when compared with the secondary care facility at each health zone Figure .4This study assessed programmatic and patient outcomes of universal ART provision (Treat‐All) in a predominantly rural public sector setting in Eswatini. Compared to SOC, Treat‐All resulted in comparable retention, improved viral suppression and comparable composite outcomes of retention without viral failure, after adjusting for differences between patients accessing each service. Although crudely a higher proportion of patients were lost to care under Treat‐All, this service also enrolled more patients with higher CD4 counts 4.13, a pattern confirmed by two other Treat‐All trials 3Similarly to other settings 3), possibly explained by concurrent expansion of treatment eligibility criteria under SOC during the study period. Pregnant and lactating women were already eligible for prompt ART (PMTCTB+) under SOC and treatment eligibility for non‐pregnant adults was expanded from ≤350 to ≤500 cell/mm3. Restricting analysis to non‐pregnant adults under period‐1 (WHO 2010 treatment guideline implementation), the difference in median CD4 cell count increased to 73.5 cells/mm3.Overall, the median CD4 cell count at ART initiation was only slightly higher under Treat‐All  showed a lower risk of an unfavourable outcome under SOC. Temporal trends have also been reported from other settings 3, covariate‐adjusted analysis indicated that the risk was similar under Treat‐All and SOC. In addition, TB co‐infection emerged as a protective factor during early treatment. As per national guideline recommendations, co‐infected patients may have received more attention by health workers given their high risk of mortality, resulting in less loss to care. Although median CD4 cell count increased during ART programme expansion internationally WHO emphasizes that patients in greatest need of ART should not be de‐prioritized during treatment scale‐up 4.2Overall retention was comparable to ART programmes in low‐ and middle‐income countries While VL testing uptake was low and delayed in both health zones, crude viral suppression tended to be slightly higher under Treat‐All and comparable to other settings 4.3p < 0.001) in this setting First, our estimates of ART retention are conservative. Previous studies showed that transient treatment interruptions and movements between clinics are common and many patients recorded with LTFU are retained Despite the wide‐scale adoption of Treat‐All in RLS 5Compared to SOC, Treat‐All resulted in comparable retention, improved viral suppression and comparable composite outcomes of retention without viral failure. Patients with advanced HIV disease were possibly not de‐prioritized and predictors of unfavourable outcomes were comparable between Treat‐All and SOC. This study contributes to evidence that treatment expansion through the Treat‐All programmatic approach may be feasible in RLS without increasing unfavourable outcomes, and as such is likely to have public health benefits.The authors declare no conflict of interest.BK, KJ and RT designed the study. BK, KJ and SMK established the cohort and were involved in data acquisition. BK, MS, AB and IC led the data analysis plan and SMK, EM, SMH and BR contributed to the analysis. BK performed the statistical analyses and wrote the first draft of the manuscript. MS, AB and IC advised on final analyses. BK, MS, KJ, SMK, RT, EM, SMH, BR, IC and AB interpreted the data, contributed to the writing of the manuscript and approved the final version.aHR, Adjusted hazard ratio; ALT, Alanine aminotransferase; ART, Antiretroviral therapy/treatment; BMI, Body mass index; CI, Confidence interval; EFV, Efavirenz; IQR, Interquartile range; LTFU, Loss to follow‐up; PMTCT B+; Prevention of mother‐to‐child transmission option B+; RLS, Resource‐limited setting; SOC, Standard of care; TB, Tuberculosis; TDF, Tenofovir disoproxil fumarate; VL, Viral load; WHO, World Health Organization.Table S1. Complete and missing values for covariate and imputation procedures.Table S2. Distribution of CD4 cell count and WHO clinical staging for patients with advanced IV disease under Treat‐All and SOC (n = 1060).Table S3. Kaplan‐Meier estimates of retention under Treat‐All for selected variables.Table S4. Predictors of the unfavourable outcome for the entire cohort (Treat‐All and SOC combined) initiated on first‐line ART (n = 3170).Figure S1. Trace plots of imputed data for all covariates with missing values.Figure S2. Kernel density plots for imputed haemoglobin for all imputed datasets as an example using the midiagplots command in Stata.Figure S3. Kaplan‐Meier graphs of retention under Treat‐All for selected variables.Figure S4. Absolute difference in hazard of an unfavourable outcome by TB status for the entire cohort (Treat‐All and SOC combined).Figure S5. Variations in adjusted hazard ratios of the composite unfavourable outcome comparing primary care facilities with the secondary care facility under Treat‐All (facility 1) and under standard of care (facility 10).Click here for additional data file.


Life expectancy among persons living with HIV (PLWH) has improved with increasing access to antiretroviral therapy (ART), however incidence of chronic comorbidities has simultaneously increased. No data are available regarding the incidence of hypertension among Chinese PLWH.We analyzed data collected from patients enrolled in two prospective longitudinal multicenter studies of PLWH initiating ART in China. Incidence rate of hypertension per 100 person-years (PYs) among PLWH was calculated, and Cox proportional hazards models was used to evaluate the association between incident hypertension and traditional and HIV-associated risk factors.p = 0.02] and recent viral load , and negatively associated with recent CD4+/CD8+ ratio , zidovudine exposure  and tenofovir disoproxil fumarate exposure .Of 1078 patients included in this analysis, 984 ART-naïve patients were hypertension-free at baseline, and contributed 2337.7 PYs of follow up, with a median follow-up period of 1.8 years (range: 1.2–3.2) after initiation of ART. Incidence of hypertension was 7.6 [95% confidence interval (CI): 6.5–8.7] per 100 PYs. In the Cox regression analysis, incidence of hypertension was positively associated with body mass index [adjusted hazard ratio (aHR) 1.07 , The incidence of hypertension was relatively high among Chinese PLWH initiating ART. Recent low CD4+/CD8+ ratio and detectable HIV viremia were associated with incident hypertension, whereas receipt of ART was associated with reduced risk. Hypertension may be mitigated, in part, by excellent HIV care, including viral suppression with ART.NCT00872417 registered on 31 March, 2009, and NCT01844297 registered on 1 May, 2013.ClinicalTrials.gov Identifier:  Due to the increased life expectancy of persons living with HIV (PLWH) after successful antiretroviral therapy (ART), management of aging-related non-communicable diseases  has become a routine part of HIV care . HyperteLimited studies have focused on hypertension prevalence among PLWH in Asia –14, and The risk factors contributing to hypertension among PLWH are multifactorial, controversial, and include traditional contributors  , 10, 11,In order to provide important data regarding hypertension incidence among Chinese PLWH after initiation of ART, and to examine the association of traditional and HIV-associated risk factors with incident hypertension in this population, we designed the present analysis, leveraging data collected as part of two large prospective multicenter studies among Chinese PLWH.We performed a secondary analysis of data collected as part of two large prospective multicenter studies of adult patients with HIV in China carried out by the same collaborative research network. These studies recruited patients from regions of high HIV prevalence across China, and were established to systematically evaluate the efficacy, toxicities and co-morbidities associated with the first-line government-sponsored free ART regimens available at the time each study was initiated.clinicaltrials.gov ID: NCT00872417], initiated in 2008, was carried out in 8 cities across China , and recruited a total of 543 treatment-naïve adult patients with HIV from November 8, 2008 to August 6, 2010 . Subsequent funding also allowed an extension of this study beyond the initial 96-week follow up period through the time of the present analysis.The second study, (CACT1215 3 (for CACT1810) or < 500 cells/mm3 (for CACT1215), and lack of prior exposure to ART. After enrollment, participants initiated treatment with ART, and returned for follow-up evaluations at weeks 2, 4, 8, 12, 24, and once every 12 weeks thereafter for clinical and laboratory evaluations. Trained study staff at each study site performed detailed clinical evaluations and recorded data in an electronic study database.Both studies collected sociodemographic data, clinical data related to HIV and HIV-related risk factors, and serologic biospecimens. Eligibility criteria at baseline included age 18–65 years, confirmed HIV-infection status via Western blot, CD4+ cell count < 350 cells/mmThe Declaration of Helsinki.Peking Union Medical College Hospital (PUMCH) in Beijing, China served as the primary study center for both studies, and training and monitoring of study sites was overseen by the same contract research organization. Both protocols were approved by the PUMCH institutional review board prior to initiation of study activities. All study participants provided written informed consent at the time of enrollment, and all procedures were performed in compliance with the ethical standards of For the present analysis, we included patients enrolled in both parent studies in order to encompass ART treatment regimens utilized in China over the past decade. Patients who did not complete at least 2 visits (including the baseline visit) were excluded from our analysis (database cutoff date June 2015).Hypertension was defined based upon the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure Recommendations , namely 2 .The 984 study participants included in the longitudinal analysis contributed a total of 2337.7 PYs of follow-up. One hundred seventy-seven participants developed hypertension during the follow-up period, yielding an incidence of 7.6 (95% CI: 6.5–8.7) per 100 PYs. When stratified by cohort, a total of 476 patients from CACT1810 contributed 1549.95 PYs of follow-up (median follow-up time of 3.9 years) and 123 patients developed hypertension during this time. A total of 508 patients from CACT1215 contributed 787.72 PYs (median follow-up time of 1.8 years) and 54 patients developed hypertension. The incidence of hypertension was not significantly different between the participants in the two groups . Zidovudine exposure  and TDF exposure  correlated with a lower risk of hypertension. At the time of hypertension diagnosis or the last encounter (for those who did not develop hypertension), a lower recent CD4+/CD8+ ratio  and a higher recent VL  were also associated with incident hypertension  per 100 PYs, and higher incidence was significantly associated with specific traditional (high BMI), and HIV-related risk factors .While hypertension is commonly seen among PLWH, data conflict regarding whether hypertension is more prevalent among ART-naive PLWH compared with HIV-negative controls, as there is significant heterogeneity across different study designs . The preBy contrast, the incidence of hypertension in our cohort was slightly higher than that reported in the general Chinese population (7.6 vs. 5.2–5.3 per 100 PYs) , 25. In Interestingly, in our study, recent CD4+/CD8+ ratio among PLWH was associated with incident hypertension . CD4+/CD8+ ratio has been used in prior studies as a strong marker of immune activation and immune senescence , and a l]. CD4+/CA novel finding in this present study was that persistent HIV viremia was associated with incident hypertension among PLWH. Okeke et al. previously reported that HIV-related immunosuppression and ongoing viral replication may contribute to a higher risk of hypertension ; howeverData regarding the relationship between specific antiretrovirals and hypertension have yielded conflicting results. Some studies have found that exposure to protease inhibitors, especially lopinavir/ritonavir, is associated with development of hypertension , 42, whiIn our univariate analysis, baseline CD4+ cell count was not associated with hypertension incidence [Crude HR:0.999 ], however in the adjusted model, baseline CD4+ cell count was associated with hypertension incidence [Adjusted HR:1.004 ]. Given the weak magnitude of the relationships observed in this regard, we feel this finding does not likely carry strong clinical implications for our study population and should not be over-interpreted.Our study has a few limitations. First, our study population represents patients enrolled in two multi-center prospective studies of treatment-naïve patients initiating government-sponsored, currently available ART regimens at the time of enrollment. Therefore, our findings may be influenced by differences in the two studies. However, we did not detect a significant difference in the incidence rates between patients in the two groups, and given the patients were recruited from study sites within the same research network there was a high degree of consistency in the enrollment criteria and technique for study evaluations. We also acknowledge that the sample does not fully represent the entire population of patients with HIV in China, as participants were able to meet criteria for entry into the study and maintain follow-up care. However, if anything, we expect that this would underestimate the magnitude of our findings. Furthermore, while our sample size was smaller compared with studies from European and the United States , 7–9, 11Hypertension is a major modifiable risk factor for cardiovascular disease, an important cause of mortality among PLWH. We found that incidence of hypertension was high compared with rates among the general population. Recent low CD4+/CD8+ ratio and detectable HIV viremia were associated with incident hypertension, while receipt of ART was associated with reduced risk. Hypertension may be mitigated, in part, by excellent HIV care, including viral suppression with ART.


Participants. Eligible patients on ART  were categorized into one-to-two ratios of exposed groups to IPT (n = 621) and nonexposed groups to IPT . Exposed groups entered the cohort at their first prescription of IPT, and unexposed groups entered into the study at the first prescription of ART and then followed until the occurrence of the outcome or date of administrative censoring . The outcome endpoints were TB incidence, follow-up CD4+ T cells, and all-cause mortality rate.  Early antiretroviral therapy (ART), isoniazid preventive therapy (IPT), and isoniazid-rifapentine (3HP) are effective strategies for preventing tuberculosis (TB) among people living with HIV (PLHIV). The study aimed to determine the effect of IPT on the TB incidence, follow-up CD4+ T cells for the exposed and nonexposed groups were 405.74 and 366.95 cells/mm , 2017), respectively, a statistically significant finding . Nine percent of the exposed patients ) and 21.9% of the nonexposed patients  developed TB. Mortality rate  was 440 for the exposed and 1490 for the unexposed patients. Statistically significant determinants of the all-cause mortality were unscheduled follow-up  and unable to work properly .  The follow-up CD4+ T cells. Promoting IPT use can help to achieve the TB eradicating national agenda in Ethiopia. This study demonstrates the effect of IPT in reducing incidence of TB and all-cause mortality rate and improving follow-up CD4 As one of the most serious opportunistic infections (OIs) among people living with HIV/AIDS (PLHIV), tuberculosis (TB) often leads to mortality in low-income African countries , 2. HIV/The 2016 global report estimated about 6.3 million incident cases of TB, equivalent to 61% of the estimated incidence of 10.4 million. There were 476,774 reported cases of HIV/TB coinfections, in which 85% were on antiretroviral therapy (ART) . Rates oSome preventive strategies such as ART, IPT, and isoniazid-rifapentine (3HP) are required to reduce the risk of LTBI progression to active disease to achieve the 2035 target of eliminating TB , 19–21. + T cells and rate of mortality among PLHIV on chronic HIV care follow-up is poorly understood with conflicting results. Reduction of all-cause mortality was not evidenced in some studies [+ T cells independent effect of ART on the incidence of TB, CD4+ T cells, and mortality among PLHIV in Tigray region, Ethiopia.The effect of IPT together with ART on the CD4 studies , 19. The studies , 28. In A regional-based propensity-matched retrospective cohort study was conducted in six ART clinics of selected hospitals in Northern Ethiopia, Tigray Regional State. We selected six sites, namely, Alamata Hospital, Ayder Comprehensive Specialized Hospital, Lemlem Karl Hospital, St. Marry Hospital, Suhul Hospital, and Wukro Hospital, randomly from the 14 hospitals  using a The Kelsey method was employed in the sample size determination . Accordi+ T cells count, treatment categories, and adherence status  were randomly selected after adjustment for the WHO clinical stage, baseline CD4 Figures .+ T cells counts, and mortality status was the treatment outcome variables.Eligible patients were selected based on the following criteria: PLHIV having at least two or more visits starting from the index period and receiving their healthcare at the clinics. On the contrary, PLHIV were on anti-TB treatment before the enrollment, with altered or elevated liver function tests at baseline , with adherence rate of <85% or missed ≥6 doses out of 30 doses, and with unknown period (month and year) of starting both regimens and treatment outcome were excluded from the study . DetermiA customized data collection form was adopted from the format of Federal Ministry of Health. The data abstraction form was piloted before implementation, and 12 data collectors, who were recruited from the staff members of the hospital and trained as data collectors for two days, collected the data. The patients' medical records were followed until occurrence of the outcome  or date of administrative censoring . Completeness of the collected data was supervised and monitored adequately by the investigators and supervisors during the data collection process. The duration of IPT is 6 months, and it is given at a daily dose of 5 mg/kg (maximum 300 mg). IPT and ART visits were given as integrative services at the clinic.Unscheduled follow-up was defined when the participant did not attend at least one routine follow-up visit on the appointment date. Otherwise, the participant was deemed to have a scheduled follow-up.The index period was identified when exposed groups entered the cohort at their first prescription of IPT, and unexposed groups entered into the study at the first prescription of ART.Diagnosis of TB was done according to the Ethiopian Tuberculosis, Leprosy and TB/HIV Prevention and Control Program Manual , where ap-value for T_COV = 0.778). A sensitivity analysis, using propensity score matching, was performed to evaluate and address confounding by indication .Data were analyzed using Statistical Package for Social Sciences (SPSS® Statistics) program version 21 , STATA® version 12, and R®-software (R i386 2.15.3). Kaplan–Meier (KM) analyses were used to compare the mortality rates and TB incidence-free survival time between the two cohorts. The assumption for proportional hazard was assessed graphically by log minus log survival curve  of follow-up were employed. We used exact dates to calculate person-years by summing of total time contributed by all subjects. In the propensity-matched cohort, an adjusted Cox proportional hazard model was repeated to find out the effects of sociodemographics, clinical characteristics, and treatment categories on the outcome variables. Cohen's d was used as an index for determining the strength of the effect size. In all the analyses, significance testing was done using two-sided p values and 95% CI, and a p value <0.05 was considered as statistically significant. Lastly, missing data for continuous variables were accounted by the expectation maximization model.An independent samples This study was conducted in medical records of patients using standardized formats prepared by the Ethiopian Federal Ministry of Health, and hence, there was no direct involvement of the patients and the public.An ethical clearance was obtained from “Health Research and Ethics Review Committee” of College of Health Sciences (Reference number: ERC 0877/2016), Mekelle University. In addition, the Research Committee of Tigray Regional Health Bureau granted ethical permission to conduct the study (Reference number: 4366/7767/09). Permission to utilize patient data was also obtained officially from the administrative offices of the selected hospitals. To ensure confidentiality, name and other identifiers of patients, physicians, and other staff members of the centers were not recorded on the data abstraction instrument.This study was funded by Mekelle University (Grant Number: CRPO/CHS/SM/015/09). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Lastly, this study was done in accordance with STROBE cohort reporting guidelines .Nearly one-third of females (34.9%) and males (30.9%) were exposed to IPT. Comparably, about one in three of the participants in the age group of 30–44 (34.1%) and participants dwelling in urban areas (33.5%) were exposed to IPT. Approximately one-third of the patients had a working functional status (33.7%), and those participants with a WHO clinical stage III at the baseline (38.9%) were exposed to IPT .2 for both cohorts. Over the nine-year period, the weight was increased by about 6.6 kg for both cohorts; and the BMI was increased by 2.8 kg/m2 for the exposed group and by 3.8 kg/m2 for the unexposed group, interpreting into about 15% and 16% increase from baseline to 2017, respectively  and unexposed patients (49.2 kg). The average baseline BMI was also about 19.8 kg/mNearly one-third (32.31%) of the patients were initiated with d4T + 3TC + NVP followed by AZT + 3TC + NVP, in which this regimen was taken by about a quarter of the patients (24.3%). Majority of the study participants (93.5%) were on the first line ART regimen. The mean duration on ART for both groups was 6.8 years. Furthermore, the average time between ART initiation and IPT initiation is 239 days.p < 0.0001)  .+ T cells (in cells per mm3) were 405.74 for IPT exposed patients and 366.95 for IPT unexposed patients. For the exposed group, the CD4+ T cells showed increase by 177.61%  over the past nine years, with an average of 538.94 in 2017, up from a mean of 194.14 at the baseline. Likewise, for the second cohort, the CD4+ T cells showed increase by 187.67%  over the past nine years, with an average of 511.33 in 2017, up from a mean of 177.75 at the baseline . The average CD4+ T cells for patients not exposed to IPT (mean = 366.951 cells/mm [3) was 38.792 cells/mm3 (95% CI: −58.970 to −18.614 cells/mm3) lower than the average CD4+ T cells for patients exposed to IPT (mean = 405.742 cells/mm [d = 0.186). The mean CD4 cells in different years are given in After propensity score matching, there was a statistically significant difference in mean CD4p value < 0.0001) for the exposed groups and 1490 per 100,000 PYs  for the unexposed groups. The KM analysis for survival function illustrated that exposed patients had a better survival chance than unexposed patients at all levels of time (p < 0.0001)  of observation for patients exposed to IPT and for those not exposed to IPT were 4,512 and 8,567, respectively. The incidence rate of mortality was 440 per 100,000 PYs  .3) ≥ 250 compared to <250 , and exposure to IPT . On the other hand, unscheduled follow-up  and unable to work properly  were statistically associated with mortality , CD4+ T . This increases morbidity and hastens progression of HIV to AIDS and mortality [There is fivefold more risk of death among patients with low CD4 count compared to patients with higher CD4 count. Several other studies are consistent with this finding, and they also pointed to the fact that severe immune suppression is observed in those with CD4+ T cell count below 200 cells/mm3 , 59. Insortality .+ T cells in Tigray region. Rural residence, lower CD4+ T cell values, nonexposure to IPT, and having unscheduled follow-up were independent predictors of increased likelihood of the all-cause mortality. Moving forward, we call for the healthcare providers to closely monitor the treatment outcome of patients taking ART alone and place a special effort in optimizing the outcome. Promoting IPT use can help achieving the TB eradicating national agenda in Ethiopia.This study demonstrates the effect of IPT, when used with ART, in reducing incidence of TB and all-cause mortality rate and improving CD4