Changes in cerebrospinal fluid proteins across the spectrum of untreated and treated chronic HIV-1 infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers contributed by uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of CSF proteins in HIV-associated dementia (HAD) and neurosymptomatic CSF escape (NSE). These reveal a complex but coherent picture of CSF protein changes with highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of systemic HIV-1 progression that included two common patterns, designated as lymphoid and myeloid patterns, related to principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will supplement this report to provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, advancing the mechanistic understanding of HIV-1-related CNS pathobiology.

Epidemiology, clinical presentation and management of COVID-19 associated mucormycosis: A single centre experience from Pune, Western India.

BACKGROUND: The second COVID-19 wave in India has been associated with an unprecedented increase in cases of COVID-19 associated mucormycosis (CAM), mainly Rhino-orbito-cerebral mucormycosis (ROCM). METHODS: This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India, between 1 April, 2020, and 1 August, 2021, to identify CAM patients and assess their management outcomes. The primary endpoint was incidence of all-cause mortality due to CAM. RESULTS: 59 patients were diagnosed with CAM. Median duration from the first positive COVID-19 RT PCR test to diagnosis of CAM was 17 (IQR: 12,22) days. 90% patients were diabetic with 89% having uncontrolled sugar level (HbA1c >7%). All patients were prescribed steroids during treatment for COVID-19. 56% patients were prescribed steroids for non-hypoxemic, mild COVID-19 (irrational steroid therapy), while in 9%, steroids were prescribed in inappropriately high dose. Patients were treated with a combination of surgical debridement (94%), intravenous liposomal Amphotericin B (91%) and concomitant oral Posaconazole (95.4%). 74.6% patients were discharged after clinical and radiologic recovery while 25.4% died. On relative risk analysis, COVID-19 CT severity index ≥18 (p = .017), presence of orbital symptoms (p = .002), presence of diabetic ketoacidosis (p = .011) and cerebral involvement (p = .0004) were associated with increased risk of death. CONCLUSIONS: CAM is a rapidly progressive, angio-invasive, opportunistic fungal infection, which is fatal if left untreated. Combination of surgical debridement and antifungal therapy leads to clinical and radiologic improvement in majority of cases.

Online Registry of COVID-19-Associated Mucormycosis Cases, India, 2021.

We established an online registry of coronavirus disease-associated mucormycosis cases in India. We analyzed data from 65 cases diagnosed during April-June 2021, when the Delta variant predominated, and found that patients frequently received antibacterial drugs and zinc supplementation. Online registries rapidly provide relevant data for emerging infections.

Incidence of tuberculosis among HIV infected individuals on long term antiretroviral therapy in private healthcare sector in Pune, Western India.

BACKGROUND: Despite rapid scale up of antiretroviral therapy (ART), Tuberculosis (TB) remains the commonest opportunistic infection and cause of death among HIV infected individuals in resource limited settings like India. Incidence of TB in individuals on ART in private healthcare sector in India is infrequently studied. METHODS: This retrospective cohort study conducted between 1st March 2009 and 1st March 2017 aimed to evaluate rate of incident TB in individuals initiated on ART at 3 private sector ART clinics in Pune, India. Individuals more than 12 years of age with ART duration of atleast 6 months were included. Patients were classified as having prevalent TB if they had a TB episode within the year prior to ART initiation or if they developed TB within 6 months of starting ART. Individuals who were diagnosed with TB after 6 months of starting ART were classified as incident TB cases. A recurrent episode of TB after treatment completion or cure of prevalent TB was also regarded as incident TB. Patients were classified as definitive TB if Mycobacterium tuberculosis was grown in culture from a biological sample or a positive rapid molecular test. Patients were classified as probable TB if there was radiologic evidence of TB in absence of confirmatory culture or PCR. RESULTS: 1904 patients with a median duration of follow up on ART of 57 (IQR = 32.0, 84.0) months were included. Of these, 182 developed incident TB (22% definitive TB, 38% recurrent cases). TB incidence at 6-12 months, 13-24 months, 25-60 months and > 60 months of ART was 24.32, 5.46, 2.54 and 0.75 cases per 100 person years respectively. Current time updated CD4 count < 500 cells/mm3 (p < 0.0001), virologic failure on ART (adjusted Hazard Ratio (aHR): 3.05 (95% CI: 2.094, 4.454), p < 0.0001) and receipt of ART without IPT (aHR: 8.24 (95% CI, 3.358, 20.204), p < 0.0001) were associated with higher risk of incident TB. CONCLUSION: Starting ART early in treatment naïve individuals, prompt detection of virologic failure on ART and providing IPT along with ART will be useful in reducing incident TB. Efforts from private sector are crucial in achieving Sustainable Development Goals set by Government of India and attaining the vision of a TB free India.

Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation.

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Changes in Cerebrospinal Fluid Proteins across the Spectrum of Untreated and Treated Chronic HIV-1 Infection.

Using the Olink Explore 1536 platform, we measured 1,463 unique proteins in 303 cerebrospinal fluid (CSF) specimens from four clinical centers that included uninfected controls and 12 groups of people living with HIV-1 infection representing the spectrum of progressive untreated and treated chronic infection. We present three initial analyses of these measurements: an overview of the CSF protein features of the sample; correlations of the CSF proteins with CSF HIV-1 RNA and neurofilament light chain protein (NfL) concentrations; and comparison of the CSF proteins in HIV-associated dementia ( HAD ) and neurosymptomatic CSF escape ( NSE ). These reveal a complex but coherent picture of CSF protein changes that includes highest concentrations of many proteins during CNS injury in the HAD and NSE groups and variable protein changes across the course of neuroasymptomatic systemic HIV-1 progression, including two common patterns, designated as lymphoid and myeloid patterns, related to the principal involvement of their underlying inflammatory cell lineages. Antiretroviral therapy reduced CSF protein perturbations, though not always to control levels. The dataset of these CSF protein measurements, along with background clinical information, is posted online. Extended studies of this unique dataset will provide more detailed characterization of the dynamic impact of HIV-1 infection on the CSF proteome across the spectrum of HIV-1 infection, and further the mechanistic understanding of HIV-1-related CNS pathobiology.

Safety of low dose efavirenz regimen in Indian adults with HIV-1 infection: Insights from a phase 4 interventional randomised trial.

BACKGROUND: A randomized interventional phase 4 study in the Indian population confirmed the non-inferiority of the combination tenofovir/lamivudine/efavirenz (TLE)-400 to TLE600. The current manuscript describes in detail the safety profile and patient-reported safety outcomes obtained from the phase 4 study. METHODS: This investigation was part of a phase 4 non-inferiority study with a blinded assessment, conducted across 17 sites in India. The duration of the study was 24 weeks. Safety endpoints assessed included all the adverse events (AEs) related to the study treatment (TLE400 and TLE600). The depression anxiety stress 21-item scale questionnaire and efavirenz-related symptom questionnaire were also used to measure depression, anxiety, stress, and patient experience. RESULTS: A total of 68 patients (52.3%) reported 261 AEs and 87 patients (64.9%) reported 379 AEs related to study treatment in TLE400 group and TLE600 group respectively, P = .037. The reported AEs associated with central nervous system disorders were lower in the TLE400 group with 41 patients (31.5%) to 61 patients (45.5%) in the TLE600 group. The change from mean baseline value for depression anxiety stress 21-item scale at week 28 in TLE400 group and TLE600 group was -5.1 and -6.2 respectively. Similarly, the mean change from baseline score of efavirenz-related symptoms at week 28 in TLE400 group and TLE600 group were -5.1 and -4.1 respectively. CONCLUSION: The low dose efavirenz (400 mg) in combination with tenofovir and lamivudine had a better safety and tolerability profile than the standard dose of efavirenz (600 mg) in combination with tenofovir and lamivudine. Thus, low dose efavirenz should be preferred over the standard dose.

Clinico-Epidemiologic Characteristics of Patients Reported in the Mycotic Infections in COVID-19 Registry.

We update results from the Mycotic Infections in COVID-19 (MUNCO) Registry, May-September 2021. Data collection from May to September 2021 yielded 728 cases from India, Nepal, Bangladesh, Thailand, and the United States. The cases consisted of mostly mucormycosis (97.6%), primarily rhinocerebral, and were analyzed to investigate clinical characteristics associated with negative outcomes. Patients were mostly diabetic (85%) and male (76%), with significant mortality (11.7%). All patients received treatment of coronavirus disease 2019 (COVID-19) as well as antifungal treatment. The crude mortality rate was 11.3% for mucormycosis and 22.7% formixed infections. This study demonstrates the utility of online databases in the collection of high-caliber data.

Cognitive impairment in people living with HIV: consensus recommendations for a new approach.

Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury - including active or pretreatment legacy damage - from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies.

A Phase IV Study on Safety, Tolerability and Efficacy of Dolutegravir, Lamivudine, and Tenofovir Disoproxil Fumarate in Treatment Naïve Adult Indian Patients Living with HIV-1.

Purpose: WHO recommends dolutegravir (DTG) based regimens as first-line treatment for HIV-1 infection. However, few studies have been conducted in Indian population. Hence, our study evaluated the safety, tolerability, and efficacy of DTG 50 mg with Tenofovir and Lamivudine (300/300mg) fixed dose combination in treatment naïve adult Indian patients. Methods: This was an open label, multicenter, prospective, interventional, phase IV study conducted across 14 sites between February 2019 and July 2020. 24 weeks was the treatment duration for each subject. The primary end point was to assess the incidence of adverse events (AEs) and secondary end points were to assess the proportion of patients achieving plasma HIV-1 RNA levels <50 copies/mL at week 24 and change in CD4+ cell count from the baseline. Safety analysis was conducted using Safety Analysis Set and efficacy analysis was carried out using Full Analysis Set and Per protocol set. Results: A total of 288 patients were screened; 250 were enrolled; and 229 completed the study. 389 AEs were reported from 58% of patients. Of these, 61 were related to study treatment. One event of decreased creatinine clearance led to study discontinuation. One serious event of pyrexia was reported, which was unrelated to the study drug. The most common AEs were headache (18%), pyrexia (14%), vomiting (6.4%) and upper respiratory tract infections (6%). No deaths were reported. At week 24, 86.8% of the patients achieved plasma HIV-1 RNA levels <50 copies/mL and the mean CD4 cell count increased from 350.2 (SD, 239.73) at baseline to 494.6 (SD, 261.40) with an average increase of 143.2 (SD, 226.14) cells. Conclusion: This study demonstrated the safety and efficacy of DTG based regimen in treatment naïve HIV-1 patients in Indian population and support use of DTG as first-line treatment regimen.

Efficacy and safety of 400 mg efavirenz versus standard 600 mg dose when taken with tenofovir and lamivudine combination in Indian adult patients with HIV-1 infection: An open-label, interventional, randomized, non-inferiority trial.

BACKGROUND: To evaluate the non-inferiority of low dose efavirenz (400 mg) to standard dose efavirenz (600 mg), when taken in combination with tenofovir and lamivudine in Indian patients with HIV-1 infection. METHODS: An open-label, interventional phase IV study with blinded assessment was conducted across 17 sites in India. HIV-1-infected antiretroviral therapy-naive adult patients (≥18 years of age) with a plasma HIV-1 viral load of at least 1000 copies per mL were randomized to receive either tenofovir/lamivudine/efavirenz (TLE) 400 or TLE 600. The primary endpoint was the difference in the proportion of patients achieving < 200 copies per mL at the end of 24 weeks. RESULTS: A total of 265 patients were enrolled and were randomized in 1:1 ratio to TLE 400 group (130 patients) and TLE 600 group (135 patients). At week 24, the proportion of patients with a viral load of less than 200 copies per mL was 80.70% for TLE 400 and 78.95% for TLE 600 (difference 1.75%, 90% confidence interval: -7.01, 10.49) which was within the predefined margin of -10% (90% confidence interval). Significantly lower study drug-related adverse events were observed in TLE 400 group compared to TLE 600 group (52.30%, n = 68 vs 64.92%, n = 87; P = .037). The treatment discontinuation percentage was marginally higher by 2.08% in TLE 600 group. CONCLUSION: The fixed-dose combination of TLE 400 is non-inferior to TLE 600 in terms of viral suppression and has an improved safety profile over 24 weeks in adult Indian patients with HIV-1 infection.

Factors Associated with Mortality in Coronavirus-Associated Mucormycosis: Results from Mycotic Infections in COVID-19 (MUNCO) Online Registry.

BACKGROUND: COVID-19-associated mucormycosis (CAM) is associated with high morbidity and mortality. MUNCO is an international database used to collect clinical data on cases of CAM in real time. Preliminary data from the Mycotic Infections in COVID-19 (MUNCO) online registry yielded 728 cases from May to September 2021 in four South Asian countries and the United States. A majority of the cases (694; 97.6%) consisted of a mucormycosis infection. The dataset allowed for the analysis of the risk factors for adverse outcomes from CAM and this analysis is presented in this paper. METHODS: The submission of cases was aided by a direct solicitation and social media online. The primary endpoints were full recovery or death measured on day 42 of the diagnosis. All patients had histopathologically confirmed CAM. The groups were compared to determine the contribution of each patient characteristic to the outcome. Multivariable logistic regression models were used to model the probability of death after a CAM diagnosis. RESULTS: The registry captured 694 cases of CAM. Within this, 341 could be analyzed as the study excluded patients with an unknown CAM recovery status due to either an interruption or a lack of follow up. The 341 viable cases consisted of 258 patients who survived after the completion of treatment and 83 patients who died during the period of observation. In a multivariable logistic regression model, the factors associated with an increased risk of mortality include old age (OR = 1.04, 95% CI 1.02-1.07, p = 0.001), history of diabetes mellitus (OR 3.5, 95% CI 1.01-11.9, p = 0.02) and a lower BMI (OR 0.9, 95% CI 0.82-0.98, p = 0.03). Mucor localized to sinus disease was associated with 77% reduced odds of death (OR = 0.23, 95% CI 0.09-0.57, p = 0.001), while cerebral mucor was associated with an increased odds of death (OR = 10.96, 95% CI 4.93-24.36, p = ≤0.0001). CONCLUSION: In patients with CAM, older age, a history of diabetes and a lower body mass index is associated with increased mortality. Disease limited to the sinuses without a cerebral extension is associated with a lower risk of mortality. Interestingly, the use of zinc and azithromycin were not associated with increased mortality in our study.

Neurological issues during severe COVID-19 in a tertiary level hospital in Western India.

BACKGROUND: India has the second largest COVID-19 epidemic in the world as per current estimates. Central and peripheral nervous system involvement in COVID-19 (Neuro COVID-19) has been increasingly identified and reported. This letter is the first report of the spectrum of neurological disorders observed in patients with severe COVID-19 from a resource limited setting like India. Till October 30th 2020, Noble hospital and research center, Pune, India has admitted 2631 patients of COVID-19. Out of these, 423 patients had severe COVID-19. NEUROLOGIC COMPLICATIONS IN SEVERE COVID-19 IN PUNE, INDIA: Of the 423 patients with severe COVID-19, 20 (4.7%) had pre-existing neurologic co-morbidities, with cerebrovascular disease (8 patients) being the most common. Poliomyelitis (4 patients) was also an important co-morbidity associated with severe COVID-19. Bodyache or myalgia (207/423, 49 %) and headache (59/423, 13.9 %) were the most common neurologic symptoms observed in patients. Encephalopathy (22/423, 5.2 %) and new onset large vessel ischemic stroke secondary to cerebral artery thrombosis (5/423, 1.1%) were the most common secondary neurologic complications noted in our cohort. Two cases of COVID-19/central nervous system tuberculosis co-infection were also identified. CHALLENGES IN MANAGEMENT OF NEURO COVID-19 IN INDIA: Various challenges like an overwhelmed health care system, inadequate workforce, lack of exhaustive reporting of symptoms and poor availability of neuroimaging in ventilated COVID-19 patients leads to underestimation of Neuro COVID-19 in resource limited settings like India.

Combination therapy of Tocilizumab and steroid for management of COVID-19 associated cytokine release syndrome: A single center experience from Pune, Western India.

ABSTRACT: Cytokine release syndrome (CRS) or cytokine storm is thought to be the cause of inflammatory lung damage, worsening pneumonia and death in patients with COVID-19. Steroids (Methylprednislone or Dexamethasone) and Tocilizumab (TCZ), an interleukin-6 receptor antagonist, are approved for treatment of CRS in India. The aim of this study was to evaluate the efficacy and safety of combination therapy of TCZ and steroid in COVID-19 associated CRS.This retrospective cohort study was conducted at Noble hospital and Research Centre (NHRC), Pune, India between April 2 and November 2, 2020. All patients administered TCZ and steroids during this period were included. The primary endpoint was incidence of all cause mortality. Secondary outcomes studied were need for mechanical ventilation and incidence of systemic and infectious complications. Baseline and time dependent risk factors significantly associated with death were identified by Relative risk estimation.Out of 2831 admitted patients, 515 (24.3% females) were administered TCZ and steroids. There were 135 deaths (26.2%), while 380 patients (73.8%) had clinical improvement. Mechanical ventilation was required in 242 (47%) patients. Of these, 44.2% (107/242) recovered and were weaned off the ventilator. Thirty seven percent patients were managed in wards and did not need intensive care unit (ICU) admission. Infectious complications like hospital acquired pneumonia, blood stream bacterial and fungal infections were observed in 2.13%, 2.13% and 0.06% patients respectively. Age ≥ 60 years (P = .014), presence of co-morbidities like hypertension (P = .011), IL-6 ≥ 100 pg/ml (P = .002), D-dimer ≥ 1000 ng/ml (P < .0001), CT severity index ≥ 18 (P < .0001) and systemic complications like lung fibrosis (P = .019), cardiac arrhythmia (P < .0001), hypotension (P < .0001) and encephalopathy (P < .0001) were associated with increased risk of death.Combination therapy of TCZ and steroids is likely to be safe and effective in management of COVID-19 associated cytokine release syndrome. Efficacy of this anti-inflammatory combination therapy needs to be validated in randomized controlled trials.

Two treatment strategies for management of Neurosymptomatic cerebrospinal fluid HIV escape in Pune, India.

Symptomatic cerebrospinal fluid (CSF) viral escape (sCVE) is reported in people with HIV, who are on ritonavir-boosted protease inhibitor (PI/r) containing antiretroviral therapy (ART). Management of sCVE includes performing genotypic HIV-1 resistance testing (GRT) on CSF and plasma HIV and changing ART accordingly. Neither GRT nor newer drugs (Dolutegravir and Darunavir/ritonavir) are routinely available in India. As a result, management of sCVE includes 2 modalities: a) ART intensification by adding drugs that reach therapeutic concentrations in CSF, like Zidovudine, to existing ART or b) Changing to a regimen containing newer boosted PI/r and integrase strand transfer inhibitor (INSTI) as per GRT or expert opinion. In this retrospective study, we report the outcomes of above 2 modalities in treatment of sCVE in Pune, India.Fifty-seven episodes of sCVE in 54 people with HIV taking PI/r-containing ART were identified. Clinical, demographic, laboratory and ART data were recorded. Forty-seven cases had follow-up data available after ART change including measurement of plasma and CSF viral load (VL).Of the 47 cases, 23 received zidovudine intensification (Group A, median VL: plasma- 290, CSF- 5200 copies/mL) and 24 received PI/INSTI intensification (Group B, median VL: plasma- 265, CSF-4750 copies/mL). CSF GRT was performed in 16 participants: 8 had triple class resistance. After ART change, complete resolution of neurologic symptoms occurred in most participants (Group A: 18, Group B: 17). In Group A, follow-up plasma and CSF VL were available for 21 participants, most of whom achieved virologic suppression (VL < 20 copies/mL) in plasma (17) and CSF (15). Four participants were shifted to the PI/INSTI intensification group due to virologic failure (plasma or CSF VL > 200 copies/mL). In Group B, follow-up plasma and CSF VL were available for 23 participants, most of whom also achieved virologic suppression in plasma (21) and CSF (18). Four deaths were noted, 2 of which were in individuals who interrupted ART.This is a unique sCVE cohort that was managed with 1 of 2 approaches based on treatment history and the availability of GRT. At least 75% of participants responded to either approach with virologic suppression and improvement in symptoms.

Strongyloidosis Hyperinfection Syndrome in an HIV-Infected Patient: A Rare Manifestation of Immune Reconstitution Inflammatory Syndrome.

Parasitic infections such as Strongyloides stercoralis and HIV have been reported to coexist, particularly in resource-limited settings such as India. In an immunocompromised host, S. stercoralis can progress to strongyloidiasis hyperinfection syndrome (SHS). However, SHS is not common in patients with advanced HIV disease. Immune reconstitution inflammatory syndrome (IRIS) developing after initiation of antiretroviral therapy (ART) can target multiple pathogens including S. stercoralis. The authors present here a 46-year-old HIV-infected female who was recently diagnosed with HIV-1 infection, started ART, and developed SHS. Her upper GI endoscopy revealed severe gastroduodenitis, and X-ray chest showed extensive bilateral pneumonitis. We could identify S. stercoralis in induced sputum and duodenal biopsy. We could also identify gut inflammation to restrict invading parasites. After receiving antihelminthic therapy, she showed improvement, a course of events that fit the diagnosis of unmasking S. stercoralis IRIS.

Discordant CSF/plasma HIV-1 RNA in individuals on virologically suppressive antiretroviral therapy in Western India.

Aim of this study was to estimate the prevalence of cerebrospinal fluid (CSF)/Plasma HIV-1 RNA discordance in virologically suppressed individuals presenting with incident neurologic symptoms.In this retrospective cohort study conducted between March 1, 2009, and March 1, 2017, HIV-1 infected adults exposed to atleast 12 months of antiretroviral therapy (ART) and having plasma viral load (VL) <1000 copies/mL (virologically suppressed) were included. Among these, individuals presenting with neurologic symptoms during follow-up were assessed for CSF/Plasma HIV-1 RNA discordance by measuring HIV-1 RNA in collected plasma and CSF samples. CSF/plasma HIV-1 RNA discordance was defined as either detectable CSF HIV-1 RNA (VL > 20 copies/mL) with an undetectable plasma RNA (complete viral suppression, VL ≤20 copies/mL) or CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma RNA when plasma VL was between 20 and 1000 copies/mL (low-level viremia, LLV).Out of 1584 virologically suppressed patients, 71 (4.4%) presented with incident neurologic symptoms. Twenty out of 71 (28.2%) patients were diagnosed with CSF/Plasma HIV-1 discordance. Median plasma and CSF VL in patients with discordance was 120 [interquartile range (IQR): <20 to 332.5] and 4250 (IQR: 2550.0- 9615.0) copies/mL, respectively. All 9 individuals in which CSF HIV-1 genotypic resistance testing was done showed mutations that would compromise efficacy of prescribed ART regimen. Prevalence of CSF/plasma HIV-1 RNA discordance was higher among neurologically symptomatic patients with plasma LLV as compared with those with complete viral suppression (70% vs 11.8%, P < .001). The risk of discordance was also greater in patients who received protease inhibitor (PI) containing ART (P < .001) and those on ART regimens with central nervous system (CNS) penetration effectiveness (CPE) value <6 (P = .006).CSF/plasma HIV-1 RNA discordance indicates replication of HIV-1 that has adapted to the CNS or has developed antiretroviral drug resistance. Larger studies should be performed to study incidence of discordance in India. This will help in managing patients presenting with neurologic symptoms on suppressive ART with appropriate neuroeffective therapy.

Highlights of the Global HIV-1 CSF Escape Consortium Meeting, 9 June 2016, Bethesda, MD, USA.

CSF HIV escape is a recently recognised phenomenon that suggests that despite suppressive treatment, HIV RNA may be detected in the CNS compartment in some individuals. In rare cases this is associated with clinical neurological disease, while in most cases, neurological consequences are not apparent. Attempts at characterising the biological substrates of CSF escape and further investigating the neurological consequences need to be made to better understand the implications of this condition for the HIV cure agenda as well as for clinical outcomes. The Global CSF HIV-1 Escape Consortium meeting, convened by the US National Institute of Mental Health, was a first step to gather investigators from diverse sites to discuss opportunities for future collaborative work on this emerging issue. To better understand CSF HIV escape and allow cross-site data reconciliation, it will be useful to reach a consensus set of definitions of the distinct forms of CSF escape, without which concerted cross-site efforts are difficult.