CME INDIA Presentation by Dr. B. B. Rewari MD, FRCP(Ireland), FICP, FIACM, FIAMS, FIMSA, FCCP, FGSI, MPH. Former Regional Advisor, Hepatitis, HIV, STI WHO SEARO Clinical Professor, Global health, University of Washington, USA. Former Professor of Medicine, PGIMER & RML Hospital, New Delhi, Vice Dean, Indian College of Physicians.

Musculoskeletal complications

Includes pain in shoulder, neck, back, knee problems, muscle stiffness and weakness

• Should get better with proper physiotherapy.
• Less active = muscle stiffness/pain.
• Patients having COVID – 19 infections have reported an increased incidence of back pain.
• Some patients have also reported altered/odd sensations like pins and needles in arms and legs.
• Muscle weakness can interfere with daily activities like climbing stairs, standing, gripping objects.
• Usually symptoms improve after recovery from COVID – 19 infections.
• r/o –
  • Fibromyalgia
  • Chronic fatigue syndrome
  • Inflammatory myopathies
  • Hypothyroidism
  • Low calcium

Dermatological complications

Co-morbid complications

Diabetes and Covid: Bidirectional relationship

• Poorly controlled diabetes increases the severity of COVID – 19, mortality and morbidity.
• Long-standing diabetes causes microvascular injury which can be aggravated during COVID-19 infection which can contribute to PCS.
• Diabetics also have a low-grade inflammatory state that contributes to PCS.
• Corticosteroid therapy which is widely used in treating COVID-19 infection also raises blood sugar which can cause diabetes.
• pulmonary fibrosis a known complication of long covid is common in diabetics.
• In diabetes, neuropathy and myopathy contribute to muscle atrophy and sarcopenia which can lead to fatigue another symptom of long covid.

Mucor mycosis

• Common post covid fungal infection.
• Lethal, opportunistic infection of the paranasal sinuses and brain caused by fungi of the Mucorales, most commonly with Rhizopus spp.
• High fatality.
• Root cause is the same, uncontrolled diabetes and unregulated use of steroids to control cytokine storm during COVID – 19 infection.
• The management includes early diagnosis, control of the underlying diseases, and aggressive medical and surgical intervention.

Cancer

• Chronic inflammation can lead to oncogenesis.
• The association between viral infections and several cancers is well known.
• Immune responses in COVID-19 patients are orchestrated by proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α).
• Cytokine storm is associated with T-cell depletion and activation of oncogenic pathway which increases the risk of cancer development.

Hypoxia due to inflammation or virus-induced angiotensin converting enzyme 2 depletion can induce oxidative stress and malignant transformation

• Both chronic inflammation and oxidative stress can lead to DNA damage and subsequent carcinogenesis.
• Moreover, COVID – 19 is known to cause multiorgan damage, and extensive tissue damage is an oncogenic driver.

Hypertension

• Hypertension was reported alone of the most common pre-existing comorbidities and majority of hypertensive patients reported uncontrolled blood pressure level in post-COVID-19 recovery.
• Major factors contributing to the development of HTN are anxiety and medications used to treat COVID – 19
• COVID – 19 treatment includes medications like steroids and tocilizumab which cause fluid retention leading to a rise in blood pressure.

Post COVID mental health issues

Common symptoms include:

• Physical symptoms: deceased energy, sleep disturbances, reduced appetite and unexplained physical symptoms such as pain.
• Mood changes: rapid changes in mood, experiencing sadness, anxiety, fear, irritability, crying spells, helplessness, or emotional exhaustion.
• Behavioural changes: restlessness, drowsiness, reduced work efficiency, isolation, absenteeism, excessive use of drugs, sleep disturbances and decreased appetite.
• Impact on ways of thinking: negative thoughts about self, others and the world, Persistent preoccupation with illness worries; or suicidal thoughts.

Who are the most vulnerable?

• Children
• Elderly
• Pregnant women
• Individuals with poor social support & lower economic status
• Life-threatening chronic medical conditions like cancer, chronic renal failure, liver diseases, asthma/COPD, immunocompromised patients
• Marginalised communities
• History of mental illness
• Persons with disability
• Homeless individuals

Screening

• GAD-7 or PHQ-9 can be used screening of mental disorders in disaster settings.
• Screening Instrument of Clinical Schedule for Clinical Psychiatry Ver 2.3 is used by frontline medical professional
• It’s brief and reduces the risk of prolonged exposure.

PLHIV and COVID-19

Risk of developing severe fatal COVID-19 was found to be 38% greater among PLHIV when compared to people without HIV infection

• They also have a high prevalence of some comorbidities associated with poorer COVID19 outcomes, such as cardiovascular disease, diabetes, chronic respiratory disease and hypertension.
• Additionally, lower CD4 T-cell counts are associated with advanced HIV disease and several epidemiological studies showed that this HIV subpopulation are at greater risk for hospitalization due to COVID-19 and mortality.
• PLHIV frequently face adverse social determinants of health and structural factors that may lead to higher SARS-CoV-2 exposure.

Prospective, observational study to assess the prevalence of long‐COVID among PLHIV (Nov 2020 –Jan 2021)

• 94 PLHIV in Western India, unvaccinated at the time of COVID-19, mostly middle-aged men (median age 51, 73% men), majority (76.6%) had a history of asymptomatic–mild COVID‐19 illness.
• 91% were on suppressive antiretroviral therapy (ART).
• 44% had at least one Long COVID symptom 30 or more days post infection, more among those with moderate COVID.
• Cough (22%) and fatigue (16%) were the most commonly reported symptoms, resolved in median of 15 days (7-30 Days).
• 10% had persistent symptoms at median of 109 days from onset of COVID symptoms.

PLHIV and Long COVID prevalence

PLWH in care at the Infectious and Tropical diseases Unit in Padua, February 2020 to 31 March 2021

• 75 PLHIV PLWH on suppressive ART, unvaccinated at the time of symptomatic COVID-19, followed for a median time of 6 months, mostly middle-aged men (>80% men).
• with good immune reconstitution, (median CD4þ T-cell count >500 cells/ml).
• 27% had one or more COVID-attributable symptoms or sequelae 4 or more weeks after symptom onset, mostly among those with moderate to- severe COVID-19.
• asthenia (80.0%), shortness of breath (50.0%) and recurrent headache (25.0%) were the three most common complaints.

PLHIV and Long COVID prevalence – Increased likelihood?

An analysis of 530 individuals who had presented to the emergency department or were hospitalized at NY Presbyterian Hospital-Cornell University in the spring of 2020.

• PLHIV were more likely to report one or more Long COVID symptoms 12 months after COVID-19, after adjusting for age, sex, race, poverty, comorbidities, and severity of acute COVID-19 [adjusted risk ratio 1.75, 95% confidence interval (CI) 1.14–2.69] [50].
• However, the cohort included only 10 PLHIV (< 2% of the total population studied).

Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, UCLA

• Measured SARS-CoV-2-specific humoral and cellular responses in people with and without HIV recovering from COVID-19 (n = 39 and n = 43, respectively).
• PLHIV had 70% lower relative levels of SARS-CoV-2-specific memory CD8 + T cells (P = 0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2-specific CD4 + T cells (P = 0.007).
• Following adjustment for age, sex, hospitalization status, and time since infection, the authors found that PLWH had 4.01 the odds of reporting at least one COVID-attributed symptom and 2.72 the odds of reporting three or more COVID-attributed symptoms at a median of 4 months post-COVID. HIV status strongly predicted the presence of PASC Certain symptoms, including fatigue, gastrointestinal symptoms, neurocognitive symptoms, and sleep problems were reported more commonly in PLWH.

Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort, UCLA

• Evaluated 54 PLHIV as part of an analysis of 280 individuals with prior SARS-CoV-2 infection to assess the contribution of chronic viral infections such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), and HIV.
• Observed that recent EBV reactivation was most strongly associated with fatigue (OR = 2.12).
• Underlying HIV infection was also independently associated with neurocognitive LC (OR = 2.5).
• But participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR = 0.52).

TriNetX health research database from 69 US healthcare organizations,

• 3,048,792 people with confirmed SARS-CoV-2 infection, 1% were PLHIV, with 9% of PLHIV (were vaccinated, January 2020 and September 2022.
• The primary outcome of study was risk of PASC, compared by HIV and vaccination status after 1:1 propensity score matching.
• PASC was defined as persistence or occurrence of new-onset health conditions at least 28 days following COVID-19.
• At 28 days post-COVID-19 diagnosis, PLHIV had lower mortality compared with their non-HIV counterparts (OR 0.78, 95% CI 0.70-0.87), had higher risk of developing new-onset diabetes (DM) (OR 1·26, 95% CI 1·11-1·42), heart disease (OR 1·27, 95% 1·14-1·41), malignancy (OR 1·66, 95% CI 1·45-1·89), thrombosis (OR 1·25, 95% CI 1·12-1·39) and mental health disorders (OR 1·70 (95% CI 1·53-1·90).

TriNetX health research database from 69 US healthcare organizations

• The risk of PASC was higher during the pre-Delta variant period but did not vary based on CD4 count, HIV viremia or antiretroviral therapy.
• HIV positive status confers a higher risk of PASC. Importantly, COVID-19 vaccination significantly lowered mortality and was protective against PASC among PLHIV.

Studies have shown that HIV status is a risk factor for severe outcomes even among the virologically suppressed This risk is most pronounced in those with comorbidities, viremia, and/or poor immune reconstitution

• Rial-Crestelo D, BisbalO, Font R, et al. Incidence and severity of SARS-CoV- 2 infection in HIV-infected individuals during the first year of the pandemic. J Acquir Immune Defic Syndr 2021; 89:511–518.
• Nomah DK, Reyes-Uruen˜a J, Dı´az Y, et al., PISCIS study group. Sociodemographic, clinical, and immunological factors associated with SARSCoV-2 diagnosis and severe COVID-19 outcomes in people living with HIV: a retrospective cohort study. Lancet HIV 2021; 8:e701–e710.
• Yang X, Sun J, Patel RC, et al., National COVID Cohort Collaborative Consortium. Associations between HIV infection and clinical spectrum of COVID-19: a population level analysis based on US National COVID Cohort Collaborative (N3C) data. Lancet HIV 2021; 8:e690–e700.
• Bertagnolio S, Thwin S, Silva R, et al. Clinical characteristics and prognostic factors in people living with HIV hospitalized with COVID-19: findings from the WHO Global Clinical Platform. In 11th International AIDS Society Conference on HIV Science. 2021. pp. 18–21.

Other contributors to Long COVID like mental health conditions, substance abuse, and lower socioeconomic status are common among PLHIV.

• People with well controlled HIV infection can also exhibit neurocognitive impairment despite ART. The HIV-associated neurocognitive disorder (HAND) in some ways resembles the types of deficits present in neurocognitive Long COVID. Because of these issues, PLHIV may be at increased risk for developing Long COVID.

The persistence of viral genetic material or antigen drives Long COVID

• PLHIV exhibit reduced SARSCoV- 2 viral clearance from tissue reservoirs because of HIVinduced loss or dysfunction of tissue-specific immune cells.
• The role of the SARS-CoV-2 immune response in Long COVID and whether adaptive immune responses to SARSCoV- 2 differ by HIV status are unclear.
• Microvascular dysfunction, platelet activation, and clotting are currently under investigation as potential drivers of Long COVID.

Disruption of the gut epithelial barrier and microbiome dysbiosis are associated with HIV , and so PLHIV might be at increased risk of Long COVID because of gut dysfunction.

• PLHIV may also be primed to develop autoreactive immunity, which has been demonstrated during and just after acute SARS-CoV- 2 infection.
• HIV-specific factors including viral activity and immune responses could contribute to long COVID.
• Two independent studies identified an association of low cortisol levels with Long COVID. Many symptoms of Long COVID overlap with those of adrenal insufficiency ( SACRS COV2 affects adrenals), although most adrenal insufficiency among PLHIV in the ART era is subclinical.

94 participants Zambia,34.1%of had long COVID, Respiratory symptoms (59.5%), musculoskeletal symptoms (28.1%).

• HIV was an independent predictor of long COVID with about 2.7 higher odds (adjusted odds ratio = 2.7; p = .037).
• After stratifying by HIV, IL6 was significantly higher among HIV positives than controls in the HIV‐ group (2.06 vs. 0.81 pg/mL; p = .02). IFN‐β was significantly higher among controls than cases in the HIV+ group (251 vs. 0 pg/mL; p = .01).
• HIV infection is a risk factor for long COVID, and inflammatory markers associated with long COVID are different for HIV− and HIV+ individuals.

Key points – Long COVID among PLHIV

Management of HIV in Long COVID

The principles of ART remain the same in PLHIV with COVID-19

• TREAT All irrespective of CD4 or clinical stage.
• Preferred first line ART regimen for all adult and adolescents is Tenofovir (300 mg) + Lamivudine (300 mg) + Dolutegravir (50 mg) –TLD One tablet once daily (at bedtime or any time fixed as per patient’s convenience)
• Need to take care of drug drug interaction with those taking – Polyvalent cation products containing Al, Ca, Fe, Mg and Zn (e.g.: antacids, multivitamins & supplements). -Administer DTG at least 2 hours before or at least 6 hours after such formulations.
• Rifampicin-Use DTG twice daily or substitute with rifabutin.
• Metformin- Limit daily dose of metformin to 1000mg when used with DTG & monitor glycemic control.

Non-Communicable Diseases (NCD) among PLHIV

NCDs are now becoming one of the leading causes of non–AIDS-related morbidity and mortality in PLHIV

• Common NCDs among PLHIV:
• Cardiovascular disease
• Type 2 diabetes
• Cancer
• Mental health issues, including depression
• Result from a mix of
  • Chronic immune activation
  • Medication side effects
  • Co-infections
  • And the aging process itself

Management of Long COVID among PLHIV

• Needs a holistic, patient-centered approach, focused on ruling out other medically treatable conditions that might mimic symptoms of Long COVID, detection of treatable complications of COVID-19, management of unexplained symptoms, and referral as appropriate for more intensive testing. For PLHIV, evaluate medication adherence and adverse effects, confirm virological suppression and stable immune status, and attend to co morbid medical and psychosocial conditions.
• Deliver coordinated care through a core team that partners with many medical subspecialties (e.g., pulmonology, neurology, cardiology, and psychiatry) and support services (e.g., pharmacy, physical and occupational therapy, social work, and behavioral health).

References:

1. https://www.mohfw.gov.in/
2. Naik, Shivas, Soumendra Nath Haldar, Manish Soneja, Netto George Mundadan, Prerna Garg, Ankit Mittal, Devashish Desai et al. “Post COVID-19 sequelae: a prospective observational study from Northern India.” Drug Discoveries & Therapeutics (2021)
3. Bertagnolio S et al. Clinical features of, and risk factors for, severe or fatal COVID-19 among people living with HIV admitted to hospital: analysis of data from the WHO Global Clinical Platform of COVID-19. Lancet HIV, on line 10 May 2022. https://doi.org/10.1016/S2352-3018(22)00097-2.
4. Pujari S, Gaikwad S, Chitalikar A, et al. Long-coronavirus disease among people living with HIV in western India: an observational study. Immun Inflamm Dis 2021; 9:1037–1043
5. Mazzitelli M, Trunfio M, Sasset L, et al. Factors Associated with Severe COVID-19 and Post-Acute COVID-19 Syndrome in a Cohort of People Living with HIV on Antiretroviral Treatment and with Undetectable HIV RNA. Viruses 2022; 14:493.
6. Peluso MJ, Spinelli MA, Deveau T-M, et al. Postacute sequelae and adaptive immune responses in people with HIV recovering from SARS-COV-2 infection. AIDS 2022; 36:F7–F16.
7. Peluso MJ, Deveau T-M, Munter SE, et al. Chronic viral coinfections differentially affect the likelihood of developing long COVID. J Clin Invest 2022; 133:e16366
8. Yendewa G, Perez JA, Patil N, McComsey GA. HIV infection is associated with higher risk of post-acute sequelae of SARS-CoV-2 (PASC) however vaccination is protective. Available at SSRN: https://ssrn.com/abstract= 4276609 or http://dx.doi.org/10.2139/ssrn.4276609.
9. Peluso MJ, AntarAAR. Long COVID in people living with HIV. Curr Opin HIV AIDS.2023 May 1;18(3):126-134
10. Peluso MJ, AntarAAR. Long COVID in people living with HIV. Curr Opin HIV AIDS.2023 May 1;18(3):126-134
11. Patrick Kamanzi1,Gina Mulundu, Keagan Mutale,Chibamba Mumba, Owen Ngalamika. HIV and inflammatory markers are associated with persistent COVID‐19 symptoms Immun Inflamm Dis. 2023;11:e859.

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