CME INDIA Presentation by Dr. B. B. Rewari, MD, FRCP, FICP, MPH Regional Advisor-Hepatitis/HIV/STIs World Health Organization, Regional Office for South-East Asia, New Delhi; Bbrewari@hotmail.com.
On 1 December WHO Joins Partners To Commemorate World AIDS Day 2022, Under The Theme “Equalize.”
What You May Already Know About ART?
|The preferred first line regimen for initiation of ART Naive PLHIV, including women of Child-Bearing Age-Group:|
|Fixed dose combination of Tenofovir (300 Mg) + Lamivudine (300 Mg) + Dolutegravir (50 Mg) (TLD)|
- ART is to be provided to all HIV infected persons irrespective of cd4 count or viral load.
- It is a lifelong therapy as it does not cure HIV.
- Persons on ART need to be monitored with viral load at 6 months after initiating ART and then annually.
- people with advanced disease need more focused interventions.
Management of HIV
- Multi-Disciplinary Approach-Physician, Lab Expert, Nutritionist, Psychologist, Care Giver.
- Early suspicion, diagnosis and linkage to care.
- 4 Pillars on Management:
- General Management.
- Treatment of Opportunistic Infections.
- Chemo Prophylaxis of Opportunistic Infections.
- Antiretroviral Treatment.
- Prevention of Transmission.
Initial Quick Strides on HIV Care
Antiretroviral Therapy (ART)
- ART is the combination of different classes of ARV Drugs:
- To achieve maximal and most durable suppression of viral replication.
- To prevent emergence of drug resistant mutants.
- To improve survival and quality of life.
Impact of ART
Credit: Images Courtesy Paediatric Coe, Sion, Mumbai And GHTM Tambaram.
Goals Of ART
|Clinical Goals||Improvement in quality of life and prolongation of life|
|Virological Goals||Greatest possible sustained reduction in viral load|
|Immunological Goals||Immune reconstitution, that is both quantitative and qualitative|
|Therapeutic Goals||Rational sequencing of drugs in a manner that achieves clinical, virological and immunological goals while maintaining future treatment options, limiting drug toxicity and facilitating adherence|
|Prevention Goals||Reduction of HIV transmission due to suppression of viral load|
Classes of ARV Drugs
When do we start art in an HIV infected person?
Overview of when to start ART studies
Timely initiation of ART-Treat all
Why we need three drugs?
Why we cannot still cure HIV with ART
How has ART evolved over years?
- The problems with pi based regimen were high costs, large number of pills and high frequency of side effects of these drugs.
- In 2000 – discovery of nevirapine simplified the therapy, the newer drug reduced side effects.
- An Indian pharma company announced to make ARV fixed dose combinations in generic form @ one USD/day, FDC the number of pills reduced from 32 to 1 per day.
- WHO 3 by 5 programme for free ART in developing countries gave a big push to expansion of art access.
- Art reduced progression to AIDS, reduced ois, reduced hospitalizations, reduced mortality and increased people returned to work.
ART has changed the outlook of HIV/AIDS from a ‘Virtual Death Sentence’ to a ‘Chronic Manageable Disease.’
Changing paradigm on when to start, what to start and how to monitor?
What ART regimen to start within PLHIV (Till 2016)?
- Two Nrtis (Nucleotide / Nucleoside Reverse Transcriptase Inhibitors)
- Tenofovir (TDF) 300 Mg + Lamivudine (3TC) 300mg
- One NNRTI (Non Nucleoside Reverse Transcriptase Inhibitor)
- Efavirenz (EFV) 600mg
- Preferred Regimen:
- Tenofovir (300 Mg) + Lamivudine (300 Mg) + Efavirenz (600 Mg), one tablet daily at bedtime
What are updates in ART 2019 – 2021?
- Dolutegravir (DTG) is an integrase inhibitor (INSTI) first approved in 2013 by USFDA.
- Effective (Rapid Viral Load Suppression).
- Well tolerated.
- High genetic barrier to resistance.
- Few drug interactions.
- Single and as fixed dose formulation (TLD).
- Rapid viral suppression: Achieves viral suppression sooner than EFV (Avg. 4 weeks for DTG Vs 12 weeks for EFV).
- Fewer toxicities and side effects: Minimal discontinuations (<2%), less than with EFV. Rash (2% Vs 13%) and neuropsychiatric events (including dizziness) were significantly more common with EFV (5% Vs 35%), while insomnia was reported more frequent in DTG (13% Vs 7%) (SINGLE Study).
- More potent regimen: No known treatment-emergent resistance across trials.
- Minimal drug interactions: Currently recommended to increase to 50mg BID for TB-coinfection treatment with rifampicin.
- High genetic barrier.
- Effective against HIV 2.
- Harmonization across patient populations.
Current standard of care 2022
|Fixed dose combination (FDC) of Tenofovir (300 Mg) + Emtricitabine 200mg/ Lamivudine (300 Mg) + Dolutegravir (50 Mg), in one tablet daily is preferred first line regimen for all adults and adolescents|
|DTG is approved by the USFDA for use, in combination with other ARV drugs, in pediatric patients at least 4 weeks of age and weighing at least 3 Kg who are treatment-naive or treatment-experienced but INSTI-Naive|
|Viral load monitoring is preferred option for monitoring PLHIV on ART. Use of POC technologies helps get results faster to patients.|
|urgent need to focus on patients presenting late to care to reduce mortality (Advance HIV Disease).|
Side effects of DTG
- Allergic Reactions.
- DTG-Associated Weight Gain.
(WHO recommendations also highlight the importance of a healthy diet and regular exercise to help manage weight).
Precautions While Giving Tenofovir
- Closer monitoring of S. Creatinine should be done in following patients:
- Age >40yrs.
- Underlying renal disease.
- Diabetes mellitus.
- Concomitant use of nephrotoxic drugs.
- If creatinine level is high (Above ULN For Lab), calculate creatinine clearance rate (Cr Cl).
- TDF should be avoided if Crcl is <50ml/Min.
ART regimen in ART naive adults and adolescents
Preferred first line ART regimen for all* PLHIV with Age >10 Years and Weight >30kg
Tenofovir (300 Mg) + Lamivudine (300 Mg) + Dolutegravir (50 Mg) – FDC one tablet one tablet once daily (at bedtime or any time fixed as per patient’s convenience).
*Including: HIV 1, HIV 2, HIV 1 & 2, women exposed to single dose nevirapine in past and PLHIV coinfected with TB or Hepatitis B & C.
Note: women of child bearing age or potential should be provided informed choice about the immense benefits and very small risks for the use of dolutegravir (DTG) in first trimester.
NACO Guidelines: Special Situations
|Condition (Exception)||Alternate Regimen|
|PLHIV With Body Weight <30 Kg||Abacavir 600mg + Lamivudine 300mg, One Tablet + Dolutegravir (50 Mg) Once Daily ALD|
|All patients with high (above ULN For Lab) serum creatinine values (calculate creatinine clearance)||Abacavir 600 Mg OD, Lamivudine (as per creatinine clearance) and Dolutegravir 50 Mg once daily (As Separate Drugs)|
|PLHIV on Rifampicin containing ATT Regimen*||Tenofovir (300 Mg) + Lamivudine (300 Mg) + Dolutegravir (50 Mg) once daily (FDC In Evening) Additionally Dolutegravir 50 Mg (Morning)|
Considerations Before Initiation Of ART
- Patient should be adequately prepared and consent should be obtained from the patient or from caregiver, in-case, patient being a minor, before initiating into HIV care, including ART.
- Treatment should be started based on a person’s informed decision and preparedness to initiate ART on the benefits of treatment, understanding of lifelong medication, adherence issues and positive prevention.
- A caregiver should be identified for each person to provide adequate support. Caregivers must be counselled and trained to support treatment adherence, follow-up visits and shared decision-making.
- All patients with clinical stage 3 and 4 and those with CD4 less than 350 Cells/Cmm need to be put on Co-Trimoxazole Preventive Therapy (CPT)
Baseline investigations: Essential tests for all patients registering in HIV care at ART centre
- Urine for routine and microscopic examination.
- Fasting blood sugar.
- Blood urea, serum creatinine.
- Serum Bilirubin, ALT (SGPT).
- CD4 Count.
- Lipid profile (if available).
- Hbsag and Anti-HCV Igg (if available).
Updated PEP Guidelines
What else is new in HIV?
WHO definition of advanced HIV disease:
- For adults and adolescents, and children older than five years, advanced HIV disease is defined as CD4 cell count <200 Cells/Cmm or WHO stage 3 or 4 event
- All children younger than five years old with HIV are considered as having advanced HIV disease.
- CD4 count at baseline remains essential.
- Relying on clinical stage alone risks missing substantial numbers of people living with HIV with severe immunosuppression.
Recommendations for rapid ART initiation
- Rapid initiation is defined as within seven days from the day of HIV diagnosis; people with advanced HIV disease should be given priority for assessment and initiation.
- Rapid ART initiation should be offered to all people living with HIV following a confirmed HIV diagnosis and clinical assessment.
- ART initiation should be offered on the same day to people who are ready to start.
What is in future?
2 Prominent trends in ART guidelines:
- Fewer Drugs: Dual therapy options emerging and in development that reduce the burden of drug classes.
- Long-Acting Formulations: Injectables, implants; much less frequent dosing to simplify disease management.
HIV Cure Research:
- Evidence from HIV cure in timothy brown in Germany and one more patient in UK do offer some hope in future.
- An immune therapy approach is more likely to deliver long-term remission of HIV.
- The combination of injectable antiretroviral therapy soon after infection and vesatolimod (a novel immune-activating drug) quickly suppressed viral load and is being researched further.
- An HIV vaccine that induces cells to make their own virus-like particles that look like HIV is under investigation.
CME INDIA Learning Points
|All PLHIV should undergo a comprehensive clinical and laboratory evaluation to assess baseline status before art initiation.|
|CD4 is no longer a requirement to start ART but is needed to diagnose and manage advanced disease.|
|Assessment and management of advanced HIV disease will help reduce morbidity and mortality.|
|NACO’s “TREAT ALL Concept” means “all persons diagnosed with HIV infection are eligible for art initiation regardless of CD4 count or who clinical staging.”|
|Counseling of PLHIV and caregiver for preparedness and healthy living practices is essential before starting ART.|
|Recommended first line regimen is TDF+3TC+DTG.|
|Monitor patients on ART by viral load at six months after initiation and then annually if virally suppressed.|
CME INDIA Tail-Piece
Key Facts (WHO)
- To reach the new proposed global 95–95–95 targets set by UNAIDS, we will need to redouble our efforts to avoid the worst-case scenario of 7.7 Million HIV-Related deaths over the next 10 years, increasing HIV infections due to HIV service disruptions during COVID-19, and the slowing public health response to HIV.
- HIV continues to be a major global public health issue, having claimed 40.1 Million [33.6–48.6 Million] Lives So Far.
- In 2021, 650 000 [510 000–860 000] People Died From HIV-Related Causes And 1.5 Million [1.1–2.0 Million] People Acquired HIV.
- There is no cure for HIV infection. However, with increasing access to effective HIV prevention, diagnosis, treatment and care, including for opportunistic infections, HIV infection has become a manageable chronic health condition, enabling people living with HIV to lead long and healthy lives.
- There were an estimated 38.4 Million [33.9–43.8 Million] people living with HIV at the end of 2021, two thirds of whom (25.6 Million) are in the WHO African region.
Based on a presentation at BAPICON-2022, Muzaffarpur.
- SINGLE: J Acquir Immune Defic Syndr. 2015 [Epub Ahead Of Print]
- FLAMINGO: Lancet 2014;383:2222-31
- SPRING-2: Lancet 2013,381:735-43
- SAILIN:, Lancet. 2013, 382:700-8
- VIKING: J Infect Dis. 2014, 210:354-62; Adapted From Walmsley S, Et Al. N Engl J Med 2013; 369:1807-18
- Ford Et Al, AIDS 2018; Rosen Et Al Plos Med 2016
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