Prof. Dr. Alaka Deshpande comments on WHO's latest recommendation for the use of Dolutegravir as the preferred first-line ARV for HIV positive patients. She also mentions that while NACO may follow in this direction, patient counselling and rigid adherence are still key to success.

WHO’s latest antiretroviral therapy guidelines have recommended Dolutegravir to be used as a first and second-line Anti-Retroviral therapy. The 2019 updated guidelines provide the latest recommendations based on rapidly evolving evidence of safety and efficacy and programmatic experience using dolutegravir (DTG) and efavirenz (EFV) 400 mg in pregnant women and people coinfected with TB.

It has been four decades that attempts to eradicate the HIV have not been successful, although the multipronged approach has met with some success of limiting the epidemic. The various therapeutic strategies have decreased the morbidity, increased the longevity of patients, and the infection has changed into a chronic manageable infection. As in any chronic disease one has to have a planned therapeutic strategy in the form of first-line, second-line, third-line treatments and salvage therapy.

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After understanding the HIV viral lifecycle, various enzymes necessary for its replication were identified as therapy targets.

Reverse Transcriptase enzyme	NRTI, NtRTI, NNRTI group of drugs
Protease enzyme	Protease inhibitors (with pharmaco-enhancers)
Integrase Enzyme	InSTI... Raltegravir, Dolutegravir

The therapy is lifelong. Very high replicative rate of the virus and rapid emergence of drug resistance necessitates a rigid adherence to therapy. Long-term toxicities of the existing drugs and emergence of drug resistance compels the development of new molecules.

Therapy guidelines are revised from time to time based on expanded evidence whenever a new drug or a class of drugs are added to armamentarium.

The treatment success of a new class of drugs depends on its:

• Long-term efficacy
• Better safety profile
• High tolerability
• High genetic barrier
• Activity on resistant strains
• Ease of daily administration
• Limited pill burden
• Activity against HIV-1 and HIV -2

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DHHS guidelines 2009, has included Raltegravir, the first ITI, in a PREFERED (first-line) regimen along with NRTI backbone.

Dolutegravir is the second-generation Integrase strand transfer inhibitor (InSTI). Unique features of DTG are:

1. Half-life of 14 hours so dosing is daily one tablet
2. Ease of administration improves drug adherence
3. A high antiviral potency to wild type and virus resistant to the existing classes of antiretroviral agents including Raltegravir
4. Does not require pharmacological enhancers or boosters
5. A very rapid inhibition of viral replication both HIV-1 & HIV 2 with a maximal effect obtained within week 8 and week 12, shorter than with any other standard regimen
6. High tolerability without any undesirable metabolic effects including dyslipidaemia, glucose intolerance or lipodystrophy
7. Has a higher barrier for the development of drug resistance
8. Effective in treating virus that is resistant to the first generation of INI
9. DTG is not an inhibitor or inducer of CYP isozymes, and therefore has a low propensity to cause significant drug interactions
10. With regard to antiretroviral drugs, DTG had no significant effect on tenofovir exposure

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WHO reccomendations are given below

DTG is now included as a preferred drug with NRTI backbone for all groups. It is also recommended as a second-line drug for ARV experienced cases with treatment failure.

HIV & Pregnancy

The 2019 updated guidelines provide the latest recommendations based on rapidly evolving evidence of safety and efficacy and programmatic experience using DTG in HIV-TB co-infection and pregnancy.

The risk of neural tube defects associated with using DTG at conception has declined since the initial report released in May 2018 yet remains statistically significantly higher than in other ARV drug exposure groups. ‘It may also be pointed that food fortification with folate seen in developed countries is lacking in underprivileged.

With recent data made available from expanded Ministry of Health and CDC surveillance from Botswana, the weighted estimate risk remains low at 0.36% (95% CI 0.10 – 0.62). Continued surveillance is needed to more definitively confirm or refute the neural tube defect signal, and several studies are ongoing to address this.’

The WHO release in this week states, "But new data from two large clinical trials comparing the efficacy and safety of DTG and efavirenz (EFV) in Africa have now expanded the evidence base.The risks of neural tube defects are significantly lower than what the initial studies may have suggested,’’ the release said.

• Counselling of the mother is essential. A woman-centred approach is underpinned by two guiding principles: promoting human rights and gender equality
• Instead of DTG, Raltegravir may be used at periconception
• The therapy option is to be discussed with the prospective mother

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HIV-TB

Among people coinfected with HIV and TB, the dose of DTG needs to be increased to 50 mg twice daily because of drug–drug interactions with rifampicin. This extra dose of DTG is well tolerated, with equivalent efficacy in viral suppression and recovery of CD4 cell count compared with EFV.

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HIV & Children

1. DTG is approved for use among children older than six years and is widely available for children weighing at least 20 kg who can take 50 mg film coated adult tablets.
2. DTG dosing for children weighing less than 20 kg is expected in late 2019, and a dispersible tablet for children is being developed, with approval expected in mid-2020.
3. Among children for whom approved dosing of DTG is not available, raltegravir (RAL) is considered an effective option and is approved for use from birth. RAL successfully reduces viral load among highly viraemic infants and is safe and well-tolerated among neonates and infants at high risk of infection.

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Post-exposure prophylaxis (PEP)

CDC recommended DTG along with TDF+ 3 TC for PEP considering a risk of needle stick injury from treatment experienced population with a risk of acquisition of a drug-resistant virus. Recently CDC has recommended Raltegravir in place of DTG particularly for female HCW in view of conception.

In 2019, 12 of the 18 countries surveyed by WHO reported pre-treatment drug resistance levels exceeding the recommended threshold of 10%.

Considering the situation, the recommendations of WHO 2019 include DTG as preferred first-line ARV along with NRTI backbone. It is also recommended as a second-line drug for treatment experienced cases.

Population	Preferred first-line regimen	Alternative first line
Adults and adolescents	TDF + 3TC (or FTC) + DTG	TDF + 3TC (or FTC) + EFV 400
Children >4 years of age; >20 kg weight	ABC + 3TC + DTG (age & weight)	ABC + 3TC + LPV/r ABC + 3TC + RAL TAF + 3TC (or FTC) + DTG
Neonates	AZT + 3TC + RAL	AZT + 3TC + NVP

As the number of cases who are exposed to earlier first-line therapy or cases of treatment failure with raised viral load are increasing in third world countries, DTG is a drug of choice for second-line ART considering its efficacy and resistance pattern.

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