Discovery of antiretroviral drugs (ARVs) in 1996 has sparked a revolution in the treatment of people with HIV-AIDS (PLWHA). The medical management of HIV infection involves ARV treatment, which aims to reduce the rate of HIV transmission in the community, decrease morbidity and mortality, improve the quality of life of PLWHA, restore/maintain immune system function, suppress viral replication maximally and continuously.

Currently, there are more than 40 types of antiretroviral drugs approved for the treatment of HIV. Over time, modern ARV therapy has evolved to a point where drug side effects have been reduced, and they remain effective in suppressing the virus.

Antiretrovirals (ARVs) are part of the HIV and AIDS treatment to reduce the risk of HIV transmission, inhibit opportunistic infections, improve the quality of life of HIV patients, and reduce the viral load in the blood to undetectable levels.

So far, there are three main groups of ARV drugs used for HIV treatment in Indonesia:

1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs), such as Zidovudine, Lamivudine, Abacavir, Tenofovir, Didanosine, and Emtricitabine.

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), such as Efavirenz, Nevirapine, and Rilpivirine.

3. Protease Inhibitors (PIs), such as Lopinavir/Ritonavir.

In July 2018, WHO recommended dolutegravir, which belongs to the class of Integrase Inhibitors (INIs), as an alternative for HIV treatment, particularly for those who were previously using efavirenz. This has expanded the range of ARVs used in Indonesia.

Mechanism of Action of Dolutegravir

Dolutegravir works by inhibiting integrase, an enzyme that HIV needs to insert the virus into the DNA of host CD4 T-cells. When HIV infects a cell in the human body, the genetic code of HIV is integrated into the host cell's DNA with the help of the integrase enzyme. Dolutegravir inhibits the action of this enzyme, preventing the integration of HIV DNA into the host cell's DNA. As a result, HIV can infect the cell but cannot replicate itself.

Dosage

- 50 mg once daily for adults and adolescents aged 12 and above with a body weight of 40 kg or more, who have never used ARVs before or have previously used ARVs other than integrase inhibitors.
- 50 mg twice daily for patients who have previously used integrase inhibitors and patients with known or suspected resistance to other integrase inhibitors.
- 50 mg twice daily for those taking the following drugs without considering prior exposure to integrase inhibitors: efavirenz, rifampin, fosamprenavir/ritonavir, tipranavir/ritonavir.

Side Effects

Dolutegravir's inhibition of the integrase enzyme doesn't cause toxicity in humans because human cells lack this enzyme. Common side effects include headaches, nausea, and diarrhea, with only 1% experiencing severe reactions. Compared to efavirenz and PI-based regimens, dolutegravir rarely leads to treatment discontinuation due to side effects. Nevertheless, dolutegravir is still considered to have neuropsychiatric-related side effects that may lead to treatment discontinuation.

Drug Interactions

Dolutegravir interacts with some other antiretroviral drugs and other medications:

- Nevirapine: can lower dolutegravir levels.
- Oskabamarzepin, phenytoin, phenobarbital, carbamazepin: can lower dolutegravir levels.
- Antacids or cation-containing laxatives, sucralfate: can decrease dolutegravir levels.
- Metformin: can increase dolutegravir levels.
- Rifampicin: can lower dolutegravir levels.

Special Populations

Dolutegravir is contraindicated in patients with a history of hypersensitivity reactions to dolutegravir, children under 6 years of age, women planning pregnancy or in the first trimester of pregnancy, and some patients with organ function abnormalities requiring adequate dosage adjustment and monitoring.

Efficacy of Dolutegravir

Studies have shown the efficacy of dolutegravir:

1. Christopher & Sharon (2015) stated that dolutegravir, the latest INSTI, is an effective antiretroviral agent for treatment-naive patients and treatment-experienced patients infected with HIV. This is driven by effective virological suppression, good tolerability, rare drug-drug interactions, and once-daily dosing. The co-formulation of dolutegravir with abacavir-lamivudine maximizes compliance and should be considered as an initial option for treatment-naive patients.

2. Analú Correa et al. (2020) concluded that dolutegravir has proven to be a drug with a high virological response and good tolerability, with a low frequency of mild and moderate side effects.

3. Eugenia et al. (2018) mentioned that the main advantage of DTG-based regimens is the potential to reduce the pill burden to two pills once a day, improving treatment adherence and a low risk of additional drug resistance mutations.

4. Nsirimobu & Rosemary (2020) showed that DTG-based fixed-dose combination (FDC) is effective in treating children and adolescents with HIV/AIDS, with significant viral load suppression in all age groups, genders, and social classes. Adverse drug reactions with DTG-based ARVs are low.

Availability of Dolutegravir

Dolutegravir is currently available in Indonesia in both single form (dolutegravir 50mg tablet) and as a fixed-dose combination (FDC) consisting of tenofovir 300mg, lamivudine 300mg, and dolutegravir 50mg, known as FDC TLD.

The Indonesian government has ensured the safety and legality of FDC TLD, which has been approved by the National Agency of Drug and Food Control (BPOM) under the trade name Acriptega® since September 2020. Additionally, both the single form and FDC TLD of dolutegravir have been included in the National Formulary (Fornas) as part of the HIV program in 2021.

Advantages of Dolutegravir

1. Proven to be more effective at rapidly suppressing HIV, especially in treatment-naive patients and those with resistance issues to other antiretrovirals.
2. Good tolerability, with fewer and milder side effects and minimal drug interactions compared to other agents.
3. Smaller tablet size for easier swallowing.
4. Available as a fixed-dose combination (FDC TLD), reducing the number of pills to be taken to one tablet once daily.
5. Can be taken with or without food.
6. Lower likelihood of treatment failure.

Conclusion

Since its introduction, dolutegravir has garnered attention as a promising option for the treatment of HIV, with high effectiveness in suppressing the virus

. Further clinical studies are ongoing to assess the efficacy and safety of dolutegravir. From the cited research, it can be concluded that dolutegravir is currently recommended as a primary choice for HIV treatment. Dolutegravir has demonstrated high virological suppression with milder side effects and fewer drug interactions. Therefore, it offers hope for reducing morbidity and mortality from HIV-AIDS through optimal treatment, contributing to the achievement of the "Three Zero" targets by 2030.

Author: apt. Hafiz Surahman, S.Farm.
References: 

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6.     Cristopher & Sharon. 2015. Dolutegravir – a review of the pharmacology, efficacy, and safety in the treatment of HIV. Dalam website : https://www-ncbi-nlm-nih.gov.

7.     Correa Analú et al (2020). Dolutegravir: Virologic response and tolerability of initial antiretroviral regimens for adults living with HIV. https://doi.org/10.1371/journal.pone.0238052.

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