Table of Contents
I. Introduction
• Number of people living with HIV
• Antiretroviral therapy and drug resistance
• Impact of drug resistance in low-middle income countries
II. Types of HIV Drug Resistance (HIVDR)
• Acquired HIVDR
• Transmitted HIVDR
• Pretreatment HIVDR
III. HIV Drug-resistance testing
• Genotypic Assays
• Phenotypic Assays
• Viral load testing
IV. Challenges of Health-Care Providers
• Results of WHO online survey of healthcare workers
• Challenges in changing to non-NNRTI-containing first-line regimen
• Preferred and alternative regimens by age and drug class
V. Treatment scope
• 2016 WHO consolidated ARV guideline for first-line ART regimens
VI. Conclusion
An estimated 36.7 million people in the world today are living with HIV, and around 19.5 million people are undergoing antiretroviral therapy. Though the treatment is highly effective in managing the illness, an increased number of patients are currently experiencing drug resistance.
HIVDR occurs with a mutation of HIV thus affecting the ability of drugs to prevent the replication of the virus. It is a severe threat particularly in sub-Saharan Africa and other low-middle income countries where poor access to diagnostics can make the management of the disease even more challenging.
The current antiretroviral (ARV) drugs including the newer classes are at the risk of becoming wholly or partially inactive due to the drug-resistant virus. This risk affects the success rate of an effective treatment for HIV and preventing the target to end AIDS epidemic as a global threat. In 2016, WHO guidelines on the use of antiretroviral drugs as the treatment of HIV infection recommended treating everyone diagnosed with HIV regardless of the CD4 count. The recommended first-line ART regimen for HIV patients is based on non-nucleoside reverse transcriptase inhibitors (NNRTI). World Health Organization in 2017 has recommended an alternative treatment particularly for countries with drug resistance prevalence at above 10%.
Types of HIV Drug Resistance (HIVDR)
Acquired HIVDR- This occurs with HIV mutation developing among individuals receiving the treatment with ARV drug. It can be of poor health service quality, treatment interruptions, sub-optimal treatment adherence or insufficient drug concentrations in the body.
Transmitted HIVDR – This occurs when an uninfected individual with no history of exposure to ARV drug is infected with a drug-resistant strain of HIV from an individual with HIVDR mutations.
Pretreatment HIVDR – It is detected among those with no history of ARV drug or reinitiating first-line ART therapy after treatment interruption. It can also be the result of either acquired, transmitted HIVDR or both. With ARV drugs as the treatment option among HIV infected individuals, an increase in pretreatment HIVDR has been confirmed by various nationally representative surveys.
HIV Drug-resistance testing
HIV drug resistance test identifies the drugs no longer effective against an individual’s strain of HIV. Normally, the drug resistance test is performed before the initiation of HIV treatment in order to detect infection with a drug-resistant strain of HIV and also to select suitable treatment strategies as the first HIV regime. The testing can deliver information on resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (INSTIs) and protease inhibitors (PIs).
- Genotypic Assays: most involve sequencing the reverse transcriptase (RT), integrase (IT) and protease (PR) genes to identify mutations. The assays are relatively fast, delivering results within 1 to 2 weeks. The interpretation of the results can be difficult and thus, International AIDS Society-US offers an updated list of resistance-associated mutations in the RT, PR, IN and envelope gene.
- Phenotypic Assays: monitors the capacity of the virus to multiply in various concentrations of ARV drugs. Automated phenotypic assays can deliver results within 2 to 3 weeks.
HIV Phenotypic testing
- Viral load testing: this helps monitor viral load and to detect possible drug resistance when genotypic and phenotypic testing are unavailable. This test detects the quantity of virus in an individual acting as a marker of either the success or the failure of HIV treatment.
Challenges of Health-Care Providers
In an online survey of health care workers by WHO conducted in 2017, a total of 396 responses were received from 61 countries of which 85% were from low to middle-income countries. One of the major challenges of altering from the current first-line ART regimen to a non-NNRTI-containing first-line regimen was the unavailability and unaffordability to alternative regimens. An estimated 42% of the respondents said that current practice was to initiate everyone on the same NNRTI-based first-line ART regimen even with the perceived pretreatment HIVDR risk. However, some of the challenges involved in changing to the alternative non-NNRTI-containing regimen are; training of the health-care workers, the identification of eligible people and availability of the regimens at the clinic.
Preferred and alternative regimens by age and drug class
In 2017, Brazil’s Ministry of Health implemented DTG for those initiating first-line ART because of improved viral response and with the overall NNRTI resistance prevalence reaching about 7% and 11% in south-eastern Brazil. However, among the middle–high income countries, a non-NNRTI regimen is used only for people identified as high risk of pretreatment HIVDR.
In terms of HIVDR testing, a survey conducted by WHO shows that the majority of health-care workers (57%) mentioned that access to routine HIVDR testing is not available at the clinics and only 14% respondents (from low – middle income countries) mention they perform HIVDR testing before initiation of the treatment.
Treatment scope
In accordance with 2016 WHO consolidated ARV guideline, the recommended first-line antiretroviral therapy (ART) regimens for adults include tenofovir disoproxil fumarate (TDF) + lamivudine or emtricitabine (XTC) + efavirenz (EFV) as a fixed dose combination. The alternative non-NNRTI-containing first-line ART regimens include TDF+ XTC + dolutegravir (DTG) as the alternative option and regimens containing co-formulated boosted protease inhibitors (Pl/r) including boosted atazanavir (ATV/r), LPV/r and darunavir (DRV/r) as alternative options.
Since NNRTI-containing regimens are the recommended first-line regimen and HIVDR testing is not readily available in low-income countries, hence a fully effective treatment is not established in the case of drug resistance thereby encouraging the transmission of HIVDR.
WHO treatment guidance
According to WHO 2017 HIVDR guidelines, it recommends that in the case of countries presenting prevalence of NNRTI resistance of 10%, an alternative non-NNRTI treatment regime should be considered. This calls for the integrase inhibitor, doultegravir as the first-line of treatment for all individuals starting initial treatment. As low resource countries may not be able to provide doultegravir, priority should be considered for those at the risk of developing HIVDR.
A new complete regimen as an alternative option
Delstrigo
Delstrigo was recently approved by the U.S Food and Drug Administration (FDA) for the treatment of HIV individual. It is a complete regimen and should not be used in combination with other HIV drugs. Delstrigo contains doravirine (NNRTI), lamivudine (NRTI) and tenofovir disoproxil fumarate (NRTI). This drug blocks an HIV enzyme called reverse transcriptase by suppressing the multiplication and therefore decreasing the amount of HIV.
Pifeltro
Pifeltro is also approved by the FDA based on the findings from randomized, active controlled Phase 3 trial. It is administered orally once a day for the treatment of HIV-1 infection among adults without a prior antiretroviral treatment.
References
http://apps.who.int/iris/bitstream/handle/10665/255880/9789241550055-eng.pdf?sequence=1
https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/56/drug-resistance
https://www.avert.org/professionals/hiv-programming/treatment/drug-resistance
http://aidsinfonet.org/fact_sheets/view/126?lang=eng
http://www.who.int/news-room/detail/20-07-2017-who-urges-action-against-hiv-drug-resistance-threat
http://apps.who.int/iris/bitstream/handle/10665/255883/9789241512848-eng.pdf?sequence=1
https://aidsinfo.nih.gov/drugs/600/delstrigo/0/patient
https://www.pharmafield.co.uk/pharma_news/new-hiv-drugs-delstrigo-pifeltro-approved-by-fda/