Francesca Tomasi received her B.A. from the University of Chicago and is now a microbiologist.
As with any infectious disease capable of varying levels of pathogenicity and drug resistance, the World Health Organization has an established treatment regimen for Human Immunodeficiency Virus (HIV) to outline the most effective drugs in the order they should be considered. An emerging first-line drug for HIV-1, one of the two main genetic types of the virus, is an antiretroviral called tenofovir. This nucleotide reverse transcriptase inhibitor (NRTI) stops the enzyme that converts HIV genetic information (RNA) into DNA that can be integrated into a person’s own genome. Tenofovir is used in combination with other drugs to prevent immunological deterioration in newly-diagnosed individuals and to halt the spread of HIV-1 from these patients to others. This regimen is commonly referred to as “treatment as prevention” and is especially important in high-risk and high-incidence regions. Pre-exposure prophylaxis (PrEP), which is supposed to prevent the acquisition of HIV should somebody be exposed, fully depends on tenofovir.
Resistance to to the nucleotide reverse transcriptase inhibitor is typically the consequence of a single point mutation in the reverse transcriptase gene itself that allows it to continue its role uninhibited. Interestingly, tenofovir has been shown to have differing resistance profiles between different income settings: high-income regions tend to report low prevalence of HIV-1 resistance to tenofovir, whereas low to middle-income regions tend to report a much higher prevalence. Because of the seemingly low genetic barrier to first-line HIV-1 drug resistance, a group of researchers recently performed a global epidemiological assessment of the situation in 36 countries spanning Europe, Latin America, North America, sub-Saharan Africa, and Asia.
The study has three principle findings re: prevalence, risk factors, and transmissibility of tenofovir resistance. With regards to prevalence, the range of resistance goes from 20% in Europe to over 50% in sub-Saharan Africa. Risk factors include different drug combinations – for instance, treatment with nevirapine versus efavirenz and lamivudine versus emtricitabine are associated with a 50% increase in tenofovir resistance odds. In terms of transmissibility, viral loads – the amount of HIV-1 virus detected in a patient, which correlates to the likelihood of passing the virus on – were similar in the presence or absence of tenofovir resistance in patients with viral failure (when antiretroviral therapy fails to sustainably suppress one’s viral load).
These findings are significant when considering the aforementioned genetic barrier to resistance: it turns out that every drug in the first-line strategies in resource-limited settings can be compromised by a single point mutation (switch from one amino acid in the genetic code to another). As a result, combination therapy could inherently be brittle, and it is important to figure out the best ways to detect or prevent the emergence of drug resistance. The authors of this study speculate that the regional variation in tenofovir resistance is a consequence of varying levels in patient follow-up and viral load monitoring. Viral load monitoring is not a routine procedure in low to middle-income countries, whereas in high-income countries it is tested three to four times a year along with frequent patient follow-up and support for therapy adherence. Such consistent habits lead to earlier detection of viral failure, which likely precedes the appearance of resistance mutations – drug resistance is a lot less likely to occur in a low viral load simply because resistance mutations are a numbers game. The more virus, the higher the chance that one particle acquires a resistance mutation that can then be amplified into the norm. Therefore, monitoring viral load is key to ensuring that a specific drug is working well enough to hold the virus at bay.
With regards to the risk factor of different drug combinations increasing the likelihood of resistance, one very important feature can account for a substantial piece of the puzzle. Efavirenz, one of the drugs found in the study to be less of a risk factor for increased tenofovir resistance, is associated with more significant central nervous system side effects than its potential replacement nevirapine. Distressing side effects alone could be the reason for treatment failure: why would someone want to continue taking the drug if it interrupted their sleep? Even though nevirapine is found to be associated with a 50% increase in tenofovir resistance, it does not have as severe side effects and is therefore a more likely first choice for patients.
Despite some limitations to the study which are discussed in the paper, the aforementioned findings shed a light on the circumstances surrounding drug resistance in first-line HIV-1 treatment regimens. Tenofovir resistance tends to emerge in a higher proportion of patients with viral failure in low to middle-income regions. As a result, it is important to optimize treatment programs and drug resistance transmission surveillance. There is a reason first line drugs are deemed “first line” – the second and third lines tend to be more toxic to the patient and/or less effective. They are a backup, not the drug of choice; therefore, it is in everybody’s best interest to figure out what it takes to keep the first-line drugs as safe and effective as possible.