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Understanding HIV Drug Resistance, Minimizing Disease Transmission

Minimizing HIV transmission requires a multifaceted approach, including understanding HIV drug resistance and its implications.

Veronica Salib
By
Published: 16 Aug 2023

Despite having multiple tools and resources to minimize the transmission of human immunodeficiency virus (HIV), the growing rate of drug resistance has forced scientists and medical professionals to explore viral mutations more closely.

Acquired immunodeficiency syndrome (AIDS) was, at one point, the inevitable death sentence that resulted from infection with HIV — viral mutations in the positive-sense single-stranded RNA of HIV cause the condition.

The more aggressive version of HIV is HIV-1, which tends to transition into AIDS. A 2023 article published in Microorganisms notes that, while the HIV-1 virus was present in Africa and the United States in the 1950s and 1970s, respectively, the first isolation of HIV-1 was not until 1983. However, two years later, researchers also isolated HIV-2 and noted that HIV-2 contributes to the development of AIDS at a slower rate.

Since the discovery of HIV/AIDS, clinicians and researchers have worked to understand and manage the conditions so they are no longer fatal.

Aside from preventative care measures, such as safe sex practices and pre-exposure prophylaxis (PrEP), to prevent HIV, researchers have also developed new treatment options, such as antiretroviral therapy (ART), to manage the condition and prevent additional transmission. These treatments have revolutionized AIDS prevention, HIV care, and public health. In fact, in a report by UNIAIDS published in July 2023, the organization outlines a path to end AIDS by 2030.

Unfortunately, as more and more patients gain access to these life-saving treatments, a new issue has arisen: HIV drug resistance.

HIV Treatment

According to the World Health Organization (WHO), antiretroviral therapy (ART) for HIV treatment has unprecedentedly impacted patients with HIV. Statistics from 2021 imply that 28.7 million of 38.4 million people living with HIV were being treated with antiretroviral drugs to manage their viral load.

The first approved ART in the US was zidovudine, a nucleoside reverse-transcriptase inhibitor (NRTI). Today, ART can involve multiple drug classes, including nucleoside reverse-transcriptase inhibitors (NRTIs), non-nucleoside reverse-transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and entry inhibitors.

The following are some FDA-approved drug combinations for HIV treatment:

  • Abacavir, dolutegravir, and lamivudine
  • Atazanavir and cobicistat
  • Bictegravir, emtricitabine, and tenofovir alafenamide
  • Darunavir and cobicistat
  • Dolutegravir and rilpivirine
  • Efavirenz, emtricitabine, and tenofovir disoproxil fumarate
  • Elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate
  • Emtricitabine, rilpivirine, and tenofovir alafenamide
  • Lamivudine and tenofovir disoproxil fumarate
  • Lopinavir and ritonavir

HIV Drug Resistance

Despite the benefits of ART, its widespread use has caused the virus that causes HIV infections to mutate into a drug-resistant HIV. The WHO notes that the emergence of drug-resistant viruses can cause partially or fully inactive antiretroviral drugs, which may increase HIV infections, morbidity, and mortality.

According to UpToDate, multiple factors can contribute to HIV drug resistance, including HIV biology, genetic barriers, regimen potency, pharmacokinetics of ART, and medication adherence.

HIV-1 viruses have a rapid mutation rate, with an average of one nucleotide mutation per replication cycle. A high mutation rate means that each day patients can produce multiple variants of the virus, increasing the probability that the virus will mutate to circumvent the available drug mechanisms, causing treatment failures.

Adverse treatment outcomes can result from two types of HIV drug resistance: transmitted and acquired drug resistance (ADR). Transmitted resistance refers to resistance transmitted when a patient gets infected if the person gets infected by someone who has a drug-resistant mutation of HIV.

While some people acquire resistance when infected, others can develop resistance over time. Acquired drug resistance (ADR) is developed by patients already receiving ART. Much like the development of antibiotic resistance, poor medication adherence can increase mutation susceptibility and, consequently, the risk of ARD.

“When virus replication occurs in the presence of suboptimal concentrations of the drug, drug-resistant viruses are selected, and the replication of drug-resistant viruses in the presence of the drug can further increase the virus’ mutation rate,” noted researchers in Microorganisms.

The WHO notes that patients can also develop HIV drug resistance before treatment if they are exposed to the medications in another way, like preventing mother-to-child HIV transmission through ART. Another category of HIV drug resistance is a naturally resistant virus; however, there is an extremely low prevalence of these viral HIV infections.

Cross-Resistance

A mutation that yields drug resistance to one HIV drug often causes cross-resistance across a drug class.

“Most drug resistance mutations in a specific antiretroviral class decrease susceptibility to one or more antiretroviral drugs of the same class. In contrast, viruses with high levels of drug resistance in one specific antiretroviral class are generally susceptible to drugs that belong to another class. However, there are few cases of cross-resistance between drug classes,” explained researchers in Microorganisms.

NRTI

NRTIs are the baseline of ART, used in nearly every treatment regimen.

There are two types of NRTI drug resistance. In the first mechanism, HIV reverse transcriptase (RT) can recognize and avoid binding to NRTI. Alternatively, the virus can continue synthesizing DNA via hydrolytic elimination of chain-terminating NRTI.

NNRTIs

HIV viruses can also resist NNRTIs, which have a low genetic barrier. An estimated 10% of adults prescribed an HIV drug regimen have developed a resistance to the non-nucleoside reverse transcriptase inhibitors (NNRTIs) often used for treatment.

NNRTIs work by inhibiting HIV-1 reverse transcriptase via hydrophobic interactions. Mutations in the hydrophobic pocket of RT can result in NNRTI drug resistance. With a relatively low genetic barrier, cross-resistance is extremely common in this class of transformations.

To address NNRTI resistance, the WHO recommends transitioning to dolutegravir-based treatments.

PIs

Conversely, protease inhibitors have a high genetic barrier, as they competitively inhibit Gag and Gag/Pol binding to the HIV-1 protease active site, preventing the virus from maturing.

INTIs

INSTIs, sometimes also called integrase inhibitors, “block the action of the integrase viral enzyme (responsible for the insertion of the HIV-1 genome into the host DNA) by impeding the correct positioning of viral DNA at the active site of the enzyme and by binding to the catalytic metal cations inside the retroviral IN active site.”

Preventing and Addressing Resistance

While many countries have begun developing national action plans to minimize the risk of HIV drug resistance, healthcare providers and researchers continue to disclose concerns about resistant strains.

One of the best tools for preventing HIV infections — and inevitable mutations — is practicing safe sex. As one of the only forms of birth control that provides a physical barrier and prevents sexually transmitted infections, including HIV, condoms are vital for HIV prevention.

Another habit that may mitigate disease spread is knowing HIV status. Sexually active patients should have regular STI screenings to detect any potential infections.

Pre-exposure prophylaxis (PrEP) is another tool for preventing HIV in high-risk HIV-negative patients.

Medication adherence is also a vital tool for preventing HIV drug resistance. To minimize the risk of HIV drug resistance, patients are advised to adhere to their medication plan strictly. When patients skip doses, viral replication can continue, increasing the probability that drug-resistant strains of HIV will develop.

HIV Drug Resistance Testing

The WHO maintains that providers should conduct HIV drug-resistance testing before prescribing a treatment regimen for HIV prevention or treatment. According to the San Fransisco AIDS Foundation, there are two types of resistance testing: genotypic and phenotypic.

Phenotypic testing is typically experimental and requires assessing a patient’s viral load on different drug concentrations or treatment plans to determine whether the virus continues to replicate.

While phenotypic testing can be an excellent tool for patients already on ART, genotypic testing is the preferred method of detecting ART drug resistance, recommended by the US Department of Health and Human Services HIV treatment guidelines.

Genotypic test results can provide more in-depth insight into the mutations that may cause drug resistance, guiding healthcare providers to prescribe or avoid prescribing certain drug combinations.

Typically, genotypic assays involve Sanger sequencing of RT, PR, and IN genes of circulating plasma RNA. Unfortunately, making sense of genotypic testing hinges on existing knowledge of HIV mutations that cause drug resistance and cross-resistant mutations. Multiple tools and datasets are available to compare mutations and associated resistance, including a list of mutations kept by the International AIDS Society of the USA and the Stanford University HIV Drug Resistance Database.

Ongoing Research

As scientific discoveries and development advance, medical researchers look for new ways to prevent and treat HIV.

Many studies and initiatives have focused on developing an HIV vaccine to prevent infection. For example, in September 2022, Stephaun E. Wallace, PhD, MS, a staff scientist in the Vaccine and Infectious Disease Division at Fred Hutch and Director of External Relations for the HIV Vaccine Trials Network (HVTN) spoke to PharmaNewsIntelligence, explaining a study that led to the discovery of PT80. This biomarker may be used to develop future HIV vaccines.

Beyond that, a recent study published in Nature revealed that three patients had been cured of HIV through a stem cell transplant with HIV-resistant stem cells. While these three patients have been cured, the treatment is lengthy, complex, and experimental and has only been assessed in patients with leukemia who already need a stem cell transplant. However, insight from these patients can provide background for next-generation cell therapies that may address the virus.

More recently, in May 2023, researchers from the Lewis Katz School of Medicine at Temple University and the University of Nebraska Medical Center used CRISPR gene editing technology to eliminate HIV in an infected mouse.

As the research continues, cell and gene therapy alternatives could be powerful tools for managing patients with treatment-resistant HIV.

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