Drug resistance

Overview

  • Antimicrobial resistance (AMR) is a broad term, encompassing resistance to drugs used to treat infections caused by microbes. These microbial infections may include bacterial (eg. Bronchitis), viral (eg. HIV), parasitic (eg. Malaria) or fungal (eg. Candida). AMR is one of the greatest threats to global health; hence the need to preserve the power of drugs through their appropriate use. Without effective treatment, infections will become harder to control.
  • Antibiotic resistance refers specifically to the resistance to antibiotics used to combat bacterial infections.

HIV Drug Resistance refers to the reduced ability of a drug, or combination of drugs, to block replication of HIV. Increased rates of HIVDR will have a severe negative impact on WHO / UN AIDS 95-95-95 targets for 2030, to bring about epidemic control. Currently, there is an embarrassment of riches when it comes to the number of antiretroviral medicines prescribed for the treatment of HIV disease. There are over 35 different ARVs available to control HIV/AIDS, which are prescribed as single or fixed drug combinations (FDC). Not all ARVs are available in South Africa’s public sector.

HIV drug resistance may be categorized as follows:

  1. Transmitted drug resistance (TDR), (or primary drug resistance), is detected in ARV naïve patients, with no history of ARV drug exposure. TDR occurs when previously uninfected individuals are infected with HIV, that has drug resistance mutations. This usually occurs when a patient is infected by a sexual partner, or in infants by the mother, who has already developed HIVDR.
  2. Acquired HIV drug resistance (ADR), (or secondary or induced resistance), is the most common form of HIVDR, and occurs when resistance mutations emerge due to drug-selective pressure in individuals receiving ARV drugs i.e. the HIV continues to replicate in the presence of ART. For this to happen, the level of the drug is too low to block viral replication, but high enough to exert a positive selection pressure on the virus.
  3. Pre-treatment HIVDR (PDR) is detected in ARV drug naïve individuals initiating ART or in individuals that have prior ARV drug exposure(s) initiating or re-initiating first line ART. PDR is either transmitted or acquired drug resistance, or both. PDR may have been transmitted at the time of infection (ie. TDR), or it may be acquired by virtue of prior ARV drug exposure(s), eg. women exposed to ARV drugs for the prevention of mother-to-child transmission (PMTCT), individuals who have received pre-exposure prophylaxis (PrEP), or individuals reinitiating ART after a period of treatment interruption without documented viral failure (VL).

South African overview of HIVDR

There were an estimated 8.2 million in South Africa in 2021, of which 4.4 million were reported to be on ART in the public health sector.

HIVDR testing was included in the South African National HIV household survey (2017), with the following results:

  • 27.4% had HIVDR
  • 18.9% had resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) only
  • 7.8% had resistance to NNRTIs and nucleoside reverse transcriptase inhibitors (NRTI)
  • 0.5% had resistance to protease inhibitors (PI)

Prevention of resistance to HIV

Classes of Anti-retroviral Therapy:

There are multiple classes of ART used to maintain the health of an HIV infected individual (see Table­ 1 below). Different modes of action allow more than one ARV to be used in combination with other ARVs. Although HIV infection cannot be cured, the combination of ARV drugs allows for the successful control of the infection for many years.

Adherence to Anti-retroviral Therapy:

Patient compliance or adherence is the degree to which a patient correctly follows medical advice. More specifically, treatment or drug adherence refers to medication or drug compliance as prescribed. Treatment adherence is regarded as an important factor in achieving optimal health outcomes across most diseases.

In the treatment of HIV, poor adherence to ART has the potential to impact outcomes on multiple levels. It is associated with less effective viral suppression and increases the risk of creating permanent HIVDR to a particular agent, or group of agents within a given combination therapy regimen.

It is fundamental to assist patients in understanding the importance of them adhering to their HIV medications. If one can ensure the patient has good adherence to ART, the possibility of HIVDR is markedly reduced. Prevention of the development of any HIV drug resistance can go a long way to assist the overall HIV programme and bring about HIV epidemic control.

Studies have shown that the better the adherence to HIV treatment, the more likely HIV suppression will occur, i.e. suppressed viral load. Very low ARV adherence to ART reduces the drug pressure, and increases the risk of HIV mutations, and ultimately HIVDR emerging. At the other end of the spectrum, very good adherence ensures the " virus goes to sleep", limiting replication of the HIV virus and mutations thereof.

Drug surveillance

Drug surveillance or drug screening is the evaluation of a drug(s) taken by individuals, under a wide range of circumstances, and over an extended period. Such surveys enable the detection of previously unrecognized positive or negative effects that may be associated with a drug. Surveillance of HIVDR provides evidence that can be used to optimize patient and population-level treatment outcomes.

When antibiotics are prescribed for sexually transmitted infections (STI), clinicians may prescribe medication using standardised protocols, with no blood drawn from the patient for analysis or respective laboratory results required. This is because of drug surveillance whereby regular anonymous screening of patients with STIs occurs, to determine the efficacy of set guideline treatments indicated in the standard treatment protocols. If samples from the drug surveillance detect resistant microbes, protocols are changed accordingly e.g. When quinolone resistance was detected for the treatment of certain STIs, this class of antimicrobial was abandoned and replaced with more effective Cephalosporins.

Similarly, in SA, ART is prescribed to HIV positive patients using standardised national protocols and algorithms. Regular country surveillance is conducted to review drug efficacy, and changes made accordingly if necessary. HIV drug surveillance is conducted intermittently, whereby HIV patient bloods are analysed for the emergence of HIVDR. Between 2004 and 2021, 66 countries implemented surveys of HIV drug resistance using WHO-recommended standard methods. Through this, it was determined that among populations failing NNRTIs-based ART, the levels of resistance to commonly used NNRTIs ranged from 50% to 97%. The growing percentage of patients with resistance to this class of anti-retroviral resulted in the switch from efavirenz to dolutegravir, minimising the risk of treatment failure.

Measuring adherence

Measuring adherence to HIV treatment regimens is important in determining whether patients will develop undetectable HIV viremia or drug-resistant HIV. Although a comprehensive approach to the measurement of ARV drug adherence is recommended, this may be difficult in limited resourced settings. Three commonly used adherence tools are:

  • Patient interviews are the most feasible option for measuring adherence. Tools such as the Simplified Medication Adherence Questionnaire have been shown to be adequate instruments to assess adherence in HIV-infected patients and can be easily applied in most clinical settings.
  • Pill counts are conducted and recorded using Department of Health HIV stationary summary (Integrated Clinical Stationary). However, it is important not to rely solely on this method, as patients may dispose of pills not taken, just before their clinic follow-up visit.
  • Electronic monitoring is when a medication bottle is fitted with a pressure activated microprocessor which records each opening and lists date, time and duration open which is stored in a database. Although it cannot prove the drug was taken by the patient, but prolonged deception by a patient has been shown to be unlikely.

When HIVDR is suspected:

When HIVDR is suspected in a patient, the following steps need to be taken:

  • Ensure that the patient’s ARV drug history is complete, and all old clinical records reviewed. Remember that some patients move between private and public healthcare providers, so it is crucial to align ARV regimes to ensure ongoing availability for the patient.
  • Conduct a detailed adherence interview with your patient
  • Ensure patient is taking ARVs and adherent at the time the resistance testing is performed
  • Ensure VL is >1000 copies/ml before conducting the resistance test
  • Adding a new class of drug is useful in failing ARV regimens (see later sections).
  • Follow updates and new guidelines