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This is the first of a three-part webinar series on HIV drug resistance in patient management. The following is based on their webinar presentation.
The HIV virus produces 10 billion new viruses per day. It also makes mistakes when it reproduces itself. One mistake occurs for every cycle of replication. The reverse transcriptase enzyme has no proofreading mechanism and can’t correct the mistakes, which are known as mutations. Millions of mutations are formed daily. If there is no antiretroviral drug around, the mutations quickly disappear.
If a mutation causes resistance to a drug, then that quasi species will continue to multiply while the other quasi species are suppressed by that ARV drug. This will lead to outgrowth of a resistant HIV strain.
We need two things for resistance to develop: Viral multiplication (replication) and low levels of ARVs in the body. Some drugs with high and others with low barriers to resistance. For instance, raltegravir has a low genetic barrier to resistance while dolutegravir (DTG) has a high barrier to resistance, is highly potent, but may be compromised by mutations that accumulate from failing raltegravir. Resistance mutations can decrease sensitivity to one drug but increase susceptibility to another.
Reducing the risk of resistance
- Drugs. Use pre-exposure prophylaxis (PREP) to prevent The best treatment regimen provides the highest genetic barrier for viral resistance. DTG has a higher genetic barrier to viral resistance and is used in first-, second- and third-line regimens. New, long-acting drugs such as cabotegravir, rilpivirine, islatravir and lenacapavir play a role here. Do regular viral load (VL) monitoring.
- Clinician factors. Educate patient (virus, drugs, defaulting). Fixed-dose combination drugs, potency, genetic barriers, side effects and correct dosing all play a role in reducing the risk of resistance.
- Patient factors. Educate patients appropriately. Adherence is the key to preventing resistance. Support key populations (MSM, female sex workers, prisoners) to stop stigma. Herbal drug interactions could impact ARV bioavailability and lead to the development of resistance.
- Viral factors. This includes high replication rates and mutations.
- Drug factors. These include:
- High genetic barrier drug regimens
- Inappropriate dosing
- Drug interactions
- Poor absorption.
Proviral DNA Genotypic Resistance testing
Standard resistance tests can be done if the VL is >1000 copies/ml (400 copies/ml) and tests circulating HIV RNA. What if the VL is <50 copies/ml?
Proviral DNA sequencing examines HIV DNA that has integrated into the DNA of peripheral blood mononuclear cells. Because proviral DNA reflects an archive of the viral mutations that emerge over the course of infection, it can provide a historical record of drug resistance mutations.
This is useful for analysing previous resistance mutations of patients with suppressed VL to see if regimens can be simplified. Unfortunately, sensitivity and specificity are a problem. This test is not routinely available in South Africa and is only useful for detecting resistance to the drugs the patient is presently taking (or within four weeks of stopping it). It will not necessarily show resistance to ARVs the patient was previously exposed to.
In treated persons, resistance test results obtained after therapy is discontinued are not reliable.
Resistance is long-lasting, even if undetectable. Resistance results must be interpreted in the context of the patient’s treatment history. Also consider patients previous resistance test results if available. This helps to exclude drugs from a regimen but won’t necessarily indicate which drugs will work.
Resistance testing in South Africa
This won’t detect resistance in minor variants (< 20%-30%), as minor variant assays are not available in South Africa. VL must be >1000 copies/ml. Resistance test results are very clearly presented but there are pitfalls in interpretation and expert consultation is advised. These tests are very expensive at present.
Consequences of keeping a patient on a failing regimen?
Keeping a patient on a failing regimen results in more resistance against the current ARVs, cross resistance and compensatory mutations, which increase the viral fitness and cause the VL to increase. Therefore, make certain that the patient is adherent before doing resistance testing. Maintain the patient on current antiretroviral therapy. Resistance testing must be performed while the patient is taking the antiretroviral therapy regimen they are failing. Ask the patient to take ARVs regularly for one month and then do resistance testing.
HIV resistance testing and the approach to treatment failure are highly complex and changing all the time. Our South African guidelines in both the private and state sectors are about to change, making it even more complex. At all times, feel free to contact Right to Care’s helplines for advice on 082 352 6642.