Here we provide you with cases published in the HIV/TB Drug Resistance & Clinical Management Case Book. These cases have been presented to over 1000 medical doctors in southern Africa at the annual SATuRN Drug Resistance Workshops.
The objective is to capacitate doctors, nurses and allied medical staff at all levels of the health system to prevent and manage HIV and TB drug resistance.
Authors: Richard Lessells, Theresa Rossouw & Tulio de Oliveira
This 29 year old patient transferred into the programme from another public sector programme in the province. She had initiated TDF/3TC/NVP in November 2010 with a baseline CD4+ cell count of 2 cells/ul.
The transfer letter states that after 6-month of ART, her CD4+ cell count was 23 cells/ul and viral load 240,508 copies/ml.
CD4+ cell count and viral load were repeated on transfer (12 months on ART) and show persistent high-level viraemia and CD4+ cell count <50 cells/ul.
Initial questioning does not reveal any adherence problems. However, in-depth counselling reveals deep psychological issues around the death of her grandmother the same year. She is now living with her mother who is also on ART and is documented to have excellent adherence and VL <40 copies/ml.
She reports no previous use of ART or PMTCT before November 2010. She reports that, although her partner HIV status is not known to her, she is aware that the partner has concurrent sexual partners, and knows at least one of them to be taking ART.
Clinical chart:This patient has had no virological or immunological response to ART. This would normally suggest substantial problems with adherence to ART. Other possibilities to think about would be malabsorption, incorrect drug dosage or major drug-drug interaction. It is also important to consider the possibility of pre-existing antiretroviral resistance, either from previous PMTCT or from acquisition of resistant virus.
Resistance genotype: Dual class resistance has seemingly developed within one year of therapy which is of major concern. The M184I mutation confers high-level resistance to 3TC and FTC. K65R confers intermediate resistance to TDF, ABC, ddI, 3TC and FTC. Y181C confers high-level resistance to NVP and EFV. The rapid emergence of mutations and lack of any virological response to ART does raise the possibility of primary drug resistance in this case.
Treatment recommendation: The viral populations remain fully susceptible to AZT . Indeed both the K65R and Y181C mutations cause AZT hypersusceptibility. So a standard second-line regimen of AZT, 3TC and LPV/r would be appropriate in this case.
Adherence: It is essential that the psychological issues that have been identified are comprehensively addressed. This might include referral to a clinical psychologist or consideration of pharmacological therapy. It is important to ensure that the patient now also enrolls the full support of her mother, especially given the documented good adherence of the mother.
General comments: A full drug history should be taken to ensure no potential drug-drug interactions with her second-line regimen. She needs to be screened for TB disease and for sexually transmitted infections. It is important to ensure that she is currently taking cotrimoxazole therapy. Counselling about condom use is particularly important given the knowledge of the partner concurrent sexual partners.
I. We are much more used to seeing the M18V mutation ?
What is the significance of the M184I mutation seen in this case?
II. How do certain mutations cause hypersusceptibility to certain antiretroviral drugs, e.g. K65R and AZT?
I. M184I arises as a result of a G to A substitution at position 184 (ATG, methionine to ATA, isoleucine). M184V in contrast arises as a result of an A to G substitution (ATG, methionine to GTG, valine). M184I mutants are generally observed earlier during therapy than M184V as RT is more prone to G to A substitutions. M184I confers high-level resistance to 3TC and FTC but also significantly reduces the replication rate of the virus. In the presence of continued drug pressure, the frequency of M184V mutants increases, as the M184V mutants have a fitness advantage over M184I mutants.
II.K65R confers hypersusceptibility to AZT by partially preventing the excision of incorporated AZT. This leads to increased stability of AZT as a chain terminator. The mechanism by which the K65R mutation counteracts TAM-mediated NRTI excision seems to be that the K65R mutation constrains the mobility of the RT fingers loop domain, explaining the decreased incorporation and decreased excision of NRTIs observed for K65R. The clinical impact of this hypersusceptibility is not entirely clear.
I. Initiation of ART in the presence of primary drug resistance may lead to further rapid accumulation of antiretroviral resistance. The possibility of primary drug resistance should be considered in patients who exhibit poor early virological response to ART. Lack of response should not always be assumed to be due to suboptimal adherence
II. The M184I mutation appears earlier in therapy than the M184V mutation but also confers high-level resistance to 3TC and FTC
Frost SDW, Nijhuis M, Schuurman R et al. Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection. J Virol 2000, 74: 6262-6268
a href="http://www.ncbi.nlm.nih.gov/pubmed/16640096">White KL, Chen JM, Feng JY, et al. The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antivir Ther 2006, 11: 155-163.
Although every attempt has been made to ensure that the information in this book is accurate and up-to-date, the authors and publishers accept no responsibility for any loss or damage resulting from use of the information herein.
It is the responsibility of the individual clinician or health care worker to abide by national and local guidelines and protocols regarding management of HIV and TB. Information regarding drug indications and dosages should be checked with the national or local formulary, or with the pharmaceutical package insert.
None of the authors has declared any competing financial interests with regards to any material discussed within the HIV and TB Drug Resistance and Clinical Management Case Book.