1. CHAPTER 1 INTRODUCTION AND LITERATURE REVIEW
1.10 Drug resistance
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Table 1-1 Overview of available treatment options for first-line, second-line and third-line treatment regimens in SA.
First-Line ARV regimen (2 NRTI’s + 1 NNRTI)
Second-Line ARV regimens (2 NRTI’s + 1 Boosted PI)
Third-line ARV regimen (1 NNRTI + 1 PI + 1 InSTI)
NRTI’s NNRTI’s NRTI’s PI with Booster NNRTI PI InSTI’s
Tenofovir (TDF) Nevirapine (NVP) Zidovudine (AZT) Lopinavir (LPV)/
Ritonavir (r) (Kaletra)*
Etravirine (ETR)
Darunavir (DRV/r)
Raltegravir (RAL) Emitricitabine (FTC) Efavirenz (EFV) Lamivudine (3TC) Atazanvir (ATV)/r **
Lamivudine (3TC) Tenofovir (TDF)
Abacavir (ABC) Emitricitabine (FTC)
Abacavir (ABC) NB* TDF + FTC/3TC + EFV are provided as
a fixed dose combination pill and comprise the standard first-line
treatment for HIV-1 infection. If patients do not respond to the FDC pill they can be placed on a combination of any 3 ARVs available in the first line regimen list.
NB* combinations of other NNRTI’s and NRTI’s can be used in third line
treatment depending on the patients resistance profile and ART history.
* Protease inhibitors in regimen 2 are administered with a sub-therapeutic dose of Ritonavir to increase half-life.
** Is only used when apatient presents with dyslipidaemia or intractable diarrhoea associated with LPR/r
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treatment. Transmitted drug resistance occurs when individuals who were not previously infected with HIV-1 become infected with a drug-resistant strain (231).
The most important viral factors responsible for the development of drug resistance are:
the error prone de novo replication of HIV-1 caused by the use of its low fidelity RT during reverse transcription, the absence of an error correcting/proofreading mechanism during viral replication, rapid rate of viral replication, collection of archived proviral reservoirs during infection and genetic recombination when viruses with two different sequences infect the same cell (232-234).
It has been estimated that on each replication cycle, up to five incorrect nucleotides could be incorporated into the HIV-1 genome copied, with the likelihood of every single-base mutation possible in the HIV-1 genome occurring on a daily basis (232, 233). Since HIV-1 lacks error detection and correction mechanisms, these erroneous nucleotides cannot be corrected (235). The result is the production of HIV-1 virions which differ from wild-type (WT) HIV-1 (i.e. the quasispecies) in a matter of months after primary infection (232).
In the instance where mutations in sequences which code for viral enzymes occur, the result is the production of enzymes which differ slightly from the wild-type (i.e. production of mutant variants). If viral enzymes are altered/include mutations, the action of ARV’s on these enzymes could be compromised thereby resulting in ARV resistance and prolonged viral replication (182).
In the absence of ARV drugs, the dominating population of HIV-1 is the WT virus. Mutant viruses still continues to replicate but are found in low levels. Commencement of drug therapy exerts a selective pressure on the viral population in which the WT virus is prevented from replicating and the viral load decreases. If there is a mutant variant of HIV- 1 present, which displays resistance to the ARV treatment, replication will continue and the viral load of mutant virus will gradually increase. This can lead to failure of a regimen as well as the possible transmission of drug resistant variants (236, 237).
The location and pattern of mutations determines the type of resistance conferred. In some cases only one mutation is required to cause drug resistance (low genetic barrier); whilst in other cases more than one mutation is required to cause drug resistance (high genetic barrier) (237-239). In either instance, drug resistance impacts the concentration of an ARV
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required to reduce viral replication by 50% (i.e. IC50), with IC50 being greater in mutant viruses in comparison to the WT virus.
The use of combination therapy to treat HIV-1 infection is employed to target as many viral variants as possible, even those which may be resistant to an ARV in the regimen. In doing so viral replication is controlled more efficiently and the chances of replication of mutant viruses and transmission of drug resistant strains of HIV-1 are less likely.
Successful drug therapy however, is dependent upon high levels of adherence to treatment. Poor drug adherence leads to suboptimal concentrations of drugs which results in viral rebound (240). The subsequent ongoing viral replication increases the probability of RAMs developing and this in turn increases the risk of transmitting drug resistant viral variants (226, 232, 237).
In order to monitor the emergence and transmission of drug resistance, the World Health Organization (WHO) implemented the global HIV drug resistance surveillance network in 2004. This network aimed to monitor the prevalence of acquired and TDR and to use such information to inform decisions on treatment and management strategies for HIV in low and high income countries whilst access to ARV’s was scaled up (231).
Data from the WHO has shown that, over time high-income countries have experienced an increase in the number of HIV-1 positive treated patients who have achieved full viral suppression. This has in turn reduced emergence and subsequent transmission of drug resistance within these countries (231). In contrast, some low-income countries, such as SA, are experiencing difficulty in achieving full viral suppression of HIV-1 positive patients on ARVs. As a result of this, acquired drug resistance continues to persist and TDR is increasing, particularly in KZN, the site of the current study and the epicentre of the HIV epidemic (231, 241).
According to the WHO, TDR related to NNRTI’s and NRTI’s, in KZN, has increased from a low threshold level (5%) to a moderate threshold level (5-15%) between 2007 and 2012 (231). Two surveillance studies conducted in KZN in 2005 and 2009 identified TDR to be within the low threshold level (<5%), with the initial survey identifying no TDR and the follow up study showing one patient with an NNRTI associated TDR mutation (i.e. the K103N mutation) (231, 242). At the time of both surveys, <30% of HIV-1 infected individuals in SA were on cART and those who were receiving cART only did so for <5
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years. Both surveys were thus in line with statistical models which suggested that the 5%
(low) TDR threshold level may only be exceeded when >30% of HIV positive eligible individuals were on ARV treatment or 10 years after large scale rollout of ARV’s (243). The 2012 WHO report, which showed an increase in TDR above 5%, was also in line with this model since SA had an ARV coverage of between 40-60% of HIV positive eligible individuals at the time of development of this survey (218).
The majority of drug resistance associated mutations found in KZN thus far have been related to NNRTI’s and NRTI’s, with very few PI resistance mutations being identified.