Moderate Levels of Pre-Treatment HIV-1 Antiretroviral Drug Resistance Detected in the First South African National Survey

Background In order to assess the level of transmitted and/or pre-treatment antiretroviral drug resistance to HIV-1, the World Health Organization (WHO) recommends that regular surveys are conducted. This study’s objective was to assess the frequency of HIV-1 antiretroviral drug resistance in patients initiating antiretroviral treatment (ART) in the public sector throughout South Africa. Methods A prospective cross-sectional survey was conducted using probability proportional to size sampling. This method ensured that samples from each province were proportionally collected, based on the number of patients receiving ART in each region. Samples were collected between March 2013 and October 2014. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to the Stanford Calibrated Population Resistance tool v6.0. Results A total of 277 sequences were available for analysis. Most participants were female (58.8%) and the median age was 34 years (IQR: 29–42). The median baseline CD4-count was 149 cells/mm3 (IQR: 62–249) and, based on self-reporting, participants had been diagnosed as HIV-positive approximately 44 days prior to sample collection (IQR: 23–179). Subtyping revealed that 98.2% were infected with HIV-1 subtype C. Overall, 25 out of 277 patients presented with ≥1 surveillance drug resistance mutation (SDRM, 9.0%, 95% CI: 6.1–13.0%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations were the most numerous mutations detected (n = 23). Only two patients presented with a protease inhibitor (PI) mutation. In four patients ≥4 SDRMs were detected, which might indicate that these patients were not truly ART-naïve or were infected with a multi-resistant virus. Conclusions These results show that the level of antiretroviral drug resistance in ART-naïve South Africans has reached moderate levels, as per the WHO classification. Therefore, regular surveys of pre-treatment drug resistance levels in all regions of South Africa is highly recommended to monitor the changing levels of pre-treatment antiretroviral drug resistance.

[1]  Bikram Chakraborty,et al.  Diminished Replicative Fitness of Primary Human Immunodeficiency Virus Type 1 Isolates Harboring the K65R Mutation , 2005, Journal of Clinical Microbiology.

[2]  J. Mellors,et al.  Prevalence of HIV-1 Drug Resistance among Women Screening for HIV Prevention Trials in KwaZulu-Natal, South Africa (MTN-009) , 2013, PloS one.

[3]  Anne-Mieke Vandamme,et al.  Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update , 2009, PloS one.

[4]  Mark A Wainburg.  The impact of the M184V substitution on drug resistance and viral fitness , 2004 .

[5]  L. Naeger,et al.  Molecular Mechanisms of Resistance to Human Immunodeficiency Virus Type 1 with Reverse Transcriptase Mutations K65R and K65R+M184V and Their Effects on Enzyme Function and Viral Replication Capacity , 2002, Antimicrobial Agents and Chemotherapy.

[6]  A. Phillips,et al.  Outcomes Following Virological Failure and Predictors of Switching to Second-line Antiretroviral Therapy in a South African Treatment Program , 2012, Journal of acquired immune deficiency syndromes.

[7]  R. Parboosing,et al.  Resistance to antiretroviral drugs in newly diagnosed, young treatment‐naïve HIV‐positive pregnant women in the province of KwaZulu‐Natal, South Africa , 2011, Journal of medical virology.

[8]  R. Baltussen,et al.  Increasing the use of second-line therapy is a cost-effective approach to prevent the spread of drug-resistant HIV: a mathematical modelling study , 2014, Journal of the International AIDS Society.

[9]  P. Klenerman,et al.  Prevalence of HIV type-1 drug-associated mutations in pre-therapy patients in the Free State, South Africa , 2009, Antiviral therapy.

[10]  Elena Losina,et al.  HIV type-1 clade C resistance genotypes in treatment-naive patients and after first virological failure in a large community antiretroviral therapy programme , 2009, Antiviral therapy.

[11]  A. Phillips,et al.  Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource-limited settings. , 2013, The Journal of infectious diseases.

[12]  P. Bessong,et al.  Prevalence of Antiretroviral Drug Resistance Mutations and HIV-1 Subtypes among Newly-diagnosed Drug-naïve Persons Visiting a Voluntary Testing and Counselling Centre in Northeastern South Africa , 2011, Journal of health, population, and nutrition.

[13]  Michel Roger,et al.  Transmission clustering drives the onward spread of the HIV epidemic among men who have sex with men in Quebec. , 2011, The Journal of infectious diseases.

[14]  Kishor Mandaliya,et al.  HIV-1 drug resistance in antiretroviral-naive individuals in sub-Saharan Africa after rollout of antiretroviral therapy: a multicentre observational study. , 2011, The Lancet. Infectious diseases.

[15]  Linos Vandekerckhove,et al.  Epidemiological study of phylogenetic transmission clusters in a local HIV-1 epidemic reveals distinct differences between subtype B and non-B infections , 2010, BMC infectious diseases.

[16]  Justen Manasa,et al.  Primary drug resistance in South Africa: data from 10 years of surveys. , 2012, AIDS research and human retroviruses.

[17]  C. Petropoulos,et al.  High prevalence of antiretroviral resistance in treated Ugandans infected with non-subtype B human immunodeficiency virus type 1. , 2004, AIDS research and human retroviruses.

[18]  F. Wit,et al.  Effect of pretreatment HIV-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-Saharan Africa: a multicentre cohort study. , 2012, The Lancet. Infectious diseases.

[19]  A. Puren,et al.  Surveillance of transmitted HIV-1 drug resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005-2009. , 2012, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[20]  W. Preiser,et al.  Phylogenetic diversity and low level antiretroviral resistance mutations in HIV type 1 treatment-naive patients from Cape Town, South Africa. , 2008, AIDS research and human retroviruses.

[21]  A. Wensing,et al.  Evolutionary pathways of transmitted drug-resistant HIV-1. , 2011, The Journal of antimicrobial chemotherapy.

[22]  Mark Myatt,et al.  Recommendations for surveillance of transmitted HIV drug resistance in countries scaling up antiretroviral treatment , 2008, Antiviral therapy.

[23]  S. Seedat,et al.  HIV-1 Subtypes B and C Unique Recombinant Forms (URFs) and Transmitted Drug Resistance Identified in the Western Cape Province, South Africa , 2014, PloS one.

[24]  A. Puren,et al.  Antiretroviral drug resistance surveillance among drug-naive HIV-1-infected individuals in Gauteng Province, South Africa in 2002 and 2004 , 2008, Antiviral therapy.

[25]  Justen Manasa,et al.  Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa , 2016, AIDS research and human retroviruses.

[26]  Jerome H. Kim,et al.  Geographic and Temporal Trends in the Molecular Epidemiology and Genetic Mechanisms of Transmitted HIV-1 Drug Resistance: An Individual-Patient- and Sequence-Level Meta-Analysis , 2015, PLoS medicine.

[27]  M. Kozal,et al.  Relationship between minority nonnucleoside reverse transcriptase inhibitor resistance mutations, adherence, and the risk of virologic failure , 2012, AIDS.