Prevalence and Significance of HIV-1 Drug Resistance Mutations among Patients on Antiretroviral Therapy with Detectable Low-Level Viremia

ABSTRACTHIV-1 resistance testing was performed in 47 antiretroviral (ARV)-treated subjects with low-level viremia (LLV) of <1,000 copies/ml. The median viral load was 267 copies/ml. In those with ≥2 LLV episodes, 44% accumulated additional resistance mutations. Fewer active ARVs and longer elapsed time were associated with an increased risk of resistance accumulation after controlling for adherence and viral load. Virologic failure followed 16% of LLV time points. Strategies for early intervention after LLV episodes should be further studied.

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Detectable viral load among HIV -1 positive pregnant women on ART (Option B +) in northern Tanzania: Baseline results from the HIVDR study

East Africa Science ◽

10.24248/easci-d-20-00009 ◽

2021 ◽

Vol 3 (1) ◽

pp. 44-50

Author(s):

Nicholaus Steven Mazuguni ◽

Festo Mazuguni ◽

Eva Prosper Muro

Keyword(s):

Drug Resistance ◽

Viral Load ◽

Virological Failure ◽

Virologic Failure ◽

Resistance Mutation ◽

Resistance Testing ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Hiv 1 ◽

Level Resistance

Introduction: In Tanzania, the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDEC) has implemented the Option B+ as one of the strategies to facilitate achievement of elimination of mother to child transmission of HIV. To prevent emergence of drug resistance mutations early identification of option B+ failure is critical. The emergence of drug resistance mutation and subsequent treatment failure poses a major concern for HIV program in low- and middle-income resource settings where treatment options are limited. Methodology: We recruited treatment naïve, treatment experienced HIV-1 positive pregnant women and those who had prophylaxis in their previous pregnancy in Kilimanjaro, northern Tanzania August 2016 to February 2017. Whole blood (2ml) for biochemistry, viral load and drug resistance testing were taken at baseline. ARV drug resistance testing was done on women with VL ≥ 1000 copies/ml. We used descriptive statistic and logistic regression to determine the strength of association between virologic outcome (virologic failure) and independent predictors. Results: One hundred and forty eight (148) pregnant HIV-positive women were enrolled in the study with mean age of 29.82 years (SD=6.17) from August, 2016 to February, 2017. Virologic failure was demonstrated in 34 (23%) with viral load ≥ 1,000 copies/ml. Genotyping results were available from 26 women, mutations associated with ARV resistance were detected in 23.1% (n = 6/26). Among the six women with ARV resistance mutation 4(66.7%) had high level resistance and 2(33.3%) had low level resistance. Among the 26 samples genotyped 15(58%) viruses were subtype A, while eight were subtype C (31%) and three subtypes D (11%). The most dominant drug resistance mutations against the reverse transcriptase inhibitors for the women with high level resistance were K103N, Y188L, D67N, K70R, M184V, T215F, K219EQ, and the low-level resistance was E138A. The older age was associated with virological failure compared to those who were < 20 year of age. Conclusion: Viral load testing should be done on women who were already on antiretroviral treatment on their first antenatal visit to ensure early detection of virological failure and enable clinicians to take an appropriate course of action on their management. Educational intervention on adherence should be targeted at an early stage to women with virological failure during pregnancy to reduce the emergence of HIV-1 drug resistance mutations.

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Proviral DNA as a Target for HIV-1 Resistance Analysis

Intervirology ◽

10.1159/000431093 ◽

2015 ◽

Vol 58 (3) ◽

pp. 184-189 ◽

Cited By ~ 12

Author(s):

Nadine Lübke ◽

Veronica Di Cristanziano ◽

Saleta Sierra ◽

Elena Knops ◽

Eugen Schülter ◽

...

Keyword(s):

Resistance Testing ◽

Detectable Viral Load ◽

Resistance Mutations ◽

Proviral Dna ◽

Drug Resistance Mutations ◽

Resistance Analysis ◽

Additional Resistance ◽

Plasma Rna ◽

Hiv 1 ◽

Rna And Dna

Background: Resistance analysis from viral RNA is restricted to detectable viral load. Therefore, analysis from proviral DNA could help in cases with low-level or suppressed viremia. Methods: Viral plasma RNA and the corresponding cellular proviral DNA of 78 EDTA samples from 48 therapy-naïve (TN) and 30 therapy-experienced (TE) HIV-1-infected patients were isolated and analyzed for their resistance profiles in the protease and reverse transcriptase genes. Results: Overall, 175 drug-resistance mutations (DRMs) were detected in 25/30 TE (83.3%) and 5/48 TN (10.4%) samples. The TE patients displayed a mean number of 6.68 DRMs in RNA and 5.20 in DNA. In the TN patients, a mean of 0.8 DRMs was found in RNA and 1.0 in DNA; 75% of the DRMs were detected in RNA and DNA simultaneously. In the TE samples, 76% of the DRMs were detected simultaneously in RNA and DNA, 23% exclusively in RNA and 1% in DNA only. The TN samples revealed a significantly higher frequency of DRMs in DNA than in RNA. Conclusions: Proviral DNA resistance testing provides additional resistance information for TN patients. It is also a reliable alternative for TE patients with unsuccessful RNA testing and can provide valuable information when no records are available.

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1021. HIV-1 RNA Blips and Low-Level Replication During Phase III/IIIb Cabotegravir + Rilpivirine Long-Acting Studies Are Similar to Oral 3-Drug Therapy and Not Associated with Week 48 Virologic Outcome

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1207 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S540-S541

Author(s):

Christine L Talarico ◽

Sterling Wu ◽

Ojesh R Upadhyay ◽

Marty St Clair ◽

Veerle Van Eygen ◽

...

Keyword(s):

Viral Load ◽

Virologic Failure ◽

Phase Iii ◽

Individual Study ◽

Treatment Groups ◽

Qualitative And Quantitative ◽

Low Level ◽

Long Acting ◽

Study Participants ◽

Hiv 1

Abstract Background Phase III/IIIb studies demonstrated cabotegravir (CAB) + rilpivirine (RPV) long-acting (LA) dosed every 4 weeks (Q4W) was noninferior to current antiviral regimen (CAR) (FLAIR and ATLAS) and CAB + RPV LA dosed every 8 weeks (Q8W) was noninferior to Q4W (ATLAS-2M) through Week 48 (W48). HIV-1 ribonucleic acid (RNA) blips (viral load [VL] ≥50 to < 200 c/mL) are common during antiretroviral therapy (ART) and generally not associated with subsequent virologic failure (2 consecutive HIV-1 RNA ≥200 c/mL). We compared the frequency of HIV-1 RNA blips and low-level qualitative and quantitative HIV-1 RNA replication among participants treated with CAB+RPV LA and oral CAR and assessed impact on virologic outcome. Methods Plasma samples collected at study visits were analyzed for HIV-1 RNA viral load using the Abbott RealTime HIV-1 assay and qualitative target detected (TD) or target not detected (TND) outcomes were provided for HIV-1 RNA < 40 c/mL. The HIV-1 SuperLow assay (bioMONTR Labs) was used to measure HIV-1 RNA < 2 c/mL at Baseline and W48. Results The proportion of participants with HIV-1 RNA blips was similar overall between Q4W CAB + RPV LA and CAR arms in FLAIR (38/283 [13%] vs 39/283 [14%]) and ATLAS (17/308 [6%] vs 23/308 [7%]). Presence of HIV-1 RNA blips in either arm was not associated with virologic non-response at W48 (HIV-1 RNA ≥50 c/mL per US Food and Drug Administration Snapshot). In ATLAS-2M, HIV-1 RNA blips were observed in 32/523 (6%; Q4W) and 18/522 (3%; Q8W) of participants, with W48 virologic nonresponse in 2 Q4W and 0 Q8W participants. TD outcomes at individual study visits were comparable between study arms for the 3 studies. At W48, the proportion of participants with HIV-1 RNA < 2 c/mL was similar to Baseline and similar between treatment groups in all studies. Conclusion The proportions of study participants with HIV-1 RNA blips, TD viral load results, and HIV-1 < 2 c/mL were similar between the Q4W and Q8W CAB+RPV LA and the oral 3-drug CAR arms through W48 in phase III/IIIb studies. HIV-1 RNA blips did not predict virologic nonresponse (Snapshot analysis) at W48. Disclosures Christine L. Talarico, M.S, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sterling Wu, PhD, GlaxoSmithKline (Employee, Shareholder) Marty St. Clair, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Veerle Van Eygen, MSc, Janssen Pharmaceutica NV (Employee) Krischan J. Hudson, PhD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Sandy Griffith, PharmD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Conn M. Harrington, BA, ViiV Healthcare (Employee) Jan van Lunzen, MD, PhD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) David Margolis, MD, MPH, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) William Spreen, PharmD, ViiV Healthcare (Employee, Shareholder)

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Predictors of first-line antiretroviral therapy failure among adults and adolescents living with HIV/AIDS in a large prevention and treatment program in Nigeria

AIDS Research and Therapy ◽

10.1186/s12981-020-00317-9 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Nicaise Ndembi ◽

Fati Murtala-Ibrahim ◽

Monday Tola ◽

Jibreel Jumare ◽

Ahmad Aliyu ◽

...

Keyword(s):

Drug Resistance ◽

Virologic Failure ◽

Resistance Mutations ◽

First Line ◽

Drug Resistance Mutations ◽

Entry Points ◽

The Mean ◽

Living With Hiv ◽

Hiv 1

Abstract Background A substantial number of persons living with HIV (PLWH) in Nigeria do not experience durable viral suppression on first-line antiretroviral therapy (ART). Understanding risk factors for first-line treatment failure informs patient monitoring practices and distribution of limited resources for second-line regimens. We determined predictors of immunologic and virologic failures in a large ART delivery program in Abuja, Nigeria. Methods A retrospective cohort study was conducted at the University of Abuja Teaching Hospital, a tertiary health care facility, using data from February 2005 to December 2014 in Abuja, Nigeria. All PLWH aged ≥ 15 years who initiated ART with at least 6-month follow-up and one CD4 measurement were included. Immunologic failure was defined as a CD4 decrease to or below pre-ART level or persistent CD4 < 100 cells per mm3 after 6 months on ART. Virologic failure (VF) was defined as two consecutive HIV-1 RNA levels > 1000 copies/mL after at least 6 months of ART and enhanced adherence counselling. HIV drug resistance (Sanger sequences) was analyzed using the Stanford HIV database algorithm and scored for resistance to common nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Univariate and multivariate log binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results Of 12,452 patients followed, a total of 5928 initiated ART with at least 6 months of follow-up and one CD4 measurement. The entry point for 3924 (66.2%) was through the program’s own voluntary counseling and testing (VCT) center, while 1310 (22.1%) were referred from an outside clinic/program, 332 (5.6%) in-patients, and 373 (6.3%) through other entry points including prevention of mother to child transmission (PMTCT) and transferred from other programs. The mean CD4 at enrollment in care was 268 ± 23.7 cells per mm3, and the mean HIV-1 RNA was 3.3 ± 1.3.log10 copies/mL. A total of 3468 (80.5%) received nevirapine (NVP) and 2260 (19.5%) received efavirenz (EFV)—based regimens. A total of 2140 (36.1%) received tenofovir (TDF); 2662 (44.9%) zidovudine (AZT); and 1126 (19.0%) stavudine (d4T). Among those receiving TDF, 45.0% also received emtricitabine (FTC). In a multivariate model, immunologic failure was more common among PLWH with female gender as compared to male [RR (95% CI) 1.22 (1.07–1.40)] and less common among those who entered care at the program’s VCT center as compared to other entry points [0.79 (0.64–0.91)], WHO stage 3/4 as compared to 1/2 [0.19 (0.16–0.22)], or CD4 200 + cells per mm3 as compared to lower [0.19 (0.16–0.22)]. Virologic failure was more common among PLWH who entered care at the program’s VCT center as compared to other entry points [RR (95% CI) 1.45 (1.11–1.91) and those with CD4 < 200 cells per mm3 at entry into care as compared to higher [1.71 (1.36–2.16)]. Of 198 patient-derived samples sequenced during virologic failure, 42 (21%) were wild-type; 145 (73%) carried NNRTI drug resistance mutations; 151 (76.3%) M184I/V; 29 (14.6%) had ≥ 3 TAMs, and 37 (18.7%) had K65R, of whom all were on TDF-containing first-line regimens. Conclusions In this cohort of Nigerian PLWH followed for a period of 9 years, immunologic criteria poorly predicted virologic failure. Furthermore, a subset of samples showed that patients failing ART for extended periods of time had HIV-1 strains harboring drug resistance mutations.

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Increase in HIV-1 transmitted drug resistance among untreated 16~25-y-old youths in the China-Myanmar border areas during 2009~2017

10.21203/rs.3.rs-42813/v1 ◽

2020 ◽

Author(s):

Yibo DING ◽

Min CHEN ◽

Jibao WANG ◽

Yuecheng YANG ◽

Yi FENG ◽

...

Keyword(s):

Drug Resistance ◽

Phylogenetic Trees ◽

Cd4 Count ◽

Molecular Networks ◽

Resistance Testing ◽

Transmitted Drug Resistance ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

The Mean ◽

Hiv 1

Abstract Background Transmitted drug resistance (TDR) can affect antiretroviral therapy (ART) efficacy. Surveillance drug resistance mutations in untreated youths newly reported with HIV-1 are highly representative of local TDR. We investigated HIV-1 TDR, TDR transmission based on molecular networks, and the effect of TDR mutations (TDRMs) on the CD4 count among youths in the China-Myanmar border area near the "Golden Triangle" to better understand TDR and guide ART.Methods From 2009 to 2017, 573 ART-naïve youths (16~25 y) newly reported with HIV-1 were enrolled. CD4 counts were obtained from whole blood. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and phylogenetic trees were used to determine genotypes. TDRMs were analyzed using the Stanford Calibrated Population Resistance tool. TDR transmission was evaluated from molecular networks of HIV-1 pol genes.Results The average prevalence of TDR was 6.3%, and the resistance to NNRTIs, NRTIs, and PIs was 3.49%, 2.62%, and 0.52%, respectively. TDR prevalence increased significantly during the period 2009~2017 (3.92%~9.48%, p<0.05). The mean CD4 count was significantly lower among individuals with TDRMs (373/mm3 vs. 496/mm3, p=0.013). The rate of network entry of youths harboring TDRMs (63.89%) was significantly higher than that of youths without TDRMs (44.9%).Conclusions The HIV-1 TDR increase and low CD4 count of patients with TDRMs in Dehong at the China-Myanmar border suggest the need for early ART and completion of resistance testing before initiating ART in HIV hotspots. Youths with TDRMs are likely to have links to others, necessitating intervention in onward transmission.

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Safety and Effectiveness of Switching to Abacavir/Lamivudine Plus Rilpivirine for Maintenance Therapy in Virologically Suppressed HIV-1 Patients in Singapore (SEALS)

10.21203/rs.3.rs-100235/v1 ◽

2020 ◽

Author(s):

Alvin ZC Lim ◽

Grace SR ◽

Junhao Ang ◽

Christine BC Teng ◽

Li Wei Ang ◽

...

Keyword(s):

Adverse Events ◽

Maintenance Therapy ◽

Primary Outcome ◽

Virologic Failure ◽

Resistance Testing ◽

Virologic Suppression ◽

International Studies ◽

Resistance Mutations ◽

Hiv 1

Abstract BackgroundThe efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC+RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed patients. This study evaluated the effectiveness and safety of switching to ABC/3TC+RPV as maintenance therapy in virologically suppressed HIV-1 infected patients in Singapore.MethodsIn this retrospective, single-centre study, we included patients who were prescribed ABC/3TC+RPV, had HIV-1 RNA <50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. Patients were followed up for 48+12 weeks. The primary outcome was the proportion of patients who maintained virologic suppression of HIV-1 RNA <50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance profiles associated with virologic failure, changes in immunologic and metabolic parameters, and the safety profile of ABC/3TC+RPV.ResultsA total of 222 patients were included in the study. The primary outcome was achieved in 197 patients [88.8%, 95% confidence interval: 83.7%-92.4%]. There were 21 patients (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 patients experienced virologic failure, of whom, 3 of these patients had developed emergent antiretroviral resistance and had HIV-1 RNA >500 copies/ml at the end of the 48+12 weeks follow-up period. The remaining patient experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 patients (14.0%), which led to 13 patients discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (57.1%). A statistically significant increase in CD4 was observed (p<0.01), with a median absolute change of 31 cells/uL (interquartile range: -31.50 to 140.75). No significant changes in lipid profiles were detected. ConclusionABC/3TC+RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 patients with in Singapore.

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Safety and effectiveness of switching to Abacavir/Lamivudine plus rilpivirine for maintenance therapy in virologically suppressed HIV-1 individuals in Singapore (SEALS)

AIDS Research and Therapy ◽

10.1186/s12981-021-00402-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Z. C. Lim ◽

G. S. Hoo ◽

J. H. Ang ◽

C. B. Teng ◽

L. W. Ang ◽

...

Keyword(s):

Adverse Events ◽

Maintenance Therapy ◽

Primary Outcome ◽

Virologic Failure ◽

Resistance Testing ◽

Virologic Suppression ◽

International Studies ◽

Resistance Mutations ◽

Hiv 1

Abstract Background The efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC + RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed individuals. This study evaluated the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy in virologically suppressed HIV-1 infected individuals in Singapore. Methods In this retrospective, single-centre study, we included individuals who were prescribed ABC/3TC + RPV, had HIV-1 viral load (VL) < 50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. The follow-up period was 48 ± 12 weeks. The primary outcome was the proportion of individuals who maintained virologic suppression of HIV-1 VL < 50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance profiles associated with virologic failure, changes in immunologic and metabolic parameters, and the safety profile of ABC/3TC + RPV. Results A total of 222 individuals were included in the study. The primary outcome was achieved in 197 individuals [88.8%, 95% confidence interval: 83.7–92.4%]. There were 21 individuals (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 individuals experienced virologic failure, of whom, 3 of these individuals had developed emergent antiretroviral resistance and had HIV-1 VL > 500 copies/ml at the end of the 48 ± 12 weeks follow-up period. The remaining individual experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 individuals (14.0%), which led to 13 individuals discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (53.1%). A statistically significant increase in CD4 was observed (p < 0.01), with a median absolute change of 31 cells/uL (interquartile range: − 31.50 to 140.75). No significant changes in lipid profiles were detected. Conclusion ABC/3TC + RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 individuals with in Singapore.

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Drug resistance mutations and viral load in human immunodeficiency virus type 2 and dual HIV-1/HIV-2 infected patients in Ghana

Medicine ◽

10.1097/md.0000000000014313 ◽

2019 ◽

Vol 98 (6) ◽

pp. e14313 ◽

Cited By ~ 1

Author(s):

Christopher Z. Abana ◽

Kwamena W.C. Sagoe ◽

Evelyn Y. Bonney ◽

Edward K. Maina ◽

Ishmael D. Aziati ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Viral Load ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus ◽

Hiv 1

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Persistent Low-level Viremia Predicts Subsequent Virologic Failure: Is It Time to Change the Third 90?

Clinical Infectious Diseases ◽

10.1093/cid/ciy989 ◽

2018 ◽

Vol 69 (5) ◽

pp. 805-812 ◽

Cited By ~ 11

Author(s):

Allahna Esber ◽

Christina Polyak ◽

Francis Kiweewa ◽

Jonah Maswai ◽

John Owuoth ◽

...

Keyword(s):

Viral Load ◽

Virologic Failure ◽

Multinomial Logistic Regression ◽

Cox Proportional Hazards ◽

World Health ◽

Hiv Care ◽

Time To Failure ◽

Hiv Viral Load ◽

Low Level ◽

Increased Risk

Abstract Background World Health Organization (WHO) guidelines identify human immunodeficiency virus (HIV) viral load <1000 copies/mL as the goal of antiretroviral therapy (ART). However, the clinical implications of viremia below this threshold are unclear in the African context. We examined factors associated with persistent low-level viremia (pLLV) and quantified the risk of subsequent virologic. Methods The African Cohort Study enrolled HIV-infected adults at clinics in Uganda, Kenya, Tanzania, and Nigeria, with assessments every 6 months. We evaluated participants prescribed ART for at least 6 months without virologic failure for pLLV. We used multinomial logistic regression to evaluate associations between prespecified factors of interest and 3 levels of pLLV (<200, 200–499, and 500–999 copies/mL). We used Anderson-Gill extended Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for viremia category associations with time to failure. Results We included 1511 participants with 4382 person-years of follow-up. PLLV <200 copies/mL was observed at 20% of visits while 2% of visits had pLLV 200–499 and 500–999 copies/mL each, with substantial variation by site. Protease inhibitor–containing ART was associated with increased risk of pLLV. Compared to undetectable viral load, pLLV ≥200 copies/mL doubled the risk of developing virologic failure (pLLV 200–499: HR, 1.81 [95% CI, 1.08–3.02]); pLLV 500–999: HR, 2.36 [95% CI, 1.52–3.67]). Conclusions Participants with pLLV ≥200 copies/mL were at increased risk of subsequent virologic failure. Optimized HIV care in this setting should target viral suppression <200 copies/mL.

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