First-line ART Failure Research Articles

Virological impact of HIV drug-resistance testing in children, adolescents, and adults failing first-line ART in Tanzania

BackgroundProspective data on the effectiveness of resistance testing in informing treatment decisions and outcomes in with first-line failure in these settings is limited. This study aimed to assess the virological impact of HIV drug-resistance testing in patients with virological failure in Tanzania. MethodsParticipants were randomly assigned to either the control or the experimental group. In addition to the standard of care, patients in the experimental group had access to genotypic drug-resistance testing, information used during treatment change and were followed up at six-and 12-months to determine virological suppression. ResultsA total of 261 patients with a median age of 32 (14.7–44.7) years were enrolled. In the intention-to-treat analysis, at 6-months, suppression was achieved in 58 (42.3%; 95% CI, 34.1–50.1) experimental group patients versus 51 (41.1%; 95% CI, 32.5–49.8) control group patients, with a p-value of 0.4. At-12 months, suppression was achieved in 110 (80.3%; 95% CI, 73.6–87) experimental patients versus 99 (79.8%; 95% CI, 72.8–86.9) control patients, with a P-value of 0.5. In the per-protocol analysis, at 6-months, suppression was observed in 38.46% (95% CI, 27.6–49.3) experimental patients versus 38.6% (95% CI, 26.0–51.2) control patients, with a P-value of 0.5. At 12-months, suppression was observed in 79.49% (95% CI, 70.5–88.5) of experimental patients versus 75.44% (95% CI, 64.3–86.6) of control patients, with a P-value of 0.3. ConclusionConducting HIV drug-resistance testing, and switch to individualised second-line regimens did not significantly improve virological suppression in patients experiencing first-line ART failure in Tanzania.

Determinants of virologic failure among adult HIV patients on first line antiretroviral treatment in Oromia, Central Ethiopia: 2022 a case-control study

BackgroundEthiopia’s viral suppression rate was less than 90% by 2020, and more than 10% of adult clients on ART in Woliso Town were unsuppressed at the end of March 2022. This study aims to identify determinants of virologic failure among adult clients on ART at health facilities in Oromia region of Ethiopia.MethodsA facility-based unmatched case-control study was conducted at health facilities in Oromia region from August 1 to September 1, 2022. The study cases were clients with virologic-confirmed first-line ART failure, while controls were clients on first-line ART with a suppressed viral load. A total of 135 cases and 268 control participants were selected using simple random sampling techniques, and data were collected by reviewing the client’s document. Epi-Info7 was used for data entry and SPSS version 20 for data analysis. Variables having a P-value of less than 0.25 in the bi-variable analysis were included in multivariable logistic regression. Determinants of virologic failure were determined based on an adjusted odds ratio using 95% CI and a P-value of < 0.05.ResultIn this study, clients with an age ≥ 35 years (AOR = 3.4, 95% CI: 1.6, 7.0), clients with a baseline regimen of AZT + 3TC + NVP (AOR = 3.5, 95% CI: 1.4, 8.8), clients with a base-line CD4 count < 350 mm3 (AOR = 2.3, 95% CI: 1.1, 4.5), being single marital status (AOR = 3.7, 95% CI: 1.4, 10.5), TB-HIV coinfection (AOR = 2.58, 95% CI: 1.3, 5.1), and having opportunistic infection other than TB in the last six months (AOR = 3.06, 95% CI: 1.5, 6.3) were factors significantly associated with virologic failure while clients within the appointment spacing model (AOR = 0.05, 95% CI: 0.03, 0.10) is inversely associated with virologic failure.ConclusionThis study showed that age ≥ 35 years, being single, baseline ART regimen with (AZT + 3TC + NVP), baseline CD4 cell count < 350 mm3, Tb-co infection, and opportunistic infection in the last 6 months were factors associated with virologic failure. Involvement in the appointment spacing model was found to be protective.

Risk assessment of first-line treatment failure in untreated HIV patients in Northwestern Federal District of the Russian Federation

The HIV infection epidemic in Russia continues to evolve, and HIV infection cases have been registered in all territorial entities of the Russian Federation. 2021 Treatment coverage was 82.2% and 56.4% individuals under dispensary observation and living with diagnosed HIV infection. 79.9% receiving ART subjects were shown to achieve undetectable viral load. Highly active antiretroviral therapy (HAART) currently represents a combination of three (less frequently four) antiretroviral drugs targeting pathways involved in various stages of HIV replication in vivo. Treatment failure is a problem facing doctors and patients using HAART. The most common cause of therapeutic failure is the development of HIV drug resistance. The emergence of resistance is associated with processes involving mutation occurring in the viral genome influenced by evolutionary factors. Therefore, it is important clinically and programmatically to learn more about the rate of first-line treatment failure, the rate of switching to a second-line ART regimen, and to identify patients at risk to develop strategies for preventing development of further failure cases. The study was aimed at analyzing ineffectiveness of first-line ART therapy in patients in Northwestern Federal District of the Russian Federation. Materials and methods. Sequencing reactions were performed using the AmpliSens HIV Resist-Seq. Assembly of consensus sequences from fragments obtained during sequencing was carried out using Unipro UGENE software. Isolate genotyping was performed using the MEGA-X software with the Neighbor-joining algorithm. Results. The HIV pol genes in 239 patients with first-line ART failure and 100 nave patients were sequenced; all sequences genotyped as HIV-1 subsubtype A6. According to analysis, 82% of patients had at least one significant mutation associated with drug resistance for the corresponding viral subtype. In total, we encountered 87 different drug resistance mutations. Conclusion. We have shown increased proportion of patients with first-line ART failure among all patients with treatment failure. The main cause for such changes is probably related to the prevalence of primary drug resistance, estimated here at 8%. Specific differences were found between drug resistance mutation profiles in patients without suppressed viral load and patients with virological breakthrough. The overall results of the study indicate a need to diagnose and characterize HIV drug resistance prior to initiation of therapy in order to avoid ineffective first-line antiretroviral treatment.

Prevalence of, and Factors Influencing First Line Antiretroviral Treatment Failure among Adult HIV Patients at Antiretroviral Treatment Clinic of Mettu Karl Referral Hospital, South Western, Ethiopia: A Prospective Cross Sectional Study, 2021

Antiretroviral treatment failure is defined as progression of disease and high risk of mortality after beginning of highly active anti-retroviral therapy. First-line ART failure has emerged as a growing concern. ART failure is a major challenge to HIV/AIDS management in resource-limited settings including Ethiopia where the diagnosis and management of ART failure is a key problem. Principal factors involving fist-line antiretroviral regimen failure include poor adherence to medication, younger age, lower baseline CD4+ count and higher baseline viral load.

Incidence and Predictors of Treatment Failure Among Children Receiving First-Line Antiretroviral Treatment in General Hospitals of Two Zones, Tigray, Ethiopia, 2019.

BackgroundDespite many efforts undertaken to control the human immunodeficiency virus epidemic, it remains to be the major global public health challenge. With expanding access to pediatric antiretroviral therapy, children are more likely to experience treatment failure. All previous studies conducted in Ethiopia estimated treatment failure using only clinical and CD4 criteria. Thus, the ART failure rate is expected to be underestimated in our country.Objectives of the StudyTo assess the incidence and predictors of treatment failure among children receiving first-line ART in general hospitals of Mekelle and Southern Zones of Tigray region, Ethiopia, 2019.MethodsRetrospective follow up study was employed. The sample size was estimated based on a Log rank test using Stata V-13 and all 404 charts were taken for review. Data were collected by extraction tool; entered using Epi-data manager; cleaned and analyzed by Stata V-14. Data were described using the Kaplan-Meier curve, Log rank test, life table, and crude hazard ratios and analyzed using adjusted hazard ratios and p-value by Cox proportional hazard regression. Any variable at P <0.05 in the bi–variable analysis was taken to multi–variate analysis and significance was declared at P≤ 0.05. Data were presented using tables, charts, and texts.ResultsThe incidence rate of ART failure was 8.68 (95% CI 7.1 to 10.6) per 1000 person-month observations with a total of 11,061.5 person-month observations. Children who had tuberculosis at baseline [AHR=2.27; 95% CI 1.12–4.57], advanced recent WHO stage [AHR=5.21; 95% CI 2.75–9.88] and sub-optimal ART adherence [AHR=2.84, 95% CI 1.71–4.72] were at higher hazard for first-line treatment failure. Besides this having a long duration of ART follow up [AHR=0.85; 95% CI 0.82–0.87] was found to be protective against treatment failure.Conclusion and RecommendationThe incidence of first-line ART failure was grown as a major public health concern. Treatment failure was predicted by the duration of follow up, advanced recent WHO stage, sub-optimal adherence, as well as the presence of tuberculosis at baseline. Hence, it is better to give priority for strengthening the focused evaluation of the WHO clinical stage and tuberculosis co-infection at baseline with continuous adherence monitoring.

Study of Immunological and Virological Recovery in HIV/AIDS Patients on Second Line Anti-Retroviral Therapy: A Prospective Study

AIMS/BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). Highly active antiretroviral therapy (HAART), is the cornerstone of management of patients with HIV infection. Following the initiation of widespread use of HAART, drug resistance and failure of first line ART is an emerging problem. Hence use of second line ART is on rise, therefore there is a need to study the factors affecting the immunological and virological recovery and specific opportunistic infections during second line ART. In India, the second line regimen has still not been studied extensively when compared to its first line counterpart. This study aims at determining the immunological and virological recovery as well as to study the incidence of various opportunistic infections in HIV/AIDS patients on second line ART. METHODS: The study was conducted at Bowring & Lady Curzon Hospital, affiliated to Bangalore Medical College from November 2015 to January 2019.The study included 72 patients, switched from first line to second line ART in the year 2015-16 and consented to participate in our study. Patients were analyzed in out-patient as well as in-patient basis, as per need. Clinical assessment was repeated every 6 months for next 3 years. RESULTS: In our study 42 males (58.3%) and 30 females (41.6%) were included. There was a gradual rise in CD4 count from baseline. 81.69% (59) cases had CD4 count 200 at the end of 3 years. Mortality was 5 cases (6.94 %). Among patients who expired, had baseline CD4 Count <100 cells/microliter, stage 3 and 4 at initiation of first line ART. Low CD4 nadir and opportunistic infections during first line ART and T4 stage while switching to second line ART. CONCLUSION: 1. There was a significant improvement in CD4 Counts and fall in viral load after initiation of Second line ART. 2. Severe immunosuppression (CD4 Count <100 cells/microliter) at baseline were associated with low CD4 counts recovery and delayed viral load suppression. FUNDING STATEMENT: None. DECLARATION OF INTERESTS: None. ETHICS APPROVAL STATEMENT: After obtaining ethical clearance and approval from the Institutional Ethics Committee of BMCRI, written informed consent was taken from the patients.

Factors for nonadherence to first line art therapy in a cohort of Human Immunodeficiency Virus positive adult patients

Background: Antiretroviral therapy is one of the reasons for falling trend of HIV epidemic at present. The clinical efficacy, toxicity and reasons for failure of first line ART is understudied. This study aimed to determine the frequency rates and reasons for discontinuation of first line ART in a cohort of HIV positive adult patients.Methods: Cross sectional study was conducted on 11,968 patients of HIV registered at Victoria Hospital ART centre from 2011 to 2017. Using a structured proforma, relevant information was collected from patients taking first line ART. Descriptive statistics was used for analysing the results obtained.Results: Total 11,968 HIV patients were registered at ART centre during our study period of which only 4,008 patients were taking ART among them, 167 patients were referred for initiation of 2nd line ART. After evaluation 28 were continued on First line,1 opted out, 20 were transferred out,1 discontinued treatment, 17 died, 14 were lost to follow up, 5 were excluded from the study and only 81 patients were started on second line ART. Failure rate of first line ART in our study was 2.02%. Immunological failure followed by clinical failure were the most common reasons for changeover in this study. Tuberculosis was the most common comorbid disease in this study.Conclusions: First line ART is very effective and well tolerated and has a low failure rate. Low CD4 count, anaemia, raised ALP, low albumin were among the factors associated with treatment failure. WHO staging did not correlate with the treatment failure, recommended routine viral load monitoring for assessing treatment failure.

Virological outcomes of second-line antiretroviral therapy for HIV-1 patients in center of excellence, Gandhi Hospital, Secundrabad, Telangana

Introduction: In India, ART service was established in 2004 and viral load facility was started in 2009 through National Public Health Laboratory (NPHL). Phased scale-up has been planned to efficiently and successfully expand viral load testing services, taking into account the targets for enrollment of People Living with HIV in to Anti Retroviral Therapy program. Methods: This is an observational study conducted at the Centre of Excellence (COE), Gandhi Hospital Secundrabad. It is a referral centre for evaluation of patients suspected of treatment failure from ART centers. Data of all patients &gt;18 years of age who were started on second line therapy due to failure of first line ART was taken in the study. The data of patients admitted between the time period of January 2009 to January 2010 was included. Results: A total of 147 HIV infected patients received second line ART of which 114 were men and 33 were women. Of these, 147 were treated with regimen TL, ATV/r. The most common cause to switch on second line ART was combined immunological and clinical failure (135) followed by all three failure (12).Mean baseline CD4 count was 220.06 (95% confidence interval [CI]: 243.73-196.38) and mean base line of PVL of patients was 291356.6 cells/mm3 (95% CI: 364843.8-217869.29) copies/ml, respectively. Conclusion: Good long term outcome as well as virological suppression in patients starting second line therapy under programmatic conditions in India. This early mortality can be circumvented by introducing routine virological monitoring in the program which will help in early detection of patients with failure.

An apparent paradox: resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy.

In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load <60 copies/mL and a median CD4 count of 466 cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48 weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95% CI 0.01-0.37; P = 0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95% CI 0.03-0.82; P = 0.028). Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

Determinants of First-line Antiretroviral Treatment Failure Among Patients on Antiretroviral Therapy in Public Hospitals Jimma, Southwest Ethiopia a Case-Control Study

Highly Active Antiretroviral Therapy (HAART) has substantially declined morbidity and mortality related to Human immunodeficiency virus/Acquired immunodeficiency syndrome (HIV/AIDS). Despite this fact, first-line ART failure has emerged as a growing concern. However, factors associated with first-line ART failure are not well empathized and studied. Hence, we aimed to identify the determinants of first-line ART failure among patients attending ART in Public Hospitals Jimma, Southwest Ethiopia. A case-control study was conducted in March 2018 on a sample of 384 (288 controls and 96 cases) adult people living with HIV/AIDS (PLWHA). Cases were HIV patients aged 15 years or older who were on first-line ART regimens with documented therapeutic failure. Controls were HIV patients aged 15 years or older who were on first-line ART regimen but without evidence of therapeutic failure. Data were extracted from electronic databases and supplemented by data collected through interviewer-administered questionnaires. Bivariate and multivariate logistic regression analyses were used. Adjusted odds ratios and 95% confidence intervals were used to report independently associated factors at P-value<0.05. In this study, higher odds of first-line ART failure was experienced among urban residents (AOR:2.2; 95%CI: 1.1, 3.6), smokers (AOR:5.9; 95%CI:3.2, 10.8), Khat users (AOR:2.2; 95%CI:1.3,3.7), poor treatment adherents (AOR:2.2; 95%CI: 1.1,4.5), tuberculosis coinfection (AOR:3.9; 95%CI:2.2, 6.8), prior exposure to ART (AOR:3.8; 95%CI:1.7, 8.1), zidovudine based regimen (AOR:4.8; 95%CI: 2.5,9.0) and longer duration on ART more than 73 months (AOR:1.9; 95%CI:1.2, 3.3). This study evidenced that being an urban resident, TB co-infection, poor medication adherence, and zidovudine-based regiment were positively and independently associated with first-line ART failure. Thus, the focus should be given assessment and management of medication compliance for urban residents and longer duration ART users. Assessment and management of substance use disorders are highly recommended besides ARV medication refills. Attention should be given enhanced adherence counseling and peer support to improve adherence. Early screening and management of tuberculosis infection should be strengthened. It is advisable to initiate ART with the recommended TDF-based first-line ART regimens instead of AZT-based.

Predictors of first line antiretroviral therapy failure and burden of second line antiretroviral therapy

BackgroundAs HIV steps into the third decade, there are more number of patients living on lifelong (antiretroviral therapy) ART and facing the threat of drug resistance with subsequent treatment failure. The aim of this study was to determine predictors of first-line ART failure with the objectives to estimate the burden of 2nd line ART. MethodsA retrospective 5-year cohort of HIV patients who were initiated on first line ART in 2008–09 was studied. Patients were followed from the time of ART initiation. Kaplan–Meier methods and Cox proportional hazards regression models were used to estimate probabilities and predictors of first line ART failure. ResultsOf the total of 195 patients initiated on first line ART, 15 patients were switched to second line ART yielding 7.69% failure rate. During the 7178 person-years of follow-up, the incidence of first line ART failure was 2.09 per 1000 person-years. The Kaplan–Meier survival analysis gave a mean survival time of 55.6 months. BMI, CD4 count at ART initiation and presence of opportunistic infections were significant predictors of first line ART failure. The burden of second line ART patients by the end of 5 years of first line ART is expected to be 151 patients. ConclusionThough the first line ART failure is quite low in this study, we still need to be vigilant for lower BMI, low baseline CD4 count and occurrence of opportunistic infections to efficiently manage failures on first line ART.

Clinical, Immunological and Virological Profile of Patients with HIV Infection on Second Line Antiretroviral Therapy

Background and Objectives: The goal of antiretroviral therapy is to maximally and durably inhibit viral replication. Objectives of this study were –  To study the various clinical features of patients on second line anti retroviral therapy.  To study the immunological and virological profile of these patients.  To study various factors determining the initiation of second line ART Material and Methodology: Retrospective analysis of 30 HIV patients on second line Antiretroviral Therapy was done. Clinical examination and various immunological profiles like CD4 count, CD8 count and virological profiles like viral load and viral resistance testing were noted if done. Details of therapy in terms of drugs, schedule, adverse effects etc. were noted. Results: Majority of patients had BMI in the normal range. Mean CD4 cell count increased from 114/mm3 at start of first line therapy to 168/mm3 at start of second line therapy. Immunological failure was the reason to switch to second line therapy in 63.33% patients. The most common second line regimen followed was Tenofovir + Abacavir + Lopinavir + Ritonavir, in 73.33% of patients, but it showed a high incidence of minor adverse effects. Viral load was estimated in 50% patients of which 36.67% patients had >20,000 HIV virus copies/ml. Tuberculosis was the main opportunistic infection encountered. Analysis and Discussion: Second line antiretroviral therapy has changed the prognosis of HIV infected patients who have first line regimen failure. The switch to second line treatment was relatively slow, due to CD4 cell count being used as the main criteria to switch therapy. This study highlights the importance of assessing viral load to monitor any early virological failure of first line ART to switch early to second line therapy. The

Determinants of virological failure and antiretroviral drug resistance in Mozambique.

The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique. This was a cross-sectional study. HIV-1-infected adults on first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression. The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age [OR = 0.97 per additional year (95% CI = 0.94-1.00), P = 0.039], ART initiation at WHO stage III/IV [OR = 2.10 (95% CI = 1.23-3.57), P = 0.003] and low ART adherence [OR = 2.69 (95% CI = 1.39-5.19), P = 0.003] were associated with virological failure. Longer time on ART [OR = 1.55 per additional year (95% CI = 1.00-2.43), P = 0.052] and illiteracy [OR = 0.24 (95% CI = 0.07-0.89), P = 0.033] were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects. Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resources.

Prevalence of HIV-1 drug resistance among patients failing first-line ART in Monrovia, Liberia: a cross-sectional study.

To assess the prevalence of acquired drug resistance in HIV-1-infected patients living in Monrovia, Liberia, who had clinical and/or immunological failure of first-line ART according to WHO criteria. Patients receiving ART for >1 year with clinical and/or immunological failure were included. Sequencing of protease and reverse transcriptase regions was performed using Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) procedures and sequences were interpreted using the ANRS resistance algorithm. Ninety patients were enrolled. They had been receiving ART for a median time of 42 months and half were receiving zidovudine/lamivudine/nevirapine. Seventy-five per cent of patients were infected with CRF02_AG. Twenty-seven per cent of patients displayed a plasma viral load <50 copies/mL. Among the 66 patients with detectable viraemia, the median viral load was 4.7 log10 copies/mL (IQR = 3.0-5.6). The prevalence of NRTI and NNRTI resistance-associated mutations (RAMs) was 63% and 71%, respectively; and the median number of NRTI and NNRTI RAMs was 2 and 3, respectively. Two patients (4%) displayed viruses with PI RAMs. Regarding NRTI drug resistance, 29%, 38%, 63%, 29% and 25% of patients had viruses resistant to zidovudine, stavudine, lamivudine/emtricitabine, abacavir and tenofovir, respectively. Regarding the NNRTI drug class, 56%, 65%, 33% and 42% of patients had viruses resistant to efavirenz, nevirapine, etravirine and rilpivirine, respectively. The high prevalence of acquired drug resistance in patients followed in two centres of the Liberian capital city, documented after a median of 3 years on a first-line ART regimen, jeopardizes the activity of second-line regimens and highlights the need for virological monitoring in these settings.

Correction: Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0044793.].

Prediction of High Level of Multiple Drug Resistance Mutations in HIV-1 Subtype C Reverse Transcriptase Gene among First Line Antiretroviral-Experienced Virological Failure Patients from North India Using Genotypic and Docking Analysis

Background: Virologic failures and development of drug resistance can result in reduced treatment options in HIV infection. Methods: RT sequence of HIV-1 subtype C isolates from 122 Antiretroviral Therapy (ART) naive and 13 virological and first line regimen failures from North India were analyzed. Mutations were defined according to Stanford Drug Resistance data base. A three dimensional HIV-1 subtype C specific computational model of RT was created from consensus sequences from naive patients to analyze mutations in therapy failures. CD4 count and viral load were measured to analyze the disease status and subtyping was done using Genotyping NCBI HIV subtyping tool. Results: All thirteen isolates from first-line ART-failure patients had mutations effecting susceptibility to RTI drugs when analyzed using Stanford DR HIV-1 database. The most common NRTI resistance mutations were in positions 118, 184, 210 and 215 indicating the possibility of high level resistance to Lamivudine (3TC) and Emtricitabine (FTC) in 92.3% of isolates. Common NNRTI resistance mutations were identified at position 98, 101, 103, 181 and 190 indicating a high level resistance to Nevirapine (NVP) in 100% therapy failures, while affecting the susceptibility to EFV in 76.92%. Energy scores were calculated after docking of various NRTIs on our newly proposed model based on the three dimensional structure of local wild type reverse transcriptase (RT) of subtype C. The presence of V75M mutation in one of the isolates (SK-206) seem to be partially neutralizing the resistance effect of mutations 118I, 184V, 210W, and 215Y for Stavudine (D4T), Didanosine (DDI) and FTC while 75M decreases the susceptibility of Zidovudine (AZT) (ΔG=0.87), causing high level of resistance. Conclusion: The data suggest that the proposed model was successful in predicting the resistance/susceptibility to various RTIs based on docking energy scores taking into consideration the cumulative effect of all the mutations together.

Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa

BackgroundIn HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.Methodology/Principle FindingsWe conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm3 (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing.Conclusions/SignificanceWe observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.

The economic crisis of 1837–1839 in Upper Canada: Case study of a temporary suspension of specie payments

As HIV steps into the third decade, there are more number of patients living on lifelong (antiretroviral therapy) ART and facing the threat of drug resistance with subsequent treatment failure. The aim of this study was to determine predictors of first-line ART failure with the objectives to estimate the burden of 2nd line ART.A retrospective 5-year cohort of HIV patients who were initiated on first line ART in 2008–09 was studied. Patients were followed from the time of ART initiation. Kaplan–Meier methods and Cox proportional hazards regression models were used to estimate probabilities and predictors of first line ART failure.Of the total of 195 patients initiated on first line ART, 15 patients were switched to second line ART yielding 7.69% failure rate. During the 7178 person-years of follow-up, the incidence of first line ART failure was 2.09 per 1000 person-years. The Kaplan–Meier survival analysis gave a mean survival time of 55.6 months. BMI, CD4 count at ART initiation and presence of opportunistic infections were significant predictors of first line ART failure. The burden of second line ART patients by the end of 5 years of first line ART is expected to be 151 patients.Though the first line ART failure is quite low in this study, we still need to be vigilant for lower BMI, low baseline CD4 count and occurrence of opportunistic infections to efficiently manage failures on first line ART.