What Is The Clinical Evidence In Support Of Tdf/abc As An Nrti Backbone
Concerns about the use of TDF/ABC were expressed following the high rates of virological failure with the triple NRTI combination of TDF/ABC/3TC in first-line therapy . Pharmacokinetic studies have not detected an interaction between TDF and ABC. In addition, data from observational and cohort studies indicated good outcomes with TDF/ABC as the NRTI backbone in combination with non-nucleoside reverse transcriptase inhibitors and PIs , although controlled prospective data in first-line therapy are lacking.
Who Is At Risk For Hiv Infection
Anyone can get HIV, but certain groups have a higher risk of getting it:
- People who have another sexually transmitted disease . Having an STD can increase your risk of getting or spreading HIV.
- People who inject drugs with shared needles.
- Gay and bisexual men.
- Black/African Americans and Hispanic/Latino Americans. They make up a higher proportion of new HIV diagnoses and people with HIV, compared to other races and ethnicities.
- People who engage in risky sexual behaviors, such as not using condoms.
Factors such as stigma, discrimination, income, education, and geographic region can also affect peoples risk for HIV.
Should A Baseline Resistance Test Be Requested
Current UK guidelines recommend that all patients should have a baseline resistance test performed at the time of diagnosis. However, there are limited data on the prevalence of resistance in drug-naive patients originally from Africa and presenting with chronic, established infection. In one study, the prevalence of transmitted resistance in the UK was found not to differ significantly in black Africans and heterosexuals relative to white and homosexual people . A second study found that, among patients newly diagnosed with an established HIV-1 infection, transmitted resistance was significantly more common in white homosexual males compared with a group of predominantly black African heterosexuals . Current recommendations take into account increasing access to antiretroviral therapy in many African countries, which may lead to growing rates of transmitted resistance. Guidelines also warn of the possibility that apparent transmitted resistance may mask undisclosed antiretroviral exposure .
While waiting for the genotype resistance test results, it was decided to start the patient on a combination of zidovudine , tenofovir and ritonavir-boosted lopinavir .
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Is The Use Of Tdf Without Lamivudine Adequate Treatment For A Patient Co
The use of 3TC as a single anti-HBV agent is effective in suppressing HBV DNA, but carries a significant risk of HBV resistance, with 20% of patients developing resistance for each year of treatment . The use of TDF as single-agent therapy is considered less likely to lead to the rapid acquisition of HBV resistance in co-infected patients. This area is currently under investigation and studies are ongoing to determine whether co-infected patients are best managed by sequential HBV monotherapy or combination therapy.
The baseline genotypic resistance test showed the following results:
- Reverse transcriptase : V75I/V, Y181C/Y, M184M/V
- Protease : L33F, M36I
Primary Hiv Infection Case Presentations
The following cases illustrate the complexities involved in recognizing and correctly diagnosing primary HIV infection . Extensive lab work, but also thorough history taking, is required. Patient 1 was not recognized as suffering from PHI until after she was discharged from the hospital. Patient 2 was recognized with PHI, and his symptoms spontaneously resolved. Patient 3 required extensive hospitalization because of pulmonary complications. Viral loads declined sharply without medication for both patients 1 and 2, upon resolution of symptoms. However, patient 3 maintained a high viral load and was started on triple-drug antiretroviral therapy. None of the patients were started on antiretroviral therapy during the acute retroviral syndrome phase of PHI, which is currently recommended in US treatment guidelines.
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What Other Options Were Available For This Patient
The options considered included:
- Structured treatment interruption . This strategy would help to avoid the development of further resistance, reduce drug exposure, and possibly favour improved adherence on resumption of therapy. However, it poses a risk of falling CD4 counts and rising viral load, with the potential for clinical events. Although the patient has a good CD4 count, a decline in count may occur rapidly in patients with nadir CD4 counts < 200 cells/l. The patient would therefore require close monitoring. Maintenance therapy with 3TC alone may be an alternative to a complete STI.
- Continuing the failing regimen. Despite repeated episodes of virological failure, the patient has achieved and maintained a high CD4 count. Continuing the current regimen would be the least favoured option because of the risk of accumulating further resistance, which may compromise future drug options.
- Entering a clinical trial. This would provide access to novel treatment options and strategies.
Late Art And Prognosis Of Hiv
Among the 34 persons for whom ART details were reported, 11 were on a tenofovir disoproxil fumarate+efavirenz+lamivudine regimen and three were on newer ART regimens: elvitegravir+cobicistat+ emtricitabine+tenofovir alafenamide , rilpivirine+tenofovir+emtricitabine , and cobicistat+elvitegravir+emtricitabine+tenofovir . Two cases who initiated ART upon admission were prescribed boosted protease inhibitors lopinavir/ritonavir before their limited efficacy against CoV was published .
Out of the 23 patients who reported the timing of ART initiation, 30.4% reported late initiation of ART around the same time of their COVID-19 diagnosis and 4 were confirmed having > 4 WHO definitive clinical outcome categories or severe clinical symptoms. Among 16 patients who had early ART initiation, only four cases were confirmed with a > 4 WHO definitive clinical outcome categories . One case was reported by Hu Y , Hu R , and Wang M who experienced a long-haul hospitalization of COVID-19 over 2 months, perhaps linked to immunosuppression and late commencement of ART.
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Results Of Search Strategy
We identified 120 records: 48 from PubMed, 22 from Web of Science, 14 from Sinomed, 23 from CNKI, and 13 from WanFang. We removed 26 duplicate records, 12 records deemed ineligible by automation tools, and 18 records that were not relevant. Among the remaining 64 reports, we further excluded 15 reports as not eligible,14 reports without specific cases information, 3 reports on laboratory technique only, and 14 secondary publications. This left 18 eligible publications for inclusion in the systematic review.
What Investigations Are Required At This Point
This patient is treatment-experienced and is currently receiving inadequate drug doses. Accurate dosing in children can be difficult using standard formulations, and can easily result in either under-dosing, leading to risk of virological failure, or over-dosing, leading to risk of toxicity. In this case, there is a substantial risk of suboptimal virological suppression and emergence of drug resistance. Investigations required include CD4 count, viral load measurement and a genotypic resistance assay.
His combination therapy was continued with Combivir and EFV pending results of the above investigations. The CD4 count was 900 cells/l and the viral load was 2214 copies/ml. The genotypic resistance test showed the following mutations:
- Reverse transcriptase : M41L, E44D, D67N, T69N, K103N, V108I, M184V, L210W, T215Y
- Protease : L10I, L63P, V77I, V82I
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Elis Dionsio Da Silva
1 Postgraduate Course of Biology applied to Health, Federal Universityof Pernambuco, PE, Brazil. E-mail: ,
2 Graduate Course on Biological Sciences, Institute of BiologicalSciences, University of Pernambuco, PE, Brazil
3 Parasitology Department, Aggeu Magalhães Research Center, OswaldoCruz Foundation, PE, Brazil. E-mails: , , ,
Why Was A Low Dose Of D4t Given
The normal recommended dose of d4T is 40 mg twice daily for > 60 kg body weight and 30 mg twice daily for a lower body weight . It has been shown that reducing the dose of d4T reduces the risk of side effects, including fat loss and blood dyslipidaemia, while preserving the antiviral activity of the drug . In view of this patient’s history of peripheral neuropathy, a reduced dose of d4T was used.
The patient tolerated the new regimen well and showed a durable suppression to < 50 copies/ml without evidence of virological blips or sustained viral load rebound. The CD4 count increased to 360 cells/l . In July 2005, after 27 months of successful therapy, the viral load rebounded to 3910 copies/ml. A genotype resistance test showed the following results:
- Reverse transcriptase: K65R, M184V
Fold change in drug susceptibility.
In July 2005, based on the genotypic test results, d4T was replaced by ZDV , while TDF and 3TC were maintained. Four weeks later, the virus load had dropped to 64 copies/ml. The patient continues on the current regimen with good adherence and tolerability, and with a viral load of < 50 copies/ml.
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How Quickly Are Tams Selected In First
In patients receiving the NRTIs ZDV and 3TC in combination, accumulation of TAMS occurs slowly over time and in a step-wise manner. A direct antagonistic effect of M184V on the emergence of TAMs has been proposed .
The patient showed a suboptimal virological response to ddI/d4T/NVP, with persistent detectable low-level viraemia at levels between 833 and 21,298 copies/ml. The CD4 count remained stable at 340 cells/l . A retrospective genotypic resistance test was performed on a stored sample collected prior to the start of the current ddI/d4T/NVP regimen, while the patient was still receiving Combivir/NFV. The retrospective sample showed the following results:
- Reverse transcriptase : K103N, M184V
- Protease : L63P
What Was The Rationale For Maintaining Tdf In The New Regimen Despite The Presence Of Resistance
The presence of K65R is likely to confer significant resistance to TDF. In single-drug intensification studies of patients with detectable viral load while on combination therapy, the addition of TDF in six patients with K65R did not produce significant changes in viral load . The rationale for maintaining TDF in the regimen was to preserve selective pressure on K65R, thereby increasing susceptibility to ZDV and antagonising the emergence of ZDV resistance. There is limited evidence that these in vitro effects translate into significant clinical benefit. Case reports have described patients with K65R failing TDF-containing highly active antiretroviral therapy who showed virological suppression after single-drug intensification with ZDV .
The patient received counselling to support his adherence as it had become apparent that there had been problems with his compliance during previous therapy. A plan for discontinuation of therapy after 12 months was discussed. After a further 6 weeks, the viral load was < 50 copies/ml and the CD4 cell count was 649 cells/l .
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Based On Current Knowledge Would The Management Have Been Different
Current UK guidelines would recommend obtaining a baseline resistance test before starting therapy. In the UK, the prevalence of resistance was 11% in drug-naive patients tested in 1999 . In addition, all current guidelines would recommend resistance testing at the time of failure to inform the choice of the second-line regimen. The major concern would be whether thymidine analogue mutations have emerged during the time of detectable viral replication prior to therapy change. The emergence of TAMs would significantly diminish susceptibility to d4T and ddI, making the NNRTI-based regimen less robust. Finally, current guidelines would recommend against the use of d4T and ddI in combination because of a significant risk of toxicity.
What Action Is Required In This Case
The recommended actions include reviewing adherence and tolerability, excluding unfavourable drugdrug interactions, measuring plasma ATV levels, and repeating the viral load measurement and the genotypic resistance test.
Adherence was reviewed and encouraged. The bilirubin levels had increased from 12 to 39 mol/l since the start of treatment, consistent with ATV dosing. The patient was not taking other prescribed or over-the-counter medications, and the ATV plasma trough levels were satisfactory. The patient continued on TDF/3TC/ATV/r. After a further 8 weeks of therapy , the viral load was 1305 copies/ml. A genotypic resistance test showed the following results:
- RT: M184I/V/M
- PR: M36I, L63P
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Can Hiv/aids Be Prevented
You can reduce the risk of spreading HIV by:
- Getting tested for HIV.
- Choosing less risky sexual behaviors. This includes limiting the number of sexual partners you have and using latex condoms every time you have sex. If your or your partner is allergic to latex, you can use polyurethane condoms.
- Getting tested and treated for sexually transmitted diseases .
- Not injecting drugs.
- Talking to your health care provider about medicines to prevent HIV:
- PrEP is for people who don’t already have HIV but are at very high risk of getting it. PrEP is daily medicine that can reduce this risk.
- PEP is for people who have possibly been exposed to HIV. It is only for emergency situations. PEP must be started within 72 hours after a possible exposure to HIV.
NIH: National Institutes of Health
What Is The Significance Of These Findings
Using the clinical cut-offs proposed by Virco , the fold changes indicate: high-level resistance to LPV/r and NFV, with at least 80% loss of virological response intermediate resistance to IDV/r and APV/r, with between 20% and 80% loss of response susceptibility to ATV/r and hypersusceptibility to SQV/r. There is also susceptibility to ritonavir-boosted tipranavir .
Salvage therapy was started with TDF, ABC, SQV/r and enfuvirtide. After 4 weeks, the viral load was < 50 copies/ml. After 6 months, the viral load remained suppressed and the patient discontinued enfuvirtide without virological rebound.
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Why Does He Have Detectable Plasma Levels Of Efv 3 Weeks After Discontinuing The Drug
The rates of metabolism of the NNRTIs are extremely variable between patients, with up to 20% showing detectable levels 3 weeks after last dosing . This is of particular importance for patients stopping a successful NNRTI-based regimen because it can result in the selection of NNRTI-resistant virus. To reduce this risk, it is generally recommended that when interrupting an NNRTI-based regimen, the NRTI backbone should be continued for 2 weeks after stopping the EFV, preferably with the addition of a ritonavir-boosted PI.
How Can These Results Be Explained
The M184V mutation could have been selected by the 3TC in Combivir. K103N is selected by exposure to NNRTIs and was unexpected given that the sample had been taken before the start of ddI/d4T/NVP. It was therefore concluded that the mutation probably represented transmitted resistance. The L63P mutation is a common polymorphism that is not associated with resistance to the protease inhibitors in the absence of other protease mutations. These findings indicated that the patient had been essentially receiving dual therapy with the two NRTIs while on ddI/d4T/NVP.
A further genotypic resistance test was performed on a current sample, with the following results:
- RT: D67N, K70R, K103N, K219Q
- PR: L63P
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Case Report: Leishmania And Hiv Co
- 1Infectious Diseases Department, Caen University Hospital, Caen, France
- 2Virology Department, Normandie Univ, UNICAEN, Normandie University Hospital, Caen, France
- 3Normandie University, UNICAEN, Groupe de Recherche sur lAdaptation Microbienne , Normandie Univ, UNICAEN, UNIROUEN, GRAM 2.0, Caen, France
- 4Virology Laboratory, Tours Hospital, Tours, France
- 5National Reference Centre for Leishmaniasis, University Hospital Centre of Montpellier, MiVEGEC, University of Montpellier, Montpellier, France
- 6Normandie University, UNICAEN, U2RM EA2128, Microbiology Department, Normandie University Hospital, PFRS, Caen, France
Clinical Presentation Of Hiv
As best we could derive from the publications, 44.2% had mild COVID-19, 9.6% were asymptomatic, 46.2% had severe COVID-19 among 52 co-infected persons for whom this was reported. In short, 53.8% of the patients exhibited mild or asymptotic. There was no moderate cases reported. The median time it took for clinical improvement in 30 cases with clinical follow-up data was 14 days . World Health Organization-recommended definitive clinical outcome categories were reported by 33 of 76 cases among these, 9.1% were not hospitalized, resuming normal activities promptly 48.5% were hospitalized, not requiring supplemental oxygen 30.3% were hospitalized, requiring supplemental oxygen 3.0% were hospitalized, requiring nasal high-flow oxygen therapy, noninvasive mechanical ventilation, or both and 9.1% died of COVID-19 .
The most prevalent presentations among 31 cases on whom clinical information was reported included fatigue and respiratory syndrome , and had gastrointestinal symptoms , including nausea, abdominal discomfort, diarrhea, anorexia, and poor appetite. The most common clinical presentations were fever and cough , though among 34 persons with reported body temperature, nine were afebrile.
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How Do You Interpret The Results Of The Genotypic Resistance Test
The detection of mixed populations of wild-type and resistant virus at multiple sites is consistent with a virus population evolving under suboptimal virological suppression. M184V is maintained by ABC, although ABC is less effective than 3TC in maintaining selective pressure on the mutation. K65R was selected by TDF and ABC, and L74V was selected by ABC. Emergence of secondary protease mutations, such as M36I, in the absence of major protease resistance mutations, has been observed in patients with detectable viral load while receiving therapy with ritonavir-boosted PIs . These changes signal virus evolution under drug pressure, but do not appear to confer significant shifts in phenotypic susceptibility to the PIs in routine phenotypic assays. The significance of the emerging mutations is currently uncertain.
Would You Consider This Response Satisfactory
The improvement in CD4 cell count is anticipated after a fall during seroconversion. After 12 weeks of therapy, the majority of patients would be expected to have achieved a viral load < 50 copies/ml. In this case, the viral load declined by less than 1 log10 . This suboptimal response may signal problems with compliance, pharmacokinetics or transmitted resistance at levels below the detection limit of the genotypic resistance assay.
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What Factors Can Affect Drug Plasma Levels
There are many factors that may affect drug levels, including genetic determinants of drug metabolism, effects of food on drug absorption, renal or hepatic impairment, drug interactions including interaction with herbal and other supplements, and other host-related factors such as age, body weight and pregnancy.