-
The Lancet. Microbe Feb 2023HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder... (Meta-Analysis)
Meta-Analysis
BACKGROUND
HIV-1 infections initiated by multiple founder variants are characterised by a higher viral load and a worse clinical prognosis than those initiated with single founder variants, yet little is known about the routes of exposure through which transmission of multiple founder variants is most probable. Here we used individual patient data to calculate the probability of multiple founders stratified by route of HIV exposure and study methodology.
METHODS
We conducted a systematic review and meta-analysis of studies that estimated founder variant multiplicity in HIV-1 infection, searching MEDLINE, Embase, and Global Health databases for papers published between Jan 1, 1990, and Sept 14, 2020. Eligible studies must have reported original estimates of founder variant multiplicity in people with acute or early HIV-1 infections, have clearly detailed the methods used, and reported the route of exposure. Studies were excluded if they reported data concerning people living with HIV-1 who had known or suspected superinfection, who were documented as having received pre-exposure prophylaxis, or if the transmitting partner was known to be receiving antiretroviral treatment. Individual patient data were collated from all studies, with authors contacted if these data were not publicly available. We applied logistic meta-regression to these data to estimate the probability that an HIV infection is initiated by multiple founder variants. We calculated a pooled estimate using a random effects model, subsequently stratifying this estimate across exposure routes in a univariable analysis. We then extended our model to adjust for different study methods in a multivariable analysis, recalculating estimates across the exposure routes. This study is registered with PROSPERO, CRD42020202672.
FINDINGS
We included 70 publications in our analysis, comprising 1657 individual patients. Our pooled estimate of the probability that an infection is initiated by multiple founder variants was 0·25 (95% CI 0·21-0·29), with moderate heterogeneity (Q=132·3, p<0·0001, I=64·2%). Our multivariable analysis uncovered differences in the probability of multiple variant infection by exposure route. Relative to a baseline of male-to-female transmission, the predicted probability for female-to-male multiple variant transmission was significantly lower at 0·13 (95% CI 0·08-0·20), and the probabilities were significantly higher for transmissions in people who inject drugs (0·37 [0·24-0·53]) and men who have sex with men (0·30 [0·33-0·40]). There was no significant difference in the probability of multiple variant transmission between male-to-female transmission (0·21 [0·14-0·31]), post-partum transmission (0·18 [0·03-0·57]), pre-partum transmission (0·17 [0·08-0·33]), and intra-partum transmission (0·27 [0·14-0·45]).
INTERPRETATION
We identified that transmissions in people who inject drugs and men who have sex with men are significantly more likely to result in an infection initiated by multiple founder variants, and female-to-male infections are significantly less probable. Quantifying how the routes of HIV infection affect the transmission of multiple variants allows us to better understand how the evolution and epidemiology of HIV-1 determine clinical outcomes.
FUNDING
Medical Research Council Precision Medicine Doctoral Training Programme and a European Research Council Starting Grant.
Topics: Humans; Male; Female; HIV Infections; HIV-1; Homosexuality, Male; Sexual and Gender Minorities; Anti-HIV Agents; HIV Seropositivity
PubMed: 36642083
DOI: 10.1016/S2666-5247(22)00327-5 -
Clinical Infectious Diseases : An... May 2023Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.
METHODS
Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222).
RESULTS
Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations.
CONCLUSIONS
There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
Topics: Adult; Adolescent; Child; Humans; Antitubercular Agents; Pyrazinamide; Ethambutol; Tuberculosis; Rifampin; Isoniazid; HIV; HIV Infections
PubMed: 36609692
DOI: 10.1093/cid/ciac973 -
Value in Health : the Journal of the... Jun 2023Heavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral...
BACKGROUND/AIMS
Heavily treatment-experienced (HTE) people with human immunodeficiency virus (HIV) (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multidrug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the phase 2/3 CAPELLA study. This study aimed to compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR) + OBR, ibalizumab (IBA) + OBR, and OBR alone in terms of VS, CD4 cell count change from baseline, immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons.
METHODS
A systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for indirect treatment comparison analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons of LEN + OBR versus comparators were conducted.
RESULTS
LEN + OBR had 6.57 times higher odds of VS at weeks 24 to 28 than FTR + OBR (95% confidence interval [CI] 1.34-32.28), 8.93 times higher odds of VS than IBA + OBR (95% CI 2.07-38.46), and 12.74 times higher odds of VS than OBR alone (95% CI 1.70-95.37). Change from baseline in CD4 cell count was similar across LEN + OBR, FTR + OBR, and IBA + OBR.
CONCLUSION
LEN + OBR has statistically significantly greater odds of VS at weeks 24 to 28 than its comparators and represents a novel treatment for people with MDR HIV.
Topics: Humans; HIV Infections; Anti-HIV Agents; HIV-1; Drug Therapy, Combination; Clinical Protocols
PubMed: 36566886
DOI: 10.1016/j.jval.2022.12.011 -
Viruses Dec 2022The Joint United Nations Program on HIV/AIDS (UNAIDS) has adopted the Sustainable Development Goals (SDGs) to end the HIV/AIDS epidemic by 2030. Several factors related... (Review)
Review
The Joint United Nations Program on HIV/AIDS (UNAIDS) has adopted the Sustainable Development Goals (SDGs) to end the HIV/AIDS epidemic by 2030. Several factors related to the non-suppression of HIV, including interruptions of antiretroviral therapy (ART) and opportunistic infections could affect and delay this projected epidemic goal. Human T-Cell leukemia virus type 1 (HTLV-1) appears to be consistently associated with a high risk of opportunistic infections, an early onset of HTLV-1 and its associated pathologies, as well as a fast progression to the AIDS phase in co-infected individuals, when compared to HIV-1 or HTLV-1 mono-infected individuals. In Gabon, the prevalence of these two retroviruses is very high and little is known about HTLV-1 and the associated pathologies, leaving most of them underdiagnosed. Hence, HTLV-1/HIV-1 co-infections could simultaneously imply a non-diagnosis of HIV-1 positive individuals having developed pathologies associated with HTLV-1, but also a high mortality rate among the co-infected individuals. All of these constitute potential obstacles to pursue targeted objectives. A systematic review was conducted to assess the negative impacts of HTLV-1/HIV-1 co-infections and related factors on the elimination of HIV/AIDS by 2030 in Gabon.
Topics: Humans; Human T-lymphotropic virus 1; Acquired Immunodeficiency Syndrome; Gabon; Coinfection; HIV Infections; HIV-1; HIV Seropositivity; Leukemia, T-Cell; Opportunistic Infections; HTLV-I Infections
PubMed: 36560812
DOI: 10.3390/v14122808 -
PharmacoEconomics May 2023Considerable evidence on the costs and cost-effectiveness of biomedical, non-surgical interventions to prevent human immunodeficiency virus (HIV) transmission has been...
BACKGROUND
Considerable evidence on the costs and cost-effectiveness of biomedical, non-surgical interventions to prevent human immunodeficiency virus (HIV) transmission has been generated over the last decade. This study aims to synthesize findings and identify remaining knowledge gaps to suggest future research priorities.
METHODS
A systematic literature review was carried out in August 2020 using the MEDLINE, Embase, Global Health and EconLit databases to retrieve economic evaluations and costing studies of oral pre-exposure prophylaxis (PrEP), injectable long-acting PrEP, vaginal microbicide rings and gels, HIV vaccines and broadly neutralizing antibodies. Studies reporting costs from the provider or societal perspective were included in the analysis. Those reporting on behavioural methods of prevention, condoms and surgical approaches (voluntary medical male circumcision) were excluded. The quality of reporting of the included studies was assessed using published checklists.
RESULTS
We identified 3007 citations, of which 87 studies were retained. Most were set in low- and middle-income countries (LMICs; n = 53) and focused on the costs and/or cost-effectiveness of oral PrEP regimens (n = 70). Model-based economic evaluations were the most frequent study design; only two trial-based cost-effectiveness analyses and nine costing studies were found. Less than half of the studies provided practical details on how the intervention would be delivered by the health system, and only three of these, all in LMICs, explicitly focused on service integration and its implication for delivery costs. 'Real-world' programme delivery mechanisms and costs of intervention delivery were rarely considered. PrEP technologies were generally found to be cost-effective only when targeting high-risk subpopulations. Single-dose HIV vaccines are expected to be cost-effective for all groups despite substantial uncertainty around pricing.
CONCLUSIONS
A lack of primary, detailed and updated cost data, including above-service level costs, from a variety of settings makes it difficult to evaluate the cost-effectiveness of specific delivery modes at scale, or to evaluate strategies for services integration. Closing this evidence gap around real-world implementation is vital, not least because the strategies targeting high-risk groups that are recommended by PrEP models may incur substantially higher costs and be of limited practical feasibility in some settings.
Topics: Female; Humans; Male; Cost-Benefit Analysis; HIV; HIV Infections; AIDS Vaccines; Cost-Effectiveness Analysis
PubMed: 36529838
DOI: 10.1007/s40273-022-01223-w -
PLoS Medicine Dec 2022Economic losses due to herpes simplex infections in low- and middle-income countries (LMICs) are unknown. We estimated economic and quality-of-life losses due to genital...
BACKGROUND
Economic losses due to herpes simplex infections in low- and middle-income countries (LMICs) are unknown. We estimated economic and quality-of-life losses due to genital herpes in 2019, in 90 LMICs, and from 2020 to 2030 in 45 countries in the World Health Organization (WHO) Africa. We additionally estimated economic losses due to human immunodeficiency virus (HIV) attributable to herpes simplex virus type 2 (HSV-2) infections.
METHODS AND FINDINGS
We estimated genital herpes-related spending on treatment, wage losses due to absenteeism, and reductions in quality of life, for individuals aged 15 to 49 years, living with genital herpes. Had HSV-2 had contributed to the transmission of HIV, we estimated the share of antiretroviral treatment costs and HIV-related wage losses in 2019 that can be attributed to incident and prevalent HSV-2 infections in 2018. For the former, we used estimates of HSV-2 incidence and prevalence from the global burden of disease (GBD) study. For the latter, we calculated population attributable fractions (PAFs), using the classic (Levin's) epidemiological formula for polytomous exposures, with relative risks (RRs) reported in literature. To extend estimates from 2020 to 2030, we modeled the transmission of HSV-2 in 45 African countries using a deterministic compartmental mathematical model, structured by age, sex, and sexual activity, which was fitted to seroprevalence gathered from a systematic review and meta-regression analysis. In the 90 LMICs, genital herpes contributed to US$813.5 million in treatment and productivity losses in 2019 (range: US$674.4 to US$952.2 million). Given observed care-seeking and absenteeism, losses are in the range of US$29.0 billion (US$25.6 billion to US$34.5 billion). Quality-of-life losses in the amount of 61.7 million quality-adjusted life years (QALYs) are also possible (50.4 million to 74.2 million). The mean annual cost of treatment and wage losses per infection is US$183.00 (95% CI: US$153.60 to US$212.55); the mean annual cost of quality-of-life losses is US$343.27 (95% CI: 272.41 to 414.14). If HSV-2 has fueled the transmission of HIV, then seroprevalent HSV-2 cases in 2018 can account for 33.2% of the incident HIV infections in 2019, with an associated antiretroviral therapy (ART) cost of US$186.3 million (range: US$163.6 to US$209.5 million) and 28.6% of HIV-related wage losses (US$21.9 million; range: US$19.2 to US$27.4 million). In the WHO Africa region, the 3.9 million seroprevalent genital herpes cases from 2020 to 2030 contributed to US$700.2 million in treatment and productivity losses. Additionally, quality-of-life losses in the range of 88 million to 871 million QALYs are also possible. If HSV-2 has contributed to the transmission of HIV, then in 2020, the PAF of HIV due to prevalent HSV-2 will be 32.8% (95% CI: 26.7% to 29.9%) and due to incident infections will be 4.2% (95% CI: 2.6% to 3.4%). The PAF due to prevalent infections will decline to 31.0% by 2030 and incident infections to 3.6%. Though we have accounted for the uncertainty in the epidemiological and economic parameter values via the sensitivity analysis, our estimates still undervalue losses due to limiting to the 15- to 49-year-old population.
CONCLUSIONS
Economic losses due to genital herpes in LMICs can be large, especially when considering the lifelong nature of the disease. Quality-of-life losses outweigh spending on treatment and reductions in productivity. If HSV-2 has contributed to the spread of HIV in LMICs, then nearly one third of antiretroviral costs and HIV-related wage losses can be attributed to HSV-2. Given the magnitude of the combined losses, a vaccine against HSV-2 must be a global priority.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Herpes Genitalis; Herpesvirus 2, Human; Developing Countries; HIV; HIV Infections; Seroepidemiologic Studies; Financial Stress; Quality of Life; Anti-Retroviral Agents
PubMed: 36520853
DOI: 10.1371/journal.pmed.1003938 -
Artificial Intelligence in Medicine Dec 2022Machine learning algorithms play an essential role in bioinformatics and allow exploring the vast and noisy biological data in unrivaled ways. This paper is a systematic... (Review)
Review
Machine learning algorithms play an essential role in bioinformatics and allow exploring the vast and noisy biological data in unrivaled ways. This paper is a systematic review of the applications of machine learning in the study of HIV neutralizing antibodies. This significant and vast research domain can pave the way to novel treatments and to a vaccine. We selected the relevant papers by investigating the available literature from the Web of Science and PubMed databases in the last decade. The computational methods are applied in neutralization potency prediction, neutralization span prediction against multiple viral strains, antibody-virus binding sites detection, enhanced antibodies design, and the study of the antibody-induced immune response. These methods are viewed from multiple angles spanning data processing, model description, feature selection, evaluation, and sometimes paper comparisons. The algorithms are diverse and include supervised, unsupervised, and generative types. Both classical machine learning and modern deep learning were taken into account. The review ends with our ideas regarding future research directions and challenges.
Topics: Humans; HIV Antibodies; Machine Learning; HIV-1; Antibodies, Neutralizing; HIV Infections
PubMed: 36462896
DOI: 10.1016/j.artmed.2022.102429 -
European Journal of Clinical... Jan 2023Leishmaniasis is a parasitic infection expressing different clinical phenotypes. Visceral leishmaniasis (VL) is considered an opportunistic infection among people with... (Meta-Analysis)
Meta-Analysis Review
Leishmaniasis is a parasitic infection expressing different clinical phenotypes. Visceral leishmaniasis (VL) is considered an opportunistic infection among people with human immunodeficiency virus (HIV). The objective of this review was to identify published data on the prevalence of Leishmania spp. infection among PWH and to define particular determinants that affect critically the epidemiological characteristics of VL-HIV coinfection and, potentially, its burden on public health. Two independent reviewers conducted a systematic literature search until June 30, 2022. Meta-analyses were conducted using random-effects models to calculate the summary prevalence and respective 95% confidence intervals (CI) of leishmaniasis among PWH. Meta-regression analysis was performed to investigate the impact of putative effect modifiers, such as the mean CD4 cell count, on the major findings. Thirty-four studies were eligible, yielding a summary prevalence of 6% (95%CI, 4-11%) for leishmaniasis (n = 1583) among PWH (n = 85,076). Higher prevalence rates were noted in Asia (17%, 95%CI, 9-30%) and America (9%, 95%CI, 5-17%) than in Europe (4%, 95%CI, 2-8%). Prevalence rates were significantly mediated by the age, sex, and CD4 cell count of participants. Heterogeneity remained significant in all meta-analyses (p < 0.0001). In the majority of included studies, people were coinfected with HIV and Leishmania species associated with VL, as opposed to those associated with cutaneous leishmaniasis. No sign of publication bias was shown (p = 0.06). Our summary of published studies on leishmaniasis among PWH is important to provide prevalence estimates and define potential underlying factors that could guide researchers to generate and further explore specific etiologic hypotheses.
Topics: Humans; Leishmaniasis, Visceral; HIV; HIV Infections; Prevalence; Leishmaniasis; Coinfection
PubMed: 36427170
DOI: 10.1007/s10096-022-04530-4 -
Sao Paulo Medical Journal = Revista... 2022The relationship with body image, which is the way the body presents itself to each subject, can be aggravated in children and adolescents diagnosed with an human...
CONTEXT
The relationship with body image, which is the way the body presents itself to each subject, can be aggravated in children and adolescents diagnosed with an human immunodeficiency virus (HIV) infection, since these patients use antiretroviral therapy and may suffer from the adverse effects of the treatment due to continuous use of medication.
OBJECTIVE
To estimate the prevalence of body image dissatisfaction, to describe the assessment methods, and to identify associated factors in children and adolescents diagnosed with HIV.
DESIGN AND SETTING
This is a systematic review. Department of Physical Education, Florianópolis - Brazil.
METHODS
We followed the procedures of the Preferred Reporting Items for Systematic Reviews (PRISMA) and the Cochrane recommendations in the selection of articles through a search performed in eight databases.
RESULTS
Prevalence of body image dissatisfaction due to thinness was between 36.7-52.0% in males and 28.1-36.4% in females, and body image dissatisfaction due to overweight was between 8.0-31.2% in males and 21.9-50.0% in females. Factors associated with body image dissatisfaction were as follows: female sex, older age, low levels of physical activity, low self-esteem, higher body fat, higher body weight, greater arm muscle area, triceps skinfold thickness, and higher body mass index.
CONCLUSION
Children and adolescents of both sexes diagnosed with HIV infection are dissatisfied by thinness and overweight of their body image.
REGISTRATION
https://www.crd.york.ac.uk/prospero/ (CRD42021257676).
Topics: Male; Humans; Child; Adolescent; Female; Body Image; Overweight; Thinness; HIV; HIV Infections; Body Mass Index; Body Weight
PubMed: 36417660
DOI: 10.1590/1516-3180.2022.0154.R2.19082022 -
Systematic Reviews Nov 2022The World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some... (Meta-Analysis)
Meta-Analysis
A systematic review and meta-analysis assessing antiretroviral therapy for treatment-experienced HIV adult patients using an optimized background therapy approach: is there evidence enough for a standardized third-line strategy?
BACKGROUND
The World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some controversy remains as to the best combinations of ART for experienced HIV-1-infected patients. Therefore, we conducted a systematic review and meta-analysis to (i) assess the efficacy of third-line therapy for adults with HIV/AIDS based on randomized controlled trials (RCT) that adopted the "new antiretroviral (ARV) + optimized background therapy (OBT)" approach and (ii) address the key issues identified in WHO's guidelines on the use of third-line therapy.
METHODS
MEDLINE, EMBASE, LILACS, ISI Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials were searched for RCTs assessing third-line ARV therapy that used an OBT approach between 1966 and 2015. Data was extracted using an Excel-structured datasheet based on the Consolidated Standards of Reporting Trials (CONSORT) recommendations. The primary outcome of this meta-analysis was the proportion of patients reaching undetectable HIV RNA levels (< 50 copies/mL) at 48 weeks of follow-up. Included studies were evaluated using the Cochrane's Risk of Bias assessment tool. Summarized evidence was rated according to the GRADE approach.
RESULTS
Eighteen trials assessing 9 new ARV + OBT combinations defined as third-line HIV therapy provided the efficacy data: 7 phase IIb trials and 11 phase III trials. Four of the 18 trials provided extension data, thus resulting in 14 trials providing 48-week efficacy data. In the meta-analysis, considering the outcome regarding the proportion of patients with a viral load below 50 copies/ml at 48 weeks, 9 out of 14 trials demonstrated the superiority of the new combination being studied (risk difference = 0.18, 95% CI 0.13-0.23). The same analysis stratified by the number of fully active ARVs demonstrated a risk difference of 0.29 (95% CI 0.12-0.46), 0.28 (95% CI 0.17-0.38) and 0.17 (95% CI 0.10-0.24) respectively from zero, one, and two or more active drugs strata. Nine of the 18 trials were considered to have a high risk of bias.
CONCLUSIONS
Efficacy results demonstrated that the groups of HIV-experienced patients receiving the new ARV + OBT were more likely to achieve viral suppression when compared to the control groups. However, most of these trials may be at a high risk of bias. Thus, there is still not enough evidence to stipulate which combinations are the most effective for therapeutic regimens that are to be used sequentially due to documented multi-resistance.
Topics: Adult; Humans; Acquired Immunodeficiency Syndrome; Anti-HIV Agents; HIV Infections; HIV-1; Viral Load; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic
PubMed: 36397111
DOI: 10.1186/s13643-022-02102-3