Global and Regional Estimates for Subtype-Specific Therapeutic and Prophylactic HIV-1 Vaccines: A Modeling Study

Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments (gag, pol, env) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on env required 2.6 million subtype E doses, and a vaccine based on pol required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on env required 1.2 billion subtype E doses, and a vaccine based on pol required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting env also need to include subtype E and those targeting pol need to include subtype G.S

Global associations of key populations with HIV-1 recombinants: a systematic review, global survey, and individual participant data meta-analysis

Introduction: Global HIV infections due to HIV-1 recombinants are increasing and impede prevention and treatment efforts. Key populations suffer most new HIV infections, but their role in the spread of HIV-1 recombinants is unknown. We conducted a global analysis of the associations between key populations and HIV-1 recombinants. Methods: We searched PubMed, EMBASE, CINAHL, and Global Health for HIV-1 subtyping studies published from 1/1/1990 to 31/12/2015. Unpublished data was collected through a global survey. We included studies with HIV-1 subtyping data of key populations collected during 1990-2015. Key populations assessed were heterosexual people (HET), men who have sex with men (MSM), people who inject drugs (PWID), vertical transmissions (VERT), commercial sex workers (CSW), and transfusion-associated infections (BLOOD). Logistic regression was used to determine associations of key populations with HIV-1 recombinants. Subgroup analyses were performed for circulating recombinant forms (CRFs), unique recombinant forms (URFs), regions, and time periods. Results: Eight hundred and eighty five datasets including 77,284 participants from 83 countries were included. Globally, PWID were associated with the greatest odds of recombinants and CRFs (OR 2.6 [95% CI 2.46-2.74] and 2.99 [2.83-3.16]), compared to HET. CSW were associated with increased odds of recombinants and URFs (1.59 [1.44-1.75] and 3.61 [3.15-4.13]). VERT and BLOOD were associated with decreased odds of recombinants (0.58 [0.54-0.63] and 0.43 [0.33-0.56]). MSM were associated with increased odds of recombinants in 2010-2015 (1.43 [1.35-1.51]). Subgroup analyses supported our main findings. Discussion: As PWID, CSW, and MSM are associated with HIV-1 recombinants, increased preventative measures and HIV-1 molecular surveillance are crucial within these key populations. Systematic review registration: PROSPERO [CRD42017067164].S

The Refinement of Genetic Predictors of Multiple Sclerosis

Medical Research Council [GRANT NUMBER G0801976], a research fellowship FISM-Fondazione Italiana Sclerosi Multipla-Cod.: [2010/B/5 to GD] and an MS Society of Great Britain and Northern Ireland Clinical Research Fellowship [GRANT NUMBER 940/10 to RD]

Global associations of key populations with HIV-1 recombinants: a systematic review, global survey, and individual participant data meta-analysis

Global HIV infections due to HIV-1 recombinants are increasing and impede prevention and treatment efforts. Key populations suffer most new HIV infections, but their role in the spread of HIV-1 recombinants is unknown. We conducted a global analysis of the associations between key populations and HIV-1 recombinants. We searched PubMed, EMBASE, CINAHL, and Global Health for HIV-1 subtyping studies published from 1/1/1990 to 31/12/2015. Unpublished data was collected through a global survey. We included studies with HIV-1 subtyping data of key populations collected during 1990–2015. Key populations assessed were heterosexual people (HET), men who have sex with men (MSM), people who inject drugs (PWID), vertical transmissions (VERT), commercial sex workers (CSW), and transfusion-associated infections (BLOOD). Logistic regression was used to determine associations of key populations with HIV-1 recombinants. Subgroup analyses were performed for circulating recombinant forms (CRFs), unique recombinant forms (URFs), regions, and time periods. Eight hundred and eighty five datasets including 77,284 participants from 83 countries were included. Globally, PWID were associated with the greatest odds of recombinants and CRFs [OR 2.6 (95% CI 2.46–2.74) and 2.99 (2.83–3.16)], compared to HET. CSW were associated with increased odds of recombinants and URFs [1.59 (1.44–1.75) and 3.61 (3.15–4.13)]. VERT and BLOOD were associated with decreased odds of recombinants [0.58 (0.54–0.63) and 0.43 (0.33–0.56)]. MSM were associated with increased odds of recombinants in 2010–2015 [1.43 (1.35–1.51)]. Subgroup analyses supported our main findings. As PWID, CSW, and MSM are associated with HIV-1 recombinants, increased preventative measures and HIV-1 molecular surveillance are crucial within these key population

GWAS statistics (OR and risk allele frequencies) were used to simulate a population of 100,000 individuals under different models considering: only HLA-DRB1, HLA-DRB1 + MS associations known in 2011 and HLA-DRB1 + all currently known MS associations.

<p><i>Categories of risk were defined based on the 95%CI of risk of each individual (see methods). Green = reduced risk, blue = average risk, yellow = elevated risk, red = high risk.</i></p

Proportion of MS patients and HC in different risk categories and median wGRS with interquartile range (IQR) of MS and HC in each model (only HLA-DRB1, HLA-DRB1 + MS associations known in 2011 and HLA-DRB1 + all currently known MS associations).

<p>In brief, the genotype at MS associated loci was used to assign each individual to the categories of risk identified using the simulated population from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0096578#pone-0096578-t001" target="_blank">table 1</a>. Furthermore, a weighted genetic risk (wGRS) was calculated by multiplying the number of risk alleles by the weight of each SNP and then taking the sum across all associations (see methods).</p

Proportion of population and 95%CIs for each category of risk considering only HLA-DRB1, HLA-DRB1 + MS associations known in 2011 and HLA-DRB1 + all currently known MS associations.

<p>In brief, GWAS statistics (OR and risk allele frequencies) are used to simulate a population of 100,000 individuals. An overall genetic risk of MS is calculated for each individual and scaled by the mean risk profile. Categories of risk are defined based on the 95%CI of risk of each individual (see methods).</p

Predictive performance of the wGRS assessed using receiver operating characteristic (ROC) curves when considering only HLA-DRB1, HLA-DRB1 + MS associations known in 2011 and HLA-DRB1 + all currently known MS associations.

<p><i>The wGRS threshold providing the best predictive performance is also shown (specificity and sensitivity within brackets).</i></p

Boxplots of weighted genetic risk score (wGRS) in MS patients and HC considering only HLA-DRB1, HLA-DRB1 + MS associations known in 2011 and HLA-DRB1 + all currently known MS associations.

<p><i>The wGRS was calculated by multiplying the number of risk alleles by the weight of each SNP and then taking the sum across all associations (see methods). The whiskers extend to the most extreme data point which is no more than 1.5 times the IQR from the box.</i></p

Global and regional molecular epidemiology of HIV-1, 1990–2015: a systematic review, global survey, and trend analysis

Erratum in: Correction to Lancet Infect Dis 2019; 19: 143-55. [Lancet Infect Dis. 2020]International audienceBACKGROUND:Global genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990-2015.METHODS:We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. We grouped countries into 14 regions and analysed data for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164.FINDINGS:This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990-2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010-15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02_AG (7·7%; 2 705 110/34 921 639), CRF01_AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005-15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02_AG decreased. CRF01_AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time.INTERPRETATION:Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines