Current Opinion in HIV and AIDS最新文献

Purpose of review: Tenofovir-based oral PrEP has been effective in reducing population-level HIV incidence in multiple settings, although disparities remain. Injectable cabotegravir-based PrEP is an alternative that may be attractive to individuals with adherence challenges or who do not desire to take a daily medication. We review promises and challenges of cabotegravir-based PrEP.

Recent findings: Cabotegravir has demonstrated higher effectiveness than oral PrEP in two randomized trials, with a hazard ratio of 0.31 for HIV incidence among MSM and transgender women across multiple settings [95% confidence interval (CI) 0.18-0.62] and 0.11 for cisgender women in sub-Saharan Africa (95% CI 0.040.32). Cabotegravir was also highly effective among populations with disproportionate HIV incidence. Although cabotegravir breakthrough was rare, diagnosis was delayed with use of antigen/antibody-based HIV tests, and resistance occurred with breakthrough infections. Implementation will need to overcome several challenges, including HIV RNA laboratory monitoring not being widely available, requirement for additional staff time and clinic space, and need to provide oral medication during interruptions in dosing.

Summary: Cabotegravir-based PrEP is a highly effective additional PrEP option that will expand HIV prevention options. For successful roll-out, strategies for streamlined and accessible delivery of cabotegravir in real-world settings will need to be developed.

Purpose of review: HIV-1 drug resistance (HIV DR) testing is routinely performed by genotyping plasma viruses using Sanger population sequencing. Next-generation sequencing (NGS) is increasingly replacing standardized Sanger sequencing. This opens up new opportunities, but also brings challenges.

Recent findings: The number of NGS applications and protocols for HIV DR testing is increasing. All of them are noninferior to Sanger sequencing when comparing NGS-derived consensus sequences to Sanger sequencing-derived sequences. In addition, NGS enables high-throughput sequencing of near full-length HIV-1 genomes and detection of low-abundance drug-resistant HIV-1 variants, although their clinical implications need further investigation. Several groups have defined remaining challenges in implementing NGS protocols for HIV-1 resistance testing. Some of them are already being addressed. One of the most important needs is quality management and consequently, if possible, standardization.

Summary: The use of NGS technologies on HIV DR testing will allow unprecedented insights into genomic structures of virus populations that may be of immediate relevance to both clinical and research areas such as personalized antiretroviral treatment. Efforts continue to tackle the remaining challenges in NGS-based HIV DR testing.

Purpose of review: Ten years since the first regulatory approval of oral HIV preexposure prophylaxis (PrEP), this review summarizes PrEP uptake, the role of ambitious PrEP targets, emerging evidence of impact on the HIV epidemic and innovative approaches to increasing PrEP uptake.

Recent findings: PrEP uptake among people at risk of HIV has been slow, but has accelerated in recent years, particularly in gay and bisexual men in a limited number of high-income settings and recently in heterosexuals at risk of HIV in sub-Saharan Africa. However, UNAIDS 2020 PrEP targets and HIV prevention targets were missed by large margins. Although UNAIDS testing and treatment targets have galvanised public health action, in contras, PrEP targets have been lower profile and insufficiently ambitious. Parts of the USA, Australia and the UK with high PrEP coverage have demonstrated striking reductions in HIV infection at the population level, as PrEP is introduced at scale. Scaling up PrEP uptake will require innovations in PrEP promotion, simplified models of care, improved adherence interventions, improved choice in the form of longer-acting PrEP and interventions to ensure that all those who can benefit from PrEP can access it.

Summary: PrEP is a revolutionary HIV prevention tool, which if ambitiously scaled up could drive HIV transmission towards elimination. Highly publicized and ambitious PrEP targets could help drive this.

Purpose of review: To summarize recent updates on the potential role of islatravir for HIV treatment and prevention.

Recent findings: Islatravir is an investigational antiretroviral agent with unique pharmacologic properties that facilitate flexible dosing regimens. Islatravir has demonstrated potent antiviral activity and a high barrier to resistance when combined with doravirine and lamivudine. A simplified two-drug HIV treatment regimen of islatravir combined with doravirine has also demonstrated comparable efficacy to standard of care three-drug regimens. The long half-life and high potency of islatravir's active metabolite may support its use as a long-acting option for HIV preexposure prophylaxis (PrEP). A once monthly oral dose of islatravir maintains effective concentrations of its active metabolite over the entire dosing interval. Furthermore, an investigational implantable formulation has been projected to provide efficacious concentrations for at least a year and exhibits comparable distribution into vaginal and rectal tissues making it a promising PrEP option for male and female individuals. Islatravir has minimal risks of drug interactions as it is not a substrate, inducer, or inhibitor of major drug metabolizers and transporters. Finally, clinical trials demonstrate islatravir's favorable safety profile revealing only mild and transient adverse events.

Summary: Leveraging the unique pharmacological properties of islatravir offers opportunities for simplified HIV treatment regimens and long-acting PrEP making it a valuable addition to the antiretroviral arsenal.

Purpose of review: This review focuses on the safety of oral tenofovir disoproxil and emtricitabine (FTC) combination for HIV preexposure prophylaxis (PrEP) in adults.

Recent findings: Gastrointestinal adverse events are common after treatment initiation but usually resolve within weeks. Although clinical trials did not report an increased risk of serious renal adverse events or tubulopathy, meta-analyses suggest that tenofovir disoproxil -FTC is associated with a slight but non-clinically relevant decline in estimated glomerular filtration rate (eGFR). A decline to less than 60 mL/min remains a rare event, which mainly occurs in users with an age >50 years or a baseline creatinine clearance < 90 mL/min. Similarly, a slight reduction in bone mineral density (BMD) was observed in clinical trials, but it did not result in an increased risk of bone fracture. BMD reduction and eGFR decline tend to resolve after treatment discontinuation. No drug interaction with contraception has been reported in women and no safety signal emerged in pregnant and breastfeeding women.

Summary: Oral tenofovir disoproxil-FTC for HIV PrEP appears safe and well tolerated for most individuals. This supports demedicalization strategies aiming at increasing the number of PrEP users.

Purpose of review: Anti-HIV-1 broadly neutralizing antibodies (bNAbs) are promising agents in the fight against the AIDS epidemic. Multiple bNAbs have been already evaluated in clinical trials with encouraging results. This review discusses the use of bNAbs for the prevention and treatment of HIV-1 infection, focusing on manufactured products that have been evaluated in clinical settings.

Recent findings: More than 17 bNAbs have been evaluated for safety and pharmacokinetics in humans. The vast majority presented a well tolerated profile and were generally well tolerated. Serum half-life varied from 12 to 73.5 days and can be improved by the addition of mutations to the Fc regions. Results from the antibody-mediated prevention (AMP) study show that VRC01, a CD4-binding-site bNAb, was effective at preventing the acquisition of sensitive HIV-1 strains but did not prevent the acquisition of strains whose in vitro sensitivity to the antibody had an IC80 of more than 1 μg/ml. New bNAb combinations to improve coverage are currently being evaluated.

Summary: In this review, we discuss the current landscape of HIV-1 bNAbs in clinical development. We also present the current strategies employed to improve the breadth, potency, serum half-life, effector function and administration of these compounds.

Purpose of review: HIV preexposure prophylaxis (PrEP) is a key tool in ending the HIV epidemic. Long-acting cabotegravir (LA- CAB) phase II/III studies revealed promising efficacy in preventing HIV acquisition. Here, we discuss key considerations for implementing LA-CAB in low- and middle-income countries (LMIC).

Recent findings: PrEP roll out in LMIC is still far from ideal, and contextual factors within LMIC vary widely. Implementation science studies are urgently needed to optimize the implementation of LA-CAB in different settings, consider effective service delivery models, and ensure program sustainability. Preferences and concerns regarding LA-CAB among potential users are unknown but likely specific to local context. Demedicalized and simplified PrEP service delivery increases uptake, and ways to safely and effectively do the same for LA- CAB need to be explored. Although ideally LA-CAB should be an additional choice of HIV prevention method, its cost will be the major determinant in deciding its position as a first line choice or restricted second-line option.

Summary: LA-CAB has the potential to enhance PrEP uptake. However, several implementation challenges need to be explored and addressed to ensure it can be accessed and utilized in different settings by those who need it the most.

Purpose of review: With oral antiretroviral therapy, HIV has become a manageable chronic illness. However, UNAIDS targets for virologic suppression have not yet been attained in many low-income and middle-income countries (LMICs). Long-acting drug formulations hold promise to improve treatment outcomes. In this rapidly evolving area of research, we aim to review recent literature on the treatment of HIV with long-acting agents and identify implementation considerations for LMICs.

Recent findings: Randomized controlled trials have shown that monthly long-acting injectable cabotegravir (CAB) and rilpivirine (RPV) is noninferior to oral ART, and 2-monthly CAB/RPV is noninferior to monthly injections. However, few people from LMICs were included. A modelling study predicts that in sub-Saharan Africa, injectable CAB/RPV is best targeted to those with poor adherence (HIV viral load >1000 copies/ml) in whom cost-effectiveness is greatest and risk of contributing to further resistance is no greater than continuation of oral ART. Other promising agents, such as lenacapavir are under investigation and may prove particularly useful in heavily treatment-experienced adults.

Summary: Long-acting regimens are a promising advance in HIV treatment. By extending the dosing interval, increasing convenience and being discreet these regimens may reduce HIV treatment challenges. However, there are multiple implementation considerations in LMICs including the need for exclusion of hepatitis B, cold chain, oral bridging in case of missed dosing and switching during tuberculosis therapy. Efficacy and safety data are also awaited for settings without routine access to baseline resistance testing or regular viral load monitoring and for special populations, such as pregnancy, children and the elderly.

Purpose of review: Broadly neutralizing antibodies (bNAbs) are a potential new therapeutic strategy to treat HIV infection. This review explores possible mechanisms of action of bNAbs and summarizes the current evidence supporting their immunomodulatory properties, which might lead to sustained virological remission - the 'vaccinal effect'.

Recent findings: Antiretroviral therapy (ART) is required to confer lasting HIV suppression; stopping ART almost invariably leads to HIV recrudescence from a persistent pool of virally infected cells - the HIV reservoir. HIV-specific broadly neutralizing antibodies (bNAbs) may confer viral control after ART cessation predominantly through blockade of viral entry into uninfected target cells. In some human and animal studies, HIV bNAbs also conferred lasting viral suppression after therapeutic bNAb plasma levels had declined. Immune-modulatory mechanisms have been postulated to underlie this observation - the 'vaccinal effect'. Hypothesized mechanisms include the formation of immune complexes between bNAbs and HIV envelope protein, thereby enhancing antigen presentation and uptake by immune cells, with boosted adaptive immune responses subsequently controlling the HIV reservoir.

Summary: There is emerging evidence for potent antiviral efficacy of bNAb therapy. Whether bNAbs can induce sustained viral suppression after dropping below therapeutic levels remains controversial. Mechanistic data from on-going and future clinical trials will help answer these questions.