Preventing HIV-1 infection is a high global priority. This study assessed prevention strategies in young women in South Africa, Uganda, and Zimbabwe using oral or vaginal antiretroviral agents. No ...approach was found to be effective. The HIV-1 incidence was 5.7 per 100 person-years.
Daily oral preexposure prophylaxis with 300 mg of tenofovir disoproxil fumarate (TDF), alone or in combination with 200 mg of emtricitabine (FTC) (TDF-FTC Truvada, Gilead Sciences), reduces the risk of acquisition of human immunodeficiency virus type 1 (HIV-1) by 50% or more among persons with high adherence to the regimen, with demonstrated efficacy in men who have sex with men, heterosexuals, and injection-drug users.
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On the basis of these observations, in July 2012 the Food and Drug Administration approved daily treatment with Truvada for the prevention of HIV-1 acquisition, and the Centers for Disease Control and Prevention has issued . . .
To review current laboratory and clinical data on the frequency and relative risk of drug resistance and range of mutations selected from approved and investigational antiretroviral agents used for ...preexposure prophylaxis (PrEP) of HIV-1 infection, including tenofovir disproxil fumarate (TDF)-based oral PrEP, dapivirine ring, injectable cabotegravir (CAB), islatravir, lenacapavir and broadly neutralizing antibodies (bNAbs).
The greatest risk of HIV-1 resistance from PrEP with oral TDF/emtricitabine (FTC) or injectable CAB is from starting or continuing PrEP after undiagnosed acute HIV infection. By contrast, the dapivirine intravaginal ring does not appear to select nonnucleoside reverse transcriptase inhibitor resistance in clinical trial settings. Investigational inhibitors including islatravir, lenacapavir, and bNAbs are promising for use as PrEP due to their potential for sustained delivery and low risk of cross-resistance to currently used antiretrovirals, but surveillance for emergence of resistance mutations in more HIV-1 gene regions (gag, env) will be important as the same drugs are being developed for HIV therapy.
PrEP is highly effective in preventing HIV infection. Although HIV drug resistance from PrEP use could impact future options in individuals who seroconvert on PrEP, the current risk is low and continued monitoring for the emergence of resistance and cross-resistance during product development, clinical studies, and product roll-out is advised to preserve antiretroviral efficacy for both treatment and prevention.
Purpose of Review
Cabotegravir is a potent integrase strand transfer inhibitor (INSTI) recently approved as a long-acting injectable formulation for HIV prevention (CAB-LA). We summarize what is ...known about cabotegravir pharmacokinetics, activity, and emergence of resistance from in vitro, macaque and clinical studies, and we evaluate the risk of resistance from CAB-LA with on-time injections and after CAB-LA discontinuation.
Recent Findings
The accumulation of multiple INSTI mutations is required for high-level cabotegravir resistance, and the same mutation combinations may cause cross-resistance to dolutegravir, which is widely used for first-line antiretroviral therapy in low- and middle-income countries. Though CAB-LA was highly effective in preventing HIV, breakthrough infections did occur in trials of CAB-LA despite on-time injections, resulting in selection of single and combinations of INSTI resistance mutations.
Summary
As CAB-LA is scaled-up, prompt HIV diagnosis to prevent resistance, and resistance monitoring could help preserve the effectiveness of INSTIs for both HIV treatment and prevention.
Abstract
Background
We studied humoral responses after coronavirus disease 2019 (COVID-19) vaccination across varying causes of immunodeficiency.
Methods
Prospective study of fully vaccinated ...immunocompromised adults (solid organ transplant SOT, hematologic malignancy, solid cancers, autoimmune conditions, human immunodeficiency virus HIV) versus nonimmunocompromised healthcare workers (HCWs). The primary outcome was the proportion with a reactive test (seropositive) for immunoglobulin G to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain. Secondary outcomes were comparisons of antibody levels and their correlation with pseudovirus neutralization titers. Stepwise logistic regression was used to identify factors associated with seropositivity.
Results
A total of 1271 participants enrolled: 1099 immunocompromised and 172 HCW. Compared with HCW (92.4% seropositive), seropositivity was lower among participants with SOT (30.7%), hematological malignancies (50.0%), autoimmune conditions (79.1%), solid tumors (78.7%), and HIV (79.8%) (P < .01). Factors associated with poor seropositivity included age, greater immunosuppression, time since vaccination, anti-CD20 monoclonal antibodies, and vaccination with BNT162b2 (Pfizer) or adenovirus vector vaccines versus messenger RNA (mRNA)-1273 (Moderna). mRNA-1273 was associated with higher antibody levels than BNT162b2 or adenovirus vector vaccines after adjusting for time since vaccination, age, and underlying condition. Antibody levels were strongly correlated with pseudovirus neutralization titers (Spearman r = 0.89, P < .0001), but in seropositive participants with intermediate antibody levels, neutralization titers were significantly lower in immunocompromised individuals versus HCW.
Conclusions
Antibody responses to COVID-19 vaccines were lowest among SOT and anti-CD20 monoclonal recipients, and recipients of vaccines other than mRNA-1273. Among those with intermediate antibody levels, pseudovirus neutralization titers were lower in immunocompromised patients than HCWs. Additional SARS-CoV-2 preventive approaches are needed for immunocompromised persons, which may need to be tailored to the cause of immunodeficiency.
In this prospective study of 1271 participants, seropositivity after COVID-19 vaccination varied by condition: HCW (92.4%), HIV (79.8%), autoimmune conditions (79.1%), solid tumors (78.7%), hematological malignancies (50.0%), and SOT (30.7%). Additional strategies are needed to protect immunocompromised patients from COVID-19.
PURPOSE OF REVIEWTo review current data on HIV-1 resistance arising from the use of fixed dose combination tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for preexposure prophylaxis (PrEP) to ...prevent HIV-1 infection.
RECENT FINDINGSResistance to tenofovir (TNV) or FTC is infrequently selected by TDF/FTC PrEP if started before HIV-1 infection has occurred, but is much more common when inadvertently started during undiagnosed acute infection. Mathematical modeling predicts that the number of HIV-1 infections averted by the use of PrEP far exceeds the increase in drug-resistant infections that could occur from PrEP. Studies in macaques show that TNV-resistant virus but not FTC-resistant virus can cause breakthrough infection despite TDF/FTC PrEP. FTC resistance with M184 V/I occurs more frequently than TFV resistance with K65R in seroconverters from clinical trials of TDF/FTC PrEP.
SUMMARYThe benefit of preventing HIV-1 infections with TDF/FTC PrEP far outweighs the risk of drug-resistant infection, provided PrEP is not started in persons with undiagnosed HIV-1 infection. We should respect but not fear HIV-1 resistance from TDF/FTC PrEP and recognize that most TNV or FTC resistance will arise from its use for antiretroviral therapy (ART). Preventing ART failure or detecting it early is most important for preventing the spread of HIV-1 resistance to TDF/FTC and preserving its effectiveness for both PrEP and ART.
Abstract
Introduction
Oral preexposure prophylaxis (PrEP) in the form of tenofovir-disoproxil-fumarate/emtricitabine is being implemented in selected sites in South Africa. Addressing outstanding ...questions on PrEP cost-effectiveness can inform further implementation.
Methods
We calibrated an individual-based model to KwaZulu-Natal to predict the impact and cost-effectiveness of PrEP, with use concentrated in periods of condomless sex, accounting for effects on drug resistance. We consider (1) PrEP availability for adolescent girls and young women aged 15–24 years and female sex workers, and (2) availability for everyone aged 15–64 years. Our primary analysis represents a level of PrEP use hypothesized to be attainable by future PrEP programs.
Results
In the context of PrEP use in adults aged 15–64 years, there was a predicted 33% reduction in incidence and 36% reduction in women aged 15–24 years. PrEP was cost-effective, including in a range of sensitivity analyses, although with substantially reduced (cost) effectiveness under a policy of ART initiation with efavirenz- rather than dolutegravir-based regimens due to PrEP undermining ART effectiveness by increasing HIV drug resistance.
Conclusions
PrEP use concentrated during time periods of condomless sex has the potential to substantively impact HIV incidence and be cost-effective.
PrEP use concentrated during time periods of condomless sex has the potential to substantively impact HIV incidence and to be cost-effective in the example setting of KwaZulu-Natal, South Africa.
Background. Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the ...cost-effectiveness of injectable PrEP is unclear. Methods. We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. Results. Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%–15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing $10 880–$19 213 per infection prevented. prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%–8%) at <1% overall coverage, costing $298–$1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEP's 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. Conclusions. Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or costsaving, but suboptimal PrEP would erode benefits and increase costs.
PURPOSE OF REVIEWSensitive, scalable and affordable assays are critically needed for monitoring the success of interventions for preventing, treating and attempting to cure HIV infection. This review ...evaluates current and emerging technologies that are applicable for both surveillance of HIV drug resistance (HIVDR) and characterization of HIV reservoirs that persist despite antiretroviral therapy and are obstacles to curing HIV infection.
RECENT FINDINGSNext-generation sequencing (NGS) has the potential to be adapted into high-throughput, cost-efficient approaches for HIVDR surveillance and monitoring during continued scale-up of antiretroviral therapy and rollout of preexposure prophylaxis. Similarly, improvements in PCR and NGS are resulting in higher throughput single genome sequencing to detect intact proviruses and to characterize HIV integration sites and clonal expansions of infected cells.
SUMMARYCurrent population genotyping methods for resistance monitoring are high cost and low throughput. NGS, combined with simpler sample collection and storage matrices (e.g. dried blood spots), has considerable potential to broaden global surveillance and patient monitoring for HIVDR. Recent adaptions of NGS to identify integration sites of HIV in the human genome and to characterize the integrated HIV proviruses are likely to facilitate investigations of the impact of experimental ‘curative’ interventions on HIV reservoirs.
Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring ...users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring.
Plasma collected on the visit at which seroconversion was detected was tested by next-generation sequencing with unique molecular identifiers for non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRM) present at ≥1% frequency. Bulk-cloned plasma-derived recombinant HIV was phenotyped in a TZM-bl-based assay for susceptibility to DPV and other NNRTI. HIV-1 RNA was retrospectively quantified in plasma samples collected before HIV seroconversion.
Among 38 participants who seroconverted in HOPE, 7 (18%) had NNRTI DRM detected by next-generation sequencing with unique molecular identifiers including A98G, K103N, V106M, E138A, and V179D. Six of 7 samples with NNRTI DRM had <3-fold reduction in susceptibility to DPV. Only 1 sample with K103N and V179I polymorphism had 9-fold reduction in susceptibility to DPV, but this genotype occurred in an individual who did not use DPV ring, likely indicating transmitted resistance. Detection of NNRTI resistance was not higher in individuals who remained on DPV ring >3 months after acquiring HIV infection.
NNRTI resistance among women who seroconverted during HOPE was infrequent and selection of DPV-specific mutations was not detected. DPV ring is considered a safe and effective option for HIV prevention in women.
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