Allison Inserro

When taken consistently pre-exposure prophylaxis (PrEP) is efficacious in preventing HIV. However, one of the challenges of PrEP is that it relies on daily adherence to a once-daily pill of tenofovir disoproxil fumarate.

describes the future landscape of therapeutics in development for what the authors call the next generation of HIV prevention, or PrEP 2.0.

Drawing from similarities from contraception research, the pipeline for future PrEP therapies includes long-acting injectables, immunotherapies, vaginal rings, multipurpose prevention technologies, implantable drug delivery strategies, and transdermal patches.

The combination of tenofovir disoproxil fumarate and emtricitabine was adopted by the World Health Organization as a strategy to reduce HIV incidence. In the United States, the pill is sold as Truvada. But remembering to take a pill once a day can be a challenge for many that the drug targets; the most at-risk populations include women, teenagers and young adults age 15 to 24, racial and ethnic minority men who have sex with men, and transgender women.

The pipeline aims to expand the range of available PrEP regimens and “offer preventive technologies that will appeal to a wide variety of individuals with different needs over the course of their sexually active lifespan,” the authors wrote.

Globally, nearly 37 million people were estimated to be living with HIV in 2017, and a quarter of those were unaware of their infection status. There is an urgent need for prevention strategies, as nearly 2 million people acquired new infection in 2017, and 20% of those on treatment were not virally suppressed. Yet antiretroviral therapy has benefits both for treatment and prevention.

In multiple studies, the effectiveness of tenofovir disoproxil fumarate and emtricitabine is positively associated with adherence as measured by biomarker correlates of dosing, in particular plasma and intracellular drug concentrations, with a 96% risk reduction in men who have sex with men (MSM) estimated from drug concentrations consistent with taking an average of 4 or more doses per week.

However, for women, it is critical that daily doses are not skipped in order to achieve optimal protection. Pharmacokinetic studies have shown substantially lower concentrations of tenofovir diphosphate in vaginal tissue than in rectal tissues; rectal tenofovir diphosphate concentration was 100-times higher than that observed in vaginal and cervical tissues after a single dose. Six to 7 doses per week are needed to reach vaginal and cervical tissue in order to reach a level considered protective. 

While tenofovir disoproxil fumarate and emtricitabine was shown in 1 trial to be 66% effective in protecting women from HIV infection, 2 other trials showed that low adherence weakened efficacy. Other populations also have lower adherence in diverse settings.

Islatravir or 4&#697;-ethynyl-2-fluoro-deoxyadenosine (also known as MK-8591) is a novel nucleoside reverse transcriptase translocation inhibitor; it will be studied in an upcoming phase 2b study in combination with doravirine, an already approved  non-nucleoside reverse transcriptase inhibitor (NNRTI) and lamivudine. It appears to be suitable for weekly, or even less frequent dosing, as it has a long half-life (50 to 60 hours in the blood and 120 hours inside cells). It blocks 2 different stages of the HIV replication lifecycle by preventing HIV from making a DNA copy of its genes and stops integrated HIV DNA inside of host cells being used to replicate new viral particles. It can be taken orally on a daily basis or over extended intervals, or via subdermal implant.

Maraviroc, a CCR5 receptor antagonist, was evaluated for safety in a phase 2, 48-week safety and tolerability study aiming to compare 4 treatment regimens: maraviroc alone, maraviroc plus emtricitabine, maraviroc plus tenofovir disoproxil fumarate, and tenofovir disoproxil fumarate and emtricitabine in MSM, trans women, and cis women. The regimens were generally safe and well tolerated. The study was not powered for efficacy, but the authors said all 5 seroconversions in MSM occurred in groups receiving maraviroc. Moreover, in those acquiring HIV infection, drug concentrations were absent, low, or variable.

Long-acting injectable drugs include cabotegravir, which could also come as a daily oral tablet. Cabotegravir (also known as GSK1265744) is chemically similar to dolutegravir.

Phase 3 trials for long-acting cabotegravir in combination with long-acting rilpivirine for HIV treatment showed safety and antiviral efficacy. One potential drawback of an injectible, however, is the prolonged subtherapeutic pharmacokinetic effect. It is still unclear whether this effect represents a prolonged period of antiviral activity or a period of vulnerability to HIV infection.

Rilpivirinehas had phase 1 and phase 2 trials. It is a nanoparticle formulation at a concentration of 300 mg/mL.39 A major concern is the potential risk of selection of NNRTI-resistant HIV-1 in newly infected people because of the prolonged subtherapeutic concentrations of long-acting rilpivirine after dosing is delayed or stopped.

Another prevention approach is to use broadly neutralizing HIV-1 monoclonal antibodies (bNAbs) There are current efforts to isolate bNAbs from chronically infected patients, long-term non-progressors, or others with extremely low levels of viral load in the absence of conventional oral ART. A group of patients called elite controllers, who make up around 1% of individuals living with HIV-1, are thought to develop bNAbs that neutralize more than 80% of circulating HIV-1 strains. bNAbs, which would require intravenous administration, are currently in pre-clinical trials or early phase 1 studies. They include VRC01 and 3BNC117 (targeting the CD4 binding site); PGT121, and PGDM1400 (targeting the V3 loop of the HIV-1 envelope protein); and 3BNC117-LS, VRC01LS, 10—1074LS, and VRC07–523LS (long-acting versions of the parent bNAbs). Previous clinical trials showed that VRC01, 3BNC117, and 10–1074 are safe and well-tolerated.

Dapivirine is an NNRTI that has activity against a broad range of HIV-1 subtypes and was developed for topical administration. It has been studied in 2 phase 3 studies and showed HIV risk reduction of 27% and 31%. Follow-on extensions showed even better results and improved adherence. 

The article, Future PrEP Drugs, Delivery Methods, Technologies Target Adherence Issue, originally appeared on 

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A new review in The Lancet HIV discusses the next generation of HIV prevention, called PrEP 2.0.

What is on the Horizon for HIV Prevention?

 in 11 states so far in 2019, a new study noting that there is no connection between the measles, mumps, rubella (MMR) vaccine and autism has been released. The new study includes an analysis of subgroups of children that some of those opposed to vaccines have claimed (mainly without evidence) might be more vulnerable to perceived effects.

, is one of the largest studies to date about the issue. The researchers involved in this study indicated they were adding to their previous body of work specifically to address previous concerns.

Researchers used a nationwide cohort of children born between 1999 and 2010, drawn from the Danish Psychiatric Central Register from Denmark, where the childhood vaccination program is voluntary and free.

The cohort included 657,461 children contributing over 5 million person-years of follow-up between January 1, 2000, through August 31, 2013; during the follow-up, 6517 children were diagnosed with autism (incident rate 129.7 per 100,000 person-years).

Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02). More importantly, no increased risk for autism after MMR vaccination was seen in subgroups of children that are the focus of concern by some hesitant to trust vaccines: children with siblings affected by autism, autism risk factors (based on a disease risk score) or other childhood vaccinations, or during specified time periods after vaccination.

In addition, researchers included children with no vaccination in the first year of life for DTaP-IPV/HIB and found no evidence of a link between MMR and autism in that group. That inclusion was also made to address concerns about other studies.

The researchers said this work adds to previous studies through "significant additional statistical power and by addressing hypotheses of susceptible subgroups and clustering of cases.”

In an accompanying editorial, physicians at Emory University wrote that, "in an ideal world vaccine safety research would be conducted only to evaluate scientifically grounded hypotheses, not in response to the conspiracy du jour.” However, they acknowledged that continued questioning put forth by those skeptical of vaccine safety can affect public confidence and vaccine uptake. On the other hand, having scientists perform additional research simply to add to the already substantial pile of evidence about the MMR’s safety comes at an opportunity cost about other lines of research.

The World Health Organization recently called 

 1 of the top 10 threats to global health in 2019. Severe cases of measles can be life-threatening; for every 1000 children infected with measles, 1 or 2 will die of it, 

according to the US Centers for Disease Control and Prevention

. Serious complications can include encephalitis and pneumonia.

In Wake of Measles Outbreaks, Another Study Dispels Myths Surrounding MMR Vaccine,

With 206 cases of measles reported so far in 11 states in 2019, a new study noting that there is no connection between the measles, mumps, rubella (MMR) vaccine and autism has been released.

Amid Measles Outbreaks, New Study Dispels MMR Vaccine Myths

In Oregon, patients with hepatitis C virus who are on Medicaid can expect to receive curative treatment in 2019 without having to wait for liver damage to set in. Despite having the 

highest rate of hepatitis C virus mortality

 in the country, per capita, Oregon’s Medicaid program had been rationing the drugs, which cost thousands of dollars.

About 100,000 Oregonians have been infected with the virus and more than 500 die every year, according to 

. The Oregon Health Authority estimates that about half of those individuals who are infected don’t know it.

The problem was made worse by opioid use disorder, which led to a 20% rise in new infections from 2015 to 2016.

About a quarter of the state’s population is covered by the Oregon Health Plan. The state plans to end the rationing in March 2019, allowing the treatment before patients sustain liver damage.

Providing the drug to everyone infected with hepatitis C would have likely bankrupted the Oregon Health Plan and led to unaffordable premiums, 

health officials told the Associated Press

“It was a complete bank-breaker. There was no way individual insurance plans or governments could afford the pill where it was priced,” Jennifer Lind, CEO of Jackson Care Connect, a provider of Oregon Health Plan coverage said.

Pharmaceutical company Gilead Sciences had charged $84,000 for a 12-week treatment of Sovaldi, and it priced another drug, Harvoni, at $94,500. However, Gilead will release a generic version of Harvoni in January 2019, pricing it at $24,000.

Falling prices due to generics will allow more people to get treatment, Josh Balloch, vice president of government affairs for AllCare Health, another provider of Oregon Health Plan coverage added in the statement to AP.

® called for a national strategy to eradicate hepatitis C virus from the United States, regardless of payer status.

The investigators found that restricting hepatitis C virus treatment for Medicaid beneficiaries based on one’s state of residence was flawed, and led to suboptimal treatment outcomes, high patient burden, and excess costs. It also worsened health disparities.

Sustained virologic response rates were 95.9% when everyone is treated, compared with 75.2% under Medicaid restrictions, and there were improved clinical outcomes, including:

8169 fewer cases of hepatocellular carcinoma;

6,173 fewer hepatitis-C-virus-related deaths;

0.84 additional life-years per patient; and

1.03 additional quality-adjusted life-years per patient.

Treating everyone, without restriction, would lead to a $3.8 billion overall savings in health care costs, according to the study authors.

An earlier version of this article appeared as, “

Oregon Medicaid Program to End HCV Treatment Rationing in 2019

Patients with the hepatitis C virus who are on Medicaid in Oregon can expect to receive curative treatment in 2019, without having to wait for liver damage to set in.

Allison Inserro

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