This summer, I wanted to send you an update on the UCSF-Bay Area Center for AIDS Research which will start its next renewal in September 2022. I hope you are able to enjoy a break this summer after a very difficult several years. The below list of awards and honors speaks to how hard members of the UCSF CFAR have been working recently. Beyond COVID-19, there is a new outbreak of monkeypox in formerly non-endemic regions, so we will start with the history of that outbreak and how CFAR is responding to it with the quick release of a grant opportunity in HIV and monkeypox.
History of current monkeypox outbreak and how CFAR is responding:
What is the cause of monkeypox?
Monkeypox is member of the Poxviridae family of viruses called Orthopoxvirus and is a double-stranded DNA virus. This subset includes the smallpox (variola), vaccinia and cowpox viruses. A nice review of monkeypox virus is in Scientific American here.
How is this virus usually transmitted and where is it usually found?
The name “monkeypox” comes from the first documented cases of the illness in animals in 1958, when two outbreaks occurred in monkeys being used for research. However, monkeys are actually not major carriers of the disease and the WHO is contemplating changing the name of the disease. The usual way in which monkeypox is transmitted to humans is by the bite by an infected animal, or by touching an infected animal’s blood, body fluids or fur. Monkeypox is mainly spread to humans by rodents, such as rats, mice, and squirrels. It's also possible to catch the disease by eating meat from an infected animal that is undercooked. This disease is usually limited to central and West Africa or to travelers who have recently come back from these regions. For example, prior to current outbreak (see below), the last case in the US was identified on July 15, 2021 in a US resident who had traveled from Nigeria to the US on two commercial flights. Contact tracing revealed 200 contacts and none developed symptoms, which gives you a sense of the fact that monkeypox is not usually transmissible by casual contact. There was another imported monkeypox case in November 2021 in the United States (in Maryland) in a person who had recently traveled to Nigeria as well. The last major event in the US related to monkeypox prior to that was an outbreak in 2003 related to pet prairie dogs here getting infected by rodents imported from Ghana. No instances of monkeypox infection in that particular outbreak seemed to occur from person-to-person contact.
Tell me about the current outbreak
There is a large monkeypox outbreak going on across the UK, Europe, Australia, Canada, the United States, and other countries. Prior to this outbreak, monkeypox had usually been reported from West and Central Africa (regions in which the infection was previously called “endemic”), or in travelers from this region. However, from May 13 to June 27, 2022, over 4119 cases have been reported in 66 non-endemic countries (the link here is updated daily) mainly among men-who-have-sex-with-men (MSM). However, in this recent outbreak, that was recognized in “non-endemic” countries, the main route of transmission seems to be close skin-to-skin contact or close respiratory contact occurring during sexual activity. Although monkeypox has been found in semen, the most likely route still seems to be the close contact during sex. Transmission via droplet respiratory particles can occur with prolonged face-to-face contact, which puts household members and other close contacts of active cases at greater risk.
Monkeypox and waning immunity from smallpox
Smallpox was eradicated in 1979 and routine smallpox vaccinations for the US populations were stopped in 1972. Remember, smallpox is the only virus to have ever been eradicated in humans due to four distinguishing features that many human pathogens do not have: 1) no animal reservoirs; 2) its symptoms are very characteristic (specifically, the “pox” rash), making it easy to isolate patients; 3) short infectious period; 4) a highly effective sterilizing vaccine. Since the global eradication of smallpox, monkeypox has emerged as the most prevalent orthopoxvirus infection in humans. Because monkeypox virus is closely related to the variola virus, the smallpox vaccine can protect people from getting monkeypox so humans are now more susceptible to monkeypox with cessation of smallpox vaccination. Past data from Africa suggests that the smallpox vaccine is at least 85% effective in preventing monkeypox.
What are the symptoms of monkeypox?
The presentation is similar to smallpox in human, but with a very distinguishing symptom of lymphadenopathy (which may be generalized or localized to the axillary regions and the neck). After an initial febrile prodrome, a centrifugally distributed maculopapular rash develops, with lesions often present on the palms of the hands and soles of the feet. The infection can last up to 4 weeks, until crusts separate and a fresh layer of skin is formed. After infection, there is an incubation period which lasts on average 7-14 days. The development of initial symptoms (e.g., fever, malaise, headache, weakness, etc.) marks the beginning of the prodromal period. Shortly after the prodrome, a rash appears. Lesions typically begin to develop simultaneously and evolve together on any given part of the body. The evolution of lesions progresses through four stages over a period of 2-3 weeks—macular, papular, vesicular, to pustular—before scabbing over and resolving. There can be severe sequelae but that is usually with the clade from the Congo and this outbreak’s clade is related to the West Africa strain, which is more mild (i.e., no deaths have been reported in this outbreak).
What are the symptoms of monkeypox in this current outbreak?
The lesions have a different distribution than usual and are found more in the genital and anal lesions in this current outbreak. Please see this NEJM paper for good pictures of the lesions.
What are preventatives and treatments?
Previously, there were no specific treatment for a monkeypox virus infection and patients are generally managed with supportive care and symptomatic treatment. However, smallpox vaccination itself is a therapeutic option for monkeypox. Beyond giving the smallpox vaccine, there are various antiviral treatments that can be considered (based on in vitro or animal studies), including Tecovirimat. Monkeypox can be tentatively diagnosed if the characteristic skin lesions are present, or if other symptoms consistent (e.g., look for the more characteristic symptom of lymphadenopathy with monkeypox) with the disease are seen during an outbreak. Specifically, If monkeypox is suspected, health workers should collect an appropriate sample and have it transported safely to a laboratory with appropriate capability. Polymerase chain reaction (PCR) is the preferred laboratory test given its accuracy and sensitivity. For this, optimal diagnostic samples for monkeypox are from skin lesions – the roof or fluid from vesicles and pustules, and dry crusts.
One vaccine, JYNNEOSTM (also known as Imvamune or Imvanex or Jynneos), has been licensed in the United States to prevent monkeypox and smallpox. On June 1, the CDC updated its recommendations to say that Jynneos is the preferred post-exposure prophylaxis for monkeypox here in the United States- this would be for close contacts (including health care workers) and laboratory workers. JYNNEOS™ is usually administered as a series of 2 injections, 4 weeks apart. People who have received smallpox vaccine in the past might only need 1 dose. Canada just signed a $56 million deal with the manufacturer of the Jynneos vaccine and Quebec has started offering the vaccine to all MSM. The UK is expanding its vaccination campaign to offer the vaccine to gay and bisexual men. The US is expanding its Jynneos vaccine supply and Chelsea Clinic in NYC opened up a clinic before the Pride Prade to vaccinate MSM who have had multiple sexual partners in the past 14 days. I wrote this piece in the Atlantic urging the US to buy more doses of Jynneos to vaccinate gay men and for the WHO to help vaccinate populations in endemic African regions.
How is CFAR responding?
We have now put out a call for rapid response pilot grants using our developmental funds. These grants will be for $30,000 each and can be in any topic related to monkeypox and HIV including clinical research grants, basic science investigations or sociobehavioral research. The grant announcement is here and the due date is August 3, 2022. We will likely give out 2-3 awards and hope this will help the UCSF CFAR contribute to this important outbreak.
List of recent selected honors in the CFAR:
Additional awards (including some previously announced) include:
- Dr. Steve Deeks was awarded the 2022 UCSF Lifetime Achievement in Mentoring Award, a very prestigious award for contributions to mentoring over a career.
- Dr. Diane Havlir was awarded the UCSF Holly Smith Award for Exceptional Service to the School of Medicine and a strong history in public service
- Dr. Sheri Weiser was named Co-Director of UC Center for Climate, Health and Equity as well as to the National Academies Climate Security Roundtable
- Dr. Laurence Huang received a Respiratory Health Award from the American Thoracic Society
- Dr. Peter Hunt was elected to the American Society for Clinical Investigation
- Drs. Melanie Ott, Charles Chiu, Charles Langelier named as new Chan Zuckerberg Biohub Investigators for 2022
List of recent selected grants awarded across the CFAR:
CFAR Mentored Scientist Awards
Jesse Deere, UC Davis, HIV Cure via Direct Cytotoxic Depletion of the HIV Reservoir
Amelia Deitchman, UCSF School of Pharmacy, Antiretroviral Drug Penetration in HIV Reservoir Sites using Tissue from Deceased Donors
Gema Mendez-Lagares, UC Davis, Modulation of mTOR signaling using metformin during therapeutic SIV vaccination to achieve stringent post-treatment control
CFAR International Mentored Scientist Awards
Juliet Namugenyi, Infectious Diseases Institute, Potential for Xpert MTB/RIF Ultra cycle threshold values to monitor early response to anti-TB treatment in HIV co-infected patients on antiretroviral therapy
CAPS- HIV Innovative Grants
Natasha Ludwig-Barron, UCSF CAPS/DPS, Characterizing PWID subgroups and geospatial HIV, HCV and overdose risks in Ciudad Juarez
Pamela Murnane, UCSF Epi/Biostats, Geographic mobility and HIV care in pregnant and postpartum women
ARI Gilead Mentored HIV Cure Grants
Ashley George, Gladstone Institutes, Deep phenotyping of NK cells from HIV+ individuals undergoing antiretroviral treatment interruption
New K Awardees, First Time R01 Awardees, and Other Recent NIH grants
Orlando Harris, UCSF School of Nursing, K23 MH130250: Jamaica CARES Project: Connecting HIV/AIDS Resources to Engage Jamaican Sexual and Gender Minorities
Stanley Vance, UCSF SOM/Pediatrics, K23 MD015044: Examining Contributors to Disparities in Gender Affirmation and Mental Health among Black and Latinx Transgender Youth
Felicia Chow, UCSF SOM/Neurology, R01 NS126086: Sex differences in the contribution of cerebrovascular injury and immune activation to neurocognitive impairment in HIV infection
Milo Santos, UCSF School of Nursing/SFDPH, K24 AA029958: ASTERISK: Alcohol and Substance use Treatment and Engagement Research on Intervention Studies among Key populations
Steve Yukl, UCSF/SFVAMC, P01 AI169606: The heterogeneous HIV expressing reservoir: dynamics, persistence mechanisms, tissue distribution, and contribution to rebound (with subprojects led by Tim Henrich, Nadia Roan, and Satish Pillai)
Judy Hahn, UCSF/HIVIDGM, R01 AA029962: Biomarkers for Alcohol/HIV Research (BAHR) Study
Marina Tolou-Shams, UCSF/Psychiatry, R01 DA056265: The Impact of Racism on Trajectories of Substance Use, Mental Health and Legal System Contact from Adolescence to Young Adulthood
Monica Gandhi and Matt Spinelli, UCSF/HIVIDGM, R21 AI167648: Evaluation of the Impact of HIV Status on the Immune Response to mRNA COVID-19 Vaccines
Notable new program in the CFAR focused on earlier stage investigators:
We have just launched (with additional NIH funds) a new program in the CFAR titled Accelerating Research Careers in Science through Early Mentored Research Experiences. The CFAR Scholars Program is an initiative funded by the NIAID led by John Sauceda and Carina Marquez, with support from Lauren Sterling and Joe Watabe, to train the next generation of researchers. This is a 16-week summer research program is bringing in undergraduate and masters-level mentees from San Francisco State University to train in HIV. We would like to welcome our six scholars to the UCSF CFAR as pictured below, along with their excellent CFAR-based mentors pictures below scholar:
Newsworthy recent findings:
Two studies from CFAR affiliated researchers have recently received a lot of media attention so I wanted to briefly summarize them here:
DoxyPEP study <
(led by Dr. Annie Luetkemeyer from UCSF):
The IPERGAY was a study performed in France to evaluate the effectiveness of a 2:1:1 or intermittent TDF/FTC based strategy for preventing HIV infection for MSM and TGW. As part of that study, there was a preliminary finding that doxycycline taken 24-72 hours after condomless sex as post-exposure prophylaxis (PEP) reduced new cases of syphilis and chlamydia by 70% (but had no effect on reducing gonorrhea although 50% of gonorrhea in France- compared to 25% here in the US- is doxy resistant). That study was preliminary and a larger study needed to be done to see whether doxycycline PEP reduces new syphilis, chlamydia and gonorrhea infections among men-who-have-sex-with-men and transgender women (TGW) on PrEP and with HIV on ART. Therefore, Drs. Annie Luetkemeyer and Connie Celum at the University of Washington received an R01 grant from the NIH to study this question in the “DoxyPEP study” and also whether there was an effect of using doxycycline on antimicrobial resistance in organisms causing STIs and in Staph aureus, etc.
The DoxyPEP study was stopped early on 5/13/2022 based on pre-specified efficacy thresholds showing that doxycycline taken after condomless sex significantly reduced the acquisition of gonorrhea, chlamydia and syphilis in MSM and TGW. This result was statistically significant both in the cohort of participants living with HIV and the cohort taking HIV PrEP. Participants in the doxyPEP arm were counseled to take 200 mg of doxycycline within 72 hours after condomless sex . The strategy of doxycycline PEP was safe and well-tolerated, with no serious adverse events. This analysis will be presented in detail at IAS in Montreal this summer. The effect on drug resistance to bacterial STIs, Staph aureus, commensal Neisseria (as a potential reservoir for transfer of tetracycline resistance), and the gut microbiome is still being evaluated.
(led by Dr. Joel Palefsky at UCSF and recently published in the NEJM)
The incidence of anal cancer is substantially higher among people with HIV than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking. Dr. Palefsky and his group thus conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod.
The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.
Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P=0.03 by log-rank test). Therefore, among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring.
I hope you all have a great summer and thanks- as always- to Lauren, Peter, and Mallory, as well as the other CFAR staff and faculty.