BCG VACCINATION: INEFFECTIVE Lost in Translation: and NEEDS to BE Are YOU an Alien ? SUBSTITUTED?

April 2018 Edition | Issue #55

INA-RESPOND NEWSLETTER INDONESIA RESEARCH PARTNERSHIP ON INFECTIOUS DISEASE April 2018

The 25th CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS

GLOBAL VACCINE & IMMUNIZATION RESEARCH FORUM 2018

BCG VACCINATION: INEFFECTIVE Lost in Translation: AND NEEDS TO BE Are YOU an Alien ? SUBSTITUTED?

NATIONAL INSTITUTE OF HEALTH RESEARCH AND DEVELOPMENT MINISTRY OF HEALTH REPUBLIC OF INDONESIA

INA-RESPOND SENIOR WRITERS newsletter Aly Diana, Dona Arlinda, Herman Kosasih, M. Helmi Aziz,

EDITOR-IN-CHIEF Mila Erastuti

M. Karyana REVIEWERS &

CONTRIBUTING WRITERS EXECUTIVE EDITOR INA-RESPOND Secretariat Anandika Pawitri, Dona Arlinda, Herman Kosasih Dedy Hidayat, Herman Kosasih, Badan Penelitian dan Lois E. Bang, Louis Grue, Maria Pengembangan Kesehatan, RI CREATIVE DIRECTOR Intan, Neneng Aini, Nurhayati Gedung 4, Lantai 5 Dedy Hidayat Jl. Percetakan Negara no.29, THANK YOU Jakarta, 10560 ART DIRECTOR INA-RESPOND Network and www.ina-respond.net Antonius Pradana Partners

4 Study Updates

7 Reports on GVIRF

14 Science and Research

18 The 25th CROI

22 Comic Corner

INA-RESPOND Newsletter. All rights reserved. Page 3 April 2018 Edition | Issue #55 NewsletterINA-RESPOND TRIPOD & INA-PROACTIVE Study Updates BY: ANANDIKA PAWITRI, CALEB L. HALIM, LOIS E. BANG, MARIA INTAN, M. IKHSAN JUFRI

Co-Principal Investigators, and Research Assistants from seven sites. This meeting began with Screening and Enrolment presentation of data and screening/enrolment

Up to 27 March 2018, sites have enrolled 269 progress which was delivered by The Secretariat subjects. Site 570, RSUD dr Soetomo, is still the top followed by presentations from sites. recruiter with 70 subjects. Enrolment by site 520, dr. Ari, Research Assistant from Sanglah Hospital, RSUP Sanglah, is temporarily stopped until the reported that the permission for the site is now in study permission is cleared. Enrolment progress until agreement process. From Dr. Wahidin the end of March 2018 can be seen in the graphic Sudirohusodo Hospital, Makassar, dr. Ira as the below. Principal Investigator gave updates and talked

NIH/Leidos Visit to INA-RESPOND Secretariat about the possibility of next enrolment. From site 560, 570, 580, and 590, each Research Assistant 2nd TRIPOD Interim Analysis Meeting was reported the ongoing enrolment process and successfully held on 3 April 2018 in Jakarta. The challenges to maintain the subjects in study. They meeting was attended by Principal Investigators, also shared subject management and retention

*Site number: 580 – RSUP dr Sardjito, Yogyakarta 590 – RSUP Persahabatan, Jakarta 520 – RSUP Sanglah, Denpasar 600 – RSUP H Adam Malik, Medan 560 – RSUP dr Kariadi, Semarang 570 – RSUD dr Soetomo, Surabaya

Research Assistant Gathering @Ancol, Jakarta

during study follow up period and how to maintain RESPOND Secretariat will become more a well communication with subjects. From Adam comprehensive and robust. Malik Hospital Medan, dr. Parluhutan as the

Principal Investigator reported the enrolment

progress and new TB center facility in the hospital, Screening and Enrolment which will be opened in near future. Four months have passed Besides showing preliminary results of TRIPOD study since INA-PROACTIVE study enrolled its first subject. to site team, the purpose of this meeting is to elicit Per 16 April 2018 a total of 62 subjects has been ideas that can be developed from TRIPOD study enrolled. Tangerang Hospital has enrolled 34 data for the next study. Site team also propose participants for INA-PROACTIVE study while Adam ideas for future publication plan. One of them is Malik Hospital and Wahidin Hospital have enrolled publishing the study in national and international 28 participants (14 participants each). The subjects conferences such as Respina in Jakarta, Congress comprises 53 adult subjects and 9 pediatric of the Asian Pacific Society of Respirology in Taipei, subjects. and Union World Conference on Lung Health in The Netherlands. Currently, eight study sites have signed the INA- PROACTIVE study contract and agreement. They Also In this occasion, an in-depth discussion took are Tangerang Hospital, Adam Malik Hospital, place between the national PI (dr. Erlina) and PIs Wahidin Sudirohusodo Hospital, Cipto from every site about the study result and Mangunkusumo Hospital, Soetomo Hospital, management of TB patient in the field. The Kariadi Hospital, Gatot Soebroto Hospital, and discussion brought up interesting ideas such as Sardjito Hospital. how TRIPOD study would benefit health regulation. The Secretariat conducted Site Preparation Visit By the end of the interim analysis meeting, dr. (SPV) for site 570 Soetomo Hospital on 20-21 March Lidya from Universitas Padjadjaran Bandung 2018 and Site Initiation Visit on 4-5 April 2018. SPV explained about future specimen testing that can was also conducted for site 560 Kariadi Hospital on be done for TRIPOD sample, and dr. Adriansjah 11-13 April 2018. The next SPV is for site 580 Sardjito from Microbiology University of Indonesia Jakarta Hospital on 18-20 April 2018. shared about Line Probe Assay for molecular testing of TB sample. can be finalized and used for Since last month, several hospitals (Ansari Saleh TRIPOD reporting. From the meetings, it is expected Hospital in Banjarmasin, Budi Kemuliaan Hospital in that the Data Management and Statistics of INA- Batam, St. Carolus Hospital in Jakarta, Wahab

Site Preparation Visit at RSUD. Soetomo, Surabaya

Sjahranie Hospital in Enrolled Site SPV SIV Activation Samarinda, Kandou Subjects Hospital in Manado, Site 610 Jayapura Hospital in 19-20 Dec 22 & 27 (Tangerang 09 Jan 2018 34 2017 Dec 2017 Jayapura) have Hospital) replied our Site 600 7-8 Feb 12-13 Feb collaboration (Adam Malik 12 Mar 2018 14 2018 2018 Hospital) invitation letter. We Site 550 conducted site 13-14 Feb 19-20 Feb (Wahidin 13 Mar 2018 14 2018 2018 assessment at Ansari Hospital) Saleh Hospital on 9 Site 530 21-22 Feb 13-14 Mar April, and the hospital - - (Cipto Hospital) 2018 2018 management gave Site 570 positive respond to 20-21 Mar 4—5 Apr (Soetomo - - our study network and 2018 2018 Hospital) to our HIV Study. As for Site 560 11—13 Apr 23 –24 Apr the other five - - (Kariadi Hospital) 2018 2018 hospitals, we will conduct site visit Site 580 18—20 Apr 17—18 - - (Sardjito Hospital) 2018 May 2018 within these two months.

INA-RESPOND Newsletter. All rights reserved. Page 6 April 2018 Edition | Issue #55 NewsletterINA-RESPOND GLOBALINA VACCINE-PROACTIVE & IMMUNIZATION PREPARATION RESEARCH WEEK FORUM 2018 BY: NURHAYATI, ANANDIKA PAWITRI, VENTY MULIANA SARI SOEROSO, M HELMI AZIZ

On 20–22 March 2018, four INA-RESPOND representa- Progress Towards in Vaccine Development tives have a great opportunity to attend the invita- HIV, TB, and Malaria vaccines tion as poster presenters and participants on the third Global Vaccine and Immunization Research The HIV Vaccine Trials Network (HVTN) launched an- Forum (GVIRF) supported by The World Health Or- other study called HVTN702, phase IIb/III clinical trial, ganization (WHO). The GVIRF was held by WHO, the a part of series from Uhambo (Journey) study. Before National Institute of Allergy and Infectious Diseases the HVTN702, the HVTN100 was conducted in smaller (NIAID), and the Bill & Melinda Gates Foundation studies to 210 people in South Africa as the I/IIa (BMGF). Vaccine scientists, developers, and public phase trial to evaluate the safety of the vaccine. The health officials from around the world discussed sci- study vaccines, called ALVAC-HIV (vCP2438) and entific and technical challenges in discovery, devel- Bivalent Subtype C gp120/MF59, were given to sero- opment, decision making, and delivery for three negative participants during HVTN100 and HVTN702. consecutive days in Shangri-La Hotel, Bangkok, Thai- Interim results from HVTN100 showed that the vac- land. This report summarizes and highlights what we cine components are safe to give and it has compa- learned at the GVIRF meeting. rable immunogenicity result with its predecessor fa-

April 2018 Edition | Issue #55

mous trial, RVV144. The aim of the HVTN702 trial is to rotavirus diarrhea in several countries. While for ETEC evaluate the efficacy aspect (whether this vaccine and Shigella, the vaccine candidates are still in clini- could prevent new HIV infection), and the results will cal study phase, and concern has been raised be shared in late 2020. whether combination of ETEC/Shigella or single vaccine should be prioritized or not. Bacille Calmette-Guerin (BCG), the famous TB vaccine, has variable and inconsistent results of TB pro- Pneumococcal vaccines: Lessons learned and the tection. Therefore, replacing BCG or boosting BCG Road Ahead was the main interest in TB vaccine development. Pneumococcal Conjugate Vaccine (PCV) is recom- Despite a lot of TB vaccine candidates such as MTB- mended by WHO as a priority in childhood national Vac, VaccaeTM, VPM1002, and M72/AS01E, the immunization program worldwide, particularly where main focus during this forum was how to develop mortality is high. This vaccine aims to complement pipeline for TB vaccination that is useful for decision other pneumonia-control measures such as case making. For Malaria vaccine, up until now no malar- management, exclusive breast feeding, or reducing ia vaccine has reached phase 3 development ex- risk factors. Since its introduction in 2000 in the U.S., cept for the RTS,S/AS01 (Mosquirix™). Blood stage PCV7 has been administered in 134 countries includ- vaccine targeting PfPh5 and transmission blocking ing in some of the high-burden countries, such as vaccines for malaria were discussed during this Sudan, Tanzania, Nigeria, Afghanistan, India and meeting as the next candidates for malaria vac- Bangladesh. After 15 years introduction of PCV, mor- cines. tality and antibacterial resistance related to pneu- Enteric vaccines monia have decreased in those countries. However, the coverage varies highly among the 10 countries Enteric diseases caused by rotavirus, enterotoxigenic that have introduced PCV (e.g. 13% in Nigeria to Eschericia coli (ETEC), and Shigella raise concern 95% in Tanzania). Since 2011, the PCV administrations towards vaccine development. Rotavirus, ETEC, and schedule has changed from PCV10 to PCV13 while Shigella are the most common pathogen among the dosing schedule differs among countries (3 + 0 or infants and young children, causing severe diarrhea 2 + 1). The research showed that there is no differ- which leads to acute dehydration. Thus, several rota- ence between PCV10 and PCV13 efficacy, and virus vaccines were licensed with different strains, there is no difference of PCV13/ 2+1 administration doses, and dosage. The introduction of rotavirus among malnourished and non-malnourished chil- vaccines has decrease the mortality rate due do dren. However, it should be noted that there is im-

portant difference between HIV and non-HIV pa- Vaccination Challenges and Regulatory tient. To achieve and sustain a high level of equita- Vaccine Delivery Strategies for Equitable High Vac- ble vaccine coverage and improve the utility of cine Coverage and Role of Regional Capacity in PCV, challenges remain with the high cost of the Vaccine Development-Biotechnology vaccine and the vaccine serotype replacement.

Several strategies were discussed in GVIRF related to Introduction of New Vaccine Pipeline achieving and sustaining equitable high vaccination Trial of formalin inactivated Respiratory Syncytial Vi- coverage. Guest speakers from India, China, Nigeria, rus (FI-RSV) vaccine in the late 1960’s hampered the and Ukraine shared their vaccination strategies such development of RSV vaccine. Currently, there is no as strengthening government commitment like Mis- approved RSV vaccine available. Four RSV vaccine sion Indradhanush in India; using social media plat- candidates are still on trial to combat the RSV infec- form like WeChat as vaccination reminder in China; tion which is the leading cause of hospitalization in and using social media to discuss health issues and infants and young children. The following are new counter vaccine hesitancy group in Ukraine. Not RSV vaccine candidates on trials: Novavax GSK RSV only did it make commitment on vaccine delivery, pre-F vaccine, VRC317, and MEDI8897. India also advance its technology in vaccine development. India has three institutions that are responsi- Human hookworm infects more than 470 million peo- ble for novel design of several new vaccines (ICGEB, ple and ranks number one in terms of Years Lost from THSTI, IISER), and ROTAVAC was one of the success Disability (YLDs). It is prevalent worldwide, causing vaccines that was developed based on local circu- anaemia, malnutrition, physical, and developmental lating strain in India. delays, hence the potential to cause future global problem. Current treatments using small molecule Perspective of Vaccine Manufacture in Developing drugs do not prevent re-infection, have low cure Countries rates and varied efficacy; which increases the drug’s It is well known that there is a gap in population, dis- failure rate. Moreover, after massive drug administra- ease burden, and vaccine sales aspect between tion (MDA) which aimed to prevent hookworm infec- vaccine markets in low- and middle-income coun- tion, the infection rate almost unchanged thus the tries (LMIC) and developed countries . Developing urgently needed vaccine against hookworm. Hu- Countries Vaccine Manufacturers Network (DCVMN) man Hookworm Vaccine (HHV) initiative, led by Tex- mentioned that LMIC are the emerging vaccine as Children’s Hospital Center for Vaccine Develop- market, but only 64 of 145 WHO prequalified vac- ment, is developing pipeline prioritization and evalu- cines are manufactured in LMIC. Therefore, vaccine ation for hookworm vaccine candidates. Indonesia, development in LMIC could be a significant invest- Brazil, and India are the initial target markets since ment although the gestation period of vaccine in- these three countries have the highest number of vestment is up to 5-7 years. The VMPA study, a study children at risk of hookworm infection. A series of performed in 54 Africa countries by UNIDO, showed Phase I clinical trial were conducted in the USA, Bra- that vaccine development in Africa needs a large zil, and Gabon in 2015 to test the recombinant pro- capital investment. Therefore, African government tein based vaccine (Na-GST-1 and Na-APR-1), and it should create a policy and plan to better promote was found to be safe and well-tolerated. Currently, vaccine production in Africa. Kate Elder, a MSF rep- HHV is also running Controlled Human Hookworm resentative, mentioned that the high price of new Infection (CHHI) model which is at phase 2 trial. vaccine, shortages of supply, refusal to sell, and ill- adapted products are the main problems of deliver- ing vaccine in LMIC. In addition, MSF strengthens its

role in vaccine patent development especially for derived poliovirus (cVDVP) cases and 40% vaccine- LMIC. associated paralytic polio (VAPP) are associated with type 2 component of OPV. Several approaches Vaccine, Outbreaks, and Public Health Emergencies were introduced to reduce risks of OPV2 withdrawal – Role of Universal Influenza Vaccine such as introduction of inactivated polio vaccine (IPV), use monovalent OPV2 in case of outbreaks, Influenza pandemic has been around since 1918, and develop new polio vaccine formula such as and the latest pandemic occurred in 2017. These new adjuvant for IPV, fractional dose administration influenza pandemics has made influenza a constant of IPV, and novel vaccines for OPV2. ongoing global threat to public health. Despite the availability of the seasonal influenza vaccine, influ- Updates on Vaccine Research and Technologies enza pandemics do occur. It has been thought that current seasonal influenza vaccines have different Emerging Technologies on Vaccine Development efficacy between strains, thus a universal influenza Several emerging technologies to improve vaccine vaccine is greatly needed. Overall, universal influen- success rate during pre-clinical test were discussed in za vaccine development has challenges related to GVRIF. MIMIC™ (Modular Immune In Vitro Construct) safety, scalability, vaccine component (including technology, established by Sanofi Pasteur carriers and adjuvants), formulation, potency deter- VaxDesign, could evaluate the immune response mination, and funding. To overcome these problems aspect of new vaccine candidate. The automatic NIAID has developed a strategic plan for universal process of MIMIC™ ensures the precision and quality influenza vaccine starting from basic research to of the result while the diverse donor pool ensures the clinical trials. immunological diversity of human immune system. Polio Endgame Strategic Plan Cytomegalovirus (CMV) vectored vaccines were discussed as the new vector vaccine candidates. The withdrawal of oral polio vaccines (OPV) began But why use CMV as the new vector for vaccines? It in April 2016 by removing Sabin type 2 component has been well known that in human, CMV develops (OPV2) from immunization programs (switched from lifelong latency and has immune evasion mecha- trivalent OPV (tOPV) to bivalent OPV (bOPV). The nism, thus enabling CMV to re-infect efficiently. Not switch was done because the wild poliovirus type 2 only that, CMV has been proven as an excellent (WPV2) had been eradicated (the last case oc- inducer of CD8+ T-cells response which is useful for curred in 1999) but almost 90% circulating vaccine- vaccination response. This mechanism has been

demonstrated in an animal study in which SIV anti- coli (E. coli) causes the majority of recurrent urinary gen is inserted in RhCMV. The last emerging technol- tract infection despite antibiotic therapy. Thus vac- ogy was the plasmid-launched, live-attenuated virus cine targeting E. coli UTI were proposed and devel- (PLAAV) vaccine platform that use transfection as oped to combat the AMR during UTI recurrence route of administration. Other advantage of PLAAV treatment. is that this platform does not need cold chain Monoclonal Antibody for Prevention and Treatment maintenance like the traditional vaccine. (HIV, Rabies, and Influenza) Immunological Updates on Vaccination Principle Passive immunization using antibody has been ap- The problem with several available pediatric vac- plied in several diseases such as tetanus, rabies, and cines is that antibody titer does not reflect the corre- diphtheria. Several monoclonal antibodies were de- late of protection, thus understanding protective veloped to prevent HIV infection, to replace rabies responses will accelerate vaccine development. immunoglobulin in order to reduce cost of pst- RTS,S/AS01 vaccine study showed that anti-CSP titers exposure prophylaxis (PEP) and to combat influenza correlated with protective response of malarial vac- infection. cine, since CSP is responsible for immobilizing malari- Despite the emerging technologies in vaccine de- al parasites. Several approaches were discussed to velopment, new innovative vaccine design, and elaborate the immunological vaccine response us- new approaches to ensure vaccine delivery, vac- ing the latest technologies such as mass spectrome- cine preventable diseases are still a major challenge try, T-cells repertoire analysis, and organoid system. especially in LMIC. Investing in vaccine develop- Vaccines and Antimicrobial Resistance ment and ensuring vaccines delivered to those who are in need will have an impact on socio-economic The emergence and spread of antimicrobial re- benefit. sistance (AMR) does not only limit the effective treatment option for infectious diseases but also increases the costs of health care systems. Several vaccines References: were developed to reduce antibiotic selective pres- sure. An alga based platform vaccine for oral deliv- All materials are obtained from GVIRF 2018, Bang- ery was developed to counter the antimicrobial re- kok, Thailand. sistance in aquaculture. Uropathogenic Eschericia

Photocredit to WHO (http://www.who.int/immunization/research/forums_and_initiatives/gvirf/en/)

INA-RESPOND Newsletter. All rights reserved. Page 13 April 2018 Edition | Issue #55 NewsletterINA-RESPOND BCG VACCINATION:INA-PROACTIVE INEFFECTIVE PREPARATION & NEEDS TO BE WEEKSUBSTITUTED? BY: MYRNA EVANDA ADELINE & M. HELMI AZIZ

Photo Credit to http://www.thelancet.com/cms/attachment/2058471115/2061959086/fx1.jpg

very year we commemorate World Tu- since 1995. Data from 2007 showed that Indone- berculosis (TB) Day on March 24. TB Day sia BCG vaccination coverage was up to 75%, is designed to increase public aware- and the latest data on 2016 the BCG coverage E ness about public health impact of TB. was 93% for the newborn (2, 3). Despite the high In 2016, it was estimated that 10.4 million people and increased coverage of BCG, TB incidence in were infected with TB, and 56% of them were Indonesia still increased from 183/100,000 (2013) from five countries, including Indonesia, which to 395/100,000 (2016) (2, 3). Therefore, this month ranked number two for the highest incidence of article will review the protective effect, BCG re- TB (1). To cope with that problem, Indonesia has vaccination, BCG side effect, and latest devel- running Bacillus Calmette–Guérin (BCG) vaccina- opment on TB vaccine research. tion program for newborn since 1956 and directly The BCG vaccine was developed from 230 pas- observed treatment short-course for TB treatment sages attenuated strain of Mycobacterium bovis

by Cammille Calmett and Albert Guerin at the Pasteur Institute between 1906−1919 (4). BCG has been proven to have protective effect against serious forms of tuberculosis (meningeal and mil- iary) but the protective effect was ranged from zero and 80% for pulmonary TB at any age (4-6). But, why does the efficacy of BCG vaccination have a wide variation for lung TB protection? Sev- eral factors including exposure to mycobacteria, genetic of the population, virulence of M. tuberculosis, nutritional status, and different BCG strains play a role in determining BCG vaccination ef- fects (4, 5).

Since 1921, BCG vaccine has been administered and distributed worldwide more than any other available vaccine nowadays (4, 7). In 1921 it was impossible to freeze-dry (lyophilize) or store BCG at -80⁰C. Therefore, the original BCG no longer exists. At the Pasteur Institute BCG was continually Figure 1. Molecular events of BCG Pasteur from the first BCG Pas- teur to the last BCG Pasteur 1173. produced using the same technique until 1173 passages and stopped until lyophilization tech- lecular events between the first BCG until the last nique was found in 1961 and at the same time to passage of BCG Pasteur (Figure1) where three keep up the BCG demand several laboratories deletions, three duplications, and one-point mu- develop their own BCG (daughter strain) (7). The tations occurred during passage (8). different laboratories using different method to cultivate BCG, thus promoted genetic modifica- Now that we know there are genetic events in tion, affecting the immunogenicity, and reac- BCG vaccine, the next question is, “what is the togenicity of BCG (4, 5). It has been shown that impact of these changes?” For a live attenuated BCG derived before 1930 or 1940 may have bet- vaccine such as BCG, the vaccine component ter immunogenicity than the widely used variants must survive long enough after inoculation to pro- (5). voke the targeted immune response (7). Methox- ymycolic acid, encoded by mma3, is the compo- But how do we prove that the different methods nent of bacterial cell wall that is responsible for of cultivation affect genetic modification of the survival of BCG inside the host (7, 8). The BCG BCG? Thanks to the development of molecular strains after 1931 did not produce methoxymycol- genomic tools which allowed us to determine the ic acids, thus dividing BCG into two groups, viru- molecular differences between BCG strains and lent and avirulent form (7, 8). During the genetic tracking the genetic events. Several studies have changes, the BCG antigens such as mpt64 also showed that there are molecular differences be- altered, affecting the immunologic response of tween BCG strains which are restriction-fragment- BCG vaccination (7). Moreover, result from BCG length polymorphism (RFLP), different numbers of trials using BCG−Pasteur 450 and BCG−Pasteur IS986 (previously IS6110), mpt64, mma3, and three 575 had an efficacy about 80% and 77% respec- deleted regions (RD1−3) (7, 8). Additionally, the tively, while BCG−Pasteur 1173 showed no pro- genomic tools are able to demonstrate the mo-

Figure2. TB vaccine candidates that were made into clinical trials (6)

tection at all (8). While the genomic tools have tion (4). The different methods between those gave us insight regarding molecular differences, studies in different countries are thought to be the phenotypic result of this genetic events re- the cause of the variation of BCG protective ef- mains to be determined. fect.

Related to the various efficacy of BCG, several Despite the controversy on BCG efficacy, there is policies related to BCG vaccination have been also a controversy related to BCG safety. applied in different countries to increase the BCG Adverse events due to BCG administration efficacy. Globally, BCG is administered to a new- ranged from local reaction up to systemic born baby as a single dose, but in several infection (4). The famous case related to BCG countries BCG revaccination policy for school safety was the Lübeck disaster in 1930 which children or older with negative tuberculin test or destroy the belief in BCG administration (9). The negative BCG scar or for higher risk groups is ap- BCG was supplied from Pasteur, prepared at plied (4). The success story of BCG revaccination Lübeck laboratory, and administered orally (9). came from Hungary, where 4-times BCG revac- From 250 vaccinated people, there were 73 cination to negative tuberculin children lowered deaths, and 135 people were infected but the pulmonary TB incidence from 83/100,000 to recovered due to the contamination of virulent 21/100,000 (4); while in Malawi, Chile, and Brazil tubercle bacilli in the Lübeck laboratory (9). BCG revaccination had no effect on TB protec- Nowadays, BCG also poses a serious threat in HIV

infected individual since BCG is a live attenuated to replace BCG have been made by health poli- vaccine. The BCG administration could induce cy maker and scientist with diverse results. In the BCG-itis (BCG-osis). This is why several countries future we hope that there will be new methods or postpone BCG administration in this population vaccines that are safe and could prevent or elim- (4). This data is supported by study cases in inate TB infections. Canada and South Africa where BCG -oOo- administration leads to death of HIV+ individuals despite the anti-retroviral medication (4).

All those controversies on BCG efficacy and safe- References: ty raise concern to new TB vaccines develop- 1. WHO. Global tuberculosis report 2017. ment. Several attempts have been made for new Geneva: World Health Organization; 2017. TB vaccine development, and some have been 2. Profil Kesehatan Indonesia 2014. Jakarta: tested in clinical trials (Figure2) (6). Currently, the Kementerian Kesehatan Republik Indonesia; new TB vaccine candidates are divided into 2015. three big groups: preventive pre-exposure vaccines, preventive post-exposure vaccines, and 3. Profil Kesehatan Indonesia Tahun 2016. therapeutic vaccines (6). The preventive vaccines Jakarta: Kementrian Kesehatan Republik Indone- are further divided into three generic types: 1) sia; 2017.

the subunit vaccines (including viral vectored 4. Pereira SM, Dantas OM, Ximenes R, Barre- (e.g MVA85A) and adjuvant-based (AERAS-402/ to ML. [BCG vaccine against tuberculosis: its pro- Crucell Ad35)), 2) viable whole-cell vaccines tective effect and vaccination policies]. Revista (VPM1002), and 3) inactivated whole-cell vac- de saude publica. 2007;41 Suppl 1:59-66. cines (SRL172) (6, 10). The antigens for the pre- 5. Monteiro-Maia R, de Pinho RT. Oral bacil- exposure vaccines are most likely the antigens lus Calmette-Guérin vaccine against tuberculosis: that are expressed during the stages of active why not? Memórias do Instituto Oswaldo Cruz. replication; while for the post-exposure vaccines, 2014;109(6):838-45. the targeted antigens are expressed during la- tent infection or dormant stage (6). The ideas of 6. Kaufmann SHE, Weiner J, von Reyn CF. developing therapeutic vaccines, such as Mw (M Novel approaches to tuberculosis vaccine devel- indicus pranii) and RUTI, were to improve treat- opment. International Journal of Infectious Dis- ment outcome in active TB. Stimulation with my- eases. 2017;56:263-7. cobacterial antigens was hypothesized to en- 7. Behr MA. BCG--different strains, different hance immune response and improve bacterial vaccines? The Lancet Infectious diseases. 2002;2 killing in active TB infection. Despite all the rigor- (2):86-92. ous attempt on TB vaccine development, none of them has been licensed to replace BCG due 8. Behr MA, Wilson MA, Gill WP, Salamon H, to the lack of compatible animal models in vac- Schoolnik GK, Rane S, et al. Comparative ge- cine development and ineffective methods to nomics of BCG vaccines by whole-genome DNA measure the correlates of protection (10). microarray. Science (New York, NY). 1999;284 (5419):1520-3. In conclusion, although BCG is not an ideal vaccine for preventing TB, but it is still widely used 9. Luca S, Mihaescu T. History of BCG Vac- and plays a role to prevent severe forms of TB. cine. Mædica. 2013;8(1):53-8. Several attempts to increase BCG efficacy and

BY: DONA ARLINDA & NENENG AINI

THE CONFERENCE had possibly led to a functional cure of the virus. But the child’s HIV ultimately rebounded, raising many im- Each year for the past twenty-five years, thousands of portant questions about how early treatment may limit HIV scientists gather at the United States–based Confer- the size of the viral reservoir, but not eliminate it. ence on Retroviruses and Opportunistic Infections (CROI) to share important scientific findings with their A new study presented at this year’s conference found peers. This year’s conference, held in Boston on March that starting HIV-positive infants on ARVs very early is 4th to 7th, is the 25th anniversary of the CROI. As always, indeed associated with the establishment of a smaller the conference aimed towards better treatment for reservoir. The researchers’ findings also indicate that the HIV, as well as finding a cure someday. Three delegates wider the gap between prophylactic use of ARVs and from INA-RESPOND, namely dr. Endang Budi Hastuti the initiation of a traditional ARV regimen in an HIV- (Head of the Sub-directorate of HIV AIDS and STIs of the confirmed infants is linked to the establishment of a Ministry of Health of Indonesia), Prof. Dr. dr. Ketut Tuti larger reservoir. To view a webcast of the conference Parwati Merati, Sp.PD-KPTI (Udayana University) and Ms. presentation, click here. Neneng Aini (INA-RESPOND Secretariat) had the oppor-

tunity to join the conference. DTG Versus LPV/r in Second Line (DAWNING): Out- The year’s CROI conference assembled more than comes by WHO-Recommended NRTI Backbone 4,000 HIV researchers in Boston, bringing together top basic, translational, and clinical researchers from 76 DAWNING is a non-inferiority study comparing dolute- countries to share the latest studies, important develop- gravir (DTG) vs lopinavir/ritonavir (LPV/r) when both ments, and best research methods in the ongoing bat- were combined with 2 nucleoside reverse transcriptase tle against HIV/AIDS and related infectious diseases inhibitors (NRTIs) in HIV-1 infected adults failing first-line (visit the conference website for abstracts, webcasts, therapy (HIV-1 RNA ≥400 copies/mL). In DAWNING, re- and other materials being released over the confer- sponse rates were highest in subjects receiving DTG + 2 ence). The conference’ topics range from HIV therapies NRTIs. Furthermore, within each arm, subjects receiving to issues that intersect with HIV care. This year, CROI WHO-recommended 2 NRTIs had higher response rates also broadened its lens from the lab to different strate- suggesting resistance testing to guide NRTI selection gies that might have impact to the people's complex may not be necessary in this population. DAWNING lives. provides important information to help guide second- line treatment decisions in resource-limited settings. To

view the abstract, click here. Limiting the Gap Between ARV Prophylaxis and ART New TB prevention treatment Initiation may Limit the Size of HIV Reservoir in Children In what has been described as a ‘game changing’ At the 2013 CROI, a presentation about the so-called new finding, researchers have discovered that effec- Mississippi Baby spurred worldwide excitement and fan- tive tuberculosis (TB) prevention can be delivered in fare. It seemed at the time, an atypically aggressive one month. The current preventative treatment being ARV regimen given to the infant immediately after birth

offered, isoniazid, must be taken every day for nine DAPIVIRINE RING months, and in high TB/HIV burden countries the World The biggest conference news in the field of so-called Health Organization recommends that it is taken for 36 biomedical prevention of HIV—using antiretrovirals months. (ARVs) among HIV-negative individuals to prevent ac- A one-month antibiotic regimen to prevent active tu- quisition of the virus—came from a pair of studies that berculosis (TB) disease was at least as safe and effec- have followed up on previously announced research tive as the standard nine-month therapy for people about the ARV-infused vaginal ring. To view a webcast living with HIV, according to the results of a large inter- of the conference presentation, click here. national clinical trial. Adults and adolescents in the trial The dapivirine vaginal ring is a silicone ring containing were more likely to complete the short-course regimen an antiretroviral that is released slowly over time. It's — consisting of daily doses of the antibiotics rifapentine been designed to be worn by women for around a and isoniazid for four weeks—than the standard nine- month. Two years ago, at CROI 2016, the ASPIRE and month regimen of daily isoniazid. This ultra-short course Ring Study results showed that the dapivirine vaginal therapy could become an important tool to control HIV ring is safe and reduces the risk of HIV infection by -related tuberculosis and has the potential to transform around 30 percent overall among women enrolled in global tuberculosis control efforts. To view the abstract, the study. At CROI 2018, interim data from the open- click here. label extension (OLE) trials of the ring—HOPE and Pre-exposure prophylaxis (PrEP) DREAM—showed that the ring reduced risk by 50 percent. Final data from HOPE and DREAM, including find- As PrEP has rolled out across the United States—Gilead ings on how well it works in those who use it consistently, Sciences estimates that more than 150,000 people are will be available in late 2018/early 2019. currently taking it—it has become increasingly appar- ent that uptake of Truvada as prevention is quite une- The European Medicines Agency (EMA) is reviewing ven. A collection of studies presented at CROI sought available data on the ring under a framework that al- to more clearly identify various disparities in the use of lows it to provide regulatory guidance for developing PrEP. countries. Its decision is expected in late 2018.

Access to PrEP was woven throughout the CROI pro- PREGNANT AND POST-PARTUM WOMEN NEED HIV PRE- gram, as data on PrEP programs and use continues to VENTION accumulate. Findings from San Francisco and Australia A presentation from Renee Heffron (University of Wash- both showed a significant uptick in PrEP use and re- ington) provided more evidence that pregnant and duced infections (primarily in men who have sex with post-partum women are at increased risk of HIV infec- men) but across both of the studies racial and ethnic tion. She and colleagues analyzed data from two stud- disparities in access remained largely unchanged. A ies of over 2,700 serodifferent couples. They found that new analysis from the US Centers for Disease Control women who were pregnant or post-partum were 3-4 and Prevention (CDC), also presented at CROI, found times more likely to acquire HIV. Implications for care that two-thirds of those who could benefit from PrEP are and prevention include counselling, more testing, treat- African-American or Latino and yet prescriptions for ment for male partners and woman-controlled preven- these populations remain stubbornly low. Gaps in ac- tion options like oral PrEP. A new HIV infection during cess were seen across racial groups but were most stark pregnancy or postpartum not only has negative conse- among non-white populations. To view the abstract, quences for the woman’s health, but also carries the click here risk of perinatal HIV transmission to her fetus or to her Looking for future forms of pre-exposure prophylaxis new-born through breastfeeding. Better understanding (PrEP), scientists conducted a study in monkeys that HIV acquisition risk during and after pregnancy is critical showed that a new class of ARV was so effective at a to ensuring that women receive the best HIV preven- low dose that humans could possibly take just 0.25 milli- tion counseling and tools at all stages of their lives. grams of the drug MK-8591 once a week and still Read the study abstract ; view the presentation. achieve good protection against HIV. By comparison, Discussions of pregnancy, contraceptives and HIV risk Truvada (tenofovir disoproxil fumarate/emtricitabine) rise as many stakeholders prepare for data from the contains a cumulative 500 mg of ARV medications.

ECHO trial. ECHO is looking at three different methods here (DMPA, copper IUD and Jadelle implant) to see if any Antiretroviral drug levels in hair strongly predict viral sup- have an impact on women's HIV risk. These data are an pression essential reminder that HIV risk is driven by many things- including pregnancy. Advocates need to push for PrEP Antiretroviral drug levels in a sample of hair were the in the ante- and post-natal context, contraceptive strongest predictor of response to HIV treatment, and choice, programs that diagnose male partners and link this method also holds promise for monitoring adher- them to effective ART-and more. Data and global and ence to pre-exposure prophylaxis (PrEP). Antiretroviral national guidelines on the use of oral PrEP (e.g., the drug levels in hair samples are a reflection of adher- WHO technical brief on preventing HIV during pregnan- ence over time. Drug levels can be measured in blood cy and breastfeeding in the context of PrEP) and the and in some cases in urine, but this only gives infor- dapivirine ring for pregnant and post-partum women mation about levels shortly before testing. Measuring are essential. drug levels within cells – where antiretrovirals must reach to be effective – is more complex. UNDETECTABLE=UNTRANSMITTABLE Hair testing avoids the "white coat" effect, in which an In the meeting, conversa- individual could take their tions about the Undetecta- medication inconsistently but ble=Untransmittable cam- do so before a medical ap- paign and its role in reducing pointment. In addition, hair is stigma were frequent and easy and cheap to collect welcomed. For the first time and samples can be stored there was a plenary session and shipped at room temper- on mental health at which ature without biohazard pre- presenter Robert Remien cautions. However, hair testing (HIV Center for Clinical and currently must be performed in Behavioral Studies, Columbia a lab and cannot be done in University) called for stepped "real time" while a patient up mental health services to waits. achieve the 90-90-90 goals. The researchers concluded Pre-treatment HIV Drug Re- that further study is warranted sistance in START Study Using to see whether early monitor- Next Generation Sequencing ing of hair drug levels, followed In START study, an interna- by targeted adherence inter- tional trial comparing immediate versus deferred ART ventions for those with low levels, could help reduce initiation among ART-naïve HIV-infected persons with virological failure. View the presentation. CD4 counts >500 cells/ μL, study entry HIV-1 was char- PRODUCTS IN THE PIPELINE acterized by next generation sequencing (NGS); a sen- sitive assay capable of detecting low-frequency vari- While there was an increased focus on implementation ants associated with pre-treatment HIV-1 drug re- work this CROI, data from early-stage research were sistance (PDR). The START trial represents one of the also being presented. Among the hundreds of posters largest global cohorts with NGS characterization of and oral abstract presentations a couple stood out in- PDR. Overall prevalence of PDR using the ≥2% detec- cluding a non-ARV vaginal insert-designed to prevent tion threshold was 19.7% for RT-PR DRMs, while only 8.3% HIV, HSV-2 and HPV infection-from PopCouncil and the using the 20% threshold and varied by region. INI DRMs long-acting ARV from Merck (MK-8591) to prevent HIV. were detected in 0.9% of the study cohort primarily as Given favorable animal data, both products are being minor variants. NGS would be expected to detect a considered for clinical development. substantially higher prevalence of PDR than traditional We thank INA-RESPOND Secretariat, especially dr. M. Sanger sequencing, particularly for DRMs occurring pre- Karyana, M.Kes and NIH-NIAID, for the support and dominately as minor variants. To view the abstract, click hard work all the way.

ommunication between patient and guage is not anti-intellectual, unsophisticated, or practitioner is essential, but it may not drab. Plain language is about clear and effective be happening as often as health pro- communication—nothing more or less. When we C fessionals think it is. We have installed are thinking that communicating with our pa- another set of dictionaries containing medical tients who has low health literacy is really hard, jargon; and through times, unconsciously, we please remember that in the past we communi- started to speak alien language. Communicating cated in the same way they do now. with a different language may lead to miscom- The patient-practitioner relationship should be munication, and the results of the miscommuni- two-way and mutually beneficial. One important cation can be benign or disastrous. Ill-informed shared concept is that people should be able to patients tend to neglect timely or appropriate both understand and use the information pre- examination/treatment which can lead to very sented. A meta-analysis shows that good com- bad outcomes. In contrast, for patients who un- munication in medical care is highly correlated derstand their conditions/health status, the aims with better patient adherence, which lead a bet- and potential of their treatment are likely to ex- ter success of the treatment. Looking at this fact perience superior outcomes. through the perspective of researchers who con- In the Institute of Medicine (IOM) report on health ducting and evaluating RCT, when we are seeing literacy, as reported by US Department of Health a negative result(s) of the treatment due to non- and Human Services, IOM finds that there is a compliance, what do we think we will blame first major mismatch between the health information then? people receive and what they understand. But Closing remarks: There are a lot of useful materials this lack of understanding is not primarily the fault and trainings available to improve our communi- of individuals receiving the information; nor is it cation skills. We just need to put in some efforts to solely the result of poor or limited literacy skills. improve our skills. Hopefully, this article can give People can be very well educated and highly us a slight motivation to move in the right direc- literate in their area of expertise, and still not fully tion. understand complex medical information. Virtu- ally everyone has experienced receiving health ‘The patient will never care how much you know, information about themselves or a loved one that until they know how much you care.’ (Tongue, et caused confusion and uncertainty. Regardless of al., 2005). one’s literacy level, when a healthcare provider References uses unfamiliar, technical language or delivers bad news, it is difficult to fully comprehend what Kyle, S. and Shaw D. 2014. Doctor–patient is being said, especially when these individuals communication, patient knowledge and health are made more vulnerable by their poor health. literacy: how difficult can it all be? Bulletin of the Royal College of Surgeons of England; 96: 16, pp. First thing first: as medical professionals, we need e9-e13. to remember that we are humans before we are aliens. We also need to understand that plain U.S. Department of Health and Human Ser- language is not a “dumbing down”. Sometimes, vices. 2005. Plain language: a promising strategy we are concerned that using plain language will for clearly communicating health information oversimplify information to the point where it is and improving health literacy. inaccurate or worthless. However, plain lan-

April 2018 Edition | Issue #55

INA-RESPOND website: www.ina-respond.net

INA-RESPOND Newsletter The Indonesia Research Partnership on Infectious Disease newsletter is an internal bulletin of INA-RESPOND research network intended to disseminate information related to the network’s studies, activities, and interests to all members of the network as well as its sponsors and related parties. The INA-RESPOND newsletter welcomes all network members and stakeholders to contribute by submitting articles related to the network’s studies and interests. Send your articles or subscribe to our latest newsletter by sending an email to [email protected]