OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Baggaley, Rebecca F

Chapman, Ruth

de Wolf, Frank

Delany, Sinead

Fraser, Christophe

Ghani, Azra C

Griffin, Jamie T

Hollingsworth, T Déirdre

Mayaud, Philippe

Nagot, Nicolas

Weiss, Helen A

English

PubMed

Objective: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impacton plasma HIV-1 viral loads(PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. Design and methods: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. Results: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% Cl, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% Cl, 30.4-137.0) and 66.5 (95% Cl, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. Conclusion: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkin

Baggaley, Rebecca F.

Griffin, Jamie T.

Hollingsworth, T. Déirdre

Ghani, Azra C.

Weiss, Helen A.

NARCIS 

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load

LSHTM Research Online

Leung, GM; Chung, PH; Tsang, T; Lim, W; Chan, SK; Chau, P;Donnelly, CA; Ghani, AC; Fraser, C; Riley, S; Ferguson, NM; An-derson, RM; Law, YL; Mok, T; Ng, T; Fu, A; Leung, PY; Peiris, JS;Lam, TH; Hedley, AJ (2004) SARS-CoV antibody prevalence in allHong Kong patient contacts. Emerging infectious diseases, 10 (9).pp. 1653-6. ISSN 1080-6040Downloaded from: http://researchonline.lshtm.ac.uk/13188/Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: Creative Commons Attribution Non-commercial No Derivativeshttp://creativecommons.org/licenses/by-nc-nd/2.5/SARS-CoV AntibodyPrevalence in AllHong Kong Patient ContactsGabriel M. Leung,* Pui-Hong Chung,† Thomas Tsang,† Wilina Lim,† Steve K.K. Chan,*Patsy Chau,* Christl A. Donnelly,‡ Azra C. Ghani,‡ Christophe Fraser,‡ Steven Riley,‡ Neil M. Ferguson,‡ Roy M. Anderson,‡ Yuk-lung Law,† Tina Mok,†Tonny Ng,† Alex Fu,† Pak-Yin Leung,† J.S. Malik Peiris,* Tai-Hing Lam,* and Anthony J. Hedley*A total of 1,068 asymptomatic close contacts ofpatients with severe acute respiratory (SARS) from the2003 epidemic in Hong Kong were serologically tested, and2 (0.19%) were positive for SARS coronavirus immuno-globulin G antibody. SARS rarely manifests as a subclinicalinfection, and at present, wild animal species are the onlyimportant natural reservoirs of the virus.Since severe acute respiratory syndrome (SARS) andthe coronavirus (SARS-CoV) that causes it haveemerged and spread, considerable progress has been madein understanding the biology, pathogenesis, and epidemio-logic features of both the virus and the disease.Epidemiologic studies of hospitalized patients suggest thatthe overall transmissibility of SARS (as indicated by thebasic reproductive number R0 = 2.7, 95% confidence inter-val [CI] 2.2–3.7) (1) is relatively low compared to otherpathogens. However, such studies could not take intoaccount possible episodes of mild or moderate illness thatdid not require inpatient medical care and could notaddress whether asymptomatic community spread played arole in the 2003 epidemic. If this type of spread occurred,sufficient herd immunity against SARS-CoV to protectagainst another large-scale outbreak might have beendeveloped in the population. The full spectrum of diseaseassociated with SARS-CoV infection should be examinedto define more precisely what constitutes a case requiringquarantine and isolation to minimize potential human-to-human spread. Understanding these issues requires thesystematic study of the seroprevalence of SARS-CoV anti-body in a large sample stratified by age and other baselinecharacteristics, especially since children were dispropor-tionately less affected by SARS, both in terms of reducedincidence and severity of infection. Serologic surveys canbe based on a random sample from the total populationwith appropriate stratification, on serum collected for otherreasons (e.g., blood donors, all hospital admissions), or onsurveys of persons who resided in sites of superspreadingevents or who have had close contact with a confirmedSARS patient. We report a serologic survey for immunoglobulin (Ig)G against SARS-CoV in a representative sample of closecontacts of all SARS patients in Hong Kong (>76% hadlaboratory confirmation of SARS by either paired serologyor repeat reverse transcription–polymerase chain reaction(RT-PCR) according to World Health Organization [WHO]criteria [2]). The StudyDuring the epidemic, close contacts were prospectivelyidentified by the Hong Kong Special AdministrativeRegion Government Department of Health through stan-dardized telephone interviews with all 1,755 confirmedSARS patients within 1 week of hospital admission(February 15–June 22, 2003). A close contact was definedas a person who had cared for, lived with (in the samehousehold), or came into direct contact with body fluids ofthe SARS patients within 10 days before hospital admis-sion. A total of 3,612 close contacts were recorded; 505were diagnosed as having SARS. Of the remaining 3,107contacts, 2,805 (90%) had a telephone number available,as reported by the primary patient. We successfully con-tacted 2,337 (83%) from October 23 to November 30,2003, and 1,776 (57% of those eligible) consented to atelephone interview after the purpose of the study wasexplained to them by trained public health nurses. Theinterview consisted of questions that assessed the relation-ship between the patients and contacts; the timing, intensi-ty and frequency of contact; precautionary measuresadopted during contact with the patient; known contactwith other SARS patients; clinical symptoms of febrile,respiratory, gastrointestinal, or constitutional illness sinceFebruary 2003; medical and travel history; and sociode-mographic details. Participants were then invited to pro-vide blood samples for serologic testing. Shoppingcoupons (worth U.S. $25.00) were given to participantsafter blood was collected as compensation for time andtravel costs.Samples were screened by the Government Virus Unitof the Department of Health by using viral lysate enzyme-linked immunosorbent assay (ELISA) (GBI Biotech,Beijing). Positive results were confirmed with immunoflu-orescence assay (IFA) and neutralization tests. For the IFA,microscopic slides coated with SARS-CoV–infectedEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004 1653*University of Hong Kong, Hong Kong Special AdministrativeRegion (SAR), China; †Department of Health, Hong Kong SAR,China; and ‡Imperial College, London, EnglandFRhK4 cells were incubated with serum samples at serialtwofold dilutions starting from1:25. A positive test is indi-cated by cytoplasmic fluorescence under UV microscopy.By using IFA as the standard, the ELISA detects antibodywith IFA titer of >25 (i.e., sensitivity of 100%) and has aspecificity of 95%. Neutralization test was performed bystandard virologic method with Vero E6 cells and SARS-CoV isolate 6109. A titer of >10 was considered positive.The reported sensitivity of 100% was for convalescent-phase serum samples taken a few weeks after the onset ofinfection in SARS patients, which should apply to ourstudy. During the early phase of infection, IgM predomi-nates; the ELISA kit we used detects IgG only. Therefore,the sensitivity is 80%–90% (depending on the number ofdays after illness onset when the serum samples weretaken). However, this sensitivity should not have affectedour findings, which were based on tests carried out at least6 months after the last reported case of SARS in HongKong. The study received ethics approval from theDepartment of Health Ethics Committee, which complieswith the Declaration of Helsinki. Results and ConclusionsOf the 1,068 samples analyzed, 2 (0.19%, exact 95% CI0.02%–0.67%) had a positive titer (1:25 to 1:50 on IFAcompared to at least 1:100 in most recovered SARS cases)for SARS-CoV IgG antibody. Neither participant with apositive sample reported a chronic medical condition orbeing sick with febrile or respiratory illness from Februaryto August. Both seropositive participants arose from twosuperspreading events in Hong Kong, i.e., Prince of WalesHospital nosocomial outbreak and Amoy Gardens environ-mental point source community outbreak (1,3). The con-tact of the Prince of Wales Hospital seropositiveparticipant reported one other close contact, who wasinterviewed but declined to be tested. The other seroposi-tive index patient living in Amoy Gardens was separatelyidentified by three intrafamilial index patients, all of whomlived in the same household and reported only each otheras close contacts. The participants who consented to test-ing were broadly similar to those who declined, except thatthe first group had relatively fewer children and fewer ofthe first group were men (Table). However, those whodeclined testing were more likely to report more frequentcontact and closer relationships with SARS patients, morefebrile or respiratory illness episodes since February, and atravel history to SARS-affected regions, which may havebiased our seroprevalence estimate upwards.The extent of seroconversion in close contacts of con-firmed patients should provide the upper limit of SARS-CoV antibody seroprevalence in the general population,given the relatively intense exposure history of these per-sons to SARS patients. Our finding of the near absence oftransmission resulting in asymptomatic infection in thisrepresentative high-risk group of close contacts indicatesthat the prevailing SARS-CoV strains in Hong Kongalmost always led to clinically apparent disease. Whereassome SARS patients, especially healthcare workers, mighthave been initially admitted to reduce transmission to fam-ily members, virtually all SARS patients (perhaps withvery few exceptions in children [4]) had severe diseaserequiring inpatient treatment; thus, we can infer that infec-tion with SARS-CoV inevitably caused severe diseaserequiring hospitalization. Although our results suggest that SARS-CoV was anew virus in humans without a close precursor or an anti-genically related virus that would have induced at least asmall degree of cross-reactivity on serologic testing, arecent study on a select group of 938 healthy Hong Kongadults, whose serum had been previously stored as part ofa hepatitis B serosurvey in 2001, indicated that 1.8% of thesample had acquired a SARS-CoV–related virus infectionat least 2 years before the 2003 SARS outbreak (5). Theinvestigators speculated that the virus that affected thesehealthy, seropositive persons was antigenically closer tothe recently isolated animal SARS-CoV–like virus (3) thanhuman SARS-CoV, but interspecies transmission from ani-mals to humans was probably inefficient, as the virusmight not have adapted in the new host. This hypothesiswould explain why only a few persons became infectedand why they were likely to have been asymptomatic. Thishypothesis would be compatible with the presumedasymptomatic infection observed in Guangdong animaltraders, especially in those who handled masked palmcivets, who had a seropositivity rate of 72.7% (exact 95%CI 49.8%–89.3%) in the absence of prior overt clinical dis-ease (6). The limitations of the study include incomplete contacttracing, especially in the earlier parts of the epidemic, andpotential recall bias from underreporting of contacts bysome patients who were too sick to answer questions.Another possible shortcoming is the lack of a survey ofclose contacts who did not report a telephone number,although there is no reason to suspect they had a systemat-ically different serologic profile. In fact, these were most-ly nonhousehold contacts who would have had less intenseexposure to SARS patients. In addition, because peakinfectivity, as indicated by viral load, usually occurred dur-ing week 2 of illness (7), when most of the patients wouldhave been isolated in hospital (the mean onset-to-admis-sion interval decreased from a maximum of 9.3 days in lateFebruary to 1.0 day by mid-May) (8), transmission to closecontacts in the later stages of the epidemic was less likely.Finally, contacts who refused to participate (561) orrefused to have serologic testing (708) might have done sobecause they were concerned about having had SARSDISPATCHES1654 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004(possibly because of having had SARS-like symptoms)and did not want to be identified and stigmatized as havingbeen infected with SARS-CoV. Surveys in other countrieswith large-scale outbreaks such as Canada, China,Singapore, and Taiwan should be undertaken to confirmour findings. AcknowledgmentsWe thank colleagues in the Disease Prevention and ControlDivision, Regional Offices, Elderly Health Service and PublicHealth Nursing Division of the Department of Health for assis-tance in recruiting participants, collecting survey data and bloodsamples, and collating and processing multiple data sources usedSeroprevalence of SARS-CoV AntibodyEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004 1655Table. Characteristics of close contacts recalled for serologic testing (N = 1,776) Characteristic Tested for IgG against  SARS-CoV, n = 1,068 (%) Declined antibody testing, n = 708 (%) p value Age (y)   ? 0.001 ?10 53 (5.0) 126 (18.1)  11–17 77 (7.2) 68 (9.7)  18–44 515 (48.3) 278 (39.8)  45–64 330 (30.9) 138 (19.8)  ?65 92 (8.6) 88 (12.6)  Sex   0.02 Female 579 (54.2) 341 (48.3)  Male 489 (45.8) 365 (51.7)  Travel history to SARS-affected areas since February, 2003a   ? 0.001 Yes 523 (49.0) 268 (37.9)  No 545 (51.0) 440 (62.1)  Relationship with SARS case   0.001 Household family member 789 (74.4) 499 (70.5)  Non-household family member or relative 230 (21.7) 164 (23.2)  Friend/classmate/colleague 25 (2.4) 12 (1.7)  Other (e.g., domestic helper) 16 (1.5) 33 (4.7)  Frequency of contact with SARS patient within 10 days of hospital admission   0.06 Daily 666 (62.6) 405 (57.9)  4–6 days per week 82 (7.7) 56 (8.0)  1–3 days per week 161 (15.1) 103 (14.7)  Very occasionally 155 (14.6) 135 (19.3)  No. of precautions adopted during SARS outbreakb   0.25 ?2 60 (6.6) 47 (8.6)  3–4 113 (12.4) 81 (14.8)  5–6 334 (36.7) 187 (34.1)  7–8 402 (44.2) 234 (42.6)  No. of febrile or respiratory illness episodes since February 2003   0.02 0 643 (61.7) 471 (68.4)  1–2 351 (33.7) 193 (28.0)  ?3 48 (4.6) 25 (3.6)  Presence of chronic medical conditions   0.10 Yes 270 (28.3) 149 (24.6)  No 683 (71.7) 457 (75.4)  Self-perceived health status in previous week   0.34 Excellent 124 (11.6) 84 (12.0)  Very good 317 (29.7) 222 (31.8)  Good 323 (30.3) 223 (31.9)  Fair 279 (26.1) 152 (21.7)  Poor 24 (2.2) 18 (2.6)  aIncludes Canada, China, Singapore, and Taiwan. bIncludes washing hands before touching mouth, eyes, and nose; washing hands with soap; wearing face mask; using serving utensils during meals; adopting precautionary measures when touching possibly contaminated objects, washing hands after touching possibly contaminated objects; adopting home preventive measures (such as maintaining good ventilation and using bleach to clean surfaces and home appliances) against SARS; and adopting workplace preventive measures (such as maintaining good ventilation, using bleach to clean surfaces and office furniture, and not allowing staff who are sick to come to work) against SARS. in this report; the Government Virus Unit for laboratory analysis;and Marie Chi for expert secretarial assistance in the preparationof the manuscript. R.M.A. thanks the Wellcome Trust for grant support; N.M.F.and A.C.G. thank the Royal Society for fellowship support.Dr. Gabriel Leung is an associate professor in Public HealthMedicine at the University of Hong Kong and chairs theScientific Committee on Advanced Data Analysis and DiseaseModeling in the Hong Kong Government Centre for HealthProtection.References1. Riley S, Fraser C, Donnelly CA, Ghani AC, Abu-Raddad LJ, HedleyAJ, et al. Transmission dynamics of the etiological agent of severeacute respiratory syndrome (SARS) in Hong Kong: the impact ofpublic health interventions. Science. 2003;300:1961–6.2. World Health Organization. Use of laboratory methods for SARSdiagnosis. [cited 2003 Dec 9]. Available from: http://www.who.int/csr/sars/labmethods/en/3. Guan Y, Zheng BJ, He YQ, Liu XL, Zhuang ZX, Cheung CL, et al.Isolation and characterization of viruses related to the SARS coron-avirus from animals in southern China. Science. 2003;302:276–8.4. Hon KL, Leung CW, Cheng WT, Chan PK, Chu WC, Kwan YW, etal. Clinical presentations and outcome of severe acute respiratorysyndrome in children. Lancet. 2003;361:1701–3. 5. Zheng BJ, Wong KH, Zhou J, Wong KL, Young BW, Lu LW, et al.SARS-related virus predating SARS outbreak, Hong Kong. EmergInfect Dis. 2004;10:176–8. 6. Centers for Disease Control and Prevention. Prevalence of IgG anti-body to SARS-associated coronavirus in animal traders—GuangdongProvince, China. MMWR Morb Mortal Wkly Rep. 2003;52:986–7.7. Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, et al.Clinical progression and viral load in a community outbreak of coro-navirus-associated SARS pneumonia: a prospective study. Lancet.2003;361:1767–72.8. Donnelly CA, Ghani AC, Leung GM, Hedley AJ, Fraser C, Riley S,et al. Epidemiological determinants of spread of causal agent ofsevere acute respiratory syndrome in Hong Kong. Lancet.2003;361:1761–6.Address for correspondence: A.J. Hedley, Department of CommunityMedicine, 21 Sassoon Road, Faculty of Medicine Building, University ofHong Kong, Pokfulam, Hong Kong, China; fax: 852-2855-9528; email:commed@hkucc.hku.hkDISPATCHES1656 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 10, No. 9, September 2004Searchpast issues

Clinical presentations and outcome of severe acute respiratory syndrome in children.

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study.

Disease Control and Prevention. Prevalence of IgG antibody to SARS-associated coronavirus in animal traders—Guangdong Province, China. MMWR Morb Mortal Wkly Rep.

Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong.

Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China.

Organization. Use of laboratory methods for SARS diagnosis. [cited

SARS-related virus predating SARS outbreak, Hong Kong. Emerg Infect Dis.

Transmission dynamics of the etiological agent of severe acute respiratory syndrome (SARS) in Hong Kong: the impact of public health interventions.

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

Objective:



Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission.



Design and methods:

By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial.



Results:

Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings.



Conclusion:

HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted

Warwick Research Archives Portal Repository

HIV-1 transmission, by stage of infection.

Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting.

Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis.

Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load.

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