Genital ulcer disease describes a breach in the continuity of genital or perianal epithelium caused by infectious or noninfectious processes. Classical sexually transmitted causes include genital herpes caused by herpes simplex virus types 1 and 2, primary syphilis caused by Treponema pallidum, chancroid caused by Haemophilus ducreyi, lymphogranuloma venereum caused by invasive Chlamydia trachomatis serovars L1-L3, and donovanosis caused by Klebsiella granulomatis. Nonvenereal causes include fixed drug eruptions, trauma, inflammatory disorders, autoimmune blistering disease, malignancy, aphthosis, Behçet disease and other dermatological conditions. GUD occupies a particularly important position in STI control because ulcerative lesions disrupt mucosal integrity and are epidemiologically associated with HIV acquisition and transmission. Earlier Indian literature emerged during periods when chancroid, syphilis, donovanosis and LGV were common clinic diagnoses. The subsequent HIV epidemic, increased use of broad-spectrum antimicrobial therapy, STI-control programmes, changes in sexual behaviour, improved health services and syndromic case management altered the relative distribution of STIs. A review of Indian STI patterns concluded that bacterial infections dominated in the 1960s and 1970s, while viral infections such as genital herpes and human papillomavirus became increasingly prominent from the 1980s onward. This transition is especially clear for genital ulcer disease. At a North Indian centre covering 1977-2000, chancroid and donovanosis fell dramatically while genital herpes approximately doubled. More recent studies consistently identify HSV as the dominant pathogen, whereas H. ducreyi is now rarely demonstrated using molecular techniques. These epidemiological changes have direct implications for diagnosis and management. Traditional textbooks describe painless indurated syphilitic chancres, painful ragged chancroid ulcers, grouped painful herpetic vesicles and beefy-red donovanosis lesions. In practice, morphology is frequently altered by stage of illness, secondary infection, host immunity, self-medication, prior antibiotics and HIV infection. Mixed infections further reduce the reliability of morphology. This has created tension between three diagnostic models: clinical etiological diagnosis based on morphology; syndromic management designed to permit immediate treatment without laboratory infrastructure; and laboratory or molecular etiological diagnosis. India’s continuing reliance on syndromic algorithms in many settings must therefore be evaluated against the modern epidemiological distribution of GUD. 2. Objectives 2.1 Primary Objective To systematically assess changing etiological trends in genital ulcer disease in India. 2.2 Secondary Objectives 1. To determine the relative importance of HSV, syphilis, chancroid, LGV and donovanosis across different periods. 2. To evaluate diagnostic accuracy and limitations of clinical and syndromic approaches. 3. To examine the contribution of PCR and other laboratory techniques. 4. To evaluate associations between GUD and HIV. 5. To identify important nonvenereal causes of genital ulceration. 6. To summarize current management strategies applicable to India. 7. To propose an integrated diagnostic and treatment approach suitable for different levels of the Indian health-care system.

.1 Study Design A systematic review was undertaken in accordance with the principles of the PRISMA 2020 statement. Because the review addressed temporal trends, etiological studies, diagnostic-accuracy studies, longitudinal clinic datasets and contemporary observational studies, a qualitative synthesis was planned in advance. 3.2 Eligibility Criteria Inclusion Criteria • Conducted in India. • Included patients with genital ulcer disease or provided extractable GUD-specific findings. • Reported etiological, epidemiological, diagnostic, longitudinal, microbiological or management-related outcomes. • Evaluated HSV, T. pallidum, H. ducreyi, LGV, donovanosis or mixed GUD. • Examined clinical or syndromic diagnostic performance. • Reported temporal STI trends containing meaningful ulcerative-disease information. • Investigated HIV status among GUD patients. Eligible designs included cross-sectional studies, retrospective clinic series, prospective observational studies, multicentre diagnostic studies, molecular etiological studies and surveillance analyses. Exclusion Criteria • No extractable Indian data. • Only nonulcerative STI syndromes. • Isolated case reports. • Exclusive focus on HIV without GUD information. • Insufficient methodological detail. • Duplicate populations without additional relevant outcomes. National surveillance reports and WHO/NACO guidelines were used for policy and management context but were not counted as primary studies. 3.3 Information Sources • PubMed/MEDLINE • Indian peer-reviewed dermatology and STI journals • Supplementary scholarly searches • Reference lists of eligible articles • National AIDS Control Organisation reports and case-management materials • WHO STI guidelines The final literature update was undertaken in June 2026. 3.4 Search Strategy The core search combined the following terms: ("genital ulcer" OR "genital ulcer disease" OR "genital herpes" OR syphilis OR chancroid OR donovanosis OR "lymphogranuloma venereum") AND (India OR Indian) AND (etiology OR epidemiology OR diagnosis OR PCR OR "syndromic management" OR trend OR HIV OR treatment) Additional searches included combinations of STI/STD, India, trend, genital ulcer, herpes, syphilis, herpetic/nonherpetic and syndromic terms. Reference-list searching was used to identify older Indian studies not readily captured by contemporary database indexing. 3.5 Study Selection Titles and abstracts were screened for relevance followed by assessment of full reports. Studies were grouped into historical trend studies, molecular etiological studies, diagnostic/syndromic validation studies, recent GUD cohorts, and broader STI longitudinal studies with relevant GUD data. Fifteen primary Indian studies were retained for the qualitative evidence synthesis. 3.6 Data Extraction • Author • Year • Location • Study period • Sample size • Study design • Diagnostic method • HSV frequency • Syphilis frequency • Chancroid frequency • LGV/donovanosis frequency • Mixed infection • HIV prevalence • Diagnostic performance • Temporal trends • Principal clinical implications 3.7 Risk-of-Bias Assessment Observational studies were appraised using domains adapted from JBI critical-appraisal tools. The assessment considered participant selection, clarity of inclusion criteria, adequacy of diagnostic methods, reliability of etiological classification, completeness of laboratory confirmation, treatment or referral bias, completeness of outcome reporting, and appropriateness of statistical analysis. Older studies relying predominantly on clinical morphology were regarded as having greater diagnostic-classification risk than molecular studies. 3.8 Synthesis Methods Formal meta-analysis was not performed because the studies differed markedly in period of recruitment, geographical setting, referral population, sex distribution, STI prevalence, diagnostic technology, definition of GUD, inclusion of nonvenereal ulcers, and microbiological reference standards. Trend evidence was therefore synthesized chronologically. Where possible, contemporary PCR-confirmed findings were contrasted with historical clinical series.

4.1 Overview of Included Evidence The evidence base covered more than four decades of Indian STI practice. Principal settings included Chandigarh, Pune, New Delhi, Mumbai, Karnataka, Kerala, Gujarat, Rajasthan, and multicentre STI clinics across multiple states. The evidence consistently demonstrated three major epidemiological phenomena: decline of chancroid, donovanosis and LGV; progressive predominance of genital herpes; and continued importance and possible recent resurgence of syphilis. 4.2 Characteristics of Key Included Studies Study Setting/period Sample Diagnostic approach Major finding Pune multiplex-PCR study Pune, 1994 302 GUD patients Multiplex PCR for HSV, T. pallidum, H. ducreyi HSV 26%; chancroid 23%; syphilis 10%; mixed 7%; unidentified 34% Kumar et al., 2002 Chandigarh, 1977-2000 Longitudinal STI-clinic records Clinical + routine laboratory methods Herpes increased 11.4%→20.5%; chancroid 12.2%→2.5%; donovanosis 6.3%→0.9% Jaiswal et al., 2002 Northeast India, 1995-1999 STI-clinic cohort Retrospective clinical data Chancroid remained common (25.7%) but declined compared with earlier period; no donovanosis Narayanan, 2005 Kerala, 1990-2000 686 STI patients Clinical/routine laboratory GUD 504/686 (73.5%); bacterial STIs declined more markedly than viral STIs Ray et al., 2006 New Delhi, 1990-2004 78,617 attendees; 12,709 STIs Clinical + standard laboratory Rise in herpes, syphilis and warts; fall in chancroid, LGV and donovanosis Grover & Rajagopal, 2009 Service hospital, 1974-2006 4,532 STI episodes Retrospective Chancroid historically dominant (37.2%); marked long-term decline in STI burden Setia et al., 2010 Mumbai, 1994-2006 3,417 Retrospective Bacterial STIs fell from 53% to 28%; proportional viral increase; HIV 28% Becker et al., 2010 Karnataka 813 Etiological laboratory testing HSV-2 most common GUD pathogen; clinical herpetic/nonherpetic distinction unhelpful Prabhakar et al., 2012 8 clinics/4 states 194 men Multiplex PCR HSV 48%; T. pallidum 23%; mixed 9%; one H. ducreyi case Muralidhar et al., 2013 New Delhi, 2010-2011 90 GUD/1,208 STI attendees Culture, serology, real-time PCR HSV overwhelmingly dominant; no LGV/donovanosis; HIV 8.9% Mehta, 2014 Gujarat, 2005-2006 50 GUD Routine laboratory confirmation Herpes 38%; primary syphilis 32%; chancroid 26%; LGV 2%; HIV 12% Bhavsar et al., 2014 Vadodara, 2011-2012 113 GUD/UDS Syndromic + laboratory validation Herpetic GUD diagnosed in 62.3%; substantial discordance with laboratory findings Nyati et al., 2017 Rajasthan, 2012-2016 4,847 STI patients Syndromic + serology Genital herpes one of the leading STIs; nonherpetic ulcers substantially less common Suresh et al., 2023 North Kerala, 1998-2017 2,470 confirmed STIs Clinical/laboratory trend analysis Herpes 39%; syphilis 17.2%; viral STIs 76.3%; later syphilis increase Patel et al., 2023 Gujarat, 2021-2022 135 GUD Clinical + routine laboratory Herpes 59%; syphilis 15%; chancroid 0.74%; HIV 6.6%; 22% nonvenereal 4.3 Changing Etiological Trends 4.3.1 Historical Dominance of Bacterial GUD Older Indian data demonstrate a very different STI landscape. In a 33-year military series covering 1974-2006, chancroid constituted 37.2% of recorded STIs and syphilis 16.2%. At Chandigarh, the proportion of chancroid was 12.2% during 1977-1985 and donovanosis 6.3%. In Northeast India during 1995-1999, chancroid remained the most frequent diagnosed STI at 25.7%, although its incidence was already declining compared with the preceding decade. These observations establish that chancroid, LGV and donovanosis were once substantial contributors to India’s ulcerative STI burden. 4.3.2 Decline in Chancroid and Donovanosis At Chandigarh, chancroid declined from 12.2% during 1977-1985 to 2.5% during 1993-2000, while donovanosis declined from 6.3% to 0.9%. By 2012, Prabhakar et al. found only one H. ducreyi infection among 194 men with genital ulcers. In the 2021-2022 Gujarat cohort, chancroid was diagnosed in only 1/135 patients (0.74%), while neither LGV nor donovanosis represented a significant contemporary burden. The cumulative evidence supports a major reduction in classical bacterial ulcer diseases. 4.4 Emergence of Herpes as the Dominant GUD At Chandigarh, genital herpes increased from 11.4% during 1977-1985 to 20.5% during 1993-2000, representing an approximately twofold proportional increase. In Pune in 1994, PCR detected HSV in 26% of genital-ulcer patients. By the multicentre molecular study reported in 2012, 48% of confirmed etiologies were HSV. In the 2021-2022 Gujarat cohort, 59% (80/135) of all GUD presentations were herpes genitalis. North Kerala data similarly found genital herpes to be the leading STI diagnosis, accounting for 964/2,470 (39%) during 1998-2017. These percentages should not be pooled directly because study populations and diagnostic methods differed; nevertheless, their direction is consistent. 4.5 Syphilis: Persistent and Potentially Re-Emerging In Pune, PCR detected T. pallidum in 10% of GUD patients in 1994. The multicentre Indian molecular study found T. pallidum in 23% of etiologically confirmed cases. Mehta reported primary syphilis in 32% of 50 ulcerative STI cases. In Gujarat in 2021-2022, syphilis accounted for 20/135 (15%) of GUD cases. North Kerala data identified 418 syphilis cases (17.2%) among 2,470 confirmed STIs. Particularly important was the renewed increase in syphilis after 2012 and increasing early syphilis after 2014. Thus, the contemporary Indian GUD landscape should not be interpreted as exclusively herpetic. 4.6 Mixed Infections Mixed infections are an important reason clinical pattern recognition fails. In Pune, 7% of ulcers contained more than one pathogen. In the multicentre molecular study, 9% had mixed etiologies. A clinician attempting to categorize every lesion as either “herpetic” or “nonherpetic” therefore risks ignoring biologically important coinfection. 4.7 HIV and Genital Ulcer Disease In the Pune molecular study, HIV seroprevalence was 22.2%. HSV-positive patients had higher HIV prevalence compared with other etiologies (OR 2.1; 95% CI 1.2-3.7; p=0.01). Muralidhar et al. reported 8/90 (8.9%) HIV positivity, Mehta reported 6/50 (12%), and Patel et al. reported approximately 9/135 (6.6%). Consequently, GUD should continue to trigger routine HIV testing and prevention counselling. 4.8 Diagnostic Challenges 4.8.1 Clinical Morphology Is Unreliable Pune data demonstrated poor agreement between clinical diagnosis and multiplex PCR. Clinicians diagnosed chancroid in 40%, HSV in 24% and syphilis in 20%, whereas PCR identified HSV in 26%, chancroid in 23% and syphilis in 10%. The Karnataka study similarly concluded that clinical distinction between herpetic and nonherpetic ulceration was not helpful. 4.8.2 Performance of India’s Syndromic Algorithm Prabhakar et al. provided one of the most important evaluations. Among 194 men, etiological diagnosis was established in 121. The national algorithm had sensitivity of 68% and specificity of 52%, and 52/121 (42%) laboratory-confirmed cases were misclassified as herpetic or nonherpetic. This misclassification potentially produced incorrect treatment in a substantial proportion of patients. A global systematic review later confirmed that clinical/syndromic algorithms have limited sensitivity, with pooled clinical diagnostic sensitivity of 43.5% for herpes and 52.8% for syphilis. 4.9 Limitations of Conventional Laboratory Tests Dark-Field Microscopy Dark-field examination can directly demonstrate T. pallidum but requires appropriate fresh lesions, immediate microscopy, experienced personnel and correct specimen collection. In the Pune study, dark-field detection of T. pallidum demonstrated only 39% sensitivity and 82% specificity relative to molecular diagnosis. Syphilis Serology RPR/VDRL combined with treponemal testing remains central to routine diagnosis, although early primary syphilis can be seronegative. In Pune, combined RPR and FTA-ABS testing had approximately 66% sensitivity and 90% specificity compared with PCR-defined infection. Tzanck Smear Tzanck cytology can demonstrate multinucleated giant cells but does not identify HSV type and lacks the sensitivity of nucleic-acid amplification. In the recent Gujarat cohort, only 56/80 (70%) clinically suspected herpes cases showed multinucleated giant cells/acantholytic cells on smear. Culture for Haemophilus ducreyi Culture is technically demanding and insensitive, particularly after prior antibiotic exposure. In the Delhi study, H. ducreyi culture performed in 75 cases yielded no positive cultures, despite occasional Gram-stain/PCR evidence. 4.10 Role of Molecular Diagnosis Molecular testing addresses several limitations simultaneously. Multiplex or species-specific PCR can identify HSV-1, HSV-2, T. pallidum, H. ducreyi and mixed infections. The Pune and multicentre Indian studies clearly demonstrated that molecular methods alter etiological classification compared with clinical assessment. WHO recommends etiological treatment based on quality-assured molecular assays of ulcer material where such testing and timely results are available. Where laboratory capacity is insufficient, syndromic treatment remains recommended to ensure same-day therapy. 4.11 Nonvenereal Genital Ulcer Disease An important contemporary diagnostic lesson is that not every genital ulcer is an STI. In the 2021-2022 Gujarat study, 30/135 (22%) of GUD cases were nonvenereal. Etiology n (%) Drug-induced genital ulcers 12 (8.8%) Traumatic ulcers 8 (5.9%) Pemphigus vulgaris 6 (4.4%) Squamous-cell carcinoma 2 (1.5%) Behçet disease 1 (0.7%) Zoon balanitis 1 (0.7%) Failure to recognize these mimics can expose patients to unnecessary antimicrobial treatment and delay diagnosis of inflammatory disease or malignancy. 5. Comparative Evolution of GUD in India Period/study HSV/herpes Syphilis Chancroid Donovanosis/LGV Chandigarh 1977-1985 11.4% - 12.2% Donovanosis 6.3% Chandigarh 1993-2000 20.5% - 2.5% Donovanosis 0.9% Pune 1994, PCR 26% 10% 23% - Gujarat 2005-2006 38% 32% 26% LGV 2% Multicentre India, PCR 48% 23% ~0.5% Rare Gujarat 2021-2022 59% 15% 0.74% Not prominent The studies are not directly comparable statistically because diagnostic methods and populations differ, but the longitudinal direction is striking: HSV rises while chancroid and donovanosis progressively disappear from routine clinical practice. 6. National Surveillance Context NACO surveillance continues to document a meaningful GUD burden. The 2023 national response report noted more than 3.31 lakh STI/RTI syndrome episodes among males accessing designated STI/RTI clinics. Urethral discharge represented 47%, nonherpetic GUD 27%, and herpetic GUD 13% of reported male syndromes. These are syndrome-level programme data rather than laboratory-confirmed etiologies and should therefore not be equated directly with microbiological disease prevalence. 7. Management Strategies 7.1 Immediate Clinical Assessment • Detailed sexual history • Onset and recurrence history • Medication history • Assessment of pain, vesicles, discharge and lymphadenopathy • Genital, anal and oral examination where relevant • Evaluation for systemic manifestations • HIV testing • Syphilis testing • Assessment of pregnancy where clinically relevant WHO similarly emphasizes medical/sexual history, genital and anal examination, HIV/syphilis testing and appropriate prevention services. 7.2 NACO Syndromic Management Genital Ulcer Disease-Nonherpetic Treatment includes coverage for syphilis and chancroid. NACO materials list benzathine penicillin G 2.4 million units intramuscularly as a single dose plus azithromycin 1 g orally as a single dose. Where penicillin cannot be administered, doxycycline-based alternatives are used for appropriate nonpregnant patients together with chancroid coverage. Genital Ulcer Disease-Herpetic NACO case-management materials list acyclovir 400 mg orally three times daily for 7 days for herpetic ulcer syndrome. The exact regimen should always be reconciled with the most recent national guideline and individual patient characteristics. 7.3 Why Contemporary Management Should Move Beyond Binary Classification The traditional binary division into herpetic and nonherpetic ulcers is operationally simple but biologically imperfect. Three findings support a broader strategy: 9% mixed infection in the molecular multicentre study; 23% syphilis detection despite frequent atypical morphology; and 42% syndromic misclassification. Where molecular diagnosis is unavailable, consideration should therefore be given to epidemiological coverage for the locally prevalent causes rather than assuming that morphology establishes a single pathogen. 7.4 Partner Management Management is incomplete without evaluation and treatment of recent sexual partners. NACO materials emphasize partner treatment, abstinence or consistent condom use during treatment, provision of condoms, safer-sex counselling, HIV testing/referral and follow-up. For syphilis, partner evaluation is especially important because asymptomatic infection is common. 7.5 HIV Testing and Prevention All patients with STI-associated GUD should be offered HIV testing according to national protocols. Patients should additionally receive condom counselling, risk-reduction education, linkage to HIV prevention and treatment services, hepatitis B vaccination where appropriate, and assessment for other STIs. 8. Proposed Tiered Diagnostic Strategy for India Tier 1: Peripheral/Primary-Care Facility Clinical examination + syndromic treatment + HIV testing + syphilis serology. Goals: same-day treatment, reduction of transmission and prevention of loss to follow-up. Tier 2: District/Tertiary Laboratory • RPR/VDRL plus treponemal confirmation • HSV lesion NAAT where available • Direct T. pallidum testing when available • Targeted microbiological testing • Evaluation for non-STI causes Tier 3: Reference/Molecular Laboratory For atypical ulcers, recurrent PCR-negative lesions, treatment failure, mixed infection, suspected outbreaks and epidemiological surveillance, use multiplex PCR, species-specific NAAT, sequencing or specialized molecular testing where indicated. 9. Diagnostic Methods for GUD Method Principal use Advantages Limitations Clinical morphology Immediate bedside assessment No equipment; rapid Poor species accuracy; atypical lesions common Tzanck smear Supportive herpes diagnosis Cheap, rapid Limited sensitivity; no HSV typing Dark-field microscopy Primary syphilis Direct visualization Expertise and fresh specimen required RPR/VDRL Syphilis screening/activity Widely available, inexpensive Early false-negatives; not pathogen-specific Treponemal test Syphilis confirmation High specificity Remains positive after previous infection H. ducreyi culture Chancroid Etiological evidence Technically difficult and insensitive HSV NAAT/PCR Herpetic ulcer High sensitivity/species identification Cost/infrastructure T. pallidum PCR Primary syphilis Detects organisms directly Limited routine availability Multiplex PCR Mixed/uncertain GUD Simultaneous pathogen detection Expense and laboratory requirements Biopsy/histopathology Persistent/atypical ulcer Detects malignancy/inflammatory disease Invasive; not first-line for routine STI

The principal finding of this systematic review is that genital ulcer disease in India has undergone a profound etiological transition. Historical Indian clinics functioned in an epidemiological environment in which chancroid, syphilis, LGV and donovanosis were frequent. Contemporary clinics function in an environment where HSV dominates, chancroid has become exceptional, donovanosis and LGV are infrequently encountered, and syphilis remains an important competing diagnosis. This shift has several possible explanations. Broad-spectrum antibiotics taken for unrelated conditions can inadvertently suppress susceptible bacterial STIs. Expansion of STI services, syndromic treatment programmes and HIV-related behaviour-change interventions may also have contributed to reductions in bacterial diseases, which can be cured after short antimicrobial courses. HSV behaves differently. Treatment reduces symptoms and viral replication but does not eradicate latent infection. Recurrences therefore continue to produce clinic presentations even when safer-sex programmes reduce new exposure. The relative rise in HSV is consequently not necessarily evidence that HSV incidence alone has increased at the same rate as its proportion among all STIs; falling bacterial disease can itself increase the proportional contribution of viral infection. The Indian molecular studies are especially important because they challenge assumptions derived from morphology. The 2012 multicentre study showed that nearly half of etiologically established ulcers were herpetic, yet clinical classification produced substantial false categorization. These findings mirror the broader global diagnostic-accuracy literature. Syphilis poses a different challenge. Unlike HSV, syphilis is curable and has major implications for systemic, neurological, cardiovascular and congenital disease. Missing primary syphilis therefore has greater consequences than simply mislabelling one ulcer phenotype. The increase in early syphilis observed in later years of the Kerala trend study is particularly relevant. Recent national and global surveillance should therefore continue to monitor whether syphilis is re-emerging in particular Indian populations. 11. Syndromic Management: Strengths and Limitations The syndromic approach remains essential in settings where molecular diagnosis is unavailable, patients may not return, laboratory turnaround is prolonged, or treatment delay could increase transmission. Its major strength is immediate action. However, the binary GUD algorithm sacrifices etiological accuracy. The Indian multicentre sensitivity of 68% and specificity of 52% illustrate the extent of this compromise. The future should not be framed as syndromic management versus laboratory diagnosis, but rather as syndromic same-day care plus progressively expanded etiological testing. WHO’s current recommendation reflects this balance: use quality-assured molecular assays where available, but retain syndromic treatment where laboratory capacity is limited. 12. Noninfectious Disease as a Growing Diagnostic Consideration As classical bacterial STIs decline, the proportion of genital ulcers caused by noninfectious conditions becomes increasingly important. The Gujarat finding that 22% of genital ulcers were nonvenereal is clinically significant. Clinicians should reconsider the diagnosis when STI tests remain repeatedly negative, the lesion is unusually persistent, treatment fails, genital disease is accompanied by oral or ocular disease, there is a recurrent medication association, lesions demonstrate unusual induration or growth, or systemic inflammatory signs are present. Biopsy should be considered for persistent unexplained ulcers, particularly where malignancy or inflammatory dermatosis is suspected. 13. Public-Health Implications 13.1 Molecular Sentinel Surveillance Periodic molecular surveillance from geographically diverse centres would permit monitoring of HSV-1 versus HSV-2, syphilis, residual chancroid, mixed infections, novel or emerging causes, and regional differences. 13.2 Strengthening Syphilis Diagnosis Because syphilis remains clinically significant, every GUD patient should have access to quality-assured syphilis testing. 13.3 Integrating HIV Services GUD clinics should remain a gateway to HIV testing, ART linkage, prevention counselling, condom provision, and targeted services for high-risk populations. 13.4 Addressing MSM and Changing Sexual Networks Recent Indian STI-clinic studies document increasing representation of men who have sex with men and changing sexual networks. Anorectal ulcers should therefore be explicitly included in history-taking and clinical examination where relevant. 14. Strengths 1. Integration of more than four decades of Indian evidence. 2. Distinction between clinic trend data and molecular etiological studies. 3. Inclusion of historical and contemporary GUD patterns. 4. Evaluation of diagnostic performance rather than assuming clinical diagnosis is correct. 5. Incorporation of recent national and WHO recommendations. 6. Inclusion of nonvenereal genital ulcer disease as an important contemporary differential. 7. Placement of changing etiologies in the context of HIV and STI-control programmes. 15. Limitations Most Indian studies were institution based rather than population based. Diagnostic methods changed substantially over time. Earlier studies relied mainly on clinical diagnosis, microscopy and serology, whereas more recent studies used multiplex or real-time PCR. Consequently, apparent temporal changes partly reflect improvements in diagnostic technology. Study populations were also heterogeneous with respect to sex, referral status, urban/rural location, HIV prevalence, high-risk behaviour, antimicrobial exposure and STI-clinic attendance. Several longitudinal studies reported all STIs rather than genital-ulcer patients alone. The available studies therefore cannot provide a single nationally representative prevalence estimate for each GUD pathogen. A statistical meta-analysis was deliberately avoided because pooling these heterogeneous studies would create a misleading estimate. 16. Recommendations for Future Research 1. Use prospective multicentre recruitment. 2. Employ multiplex NAAT on ulcer swabs. 3. Distinguish HSV-1 from HSV-2. 4. Include direct T. pallidum detection where feasible. 5. Report lesion stage and previous antibiotic use. 6. Include women, MSM and transgender populations adequately. 7. Document anorectal disease. 8. Record HIV status and other STI coinfection. 9. Report mixed infections explicitly. 10. Include noninfectious differentials. 11. Evaluate diagnostic cost-effectiveness. 12. Compare molecular diagnosis with current NACO syndromic algorithms. Repeated sentinel surveys at intervals of 3-5 years would be more informative than relying on decades-old etiological assumptions. 17. Proposed Integrated Management Framework Patient with genital/anogenital ulcer → clinical and sexual-history assessment → same-day HIV testing and syphilis serology → molecular ulcer testing where available (HSV-1/2 NAAT ± T. pallidum PCR ± multiplex GUD panel) with pathogen-directed treatment; where molecular testing is unavailable, NACO syndromic treatment with clinical follow-up. Persistent, atypical or test-negative lesions should prompt dermatology/venereology referral, biopsy or specialized investigation and consideration of fixed drug eruption, Behçet disease, autoimmune disease, trauma and malignancy. All patients require partner management, condom counselling, HIV prevention, follow-up and STI screening.

Genital ulcer disease in India has evolved from a predominantly bacterial STI syndrome into one in which genital herpes is the leading infectious etiology. Historical data demonstrate substantial burdens of chancroid, donovanosis and LGV, whereas recent molecular and clinical studies document their dramatic decline. In contrast, HSV has risen progressively and now accounts for approximately half or more of GUD in several contemporary Indian series. Syphilis remains important and should not be considered a disappearing infection; some longitudinal Indian evidence suggests renewed increases in recent years. The modern diagnostic challenge is therefore no longer simply differentiating classical chancroid from syphilis. Clinicians must distinguish HSV, syphilis, mixed infection, atypical infectious ulcers and nonvenereal disease. Clinical morphology alone performs inadequately. The Indian national syndromic algorithm remains valuable for same-day treatment where laboratory resources are absent, but molecular studies demonstrate substantial misclassification. Where feasible, quality-assured HSV and T. pallidum NAAT should increasingly supplement syndromic care. The most appropriate future strategy for India is an integrated model combining rapid syndromic treatment, routine HIV/syphilis testing, targeted molecular diagnosis, partner treatment, behavioural prevention and periodic molecular surveillance.

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