Hepatitis c presentation, for medical students

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1. Hepatitis C

2. HCV Hepatitis C is an infection caused by the HCV that attacks the liver and leads to inflammation. The WHO estimates that about 3% of the world’s population has been infected with HCV and that there are more than 170 million chronic carriers who are at risk of developing liver cirrhosis and/or liver cancer . The prevalence of HCV infection varies throughout the world. For example, Frank et al reported in 2000 that Egypt had the highest number of reported infections, largely attributed to the use of contaminated parenteral antischistosomal therapy. ] This led to a mean prevalence of anti-HCV in persons in Egypt of 22%.

3. Most patients infected with HCV have chronic liver disease, which can progress to cirrhosis and HCC. Chronic infection with HCV is one of the most important causes of chronic liver disease (see the image below) and, according to a report by Davis et al, the most common indication for orthotopic liver transplantation in the USA. Most patients with acute and chronic infection are asymptomatic. chronic HCV infection and chronic active hepatitis are slowly progressive diseases and result in severe morbidity in 20-30% of infected persons. Although acute hepatitis C virus (HCV) infection is usually mild, chronic hepatitis results in at least 75% of patients. Liver enzyme levels may be in the reference range, the presence of persistent HCV-RNA levels discloses chronic infection. Biopsy samples of the liver may reveal chronic liver disease in patients. Cirrhosis develops in 20-50% of patients with chronic HCV infection. HCC occurs in 11-19% of patients.

4. Etiology HCV, is a spherical, enveloped, single-stranded RNA virus belonging to the Flaviviridae family and Flavivirus genus. The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Viral clearance is associated with the development and persistence of strong virus-specific responses by cytotoxic T lymphocytes and helper T cells. In most infected people, viremia persists and is accompanied by variable degrees of hepatic inflammation and fibrosis. Findings from studies suggest that at least 50% of hepatocytes may be infected with HCV in patients with chronic HCV. RNA-dependent RNA polymerase, an enzyme critical in HCV replication, lacks proofreading capabilities and generates a large number of mutant viruses known as quasispecies . These represent minor molecular variations with only 1-2% nucleotide heterogeneity. HCV quasispecies pose a major challenge to immune-mediated control of HCV and may explain the variable clinical course and the difficulties in vaccine development.

5. Structural components include the core and 2 envelope proteins, E1 and E2. Two regions of the E2 protein, designated hypervariable regions 1 and 2, have an extremely high rate of mutation, thought to result from selective pressure by virus-specific antibodies. The envelope protein E2 also contains the binding site for CD-81, a tetraspanin receptor expressed on hepatocytes and B lymphocytes that acts as a receptor or coreceptor for HCV. The nonstructural components include NS2, NS3, NS4A, NS4B, NS5A, NS5B, and p7, whose proteins function as helicase -, protease-, and RNA-dependent RNA polymerase, although the exact function of p7 is unknown. One region within NS5A is linked to an interferon (IFN) response and is called the IFN sensitivity–determining region. These enzymes are critical in viral replication and are attractive targets for future antiviral therapy.

6. Genotypes HCV genomic analysis by means of arduous gene sequencing of many viruses has led to the division of HCV into 6 genotypes based on homology. Molecular differences between genotypes are relatively large, and they have a difference of at least 30% at the nucleotide level. The major HCV genotype worldwide is genotype 1, which accounts for 40-80% of all isolates. Genotype 1 also may be associated with more severe liver disease and a higher risk of HCC. Genotypes 1a and 1b are prevalent in the United States, whereas in other countries, genotype 1a is less frequent.

7. Genotypes Genotype 1a occurs in 50-60% of patients in the USA Genotype 1b occurs in 15-20% of patients in the USA; this type is most prevalent in Europe, Turkey, and Japan Genotype 1c occurs in less than 1% of patients in the USA Genotypes 2a, 2b, and 2c occur in 10-15% of patients in the USA; these subtypes are widely distributed and are most responsive to medication Genotypes 3a and 3b occur in 4-6% of patients in the USA; these subtypes are most prevalent in India, Pakistan, Thailand, Australia, and Scotland Genotype 4 occurs in less than 5% of patients in the USA; it is most prevalent in the Middle East and Africa Genotype 5 occurs in less than 5% of patients in the USA; it is most prevalent in South Africa Genotype 6 occurs in less than 5% of patients in the USA; it is most prevalent in Southeast Asia, particularly Hong Kong and Macao

8. Epidemiology Transfusion of blood contaminated with HCV was once an important source of transmission. With the use of PCR, Stramer et al reported that the risk of acquiring HCV from blood transfusions is estimated to be 1 in 230,000 donations. The newer assays have decreased the window after infection to 1-2 weeks. Persons who inject illegal drugs with nonsterile needles or who snort cocaine with shared straws are at highest risk for HCV infection. In developed countries, most new HCV infections are related to intravenous drug abuse (IVDA).

9. Epidemiology Transmission of HCV to health care workers may occur via needle-stick injuries or other occupational exposures. Needle-stick injuries in the health care setting result in a 3% risk of HCV transmission. Nosocomial patient-to-patient transmission may occur by means of a contaminated colonoscope , via dialysis, or during surgery, including organ transplantation before 1992. HCV may also be transmitted via tattooing, sharing razors, and acupuncture. The uncommon routes of transmission, which affect less than 5% of the individuals at risk, include high-risk sexual activity and maternal-fetal transmission. Coinfection with HIV type 1 appears to increase the risk of both sexual and maternal-fetal transmission of HCV. Casual household contact and contact with the saliva of those infected are inefficient modes of transmission. No risk factors are identified in approximately 10%

10. Epidemiology Worldwide, more than 170 million persons have HCV infection. The prevalence rates in healthy blood donors are 0.01-0.02% in the United Kingdom and northern Europe, 1-1.5% in southern Europe, and 6.5% in parts of equatorial Africa. Prevalence rates as high as 22% are reported in Egypt and are attributed to the use of parenteral antischistosomal therapy. In the USA, HCV infection is more common among minority populations, such as black and Hispanic persons, than other populations, in association with lower economic status and educational levels. In the third National Health and Nutrition Examination Survey, neither sex nor racial-ethnic group was independently associated with HCV infection. Those who acquire the infection at a younger age have a somewhat better prognosis than those who are infected later in life. Infection is uncommon in persons aged 20 years and younger and is more prevalent in persons older than 40 years

11. Prognosis Infection with HCV is self-limited in only a small minority of infected persons. Chronic infection develops in 70-80% of patients Cirrhosis develops within 20 years of disease onset in 20% of persons with chronic infection. The onset of chronic HCV infection early in life often leads to less serious consequences. [ HBV coinfection , iron overload, and alpha 1-antitrypsin deficiency may promote the progression of chronic HCV infection to HCV-related cirrhosis. The risk of cirrhosis and HCC doubles in patients who acquired HCV infection via transfusion. The rate and likelihood of progression is influenced by alcohol use, immunosuppression , sex, iron status, concomitant hepatitis, and age of acquisition

12. Patient who achieved an undetectable HCV viral load had a decreased risk of subsequent liver morbidity and death. Viral load suppression reduced the risk for future liver events by 27%, as well as reduced the risk of death by 45%, relative to patients who did not achieve viral load suppression. The risk for all liver events and death was higher in white patients relative to black patients, and those with HCV genotype 3 had a higher risk for all study outcomes compared with patients who had HCV genotype 2 (lowest risk) or 1

13. Chronic HCV Increases Mortality From Hepatic and Non-hepatic Diseases 23,820 adults in Taiwan prospectively followed since 1991-1992 - 2008 1095 were anti-HCV positive ; 69.4% had detectable HCV RNA Hepatic Diseases Extrahepatic Diseases Cumulative mortality (%) p <,001 for comparison among three groups p <,001 for HCV RNA detectable vs undetectable p <,001 for comparison among three groups p =,002 for HCV RNA detectable vs undetectable Lee MH, et al. J Infect Dis. 2012;206:469-477 Cumulative mortality (%)

14. SVR (Cure) Associated With Decreased All-cause Mortality 530 patients (1990-2003) with advanced fibrosis, treated with IFN-based therapy, and followed for 8.4 (IQR 6.4-11.4) years 10-year Сumulative I ncidence R ate IQR, interquartile range Van der Meer AJ, et al. JAMA. 2012;308(24):2584-2593

15. Symptoms Most patients with chronic HCV infection are asymptomatic or may have nonspecific symptoms such as fatigue or malaise in the absence of hepatic synthetic dysfunction. Patients with decompensated cirrhosis frequently have symptoms typically observed in other patients with decompensated liver disease, such as sleep inversion and pruritus . Symptoms characteristic of complications from advanced or decompensated liver disease are related to synthetic dysfunction and portal hypertension. These include mental status changes (hepatic encephalopathy), ankle edema and abdominal distention ( ascites ), and hematemesis or melena ( variceal bleeding). Symptoms often first develop as clinical findings of extrahepatic manifestations of HCV and most commonly involve the joints, muscle, and skin. 74% of medical workers with HCV infection demonstrated extrahepatic manifestations

16. Symptoms Arthralgias (23%) Paresthesias (17%) Myalgias (15%) Pruritus (15%) Sicca syndrome (11%) Sensory neuropathy (9%) Risk factors for manifestations of extrahepatic chronic HCV infection include advanced age, female sex, and liver fibrosis. Patients also present with symptoms that are less specific. ( pruritus and urticaria ). Patients with an organ failure can present with symptoms and signs in the skin. Pruritus , dryness, palmar erythema, and yellowing of the eyes and skin are examples of less specific findings in patients with end-stage liver disease with cirrhosis

17. Symptoms Most patients with HCV infection do not have abnormal physical examination findings until they develop portal hypertension or decompensated liver disease. One exception is patients with extrahepatic manifestations of HCV infection, such as porphyria cutanea tarda or necrotizing vasculitis . Signs in patients with decompensated liver disease: Hand signs - Palmar erythema, Dupuytren contracture, asterixis , leukonychia , clubbing Head signs - Icteric sclera, temporal muscle wasting, enlarged parotid, cyanosis Fetor hepaticus Gynecomastia , small testes Abdominal signs - Paraumbilical hernia - ascites , caput medusae , hepatosplenomegaly , abdominal bruit Ankle edema Scant body hair Skin signs - Spider nevi, petechiae, excoriations due to pruritus

18. Extrahepatic manifestations Cryoglobulinemia : Membranoproliferative glomerulonephritis Idiopathic thrombocytopenic purpura Lichen planus Keratoconjunctivitis sicca Raynaud syndrome Sjogren syndrome Porphyria cutanea tarda Necrotizing cutaneous vasculitis Non-Hodgkin lymphoma Approximately 10-15% of affected patients have symptoms such as weakness, arthralgias , and purpura; these are often related to vasculitis . The precise pathogenesis of these extrahepatic complications has not been determined, although most are the clinical expression of autoimmune phenomena.

19. Laboratory diagnostic Serologic screening for HCV involves an enzyme immunoassay (Anti-HCV, EIA). These assays are 97% specific but cannot distinguish acute from chronic infection. s The recombinant immunoblot assay is used to confirm HCV infection. Health care personnel who sustain a needle-stick injury involving an HCV-infected patient should undergo PCR testing for HCV immediately and then every 2 months for 6 months. Genotyping is helpful for predicting the likelihood of response and duration of treatment. Genotyping can be performed by direct sequence analysis, reverse hybridization to genotype-specific oligonucleotide probes, or restriction fragment length polymorphisms (RFLPs).

20. Laboratory diagnostic CBC with differential (10% thrombocytopenia) Liver function tests, including ALT level Thyroid function studies ( Low thyroxine levels - in approximately 10% ) , HCV Genotyping is helpful for predicting the likelihood of response and duration of treatment. Genotyping can be performed by direct sequence analysis, reverse hybridization to genotype-specific oligonucleotide probes, or restriction fragment length polymorphisms (RFLPs). Quantitative HCV RNA assay Screening tests for co-infection with HIV or HBV) Screening for alcohol abuse, drug abuse, and/or depression The single-nucleotide polymorphism (SNP) rs12979860, located near the IL28B gene on chromosome 19, which encodes type III interferon, is associated with more than a 2-fold difference in the rate of sustained virologic response to antiviral treatment with peg-IFN and ribavirin . This SNP can be detected by PCR and is an independent predictor of SVR response regardless of HCV genotype

21. Laboratory diagnostic Cryoglobulins are found in as many as 50% of persons with HCV infection. Vasculitis , arterial hypertension, purpura, lichen planus , arthralgias , and low thyroxine levels were associated with titers positive for cryoglobulin . Serologic findings in patients with chronic HCV infection : Antinuclear antibody (ANA; 41%) Rheumatoid factor (38%) Anticardiolipin antibody (27%) Antithyroid antibody (13%) Anti–smooth muscle antibody (9%)

22. Liver biopsy Liver biopsy is not considered mandatory before the initiation of treatment, but it may be helpful for assessing the activity and severity of HCV-related liver disease. However, some experts recommend biopsy only in the following situations: The diagnosis is uncertain Other co-infections or disease may be present The patient being considered for treatment has normal liver enzyme levels and no extrahepatic manifestations The patient is immunocompromised

23. Liver biopsy Lymphocytic infiltration, moderate degrees of inflammation and necrosis, and portal or bridging fibrosis are noted. Regenerative nodules are seen in patients with cirrhosis. Some patients also may have findings indicative of HCC. Most pathologists give separate measurements of disease activity (grade) and fibrosis (stage). Many scoring systems are used, including the Ishak (6-point scale) and the Knodell histologic activity index (18-point score); both are useful for assessing improvements in histologic findings in studies but are impractical for clinical use because of interobserver disagreement. The METAVIR score is frequently used in European trials. This score consists of a 3-point activity scale and 4-point fibrosis score, with good agreement among pathologists. Noninvasive methods of assessing hepatic fibrosis are in development. Current serum assays are directed at measuring breakdown products of extracellular matrix constituents ( eg , glycoproteins , propeptides ) and their regulatory enzymes ( eg , lysyl oxidase , lysyl hydroxylase , propyl hydroxylase ).

24. Radiologic Studies A liver stiffness test ( FibroScan ) is available as a noninvasive method of staging liver disease in persons with chronic HCV. The FDA (2014) gave marketing approval for the Hepatiq radiologic image processing system. The software application uses quantitative analysis of nuclear medicine liver-spleen images to determine the severity of liver disease and to predict clinical outcomes.

25. Treatment The goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response. Rating: Class I, Level A Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert. Rating: Class I, Level A Evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers is recommended for all persons with HCV infection, to facilitate an appropriate decision regarding HCV treatment strategy and to determine the need for initiating additional measures for the management of cirrhosis Rating: Class I, Level A

26. Эффективность противовирусной терапии HCV- инфекции (генотип 1) за последнее десятилетие ПегИФН - альфа + РБВ БОЦ или ТЕЛ + ПегИФН - альфа / РБВ СИМ или СОФ + ПегИФН - альфа / РБВ Комби-ции препаратов с прямым противовирусным действием УВО 42- 46 % УВО 66–79% УВО 80–90% УВО 90–100% 2005–2015

27. DAA 5 ’ NTR Structure proteins Non- structureproteins 3’NTR NS1 NS2 NS5A NS5B C E1 NS3 NS4A NS4B E2 Inhibitor proteaseNS3 paritaprevir Telaprevir ----- Boceprevir_------- Grazoprevir S imeprevir Faldaprevir Asunaprevir Sovaprevir ACH-2684 Inhibitor NS5 А Ombitasvir Daclatasvir Ledipasvir Elbasvir Velpatasvir ACH-3102 PPI-668 GSK-2336805 Samatasvir Inhibitor NS5 В polymerase Nucleotide Sofosbuvir VX-135 IDX-20963 ACH-3422 Non-nucleotide Dasabuvir Deleobuvir BMS-791325 PPI-383 GS-9669 TMC-647055

28. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C

29. elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks ( with out NS5A RAVs § for elbasvir ) Rating: Class I, Level A   ledipasvir (90 mg)/ sofosbuvi r (400 mg) -- 12 weeks Rating: Class I, Level A   paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) + 2 р / д dasabuvir (250 mg) + ribavirin ( weight ) - 12 weeks. Rating: Class I, Level A   simeprevir (150 mg) + sofosbuvir (400 mg) - 12 weeks. Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   daclatasvir (60 mg*) + sofosbuvir (400 mg) for 12 weeks Rating: Class I, Level B Genotype 1a Treatment-Naïve Patients Without Cirrhosis

30. elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks ( with out NS5A RAVs § for elbasvir ) Rating: Class I, Level A   ledipasvir (90 mg)/ sofosbuvir (400 mg) -- 12 weeks Rating: Class I, Level A sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A Genotype 1a Treatment-Naïve Patients with Compensated Cirrhosis elbasvir (50 mg)/ grazoprevir (100 mg) with/without ribavirin - 16 weeks withNS5A RAVs § for elbasvir . Rating: Class IIa , Level B Alternative

31. paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) + 2р/ д dasabuvir (250 mg) + ribavirin ( weight ) - 24 weeks Rating: Class I, Level A   simeprevir (150 mg) + sofosbuvir (400 mg) with/without ribavirin ( weight ) - for 24 weeks (с Q80K полиморфизмом) . Rating: Class II, Level B   daclatasvir (60 mg*) + sofosbuvir (400 mg) with/without ribavirin ( weight ) - 24 weeks Rating: Class IIa , Level B   elbasvir (50 mg)/ grazoprevir (100 mg) with/without ribavirin - 16 weeks с исходным NS5A RAVs § for elbasvir . Rating: Class IIa , Level B Genotype 1a Treatment-Naïve Patients with Compensated Cirrhosis - Alternative

32. elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks Rating: Class I, Level A   ledipasvir (90 mg)/ sofosbuvir (400 mg) - 12 weeks Rating: Class I, Level A   paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) + 2р/ д dasabuvir (250 mg) - 12 weeks Rating: Class I, Level A   simeprevir (150 mg) + sofosbuvir (400 mg) - 12 weeks Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   daclatasvir (60 mg*) + sofosbuvir (400 mg) - 12 weeks Rating: Class I, Level B Genotype 1b Treatment-Naïve Patients Without Cirrhosis

33. elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks Rating: Class I, Level A   ledipasvir (90 mg)/ sofosbuvir (400 mg) - 12 weeks Rating: Class I, Level A   paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) +2р/дм dasabuvir (250 mg) - 12 weeks Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A Genotype 1b Treatment-Naïve Patients with Compensated Cirrhosis daclatasvir (60 mg*) + sofosbuvir (400 mg) with/without ribavirin ( weight ) - 24 недели Rating: Class IIa , Level B   simeprevir (150 mg) + sofosbuvir (400 mg) with/without ribavirin - 24 недели Alternative

34. sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A daclatasvir (60 mg*) + sofosbuvir (400 mg) - 12 weeks. Rating: Class IIa , Level B HCV-2 without cirrohosis HCV- 2 with cirrhosis sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks weeks Rating: Class I, Level A Alternative daclatasvir (60 mg*) + sofosbuvir (400 mg) - 16-24 недели Rating: Class IIa , Level B Alternative

35. daclatasvir (60 mg*) + sofosbuvir (400 mg) - 12 weeks Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   daclatasvir (60 mg*) + sofosbuvir (400 mg) - 24 недели + ribavirin Rating: Class IIa , Level B HCV -3 naïve without cirrohosis HCV - 3 naïve with cirrhosis

36. paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) + ribavirin ( weight ) - 12 weeks Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks Rating: Class IIa , Level B   ledipasvir (90 mg)/ sofosbuvir (400 mg) - 12 weeks. Rating: Class IIa , Level B HCV - 4 naïve without cirrohosis

37. paritaprevir (150 mg)/ ritonavir (100 mg)/ ombitasvir (25 mg) + ribavirin - 12 weeks Rating: Class I, Level A   sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   elbasvir (50 mg)/ grazoprevir (100 mg) - 12 weeks Rating: Class IIa , Level B   ledipasvir (90 mg)/ sofosbuvir (400 mg) - 12 weeks Rating: Class IIa , Level B HCV 4 - with cirrhosis

38. sofosbuvir (400 mg)/ velpatasvir (100 mg) - 12 weeks Rating: Class I, Level A   ledipasvir (90 mg)/ sofosbuvir (400 mg) - 12 weeks Rating: Class IIa , Level B HCV -5,6 Naïve with/without cirrohosis

39. If the practitioner and patient have decided that a delay in treatment initiation is acceptable, monitoring for spontaneous clearance is recommended for a minimum of 6 months. When the decision is made to initiate treatment after 6 months, treating as described for chronic hepatitis C is recommended Rating: Class IIa , Level C   If a decision has been made to initiate treatment during the acute infection period, monitoring HCV RNA for at least 12 weeks to 16 weeks before starting treatment is recommended to allow for spontaneous clearance. Rating: Class IIa , Level C   Recommended Regimens for Patients with Acute HCV Infection. Owing to high efficacy and safety, the same regimens that are recommended for chronic HCV infection are recommended for acute infection. Rating: Class IIa , Level C Acute HCV infection

40. Medicines Harvoni ( Gilead Sciences) $94,500 Sofosbuvir (NS5B) + Ledipasvir (NS5A) Viekira Pak ( AbbVie ) $83,000 – 1 genotype Dasabuvir (NS5B,) + (( Ombitasvir (NS5A ) / Paritaprevir (NS3)/ ritonavir )) VIEKIRA XR™ ( dasabuvir , ombitasvir , paritaprevir and ritonavir ) - 26.06.2016 ( AbbVie ) Technivie ( AbbVie ) - 4 genotype ombitasvir / paritaprevir / ritonavir Zepatier (Merck) $54,600 -1 и 4 genotypes Elbasvir (NS5A) + Grazoprevir (NS3) Eclupsa ( Gilead Sciences) –all genotypes !!!! Sofosbuvir (NS5B) + Velpatasvir (NS5A)

41. Prevention Currently, no products are available to prevent HCV infection. The development of immunoprophylaxis for this disease is proving difficult; an effective neutralizing immune response has not been demonstrated. Patients with hepatitis C should be advised to abstain from alcohol use; they should also be advised to use barrier protection during sexual intercourse. Reducing risk from shared ancillary drug preparation equipment, such as containers, rinse water, and filters, in addition to shared syringes Addressing social and relational contexts of injecting can encourage uninfected individuals to take precautions when injecting drugs with infected sex partners Developing models to guide delivery of new prevention strategies, including already-available approaches such as increasing syringe availability and future strategies such as direct-acting antivirals that can be used prophylactically , as well as vaccines