Youngjee Choi, Courtney Chrisler, and Hilary E. L. Reno
HIV Infection and AIDS
GENERAL PRINCIPLES
· Human immunodeficiency virus (HIV) type 1 is a human retrovirus that infects T lymphocytes and other cells that bear the CD4 surface marker. Infection leads to lymphopenia, CD4 lymphocyte deficiency and dysfunction, impaired cell-mediated immune response, and polyclonal B-cell activation with impaired B-cell responses to new antigens.
· This immune derangement gives rise to the acquired immunodeficiency syndrome (AIDS), which is characterized by opportunistic infections and unusual malignancies.
· Transmission is primarily by sexual and parenteral routes.
· Major risk groups include sexual contacts of infected individuals, intravenous (IV) drug users, and children born to HIV-infected mothers.
· Because management of HIV-infected patients is a complex and rapidly evolving field, this viral infection is best managed in close coordination with an expert. The information presented here is not intended as a substitute for expert care. Excellent sources of information for physicians who wish to familiarize themselves with HIV care include http://www.aidsinfo.nih.gov and hivinsite.ucsf.edu (last accessed 1/5/15).
DIAGNOSIS
Clinical Presentation
· Patients may be symptomatic at the time of diagnosis if they have been chronically infected. Recommendations are to screen all sexually active people for HIV. It is estimated that over 20% of people with HIV are not aware that they are infected.
· Patients with HIV infection may also present acutely near the time of seroconversion.
· Symptoms that should lead to a suspicion for HIV include recurrent oral candidiasis, lymphadenopathy, weight loss, fevers, night sweats, and chronic diarrhea.
· Abnormal laboratory findings may include anemia, thrombocytopenia, leukopenia, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and elevated immunoglobulin levels.
· Diagnosis is established with an HIV antibody assay and/or HIV RNA viral load. HIV antibody assays are often nonreactive in acute HIV infection, while circulating HIV RNA viral load is very elevated. If suspicion is high for acute infection, HIV RNA viral load should be checked.
· Primary HIV infection (acute retroviral syndrome) often presents as a mononucleosis-like syndrome, with fever being the most common presenting symptom (>75% of patients). Other common symptoms include headache, rash, fatigue, and lymphadenopathy. As many as 90% of acutely infected patients experience at least some symptoms of the acute retroviral syndrome and may be identified as candidates for early therapy.
o Initial infection with HIV type 1 less commonly presents with neurologic manifestations such as aseptic meningitis, Guillain-Barré syndrome, spinal vacuolar myelopathy, peripheral neuropathy, and subacute encephalitis.
o Acute HIV infection is often not recognized in the primary care setting because of the nonspecific symptoms. Maintaining a high index of suspicion and knowing the appropriate testing modality (i.e., HIV viral load) are critical for diagnosis during this time period.
Diagnostic Testing
· Initial assessment of patients should determine the degree of immunodeficiency by measuring the absolute CD4 T-lymphocyte count (normal range for adults is 600 to 1,500 cells/µL3). Along with comorbidities and AIDS-defining illnesses, CD4 count is used to stratify those needing antiretroviral therapy (ART) and prophylactic therapy against opportunistic infections.
· The most important initial laboratory tests are the CD4 count and HIV RNA viral load.
· Given that HIV drug resistance is transmitted as much as 6% to 16% of the time, an HIV genotype should also be performed at baseline to evaluate for critical mutations.
· As HIV is a sexually transmitted disease (STD), it is important to evaluate for other STDs including gonorrhea, chlamydia, syphilis, and the viral hepatitides.
· It is also important to have baseline blood counts, basic chemistry values, liver function testing, urinalysis, fasting lipid profile, and glucose testing to monitor for HIV complications and possible medication toxicities. Many of these laboratory tests should be repeated every 3 to 6 months as part of routine monitoring prior to initiating ART and once ART is initiated or modified. Unless abnormal, urinalysis, fasting lipid profile, and glucose testing can be repeated annually. In addition, baseline testing for antibodies to opportunistic infections such as cytomegalovirus (CMV) and toxoplasmosis may be helpful.
· Finally, all HIV-infected individuals should have baseline and annual testing for TB with a tuberculin skin test (TST) or interferon-gamma release assay (IGRA).
TREATMENT
· ART should be offered to all HIV-infected individuals, with the strongest evidence for those with CD4 count <500 cells/µL3 and expert opinion suggesting treatment for CD4 count >500 cells/µL3.1,2
o Regardless of CD4 count, ART should be started in the following conditions: pregnancy, history of an AIDS-defining illness, HIV-associated nephropathy, and hepatitis B coinfection.
o Typical ART regimens for initial therapy consist of a triple-drug combination: a pair of nucleoside or nucleotide reverse transcriptase inhibitors (NRTI) plus a drug from a second class (see Table 27-1).
o Selecting a drug regimen should be individualized based on resistance testing, toxicity (e.g., hyperbilirubinemia and nephrolithiasis with atazanavir), comorbidities (e.g., pregnancy or hepatitis B coinfection), pill burden, dosing frequency, and potential drug-drug interactions. See aidsinfo.nih.gov and the 2012 International Antiviral Society-USA Panel guidelines for additional risks and benefits to various agents.1,2
o Additional information on drug regimens based on resistance testing can be found at hivdb.stanford.edu (last accessed 1/6/15). Consultation with an HIV expert is recommended.
· Prophylactic treatment against various organisms is recommended for HIV-infected patients and is largely based on the CD4 count.3
o Prophylaxis against pneumocystis pneumonia (PCP) is indicated when the CD4 count is <200 cells/µL3, when the percent of CD4 lymphocytes is <20% of the total lymphocyte count, or if the patient has thrush regardless of CD4 count. Appropriate regimens are trimethoprim-sulfamethoxazole (TMP-SMX) one double-strength tablet daily or dapsone 100 mg daily.
o Prophylaxis against toxoplasmosis is indicated when the CD4 count is <100 cells/µL3 (TMP-SMX for PCP prophylaxis is adequate).
o For patients with CD4 counts of <50 cells/µL3, weekly azithromycin (1,200 mg) should be given as prophylaxis against Mycobacterium avium complex (MAC).
o For patients with CD4 counts <50 cells/µL3, eye examinations should be conducted to evaluate for CMV retinitis.
o If immune reconstitution with ART occurs with sustained CD4 counts of >200 cells/µL3 for 3 months, PCP and MAC prophylaxis can be discontinued.
· Immunizations such as annual influenza vaccine, pneumococcal vaccine, and hepatitis B vaccine (if seronegative) should also be offered, although immunologic response with CD4 counts <200 cells/µL3may be poor.4Patients who are men who have sex with men (MSM) or have chronic liver disease should also be considered for hepatitis A vaccination.3 Vaccination for human papillomavirus (HPV) has not yet been established.5
· HIV is an STD, and therefore, the Centers for Disease Control and Prevention (CDC) recommends annual screening for other STDs including gonorrhea, chlamydia, and syphilis. More frequent screening is indicated in patients with high-risk behavior.
· Female patients with HIV should receive screening for cervical cancer with Pap smears at least annually.
· Because TB is an important complication of HIV infection, screening is warranted at the time of initial assessment and annually via TST or IGRA. Patients often become anergic as their immune deficiency progresses. Chest radiography should be performed as an alternative diagnostic procedure.
TABLE 27-1 Preferred ART Regimens
aThe addition of ritonavir is used to boost the level of the PI it is given with.
ART, antiretroviral therapy; NRTI, nucleos(t)ide reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; InSTI, integrase strand transfer inhibitor.
Data from Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2012;1-240. Available at: http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf, last accessed 12/6/15.
COMPLICATIONS
Viral Infections
Cytomegalovirus Reactivation
· CMV reactivation is common in patients with advanced AIDS (CD4 count <100 cells/µL3).
· Manifestations include viremia with fever and constitutional symptoms, chorioretinitis, esophagitis, gastritis, enterocolitis, pancreatitis, acalculous cholecystitis, bone marrow suppression, necrotizing adrenalitis, and upper and lower respiratory tract infections.
· End-organ disease is seen most often when CD4 counts are <50 cells/µL3.
· Ganciclovir 5 mg/kg IV or valganciclovir 900 mg PO every 12 hours is an effective induction therapy for chorioretinitis and gastrointestinal (GI) disease but is associated with significant hematologic toxicity.3 Blood cell counts should be monitored for neutropenia. Concomitant granulocyte colony–stimulating factor can be used as a possible means of ameliorating ganciclovir myelotoxicity.
· Relapse after drug discontinuation is common, usually necessitating maintenance therapy until CD4 counts are >100 cells/µL3 for 6 months.
· Patients with retinitis who are intolerant of systemic ganciclovir may benefit from intravitreal administration of the drug by an experienced ophthalmologist.
· Foscarnet is indicated for ganciclovir-resistant CMV or those failing ganciclovir therapy.
Other Herpesviridae
· Herpes simplex virus-2 (HSV-2), but not HSV-1, has been identified more commonly in HIV-infected individuals than in HIV-negative individuals.
o HSV-2 likely facilitates the transmission of HIV by providing a portal of entry (e.g., the genital ulcer) and by increasing HIV viral shedding in the genital tract.
o HSV-2 coinfection has also been found to speed the progression of HIV to AIDS.
o HSV infection has been associated with esophagitis, proctitis, pulmonary disease, and large, atypical, persistent cutaneous ulcerations.
o IV acyclovir is usually effective for these problems, but relapses are frequent and individuals may require chronic HSV suppression.3
· Varicella-zoster virus may cause typical dermatomal lesions or disseminate. Recurrent disease, meningoencephalitis, and cranial neuritis have been reported. Acyclovir 800 mg PO five times per day or famciclovir 500 mg PO tid is the treatment of choice.
· Evidence of Epstein-Barr virus (EBV) infection is common in patients with AIDS, particularly oral hairy leukoplakia, a benign condition on the lateral aspect of the tongue.
o Oral acyclovir may be effective but should be reserved for symptomatic cases.
o EBV is also associated with central nervous system (CNS) lymphomas in individuals with advanced AIDS (generally CD4 count <50 cells/µL3).
o Effective therapy for EBV-related malignancies includes ART.
JC Virus
· JC virus is a polyomavirus that is associated with progressive multifocal leukoencephalopathy (PML).
· Diagnosis is made by characteristic clinical features, MRI, and polymerase chain reaction (PCR) testing of cerebrospinal fluid (CSF) for JC virus. Detection of JC virus via PCR is needed for definite diagnosis, but has low sensitivity due to low viremia in the setting of ART.6
o PML is characterized by subacute (weeks to months) progressive neurologic deficits including altered mental status, visual loss, weakness, and gait abnormalities.
o MRI is the imaging modality of choice and reveals multifocal white matter hyperintensities on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images.
o No effective therapy has been identified; however, the course may be significantly altered by immune reconstitution via ART.2
Human Papillomavirus
· HPV causes a wide spectrum of disease in HIV-infected patients, from transient infection to anogenital warts (HPV types 6 and 11) and squamous cell cancers (HPV types 16 and 18).
· HIV-infected women have a 5% to 10% increase in cervical intraepithelial neoplasia over HIV-negative women. Risk of more advanced cervical cancer increases with lower CD4 counts.
· Likewise, anal intraepithelial neoplasia is more common in HIV-infected men.
· Although usually asymptomatic, cervical, vaginal, or anal lesions may cause pain or spotting.
· Annual pelvic examinations and cervical Pap smears are recommended in HIV-infected women with referral and additional testing as indicated by abnormal results.
· The role of anal pap smears in HIV-infected patients, especially MSM, is under investigation.
· There are now two vaccines available for HPV (bivalent for types 16 and 18 and quadrivalent for types 6, 11, 16, and 18).
· The efficacy of the HPV vaccine in HIV infection is unknown, but the vaccine appears to be safe and produces a robust immune response.5 It may be reasonable to vaccinate individuals aged 9 to 26 years old, as is recommended for HIV-negative individuals.
Bacterial Infections
Bacterial Pneumonia
· Bacterial pneumonias occur with increased frequency and are a common cause of morbidity.
· Pneumonias are usually due to Streptococcus pneumoniae, Staphylococcus aureus, or Haemophilus influenzae.
· Pneumonia due to gram-negative enteric organisms occurs in advanced HIV disease.
· Chest radiographs may reveal typical lobar pneumonia, but diffuse interstitial infiltrates similar to PCP have been reported.
Syphilis
· The natural history of syphilis may be altered by HIV infection.
· Reactivation of previously treated disease, active disease with negative serology, asymptomatic neurosyphilis, and relapse after standard therapy have been reported. The optimal management of syphilis in this setting remains unclear.
· Current guidelines suggest at least annual screening for syphilis in HIV-infected individuals and more frequently in patients with high-risk behavior. Additional information on diagnosis is provided later in this chapter.
· Lumbar puncture is reserved for seropositive patients with neurologic symptoms. There are also data to support performing lumbar puncture in HIV-infected individuals with a serum rapid plasma reagin (RPR) titer >1:32 or CD4 count <350 cells/µL3.
· Up to 20% of HIV-infected individuals will remain serofast after successful treatment of syphilis; serum RPR or Venereal Disease Research Laboratory (VDRL) remains reactive at a low titer, generally <1:8. The clinical relevance of this is unclear, but a fourfold rise in titer above this serofast baseline is indicative of reinfection or reactivation and may warrant a lumbar puncture to investigate for neurosyphilis.
Bacterial Diarrhea
· Bacterial diarrhea due to Salmonella spp., Campylobacter spp., and Shigella spp. is more common in HIV patients, particularly MSM.
· Nontyphoidal salmonellae (especially Salmonella typhimurium) are associated with invasive disease that often recurs or persists despite appropriate antibiotics.
o Preferred treatment is ciprofloxacin for 7 to 14 days for diarrhea or 4 to 6 weeks for bacteremia.
o Initial IV therapy should be followed by long-term oral suppressive therapy based on susceptibility testing; relapse may occur as soon as therapy is discontinued.
· Campylobacter diarrhea is treated with ciprofloxacin, but resistance is increasing.
· Shigellosis treatment is with ciprofloxacin or TMP-SMX.
Mycobacterial Infections
Tuberculosis
· TB can occur at any CD4 count, but extrapulmonary manifestations occur with increased frequency in patients with lower CD4 counts.
· In the developing world, TB is the most prominent AIDS-defining illness, and in the developed world, TB is most commonly diagnosed in substance abusers, immigrants from high-prevalence countries, and the urban poor.
· Atypical radiographic patterns and extrapulmonary disease are quite common; apical cavitary disease is uncommon in advanced HIV disease.
· See Chapter 26 for the treatment of TB.
· After ruling out active disease, isoniazid for 9 months should be considered in any HIV-infected patient with a reactive (>5-mm induration) TST or positive IGRA. Pyrazinamide plus rifampin for 2 months is an alternative, although there are significant drug interactions with ART and rifampin.
Mycobacterium Avium Complex
· MAC is one of the most frequent opportunistic pathogens in patients with advanced AIDS (usually CD4 count <50 cells/µL3).
· Generalized infection and GI disease are the most common manifestations.
· The organism can be cultured from sputum, blood, bone marrow, and tissue from the GI tract.
· Treatment with clarithromycin, ethambutol, and rifabutin is often effective.3
· For patients with CD4 counts <50 cells/µL3, MAC prophylaxis therapy should be initiated with either azithromycin 1,200 mg PO weekly or clarithromycin 500 mg PO bid.
Fungal Infections
Candidiasis
· Persistent oral, esophageal, and vaginal infections are common; dissemination is rare in the absence of other risk factors such as IV catheters.
· The severity and frequency of mucocutaneous candidiasis increase with declining immune function.
· Oral thrush is effectively treated with topical therapy: clotrimazole troches PO five times per day for 14 days.3
· Frequently recurring thrush can be prevented with fluconazole 100 mg PO daily.
· Esophagitis should be treated with fluconazole (200 mg one time followed by 100 mg daily for 14 days; higher doses up to 400 mg daily may be required in some patients).
· Vaginal candidiasis can be treated with antifungal vaginal suppositories as discussed later in this chapter.
Cryptococcosis
· Cryptococcus neoformans is the most common cause of fungal CNS disease in patients with AIDS.
· Symptoms may be mild; therefore, the threshold for performing a lumbar puncture should be low.
· Lumbar puncture results include elevated opening pressure (often >200 mm H2O), lymphocyte predominant pleocytosis, and low glucose. However, normal CSF parameters occur in as many as 25% of AIDS patients with cryptococcal meningitis, so a cryptococcal antigen should be sent for all AIDS patients in whom a lumbar puncture is performed.
· Repeat lumbar puncture is indicated for clinical deterioration as well as relief of elevated opening pressures, which are associated with poor outcomes.
· Initial treatment is with IV amphotericin B and flucytosine for 2 weeks, followed by fluconazole 400 mg daily for 8 to 10 weeks.3
· Following acute treatment, maintenance therapy is required with fluconazole 200 mg daily until CD4 count is >200 cells/µL3.
· Response is usually monitored clinically and is generally slow.
Histoplasmosis
· Histoplasma capsulatum is an important pathogen in patients with AIDS from endemic areas and may cause disseminated disease and septicemia. The organism’s endemic areas include the Ohio and Mississippi river valleys in the US, Central and South America, parts of southern Europe, Africa, eastern Asia, and Australia.
· Diagnosis is made by sending a urine H. capsulatum antigen; the organism can also be cultured from blood and bone marrow.
· Pancytopenia may result from bone marrow involvement.
· Treatment includes a 12-week induction phase with a subsequent long-term maintenance phase to complete 1 year of therapy.
· A cumulative dose of amphotericin B 1.5 to 2.0 g is given initially for severely ill patients. For patients who are intolerant of amphotericin B, liposomal amphotericin B can be considered. Itraconazole is effective for induction in milder disease. Itraconazole is also used for the maintenance phase.3
Coccidioidomycosis
· Coccidioides spp. infections occur in patients with AIDS from endemic areas (southwestern US and northern Mexico).
· In immunocompetent hosts, primary infection is a self-limited acute pneumonia known as valley fever.
· Extensive pulmonary disease with extrapulmonary spread, including meningitis and lymphadenopathy, is common in AIDS patients.
· Fluconazole 400 mg daily is usual treatment, with amphotericin B as an alternative therapy.3
· Lifelong maintenance treatment is required for coccidioidal meningitis.
Pneumocystis Pneumonia
· Pneumocystis jiroveci pneumonia remains the most common opportunistic infection in patients with AIDS and a leading cause of morbidity and mortality.
· Presenting symptoms include progressive dyspnea, fever, and cough; early disease may have a subtle presentation and a normal chest radiograph.
· The treatment of choice for PCP is TMP-SMX 5 mg/25 mg/kg PO or IV every 6 to 8 hours for 21 days.3
o Anemia or rashes can occur in AIDS patients who are treated with TMP-SMX but may not require a change in therapy.8
o For patients who do not tolerate TMP-SMX, dapsone-trimethoprim, clindamycin-primaquine, and pentamidine are other options.
· In patients with well-documented PCP and moderate-to-severe disease (arterial oxygen pressure <75 torr on room air), adjunctive use of steroids prevents adult respiratory distress syndrome and leads to a survival benefit.9Prednisone (or equivalent methylprednisolone) 40 mg PO bid for 5 days, followed by 40 mg PO daily for 5 days, followed by 20 mg PO daily for the duration of antipneumocystis therapy is recommended.
Protozoal Infections
Toxoplasma Reactivation
· Toxoplasma gondii typically presents in HIV-infected patients with CD4 counts <100 cells/µL3.
· It is characterized by multiple CNS lesions presenting as encephalitis with headache, confusion, fever, and focal neurologic findings. Extracerebral toxoplasmosis has also been reported.
· Treatment with sulfadiazine 25 mg/kg PO every 6 hours (or TMP-SMX 5 mg/25 mg/kg PO or IV every 6 to 8 hours) plus pyrimethamine 100 to 150 mg PO on day 1 and then 50 to 75 mg PO daily often results in improvement, but indefinite therapy is needed to prevent relapse.3 Folinic acid 5 to 10 mg PO daily can be added to minimize hematologic toxicity.
· For patients with sulfonamide allergy, clindamycin 600 mg PO four times per day can be substituted.
Diarrheal Diseases
· Cryptosporidium spp., Isospora belli, and Cyclospora cayetanensis may all cause severe and prolonged diarrheal illness in patients with AIDS. Isospora belli is most frequently seen in MSM.
· Diagnosis of cryptosporidiosis is by microscopy, immunoassay, or PCR. Diagnosis of isosporiasis and cyclosporiasis requires acid-fast staining and other specific staining techniques.
· No therapy has proved to be effective for cryptosporidiosis besides immune reconstitution through ART (CD4 count >100 cells/µL3). TMP-SMX treats isosporiasis and cyclosporiasis.3
Neoplasms
· Neoplasms associated with AIDS include non-Hodgkin lymphoma and Kaposi sarcoma. Primary CNS lymphomas are common and may be multicentric. The treatment of these conditions is beyond the scope of this manual.
· As noted above, women should receive annual screening for cervical cancer. In addition, there is growing literature on the need for anal screening in both men and women.
Metabolic Complications
· There are a myriad of metabolic consequences from HIV as well as ART.10
· Dyslipidemia is characterized by hypertriglyceridemia and low HDL cholesterol levels.
o Among ART, ritonavir causes the most lipid derangements. Atazanavir appears to provide improvement in the lipid profile.
o Treatment of choice is atorvastatin or pravastatin, due to relatively lower drug interactions with ART. Of note, efavirenz reduces inhibition of HMG-CoA reductase activity; therefore, higher doses of statins may be needed for efficacy.
· Peripheral lipoatrophy (thin extremities), central obesity, and buffalo humps are some prominent features of lipodystrophy. Avoiding certain older-generation ARTs (NRTIs such as stavudine and zidovudine) as well as dietary changes and exercise are strategies to improve lipodystrophy.
· Mechanisms leading to insulin resistance include lipodystrophy, hepatic steatosis, chronic inflammation from HIV, and ART (particularly protease inhibitors). Metformin and rosiglitazone have been shown to improve insulin sensitivity.
SEXUALLY TRANSMITTED DISEASES
· A standardized, thorough evaluation including a complete history and physical is important in the diagnosis of STDs.
· History should include the presence or absence of genital drainage or discharge; dysuria; sores or other lesions (including warts, growths, or bumps) on or near the genitalia; any rash; testicular pain or discomfort; abdominal, rectal, or pelvic pain; the presence of any oral or pharyngeal symptoms; and any known drug allergies.
· A detailed sexual history should also be taken and include whether the patient has sex with men, women, or both; number of sexual partners in the past year; sites of sexual contact (vaginal, penile, oral, rectal); condom use; known exposure to STDs; and, for women, menstrual history and history of pregnancy.
· Physical examination must be complete and include the lower abdomen, palpation of inguinal area for lymphadenopathy, thorough external genitalia examination, and appropriate pelvic examination for women and visual examination of the urethra in men.
· Patients diagnosed with an STD should be screened for others, particularly for HIV.
· Counseling for the prevention of STDs is also recommended for all sexually active adults, and barrier methods should be encouraged.
· Partner notification, evaluation, and treatment, if indicated, are also essential.
· Treatment recommendations discussed in this section were adapted from the CDC STDs guidelines.11
URETHRITIS AND CERVICITIS SYNDROMES
· A variety of infections, most notably gonorrhea and chlamydia, cause urethritis in men and cervicitis in women.
· Symptoms in men generally include purulent urethral discharge and dysuria. In women, vaginal discharge may occur, but many patients are asymptomatic.
· Diagnosis is supported by physical exam and appropriate microbiologic testing. Additionally, a diagnosis of urethritis or cervicitis is supported by Gram stain of urethral or vaginal secretions showing >5 WBCs per high-power field in men or >10 WBCs per high-power field in women.
Gonorrhea
· Gonorrhea is caused by infection with Neisseria gonorrhoeae and is a common cause of urethritis in men and cervicitis in women. It can also cause oropharyngeal or rectal infection in patients with sexual contact in those areas. Less commonly, it causes disseminated infection resulting in bacteremia, pustular skin lesions, tenosynovitis, septic arthritis, and/or perihepatitis.
· Gram stain of urethral, endocervical, or anal samples showing gram-negative diplococci is diagnostic. Neisseria gonorrhoeae can also be cultured from urethral, endocervical, anal, or oropharyngeal samples. Nucleic acid hybridization tests of swab specimens and nucleic acid amplification testing of urine or swab specimens have better sensitivity than Gram stain or culture techniques.
· Recommended treatment for uncomplicated gonococcal infection is single-dose ceftriaxone (250 mg IM) in addition to azithromycin (1 g PO) or doxycycline (100 mg PO bid for 7 days) given the high rate of emerging resistance and chlamydial coinfection.
· Cefixime and quinolones are no longer recommended for the treatment of gonorrhea secondary to increased antimicrobial resistance.12
· Therapy may be initiated before results of diagnostic testing are available.
· Patients with disseminated gonococcal infection should be referred for hospital admission for IV antibiotics. The diagnostic evaluation often includes cultures of blood, mucosal sites, skin lesions, and joint aspirates.
Chlamydia
· Chlamydia trachomatis is a major cause of urethritis and cervicitis, but asymptomatic infection is also common. It can also cause oropharyngeal or rectal infection in patients with sexual contact in those areas.
· Nucleic acid amplification tests are the most sensitive assays, but a variety of testing methods are available including cell culture, direct immunofluorescence, enzyme immunoassay (EIA), and nucleic acid hybridization assays. Urethral, cervical, oropharyngeal, or rectal swabs or urine specimen may be tested depending on suspected sites of exposure and infection.
· Treatment is single-dose azithromycin (1 g PO) or doxycycline (100 mg PO bid for 7 days).
· Treatment may be initiated before confirmatory testing results are available.
Nongonococcal Urethritis and Mucopurulent Cervicitis
· Nongonococcal urethritis (NGU) and mucopurulent cervicitis (MPC) are clinical syndromes that mimic infection with N. gonorrhoeae but are caused by other pathogens.
· Organisms that cause NGU or MPC include C. trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, Trichomonas vaginalis, and occasionally HSV.
· The recommended therapeutic approach is to provide adequate coverage for possible C. trachomatis infection with either single-dose azithromycin (1 g PO) or doxycycline (100 mg PO bid for 7 days)and then treatment for T. vaginalis with single-dose metronidazole (2 g PO) if patients fail to respond.
VAGINITIS AND VAGINOSIS SYNDROMES
· Bacterial vaginosis is a clinical syndrome of bacterial overgrowth that produces malodorous vaginal discharge and pruritus. Diagnosis and treatment are discussed in Chapter 3.
· Trichomoniasis is an STD caused by the parasite T. vaginalis and may be more common than C. trachomatis and N. gonorrhea. It may be a cause of NGU in men and a profuse, purulent vaginal discharge in women. Further diagnosis and treatment is discussed in Chapter 3.
· Vulvovaginal candidiasis (“yeast infection”) is suggested by the presence of vulvovaginal soreness, dyspareunia, vulvar pruritus, external dysuria, and thick or “cheesy” vaginal secretions. See Chapter 3 for diagnosis and treatment.
GENITAL ULCER SYNDROMES
Syphilis
GENERAL PRINCIPLES
· Syphilis is a systemic infection caused by Treponema pallidum.
· Primary syphilis is characterized by one or more painless, superficial ulcerations (chancres). These lesions are seen in genital, anorectal, or pharyngeal sites.
o A chancre typically has raised, sharply demarcated borders; a red, smooth, nontender base; and scant serous secretions.
o Regional lymphadenopathy may be present.
o The average time between exposure and chancre development is 3 weeks.
o Spontaneous resolution of lesions generally occurs in 3 to 6 weeks, even without treatment.
· Secondary syphilis typically occurs 6 weeks after exposure and is characterized by a macular, maculopapular, or papular rash that can involve the palms, soles, and flexor areas of the extremities. Any body site, including mucous membranes, may be involved.
· Tertiary syphilis is rare and refers to development of mucocutaneous/osseous lesions (gummas) or cardiovascular lesions (aortitis).
· Neurosyphilis may present with variable neurologic manifestations including syphilitic meningitis, cranial nerve dysfunction, stroke, altered mental status, loss of vibration sense, auditory abnormalities, or uveitis. CNS involvement can occur during any stage of syphilis.
· Latent syphilis is infection that is diagnosed serologically in the absence of primary or secondary symptoms.
o Early disease (<1 year) is differentiated from late disease (>1 year) for treatment purposes.
o If a negative serology within the past year cannot be documented, the patient should be treated for late latent disease.
DIAGNOSIS
· Dark-field microscopy of lesion exudate or tissue is the definitive method for diagnosis, but this is seldom available and is insensitive.
· Two types of serologic tests are used for diagnostic purposes: nontreponemal tests (RPR and VDRL) and treponemal tests (e.g., fluorescent treponemal antibody absorbed [FTA-ABS] tests and the T. pallidum passive particle agglutination [TP-PA] assay). Both types of tests have limitations, and so they are used in a complementary manner to support the diagnosis.
· RPR and VDRL are often reactive within 1 to 2 weeks of onset of the chancre, but up to 30% may have negative RPR at the time of initial examination (chancre present). Titers decline after treatment, and the tests may become nonreactive with time.
· False-positive nontreponemal tests occur in a variety of conditions (e.g., autoimmune disease, pregnancy, older age, and intravenous drug use).
· When a patient has a reactive RPR or VDRL, confirmatory testing by FTA-ABS or TP-PA is recommended.
· CSF analysis is indicated if there is concern for neurosyphilis. In cases of neurosyphilis, CSF abnormalities may or may not be present. The VDRL in the CSF is the standard serologic test for CSF and is highly specific but insensitive. CSF FTA-ABS is less specific for neurosyphilis but is highly sensitive.
· All patients with syphilis should be tested for HIV.
TREATMENT
· Penicillin is the treatment of choice for all stages of syphilis.
· For pregnant patients with a history of penicillin allergy, penicillin skin testing and desensitization are recommended, because alternative regimens do not treat the fetus.
· For primary, secondary, and early latent infection (<1 year duration):
o Single-dose benzathine penicillin G (2.4 million units IM) is recommended.
o Effective alternatives include doxycycline (100 mg PO bid for 14 days) or tetracycline (500 mg PO qid for 14 days). Azithromycin (2 g PO once) can be used with caution in non-MSM and nonpregnant women if treatment with penicillin or doxycycline is not feasible. Ceftriaxone (1 g daily either IM or IV for 10 to 14 days) has been effective in trials, but the optimal dose and duration of therapy have not been defined.
o Follow-up and repeat serology should be done at 6 and 12 months.
o The RPR should show a fourfold decrease in titer within 6 months of treatment.
o One must consider treatment failure or reinfection if symptoms persist or recur or if nontreponemal titer increases fourfold.
· For late syphilis (>1-year duration—except neurosyphilis):
o Benzathine penicillin G (2.4 million units IM weekly for 3 weeks) is recommended.
o Alternatives are tetracycline (500 mg PO qid for 28 days) or doxycycline (100 mg PO bid for 28 days).
o Repeat serologies should be conducted at 6, 12, and 24 months.
o Evaluate for neurosyphilis if the nontreponemal titer increases fourfold, if initially high titer ≥1:32 fails to fall fourfold in 12 to 24 months, or if signs or symptoms of neurosyphilis develop.
· For neurosyphilis:
o Aqueous penicillin G (18 to 24 million units daily IV, 3 to 4 million units every 4 hours for 14 days) is recommended.
o Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10 to 14 days may be an effective alternative treatment.
o Repeat serologies at 3, 6, 12, and 24 months and follow-up lumbar puncture at 6-month intervals are indicated until the CSF cell count is normal.
o Retreatment should be considered if cell count has not decreased at 6 months or CSF is not entirely normal at 2 years.
· HIV-positive patients with syphilis require closer clinical follow-up with clinical examination at 1 week and repeat serology in 3, 6, 9, 12, and 24 months and then yearly, even if RPR becomes negative.
Herpes
GENERAL PRINCIPLES
· Herpes simplex virus (HSV) causes a chronic, lifelong latent infection and can cause episodic symptoms during periods of viral reactivation.
· HSV types 1 and 2 can be sexually transmitted, but most genital infections are caused by HSV-2.
· HSV typically produces painful grouped vesicles on or near the genitalia. Over several days, the lesions evolve into shallow ulcers, which generally heal within 1 to 2 weeks.
· Most patients with genital HSV are asymptomatic or have mild or nonspecific symptoms.
· Extragenital lesions of HSV may develop in the buttock, groin, or thigh areas.
· HSV can also cause neurologic syndromes including encephalitis, aseptic meningitis, transverse myelitis, and sacral radiculopathy. Disseminated disease, hepatitis, and pneumonitis may also occur, particularly in immunocompromised hosts.
· HSV recurrences usually cause fewer lesions and less frequent occurrence of systemic symptoms than are seen during primary genital HSV infection.
· Reactivation of HSV-1 is less frequent, and almost all patients with HSV-2 experience recurrence, though the rates decrease over time.
DIAGNOSIS
· Clinical diagnosis relies on detection of grouped, tender vesicular or pustular lesions on an erythematous base. Lymphadenopathy, fever, headache, myalgias, urethritis, or cervicitis is variably present.
· Cell culture and PCR are the preferred testing methods for HSV.
· HSV PCR is a more sensitive method for diagnosis and is available for samples from oral or genital lesions, CSF, and ocular fluid.
TREATMENT
· Recommended treatments for genital HSV outbreaks:
o Acyclovir, 400 mg PO tid or 200 mg PO five times a day for 7 to 10 days
o Famciclovir, 250 mg PO tid for 7 to 10 days
o Valacyclovir, 1 g PO bid for 7 to 10 days
· Early treatment usually reduces the symptomatic interval and may result in accelerated healing.
· Suppressive therapy may be recommended for patients with recurrent symptomatic infection.
o Acyclovir, 400 mg PO bid
o Famciclovir, 250 mg PO bid
o Valacyclovir, 500 mg PO bid or 1 g PO daily
· Continuation of suppressive therapy should be reevaluated on a yearly basis.
· Patients should be counseled that therapy decreases but does not eliminate the risk of transmitting HSV to their sexual partners and that they may be infectious even when they have no visible ulcers.
· Patients with severe HSV disease, including those with CNS disease and those that require hospitalization, should receive IV therapy.
Chancroid
GENERAL PRINCIPLES
· Chancroid is caused by infection with Haemophilus ducreyi.
· Chancroid is distributed worldwide, with concentrations in Africa and the Caribbean, but the incidence has declined in the United States. Clusters occur in New York City and the Gulf Coast states, where most cases are in non-Caucasian uncircumcised men or are associated with prostitute contact.
· The typical lesions are painful, nonindurated, excavated genital ulcers with undermined borders. Tender, enlarged inguinal lymph nodes are often present. Fever and other systemic symptoms are generally absent.
· The incubation period is usually 5 to 7 days.
DIAGNOSIS
· Laboratory diagnosis relies on culture or Gram stain from a lymph node aspirate, but culture techniques are <80% sensitive and require special media. Identification of small, gram-negative bacilli on Gram stain provides a presumptive diagnosis.
· Clinical diagnosis may be made in patients with typical clinical features and for whom syphilis and HSV have been excluded.
TREATMENT
· Treatment is single-dose azithromycin (1 g PO), single-dose ceftriaxone (250 mg IM), ciprofloxacin (500 mg PO bid for 3 days), or erythromycin base (500 mg PO qid for 7 days).
· The patient should be reexamined in 3 to 7 days to assess for clinical improvement. Large ulcers may take more than 2 weeks to heal, and scarring may result despite successful therapy.
Lymphogranuloma Venereum
GENERAL PRINCIPLES
· Lymphogranuloma venereum is caused by C. trachomatis serovars L1, L2, or L3, which predominantly infect the lymphatic tissue.
· Historically, this infection has occurred in underdeveloped tropical and subtropical areas, but outbreaks in Europe and the United States have been reported, mostly in MSM.
· The primary stage is often unnoticed and consists of a self-limited ulcer at the inoculation site, after which, a secondary invasive stage occurs with varied complications based on the original location of inoculation.
· The inguinal syndrome occurs after inoculation at the genital mucosa and produces tender inguinal lymphadenopathy and even buboes, which may spontaneously rupture.
· The anorectal syndrome occurs via infection of the rectal mucosa and results in proctitis and inflammation of the surrounding lymphatic tissue. Chronic, colorectal fistulas and strictures may occur.
· Infection may also occur via the pharyngeal mucosa and result in the pharyngeal syndrome.
DIAGNOSIS
· Diagnosis is largely clinical.
· Genital and lymph node specimens can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection.
· PCR-based testing of lesion swab or bubo aspirate can differentiate LGV from non-LGV C. trachomatis, but this testing is not widely available.
· Chlamydial serology, though not type specific, may be supportive if the titer is high, although acute and convalescent sera are preferred.
TREATMENT
· Recommended treatment is doxycycline (100 mg PO bid for 3 weeks). Alternatively, erythromycin base (500 mg PO qid for 3 weeks) may be used.
· Azithromycin 1 g PO once weekly for 3 weeks and fluoroquinolone-based treatments may also be effective, but clinical data are lacking.
Granuloma Inguinale
GENERAL PRINCIPLES
· Granuloma inguinale (also known as donovanosis, with reference to characteristic intracellular inclusions called Donovan bodies) is a progressive ulcerative condition caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis or Donovania granulomatis).
· It is endemic to India, Papua New Guinea, southern Africa, and central Australia. Rare cases are reported in the United States via foreign travel.
· Presents as painless, slowly progressive, beefy-red ulcers without associated lymphadenopathy. The typical ulcers are often highly vascular and bleed easily on contact.
· Hypertrophic, necrotic, and sclerotic variants have been described.
· Extragenital infection can occur with extension of infection into the pelvis and dissemination to the intra-abdominal organs, to bones, or in the mouth.
DIAGNOSIS
Clinical diagnosis may be supported by tissue crush preparation or biopsy showing classic bipolar-staining Donovan bodies. The organism cannot be grown in standard culture media.
TREATMENT
· First-line recommended treatment is doxycycline (100 mg PO bid). Alternatives include TMP-SMX (160 mg/800 mg PO bid), ciprofloxacin (750 mg PO bid), azithromycin (1,000 mg once per week), or erythromycin base (500 mg PO qid).
· Duration of therapy for any agent is at least 3 weeks and until all lesions have completely healed.
· Addition of an aminoglycoside (e.g., gentamicin, 5 mg/kg IV daily) may be considered if lesions do not respond after the first few days of oral therapy.
EXOPHYTIC PROCESSES
Human Papillomavirus
GENERAL PRINCIPLES
· HPV can result in a wide variety of epithelial manifestations including common, plantar, flat/juvenile warts.
· 90% of anogenital warts (condylomata acuminata) are also caused by HPV subtypes 6 and 11.
· Serotypes 16 and 18 are associated with approximately 70% of all cervical cancers. HPV is also linked to the development of anal intraepithelial neoplasia and invasive squamous cell carcinoma.
· Most HPV infections are asymptomatic and most clear spontaneously.
DIAGNOSIS
· The diagnosis of anogenital warts is usually made by inspection, which reveals typical flesh-colored “cauliflower” or wart-like masses, usually involving the external genitalia, perineum, or perianal area. The lesions are typically asymptomatic, but minor complaints such as pruritus may be present.
· The differential diagnosis includes molluscum contagiosum or condyloma lata (secondary syphilis).
· A weak acetic acid solution (3% to 5%) can be used to highlight exophytic warts on the skin surface. The lesions turn white as the solution dries (do not apply to mucous membranes).
· A dermatologic consultation may be desirable for evaluation and biopsy of a lesion.
· Cervical cytology should be performed for women with diagnosed HPV infection and for female partners of infected men.
TREATMENT
· The treatment of warts is typically with application of liquid nitrogen, podophyllin, or trichloroacetic acid.
· Liquid nitrogen (cryotherapy) is applied by a 10- to 15-second spray followed by a thaw and a single repeat application.
· Trichloroacetic acid, 80% to 90%, is very caustic and physically destroys the lesions after repeated applications. It may be used during pregnancy.
· Podophyllin, 10% to 25% in tincture of benzoin, is applied once or twice a week and washed off 1 hour after each application. Podophyllotoxin is an antimitotic agent.
· Home therapy with podofilox, imiquimod, or sinecatechins can also be tried.
· Surgical removal of warts may be necessary for extensive disease.
· There are now two approved HPV vaccines, one for serotypes 16 and 18 and a quadrivalent vaccine for serotypes 16 and 18 as well as serotypes 6 and 11. The divalent vaccine is currently indicated for women aged 13 to 26 years, and the quadrivalent vaccine can also be used in males 9 to 26 years of age.
Molluscum Contagiosum
GENERAL PRINCIPLES
· Molluscum contagiosum is a benign papular lesion caused by the molluscum contagiosum virus (a poxvirus), of which there are four types, MCV-1 to MCV-4.
· It can be transmitted sexually or nonsexually through close physical contact and is more common in children.
· In healthy patients, it is a self-limited infection and lesions usually resolve spontaneously.
· HIV positivity is a significant risk factor, and HIV-positive patients may have more widespread, larger lesions.
DIAGNOSIS
· Typical lesions are firm, small (1- to 5-mm diameter), fleshy papules that are often umbilicated. A firm white “pearl” is sometimes expressed on compression, followed by bleeding from the lesion.
· Very similar skin lesions may occur with disseminated C. neoformans or less commonly by H. capsulatum.
· Standard histology (molluscum bodies) or electron microscopy (visualization of poxvirus particles) can be used for a specific diagnosis.
TREATMENT
· Successful treatment of lesions may be with liquid nitrogen or trichloroacetic acid in the same fashion as described for warts.
· For those with concomitant HIV infection, more aggressive treatment and referral to a dermatologist may be appropriate. However, resolution usually occurs with treatment of the underlying HIV disease and immune reconstitution.
ECTOPARASITIC INFECTIONS
Pediculosis Pubis
· Pediculosis pubis, also known as pubic lice and crabs, is caused by the crab louse, Phthirus pubis.
· The parasite infests the pubic hair and causes intense itching in the pubic area.
· Nits or live lice may be visible to the human eye.
· Recommended first-line treatment entails topical permethrin 1% cream rinse or pyrethrins with piperonyl butoxide applied to the affected areas and washed off after 10 minutes.
· Alternatives for suspected treatment failures include topical malathion or systemic ivermectin.
· Bedding and clothing should be decontaminated, and sexual partners should also be evaluated and treated.
Scabies
· Scabies is caused by infestation with the mite Sarcoptes scabiei and is typically transmitted by skin-to-skin contact. The mite burrows into the skin, typically on the hands, feet, wrists, elbows, back, buttocks, and external genitals, causing intense allergic itching and sometimes small pimple-like bumps along the burrowing trails.
· Recommended treatments include topical permethrin cream (5%) or systemic ivermectin 200 μg/kg orally once and then repeated in 2 weeks time.
· Treatment with 1% lindane may be used as an alternative treatment but should not be used as first line, given concerns for drug toxicity.
· Bedding and clothing should be decontaminated, and sexual partners and household contacts should be evaluated and treated.
SYSTEMIC SEXUALLY TRANSMITTED DISEASE Syndromes
Pelvic Inflammatory Disease
GENERAL PRINCIPLES
· Pelvic inflammatory disease (PID) is a spectrum of upper genital tract infection. It may include any combination of endometritis, salpingitis, tubo-ovarian abscess, and pelvic peritonitis.
· Neisseria gonorrhoeae and C. trachomatis are the most common sexually transmitted causes, although infections are often polymicrobial involving normal flora of the female GU tract.
· Most cases occur proximate to the menses.
· Risk factors include multiple sexual partners, age 15 to 25 years, recent intrauterine device (IUD) placement, and prior PID.
DIAGNOSIS
· PID is characterized by lower abdominal or pelvic pain; adnexal, uterine, or cervical motion tenderness; and systemic signs and symptoms of infection. Other signs and symptoms may include dyspareunia, vaginal discharge, and menorrhagia or metrorrhagia.
· The differential diagnosis is extensive and includes several causes of acute abdomen such as appendicitis, ectopic pregnancy, septic abortion, and ovarian torsion.
· All patients with PID should be tested for pregnancy and HIV.
· Radiography, including ultrasound and CT, may assist with making a diagnosis of PID, but sensitivity is variable depending on the extent of the disease.
TREATMENT
· Treatment regimens should include broad-spectrum antimicrobial coverage, including coverage for N. gonorrhoeae and C. trachomatis, vaginal flora and anaerobes, such as Bacteroides spp.
· Patients with mild-moderately severe PID may be treated as outpatients, but others require admission for IV antibiotics and occasionally surgical intervention.
· CDC guidelines for hospital admission should be reviewed prior to consideration of outpatient treatment. They are as follows:
o Other surgical emergencies (e.g., appendicitis) cannot be excluded.
o The patient is pregnant.
o Outpatient therapy has failed.
o The patient is unable to follow or tolerate outpatient treatment.
o The illness is severe, with nausea, vomiting, and high fever.
o Tubo-ovarian abscess is strongly suspected.
· Duration of therapy is typically at least 2 weeks but may be longer in severe cases.
· Recommended parenteral regimens include cefotetan 2 g IV q12 hours or cefoxitin 2 g IV q6 hours plus doxycycline 100 mg orally or IV every 12 hours or clindamycin 900 mg IV q8 hours plus gentamicin dosed based on body weight and renal function.
· Outpatient treatment should include single-dose ceftriaxone (250 mg IM) or cefoxitin 2 g IM with probenecid 1 g orally plus doxycycline (100 mg PO bid for 14 days) with or without metronidazole(500 mg PO bid for 14 days). A follow-up examination within 72 hours is essential to ensure that an adequate response to therapy has occurred.
· Intrauterine devices should be removed if present.
Hepatitis B Virus
· Refer to Chapter 30 for a detailed discussion of hepatitis B.
· Hepatitis B can be transmitted sexually, parenterally, or from mother to child during pregnancy. Epidemiologic studies suggest that in the United States, 40% to 60% of cases of HBV infection are sexually transmitted.
· Symptoms of infection may include malaise, fever, loss of appetite, abdominal pain, nausea, vomiting, jaundice, dark urine, arthralgias, or polyarthritis, but up to 50% of people may be asymptomatic.
· The physical examination may detect right upper quadrant abdominal tenderness, hepatic enlargement, or scleral or cutaneous jaundice.
· Laboratory diagnostic studies should include serologic testing for HBV, including hepatitis B surface antigen. Other useful diagnostic tests may include hepatitis A IgM, hepatitis C virus enzyme–linked immunosorbent assay test, complete blood count, and liver function tests.
· Treatment for acute HBV is supportive.
· Hepatitis B vaccination is recommended for all unvaccinated adolescents and for all unvaccinated adults at risk for infection.
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