Prevention and treatment of opportunistic infections and other coinfections in HIV-infected patients: May 2015

Abstract

Despite the huge advance that antiretroviral therapy represents for the prognosis of infection by the human immunodeficiency virus (HIV), opportunistic infections (OIs) continue to be a cause of morbidity and mortality in HIV-infected patients. OIs often arise because of severe immunosuppression resulting from poor adherence to antiretroviral therapy, failure of antiretroviral therapy, or unawareness of HIV infection by patients whose first clinical manifestation of AIDS is an OI.

The present article updates our previous guidelines on the prevention and treatment of various OIs in HIV-infected patients, namely, infections by parasites, fungi, viruses, mycobacteria, and bacteria, as well as imported infections. The article also addresses immune reconstitution inflammatory syndrome.

Resumen

A pesar del gran avance que ha supuesto el tratamiento antirretroviral (TAR) para el pronóstico de la infección por el VIH, las infecciones oportunistas (IO) continúan siendo causa de morbilidad y mortalidad en estos pacientes. Ello ocurre en muchos casos debido a la inmunodepresión grave, bien ante la falta de adherencia al TAR, el fracaso del mismo o el desconocimiento de la existencia de la infección por el VIH en pacientes que comienzan con una IO.

El presente artículo actualiza las recomendaciones de prevención y tratamiento de diferentes infecciones en pacientes con infección por VIH: parasitarias, fúngicas, víricas, micobacterianas, bacterianas e importadas, además del síndrome de reconstitución inmune.

Introduction

Opportunistic infections (OIs) have been the main cause of morbidity and mortality in HIV-infected patients since the beginning of the HIV epidemic.¹

Efficacious regimens for primary and secondary prophylaxis to prevent OIs were the first major advance in therapy for HIV-infected patients, significantly decreasing mortality, even before the advent of highly active antiretroviral therapy (ART).² ART brought about a notable change in the progression of HIV infection by dramatically reducing mortality and the incidence of OIs.³ However, today, we continue to see cases of OI in various settings: patients who are unaware of their HIV infection and whose first manifestation is an OI; patients who do not receive ART; and failure of ART due to poor adherence or other causes.⁴ Accordingly, treatment of OIs continues to be a relevant topic in the care of HIV-infected patients.

The present document is an update of our previous recommendations on prevention and treatment of OIs in HIV-infected patients.^5,6 The strength of the recommendation and ranking of the tests that support it are based on a modification of the criteria of the Infectious Diseases Society of America.⁷ According to these criteria, each recommendation should be offered always (A), generally (B), or optionally (C), based on data from 1 or more randomized clinical trials with clinical or laboratory results (I), 1 or more nonrandomized trials or observational cohort data (II), or expert opinion (III).

Owing to space limitations, the reader should consult the tables, which display the various prophylaxis and treatment regimens (both preferred and alternative) and the corresponding doses.

Parasitic infections (Table 1)

Toxoplasma gondii

Patients who have not been exposed to Toxoplasma gondii (confirmed by a negative anti-Toxoplasma gondii IgG result) should avoid contact with the parasite. Handwashing is recommended after contact with animals, especially cats, and after handling raw meat. Patients should try to eat meat that has been adequately cooked (or previously frozen to −20 °C) and wash fruit and vegetables that are to be eaten raw (BIII).^5,8,9

Table 1.

Regimens recommended for prevention and treatment of parasitic infections.

Toxoplasma gondii
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
- Anti-Toxoplasma gondii IgG and CD4+ <100/μL (AII) - All the regimens recommended as primary prophylaxis against Toxoplasma gondii infection are efficacious against Pneumocystis Prevention of exposure: Patients with negative anti-Toxoplasma gondii IgG: - Eat meat that has been adequately cooked (or previously frozen to −20 °C), wash fruit and vegetables, and use gloves when handling raw meat or gardening (BIII). - Use gloves and take appropriate hand hygiene measures when in close contact with pets (cats) and their excrement. - Ensure that cats remain at home and try to avoid giving them raw or inadequately cooked meat (BIII).	Cotrimoxazole 1 “forte” tab (trimethoprim/sulfamethoxazole 160/800 mg) po/d (AII)	- Cotrimoxazole 1 “forte” tab × 3 d/wk po (BIII) - Cotrimoxazole 1 tab (trimethoprim/sulfamethoxazole 80/400 mg)/d po (BIII) - Dapsone 50 mg/d po + (pyrimethamine 25 mg + folinic acid 25 mg) × 2 d/wk po (BI) - (Dapsone 200 mg + pyrimethamine 75 mg + folinic acid 25 mg)/wk po (BI) - Atovaquone 1500 mg with/without (pyrimethamine 25 mg + folinic acid 15 mg)/d po (CIII)	- Suspend prophylaxis after ≥6 mo of efficacious ART, if CD4+ >200 cells/μL, and undetectable viral load for ≥3 mo (AI) - Restart prophylaxis if CD4+ <100–200 cells/μL (AIII)

Treatment
Disease	First choice	Second choice	Remarks
Focal CNS lesions (abscesses), chorioretinitis	Pyrimethamine 200 mg po (loading dose), followed by: - Pyrimethamine 50 mg/d po + sulfadiazine 1000 mg/6 h po (if <60 kg) or - Pyrimethamine 75 mg/d po + sulfadiazine 1500 mg/6 h po (if ≥60 kg) Add folinic acid 15 mg/d po in all cases (AI)	- Pyrimethamine 50–75 mg/d po + clindamycin 600 mg/6 h IV or po + folinic acid 15 mg/d po (AI) - Cotrimoxazole (trimethoprim 5 mg/kg/d + sulfamethoxazole 25 mg/kg/d) IV or po in 3–4 doses (BI) - Atovaquone 1500 mg/12 h po + pyrimethamine 50–75 mg/d po (and folinic acid 15 mg/d po) or + sulfadiazine 1000–1500 mg/6 h (BII) - Pyrimethamine 50–75 mg/d po + azithromycin 900–1200 mg/d po + folinic acid 15 mg/d po (CII)	- Minimum duration: 6 wk (prolong in extensive disease and/or slow/incomplete response) (BII) - Regimen based on clindamycin (as opposed to sulfadiazine) does not protect against pneumocystosis (add specific prophylaxis) (AII) - In cases of intracranial hypertension, add dexamethasone (BIII) - In cases of epilepsy, add anticonvulsant treatment (not as prophylaxis) (AIII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
All patients who have completed treatment of acute infection	- Pyrimethamine 25–50 mg/d po + sulfadiazine 1000 mg/6–12 h po + folinic acid 15 mg/d po (AI)	- Pyrimethamine 25–50 mg/d po + clindamycin 600 mg/8 h po + folinic acid 15 mg/d po (BI) - Cotrimoxazole 1 “forte” tab/12 h po (BII) - Atovaquone 750–1500 mg/12 h po + pyrimethamine 25 mg/d po (and folinic acid 15 mg/d po) or sulfadiazine 1000 mg/6–12 h (BII) - Pyrimethamine 25–50 mg/d po + azithromycin 500–1000 mg/d po + folinic acid 15 mg/d po	- Suspend prophylaxis if CD4+ >200 cells/μL and ART >6 mo, with undetectable viral load (BI) - Restart prophylaxis if CD4+ <200 cells/μL (AIII)

Leishmania spp.
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: Canine health surveillance (in endemic areas), use of insecticide and prevention of sandfly bites	No indication		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Visceral leishmaniasis (kala-azar): systemic disease, possible atypical local involvement	Liposomal amphotericin B 2–4 mg/kg/d IV (AII) or 4 mg/kg on days 1–5, 10, 17, 24, 31, and 38 (AII) in both cases until a total dose of 20–60 mg/kg has been reached (AII)	- Amphotericin B lipid complex 3 mg/kg/d IV (10 d) - Amphotericin B 0.5–1 mg/kg/d IV (total dose, 1.5–2 g) (BII) - Pentavalent antimony 20 mg/kg/d IV or IM ×4 wk (BII) - Miltefosine 100 mg/d po ×4 wk (CIII)	- Initiation (or optimization) of ART is essential - Some in vitro results (increased replication of HIV) cast doubt on the indication of pentavalent antimonials

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
As continuation of treatment of the acute infection, especially in patients with CD4+ <200 cells/μL	- Liposomal amphotericin B 4 mg/kg/2–4 wk (AII) - Amphotericin B lipid complex 3 mg/kg/3 wk (BI)	- Pentavalent antimony 20 mg/kg IV or IM every 4 wk (BII) - Miltefosine 100 mg/d po (CIII) - Pentamidine 300 mg/3–4 wk IV (CIII)	- Suspend prophylaxis if CD4+ >200–350 cells/μL, for >3 mo, with ART and undetectable viral load and no relapse of leishmaniasis during the previous 6 months (no consensus: some experts recommend indefinite secondary prophylaxis) - Restart prophylaxis if CD4+ <200 cells/μL

Cryptosporidium spp.
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: - Avoid consumption of contaminated water or raw foods (e.g., oysters, fruit, and vegetables). Ensure strict hygiene measures in cases of contact with infected persons or animals (BIII)	- There are no efficacious specific measures - Early ART prevents profound immunodepression and infection by Cryptosporidium		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Mainly affects patients with CD4+ <100 cells/μL - Enteritis with acute/chronic watery diarrhea - Possible sclerosing cholangitis or pancreatitis	Start ART to achieve immune recovery (CD4+ >100 cells/μL) (AII)	Can be administered as a complement to ART (CIII): - Nitazoxanide 500–1000 mg/12 h po (14 d) o - Paromomycin 500 mg/6 h po (14–21 d)	- Take strong measures to replace electrolytes (orally and IV) (AIII) - Symptomatic treatment of diarrhea with intestinal motility inhibitors (AIII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After acute infection	Maintain ART to ensure sustained immune recovery		Not applicable

Microsporidia
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: - Hand hygiene and avoid contact with/exposure to contaminated water	- No specific efficacious measures		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
More frequent involvement if CD4+ <100 cells/μL - Enteritis with watery diarrhea - Disseminated infection, e.g., keratoconjunctivitis, hepatitis, encephalitis	Start ART to achieve immune recovery (AII) + specific therapy: Gastrointestinal involvement - Enterocytozoon bieneusi: Fumagillin 20 mg/8 h po (BIII) - Other species: Albendazole 400 mg/12 h po (AII) Ocular involvement - Topical fumagillin (BII) + albendazole 400 mg/12 h po (BIII)	Gastrointestinal involvement Nitazoxanide 1000 mg/12 h po (CIII) Disseminated disease caused byTrachipleistophora species or Anncaliia species: Itraconazole 400 mg/d po + albendazole 400 mg/12 h po (CIII)	If diarrhea is intense, intestinal motility drugs could prove useful (BIII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After acute infection	Prolong treatment until clinical cure and immune recovery		- Suspend if clinical cure, with CD4+ >200 cells/μL and ART >6 mo, with undetectable viral load (CIII) - No recommendations on restarting prophylaxis

Isospora belli
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: - Avoid contact with contaminated food and water, especially in tropical and subtropical areas	Oral cotrimoxazole (trimethoprim/sulfamethoxazole) could reduce the incidence of isosporiasis, although evidence is insufficient		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Enteritis and, exceptionally, extraintestinal involvement	- Cotrimoxazole po or IV (trimethoprim/sulfamethoxazole) 160/800 mg/6 h ×10 d (AII) or 160/800 mg/12 h ×7–10 d (BI)	- Pyrimethamine 50–75 mg/d po + folinic acid 15 mg/d po (BIII) - Ciprofloxacin 500 mg/12 h po ×7 d (CI)	Adjust cotrimoxazole according to severity and patient's response (BIII) If necessary, administer nutritional and electrolyte supplements (AIII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After acute infection, if CD4+ <200 cells/μL	Cotrimoxazole (trimethoprim/sulfamethoxazole) 160/800 mg ×3 d/wk po (AI) or 160/800 mg/d po or 320/1600 mg ×3 d/wk po (BIII)	- Pyrimethamine 25 mg/d po + folinic acid 15 mg/d po (BIII) - Ciprofloxacin 500 mg ×3 d/wk po (CI)	- Suspend if no symptoms, CD4+ >200 cells/μL, and ART >6 mo, with undetectable viral load (BIII) - No recommendations on restarting prophylaxis

Primary prophylaxis should be with cotrimoxazole in patients with anti-Toxoplasma gondii IgG and a CD4+ T-lymphocyte count <100 cells/μL (AII); alternatives include pyrimethamine combined with dapsone or atovaquone.^5,8,9 These regimens also protect against Pneumocystis jiroveci infection. Inhaled pentamidine does not protect against Toxoplasma gondii infection.

When cerebral toxoplasmosis is suspected, treatment should be started with sulfadiazine combined with pyrimethamine (and folinic acid to reduce blood toxicity) (AI) and maintained for at least 6 weeks (BII).^6,8,9 A brain biopsy should be performed if no response is observed at 7–14 days. If the diagnosis is confirmed, switching treatment to clindamycin + pyrimethamine (with folinic acid) should be considered (AI).^6,8,9 If therapy cannot be administered through a nasogastric tube, intravenous cotrimoxazole can be used (BI).¹⁰ Dexamethasone should be used in cases of intracranial hypertension (BIII). Treatment with anticonvulsants—preferably levetiracetam—should be added in patients who experience convulsions (AIII).^6,8,9

Once treatment is complete, secondary prophylaxis can be started (same regimen, reduced dose) (AI).^5,8,9

Prophylaxis can be discontinued after 6 months on ART, providing the patient has maintained an undetectable viral load and a CD4+ T-lymphocyte count >200 cells/μL for ≥3 months (primary) or ≥6 months (secondary) (AI),¹¹ probably owing to recovery of the anti-Toxoplasma gondii cellular response (CD4+ T lymphocytes).¹² Prophylaxis should be restarted if the CD4+ T-lymphocyte count returns to <100–200 cells/μL (AIII).^5,8,9

Leishmania species

Prevention of exposure to parasites of Leishmania species should be based on canine health surveillance in regions where the disease is prevalent (Mediterranean basin, where L. infantum is predominant) and avoiding exposure to dogs (especially in the case of immunodepressed patients) (CIII), sandfly bites, and needle sharing. There are no primary prophylaxis measures.^5,8,9

The treatment of choice for visceral leishmaniasis is liposomal amphotericin B (AII) or amphotericin B lipid complex,^6,8,9 in various regimens. Alternatives include amphotericin B deoxycholate (renal toxicity) or pentavalent antimonials (pancreatic and cardiac toxicity) (BII). The efficacy of miltefosine and paromomycin has not been demonstrated in HIV-infected patients (CIII).¹³

Secondary prophylaxis should be administered once the acute infection has been treated (BII). Lipid formulations of amphotericin B (liposomal [AII] or lipid complex [BI]) are also drugs of choice.^5,8,9 In cases of relapse (common in very immunodepressed patients), it is necessary to repeat the initial treatment, use another regimen,^6,8,9 or administer a combination of the drugs mentioned above.

No safe recommendation can be made about withdrawal of secondary prophylaxis against Leishmania.^5,8,9 Although some experts recommend maintaining prophylaxis indefinitely, suspension should be considered in patients who remain relapse-free for 6 months, maintain a CD4+ T-lymphocyte count >200–350 cells/μL and an undetectable viral load for >3 months, and, if possible, test negative in PCR for the Leishmania antigen in blood or urine¹⁴ (CIII). Prophylaxis should be restarted if the CD4+ T-lymphocyte count falls to <200 cells/μL.^5,8,9

Cryptosporidium species, microsporidia, and Isospora belli

These ubiquitous parasites (Isospora belli predominates in tropical areas) cause mainly intestinal infection. As they are transmitted through contaminated food and water, contact should be avoided and appropriate hand hygiene measures should be taken to prevent exposure.^5,8,9 There are no efficacious primary prophylaxis regimens.

There is no specific treatment for cryptosporidiosis (CIII), and cure is based on ART-associated immune recovery (AII).^6,8,9 Treatment of microsporidiosis also depends on ART (AII), although efficacious complementary drugs are available. In intestinal infections and infections caused by Enterocytozoon bieneusi, the treatment of choice is oral fumagillin (BIII). Albendazole is recommended if other species are involved (AII). In patients with ocular involvement, albendazole can be combined with topical fumagillin (BIII).^6,8,9 The treatment of choice for isosporiasis is cotrimoxazole (BI).^6,8,9

Secondary prophylaxis for microsporidiosis and isosporiasis involves maintaining the same regimen as for treatment. This can be suspended when a CD4+ T-lymphocyte count >200 cells/μL is reached after 6 months of efficacious ART (CIII and BIII, respectively). Suspension would be questionable in ocular microsporidiosis.^5,8,9 In a recent report, isosporiasis persisted despite appropriate prophylaxis and treatment and optimal immune recovery.¹⁵

Fungal infections (Table 2)

Pneumocystis jiroveci

Prevention of exposure. Although available epidemiologic data indicate that respiratory isolation should be considered in patients with Pneumocystis jiroveci pneumonia, there is insufficient evidence to support this recommendation (CIII).¹⁶

Table 2.

Recommended regimens for the prevention and treatment of fungal infections.

Pneumocystis jiroveci
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
CD4+ <200 cells/μL (AI) or <14% (BII), history of oropharyngeal candidiasis (AII), AIDS-defining disease (BII), or if 3-monthly visits cannot be guaranteed (BII) in patients with CD4 count 200–250 cells/μL	Cotrimoxazole 1 “forte” tab (trimethoprim/sulfamethoxazole 160/800 mg) 3 times per wk po (AI)	- Dapsone 50 mg/d po + (pyrimethamine 50 mg + folinic acid 15 mg)/7 d (BI) - Atovaquone 1500 mg/d with (CIII)/without (BI) (pyrimethamine 50 mg + folinic acid 15 mg)/7 d (CIII) - Inhaled pentamidine 300 mg/mo if negative for toxoplasma IgG (−) (BI)	- Suspend prophylaxis after ≥6 mo of ART, with undetectable viral load and CD4+ >200 cells/μL ≥3 mo (AI) - Restart if CD4+ <200 cells/μl

Treatment
Disease	First choice	Second choice	Remarks
P jiroveci pneumonia	Severe forms: - Cotrimoxazole 15–20/75–100 mg/kg/d in 3–4 doses IV + oral prednisone (days 1–5: 40 mg bid; days 6–10: 40 mg qd; days 11–21: 20 mg qd (AI) Mild forms: Cotrimoxazole at same doses po (AI)	- Clindamycin 600 mg IV/po 6–8 h + primaquine 30 mg/d po (BI). Rule out G6PDH deficiency before administering primaquine - Pentamidine 4 mg/kg/d IV × 21 d (BI) - Atovaquone 750 mg/12 h po in mild forms (BI)	Severe forms: pO2 <70 mmHg or alveolar-capillary gradient >35 mmHg. When the patient's condition improves, treatment can be switched to oral cotrimoxazole

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
All patients who have completed treatment of acute infection (AI)	Cotrimoxazole 1 “forte” tab (trimethoprim/sulfamethoxazole 160/800 mg) po/d (AI)	- Dapsone 50 mg/d po + (pyrimethamine 50 mg + folinic acid 15 mg)/7 d (BI) - Atovaquone 1500 mg/d with(out) (pyrimethamine 50 mg + folinic acid 15 mg)/7 d (BI)	- Suspend prophylaxis after ≥6 mo of ART, undetectable viral load and if CD4+ >200 cells/μL ≥3 mo (AI) - Restart if CD4+ <200 cells/μl or relapse

Cryptococcus species
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
Infection by Cryptococcus species	Induction (2 wk): - Lipid amphotericin^* IV + flucytosine 25 mg/kg/6 h po (AI) Maintenance: - Fluconazole 400 mg/d po × 10 wk (AI)	Induction: - Lipid amphotericin^* IV + fluconazole 800 mg/d IV/po (BII) - Fluconazole 800–1200 mg/d IV/po ± flucytosine (BII) Maintenance: - Itraconazole 200 mg/d po (BII)	- Defer initiation of ART 5 wk (AI) - In patients with meningitis and intracranial hypertension, repeated lumbar puncture or CSF shunt (BIII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
As continuation of treatment of acute infection	- Fluconazole 200 mg/d po (AI)	- Lipid amphotericin^* every 7 d (BIII) - Itraconazole 200 mg/d po (BIII)	- Suppress prophylaxis if CD4+ >100 cells/μL and undetectable viral load for 3 mo (BII)

Candida species
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
Signs and/or symptoms of oral, esophageal, or vulvovaginal disease	Oral: - Fluconazole 100 mg/d × 7–14 d (AI) Esophageal: Fluconazole 100–200 mg/d po × 7–14 d (AI) In cases of oral intolerance, fluconazole IV (up to 400 mg/d) (AI) Vulvovaginitis: - Fluconazole 150 mg/d in a single dose (AII)	Oral (for 7–14 d): - Itraconazole 200 mg/d (BI) - Posaconazole 400 mg/d (BI) - Clotrimazole 10 mg 4–5 times per day (BI) - Nystatin suspension 5 ml/6 h (BI) - Miconazole oral gel 125 mg/6 h (BI) Esophageal (×7–14 d): - Caspofungin 70 mg first day followed by 50 mg/d IV (AI) - Voriconazole 200 mg/d (BI) - Itraconazole 200 mg/d (BI) - Posaconazole 400 mg/d (BI) - Micafungin 150 mg/d IV (BI) Vulvovaginitis (×3–7 d): - Topical clotrimazole (AII) - Topical miconazole (AII)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
	No indication

Aspergillus species
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
Focal or disseminated disease	Induction: - Voriconazole 6 mg/kg/12 h IV on day 1 followed by 4 mg/kg/12 h IV on subsequent days (AI) Maintenance: - Voriconazole 200 mg/12 h po (AI)	- Lipid amphotericin^* (AII) - Caspofungin 70 mg on day 1 followed by 50 mg/d IV (BIII) - Micafungin 100–150 mg/d IV (BIII) - Anidulafungin 200 mg el on day 1 followed by 100 mg IV/d (BIII) - Posaconazole 400 mg/12 po (BIII)	Duration not established, but should be maintained until immune recovery (CD4+ >200 cells/μL)

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
	No indication

Histoplasma capsulatum
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
Focal or disseminated disease	Severe disease: - Lipid amphotericin^* × 2 wk (AI) followed by itraconazole 200 mg/8 h po × 3 d subsequently 200 mg/12 h >12 mo (AII) Meningitis: - Lipid amphotericin^* × 4–6 wk followed by itraconazole 200 mg/8–12 h po >12 mo (AIII) Mild disease: - Itraconazole 200 mg/12 h po (AII)	Mild disease: - Posaconazole 400 mg/12 h po (BIII) Voriconazole 400 mg/12 h po × 1 d followed by 200 mg/12 h po (BIII) - Fluconazole 800 mg/d po (CII)	- H capsulatum is resistant to echinocandins

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After treatment of acute infection for 12 mo	- Itraconazole 200 mg/d (AIII)	- Fluconazole 400 mg/d po (BIII)	- Suppress prophylaxis if CD4+ >150 cells/μL × 6 mo and serum antigen <2 ng/mL (AI).

Coccidioides immitis
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
Focal or disseminated disease	Disseminated disease: - Lipid amphotericin^* until improvement followed by fluconazole 400–800 mg/d po or itraconazole 200 mg/12 h po (AII) Meningitis: - Fluconazole 400–800 mg/d IV/po (AII) Pneumonia: - Fluconazole 400 mg/d (BII) - Itraconazole 200 mg/12 h po (BII)	Disseminated disease: - Combine lipid amphotericin^* with fluconazole 400 mg/d or itraconazole 400 mg/d (BIII) Meningitis: - Itraconazole 200 mg/8 h po × 3 d followed by 200 mg/12 h (BIII) - Posaconazole 200 mg/12 h po (BIII) - Voriconazole 200–400 mg/12 h po (BIII) - Administer intrathecal amphotericin if triazoles fail (AIII) Pneumonia: - Posaconazole 200 mg/12 h po (BII) - Voriconazole 200 mg/12 h po (BIII)	- Use in meningitis. Use intrathecal amphotericin B if triazoles fail.

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After acute infection indefinitely	- Fluconazole 400 mg/d po (AII) - Itraconazole 200 mg/12 h po (AII)	- Posaconazole 200 mg/12 h po (BII) - Voriconazole 200 mg/12 h po (BIII)	In patients with pneumonia, suspend prophylaxis if CD4+ >250 cells/μL for >12 mo (AII)

Penicillium marneffei
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
	No indication

Treatment
Disease	First choice	Second choice	Remarks
	Severe disease: - Lipid amphotericin^* × 2 wk followed by itraconazole 200 g/12 h po × 10 wk (AII) Mild disease: - Itraconazole 200 mg/12 h po × 8–12 wk (BII)	Severe disease: - Voriconazole 6 mg/kg/12 h IV × 1 d, 4 mg/kg/12 h IV × 3 d, 200 mg/12 h po × 8–12 wk (BII) Mild disease: - Voriconazole 400 mg/12 h po 1 d followed by 200 mg/12 h po (BII)	- P. marneffei is resistant to fluconazole

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
After acute infection	- Itraconazole 200 mg/d po (AI)		Suppress prophylaxis if CD4+ >100 cells/μL for ≥6 mo (BII)

*

Lipid amphotericin: liposomal amphotericin B IV (3–5 mg/kg/d) (preferred owing to greater experience) or amphotericin B lipid complex IV (5 mg/kg/d).

Primary prophylaxis is indicated in patients with a CD4+ T-lymphocyte count <200 cells/μL (AI), previous oropharyngeal candidiasis (AII), CD4+ <14% (BII), or a previous AIDS-defining disease (BII). It should be considered in patients with 200–250 CD4+ cells/μL if 3-monthly visits cannot be guaranteed (BII). Secondary prophylaxis is always indicated in patients with a history of pneumonia (AI).

Cotrimoxazole is the drug of choice both for primary and for secondary prophylaxis (AI). Patients with hypersensitivity can undergo desensitization or receive alternatives such as dapsone/pyrimethamine (BI) or atovaquone with(out) pyrimethamine (BI). Inhaled pentamidine does not prevent extrapulmonary involvement; if this drug is used, it should be restricted to patients with negative toxoplasma serology results (BI). Prophylaxis can be suspended if the CD4+ T-lymphocyte count exceeds 200 cells/μL for at least 3 months after starting ART (A1).¹⁷ Some data suggest that primary prophylaxis could be suspended even with 100–200 cells/μL and an undetectable viral load (CIII).¹⁸ A recent study in children and adolescents in Africa showed that maintenance of prophylaxis with trimethoprim-sulfamethoxazole in patients with >200 CD4+ cells/μL reduced the risk of admission for bacterial infections and malaria (CI).¹⁹

Intravenous cotrimoxazole (21 days) is the treatment of choice for P. jiroveci pneumonia (AI). Treatment can be administered orally when the patient's condition improves or when the disease is mild/moderate (AI). Folinic acid is not recommended because it can increase the risk of therapeutic failure. Patients with moderate/severe disease (pO₂ <70 mmHg or alveolar-capillary gradient >35 mmHg) should start therapy with corticosteroids combined with cotrimoxazole (AI). Alternative treatments include clindamycin + primaquine or intravenous pentamidine or atovaquone (BI), although atovaquone should only be administered in mild cases.

Cryptococcus neoformans

Primary prophylaxis for infection by Cryptococcus neoformans is not indicated in Spain owing to the low incidence of the disease.

Induction treatment of meningitis should be with liposomal amphotericin + flucytosine for at least 2 weeks (AI). Alternatives include liposomal amphotericin + fluconazole or fluconazole with(out) flucytosine (BII). After 2 weeks of treatment, the regimen can be switched to fluconazole for at least 10 weeks, providing that the patient's condition has improved and the cerebrospinal fluid (CSF) culture is negative (AI). Initiation of ART should be deferred by 5 weeks owing to the risk of greater mortality associated with early initiation²⁰ (AI). Cryptococcal meningitis is often associated with increased intracranial pressure, which is treated using repeated lumbar puncture or even placement of a CSF shunt (BIII). In extrameningeal forms, the treatment of choice is fluconazole (400 mg/d) or liposomal amphotericin if the patient's condition is severe (AIII).

Secondary prophylaxis is always indicated once at least 10 weeks of treatment has been completed. The drug of choice is fluconazole (AI). Alternatives include itraconazole or weekly liposomal amphotericin (BIII). Secondary prophylaxis can be suspended when the CD4+ T-lymphocyte count exceeds 100 cells/μL with an undetectable viral load for at least 3 months (BII).²¹

Candida albicans

Primary prophylaxis of infections by Candida species is not indicated owing to the scarce morbidity and mortality associated with this disease and the risk of resistance.

Fluconazole is the treatment of choice for oral and esophageal candidiasis (AI). Alternatives include itraconazole and posaconazole (BI). In cases of exclusively oropharyngeal involvement, treatment is with topical clotrimazole or miconazole. Alternatives include nystatin suspension (BI). In the case of esophagitis, and depending on the severity of the condition, it may be necessary to use intravenous fluconazole (AI), with voriconazole or echinocandins as alternatives (in patients with resistance or toxicity) (BI).²² If no improvement is observed after 7 days of treatment, other microorganisms should be ruled out using endoscopy in the case of esophagitis and/or ruling out resistance to azoles.

Vulvovaginitis caused by Candida species can be treated with oral fluconazole (AII) or topical clotrimazole or miconazole (AII).

Secondary prophylaxis is not recommended. Fluconazole (3 times weekly) can be used in the case of very frequent relapses (CIII). However, in these cases, recurrence at any site should be considered indicative of azole resistance.⁶

Aspergillus fumigatus

Primary prophylaxis is not recommended.

The treatment of invasive aspergillosis depends on the severity of symptoms.²² Voriconazole is generally considered the drug of choice (AI). Alternatives include liposomal amphotericin (AII), caspofungin, and posaconazole (BIII). ART should be started as soon as possible, and potential drug interactions should be evaluated. The optimal duration remains unknown, although treatment should be maintained at least until the CD4+ T-lymphocyte count is >200 cells/μL.

The lack of data prevents us from making recommendations on secondary prophylaxis.

Histoplasma capsulatum

Primary prophylaxis is not recommended in Spain.

Treatment of severe infections is with liposomal amphotericin (AI) for 2 weeks,²³ followed by itraconazole for 12 months (AII) (monitor levels after 2 weeks to ensure >1 μg/mL). In patients with meningitis, administer liposomal amphotericin for 4–6 weeks (AIII) followed by itraconazole for at least 12 months (AIII). In mild forms, the drug of choice is itraconazole (AII). Alternatives include posaconazole and voriconazole (BIII) or fluconazole (CII). Histoplasma capsulatum is resistant to echinocandins.

Secondary prophylaxis is always indicated after 12 months of treatment and is with itraconazole (AIII) or fluconazole (less efficacious) (BIII). It can be suspended when the CD4+ T-lymphocyte count is >150 cells/μL for at least 6 months with undetectable HIV viral load and serum antigen <2 ng/mL (AI). Secondary prophylaxis should be restarted if the CD4+ T-lymphocyte count falls below 150 cells/μL (BIII).²⁴

Coccidioides immitis

Primary prophylaxis is not indicated in Spain.⁶

Pneumonia should be treated with fluconazole or itraconazole (BII). Alternatives include posaconazole (BII) and voriconazole (BIII). Disseminated disease is treated with liposomal amphotericin until the patient's clinical condition improves (AII) and then with fluconazole or itraconazole. Some experts recommend combining liposomal amphotericin with a triazole (BIII). Meningitis is treated with fluconazole (AII) or with itraconazole, posaconazole, or voriconazole (BIII). Intrathecal amphotericin B should be used if treatment with triazoles is inefficacious (AIII). If possible, the response should be monitored using serum antibody titers.

Secondary prophylaxis is always indicated with fluconazole or itraconazole (AII). In the absence of a response, posaconazole (BII) or voriconazole (BIII) can be administered. Given the high risk of relapse, indefinite prophylaxis is recommended in meningitis (AII) and in disseminated disease (BIII). Secondary prophylaxis can be suspended after >12 months in patients with a CD4+ T-lymphocyte count >250 cells/μL (AII).

Blastomyces dermatitidis

Prophylaxis and treatment are similar to those of histoplasmosis.

Penicillium marneffei

Primary prophylaxis is not recommended in Spain.

Treatment of the severe form is with liposomal amphotericin for 2 weeks followed by itraconazole for a further 10 weeks (AII). Voriconazole can be used as an alternative during the first 12 weeks (BII). Mild disease is treated with itraconazole (BII) or voriconazole (BII) for 8–12 weeks. P. marneffei is resistant to fluconazole.

Secondary prophylaxis, which is always indicated, is with itraconazole (AI).²⁵ It can be suspended when the CD4+ T-lymphocyte count exceeds 100 cells/μL for at least 6 months and HIV viral load remains suppressed (BII). It should be restarted if the CD4+ T-lymphocyte count falls again (AIII) or the patient experiences a recurrence with >100 cells/μL (CIII).

Viral infections

Herpes simplex virus

The most common clinical forms of herpes simplex virus (HSV) are genital herpes, which is generally caused by HSV-2, and orolabial herpes, which is usually caused by HSV-1. Recurrences are more common in genital herpes. Treatment is more efficacious if started early, during the prodromal phase, or on the day immediately following the appearance of lesions.

Antiviral therapy with nucleoside analogs is efficacious, safe, and well-tolerated. In genital herpes, it can reduce the risk of transmission of HIV-1.

Treatment of herpesvirus encephalitis is similar in HIV-infected patients and immunocompetent patients. It should be started empirically as soon as the diagnosis is suspected.

Herpetic proctitis and esophagitis respond to systemic acyclovir. Treatment is usually started intravenously and continued orally.

The possibility of resistance to antiviral drugs must be taken into consideration when lesions do not improve after 7–10 days of correctly administered treatment. Resistance should be confirmed using a sensitivity study.

Primary prophylaxis is not recommended. No vaccines are available. Secondary prophylaxis should be considered in the case of severe recurrence or to reduce the number of recurrences.²⁶

Varicella zoster virus

The incidence of infections by varicella zoster virus (VVZ) is much greater in HIV-infected patients than in the general population. VVZ infection can appear regardless of the CD4+ T-lymphocyte count. VVZ infection in adults with no known causes of immunosuppression requires HIV infection to be ruled out. The presentation and clinical course of VVZ infection can be modified in patients with advanced immunosuppression. Retinal necrosis is one of the best-characterized clinical syndromes in patients with VVZ infection.

Treatment of localized herpes zoster infection is aimed at preventing dissemination of infection (especially in immunodepressed patients and patients aged >50 years), reducing the duration of symptoms, and reducing the risk of postherpetic neuralgia. Corticosteroids are not recommended.

Initiation of acyclovir IV is recommended in patients with varicella, disseminated herpes zoster infection, or visceral involvement (see Table 3 for levels of evidence).²⁷ Acute retinal necrosis usually responds to treatment with high-dose intravenous acyclovir, which can be continued with oral valacyclovir (BIII). Intravitreal treatment can also be considered in some cases (BII).²⁸

Table 3.

Recommended regimens for prevention and treatment of viral infections.

Herpes simplex virus
Secondary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
Recurrent genital herpes	Chronic suppressive therapy with: -Valacyclovir 500 mg po/12 h (AI) or -Famciclovir 500 mg po/12 h (AI) or -Acyclovir 400 mg po/12 h (AI)		No applicable

Treatment
Disease	First choice	Second choice	Remarks
Orolabial or nonsevere genital herpes Orolabial or severe genital herpes Herpes encephalitis	-Valacyclovir 1 g po/12 h, or -Famciclovir 500 mg po/12 h, or -Acyclovir 400 mg po/8 h, Orolabial (AIII) 5–10 d, genital (AI) 5–14 d -Initial treatment with acyclovir 5 mg/kg/8 h IV until lesions begin to regress and continue with one of the oral regimens mentioned above until the lesions have resolved (AIII) -Acyclovir 10 mg/kg/8 h IV for 14–21 d (AIII)	- Herpes refractory or resistant to acyclovir, -Foscarnet 40 mg/kg IV/8 h or 60 mg/kg IV/12 h (AI), or -Cidofovir 5 mg/kg/wk IV or topical treatment with cidofovir, trifluridine, or imiquimod (compounded formulations) (CIII)

Varicella zoster virus
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
Postexposure prophylaxis Close contact with a person with active varicella or herpes zoster and susceptible to VVZ (no history of vaccination or seronegativity)	Specific immunoglobulin, as soon as possible, within 10 days of exposure (AIII)	- Acyclovir 800 mg po 5 times/d or - Valacyclovir 1 g/8 h po, 5–7 d (BIII) as long as it is started within the 7–10 days following exposure	Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Uncomplicated varicella Severe forms of varicella Localized herpes zoster Disseminated herpes zoster or herpes zoster with visceral involvement Acute retinal necrosis Rapidly progressive outer retinal necrosis Refractory herpes zoster/acyclovir-resistant VVZ	Duration: 5–7 d -Valacyclovir 1 g po/8 h (AII), or -Famciclovir 500 mg po/8 h (AII) -Acyclovir IV 10–15 mg/kg/8 h for 7–10 d (AIII) (if no visceral involvement, treatment can be completed with oral valacyclovir, famciclovir, or acyclovir) (BIII) Duration: 7–10 d -Valacyclovir 1 g po/8 h (AII), -Famciclovir 500 mg po/8 h (AII) Treatment with corticosteroids is not recommended. -Acyclovir 10–15 mg/kg/8 h IV until clear improvement in skin and/or visceral lesions (AII); oral regimens can then be started for up to 10–14 d (BIII) Acyclovir IV 10–15 mg/kg/8 h × 10–14 d followed by valacyclovir 1 g po/8 h for 6 wk (AIII) ±1 or 2 doses of intravitreal ganciclovir during the first week (BII) (Ganciclovir 5 mg/kg ± foscarnet 90 mg/kg) IV every 12 h + (ganciclovir 2 mg/0.05 mL ± foscarnet 1.2 mg/0.05 mL) administered by intravitreal injection twice weekly (AIII) • Start or optimize ART (AIII) Foscarnet 40 mg/kg IV/8 h or foscarnet 60 mg/kg IV/12 h (AII)	- Acyclovir 800 mg po, 5 times daily (BII) Acyclovir 800 mg po, 5 times daily (BII). Cidofovir 5 mg/kg IV weekly for the first 2 weeks, and fortnightly thereafter

Cytomegalovirus
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	The best form of prevention is to maintain CD4+ >100 cells/μL with antiretroviral treatment		Not applicable

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
Retinitis Other sites	Valganciclovir 900 mg/d po (AI) If the patient has received an intraocular implant, this should be replaced every 6–8 mo until the immune system has recovered (BI) There is no evidence that maintenance treatment should be administered. Induction treatment could be extended for a few weeks in cases of slow recovery	Ganciclovir 5 mg/kg IV 5–7 d/wk (AI), or Ganciclovir 10 mg/kg IV 3 d/wk (BI), or Foscarnet 90–120 mg/kg IV 5–7 d/wk (BI), or -Cidofovir 5 mg/kg IV every 2 wk with saline solution and probenecid (BI)	Suspend if CD4+ >100 cells/μL for at least 3–6 mo

Treatment
Disease	First choice	Second choice	Remarks
Retinitis with risk of blindness Peripheral retinitis Esophagitis or colitis Pneumonitis Neurologic disease Uveitis in a patient with immune reconstitution syndrome	Intravitreal injection of ganciclovir 2 mg or foscarnet 2.4 mg × 1–4 doses over 7–10 d (AIII) + valganciclovir 900 mg po/12 h for 14–21 d (AI), or a second-choice drug Valganciclovir 900 mg po/12 h durante 14–21 d (AI) Ganciclovir 5 mg/kg/12 h IV, which can be switched to oral valganciclovir 900 mg/12 h as soon as the patient is able to tolerate oral therapy (BI) for 3–4 wk or until resolution of symptoms Ganciclovir IV 5 mg/kg/12 h (CIII) or Foscarnet 60 mg/kg/8 h IV, or 90 mg/kg/12 h IV (CIII) for 3–4 wk or until symptoms have resolved Ganciclovir IV combined with foscarnet until symptoms have improved (CIII) Periocular corticosteroids or a short cycle of systemic corticosteroids (BIII)	Ganciclovir 5 mg/kg/12 h IV for 14–21 d (AI) or Foscarnet 60 mg/kg/8 h IV or 90 mg/kg/12 h IV for 14–21 d (AI), or Cidofovir 5 mg/kg/wk IV for 2 wk (BI) Ganciclovir 5 mg/kg/12 h IV for 14–21 d (AI) or Foscarnet 60 mg/kg/8 h IV or 90 mg/kg/12 h IV for 14–21 d (AI), or Cidofovir 5 mg/kg/wk IV for 2 wk (BI) Foscarnet 60 mg/kg/8 h, or foscarnet 90 mg/kg/12 h IV (BI) or Valganciclovir 900 mg/12 h po in moderate disease and providing the patient can tolerate oral therapy (BII) Ganciclovir + foscarnet (CIII)	Intravitreal injection aims to reach suitable intraocular concentrations quickly

Progressive multifocal leukoencephalopathy
Secondary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	The best form of prevention is to maintain CD4+ >100 cells/μL with antiretroviral treatment		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
	Initiate ART (AII) or optimize ART (AIII) with potent regimens that have good CNS penetration.		Corticosteroids can be used in IRIS occurring with PML (BIII)

Influenza virus
Primary prophylaxis
Indication	First choice	Second choice	Suspend/Restart
	HIV-infected patients should receive the seasonal inactivated influenza vaccine yearly (AI)		Not applicable

Resistance of VVZ to nucleoside analogs is exceptional, although it can emerge and responds to foscarnet.

Cytomegalovirus

Cytomegalovirus (CMV) disease is mainly due to reactivation in severely immunosuppressed patients (CD4+ <50 cells/μL). The most common clinical manifestations are retinitis, colitis, esophagitis, pneumonitis, polyradiculoneuritis, and encephalitis. Regular funduscopy is recommended for severely immunodepressed patients, and patients should be advised to see their doctor immediately if they experience visual disturbances. Retinitis is the most common condition. Cases involving an imminent risk of blindness (lesions near the optic nerve or macula) must be treated quickly to preserve vision. Treatment of visceral CMV infection should be on an individual basis depending on the location and severity of the process (Table 3). The treatment of choice is usually oral valganciclovir because of its efficacy, safety, and ease of administration (AI).²⁹ The best results in CMV retinitis with a high risk of loss of vision were obtained with an intraocular ganciclovir implant (BI),³⁰ which is not currently marketed. In these cases, treatment should be started with valganciclovir (AI). A 2-mg dose of intravitreal ganciclovir should also be administered and repeated at 48 h (AIII) (Table 3). CMV encephalitis should be treated with ganciclovir + foscarnet (CIII).

Progressive multifocal leukoencephalopathy

ART is the only approach to prevent progressive multifocal leukoencephalopathy (PML) and improve the T lymphocyte-mediated cell response, which is essential for control of intracerebral replication of the JC virus. Low CSF viral load and a specific cellular immune response in blood and CSF are associated with a better prognosis. Among HIV-infected patients, mortality is greater in those who have CD4+ <100 cells/μL.

Numerous drugs have been used empirically or in clinical trials in patients with PML, although none has proven effective. The best option in HIV-infected patients is to initiate ART (AII) or optimize ART (AIII) with potent regimens and good central nervous system (CNS) penetration.³¹ Prognosis improved with the advent of ART, and survival rates range from 10% per year to 40–75%, although a large percentage of patients present neurological sequelae.³² In patients who experience clinical or radiological deterioration with ART, which is suggestive of immune reconstitution inflammatory syndrome (IRIS), observational studies suggest prescribing dexamethasone without interrupting ART (BIII).

Influenza virus

Seasonal influenza is a frequent cause of respiratory disease in HIV-infected patients. Early studies from the pre-ART era showed that the mortality and complication rates were higher in this population. Studies carried out during the influenza pandemic revealed a greater incidence and more complications in patients with ART or low CD4+ T-lymphocyte counts. However, patients with good virological control who were taking ART had complication rates that were similar to those of the general population.

Early treatment with oseltamivir or zanamivir is recommended in HIV-infected patients suspected of having severe influenza (AI). Prophylaxis with these drugs is recommended in unvaccinated patients with low CD4+ T-lymphocyte counts who have been in close contact with patients with influenza (AI).³³ HIV-infected patients should receive the seasonal inactivated influenza vaccine yearly (AI).³⁴

Mycobacterial infection

Mycobacterium tuberculosis

Treatment of mycobacterial infections in HIV-infected patients is generally the same as in non-HIV-infected patients. As a rule, patients infected with Mycobacterium tuberculosis who are sensitive to all drugs should receive isoniazid, rifampicin, pyrazinamide, and ethambutol (2 months) followed by isoniazid and rifampicin (for a further 4–7 months) (AI). A 6-month course is sufficient for most HIV-infected patients with tuberculosis (TB). The continuation phase should be extended to 7 months if there is a delay in reaching negative values in the sputum culture (>2 months), in patients with a CD4+ T-lymphocyte count <100 cells/μL, and in patients whose adherence is questionable (in these cases every attempt should be made to administer therapy directly) (BII). Drugs should be taken daily, as opposed to regimens of 3 or 5 days per week (AI). Fixed-dose combinations should be used (BI). For specific situations, please consult our TB consensus document.³⁵

All HIV-infected patients who develop TB should receive ART, regardless of their CD4+ T-lymphocyte count and viral load, since it reduces the risk of death (AI). The best time to start depends on the CD4+ count. If it is <50 cells/μL, ART should be started as soon as possible after verifying tolerance to TB treatment and no later than the first 2 weeks after starting tuberculostatic treatment (AI). If the CD4+ count is >50 cells/μL, initiation of ART can be deferred until the intensive phase of TB treatment has been completed (8 weeks). With this approach, the risk of adverse effects and IRIS is reduced without compromising survival (AI).^36–38 However, the ideal time to initiate ART in patients whose disease first manifests with tuberculous meningitis remains unknown. Rifampicin interacts with antiretroviral drugs that are metabolized via the CYP3A4 enzyme system. Rifampicin must be included in anti-TB treatment regimens in HIV-infected patients. Therefore, ART should be adjusted to take potential drug interactions into account (Table 4).³⁹

Table 4.

Recommendations for using antiretroviral drugs with rifampicin.^a

Drug of choice	Alternative^a^,^b	Do not administer
Efavirenz (600 mg/d)	Nevirapine (200 mg/12 h) Raltegravir (800 mg/12 h)^c	Etravirine Rilpivirine Elvitegravir Ritonavir-boosted protease inhibitor^d

a

No interactions have been reported with nucleoside reverse transcriptase inhibitors. Therefore, all members of the family can be used. The table only shows drugs used as a third agent.

b

Alternatives with which little clinical experience is available and which are based mainly on pharmacokinetic models include maraviroc (600 mg/12 h) or dolutegravir (50 mg/12 h in patients without integrase inhibitor mutations).

c

The results of a phase II trial showed no differences in the outcome of patients with tuberculosis between doses of 400 mg/12 h and 800 mg/12 h. Given that this was not the main endpoint, the Summary of Product Characteristics continues to recommend 800 mg/12 h.

d

If it is necessary to use a ritonavir-boosted protease inhibitor, rifampicin can be replaced by rifabutin, taking into account the necessary dose adjustments.

As for prevention of TB, all HIV-infected patients should undergo screening for latent TB using the tuberculin skin test or a specific interferon gamma release assay to evaluate the risk of developing TB (AI). Specific testing for cutaneous anergy is not required. The ideal frequency for repeating the tuberculin skin test is unknown in patients whose first result is negative. We suggest that it should always be repeated after confirmed exposure to a patient with active bacilliferous TB and every 2–3 years in all patients with a negative result in the first test (BIII). There are no data to support recommending a prevalence threshold above which the frequency of the tuberculin skin test should be repeated.

Treatment of latent tuberculosis infection is indicated in all patients with a positive tuberculin skin test result (induration of ≥5 mm) or who have had a positive result in the past, regardless of the CD4+ T-lymphocyte count, and in whom active disease can reasonably be ruled out (AI).

The regimen of choice continues to be daily isoniazid for 6–9 months (AI). Alternatives include isoniazid (300 mg/d) + rifampicin (600 mg/d) for 3 months (AII) or rifampicin (600 mg/d) for 4 months in cases of toxicity or resistance to isoniazid (BIII). Secondary prophylaxis (maintenance treatment) is not required.

Mycobacterium avium complex

Treatment of disseminated Mycobacterium avium complex (MAC) should be with a combination of drugs. Clinical trials performed during the pre-ART era^40,41 showed that a regimen containing clarithromycin (500 mg/12 h) + ethambutol (15 mg/kg/d) ± rifabutin (300 mg/d) administered over 12 months to reduce resistance is efficacious and the treatment of choice (AI). If rifabutin is used, the dose should be adjusted if the antiretroviral regimen includes a protease inhibitor or efavirenz. The interaction between clarithromycin and efavirenz should be taken into account.

The regimens of choice for preventing disseminated MAC infection are clarithromycin (500 mg/12 h) or azithromycin (1200 mg, once weekly)^42,43 (AI). However, this prophylaxis has never been recommended in Spain in severely immunodepressed patients (<100 cells/μL) owing to the low incidence of the disease. Primary prophylaxis can be interrupted when patients reach a CD4+ T-lymphocyte count >100 cells/μL for a period longer than 3–6 months with antiretroviral therapy (AI). Secondary prophylaxis cannot be used in MAC, and treatment must be maintained until the CD4+ T-lymphocyte count recovers to >100 cells/μL (AI).

Other mycobacteria

Mycobacteria other than M. tuberculosis and MAC can occasionally cause OIs in HIV-infected patients with different degrees of immunosuppression. No specific recommendations are available for treatment and prevention of these diseases except for those that apply to non-HIV-infected patients with infection by environmental mycobacteria.

Infections caused by other bacteria

Recommendations for the treatment of bacterial respiratory infection caused by Streptococcus pneumoniae, less prevalent bacteria (Haemophilus influenzae type b, Pseudomonas aeruginosa, and Staphylococcus aureus), and unusual bacteria (Nocardia species or Rhodococcus equi) are similar for HIV-infected and non-HIV-infected individuals.^6,9 Treatment of intestinal infections caused by Salmonella species, Campylobacter species, or Clostridium difficile is similar to that administered to the general population, except in the case of severely immunodepressed HIV-infected patients, who are at risk of recurrent bacteremia caused by Salmonella species.^6,9 The incidence of infections by Bartonella species and Listeria monocytogenes is very low and recommendations for treatment are similar to those of the general population.^6,9 Please see Table 5 for the indications for specific treatment.

Table 5.

Recommended regimens for prevention and treatment of bacterial infections.

Streptococcus pneumoniae
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
All adult patients Prevention: Annual seasonal influenza vaccination (A-I) Smoking cessation (A-III)	No recommendation for prophylactic antibiotic treatment. -Patients not previously vaccinated: 13-valent pneumococcal conjugate vaccine (13-PCV) 1 dose, regardless of CD4+ (A-II) At 8 weeks: 23-PPV - If CD4+ >200: 1 dose (A-II) - If CD4+ <200: same regimen as CD4+ >200 or wait until CD4+ >200 (C-III) -Patients who have previously received 23-PPV Consider 1 dose of 13-PCV at 12 months (C-III) Similarly, consider revaccination with 23-PPV at 5 years (CIII) and recommend a dose after age 65 (BIII)	Not applicable	Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Pneumonia Sinusitis	Intermediate resistance and sensitivity: Penicillin G sodium 6–12 MU/d IV (A-II) Amoxicillin 1 g/8 h po (A-II) Amoxicillin-clavulanic acid 2000/125 mg/12 h po (A-II) Ceftriaxone 2 g/d IV A-II) Resistance Ceftriaxone 2 g/d IV (A-II)	Levofloxacin 500 mg IV/po (A-II) Vancomycin 1 g/12 h IV (B-III)	Early initiation of empirical therapy Duration: 7–10 d

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Does not require suppressive antibiotic therapy (B-III)

Haemophilus influenzae
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
All adult patients	No recommendation for antibiotic prophylaxis No recommendation for anti- Haemophilus influenzae b vaccine	Not applicable	Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Pneumonia Sinusitis	Non-betalactamase-producing strain Ampicillin 1–2 g/4–6 h IV (A-II) Amoxicillin 500 mg/8 h po (A-II) Betalactamase-producing strain Amoxicillin-clavulanic acid 2000/125 mg/12 h po (A-II) Ceftriaxone 2 g/d IV (A-II)	Levofloxacin 500 mg IV/po (A-II) Azithromycin 500 mg po (B-III)	Non-typable strains are more common in adults and not covered by the vaccine

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Does not require suppressive antibiotic therapy (B-III)

ART has proven to be the most effective measure for reducing the incidence of HIV-associated bacterial infections. During 2002–2007, the incidence of invasive infections caused by S. pneumoniae was higher than in the general population, with increased mortality associated with disease severity and the presence of comorbid conditions, especially in patients with liver cirrhosis.^9,44

These data supported the recommendation for primary prophylaxis with the 23-valent pneumococcal polysaccharide vaccine (23-PPV),⁴⁵ whose efficacy was considered controversial until the extended follow-up of the only randomized clinical trial and results from observational studies suggested a moderate benefit.^45,46

The 7-valent pneumococcal conjugate vaccine (7-PCV) proved highly efficacious in children and had an indirect effect on adults. 7-PCV has been replaced by the 13-valent pneumococcal conjugate vaccine (13-PCV). No data are available on 13-PCV in HIV-infected patients. However, a double-blind randomized trial comparing 7-PCV with placebo performed in patients in Malawi, most of whom had not received ART and who had experienced a previous episode of invasive pneumococcal disease, revealed an efficacy of 75%.⁴⁷ Other studies revealed a more favorable immunogenic response with a dose of 7-PCV followed by a dose of 23-PPV.^45,48

HIV-infected adults who have not been vaccinated should receive a dose of 13-PCV, regardless of their CD4+ T-lymphocyte count (AII). Patients with CD4+ ≥200/μL should subsequently receive a dose of 23-PPV at least 8 weeks after the dose of 13-PCV^45,48,49 (AII). In the case of patients with a CD4+ T-lymphocyte count <200 cells/μL, the same strategy can be used or the dose of 23-PPV can be deferred until the CD4+ T-lymphocyte count increases to >200 cells/μL^45,49 (CIII).

The duration of protection with 23-PPV is unknown. In the case of patients who have already received 23-PPV, a dose of 13-PCV can be considered after at least 12 months^45,48,49 (CIII). Similarly, revaccination with 23-PPV can be considered after 5 years (CIII), and a dose can be recommended after age 65 years (BIII).⁴⁵

The annual seasonal influenza vaccination is recommended for prevention of bacterial pneumonia (AI), as is smoking cessation (AIII).^9,49

No indications have been proposed for vaccination against H. influenzae type b or N. meningitidis in HIV-infected adults.^9,49 Primary antibiotic prophylaxis is not recommended against diseases associated with Bartonella species or Listeria monocytogenes.⁹

Imported parasitic diseases

Immigration, international travel, and more favorable prognosis in HIV-infected persons mean that imported parasitic infections are increasingly common in the HIV-infected population. This section only addresses more severe parasitic diseases or those that act opportunistically in HIV-infected patients.

Malaria (especially malaria caused by Plasmodium falciparum) is one of the most relevant infections, since it affects both severely immunodepressed patients and those with normal CD4+ T-lymphocyte counts. Furthermore, a bidirectional negative interaction has been identified between HIV and Plasmodium species.⁵⁰ Undoubtedly, the population most at risk of infection by Plasmodium species in our setting is that formed by immigrants who travel to their home country without having received chemoprophylaxis. Malaria is a key cause of fever in travelers who return from tropical countries, especially if they are from Sub-Saharan Africa. Given that the patient's condition can deteriorate rapidly (in only a few hours), a high level of diagnostic suspicion and early treatment are necessary. The indications for treatment are the same as for non-HIV-infected persons (Table 6).⁵¹ Close monitoring is recommended, especially in patients with low CD4+ T-lymphocyte counts, since the clinical manifestations in this group are usually more severe. Please consult potential interactions between antimalarial and antiretroviral drugs when considering treatment and chemoprophylaxis (www.interaccionesvih.com;http://www.hiv-druginteractions.org).⁵²

Table 6.

Recommended regimens for the prevention and treatment of imported parasitic diseases.

Plasmodium falciparum
Primary prophylaxis^*
Indication	First choice	Second choice	Suspend/restart/remarks
Prevention of exposure Pretravel consultation on the need for chemoprophylaxis and best drug. Antimosquito measures: repellent, long trousers and sleeves, mosquito nets.	Atovaquone-proguanil (Malarone^® 250 mg/100 mg) 1 tab/d. Start 1 day before arrival, take throughout stay, and continue 7 days after leaving the malaria-endemic region (AIII). Mefloquine (Lariam^® 250 mg), 1 tab once weekly. Start 1 wk before arrival, take throughout stay, and continue 4 wk after leaving the malaria-endemic region (AIII). Doxycycline, 100 mg/d. Start 1 day before arrival, take throughout stay, and continue 4 wk after leaving the malaria-endemic region (AIII).		Not applicable Doxycycline is contraindicated as chemoprophylaxis during pregnancy. Atovaquone-proguanil is contraindicated during the first trimester, although it could be considered during the second and third trimesters (AIII).

Treatment^*
	First choice	Second choice	Remarks
Nonsevere malaria	Dihydroartemisinin-piperaquine (Eurartesim^® 40 mg/320 mg) <75 kg, 3 tab/d × 3 d (total of 9 tabs) 75–100 kg, 4 tab/d × 3 d (total of 12 tabs), or Atovaquone-proguanil (Malarone^® 250 mg/100 mg) 4 tabs/d × 3 d (total of 12 tabs), or Artemether-lumefantrine (Riamet^® or Coartem^® 20 mg/120 mg) 4 tabs at 0, 8, 24, 36, 48, and 60 h (total of 24 tabs) (AIII)	Quinine sulfate (300–325 mg tab) 2 tabs/8 h + doxycycline 100 mg/12 h × 7 d (total of 56 tabs) (AIII)	Artemisinin derivatives are contraindicated during the first trimester. In these cases, quinine sulfate should be administered (300–325 mg tab) as 2 tabs/8 h + oral clindamycin 450 mg/8 h for 7 d.
Severe malaria	Artesunate 2.4 mg/kg IV. Repeat dose at 12 h, 24 h, and every 24 h until oral treatment can be started. It should be administered for at least 24 h (3 doses). Sequential treatment should also be administered after IV artesunate (AIII)	Quinine 20 mg/kg IV as the initial dose in dextrose solution over 4 h, followed by 10 mg/kg over 4 h every 8 h (maximum 1800 mg/d) associated with clindamycin 10 mg/kg/12 h IV or doxycycline 100 mg/12 h for 7 d. The patients should be monitored for hypoglycemia and heart arrhythmias when quinine is administered intravenously. Do not administer loading dose and start with 10 mg/kg if the patient has been exposed to chloroquine, oral quinine, or mefloquine (AIII).	Artemisinin derivatives are contraindicated during the first trimester (although the risk-benefit ratio should be evaluated in very severe cases). Quinine IV combined with clindamycin IV should be used in the first trimester.

P. vivax, P. ovale, P. malariae, and P. knowlesi
Primary prophylaxis^*
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: As in P. falciparum	Oral chloroquine (Resochin^® o Dolquine^® 155 mg base), 2 tabs once weekly. Start 1 wk before arrival, administer during the stay, and continue 4 wk after leaving the malaria-endemic region (AIII). Atovaquone-proguanil (Malarone^® 250 mg/100 mg) or mefloquine (Lariam^® 250 mg) at the same doses and in the same regimens as for prevention of P falciparum (AIII).		Not applicable Doxycycline is contraindicated as chemoprophylaxis during pregnancy. Atovaquone-proguanil is contraindicated during the first trimester, although it could be considered during the second and third trimesters (AIII).

Treatment
Disease	First choice	Second choice	Remarks
Nonsevere malaria	Oral chloroquine (Resochin^® o Dolquine^® 155 mg base) at an initial dose of 4 tabs followed by 2 tabs at 6, 24, and 48 h (4 + 2 + 2 + 2 = 10 tabs) If P. vivax, add primaquine (Primaquine^® 7.5 mg base) 30 mg base = 4 tabs/d × 2 wk Si P. ovale, add primaquine (Primaquine^® 7.5 mg base) 15 mg base = 2 tabs/d × 2 wk (AII)	Artemether-lumefantrine (Riamet^® or Coartem^® 20 mg/120 mg) 4 tabs at 0, 8, 24, 36, 48, and 60 h (total 24 tabs)	Primaquine can cause severe hemolytic anemia in persons with G6PDH deficiency. It is contraindicated during pregnancy owing to the risk of hemolytic anemia in the fetus. Oral chloroquine should be given in 2 tabs (300 mg)/wk until delivery in order to prevent relapse.

Trypanosoma cruzi (Chagas disease)
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: Avoid vector stings/bites and consumption of potentially contaminated juices in endemic areas. Transmission via blood transfusion is possible but rare (AIII)	- Early ART prevents severe immunodepression and reduces the risk of reactivation		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Treat acute infections, chronic infections (especially recent infections) if no contraindications or advanced heart disease, and reactivations. Reactivations affect patients with a CD4+ T-lymphocyte count <200 cells/μL (especially <100 cells/μL)	Benznidazole 5–8 mg/kg/d po divided into 2 doses for 60 d (AIII)	Nifurtimox 8–10 mg/kg/d po divided into 2–3 doses for 60–90 d (AIII)	Start antiretroviral therapy early in reactivations. Benznidazole and nifurtimox are contraindicated during pregnancy, except for reactivations, in which case it is necessary to evaluate the risk of a disease that can place the mother's life in danger against the theoretical risk of fetal malformations. Both drugs should be used with caution in patients with kidney or liver failure.

Secondary prophylaxis
Indication	First choice	Second choice	Suspend/restart
After a reactivation	Early initiation and maintenance of ART Benznidazole 5 mg/kg/d for 3 d/wk or 200 mg/d (CIII)		Suspend when the CD4+ T-lymphocyte count reaches 200–250 cells/μL and viral load is undetectable for at least 6 months

Strongyloides stercoralis
Primary prophylaxis
Indication	First choice	Second choice	Suspend/restart
Prevention of exposure: Avoid walking barefoot or allowing skin to come into contact with potentially contaminated surfaces in order to prevent contact with infective filariform larvae.	Not applicable		Not applicable

Treatment
Disease	First choice	Second choice	Remarks
Acute and chronic strongyloidiasis	Ivermectin 200 μg/kg/d po in a single dose. Repeat the dose after 1 wk or 2 wk. In the case of hyperinfestation syndrome or disseminated strongyloidosis, administer a daily dose of ivermectin until stool and/or sputum samples are negative (AIII).	Albendazole 400 mg twice daily for 7 d po (BIII)	Treat early if strongyloidosis is suspected or confirmed, especially if antiretroviral therapy has not been initiated (CIII)

*

Before prescribing, consult potential interactions between the antiparasitic drugs selected and antiretroviral drugs (www.interaccionesvih.com;http://www.hiv-druginteractions.org).

Acute Trypanosoma cruzi infection is almost exclusive to endemic areas (from the south of the United States of America to the north of Chile and Argentina). It is often asymptomatic and, if not treated, can progress to chronic disease. Approximately 20–40% of patients develop visceral involvement (mainly the heart). In Europe, the most common form of transmission is vertical transmission (5% risk); infection associated with transfusions or organ transplantation has been reported only exceptionally. In HIV-infected patients with chronic T. cruzi infection, this protozoan disease behaves like an OI; therefore, patients from an endemic area should be screened (AIII).⁵³ Reactivations usually affect patients with CD4+ T-lymphocyte counts <200 cells/μL, especially when counts fall to below 100 cells/μL. At this level of immunodepression, Chagas disease more commonly affects the central nervous system (in the form of space occupying lesions [chagomas] or meningoencephalitis), followed by the heart (mainly myocarditis). Cardiac involvement during a reactivation is sometimes difficult to distinguish from heart disease in a chronically infected patient. Diagnosis of chronic disease is based on serology findings, whereas diagnosis of reactivations is essentially based on direct parasitology (blood, CSF, or other body fluids) or histopathology. Benznidazole is the first choice for treatment, followed by nifurtimox, with which less experience is available (AIII) (Table 6). Duration, dose, interactions, and need for secondary prophylaxis have yet to be resolved.^52,53 Posaconazole has not proven useful for this indication.⁵⁴ The scarce data available on the effect of early initiation of ART does not seem to indicate the involvement of immune reconstitution phenomena in the CNS. Therefore, and given the high morbidity and mortality of reactivations, early initiation of ART is recommended (AIII).

Strongyloidiasis is a helminth infestation that can become chronic owing to an autoinfection cycle; therefore, it should be suspected even many years after the patient has resided in or traveled to an endemic area. The most severe form is hyperinfection syndrome, which is more common in persons treated with corticosteroids or coinfected by HTLV-1.⁵⁵ However, in HIV-infected patients, this clinical presentation is very unusual and is observed more as IRIS (when the CD4+ T-lymphocyte count recovers) than a condition associated with severe immunodepression.^56,57 Treatment is summarized in Table 6.

Immune reconstitution inflammatory syndrome

IRIS is caused by restoration of the cellular inflammatory response in very immunodepressed patients who initiate ART.⁵⁸ It has 2 manifestations: unmasking IRIS, which reveals a pre-existing occult OI, and paradoxical IRIS, which involves clinical deterioration of a previously diagnosed OI that has been treated appropriately.⁵⁹

Diagnosis is by exclusion, that is, ruling out other possible causes of worsening after initiating ART, such as drug-induced toxicity, failure of ART, failure of antimicrobial therapy, or the presence of intercurrent diseases.

The severity of symptoms should be evaluated to determine the need for treatment and the risk-benefit ratio of potential interventions.⁶⁰ The objectives of treatment are to minimize morbidity and mortality and sequelae, improve symptoms, and reduce disease duration. Corticosteroids are the treatment of choice and are used mainly in IRIS caused by mycobacteria and fungi; their use is controversial in viral infections, and they are contraindicated in Kaposi sarcoma. The only randomized trial available⁶¹ compared prednisone (1.5 mg/kg/d for 2 weeks and 0.75 mg/kg/d for a further 2 weeks) blind with placebo in patients with TB or IRIS. In patients whose condition worsened, prednisone was added open-label. Prednisone reduced the duration of hospitalization and symptoms, with no differences in mortality. Some patients required a longer course of treatment. Nonsteroidal anti-inflammatory drugs can prove useful in patients with mild symptoms.⁶² Other drugs (IL-2, GM-CSF, infliximab, and maraviroc) are considered experimental. Patients with lymph node abscess may require repeated aspiration or surgical drainage. Lastly, it is important to remember that antimicrobial treatment must be optimized when possible and that it is not recommended to suspend ART.

Our observations for IRIS can be summarized as follows: (a) In the presence of IRIS, neither ART nor antimicrobial therapy can be suspended; (b) Mild forms of IRIS can improve with nonsteroidal anti-inflammatory drugs (B-III); and (c) Corticosteroids are recommended for treatment of IRIS in patients with moderate-severe manifestations associated with mycobacteria and CNS involvement (A-II).

Conflict of interest

These authors and reviewers have not received any aid or grant related to this document.