Approach

For most people living with HIV (PLWH) with an acute opportunistic infection (OI), antiretroviral treatment (ART) should be considered within the first 2 weeks of initiation of acute OI treatment, unless the patient has cryptococcosis or tuberculous meningitis. Early initiation of ART reduces HIV progression and mortality in people with acute OIs.[194][195][196]​​

When an OI occurs within 12 weeks of starting ART, treatment for the OI should be started and ART should be continued.

This topic covers management of HIV-related opportunistic infections in non-pregnant adults. Consult guidelines for management during pregnancy and in children.

Mycobacterium tuberculosis infection

In PLWH with negative acid-fast smears but high clinical suspicion of tuberculosis (TB), antituberculous therapy should be given regardless of the results of rapid diagnostic tests.[144][197]

Early diagnosis and treatment of TB are critical and should follow the general principles developed for TB treatment in non-PLWH. Directly observed therapy is strongly encouraged to provide effective therapy, prevent resistance, and to allow cure with a relatively short course of treatment (6-9 months). Video directly observed therapy (vDOT) is the use of video calls to view patients ingesting their medications remotely. The Centers for Disease Control and Prevention recommend the use of vDOT as equivalent to in-person DOT for patients undergoing tuberculosis treatment.[198]​ The treatment plan should be based on completion of the total number of recommended doses ingested rather than the duration of treatment administration.

Treatment of TB is provided in two phases: an initial intensive phase, followed immediately by a continuation phase. The use of ART among patients treated for TB is complicated by drug interactions, drug toxicity profiles and immune reconstitution. Empirical 4- (or 5-) antituberculous drug therapy should be started while susceptibility tests are pending. Potential drug-drug interactions should be carefully assessed and ART and TB regimens should be adjusted accordingly.

Preferred therapy

  • Intensive phase: isoniazid, rifampicin or rifabutin, pyrazinamide, and ethambutol are given daily (5-7 days per week) for 2 months (8 weeks).[1][199][200]​​ Ethambutol should be stopped if the isolate is sensitive to isoniazid, rifampicin, or rifabutin.[1]

  • Continuation phase: isoniazid and rifampicin or rifabutin are continued, usually for 4 months (18 weeks).[1][199][200]

  • The optimal duration of treatment is not known. For the majority of patients, 6 months of therapy is probably adequate (2 months of initial phase and 4 months of continuation phase), but prolonged therapy is recommended in some cases. A total duration of therapy of 6 months is recommended for drug-susceptible pulmonary TB, and for extrapulmonary TB other than disseminated extrapulmonary TB or TB of the central nervous system (CNS), bone or joint. A total of 9 months is recommended for pulmonary TB with positive culture at 2 months of treatment, severe cavitary disease or disseminated extrapulmonary TB, 9-12 months for extrapulmonary TB with CNS involvement, and 6-9 months for extrapulmonary TB with bone or joint involvement.[1][199][200]

Alternative therapy

  • An alternative treatment option for patients with drug-susceptible pulmonary TB and HIV infection with a CD4 count ≥100 cell/microlitre who are receiving an efavirenz-based antiretroviral regimen is a 4-month rifapentine-moxifloxacin-based regimen. This regimen is not recommended for patients with extrapulmonary TB.[1][200]

  • Intensive phase: isoniazid, rifapentine, moxifloxacin, and pyrazinamide are given daily for 2 months (8 weeks).

  • Continuation phase: isoniazid, rifapentine, and moxifloxacin are given daily for 9 weeks.

  • An international, randomised, controlled, open-label phase 3 non-inferiority clinical trial found that a 4-month daily treatment regimen containing high-dose (optimised) rifapentine with moxifloxacin is as effective as the standard daily 6-month regimen in the treatment of pulmonary TB.[201]

All PLWH treated with isoniazid should receive pyridoxine supplementation to help prevent isoniazid-associated neuropathy.[1]

Adjunctive corticosteroid therapy should be considered in PLWH with TB involving the CNS.[1]

For patients with a low risk of exposure and transmission of M tuberculosis infection, chronic suppressive treatment after successful completion of initiation and continuation phases of treatment for latent or active TB infection is not necessary.

Resistant cases and treatment failure of TB

  • Patients with isoniazid resistance should receive a regimen consisting of rifabutin or rifampicin, pyrazinamide, and ethambutol, with a fluoroquinolone (moxifloxacin or levofloxacin) for 6 months.[1]​​[202]

  • For TB resistant to other TB drugs, therapy depends on individual resistance pattern and consultation with an experienced specialist is needed for multidrug-resistant TB (MDR-TB). A history of treatment for TB has been the only predictor for MDR-TB in a cohort of PLWH with TB.[203] Patients with MDR-TB are at high risk for treatment failure and relapse. Treatment regimens for MDR-TB should be individualised.[1][202]​​

Patients on ART and TB treatment

  • Rifamycins are essential components of regimens for treatment of TB. However, substantial adverse pharmacological interactions occur between rifamycins and commonly used ART medicines (e.g., protease inhibitors [PIs] and non-nucleoside reverse transcriptase inhibitors [NNRTIs]) as a result of changes in drug metabolism resulting from induction of the hepatic cytochrome P-450 (CYP450) enzyme system. Rifabutin and rifampicin are considered to be comparable in efficacy. Rifabutin has fewer drug-drug interactions than rifampicin since it is a less potent CYP inducer, yet it tends to be more expensive and less widely available.[204]

  • ART is recommended in all PLWH with TB.[1][200][205]​​​ For ART-naïve patients, US guidelines recommend that ART should be started within 2 weeks of TB therapy when the CD4 count is <50 cells/microlitre, and within 8 weeks for those with higher CD4 counts.[1][199]​​ Guidelines also recommend that in those with TB involving the central nervous system, initiation of ART should be delayed until 8 weeks of TB treatment has been completed, regardless of CD4 count.[1][199]​​ World Health Organization guidelines recommend that ART be started as soon as possible within two weeks of starting TB treatment, regardless of CD4 count unless the patient has TB meningitis (when ART is delayed for 4-8 weeks).[200] Starting ART early in severely immunosuppressed PLWH with TB is associated with decreased mortality and a lower rate of disease progression, but with a high rate of immune reconstitution inflammatory syndrome (IRIS). In one meta-analysis, early initiation of ART in PLWH with newly diagnosed TB improved survival only in those with CD4 count less than 50 cells/microlitre, but was associated with a twofold higher frequency of TB-IRIS.[206] Considering that patients need to start 5-7 new medications in a short time, it is important to offer them adherence support.

Disseminated Mycobacterium avium complex (MAC) disease

Initial treatment

  • All isolates should be tested for drug susceptibility since rates of drug resistance are high.[207]

  • It is imperative that PLWH with disseminated MAC receive suppressive ART, since concurrent treatment with ART and MAC medications is associated with improved outcomes and lower rates of relapse. Since disseminated MAC may lead to impaired gastrointestinal absorption, monitoring therapeutic drug levels may be considered.[208]

  • Treatment should include a macrolide (either azithromycin or clarithromycin) plus ethambutol. Some experts also recommend the addition of rifabutin, while carefully considering potential drug-drug interactions, especially if the patient is not responding to ART or has severe disease.[1][209]

  • The addition of an intravenous aminoglycoside (such as amikacin) should be considered as part of the initial regimen for patients with advanced immunosuppression (CD4 count <50 cells/microlitre), high mycobacterial load, or those who are not receiving suppressive ART. Additional agents that may be considered in combination with the above, if active, include streptomycin and the fluoroquinolones (levofloxacin or moxifloxacin).[1][210]

  • For patients already on ART, close monitoring for any drug interactions between ART and anti-mycobacterial drugs is important.

  • ART should be initiated as soon as possible after the diagnosis of disseminated MAC and preferably at the same time, if the patient is not already on ART.[1]

Lifelong secondary prophylaxis (chronic maintenance therapy) is recommended for patients with disseminated MAC infection, unless immune reconstitution occurs as a result of ART.[211] Patients who remain asymptomatic after completing more than 12 months of treatment for MAC, and have a sustained increase (>6 months) in their CD4 counts to greater than 100 cells/microlitre after ART, can discontinue secondary prophylaxis. Chronic maintenance therapy/secondary prophylaxis may be reintroduced if CD4 count decreases to levels consistently below 100 cells/microlitre and a fully suppressive ART regimen is not possible.[1]

Pneumocystis jirovecii pneumonia (PCP)

Trimethoprim/sulfamethoxazole (TMP/SMX) is the treatment of choice and should be given orally to those with mild disease who do not have gastrointestinal dysfunction; it should be given intravenously for patients with severe disease or for patients who are unable to receive or absorb medications.[1][212]​​ Patients who develop PCP while on TMP/SMX for prophylaxis are usually effectively treated with standard doses of TMP/SMX.

For stable patients with mild-to-moderate disease (defined as arterial blood gas room air pO₂ ≥70 mmHg or an alveolar-arterial [A-a] gradient ≤35 mmHg), oral outpatient therapy with TMP/SMX is highly effective. Alternative treatments include dapsone plus trimethoprim, primaquine plus clindamycin, and atovaquone suspension.[1]

Duration of therapy is 21 days.[28]

Moderate-to-severe disease is defined as pO₂ <70 mmHg or arterial-alveolar O₂ gradient >35 mmHg on room air. For patients with respiratory compromise, intensive care unit admission and ventilator support should be offered when appropriate.[213]

Intravenous TMP/SMX is initiated with switching to oral therapy after clinical improvement. Patients generally improve clinically within 4-8 days.[214]​ Alternative regimens may be considered if there is no clinical improvement after 4-5 days or if the patient is intolerant of TMP/SMX. These include intravenous pentamidine , or clindamycin plus primaquine. While it has been shown to be effective, pentamidine is associated with potentially life-threatening toxicities, including severe renal dysfunction and QT interval prolongation.[215]

Adjunctive corticosteroids should be given to all patients with moderate to severe disease, i.e., those with a partial pressure of oxygen of <70 mm Hg on room air or an A-a oxygen gradient of ≥35 mmHg. If an arterial blood glass is not obtained, an oxygen saturation of <92% on room air can be used as a surrogate marker for moderate to severe disease.[1][216] Corticosteroids should also be considered for patients who develop worsening respiratory symptoms after initiation of treatment.

ART should be initiated in patients not already on it within 2 weeks of diagnosis of PCP when possible.[1]

Lifelong secondary prophylaxis should be considered for all the patients who have a history of PCP, unless immune reconstitution occurs as a result of ART.[1][213][217] Secondary prophylaxis options are based around those regimens used to treat initial disease. These include TMP/SMX, dapsone, dapsone plus pyrimethamine and folinic acid, atovaquone, and aerosolised pentamidine.

Toxoplasma gondii encephalitis

Initial therapy should consist of the combination of pyrimethamine plus sulfadiazine plus folinic acid, all administered orally. Folinic acid is used to protect against the haematological toxicities associated with pyrimethamine.[218]​ Although this is the preferred regimen, the high cost and limited availability have become a major barrier to its use in the US. TMP/SMX has become an alternative, and can be given orally or intravenously.[219]​ While the clinical trial data in support of TMP/SMX are not as robust, several trials have demonstrated that it has comparable efficacy and safety.[219][220]​​ For patients with a sulfa allergy history, desensitisation should be considered.[1]

Other alternative regimens include pyrimethamine plus folinic acid plus either clindamycin or atovaquone, atovaquone plus sulfadiazine, or atovaquone alone.[1] Clinical and radiographic improvement should be expected within 10-21 days of therapy.[115]​ Treatment should be continued for at least 6 weeks after resolution of symptoms.

Adjunctive corticosteroids are not routinely recommended but should be considered if there are clinical signs of increased intracranial pressure or evidence of mass effect due to focal lesions or oedema.[1] Anticonvulsants should be administered to patients with T gondii encephalitis who have a history of seizures, but should not be administered as prophylactics to all patients.[1]

Patients with T gondii encephalitis should be routinely monitored for adverse events and clinical and radiological improvement. Changes in the antibody titres are not useful for monitoring responses to therapy.

Patients who show clinical or radiographic deterioration during the first week despite adequate therapy, or lack of clinical improvement within 2 weeks, should undergo brain biopsy. A switch to an alternative regimen should be considered if there is histopathological evidence of T gondii encephalitis from the brain biopsy.[1]

Patients who have completed initial therapy should be given suppressive therapy with maintenance prophylaxis. The recommended regimen for secondary prophylaxis is pyrimethamine plus sulfadiazine plus folinic acid. Alternative regimens include clindamycin plus pyrimethamine plus folinic acid, TMP/SMX, atovaquone plus sulfadiazine, or atovaquone with or without pyrimethamine and folinic acid.[1] Chronic maintenance therapy may be discontinued in patients who have successfully completed initial therapy for toxoplasmic encephalitis, remain asymptomatic, and have an increase in their CD4 counts to >200 cells/microlitre after ART sustained for more than 6 months.[1] Secondary prophylaxis should be reintroduced if the CD4 count decreases to <200 cells/microlitre.

Cryptococcus infection

The preferred regimen recommended by US guidelines for induction therapy is at least 2 weeks of intravenous liposomal amphotericin-B plus oral flucytosine.[1] Amphotericin-B deoxycholate can be used as an alternative formulation if risk of renal dysfunction is low or if cost is prohibitive. The World Health Organization (WHO) recommends an induction regimen that consists of a single high dose of liposomal amphotericin-B combined plus 14 days of flucytosine and fluconazole, especially in resource-limited settings.[70] An alternative regimen recommended by WHO where liposomal amphotericin-B is not available is 1-week of amphotericin-B deoxycholate and flucytosine followed by 1 week of fluconazole.[70] The addition of flucytosine during acute treatment is associated with more rapid sterilisation of the cerebrospinal fluid (CSF), fewer relapses, and improved survival.[221][222]​ Flucytosine is contraindicated in patients with known complete dihydropyrimidine dehydrogenase deficiency due to the risk of life-threatening toxicity.[223][224]

Alternative induction regimens recommended by US guidelines and WHO are 2 weeks of intravenous or oral fluconazole plus oral flucytosine, 2 weeks of intravenous amphotericin-B deoxycholate plus oral or intravenous high-dose fluconazole, or 2 weeks of liposomal amphotericin plus fluconazole.[1][70]​ Other options included in US guidelines are amphotericin-B lipid complex plus flucytosine; liposomal amphotericin-B alone; amphotericin-B deoxycholate alone; liposomal amphotericin-B plus flucytosine followed by fluconazole; and high-dose fluconazole alone.[1]

After successful induction therapy, consolidation therapy with fluconazole can be started and should be continued for at least 8 weeks and at least until after ART has been initiated and CSF cultures have sterilised.[1][70]

Daily lumbar punctures may be needed for patients with ongoing neurological symptoms and increased intra-cranial pressure (≥25 cm of CSF). For patients not responding to or tolerating daily lumbar punctures, CSF shunting should be considered. A repeat lumbar puncture should be performed after the first 2 weeks of treatment to ensure clearance of the organism from the CSF. If CSF cultures remain positive after the 2 weeks of treatment, future relapse and generally less favourable outcomes are likely.[1]Patients with positive CSF cultures but who have improved clinically after 2 weeks of induction therapy should receive a higher dose of fluconazole for consolidation therapy, and have repeat lumbar puncture in another 2 weeks.[1] Alternatively, non-hospitalised patients can receive flucytosine plus fluconazole for an additional 2 weeks before starting single-drug consolidation therapy.[1] The duration of consolidation therapy should be 8 weeks from the point at which CSF cultures are negative.[1][70]

Maintenance therapy is with fluconazole.[1][70]​​ Treatment should continue for at least 1 year following initiation of antifungal therapy. Maintenance therapy can be discontinued once the CD4 count is ≥100 cells/microlitre for at least 3 months, HIV RNA levels are undetectable, and symptoms have resolved.[1] Maintenance therapy should be re-instituted if the CD4 count decreases to <100 cells/microlitre.[1][221][225][226]

The optimal time to begin ART in patients with cryptococcal meningitis remains unclear.[1] Initiation of ART is generally delayed for 4 to 6 weeks after starting antifungal therapy; however, the exact timing should be individualised, based on circumstances and local experience.[1][70]​ Patients should be monitored for immune reconstitution inflammatory syndrome. Caution should be applied when using azole antifungal drugs together with antiretroviral drugs as there is a risk for significant drug interactions through the CYP450 enzyme system.[1]

Cytomegalovirus disease (CMV)

Initial therapy should be individualised based on level of immunosuppression, location and severity of the lesion, adherence to treatment, and concomitant medicine.[1] Forms of ganciclovir are the usual first choice for CMV infection or disease.

CMV retinitis

  • An ophthalmologist familiar with CMV retinitis should ideally be involved in management.[1]

  • Systemic therapy reduces morbidity in the contralateral eye; this should be taken into consideration when choosing the route of administration.

  • Intravenous ganciclovir or oral valganciclovir with or without intravitreal ganciclovir or foscarnet is the preferred initial therapy for patients with immediate sight-threatening lesions.

  • Alternative options include intravitreal ganciclovir or foscarnet in combination with intravenous foscarnet or cidofovir (with probenecid and saline hydration therapy before and after cidofovir therapy).

  • For small peripheral lesions, oral valganciclovir alone may be adequate.

  • Early relapse is most often caused by the limited intra-ocular penetration of systematically administered drugs.[227] If patients relapse while receiving maintenance therapy, reinduction with the same drug followed by reinstitution of maintenance therapy is recommended. Changing to an alternative drug at the time of first relapse should be considered if drug resistance is suspected or if side effects or toxicities interfere with optimal courses of the initial agent.

CMV colitis or oesophagitis

  • Preferred agents include intravenous ganciclovir with a transition to oral valganciclovir if tolerating and absorbing medications for a total of 21-42 days or until signs and symptoms have resolved. Oral valganciclovir is a first-line treatment if symptoms are not severe enough to interfere with oral absorption. Foscarnet is an alternative agent for those with ganciclovir resistance or intolerance.

CMV neurological disease

  • Intravenous ganciclovir and foscarnet combination regimen is recommended to stabilise disease and maximise response. The optimal duration is unknown.

CMV and IRIS

  • ART may be delayed in patients with CMV infection due to risk of IRIS, particularly in patients with neurological disease, but timing should be individualised to the patient. Guidelines suggest that most experts would not delay ART for more than 2 weeks after starting CMV treatment.[1]

Mucocutaneous candidiasis

Oropharyngeal candidiasis

  • Oral fluconazole is considered the drug of choice. Although itraconazole and posaconazole are as effective as fluconazole, they should only be used as second-line therapy.[228] Posaconazole is generally better tolerated than itraconazole. Other options include miconazole buccal tablets, clotrimazole oral troches, and nystatin oral suspension.

  • Voriconazole can also be used in refractory cases. In severe, refractory cases, an intravenous echinocandin or amphotericin B can be considered, yet are rarely indicated.[228][229]

  • Initial episodes of oropharyngeal candidiasis should be treated for 7-14 days. Chronic or prolonged use of azole antifungals may promote development of resistance and hepatotoxicity.

Oesophageal candidiasis

  • For oesophageal candidiasis, systemic antifungals are required for effective treatment. Oral or intravenous fluconazole is considered to be first-line therapy. For fluconazole-refractory disease, oral itraconazole is considered second-line. Other azoles are alternative options, as are echinocandins and amphotericin B.[1][228] Higher relapse rate of oesophageal candidiasis with echinocandins than with fluconazole has been reported.

Vulvovaginal candidiasis

  • Uncomplicated vulvovaginal candidiasis in women living with HIV usually responds to short-course oral fluconazole or itraconazole, or topical treatment with azole antifungals. Severe or recurrent episodes of vaginitis require oral fluconazole (a longer course) or topical antifungal therapy for at least 7 days.[1]

Coccidioidomycosis

All immunocompromised individuals with clinically active coccidioidomycosis should receive antifungal therapy, as they have an increased risk for complications. Relapse is common in all individuals with coccidioidomycosis, regardless of immune status, and all patients should be managed with an experienced infectious diseases physician.

  • For clinically mild-to-moderate pulmonary coccidioidomycosis (e.g., focal coccidioidal pneumonia), oral fluconazole or itraconazole are the preferred agents for immunocompetent and immunocompromised patients.[1][230] Alternative azoles include voriconazole and posaconazole, although data are limited.[1][231]

  • For severe pulmonary coccidioidomycosis (e.g., diffuse pulmonary infiltrates) or for extrapulmonary non-meningeal coccidioidomycosis and for those with a CD4 count less than 50 cells/microlitre, intravenous amphotericin B deoxycholate or liposomal amphotericin B should be promptly administered. Therapy can be switched to an oral azole after clinical improvement and should be continued long term, regardless of the CD4 count.[1]

  • For meningeal coccidioidomycosis, high-dose intravenous or oral fluconazole is preferred. Other azoles, such as itraconazole, can be given as alternatives, although there is less data and less clinical experience.[1][232] For refractory cases, intrathecal amphotericin B may be required. Consultation with an experienced specialist is recommended. Intrathecal therapy should be administered by a clinician very experienced in this drug delivery technique.

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