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. 2006 Jan 1;2006:0908.

HIV: prevention of opportunistic infections

John PA Ioannidis 1,#, Taryn Young 2,#
PMCID: PMC2907634

Abstract

Introduction

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count less than 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of prophylaxis for P carinii pneumonia (PCP) and toxoplasmosis? What are the effects of antituberculosis prophylaxis in people with HIV infection? What are the effects of prophylaxis for disseminated M avium complex (MAC) disease for people with, and without, previous MAC disease? What are the effects of prophylaxis for cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV)? What are the effects of prophylaxis for invasive fungal disease in people with, and without, previous fungal disease? What are the effects of discontinuing prophylaxis against opportunistic pathogens in people on highly active antiretroviral treatment (HAART)? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 61 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acyclovir; antituberculosis prophylaxis; atovaquone; azithromycin (alone or plus rifabutin); clarithromycin (alone, or plus rifabutin and ethambutol, or plus clofazimine); clofazimine plus ethambutol; discontinuing prophylaxis for CMV, MAC, and PCP; ethambutol added to clarithromycin plus clofazimine; famciclovir; fluconazole; isoniazid; itraconazole; oral ganciclovir; rifabutin (alone or plus macrolides); trimethoprim-sulfamethoxazole; and valaciclovir.

Key Points

Opportunistic infections can occur in up to 40% of people with HIV infection and a CD4 count < 250/mm3, although the risks are much lower with use of highly active antiretroviral treatment.

Trimethoprim-sulfamethoxazole or azithromycin may reduce the risk of PCP, but have not been shown to reduce toxoplasmosis infection.

  • Atovaquone may prevent PCP and toxoplasmosis in people who cannot take trimethoprim−sulfamethoxazole, although we don't know this for sure.

Tuberculosis can be prevented by standard prophylaxis in people who are tuberculin skin test positive, but not in those who are tuberculin skin test negative.

Azithromycin or clarithromycin may reduce the risk of disseminated Microbacterium avium complex (MAC) disease in people without prior MAC disease.

  • Adding rifabutin may reduce the risk of MAC disease, while adding ethambutol decreases the risk of relapse, compared with other antibiotic regimens.

  • Combination treatment with clarithromycin plus clofazimine may increase mortality and is usually avoided.

Aciclovir reduces the risk of herpes simplex virus (HSV) and varicella zoster virus infection and overall mortality, but has not been shown to reduce cytomegalovirus (CMV) infection.

  • Valaciclovir and ganciclovir may reduce the risk of CMV infection, but may be associated with serious adverse effects.

Fluconazole and itraconazole may reduce the risk of invasive fungal infections or their relapse, but can cause serious adverse effects.

In people with a CD4 cell count above 100−200/mm3, discontinuation of prophylactic treatment may not increase the risk of PCP, toxoplasmosis or MAC infection.

About this condition

Definition

Opportunistic infections are intercurrent infections that occur in people infected with HIV. Prophylaxis aims to avoid either the first occurrence of these infections (primary prophylaxis) or their recurrence (secondary prophylaxis, maintenance treatment). This review includes Pneumocystis carinii pneumonia (PCP), Toxoplasma gondii encephalitis, Mycobacterium tuberculosis, Mycobacterium avium complex (MAC) disease, cytomegalovirus (CMV) disease (most often retinitis), infections from other herpes viruses (herpes simplex virus [HSV] and varicella zoster virus [VZV]), and invasive fungal disease (Cryptococcus neoformans, Histoplasma capsulatum, and Penicillium marneffei).

Incidence/ Prevalence

The incidence of opportunistic infections is high in people with immune impairment. Data available before the introduction of highly active antiretroviral treatment (HAART) suggest that, with a CD4 < 250/mm3, the 2 year probability of developing an opportunistic infection is 40% for PCP, 22% for CMV, 18% for MAC, 6% for toxoplasmosis, and 5% for cryptococcal meningitis. The introduction of HAART has reduced the rate of opportunistic infections. One cohort study found that the introduction of HAART decreased the incidence of PCP by 94%, CMV by 82%, and MAC by 64%, as presenting AIDS events. HAART decreased the incidence of events subsequent to the diagnosis of AIDS by 84% for PCP, 82% for CMV, and 97% for MAC.

Aetiology/ Risk factors

Opportunistic infections are caused by a wide array of pathogens and result from immune system defects induced by HIV. The risk of developing opportunistic infections increases dramatically with progressive impairment of the immune system. Each opportunistic infection has a different threshold of immune impairment, beyond which the risk increases substantially. Opportunistic pathogens may infect the immunocompromised host de novo, but usually they are simply reactivations of latent pathogens in such hosts.

Prognosis

Prognosis depends on the type of opportunistic infection. Even with treatment they may cause serious morbidity and mortality. Most deaths owing to HIV infection are caused by opportunistic infections.

Aims of intervention

To prevent the occurrence and relapse of opportunistic infections; to discontinue unnecessary prophylaxis; to minimise adverse effects of prophylaxis and loss of quality of life.

Outcomes

First occurrence and relapse of opportunistic infections and adverse effects of treatments. We have not considered neoplastic diseases associated with specific opportunistic infections.

Methods

Clinical Evidence search and appraisal December 2004. We also reviewed abstract books/CDs for the following conferences held between 1995 and early 2001: European Clinical AIDS, HIV Drug Treatment, Interscience Conferences on Antimicrobial Agents and Chemotherapy, National Conferences on Human Retroviruses and Opportunistic Infections, and World AIDS Conference. We placed emphasis on systematic reviews and RCTs published after 1993.

Glossary

Penicillium marneffei infection

A common opportunistic infection in South East Asia.

WHO staging system

for HIV infection and disease consists of a “clinical axis” that is represented by a sequential list of clinical conditions believed to have prognostic significance, which subdivides the course of HIV infection into four clinical stages; and a “laboratory axis” that subdivides each clinical stage into three strata according to CD4 cell count or total lymphocyte count.

Different antiretroviral regimens (see HIV infection)

P carinii pneumonia in people with HIV

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Dr John PA Ioannidis, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Professor Taryn Young, South African Cochrane Centre, South African Medical Research Council, Tygerberg, South Africa.

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BMJ Clin Evid. 2006 Jan 1;2006:0908.

Atovaquone

Summary

We found no RCTs comparing atovaquone versus placebo. Atovaquone is usually used in people who are either intolerant of or fail to respond to trimethoprim–sulfamethoxazole. It would be considered unethical to perform a trial comparing atovaquone versus placebo. RCTs in people who are either intolerant of or fail to respond to trimethoprim–sulfamethoxazole found that atovaquone is as effective as dapsone or aerosolised pentamidine in preventing Pneumocystis carinii: pneumonia (PCP).

Benefits

Atovaquone versus placebo:

We found no RCTs (see comment below).

Atovaquone versus dapsone:

One RCT found no significant difference between atovaquone 1500 mg daily compared with dapsone 100 mg daily in the incidence of Pneumocystis carinii pneumonia (PCP) infection (1057 people intolerant of trimethoprim–sulfamethoxazole, of whom 298 had a history of PCP; cases of PCP per 100 person years: 15.7 with atovaquone v 18.4 with dapsone; P = 0.20).

Atovaquone versus pentamidine:

We found one RCT, which compared three treatments: high dose atovaquone (1500 mg/day), low dose atovaquone (750 mg/day), and aerosolised pentamidine (300 mg monthly). It found no significant difference between treatments in the incidence of PCP (549 people intolerant of trimethoprim–sulfamethoxazole; 47/188 [26%] with low dose atovaquone v 39/175 [22%] with high dose atovaquone v 31/186 [17%] with pentamidine; low dose atovaquone v pentamidine: RR 1.41, 95% CI 0.90 to 2.22; high dose atovaquone v pentamidine: RR 1.26, 95% CI 0.78 to 2.03) or mortality (42/188 [22%] with low dose atovaquone v 27/175 [15%] with high dose atovaquone v 36/186 [19%] with pentamidine; low dose atovaquone v pentamidine: RR 1.12, 95% CI 0.72 to 1.75; high dose atovaquone v pentamidine: 0.75, 95% CI 0.46 to 1.24), after a median follow up of 11.3 months.

Harms

Atovaquone versus placebo:

We found no RCTs.

Atovaquone versus dapsone:

The RCT comparing atovaquone with dapsone found no significant difference between treatments in the overall risk of stopping treatment owing to adverse effects (RR 0.94, 95% CI 0.74 to 1.19). Atovaquone was stopped significantly more frequently than dapsone in people who were receiving dapsone at baseline (RR 3.78, 95% CI 2.37 to 6.01), and significantly less frequently in people not receiving dapsone at baseline (RR 0.42, 95% CI 0.30 to 0.58).

Atovaquone versus pentamidine:

Treatment limiting adverse events were more common with atovaquone than with pentamidine (16% with low dose atovaquone v 25% with high dose atovaquone v 7% with pentamidine; P < 0.01).

Comment

See role of highly active antiretroviral treatment in comment under trimethoprim–sulfamethoxazole. In clinical practice, atovaquone is usually used in people who are either intolerant of or fail to respond to trimethoprim–sulfamethoxazole. It would be considered unethical to perform a trial comparing atovaquone versus placebo.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Azithromycin

Summary

One RCT found that azithromycin, either alone or in combination with rifabutin, reduced the risk of Pneumocystis carinii: pneumonia (PCP) compared with rifabutin alone in people receiving standard PCP prophylaxis.

Benefits

Azithromycin versus placebo:

We found no RCTs.

Azithromycin versus rifabutin:

We found one RCT which compared azithromycin, rifabutin, and both drugs in combination in people who were already receiving standard Pneumocystis carinii pneumonia (PCP) prophylaxis. It found that azithromycin or azithromycin plus rifabutin significantly reduced the rate of reported PCP infection compared with rifabutin alone at median follow up of 1.4 years (724 HIV-1 positive people; rate of reported PCP infection per 100 person years: 12 with azithromycin alone v 25 with rifabutin alone v 13 with azithromycin plus rifabutin; azithromycin alone v rifabutin alone: HR 0.54, 95% CI 0.32 to 0.94; azithromycin plus rifabutin v rifabutin alone: HR 0.55, 95% CI 0.32 to 0.94).

Harms

Azithromycin versus placebo:

We found no RCTs.

Azithromycin versus rifabutin:

Gastrointestinal adverse effects are common with azithromycin, but they are usually mild and do not lead to stopping treatment. The RCT found that withdrawals owing to adverse effects were more common with azithromycin plus rifabutin than with either drug alone (AR: 23% with combination treatment v 14% with azithromycin alone v 16% with rifabutin alone; significance not reported in this publication). A separate publication of this trial reported that the increase in withdrawals with combination treatment compared with azithromycin alone was significant (HR 1.67, 95% CI 1.10 to 2.60; comparison v rifabutin alone not reported).

Comment

See role of highly active antiretroviral treatment in comment under trimethoprim–sulfamethoxazole. The low incidence of PCP infection in people taking highly active antiretroviral treatment means that the absolute benefit of prophylaxis is smaller.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Trimethoprim–sulfamethoxazole

Summary

Systematic reviews found that trimethoprim–sulfamethoxazole reduced the incidence of Pneumocystis carinii: pneumonia (PCP) compared with placebo or pentamidine. One systematic review and one subsequent RCT found no significant difference between high and low dose trimethoprim–sulfamethoxazole for PCP prophylaxis, although adverse effects were more common with the higher dose. Two systematic reviews found that trimethoprim–sulfamethoxazole reduced incidence of PCP compared with dapsone (with or without pyrimethamine), although only one of these reviews found that the reduction was statistically significant.

Benefits

Trimethoprim–sulfamethoxazole or pentamidine versus placebo:

We found one systematic review, which analysed the effects of trimethoprim–sulfamethoxazole (co-trimoxazole) or pentamidine and placebo, and one subsequent RCT. The systematic review found that prophylaxis with trimethoprim–sulfamethoxazole or pentamidine reduced the incidence of Pneumocystis carinii pneumonia (PCP) compared with placebo (6 RCTs [1 of trimethoprim–sulfamethoxazole, 5 of pentamidine], 823 people with advanced disease; P carinii events: RR 0.32, 95% CI 0.23 to 0.46). The single RCT from the review that compared trimethoprim–sulfamethoxazole versus placebo (60 HIV positive people with a new diagnosis of Karposi's sarcoma) found that trimethoprim–sulfamethoxazole reduced the incidence of PCP over 24 months compared with placebo (0/30 [0%] with trimethoprim–sulfamethoxazole v 16/30 [53%] with placebo; significance not reported). The subsequent RCT (545 people in sub-Saharan Africa with symptomatic disease; second or third clinical stage disease in the WHO staging system; regardless of CD4 cell count) compared trimethoprim–sulfamethoxazole with placebo and found no significant difference in incidence of PCP or toxoplasmosis (no cases of PCP reported).

Trimethoprim–sulfamethoxazole versus pentamidine:

We found two systematic reviews. The first systematic review found that trimethoprim–sulfamethoxazole significantly reduced the incidence of PCP compared with aerosolised pentamidine (14 RCTs, 2248 people; P carinii events: RR 0.58, 95% CI 0.45 to 0.75; absolute data not reported). The second systematic review found no significant difference between trimethoprim–sulfamethoxazole and aerosolised pentamidine for preventing toxoplasmosis (13 RCTs, 2226 people; RR 0.78, 95% CI 0.55 to 1.11).

Trimethoprim–sulfamethoxazole versus dapsone (with or without pyrimethamine):

We found two systematic reviews. The first systematic review found no significant difference between trimethoprim–sulfamethoxazole compared with dapsone (with or without pyrimethamine), although the incidence of PCP was lower in the trimethoprim–sulfamethoxazole group (8 RCTs; RR 0.61, 95% CI 0.34 to 1.10). The second systematic review found that trimethoprim–sulfamethoxazole was significantly more effective in preventing PCP than dapsone/pyrimethamine (8 RCTs; RR 0.49, 95% CI 0.26 to 0.92). It found no significant difference between trimethoprim–sulfamethoxazole and dapsone/pyrimethamine in preventing toxoplasmosis (13 RCTs; RR 1.17, 95% CI 0.68 to 2.04).

High versus low dose trimethoprim–sulfamethoxazole:

We found one systematic review and one subsequent RCT. The systematic review found no significant difference in the rate of PCP infection between lower dose (160/800 mg 3 times/week or 80/400 mg/day) and higher dose (160/800 mg/day) trimethoprim–sulfamethoxazole (failure rate per 100 person years 1.8, 95% CI 1.0 to 3.3 with lower dose v 0.5, 95% CI 0 to 2.9 with higher dose; significance not reported). The subsequent RCT (2625 people) also found no significant difference in the rate of PCP infection in people who received trimethoprim–sulfamethoxazole 160/800 mg daily compared with three times weekly (3.5 per 100 person years with daily dose v 4.1 per 100 person years with 3 times weekly dose; RR 0.82, 95% CI 0.61 to 1.09; P = 0.16).

Harms

Trimethoprim–sulfamethoxazole versus placebo:

One RCT in sub-Saharan Africa found that trimethoprim–sulfamethoxazole reduced serious events (death or hospital admission, irrespective of the cause) compared with placebo, regardless of their initial CD4 cell count (HR 0.57, 95% CI 0.43 to 0.75; P < 0.001). It also found that trimethoprim–sulfamethoxazole significantly increased moderate neutropenia compared with placebo (AR: 62/271 [23%] with trimethoprim–sulfamethoxazole v 26/244 [10%] with placebo; RR 2.1, 95% 1.4 to 3.3; NNH 8, 95% CI 5 to 14). Two RCTs (largest 377 people) found that gradual initiation of trimethoprim–sulfamethoxazole may improve tolerance of the regimen compared with abrupt initiation. Two RCTs (238 people, 50 people) found no significant benefit from acetylcysteine in preventing trimethoprim–sulfamethoxazole hypersensitivity reactions in HIV infected people.

High versus low dose trimethoprim–sulfamethoxazole:

One systematic review found that severe adverse effects (predominantly rash, fever, and haematological effects leading to discontinuation within 1 year) occurred in more people taking higher doses of trimethoprim–sulfamethoxazole than in those taking lower doses (25% with higher doses v 15% with lower doses). The subsequent RCT comparing high dose with low dose trimethoprim–sulfamethoxazole found that discontinuation because of adverse effects was significantly more common in people taking high doses of trimethoprim–sulfamethoxazole (RR 2.14; P < 0.001).

Dapsone:

One systematic review found that adverse effects were more frequent with high doses than low doses of dapsone (29% with high dose v 12% with low dose). Another systematic review (search date 1996, 16 trials, 4267 people) evaluating dapsone toxicity found no significant difference in mortality between dapsone and other prophylaxis (OR for mortality for dapsone v other prophylaxis 1.11, 95% CI 0.96 to 1.29).

Pentamidine:

Bronchospasm occurred in 3% of people taking aerosolised pentamidine 300 mg monthly.

Comment

Role of highly active antiretroviral treatment (HAART):

We found more than 50 RCTs on the prophylaxis of PCP, toxoplasmosis, or both, but their results should be interpreted with caution because they were conducted mostly before the advent and widespread use of HAART. Although this is unlikely to affect the comparative results, HAART has resulted in a large decrease in the rate of PCP, toxoplasmosis, and other opportunistic infections; therefore, the absolute benefits of these prophylactic regimens are probably smaller when used with HAART.

Prophylaxis in Africa:

Beneficial effects of trimethoprim–sulfamethoxazole in Africa may be largely because of prophylaxis for bacterial infections rather than PCP. The largest trial conducted in Africa found that trimethoprim–sulfamethoxazole significantly reduced mortality and hospital admissions. However, a smaller trial (100 people) found no significant effect on mortality or hospital admission, although it may have lacked power to detect a significant difference (HR for death or hospital admission 1.10, 95% CI 0.57 to 2.13).

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Trimethoprim-sulfamethoxazole for toxoplasmosis

Summary

One RCT found no significant difference between trimethoprim–sulfamethoxazole and placebo for preventing toxoplasmosis. One systematic review found no significant difference between trimethoprim–sulfamethoxazole and dapsone (with or without pyrimethamine) for preventing toxoplasmosis.to be categorised separately.

Benefits

Trimethoprim–sulfamethoxazole or pentamidine versus placebo:

.

Trimethoprim–sulfamethoxazole versus pentamidine:

We found one systematic review. The review found no significant difference between trimethoprim–sulfamethoxazole and aerosolised pentamidine for preventing toxoplasmosis (13 RCTs, 2226 people; RR 0.78, 95% CI 0.55 to 1.11).

Trimethoprim–sulfamethoxazole versus dapsone (with or without pyrimethamine):

We found one systematic review. The review found no significant difference between trimethoprim–sulfamethoxazole and dapsone/pyrimethamine in preventing toxoplasmosis (13 RCTs; RR 1.17, 95% CI 0.68 to 2.04).

High versus low dose trimethoprim–sulfamethoxazole:

We found one RCT (2625 people). The RCT found no significant difference in the rate of toxoplasmosis in people who received trimethoprim–sulfamethoxazole 160/800 mg daily compared with three times weekly (1.8 per 100 person years with daily dose v 1.8 per 100 person years with 3 times weekly dose; RR 1.02, 95% CI 0.39 to 2.63).

Harms

See harms of trimethoprim–sulfamethoxazole for PCP.

Comment

Concomitant coverage for toxoplasmosis:

Standard trimethoprim–sulfamethoxazole prophylaxis or dapsone should offer adequate coverage for toxoplasmosis. Pentamidine has no intrinsic activity against T gondii. Toxoplasmosis risk is probably clinically meaningful only with CD4 < 100/mm3 and positive toxoplasma serology.

Role of highly active antiretroviral treatment (HAART):

We found more than 50 RCTs on the prophylaxis of PCP, toxoplasmosis, or both, but their results should be interpreted with caution because they were conducted mostly before the advent and widespread use of HAART. Although this is unlikely to affect the comparative results, HAART has resulted in a large decrease in the rate of PCP, toxoplasmosis, and other opportunistic infections; therefore, the absolute benefits of these prophylactic regimens are probably smaller when used with HAART.

Prophylaxis in Africa:

Beneficial effects of trimethoprim–sulfamethoxazole in Africa may be largely because of prophylaxis for bacterial infections rather than PCP. The largest trial conducted in Africa found that trimethoprim–sulfamethoxazole significantly reduced mortality and hospital admissions. However, a smaller trial (100 people) found no significant effect on mortality or hospital admission, although it may have lacked power to detect a significant difference (HR for death or hospital admission 1.10, 95% CI 0.57 to 2.13).

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Antituberculosis prophylactic regimens versus placebo

Summary

One systematic review found that in people who are HIV and tuberculin skin test positive, antituberculosis prophylaxis drugs reduced the frequency of tuberculosis compared with placebo over 1–3 years. However it found no significant difference between treatments in the risk of death from any cause. The review found no significant difference between antituberculosis prophylaxis drugs and placebo in the frequency of tuberculosis, or death from any cause in people who were HIV positive but tuberculin skin test negative. One RCT found that the benefit of prophylaxis diminished with time after treatment was stopped.

Benefits

We found one systematic review (search date 2002, 7 RCTs, 5664 HIV positive adults from Haiti, Kenya, Spain, Uganda, USA, and Zambia). The RCTs identified by the review compared isoniazid (6–12 months) or combination treatment (rifampicin plus pyrazinamide, isoniazid plus rifampicin, or isoniazid plus rifampicin plus pyrazinamide, for 2–3 months) versus placebo. Mean follow up varied from 1 to 3 years. The main outcomes, stratified by tuberculin skin test positivity, were tuberculosis (either microbiological or clinical) and death (from any cause). The review found that antituberculosis prophylaxis significantly reduced the incidence of active tuberculosis in tuberculin skin test positive adults compared with placebo (4 RCTs, 2378 people; incidence of active tuberculosis: 39/1760 [2.2%] with treatment v 46/618 [7.4%] with placebo; RR 0.38, 95% CI 0.25 to 0.57). It found no significant difference between prophylaxis and placebo in the risk of death from any cause (4 RCTs, 2378 people; 195/1760 [11.0%] with treatment v 84/618 [13.6%] with placebo; RR 0.80, 95% CI 0.63 to 1.02). In tuberculin skin test negative adults the review found no significant difference between antituberculosis prophylaxis and placebo in the risk of tuberculosis (7 RCTs, 2822 people: 66/1629 [4.1%] with treatment v 54/1193 [4.5%] with placebo; RR 0.83, 95% CI 0.58 to 1.18) or death (from any cause; 373/1629 [23%] with treatment v 298/1193 [25%] with placebo; RR 1.02, 95% CI 0.89 to 1.15). Two RCTs included in the systematic review reported the results of long term follow up of antituberculosis prophylaxis on the risk of tuberculosis infection. The first RCT, compared isoniazid or rifampicin plus pyrazinamide versus placebo after a mean of 3 years' follow up (see comment below). Intention to treat analysis found that overall, isoniazid or rifampicin plus pyrazinamide significantly reduced the overall risk of tuberculosis at 2.5 years compared with placebo (1053 Zambian adults; 161 tuberculin skin test positive, 517 negative, the rest unknown; cumulative RR of tuberculosis: 0.55, 95% CI 0.32 to 0.93), although the benefit diminished over this time. The second RCT compared four treatments, isoniazid, isoniazid plus rifampicin, isoniazid plus rifampicin plus pyrazinamide, and placebo. It found no significant difference between isoniazid (given for 6 months) and placebo in the risk of active tuberculosis in tuberculin positive people at 3 years (2736 Ugandan adults, 2018 tuberculin skin test positive and 718 negative; RR 0.67, 95% CI 0.42 to 1.07). It also found that isoniazid plus rifampicin (for 3 months), or isoniazid plus rifampicin plus pyrazinamide (for 3 months) significantly reduced the risk of active tuberculosis infection in tuberculin positive people compared with placebo at 3 years (isoniazid plus rifampicin versus placebo adjusted RR 0.49, 95% CI 0.29 to 0.82; isoniazid plus rifampicin plus pyrazinamide versus placebo adjusted RR 0.41, 95% CI 0.22 to 0.76). It found no significant difference between isoniazid (given for 6 months) and placebo in people with a negative tuberculin skin test at 1 or 2 years' follow up (at 1 year: RR 0.74, 95% CI 0.30 to 1.79; at 2 years: adjusted RR 0.61, 95% CI 0.32 to 1.16).

Harms

The systematic review found that antituberculosis prophylaxis significantly increased the risk of adverse events resulting in discontinuation of treatment compared with placebo (7 RCTs; 5427 people; 137/3554 [3.9%] with antituberculosis prophylaxis v 33/1873 [1.8%] with placebo: RR 2.49, 95% CI 1.64 to 3.77).

Comment

In one of the RCTs included in the review, many people taking placebo were offered isoniazid after randomisation. Without prophylaxis, people who are HIV and tuberculin skin test positive have a 50% or more lifetime risk of developing tuberculosis compared with a 10% lifetime risk in people who are HIV positive but tuberculin skin test negative. Clinical features of tuberculosis may be atypical in people with HIV infection and diagnosis may be more difficult, disease progression more rapid, and outcome worse.

Substantive changes

Antituberculosis prophylaxis versus placebo One systematic review added; categorisation unchanged (beneficial) but benefits and harms data updated.

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Different antituberculosis prophylactic regimens versus each other

Summary

One systematic review found no significant difference in the risk of tuberculosis or death (any cause) between isoniazid monotherapy for 6–12 months and combination treatment (isoniazid plus rifampicin, rifampicin plus pyrazinamide, or isoniazid plus rifampicin plus pyrazinamide) for 2–3 months. The review found that adverse effects leading to treatment discontinuation were more common with combination treatment than with isoniazid monotherapy.

Benefits

We found one systematic review. The review found no significant difference in the risk of active tuberculosis or death (any cause) between isoniazid monotherapy for 6–12 months and combination treatment (isoniazid plus rifampicin, rifampicin plus pyrazinamide, or isoniazid plus rifampicin plus pyrazinamide) for 2–3 months (search date 2002; tuberculosis: 3 RCTs, 1390 people; 14/683 [2.05%] with isoniazid v 14/707 [1.98%] with isoniazid plus rifampicin; RR 1.05, 95% CI 0.51 to 2.17; death: 4 RCTs, 1385 people; 71/683 [10.39%] with isoniazid v 67/702 [9.54%] with isoniazid plus rifampicin; RR 1.09, 95% CI 0.80 to 1.50; tuberculosis: 6 RCTs, 3196 people; 73/1597 [4.57%] with isoniazid v 73/1599 [4.56%] with rifampicin plus pyrazinamide: RR 1.00, 95% CI 0.73 to 1.38; death: 6 RCTs, 3137 people; 299/1597 [18.72%] with isoniazid v 283/1540 [18.37%] with rifampicin plus pyrazinamide; RR 1.03, 95% CI 0.89 to 1.19; tuberculosis: 1 RCT, 998 people; 7/536 [1.31%] with isoniazid v 10/462 [2.16%] isoniazid plus rifampicin plus pyrazinamide; RR 0.60, 95% CI 0.23 to 1.57; death: 1 RCT, 998 people; 58/536 [10.82%] with isoniazid v 58/462 [12.55%] isoniazid plus rifampicin plus pyrazinamide; RR 0.86, 95% CI 0.61 to 1.21).

Harms

The systematic review found that combination treatment (for 2–3 months) increased the risk of treatment discontinuation owing to adverse effects compared with isoniazid monotherapy for 6–12 months (3 RCTs, 1390 people; 24/683 [3.51%] with isoniazid v 33/707 [4.66%] with isoniazid plus rifampicin; RR 0.75, 95% CI 0.46 to 1.24; 4 RCTs, 3196 people; 66/1597 [4.13%] with isoniazid v 102/1599 [6.38%] with rifampicin plus pyrazinamide; RR 0.64, 95% CI 0.48 to 0.86; 1 RCT, 998 people; 3/536 [0.56%] with isoniazid v 26/462 [5.62%] with isoniazid plus rifampicin plus pyrazinamide; RR 0.10, 95% CI 0.03 to 0.33).

Comment

The systematic review did not find significant heterogeneity in outcomes in people whose tuberculin skin test result at baseline was positive, negative, or unknown. Fewer than half of the RCTs included in the systematic review reported on adherence to treatment and the definition of adherence varied between studies. One RCT identified by the review found higher rates of adherence with a 2 months course of rifampicin plus pyrazinamide compared with 6 months of isoniazid. A second RCT identified by the review reported better adherence with 3 months of isoniazid plus rifampicin compared with 12 months isoniazid. The remaining RCT identified by the review found no difference in adherence among individuals receiving isoniazid for 6 months, isoniazid plus rifampicin for 3 months, and isoniazid plus rifampicin plus pyrazinamide for 3 months. There is concern about emergence of rifampicin resistance if this drug is used in antituberculosis prophylaxis, although we found no reports of this. There is a theoretical risk that widespread, unsupervised use of isoniazid alone could promote resistance to this drug, although we found no evidence that this has happened.

Substantive changes

Different antituberculosis prophylactic regimens versus each other One systematic review added; categorisation unchanged (trade-off between benefits and harms) but benefits and harms data updated.

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Azithromycin

Summary

One RCT found that azithromycin reduced the incidence of Mycobacterium avium: complex (MAC) compared with placebo. One RCT found that both azithromycin alone and azithromycin plus rifabutin reduced the incidence of MAC compared with rifabutin alone.

Benefits

Azithromycin versus placebo:

One RCT (174 people with AIDS and CD4 < 100/mm3) found that azithromycin reduced the incidence of Mycobacterium avium complex (MAC) compared with placebo (11% with azithromycin v 25% with placebo; P = 0.004).

Azithromycin versus rifabutin:

We found one RCT, which compared three treatments: azithromycin alone, rifabutin alone, and azithromycin plus rifabutin. See benefits of rifabutin plus macrolides.

Azithromycin versus rifabutin plus azithromycin:

We found one RCT, which compared three treatments: azithromycin alone, rifabutin alone, and azithromycin plus rifabutin. See benefits of rifabutin plus macrolides.

Harms

Azithromycin versus placebo:

Gastrointestinal adverse effects were more likely with azithromycin than with placebo (71/90 [79%] with azithromycin v 25/91 [28%] with placebo; NNH 2, CI not reported), but they were rarely severe enough to cause discontinuation of treatment (8% with azithromycin v 2% with placebo; P = 0.14).

Azithromycin versus rifabutin:

See harms of rifabutin plus macrolides.

Azithromycin versus rifabutin plus azithromycin:

See harms of rifabutin plus macrolides.

Comment

Prospective cohort studies found that the risk of disseminated MAC disease increased substantially with a lower CD4 count and was clinically important only for CD4 counts below 50/mm3.

Role of highly active antiretroviral treatment (HAART):

Most of the RCTs of MAC prophylaxis were conducted before the widespread use of HAART. HAART reduces the absolute risk of MAC infection. The absolute risk reduction of prophylactic regimens may be smaller when used in people treated with HAART.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Clarithromycin

Summary

One RCT found that clarithromycin reduced the incidence of Mycobacterium avium: complex (MAC) compared with placebo. One RCT found that both clarithromycin alone and clarithromycin plus rifabutin reduced the incidence of MAC compared with rifabutin alone.

Benefits

Clarithromycin versus placebo:

We found one systematic review (search date 1997) of prophylaxis and treatment of Mycobacterium avium complex (MAC). It identified one RCT that found that clarithromycin significantly reduced the incidence of MAC compared with placebo (682 people with advanced AIDS; 6% with clarithromycin v 16% with placebo; HR 0.31, 95% CI 0.18 to 0.53). It found no significant difference between treatments in the mortality (32% with clarithromycin v 41% with placebo; HR 0.75; P = 0.026).

Clarithromycin versus rifabutin:

We found one RCT that compared three treatments: clarithromycin alone, rifabutin alone, and clarithromycin plus rifabutin. See benefits of rifabutin plus macrolides.

Clarithromycin versus rifabutin plus clarithromycin:

We found one RCT that compared three treatments: clarithromycin alone, rifabutin alone, and clarithromycin plus rifabutin. See benefits of rifabutin plus macrolides.

Harms

Clarithromycin versus placebo:

Adverse effects led to discontinuation of treatment in slightly more people taking clarithromycin than placebo (8% with clarithromycin v 6% with placebo; P = 0.45). More people taking clarithromycin suffered altered taste (11% with clarithromycin v 2% with placebo) or rectal disorders (8% with clarithromycin v 3% with placebo).

Clarithromycin versus rifabutin:

See harms of rifabutin plus macrolides.

Clarithromycin versus rifabutin plus clarithromycin:

See harms of rifabutin plus macrolides.

Comment

Prospective cohort studies found that the risk of disseminated MAC disease increased substantially with a lower CD4 count and was clinically important only for CD4 counts under 50/mm3. See role of highly active antiretroviral treatment in comment under azithromycin.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Rifabutin plus macrolides

Summary

One RCT found that rifabutin plus clarithromycin reduced the incidence of M avium: complex (MAC) compared with rifabutin alone. One RCT found that azithromycin plus rifabutin reduced the incidence of MAC compared with azithromycin alone or rifabutin alone. One systematic review and two subsequent RCTs found that toxicity, including uveitis, was more common with combination treatment than with clarithromycin or rifabutin alone.

Benefits

Rifabutin plus clarithromycin versus rifabutin alone or clarithromycin alone:

We found one RCT (1178 people with AIDS), which compared rifabutin alone versus clarithromycin alone versus clarithromycin plus rifabutin. It found that the risk of Mycobacterium avium complex (MAC) was significantly reduced in the clarithromycin alone group (RR 0.56 for clarithromycin v rifabutin; P = 0.005) and the combination group when compared with rifabutin alone (RR 0.43 for combination v rifabutin, P = 0.0003). There was no significant difference in the risk of MAC between the combination and clarithromycin arms (RR 0.79 for combination v clarithromycin, P = 0.36).

Rifabutin plus azithromycin versus rifabutin alone or azithromycin alone:

One RCT (693 HIV positive people) found that the combination of azithromycin plus rifabutin compared with azithromycin alone or rifabutin alone reduced the incidence of MAC at 1 year (15.3% with rifabutin v 7.6% with azithromycin v 2.8% with rifabutin plus azithromycin; HR 0.28 for combination v rifabutin, P < 0.001; HR 0.53 for combination v azithromycin, P = 0.03). Azithromycin alone reduced the incidence of MAC at 1 year compared with rifabutin alone (HR 0.53 for azithromycin v rifabutin, P = 0.008).

Harms

Rifabutin plus clarithromycin versus rifabutin alone or clarithromycin alone:

The RCT found that adverse events occurred in 31% of people receiving the combination of clarithromycin plus rifabutin compared with 16% with clarithromycin alone and 18% with rifabutin alone (P < 0.001). Uveitis occurred in 42 people: 33 with clarithromycin plus rifabutin, seven with rifabutin alone, and two with clarithromycin alone.

Uveitis:

We found one systematic review (search date 1994, 54 people with rifabutin associated uveitis). It found that uveitis was dose dependent. It occurred from 2 weeks to more than 7 months after initiation of rifabutin treatment, and was more likely in people taking rifabutin plus clarithromycin. In most people, uveitis resolved 1–2 months after discontinuation of rifabutin.

Rifabutin plus azithromycin versus rifabutin alone or azithromycin alone:

One RCT found that dose limiting toxicity was more likely with azithromycin plus rifabutin compared with azithromycin alone (HR 1.67; P = 0.03).

Comment

Prospective cohort studies found that the risk of disseminated MAC disease increased substantially with a lower CD4 count and was clinically important only for CD4 counts under 50/mm3. Clarithromycin may inhibit rifabutin metabolism; rifabutin may decrease levels of delavirdine and saquinavir. See role of highly active antiretroviral treatment in comment under azithromycin.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Clarithromycin plus clofazimine plus ethambutol (more effective than clarithromycin plus clofazimine)

Summary

One RCT found that clarithromycin plus rifabutin plus ethambutol reduced Mycobacterium avium: complex (MAC) relapse compared with clarithromycin plus clofazimine.

Benefits

Clarithromycin plus clofazimine plus ethambutol versus clarithromycin plus clofazimine:

We found one RCT, which found that the combination of clarithromycin 1000 mg daily plus clofazimine plus ethambutol significantly decreased relapses of Mycobacterium avium complex (MAC) compared with clarithromycin plus clofazimine without ethambutol at 36 weeks (95 people; MAC relapse: 68% with 3 drug regimen v 12% with 2 drug regimen; P = 0.004).

Harms

Combinations of drugs may lead to increased toxicity. Optic neuropathy may occur with ethambutol, but has not been reported in RCTs in people with HIV, where the dose and symptoms were carefully monitored.

Clarithromycin plus clofazimine plus ethambutol versus clarithromycin plus ethambutol:

The RCT found that clofazimine plus clarithromycin plus rifabutin significantly increased mortality compared with clarithromycin plus ethambutol (62% with 3 drug regime v 38% with 2 drug regime; P = 0.012).

Higher dose versus lower dose clarithromycin:

One RCT, which compared clarithromycin 500 mg twice daily versus 1000 mg twice daily found that, after a median follow up of 4.5 months, more people died with the higher dose (85 people; 17/40 [43%] with 1000 mg twice daily v 10/45 [22%] with 500 mg twice daily; ARI 20%, 95% CI 0.2% to 33%; NNH 5, 95% CI 3 to 470). A similar difference was seen in another RCT (154 people).

Comment

Clinical guide:

The observed increased mortality associated with clofazimine and high doses of clarithromycin has led to avoidance of these drugs.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Clarithromycin plus clofazimine

Summary

One RCT found that adding ethambutol to clarithromycin plus clofazimine reduced Mycobacterium avium: complex (MAC) relapse compared with clarithromycin plus clofazimine.

Benefits

Clarithromycin plus rifabutin plus ethambutol versus clarithromycin plus clofazimine:

We found one RCT (144 people), which found that the combination of clarithromycin plus rifabutin plus ethambutol reduced the relapse rate of MAC compared with clarithromycin plus clofazimine.

Harms

Combinations of drugs may lead to increased toxicity. Optic neuropathy may occur with ethambutol, but has not been reported in RCTs in people with HIV, where the dose and symptoms were carefully monitored.

Higher dose versus lower dose clarithromycin:

One RCT, which compared clarithromycin 500 mg twice daily versus 1000 mg twice daily found that, after a median follow up of 4.5 months, more people died with the higher dose (85 people; 17/40 [43%] with 1000 mg twice daily v 10/45 [22%] with 500 mg twice daily; ARI 20%, 95% CI 0.2% to 33%; NNH 5, 95% CI 3 to 470). A similar difference was seen in another RCT (154 people).

Comment

Clinical guide:

The observed increased mortality associated with clofazimine and high doses of clarithromycin has led to avoidance of these drugs.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Clarithromycin plus ethambutol

Summary

One RCT found no significant difference in survival by adding rifabutin to clarithromycin plus ethambutol in people with previous Mycobacterium avium: complex (MAC).

Benefits

Clarithromycin plus ethambutol versus rifabutin plus clarithromycin plus ethambutol:

We found one RCT (198 people), which found no significant difference in survival between clarithromycin plus ethambutol and clarithromycin plus ethambutol plus rifabutin.

Harms

Combinations of drugs may lead to increased toxicity. Optic neuropathy may occur with ethambutol, but has not been reported in RCTs in people with HIV, where the dose and symptoms were carefully monitored.

Higher dose versus lower dose clarithromycin:

One RCT, which compared clarithromycin 500 mg twice daily versus 1000 mg twice daily found that, after a median follow up of 4.5 months, more people died with the higher dose (85 people; 17/40 [43%] with 1000 mg twice daily v 10/45 [22%] with 500 mg twice daily; ARI 20%, 95% CI 0.2% to 33%; NNH 5, 95% CI 3 to 470). A similar difference was seen in another RCT (154 people).

Comment

Clinical guide:

The observed increased mortality associated with clofazimine and high doses of clarithromycin has led to avoidance of these drugs.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Clarithromycin plus clofazimine plus ethambutol (higher mortality than clofazimine plus ethambutol)

Summary

One RCT found that adding clarithromycin to clofazimine plus ethambutol increased mortality compared with clofazimine plus ethambutol.

Benefits

Clarithromycin plus clofazimine plus ethambutol versus clarithromycin plus ethambutol:

We found one RCT (106 people), which found that clofazimine plus clarithromycin plus ethambutol did not improve clinical response and was associated with higher mortality compared with clarithromycin plus ethambutol (see harms below).

Harms

Combinations of drugs may lead to increased toxicity. Optic neuropathy may occur with ethambutol, but has not been reported in RCTs in people with HIV, where the dose and symptoms were carefully monitored.

Higher dose versus lower dose clarithromycin:

One RCT, which compared clarithromycin 500 mg twice daily versus 1000 mg twice daily found that, after a median follow up of 4.5 months, more people died with the higher dose (85 people; 17/40 [43%] with 1000 mg twice daily v 10/45 [22%] with 500 mg twice daily; ARI 20%, 95% CI 0.2% to 33%; NNH 5, 95% CI 3 to 470). A similar difference was seen in another RCT (154 people).

Comment

Clinical guide:

The observed increased mortality associated with clofazimine and high doses of clarithromycin has led to avoidance of these drugs.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Aciclovir

Summary

One systematic review found that aciclovir reduced herpes simplex virus (HSV) and varicella zoster virus (VZV) infection, and overall mortality, compared with placebo in people at different clinical stages of HIV infection. However, it found no significant difference between treatments in the incidence of cytomegalovirus (CMV) disease. One RCT found that valaciclovir reduced the incidence of CMV disease compared with aciclovir, but may be associated with increased mortality. One RCT found no significant difference between aciclovir and valaciclovir in anogenital HSV recurrence.

Benefits

Aciclovir versus placebo:

We found one systematic review of individual patient data (search date not reported, 8 RCTs) in people with HIV infection (ranging from asymptomatic infection to full blown AIDS). It found no significant difference in protection against cytomegalovirus (CMV) disease between aciclovir compared with no treatment or placebo. However, aciclovir significantly reduced overall mortality (RR 0.81; P = 0.04) and herpes simplex virus (HSV) and varicella zoster virus (VZV) infections (P < 0.001 for both).

Aciclovir versus valaciclovir:

We found two RCTs. The first RCT compared three treatments: valaciclovir 8 g daily, high dose acyclovir 3.2 g daily, and low dose acyclovir 0.8 g daily. It found that valaciclovir reduced the incidence of CMV disease compared with aciclovir at 48 weeks (1227 CMV seropositive people with CD4 count < 100/mm3 ; 12% with valaciclovir v 18% with aciclovir [high and low dose pooled]; P = 0.03). It found a trend towards increased mortality with valaciclovir, but this difference did not reach significance (log rank P = 0.06). In pairwise comparisons, valaciclovir significantly increased mortality compared with low dose acyclovir but not high dose aciclovir (valaciclovir v low dose aciclovir: HR for death 1.28, 95% CI 1.03 to 1.59; valaciclovir v high dose aciclovir: HR for death 1.17, 95% CI 0.94 to 1.45). The second RCT compared aciclovir (400 mg twice daily) versus valaciclovir (500 mg twice daily or 1000 mg once daily). It found no significant difference between aciclovir and either dose of valaciclovir in HSV recurrence at 48 weeks (1062 HIV positive people with history of recurrent genital or anogenital HSV, and a median CD4 count of 320/mm3; valaciclovir 500 mg twice daily v aciclovir: HR for recurrence 0.73, 95% CI 0.50 to 1.06; valaciclovir 1000 mg daily v aciclovir: HR for recurrence 1.31, 95% CI 0.94 to 1.82).

Harms

Aciclovir versus placebo:

The review did not look at harms.

Aciclovir versus valaciclovir:

The first RCT found that toxicity and early medication discontinuations were significantly more frequent in the valaciclovir arm (1 year discontinuation rate: 51% for valaciclovir v 46% for high dose aciclovir v 41% for low dose aciclovir). The second RCT found a similar frequency of adverse events (including headache and nausea) with aciclovir (400 mg twice daily) and valaciclovir (500 mg twice daily or 1000 mg once daily; AR for treatment limiting adverse events: 11% with valaciclovir [dose regimens pooled] v 9% with aciclovir; significance assessment not performed).

Comment

The survival benefit with aciclovir is unclear. The absolute risk reduction may be higher in people who have frequent HSV or varicella zoster virus infections.

Substantive changes

Aciclovir One RCT added; categorisation unchanged (beneficial) but benefits and harms data updated.

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Ganciclovir

Summary

One RCT found that oral ganciclovir reduced the incidence of cytomegalovirus (CMV) in people with severe CD4 depletion compared with placebo. It found that 26% of people who took ganciclovir developed severe neutropenia. A second RCT found no significant difference in prevention of CMV between ganciclovir and placebo.

Benefits

Oral ganciclovir versus placebo:

We found two RCTs. The first RCT found that oral ganciclovir reduced the incidence of cytomegalovirus (CMV) by about 50% compared with placebo (725 people with a median CD4 count of 22/mm3 ; event rate: 16% with ganciclovir v 30% with placebo; P = 0.001). The second RCT found no significant difference in the rate of CMV in people taking oral ganciclovir compared with placebo (994 HIV-1 infected people with CD4 < 100/mm3 and CMV seropositivity; event rates: 13.1 per 100 person years with ganciclovir v 14.6 per 100 person years with placebo; HR 0.92, 95% CI 0.65 to 1.27). Both RCTs found no significant difference in overall mortality.

Harms

Oral ganciclovir versus placebo:

In the first RCT, severe neutropenia that required granulocyte colony stimulating factor, was significantly more common with ganciclovir compared with placebo (26% with ganciclovir v 13% with placebo; P =0.001). The second RCT found that significantly more people experienced at least one adverse event with ganciclovir compared with placebo (250/662 [38%] with ganciclovir v 97/332 [29%] with placebo; HR 1.39, 95% CI 1.09 to 1.76). It also found that severe neutropenia was significantly more common with ganciclovir compared with placebo (neutropenia defined as neutrophils < 750 x 106 /L; 25% with ganciclovir v 16% with placebo; P = 0.001).

Comment

Differences in the results of RCTs may have arisen by chance or owing to protocol variability; for example, no baseline ophthalmologic examinations were performed in the second trial. The low incidence of CMV disease in people taking highly active antiretroviral treatment, and the high rates of adverse events, means that the clinical value of oral ganciclovir in people who have not had active CMV disease is unclear.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Valaciclovir

Summary

One RCT found that valaciclovir reduced genital and oral herpes simplex virus (HSV) recurrence compared with placebo at 6 months in people on HAART. One RCT found that valaciclovir reduced the incidence of cytomegalovirus disease compared with aciclovir, but may be associated with increased mortality. One RCT found no significant difference between aciclovir and valaciclovir in anogenital HSV recurrence. One RCT found that valaciclovir 500 mg twice daily reduced anogenital HSV recurrence compared with valaciclovir 1000 mg once daily.

Benefits

Valaciclovir versus placebo:

We found one RCT, which compared valaciclovir 500 mg twice daily versus placebo. It found that valaciclovir significantly reduced genital herpes simplex virus (HSV) recurrence compared with placebo at 6 months (293 HIV positive with history of recurrent genital herpes; median CD4 count 336/mm3 in the valaciclovir group and 313 /mm3 in the placebo group; AR for being genital HSV recurrence free: 65% with valaciclovir v 26% with placebo; RR 2.5, 95% CI 1.8 to 3.5). There was a significant reduction in oral herpes with valaciclovir compared with placebo at 6 months (AR for being oral HSV recurrence free: 76% with valaciclovir v 62% with placebo; RR 1.24, 95% CI 1.04 to 1.48).

Different valaciclovir dosage schedules:

We found one RCT which compared three treatments: valaciclovir 500 mg twice daily, valaciclovir 1000 mg once daily, or aciclovir 400mg twice daily (see benefits of aciclovir). It found that valaciclovir 500 mg twice daily significantly reduced anogenital HSV recurrence rate compared with valaciclovir 1000 mg daily at 48 weeks (HR 0.56, 95% CI 0.39 to 0.79).

Valaciclovir versus aciclovir:

See benefits of aciclovir.

Harms

Valaciclovir versus placebo:

The RCT found that valaciclovir increased the risk of adverse events (including headache, diarrhoea, fatigue, and nausea) compared with placebo (overall adverse events: 75% with valaciclovir v 58% with placebo; significance assessment not performed).

Different valaciclovir dosage schedules:

Adverse effects were similar with the different dosage schedules (valaciclovir 500 mg twice daily v 1000 mg once daily; diarrhoea: 19% with 500 mg twice daily v 21% with 1000 mg once daily, headache: 18% in each group; significance assessment not performed).

Valaciclovir versus aciclovir:

See harms of aciclovir.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Famciclovir

Summary

One small RCT found that famciclovir reduced the rate of viral shedding compared with placebo, but provided insufficient evidence on the effect of famciclovir on herpes simplex virus (HSV) recurrence.

Benefits

Famciclovir versus placebo:

We found no systematic review. One small crossover placebo controlled RCT (48 people) found that famciclovir suppressed viral shedding of herpes simplex virus (HSV) in people with frequent recurrences (HSV was isolated in 9/1071 [0.8%] famciclovir days v 122/1114 [10.9%] placebo days; P < 0.001). Breakthrough reactivations on famciclovir were short lived and often asymptomatic.

Harms

Famciclovir versus placebo:

Famciclovir was well tolerated, and the incidence of adverse effects was similar in both groups.

Comment

The conclusions of this study are difficult to interpret. The randomisation process allocated participants to groups, but the intention to treat analysis involved the number of days with symptoms rather than the number of participants who improved. There was no assessment of statistical significance of clinical outcomes. The analysis of the trial was impeded by a high withdrawal rate.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Azoles

Summary

RCTs in people with advanced HIV disease found that both fluconazole and itraconazole reduced the incidence of invasive fungal infections compared with placebo. One RCT found that fluconazole reduced the incidence of invasive fungal disease and mucocutaneous candidiasis compared with clotrimazole. One RCT found no difference between high and low dose fluconazole. Azoles have been associated with congenital problems and potentially serious interactions with other drugs.

Benefits

Fluconazole versus placebo:

We found two RCTs. The first RCT found that fluconazole significantly reduced the incidence of candidiasis compared with placebo (323 women with CD4 ≤ 300/mm3 ; suffered at least 1 episode of candidiasis: 44% with fluconazole v 58% with placebo; RR 0.56, 95% CI 0.41 to 0.77). The second RCT found that fluconazole 400 mg weekly reduced the occurrence of cryptococcal meningitis (90 adults with CD4 count < 100/mm3 ; cryptococcal meningitis: 3/44 [6.8%] with fluconazole v 7/46 [15.2%] with placebo; HR 0.45, 95% CI 0.12 to 1.72), and increased survival (HR 0.23, 95% CI 0.05 to 1.11) compared with placebo after a median of 21 weeks follow up, but these differences did not reach significance. The study may have lacked power to detect clinically important differences.

Itraconazole versus placebo:

We found three RCTs. The first RCT found that itraconazole reduced the incidence of invasive fungal infections (295 people with advanced HIV disease; median CD4 count: 57/mm3 in the itraconazole group v 63/mm3 in the placebo group; P = 0.0007). It found no significant effect on recurrent or refractory candidiasis. The second RCT also found that itraconazole reduced invasive fungal infections compared with placebo after a median of about 40 weeks (129 people; median CD4 count: 60/mm3 in the itraconazole group v 73/mm3 in the placebo group; AR 1.6% with itraconazole v 16.7% with placebo; RR 0.1; P = 0.003; CI not reported). In the third RCT itraconazole did not significantly reduce invasive fungal infections compared with placebo (344 people with mean CD4 count < 200/mm3 ; AR: 5.9% with itraconazole v 7.0% with placebo; P = 0.42). However, the study may have lacked power to detect clinically important differences.

High dose versus low dose fluconazole:

One RCT compared fluconazole 200 mg daily with 400 mg once weekly and found no difference in the rate of invasive fungal infections over a follow up of 74 weeks (636 people; AR: 8% with 200 mg daily v 6% with 400 mg once weekly; ARR +2.2%, 95% CI –1.7% to +6.0%). However, candidiasis was twice as common in people taking the weekly dose.

Fluconazole versus clotrimazole troches:

One RCT found that fluconazole 200 mg daily reduced the incidence of invasive fungal infections compared with clotrimazole troches (10 mg five times/day) after a median follow up of 35 months (428 people; 4% with fluconazole v 11% with clotrimazole; HR 3.3, 95% CI 1.5 to 7.6).

Harms

Congenital anomalies have occurred in a few children born to mothers receiving fluconazole. Itraconazole is embryotoxic and teratogenic in animals. Trials have therefore excluded pregnant women. Azoles may interact with antiretroviral regimens. Azoles inhibit the metabolism of some drugs such as terfenadine. Theoretically they may increase the risk of sudden death because of ventricular tachycardia.

Fluconazole versus placebo:

The first RCT found that significantly more people experienced at least one adverse event with fluconazole compared with placebo (41 with fluconazole v 23 with placebo; RR 1.30; P > 0.2). The second RCT found no adverse effects associated with either fluconazole or placebo.

Itraconazole versus placebo:

The first RCT found that itraconazole significantly increased the proportion of people with skin rash compared with placebo (10.1% with itraconazole v 2.1% with placebo; P = 0.02). The second RCT found no significant difference between treatments in overall adverse events (including skin rashes; skin rashes: 25.4% with itraconazole v 22.7% with placebo; overall adverse events; P > 0.5). The third RCT found a similar frequency of adverse events in both treatment groups. It also found that early medication discontinuations were similar between treatment groups (20% with itraconazole v 23% with placebo).

High dose versus low dose fluconazole:

The RCT found that a similar proportion of people experienced gastrointestinal symptoms in both treatment groups (72.6% with 200 mg daily v 70.4% with 400 mg once weekly). It found that 3.1% of people in the fluconazole 200 mg daily group and 2.5% of of people in the fluconazole 400 mg once weekly group withdrew from treatment because of adverse effects (increased liver function tests or haematological abnormalities).

Fluconazole versus clotrimazole troches:

The RCT found a similar frequency of adverse events in both treatment groups. It also found that fluconazole did not significantly increase the number of people who discontinued treatment compared with clotrimazole (13 people with fluconazole v 6 people with clotrimazole; P = 0.11).

Comment

Azoles effectively reduce invasive fungal disease. Any absolute benefit is probably even lower in people treated with highly active antiretroviral treatment. Lack of evidence of any survival benefit, potential for complex drug interactions with current antiretroviral regimens, and potential for developing resistant fungal isolates means that there is doubt about routine antifungal prophylaxis in HIV infected people without previous invasive fungal disease.

Substantive changes

Azoles One RCT added. Categorisation unchanged (trade-off between benefits and harms) but benefits and harms data updated.

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Azoles (itraconazole for preventing Penicillium marneffei relapse)

Summary

Two RCTs found that itraconazole reduced the incidence of relapse of Penicillium marneffei: infection and candidiasis compared with placebo.

Benefits

We found no systematic review.

Itraconazole versus placebo:

We found two RCTs. The first RCT found that itraconazole significantly reduced the relapse of Penicillium marneffei infection compared with placebo (71 people with AIDS in Asia; AR for relapse within 1 year: 0/36 [0%] with itraconazole v 20/35 [57%] with placebo; P < 0.001). The second RCT compared prophylaxis with itraconazole versus placebo for 24 weeks. It found that itraconazole reduced candidiasis relapse rates (44 people with HIV infection and candidiasis, treated with itraconazole 200 mg for 4 weeks before randomisation; AR: 5/24 [21%] with itraconazole v 14/20 [70%] with placebo; ARR 49%, 95% CI 19% to 64%; NNT 2, 95% CI 2 to 5) and increased the time interval before relapse occurred (median time to relapse: 8.0 weeks with itraconazole v 10.4 weeks with placebo; P = 0.001).

Harms

The RCTs gave no information on adverse effects.

Comment

Recurrent infection is common in people with previous Cryptococcus neoformans, Histoplasma capsulatum, and P marneffei infections. Lifelong maintenance may be needed in the presence of immune impairment.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Azoles (itraconazole for preventing relapse of cryptococcal meningitis

Summary

One RCT found that itraconazole increased the risk of relapse of cryptococcal meningitis compared with fluconazole. We found no RCTs on itraconazole for histoplasmosis.

Benefits

We found no systematic review.

Itraconazole versus fluconazole:

One RCT found that fluconazole reduced relapses of successfully treated cryptococcal meningitis compared with itraconazole (108 people with HIV infection; AR for relapse: 13/57 [23%] with itraconazole v 2/51 [4%] with fluconazole; ARR 19.0%, 95% CI 6.2% to 31.7%; RR 0.17, 95% CI 0.04 to 0.71; NNT 5, 95% CI 3 to 16). The trial was stopped early because of the higher rate of relapse with itraconazole.

Harms

The RCT reported, discontinuation of itraconazole occurred in two people because of skin rashes, one because of severe anaemia, and one because of gastrointestinal effects compared with none taking fluconazole.

Comment

Recurrent infection is common in people with previous Cryptococcus neoformans, Histoplasma capsulatum, and P marneffei infections. Lifelong maintenance may be needed in the presence of immune impairment.

Substantive changes

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Discontinuing prophylaxis for P carinii pneumonia (PCP) and toxoplasmosis

Summary

One systematic review of two unblinded RCTs in people with CD4 counts over 200/mm 3 taking highly active antiretroviral treatment (HAART) found that discontinuation of prophylaxis did not increase the incidence of Pneumocystis carinii: pneumonia (PCP). Two unblinded RCTs found that discontinuation of prophylaxis did not increase the incidence of toxoplasmosis in people with a satisfactory response to HAART.

Benefits

Pneumocystis

carinii pneumonia (PCP):

We found one systematic review (search date 2001, 2 RCTs, 3584 people, 2 non-randomised controlled trials, and 10 studies with other designs) about the effects of discontinuing prophylaxis. The review found a low incidence of PCP in people discontinuing both primary and secondary prophylaxis after a mean of 1.5 years (7/3035 [0.23%] with discontinuing primary prophylaxis v 1/549 [0.18%] discontinuing secondary prophylaxis; mean annual incidence over 1.5 years 0.23%, 95% CI 0.10% to 0.46%; no statistical heterogeneity among studies). Neither of the two RCTs identified in the review found any cases of PCP after discontinuation (first RCT: 587 people with satisfactory response to highly active antiretroviral treatment (HAART), CD4 > 200/mm3, and viral load < 5000 copies/mm3 for > 3 months, AR for PCP or toxoplasma encephalitis at median 20 months 0%, whether or not prophylaxis continued; second RCT: 708 people taking HAART, CD4 > 200/mm3 for 3 months, AR for PCP at 6 months 0%).

Toxoplasmosis:

We found two RCTs. The first, which was included in the systematic review, found no cases of toxoplasma encephalitis at 6 months in people discontinuing prophylaxis (see PCP above). The second RCT (302 people with a satisfactory response to HAART) compared discontinuation versus continuation of toxoplasma prophylaxis. After a median of 10 months it found no episodes of toxoplasma encephalitis in either group.

Harms

The systematic review found no direct harms from discontinuing prophylaxis.

Comment

The risk of PCP may increase after discontinuing prophylaxis in people who do not respond to antiretroviral treatment. We found no direct evidence of the effects of different HAART regimens on the risk of PCP or toxoplasmosis. Antiretroviral regimens with different mechanisms of action may have different clinical effects on opportunistic infections and HIV disease progression, despite inducing satisfactory suppression of HIV-1 replication and adequate CD4 responses. Also, CD4 cell count is an incomplete marker of immune reconstitution. It is possible that people with the same CD4 count may have different immune deficits regarding control of PCP and other opportunistic pathogens. An extensive amount of research is being conducted on other parameters of immune reconstitution, but the clinical implications are uncertain at present. One decision analysis based on the systematic review suggested that, in the long term, discontinuation of PCP prophylaxis in people who respond to HAART should result in fewer PCP episodes and fewer prophylaxis related adverse effects.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Discontinuing prophylaxis for M avium complex (MAC)

Summary

Two RCTs in people with CD4 counts over 100/mm 3 taking highly active antiretroviral treatment (HAART) found that discontinuation of prophylaxis for Mycobacterium avium: complex (MAC) disease did not increase the incidence of MAC disease.

Benefits

We found two RCTs. The first RCT (520 people without previous Mycobacterium avium complex (MAC) disease, with CD4 > 100/mm3 in response to highly active antiretroviral treatment [HAART]) compared azithromycin with placebo. It found no episodes of confirmed MAC disease in either group over a median follow up of 12 months. The second RCT (643 people with CD4 > 100/mm3 in response to HAART) compared azithromycin 1200 mg once weekly versus placebo. Over a median follow up of 16 months there was no significant difference in the incidence of MAC between the groups (0/322 [0%] with azithromycin v 2/321 [0.62%] with placebo; difference +0.5 events per 100 person years, 95% CI –0.2 events per 100 person years to +1.2 events per 100 person years).

Harms

In both RCTs, adverse effects leading to discontinuation of treatment were more common with azithromycin than with placebo (first RCT: 7% with azithromycin v 1% with placebo; P = 0.002; second RCT: 8% with azithromycin v 2% with placebo; P < 0.001).

Comment

It is not clear whether different antiretroviral regimens have different clinical effects on opportunistic infections and on the need for specific prophylaxis.

Substantive changes

No new evidence

BMJ Clin Evid. 2006 Jan 1;2006:0908.

Discontinuing prophylaxis for cytomegalovirus (CMV)

Summary

We found insufficient evidence on the effects of discontinuation of maintenance treatment for cytomegalovirus (CMV) retinitis or other end organ disease in people with CD4 counts over 100/mm 3 taking highly active antiretroviral treatment (HAART).

Benefits

We found no systematic review or RCTs.

Harms

We found no evidence from systematic reviews or RCTs.

Comment

We found several small case series (see table 1 ). Of the two studies with the longest follow up, one found no relapses in 41 people after a mean of 20.4 months from discontinuing maintenance treatment and the other found only one relapse among 36 people after a median follow up of 21 months from discontinuing treatment. This relapse occurred in a person with immunological failure (CD4 62/mm3). However, another study with mean follow up of 14.5 months found five (29%) relapses among 17 participants who withdrew from maintenance; all of them occurred after the CD4 cell count had dropped again to below 50/mm3 (8 days/10 months after this event). In one case series, 12/14 (86%) participants had evidence of immune reconstitution retinitis even before starting withdrawal of prophylaxis. Worsening uveitis was associated with a substantial vision loss (> 3 lines) in three participants. It is difficult to conduct an RCT with adequate power to exclude modest differences in relapse rates. The observational evidence suggests that withdrawal of cytomegalovirus (CMV) maintenance treatment may be considered in selected people in whom CMV disease is in remission, CD4 counts are less than 100/mm3, and HIV replication remains suppressed. We found no clear evidence on whether CMV viral load should be considered in the decision to withdraw from maintenance. One small case series found that relapses were associated with a drop in the CD4 cell count. However, we found no randomised or other reliable evidence about when to restart CMV maintenance treatment.

Table 1.

Observational studies of discontinuation of cytomegalovirus maintenance treatment in people with previous cytomegalovirus disease (see text).

Ref Criteria for discontinuation Participants Follow up (months) Relapses
* CD4 >70 17 14.5 (mean) 5
  CD4 ≥ 75 8 8 (median) 0
  CD4 >150 14 16.4 (mean) 0
  CD4 297 (median) 15 8 (median) 0
  CD4 >100 8 11.4 (mean) 0
* CD4 183 (median) 11 5 (median) 0
  CD4 >150 VL < 200/mL –ve CMV by PCR 7 9 (median) 0
  CD4 > 143 41 20.4 (mean) 0
  CD4 > 75 VL < 30 000/mL 48 11 (mean) 2
  CD4 > 100 VL < 500 or CD4 > 150 VL < 10 0000 copies/mL 36 21 (median) 1
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Studies with more than five people are included. CD4 count is measured in cells/mm3.) *McDonald et al is an early report of the same study followed by the Torriani et al report. All relapses in the latter report occurred in people who had already experienced a decrease of CD4 to < 50 cells/mm3.) CMV, cytomegalovirus; PCR, polymerase chain reaction; Ref, reference; VL, viral load (HIV-1 RNA in plasma).

Substantive changes

No new evidence

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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