Abstract
Introduction
Pneumocystis pneumonia (PCP) is a common AIDS-defining opportunistic illness in people with HIV infection, but its incidence has fallen with use of prophylactic treatment. Without treatment, PCP is likely to be fatal in people with AIDS, so placebo-controlled studies would be considered unethical.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of adjuvant corticosteroids in people receiving first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? What are the effects of treatments for Pneumocystis pneumonia in people infected with HIV who have not responded to first-line antipneumocystis treatment? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2008 (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 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic, review we present information relating to the effectiveness and safety of the following interventions: adjuvant corticosteroids; aerosolised or intravenous pentamidine; atovaquone; clindamycin–primaquone; treatment after failure of first-line treatment, trimethoprim–dapsone; and trimethoprim–sulfamethoxazole (TMP–SMX, co-trimoxazole).
Key Points
Pneumocystis pneumonia (PCP) is a common AIDS-defining opportunistic illness in people with HIV infection, but its incidence has fallen with use of prophylactic treatment.
Without treatment, PCP is likely to be fatal in people with AIDS, so placebo-controlled studies would be considered unethical.
Most clinicians consider trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) to be standard first-line treatment for PCP.
TMP-SMX may be more effective than atovaquone, but is more likely to cause adverse effects. Clindamycin–primaquine, trimethoprim–dapsone, and intravenous pentamidine may be as effective as TMP-SMX, with similar adverse-effect rates.
Systemic absorption of aerosolised pentamidine is low, so adverse effects are few, but it may be less effective than other treatments in people with severely impaired respiratory function, and is perceived as having a high rate of treatment failure.
Adjuvant corticosteroids reduce mortality when used early in the treatment of moderate to severe PCP, but we don't know whether they are beneficial in mild PCP.
We found no information from RCTs on the effects of treatments in people who have failed to respond to first-line antipneumocystis treatment.
We found some evidence that clindamycin–primaquine may be more effective than other treatment options in people who have failed to respond to first-line antipneumocystis treatment, but we found no high-quality studies.
About this condition
Definition
Pneumocystis pneumonia (PCP) is caused by the opportunistic fungus Pneumocystis jiroveci. The infection occurs in people with impaired immune function. Most cases occur in people infected with HIV, in whom PCP is an AIDS-defining illness. The pneumonia is generally classified as mild if arterial oxygen tension (PaO2) is greater than 70 mmHg on room air, or if the alveolar–arterial oxygen gradient is less than 35 mmHg, or both. It is generally classified as moderate/severe if PaO2 is less than 70 mmHg, or if the alveolar–arterial oxygen gradient is greater than 35 mmHg, or both. This review focuses on the treatment of PCP in adults infected with HIV. Prevention of PCP is covered in the review on HIV: prevention of opportunistic infections.
Incidence/ Prevalence
PCP was the most common AIDS-defining illness in resource-rich nations before PCP prophylaxis became widespread, and is still one of the most common AIDS-defining conditions. It is probably also common throughout resource-poor countries, although the prevalence is harder to assess here because of difficulties in making the diagnosis. Before the widespread use of prophylaxis, it was estimated that up to 80% of people with AIDS would eventually develop PCP. Widespread use of prophylaxis against PCP, and of highly active antiretroviral treatment have dramatically reduced the incidence of this infection (see HIV: prevention of opportunistic infections).
Aetiology/ Risk factors
Risk factors for PCP include HIV infection, primary immune deficiencies, prematurity, cancer, use of immune suppressants after organ transplantation, and prolonged use of high-dose corticosteroids. HIV infection is now responsible for the vast majority of cases of PCP. Among adults with HIV infection, those with a CD4 cell count below 200 cells/mm3 are at highest risk, and the median CD4 cell count at diagnosis of PCP is about 50 cells/mm3.
Prognosis
It is generally believed that without treatment, PCP would almost certainly be fatal in a person with AIDS. For ethical reasons, no studies have examined short-term prognosis without treatment. People with AIDS and PCP frequently have other serious opportunistic infections, which can adversely affect their prognosis.
Aims of intervention
To reduce mortality caused by PCP, with minimal adverse effects of treatment.
Outcomes
Mortality, treatment failure (requiring change of treatment), and adverse effects.
Methods
Clinical Evidence search and appraisal May 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2. An additional search was carried out using the website: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 people. There was no minimum length of follow-up required to include studies. We did not exclude studies described as “open”, “open label”. In addition, we searched for prospective cohort studies with a comparison group and at least 50 people. We use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Studies of the treatment of PCP can be hard to analyse because many participants swap treatment arms if they do not respond to, or if they experience toxicity with, their initial treatment allocation. Many studies allow clinicians to use their own discretion when deciding if a change in treatment is warranted, without having rigorous, predefined criteria for the change. Some people may have changed treatments before they had adequate opportunity to respond to the initial treatment allocation. Mortality and treatment-failure rates were usually compared on an intention-to-treat basis, but many authors analysed adverse effects using an on-treatment analysis. The studies assessed in this systematic review included only people infected with HIV, except where otherwise specified. Most studies were done in resource-rich countries, with an over-representation of white men. Although some studies included teenagers, there were few data from this group, and most studies excluded children and pregnant women. It was therefore hard to draw conclusions about the effects of treatment in these groups. Trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) is generally regarded as the standard treatment for PCP, and most studies used this as their comparator. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for HIV: treating Pneumocystis pneumonia (PCP).
| Important outcomes | Mortality, Treatment failure | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of first-line antipneumocystis treatments for Pneumocystis pneumonia in people infected with HIV? | |||||||||
| 1 (144) | Treatment failure | Atovaquone versus intravenous pentamidine | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of blinding |
| 1 (322) | Mortality | Atovaquone versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (322) | Treatment failure | Atovaquone versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (268) | Mortality | Clindamycin–primaquine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (333) | Treatment failure | Clindamycin–primaquine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (45) | Mortality | Aerosolised pentamidine versus intravenous pentamidine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertain duration of intervention |
| 1 (45) | Treatment failure | Aerosolised pentamidine versus intravenous pentamidine | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for uncertain duration of intervention |
| 1 (367) | Mortality | Aerosolised pentamidine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| 2 (413) | Treatment failure | Aerosolised pentamidine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 2 | –1 | –1 | 0 | 0 | Low | Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results |
| 3 (279) | Mortality | Intravenous pentamidine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results |
| 1 (168) | Treatment failure | Intravenous pentamidine versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (117) | Mortality | Trimethoprim–dapsone versus clindamycin–primaquine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (117) | Treatment failure | Trimethoprim–dapsone versus clindamycin–primaquine | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (123) | Mortality | Trimethoprim–dapsone versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (241) | Treatment failure | Trimethoprim–dapsone versus trimethoprim–sulfamethoxazole (TMP-SMX, co-trimoxazole) | 4 | 0 | 0 | 0 | 0 | High | |
| What are the effects of adjuvant corticosteroids in HIV-infected people receiving first-line antipneumocystis treatments for Pneumocystis pneumonia? | |||||||||
| 1 (62) | Mortality | Adjuvant corticosteroids versus no adjuvant treatment or placebo (in people with mild PCP) | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of blinding |
| 6 (489) | Mortality | Adjuvant corticosteroids versus no adjuvant treatment or placebo (in people with moderate to severe PCP) | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for lack of blinding in largest RCT identified by review |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Prophylaxis for Pneumocystis pneumonia and other AIDS-related opportunistic infections (see HIV: prevention of opportunistic infections).
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.
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