CROI: Cotrimoxazole prophylaxis reduces risk of death by 41% during first six months of ART

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In a retrospective Malawian study involving over 1,000 patients, when antiretroviral therapy (ART) was administered with cotrimoxazole (CTX) prophylaxis, the risk of death during the first six months of treatment was reduced by 41%. The findings, presented on Tuesday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles, have significant implications for HIV treatment programmes in resource-limited settings.

All patients included in the study began ART when they had CD4 counts below 200 cells/mm3 or were evaluated as having World Health Organization (WHO) stage III or IV HIV disease.

Study background

Death rates remain high among people who begin antiretroviral therapy (ART) in Africa and Asia due to a high burden of opportunistic infections. Although cotrimoxazole prophylaxis against opportunistic infections such as pneumocystis pneumonia, toxoplasmosis and bacterial infections is recommended for all individuals with HIV who have CD4 cell counts below 500 cells/mm3, implementation is patchy.

At the time the data used in this study were collected, in July and August 2005, Malawi offered antiretroviral therapy to all adults patients meeting WHO stage III or IV criteria or who had CD4 cell counts below 200 cells/mm3. However, national guidelines on cotrimoxazole prophylaxis for people beginning antiretroviral therapy had not been widely implemented at that point, partly due to drug supply problems.

Glossary

opportunistic infection (OI)

An infection that occurs more frequently or is more severe in people with weakened immune systems, such as people with low CD4 counts, than in people with healthy immune systems. Opportunistic infections common in people with advanced HIV disease include Pneumocystis jiroveci pneumonia; Kaposi sarcoma; cryptosporidiosis; histoplasmosis; other parasitic, viral, and fungal infections; and some types of cancer. 

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

WHO stage

A simplified system to describe four clinical stages of HIV-related disease, based on clinical parameters (symptoms, weight loss and different opportunistic infections) rather than decreasing CD4 cell count. Stage I is asymptomatic, stage II mild symptoms, stage III advanced symptoms and stage IV severe symptoms (an AIDS diagnosis).

Pneumocystis carinii pneumonia (PCP)

Pneumocystis carinii pneumonia is a form of pneumonia that is an AIDS defining illness.

toxoplasmosis

A disease due to infection with the protozoa Toxoplasma gondii, usually transmitted through consuming contaminated food and drink or undercooked meat.

 

Researchers were therefore able to compare data retrospectively from clinics where cotrimoxazole (CTX) was being offered with clinics where it was unavailable.

Researchers examined nearly 1,300 abstracted medical records from patients at eleven health clinics. Five of the clinics offered CTX with ART and six offered ART alone.

After selecting for study criteria, records for 574 patients from clinics offering ART+CTX and for 478 who received ART alone were examined. The eleven clinics were similar in regard to patient census, location, and level of financial support.

Medical records recorded whether patients were alive or dead, whether they were lost to follow-up, whether they had stopped treatment or if they had transferred out of the district.

Patients at the clinics that administered ART+CTX were significantly more sick than those at the clinics that did not, as evidenced by a higher percentage of patients with CD4+ cell count <200 cells/mm3 as the indication for ART (19% vs. 7%, p <0.0001) and a higher percentage of patients with past or present active TB at the time ARV therapy was begun (14% vs. 8%, p = 0.003).

Conclusions

It was known before this study that in sub-Saharan Africa, even in the absence of ARV therapy, receipt of CTX prophylaxis was associated with a 25-46% mortality reduction in HIV-positive patients.

Now, this study demonstrates that ART taken concomitantly with CTX, a generally available and affordable drug in sub-Saharan Africa, can provide a significant reduction in six-month mortality in a resource-limited setting.

Given the high early mortality rates seen in sub-Saharan ART programs and high rates of bacterial resistance to this antibiotic, this result is even more impressive.

Further, the fact that a significant benefit was identified in a patient group with a 14% history of prior or current TB infections renders these results even more striking and could have major implications for future ART programs in resource-limited areas.

Study results

In both study groups, 62% of the patients were female. When ART was initiated, the average participant age was 38 at the six clinics offering ART+CTX and age 37 at the five clinics that offered only ART (range: 15-71 years).

Approximately 63 patients in the ART+CTX group and 76 in the ART alone group defaulted from the study, but these numbers indicate that the extra pill burden of CTX was not a factor in adherence.

By day 45 after initiation of ART+CTX therapy, a survival difference was noted. According to the authors, log-rank tests demonstrated significant improvement in Kaplan-Meier survival probabilities for the CTX group (p = 0.0011).

At six months, records for the ART+CTX group show a 41% mortality risk reduction over the ART alone group, (11.6% vs. 19.6%, p <0.0001). The odds ratio for mortality at non-CTX clinics was 1.62 (p<0.01). Men were also at higher risk of death (OR 1.54, p=0.02), as were people who started treatment with WHO stage 4 disease (OR 1.99, p=0.01).

References

Lowrance D et al. Cotrimoxazole prophylaxis reduced the early mortality of HIV-infected patients on ART in Malawi. Fourteenth Conference on Retroviruses and Opportunistic Infections, Los Angeles, abstract 83, 2007.