Preventive treatment with cotrimoxazole (CTX), a cheap, easily available antibiotic, reduced death rates by a quarter in Ugandan people with HIV who had no access to antiretroviral therapy, Ugandan researchers report in the July edition of the Journal of Acquired Immune Deficiency Syndromes. However the treatment was poorly adhered to, was associated with significant and unexplained side-effects and led to a substantial increase in bacterial resistance to cotrimoxazole, the study found.
Cotrimoxazole has become a beacon of hope since a landmark study in Cote d’Ivoire demonstrated that CTX prophylaxis in people with HIV reduced mortality and morbidity. UNAIDS has recommended a policy of CTX prophylaxis for all HIV-positive people with a CD4 cell count below 500 cells/mm3. This has been adopted in many African countries.
The benefits of CTX prophylaxis in PLWA have been confirmed in several African countries. However, there are lingering concerns about possible toxicity and selection of antifolate resistant bacteria and malaria parasites.
People with HIV are at an increased risk of serious toxicity mediated by sulfonamide-containing drugs such as CTX and sulfadoxine-pyrimethamine (SP). CTX and pyrimethamine, a component of SP, cause a reduction in granulocyte counts. Treating malaria with SP in PLWA on CTX prophylaxis might escalate this risk.
Antifolate resistance is a problem where HIV and malaria co-exist and SP is used for malaria chemotherapy. Both CTX and SP target the same enzymes and share cross-resistance. Although a Malian study reported that CTX prophylaxis had no impact on SP resistance, these results can only be extrapolated to East Africa with caution. The levels of SP resistance in West and East Africa are not comparable.
An overriding concern is therefore whether CTX is effective in areas of high bacterial and malaria resistance to CTX and SP. A team of Ugandan and CDC (USA) investigators studied the feasibility and effectiveness of daily CTX prophylaxis in PLWA in a setting of high bacterial resistance.
The study took place in a semi-urban area of Entebbe in Uganda and involved 763 HIV-positive adults. CTX prophylaxis (two tablets daily) commenced in August 2000 and the patients were followed up monthly until March 2002. A check-up for complete blood analysis was carried out 6-monthly. Drug-related toxicity was monitored as was CTX sensitivity of bacteria isolated from participants. Mortality and morbidity rates were compared during the twelve months before versus the twelve months after CTX prophylaxis.
Mortality was reduced by 24 % and there was a significant reduction in the incidence of malaria and boils during the post-CTX period. However, diarrhoea increased two-fold, fever increased slightly and oral thrush increased almost threefold in the post-CTX period; an increase in herpes zoster was not significant. The authors speculate that the increased incidence of oral thrush was due to HIV disease progression, but the median CD4 count decline during the study period was non-significant.
The two periods were comparable for all febrile events, cough, bacteremia, diagnosis of tuberculosis, pneumonia, or undiagnosed fever. Morbidity decreased with increasing CD4 counts.
The reported adverse events (3.8 %) were not life-threatening. However, total white cell, granulocyte, and CD4 counts fell significantly during CTX prophylaxis; whilst some of this decline is attributable to HIV disease progression, the long-term side-effects of CTX in large populations remain unclear, and prophylaxis may be indefinite for people with HIV in low-income settings.
During the pre-CTX period, 44 and 52 % of isolates of non-typhi salmonella and S. pneumoniae, respectively, were resistant to CTX. By contrast, during the post-CTX period, 60 and 89 % of non-typhi salmonella and S. pneumoniae, respectively, and 98 and 90 % of H. influenzae and Shigella, respectively, were resistant to CTX.
These data show an increasing and, in some bacteria, significant resistance to CTX in bacteria which cause severe illness and sepsis. The authors’ findings that there was no difference in bacterial resistance patterns in samples taken from patients on or off CTX prophylaxis seem contradictory.
Malaria resistance to CTX was not assessed but CTX prophylaxis reduced malaria incidence. This is surprising given the high prevalence of SP resistance in Uganda and cross-resistance between SP and CTX. Furthermore, antimalarial drugs act in concert with host immunity yet patients on CTX prophylaxis had reduced CD4 counts.
Only 20.8 % of participants attended scheduled clinic visits for CTX refills, and 60% of all scheduled appointments were kept. The major reasons for defaulting were lack of transport money and movement from the study area. CTX could be made more available and accessible in the community and patients continually counseled about adherence, the authors comment.
Thus, further investigations are needed to understand the mechanisms underlying the benefits of CTX prophylaxis, the basis for the increased incidence of oral thrush, reported fever, diarrhea, and herpes zoster, and the impact of the hematological toxicity.
Watera C et al. Feasibility and effectiveness of cotrimoxazole prophylaxis for HIV-1 infected adults attending an HIV/AIDS clinic in Uganda. J Acquir Immune Defic Syndr 42 (3): 373-378, 2006.