Using a well-described cohort with cumulative follow-up time of over 9,600 person-months, we found a CD4-independent additional beneficial effect of HAART compared to cotrimoxazole alone for HIV-infected adults in Côte d’Ivoire. After adjusting for current CD4 count, we estimated that HAART reduces the incidence of severe ODs by 21% during the first 6 months on HAART and 28% during subsequent follow-up on HAART. When mortality was added to the analysis, we estimated HAART reduces the incidence of a severe OD or death by 50% during the first 6 months on HAART and 60% during subsequent follow-up on HAART. The results also reveal that the risk reduction by HAART is not homogeneous across different CD4 count strata within the first 6 months on HAART.
These findings are consistent with previous studies from the United States and Europe. A similar effect was seen by Cole et al. in the Multicenter AIDS Cohort Study, McNaghten et al. in the Adult and Adolescent Spectrum of Disease Project, and Murphy et al. in the Viral Activation Transfusion Study, all in the US, as well as in Europe by Ledergerber et al. in the Swiss HIV Cohort Study, Mocroft et al. in the EuroSIDA Study, and Sabin in the Antiretroviral Therapy Cohort Collaboration [8
]. Cole et al. examined the effect of HAART on the transition to AIDS or death, finding a significant reduction in this composite outcome, but they did not analyze OD events separately and did not stratify by time on HAART. McNaghten et al. and Mocroft et al. both found a significant reduction in mortality, but like Cole et al., they did not analyze OD events or stratify results by time on HAART. In contrast, the Swiss HIV Cohort Study showed a decrease in OD rates as a function of time on HAART, but did not include mortality, did not compare with a pre-HAART group, and did not provide an explicit stratification by CD4. The current study provided all three, most importantly the comparison to a pre-HAART period, allowing us to derive relative risk reductions from HAART use.
Sabin and the Antiretroviral Therapy Cohort Collaboration divided patient-time into two periods: 0–6 months and 7–12 months. They demonstrated that the greatest effect of HAART on the reduction of ODs occurred in the lowest CD4 stratum. We also observed the greatest effect of HAART in the lowest CD4 stratum. The Antiretroviral Therapy Cohort Collaboration studies did not provide a pre-HAART comparator group, as the cotrimoxazole alone group in our analysis did, and they were therefore unable to show the incremental effect of HAART over cotrimoxazole prophylaxis. Additionally, as the ODs were grouped by etiology, their event rates are not directly comparable to our overall event rates. However, the incidence of events in months 0–6 was significantly higher than the incidence of events in months 7–12. Similarly, the current study found a greater incremental benefit from HAART in the period >6 months after HAART initiation. We hypothesize that this trend is due to the occurrence of immune reconstitution inflammatory syndrome (IRIS) within the period of time directly following HAART initiation, leading to a higher incidence of OD events in the 0–6 months following HAART initiation.
In the current analysis, we found a generally greater risk reduction for death than for severe ODs, which is consistent with the results of Murphy et al., the only other group to examine the effect of HAART on both death and OD incidence [29
]. However, they did not examine the composite outcome of OD or death, did not stratify results by current CD4 count, and did not stratify results by time. The greater effect on mortality seen in both studies may be due to the fact that many AIDS-related deaths occur from chronic causes, such as wasting and non-OD causes, and HAART may be more protective for those types of deaths than it is for ODs. This hypothesis is supported for wasting syndrome deaths, as pre-HAART body mass index has been repeatedly found to be associated with on-HAART mortality in sub-Saharan Africa [33
To examine the effects of HAART and cotrimoxazole in patients receiving both treatments, we stratified ODs based on whether they were preventable with cotrimoxazole. Our data suggest that, in patients receiving both treatments, the effect of HAART was greater on the reduction of incidence of ODs that are not preventable with cotrimoxazole. However, since the study cohort used in this analysis provided follow-up time for both patients on cotrimoxazole alone and patients on HAART plus cotrimoxazole, and not follow-up time on HAART alone, we were unable to distinguish the benefit of cotrimoxazole from the benefit of HAART on reducing the incidence of ODs. This issue should be addressed by further studies.
This study has several limitations. First, due to limited statistical power, we were not able to establish a statistically significant interaction effect between the CD4 count and the HAART effect for severe ODs when they were not considered in combination with death. We were not able to establish any interaction effect for death events alone. Additionally, the numbers of each type of OD in our dataset were not sufficient to analyze the effect of HAART on individual ODs. Second, patients from the HAART plus cotrimoxazole group may have been more likely to have a history of prior OD at baseline than those from the cotrimoxazole alone group. Given that the incidence of severe OD recurrence may differ from the incidence of first occurrence, this may have biased the analysis for the association between OD incidence and treatment period.
However, rates of OD recurrence are likely to be higher than rates of first occurrence for most ODs [37
]. Therefore, this potential bias would have acted to mask an independent, protective effect of HAART, not to enhance it. Third, in the analyses on severe OD alone, follow-up was censored at the time of death for those patients who died without a severe morbid event, introducing the risk of informative censoring. However, this risk of selection bias does not exist for the analyses considering death alone and the composite outcome (severe OD or death). Since the analyses using each of the three outcomes gave similar results, we believe that the results showing the independent HAART effect on severe morbidity and/or mortality are robust. Fourth, CD4 count measurements were available every six months during the cotrimoxazole alone period and every three months during the HAART plus cotrimoxazole period. Results of a sensitivity analysis revealed that our findings were robust to the difference in CD4 count measurement frequency between the two groups. Due to the nature of data available at the time this analysis was conducted, there is almost twice as much follow-up time for the cotrimoxazole alone group, which is composed of many patients with short follow-up, while the HAART plus cotrimoxazole group is composed of fewer patients with longer follow-up. Finally, data on plasma HIV-1 RNA were not available from the cohort studies, so we were not able to adjust these analyses for viral load.
In conclusion, in this first study from sub-Saharan Africa to examine the association between HAART and severe morbidity or death, adjusted for current CD4 count, we found that HAART had an independent protective effect against both death and severe morbidity. This effect was greater after 6 months on HAART. If the effect observed in this analysis is also applicable in patients experiencing immunological or virological failure, there may be benefit gained from continuing an initial HAART regimen in the presence of observed failure in settings where additional HAART options are not available. Further studies are warranted to examine the HAART effect in patients experiencing failure. When considering only ODs preventable by cotrimoxazole, the HAART effect additional to cotrimoxazole was negligible. This highlights the specific importance of continued efforts to expand cotrimoxazole prophylaxis in sub-Saharan Africa.