HIV significantly increased the risk of pneumococcal colonization. This conclusion rests on the following observations: 1.) A significantly higher proportion of nasopharyngeal swabs yielded pneumococci from HIV-positive mothers than HIV-negative mothers; 2.) HIV-positive mothers became newly colonized earlier than HIV-negative mothers; 3.) HIV-positive mothers were more likely to be colonized repeatedly with different strains of pneumococci over time; and 4.) repeat colonization with a homologous pneumococcal strain occurred only among the HIV-positive mothers, with most of these occurring at sequential visits. Thus, not only are HIV-positive mothers more likely to be colonized, to become newly colonized, and to be repeatedly colonized, but when they are colonized, colonization appears to persist longer than in HIV-negative mothers.
HIV infection strongly influenced the dominant serotypes of the colonizing pneumococci. HIV-positive mothers were far more likely to be colonized with the pediatric serotypes 6, 19, and 23 (and in particular 6b, 19f and 23f) than the HIV-negative mothers. This is consistent with other reports [14
] and has significant implications, given that these same serotypes are represented by the 7-valent protein conjugate vaccine. While the TZI study focused only on colonization rather than invasive disease, it remains true that the most common serotypes found colonizing our patients happen to be the same as those identified time and again in the context of invasive pneumococcal disease surveys.[25
It is worth considering why previous reports reached different conclusions about the effect of HIV on colonization. Nicolletti et al
found no association between HIV viral loads and CD4 counts and the risk of pneumococcal colonization. However, this conclusion rested on only 64 isolates and used historical controls, with no internal HIV-negative control arm to serve as a true reference group.[12
] Leibowitz actually found lower rates of pneumococcal colonization in a cross-sectional study of HIV-positive and negative orphans in Romania.[11
] However, only a minority of the children had HIV, and the HIV-positive and HIV-negative orphans were housed separately, thereby introducing a significant cluster effect not accounted for in their analysis. Several other studies finding no association between HIV and pneumococcal carriage rates were conducted cross-sectionally in the context of patients either under evaluation for or being treated for acute respiratory infections.[28
] However, whether HIV affects colonization rates in patients who may already have invasive disease is a very different question from whether HIV alters the colonization burden and the risk for future invasive disease. Because the sample collection for TZI was done systematically according to a pre-defined schedule, regardless of HIV status or of intercurrent clinical events, it should be free of such ascertainment biases.
The 23-valent polysaccharide vaccine is currently recommended for HIV-positive patients by the US Centers for Disease Control and Prevention,[30
] despite evidence of reduced efficacy among patients with HIV.[31
] Prior research suggest that this reflects attenuated immune responses among HIV-positive patients from failure to develop therapeutic level of capsule-specific IgG[32
] and more rapid declines in antibody titres over time.[33
] Quite troubling are data from the only randomized controlled trial specifically designed to test the efficacy of the 23-valent vaccine among HIV-positive patients, which failed to show benefit to the vaccine and suggested potential harm. This study showed a statistically significant increase in all-cause pneumonia among HIV-positive Ugandan adult vaccinees, with a seemingly paradoxical increased risk of invasive disease due to serotypes represented by the 23-valent vaccine.[34
] This highlights the need for more immunogenic and efficacious vaccines suitable for use in HIV-positive adults. The 7-valent conjugate protein vaccine is licensed for pediatric use. However, the increase in colonization with pediatric serotypes seen here supports a possible role for the 7-valent or similarly constructed vaccine among HIV-positive adults. Our finding that HIV increased the probability that colonization would be due to a serotype covered partially or specifically by the vaccine strengthens this argument.
One of the principal limitations of this analysis is that we had very little data on the immune status of the mothers beyond their HIV status. Only 25 of the HIV-positive women underwent CD4 testing, among whom the mean CD4 count was nearly 500. If this sub-sample is representative of the larger group of HIV-positive women in our cohort, then it is likely that most were at a relatively early stage in HIV/AIDS. Similarly, we did not have detailed information about intercurrent antibiotic use among the mothers, so were unable to determine whether the rate of colonization among HIV-positive mothers using cotrimoxazole prophylaxis might have been suppressed compared with HIV-positive non-users. Similarly, the infants of the HIV-positive mothers used cotrimoxazole prophylaxis for most of the study period. However, both of these would likely bias the effect of HIV on pneumococcal colonization towards the null. Our study participants were all post-partum Zambian women who were breastfeeding, and this could theoretically affect the generalizability of these findings.
A methodological limitation is that we were unable to determine whether a given isolate that occurred repeatedly in a given individual, consecutively or in a punctuated pattern, was the same isolate persisting over time or genetically unique isolates that happened to share the same serotype. Given that serial colonizations only occurred in the HIV-positive population, and then most often across contiguous visits, the former explanation appears more plausible. Nevertheless, the latter explanation would still suggest that HIV-positive patients were failing to develop adequate mucosal immunity to prevent re-colonization with a genetically distinct but serologically homologous serotype.
In conclusion, our analysis supports a causal association between HIV infection and increased colonization with S. pneumoniae, an observation that we hypothesize may partially explain the increased rates of invasive pneumococcal disease in patients with HIV/AIDS. The increased prevalence of pediatric serotypes among the HIV-positive patients, all of which are targeted by existing 7-valent conjugate pneumococcal vaccines should encourage further research into whether these vaccines might be used to protect HIV-positive adults, either by increasing pediatric vaccination coverage to reduce spread to the adults, or by vaccinating the adults themselves.