For anyone who has practiced medicine in sub-Saharan Africa, the complex symbiosis of HIV and tuberculosis (TB) is all too familiar. The statistics are so staggering as to invoke a momentary sense of numb futility: one-third of 33 million HIV-infected individuals worldwide infected with TB, accounting for 23% of HIV deaths; TB risk 20–30 times greater in HIV-infected individuals than among persons without HIV; increased TB-related mortality and drug resistance among HIV-infected TB cases . What is more, HIV-infected individuals are more likely than HIV-uninfected individuals to experience recurrent TB, largely as a result of exogenous reinfection .
In this issue, Komati et al.  add fuel to this fire by describing the impact of historical and incident TB in a prospective cohort of 1771 HIV-infected South Africans initiating antiretroviral therapy (ART). Their major findings indicate that historical TB was associated with increased mortality, likely as a marker for poorer baseline health status, as this association disappeared after adjustment for covariates such as CD4 cell count, body-mass index, and hemoglobin. Incident TB after ART initiation, however, was independently associated with mortality even after adjustment for covariates (hazard ratio 2.49). Most TB events occurred within the first 3 months after ART initiation, 19.88 cases per 100 person-years, compared to 4.11 cases per 100 person-years in those who had been on therapy for more than 24 months. Of note, incident TB occurred more frequently in those with virologic failure after ART initiation (hazard ratio 1.54). Alarmingly, these authors recently reported poor sputum smear sensitivity (33%) for detection of culture-positive TB, and disturbing rates of drug resistance (20.6% with multidrug resistant TB, 3.7% with extensively drug resistant TB) from the same cohort .
So long as successful comanagement of HIV–TB coinfection lags behind ART provision, TB will threaten fragile gains in survival resulting from implementation of UNAIDS universal access goals . As is often the case, the problem is not knowing what to do, but rather how best to do it in settings with underresourced and fragmented public health systems.
The first priority must be to diagnose and treat HIV at earlier stages. Since 2007, WHO has advocated ‘opt-out’ provider-initiated HIV testing and counseling to increase testing uptake . It has been proposed that expanding this further to annual, universal testing of a population, followed by immediate provision of ART, could eliminate HIV within 50 years in a theoretical population mirroring South African dynamics . Tremendous debate has ensued about the underlying tensions between individual and public health imperatives to HIV testing and ART initiation, but identifying and treating individuals at earlier stages of HIV infection will clearly diminish individual and population vulnerability to TB. Updated WHO adult treatment guidelines now advocate initiating ART in asymptomatic individuals when CD4 cell count declines below 350 cells/μl rather than 200 cells/μl, the articulated rationale for which includes not insignificantly, achievable reductions in TB transmission and incidence with wider, earlier application of ART .
Secondly, donors must direct research funding to develop better, low cost, rapid mechanisms for diagnosing TB and assessing drug resistance among HIV-infected individuals. For instance, the liquid culture microscopic observation drug susceptibility (MODS) assay allows accurate ascertainment of TB status and drug resistance within 21 days of sputum collection in HIV-infected persons, at a cost of 13.62 US dollars per person screened . Accurately diagnosing those without TB is as important as diagnosing those with TB, to identify persons who would benefit from isoniazid preventive therapy, a vastly underutilized intervention in resource-limited settings precisely because active TB is so difficult to exclude. In settings without MODS availability, a diagnostic algorithm incorporating historical assessment of fever, cough, and night sweats, followed by sputum smear, chest radiography, and CD4 cell count in patients with any one of these symptoms, allowed for reliable exclusion of TB in the vast majority of HIV-infected individuals . These and other low cost, evidence-based TB diagnostic strategies, uniquely adapted for use in HIV-infected individuals in resource-limited areas, must be widely and systematically applied without delay.
Thirdly, HIV and TB must be managed together in the same clinics. Recent results from the Starting Antiretroviral therapy at three Points In Tuberculosis therapy (SAPIT) study demonstrated a 55% mortality reduction from integrated initiation of ART during TB therapy, as compared with sequential initiation of ART after completion of TB therapy, a consistent benefit observed in individuals with CD4 cell count less than and greater than 200 cells/μl . Updated guidelines now advocate initiating ART as soon as possible in all HIV-infected persons with TB, irrespective of CD4 cell count, rather than only for those with CD4 cell count less than 350 cell/μl . Treating HIV and TB together may be complicated by the immune reconstitution inflammatory syndrome (observed in 12.4% of SAPIT individuals randomized to integrated therapy) , and also by drug interactions, requiring careful monitoring by clinicians experienced in the management of both diseases. Nonetheless, coordination of HIV and TB clinical care will lead to decreased mortality and ultimately to a cost savings by avoiding duplication of space and personnel and decreasing patients lost to follow up. Coordination must become a pressing global programmatic priority, one with particular urgency in sub-Saharan Africa.
Finally, drug susceptibility testing is essential to ensure optimal TB therapy in HIV-infected individuals, and where this is lacking, empiric use of expanded TB regimens incorporating second-line agents may warrant consideration if there are high rates of drug resistance. ‘Universal access’ must now include access to second-line TB medications and not only ART.
TB, a disease of antiquity, is testing all our ingenuity and resolve to combat the signature pandemic of our modern age, now nearly into its fourth decade. We know what to do, and we are learning how to do it most effectively in resource-limited settings. The time to act, as always, is now, if we are to prevent a very old disease from undermining all the progress made against a relatively newer one.
C.vdH. is supported by National Institute of Allergy and Infectious Diseases P30-AI50410 University of North Carolina Center for AIDS Research and FIC 5 U2R TW007373-03.
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