Studies at the 38th World Lung Health Conference reported findings in people with HIV consistent with what’s been published in the literature showing that IPT is generally well tolerated, most of the hepatitis is indeed related to asymptomatic transaminase elevations, but also, in at least one unfortunate case, failing to discontinue the drug immediately when symptoms of hepatitis appear can lead to death.
Several reports came from study projects associated with the Consortium to respond effectively to the AIDS/TB epidemic (CREATE), a Bill and Melinda Gates Foundation supported consortium of international researchers and advocates in TB and HIV seeking to identify effective public health strategies in the fight against TB. CREATE’s Project Director, Dr Lois Eldred, presented retrospective data showing no difference in the rates of liver toxicity in patients on IPT plus ART and ART alone at Johns Hopkins Moore Clinic, and low rates in patients on ART plus IPT in the retrospective study described earlier on ART and IPT in Rio (part of the THRio project in Brazil).
The case control study at the Johns Hopkins Moore clinic matched 70 cases receiving isoniazid and ART together to 95 controls (by date) starting on ART alone. Liver toxicity was defined as a change in AST/ALT from baseline to the last date of receiving isoniazid, and data were excluded if the last liver enzyme test was more than sixty days before or after the last reported IPT dose. Liver toxicity was graded 0-1, if either ALT or AST were elevated up to three times baseline levels; grade 2, 3-5 times baseline; and grade 3-4, more than five times baseline.
At baseline, CD4 cell counts were significantly lower in cases on IPT/ART (median 116 vs 252 cells; p-value 0.01); they had higher median viral loads (p<0.01), higher baseline AST (p=0.04) though there was no difference in ALT, and were more likely to be HCV coinfected (98% vs. 66%, p<0.001 — though test results were unavailable for a third of the cases).
Despite these factors, which might have predisposed the IPT/ART group to have more liver toxicity, there were no significant differences between the two groups: five out of 70 (7.1%) had grade 2 events (and four out of those five were HCV coinfected) vs four out of 95 (4.2%) on ART alone (p=0.41); while two out of 70 (2.9%) had grade 3-4 events on IPT/ART vs four out of 95 (4.2%) on ART alone (p=0.65).
Meanwhile, in the THRio study, 291 patients have been put on both ART and INH, 163 have completed six months as of September 30, 2007. Only one of these has developed hepatitis (grade 3). Overall, taking ART with IPT was not associated with hepatotoxicity.
Another Create study project, Thibela TB (‘prevent TB’ in Sotho), operating in the gold mines in South Africa, offered more prospective safety data (as well as a wealth of operational expertise) in a number of posters presented at the conference. The Thibela TB study is randomising clusters (15 gold mine shafts and their employees) rather than individuals to receive either community-wide TB screening plus nine months of IPT vs. routine TB control programme activities. When it has completed enrolment, the study could involve around 70,000 miners, about half of whom will be in the intervention sites and eligible to volunteer for TB screening and IPT.
One poster by Mngadi et al. described the adverse event data to date from four of the intervention clusters that have begun enrolling participants (with 11,293 enrolled, 9626 who have started IPT as of September this year). 98% of the participants are male with a median age of 40. They have monthly scheduled visits, and make unscheduled visits as necessary. At enrolment and at each visit to the clinic, participants are educated about side effects and encouraged to report them promptly. Adverse events are as reported by the participant or gauged by a symptom screen at each visit. Routine laboratory tests to confirm side effects are considered logistically impossible.
In the fourteen months since the study began enrolling, only 76 adverse events have been recorded. Most were graded mild or moderate: 43 hypersensitivity reactions, 29 cases of peripheral neuropathy, and four cases of hepatitis though one of these cases was severe.
A high proportion of these participants are receiving care for HIV, so only the case of hepatitis was considered ‘definitely related’ to IPT, while most of the adverse events were considered only ‘possibly related.’ Although median time for most of the reported events was within 27 days of starting IPT, this ranged between 1 to 212 days. However, the median time to hepatitis was 35.5 days (range 19-99).
“This confirms the safety profile of IPT, thus far,” the poster’s authors concluded.
Of course, there is no comparison arm in this analysis, but the event rate seems rather low. One of the reasons for this could be that, like the clinic in Seattle, the investigators believe in careful patient selection — in other words, as reported in a poster by Popane et al, “use of eligibility criteria ensures the safety of IPT.” The poster described these criteria, which might be useful for other programmes considering implementing IPT on a large scale.
Permanent ineligibility criteria in the Thibela TB study include:
- IPT inappropriate
- Increased risk of adverse events
- Alcohol intake >28 units/wk (men) and > 21 units/wk (women
- History of chronic liver disease
- History of epilepsy or psychosis
- Peripheral neuropathy of grade 2 or greater
- Rash suggestive of hypersensitivity
- Other
- Possible pregnancy or < 3 months post partum, contraindicated medications, being on investigational drugs, or weight < 40 kg
Temporary ineligibility criteria include:
- TB suspects (who then should go through the diagnostic process)
- Suspected hepatitis
- Women at screening who are not on reliable contraception but are willing to use contraception
- Suspected hypersensitivity rash
For the programme overall, so far, about 5.3% of the over 11,500 volunteers have been deemed permanently ineligible, mostly because of heavier alcohol use, while around 10% were temporarily ineligible, mostly because they were TB suspects. However, if after examination these participants are found not to have active TB, or sort out their other issues, they will be given IPT.
The BOTUSA study of IPT also excludes TB suspects and people with a history of hepatitis, pregnant women, etc — but it also has the capacity to rigorously monitor liver function tests for any hint of hepatitis. A poster at the conference presented a safety analysis looking just at IPT-associated hepatitis in the trial (Nyirenda). As part of this study, all participants receive open-label isoniazid 300 or 200 mg per day (depending upon weight) plus 25 mg of vitamin B6 for six months. People were excluded from the safety analysis if their liver enzymes were abnormal at baseline. Hepatitis was defined as any elevation of one grade or more of liver enzymes or bilirubin.
The study has enrolled 1,998 subjects; 1,768 who attended at least 5 of 6 monthly visits for follow-up and to pick up their medications, were included in the safety analysis. In contrast to Thibela TB, the majority were female (74%), median age was 33 (range 19-70), and median CD4 cell count, 303. 28% had CD4 cell counts below 200, and 27% were on ART. 13% reported that they drink alcohol.
There were 54 cases of hepatitis (3% of the cohort). As consistent with the literature on IPT, the vast majority of these were transient asymptomatic liver enzyme elevations that occurred within the first month and resolved on their own. Only 19 were severe (> grade 2), 1.1% of the entire cohort.
Sadly, there was one hepatitis-related death in a woman without any other easily identifiable risk factors: no hepatitis B coinfection, and she did not report drinking alcohol and was not also on ART. The authors wrote, “After developing jaundice, she did not stop IPT and was unfortunately given acetaminophen” [which can aggravate hepatitis].
In analyses looking at risk factors in all the patients for developing severe hepatitis, the investigators found no association between hepatitis B coinfection and hepatitis on IPT, but noted a four-fold increased risk of hepatitis in patients who had less than 200 CD4 cells or who were on ART. They concluded that “hepatic enzymes should be more closely monitored in persons on both IPT and ART.”
However, as noted by the Thibela TB study, this would be logistically impossible in most settings, and it is not clear that this would necessarily avert the risk of these events occurring any better than monitoring symptoms. It would not have prevented the death in this study.
Nor would she have been screened out using Thibela TB’s eligibility criteria, underscoring that some severe liver toxicity on IPT may be unavoidable, and it is absolutely essential to educate patients to immediately discontinue treatment and seek medical attention when they experience symptoms of hepatitis.
That being said, it is important to remember that the risk of morbidity and mortality for people living with HIV is higher for those not taking IPT, so this risk should not be a barrier to rolling out an IPT programme. People have hepatitis, or lactic acidosis or other unexpected reactions and die on ART as well. But the benefits to the community of IPT for people with HIV as a whole are too great to not offer the intervention.
Of note regarding liver enzyme monitoring, in the ongoing double-blind portion of the study, which is assessing continuous IPT (36 months versus 6 months), the Data Safety and Monitoring Board recommended performing an extra liver enzyme assessment on all patients still on treatment (active or placebo).
“The results were reassuring and did not suggest evidence of increased risk in this population,” said Dr Andrew Nunn of the Medical Research Council who sits on the study’s DSMB. Final judgements about the relative safety of three years versus just six months of IPT, and the relative risks and benefits to this population will have to wait until the trial’s conclusion in 2009.
Part 2 of this article follows in a separate email, and discusses the challenges of implementing IPT at national and district level, drawing on the experience of the Botswana programme and the views of experts in the field. Part 2 also includes full references for this article.