IAS: Studies present reassuring data on the use of ART in patients on TB treatment

Two studies presented on Monday at the 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention in Sydney provided reassuring data about the dosing and effectiveness of both efavirenz and nevirapine-based antiretroviral therapy (ART), although questions still remain about the best ART regimen to use and when is the best time to start it in people coinfected with HIV and TB.

Background

Rifampicin is the cornerstone of the combination of drugs used to treat TB however, studies have shown that it lowers the serum concentrations of efavirenz by up to 20%, and nevirapine levels by 20-50%. Because of fears that coadministration might thus compromise antiviral efficacy, many doctors in resource limited settings (where other regimens are not available or are too costly) have been afraid to start ART in people with HIV already on TB treatment — even though the patient may desperately need HIV treatment. In addition, clinicians may be unsure what to do if someone on either efavirenz- or nevirapine-based ART regimens should develop active TB. Delaying TB treatment is not an option. Should the antiretroviral doses be increased?

Efavirenz

In the case of efavirenz, a few studies now suggest that this is unnecessary. One of these, by Dr Ketan Patel and colleagues at the Infectious Diseases Clinic, Ahmedabad, India found that coadministration of standard doses of efavirenz (600 mg once daily) with TB treatment did not appear to reduce its short-term clinical effectiveness, while other studies reported that increasing the dose to 800 mg once daily did not necessarily lead to dramatically better trough levels of the drug, but did significantly increase side effects.

Nevertheless, there is a chance that coadministration could reduce the long-term effectiveness of efavirenz-based ART, so Dr Patel assessed the data from extended follow-up (at least 12 months and out to three years) of the previous cohort to ascertain whether prior TB treatment predicted an increased risk of treatment failure.

195 HIV-positive patients with TB and 188 without TB were treated with an efavirenz-containing combination antiretroviral regimen. Patients with TB received the same antiretroviral regimen plus nine months of rifampicin-containing TB treatment, and then continuing with efavirenz-containing combination antiretroviral treatment alone. All patients were medically evaluated every month with CD4 counts done every three months.

Among patients co-infected with TB, baseline median CD4 counts were lower in those with TB (90 versus 126) (p = 0.0005). However, similar improvements in CD4 count were seen in both groups at each time point up to 3 years of follow-up. The rate of irregular follow-up and those lost to follow-up or death were also similar in the two groups (p = 0.494).

There appeared to be no significant differences in long-term treatment outcomes. Immunological failure was observed in 11.79% and 10.10% of subjects with and without TB (p= 0.715) respectively. When losses to follow-up were treated as failure, there was still no significant difference. Nor was there any difference in time to treatment failure. However, it should be noted that the study has no viral load results in its subjects.

A significantly higher number of people on treatment for both TB and HIV developed hepatitis (13.3% vs 2.2%, p<0.0001) but Dr Patel said these resolved when the hepatotoxic drug was discontinued.

“Rifampicin-based TB treatment at the onset of efavirenz-based HAART didn’t predict or increase risk for efavirenz treatment among HIV infected patients, for up to three years,” concluded Dr. Patel.

Nevirapine

Because of the previously described studies, efavirenz is recommended by WHO guidelines when people on TB treatment need to start ART.

However, some people cannot take efavirenz due to allergies, side effects, pregnancy or unavailability. In these cases, nevirapine may be the sole option, but the best dosage has been unclear. So Dr Anchalee Avihingsanon of the Thai Red Cross AIDS Research Centre, Bangkok, Thailand and colleagues conducted a randomised study to find the appropriate dose of nevirapine in HIV/TB co-infected patients also on rifampicin.

The team investigated 32 HIV/TB co-infected patients, with CD4 counts <200 cells/mm³, who were receiving rifampicin for two to six weeks. The subjects (mostly male) had extremely advanced HIV disease, with baseline CD4 cell counts of 45 and 40 for the NVP400 and the NVP600 arms respectively.

Nevirapine dosing is already somewhat complicated. Participants were randomised to receive nevirapine 200mg once daily for 2 weeks then twice daily (NVP400 arm) or 200mg twice daily for two weeks then three times daily (NVP600 arm) plus two nucleoside reverse-transcriptase inhibitors. Plasma nevirapine levels were checked at weeks 2, 4, and 12.

They found that median nevirapine trough levels (C_min) at week 2 were significantly lower in the NVP400 arm than the NVP600 arm (p = 0.001). More patients had C_min levels < 3.1 mg/L at week 2 in NVP400 (79% vs 19%, p = 0.002). However, nevirapine C_min was comparable between the two arms at week 4 (p = 0.06) and week 12 (p=0.24).

The 24-week efficacy showed no difference. In an intent-to-treat (ITT) analysis 63% vs 56% had HIV RNA < 50 copies/mL, while in an on-treatment (AT) analysis 83% versus 100% of the NVP400 and NVP600 had HIV RNA < 50 copies/mL. The median (inter-quartile range) CD4 rise was actually greater on the NVP 400 arm but this did not reach statistical significance (p = 0.07).

However, NVP600 had a higher trend to hypersensitivity (25% vs. 6%, p = 0.07) and study discontinuation (44 vs 25%, p = 0.23).

Although drug levels were suboptimal in the NVP400 group's lead-in period, the NVP600 lead-in period was associated with more drug hypersensitivity. Because of these data, the NVP600 arm was discontinued. Longterm follow-up data of NVP400 at 60 weeks show that 68% of subjects have viral loads below 50 copies/ml by ITT, 87.3% by AT.

“NVP 600 with a 400 mg lead-in is not recommended due to a high rate of hypersensitivity,” said Dr. Avihingsanon. However, despite suboptimal doses in 80% of the patients at two weeks, nevirapine dosed at 200mg twice daily as part of combination antiretroviral therapy with 200 mg once daily lead-in “provided potent virological suppression and good CD4 response over 24 weeks observation,” so this regimen “should be sufficient for most Thai HIV-infected patients” receiving rifampicin.

However, it is unclear how applicable these findings are to other populations. According to Dr Avihingsanon, Thai subjects tend to have higher drug levels of nevirapine than other ethnicities. Also, the weight of the participants in this study was quite low compared to some populations (between 46-54 kg).