Treatment of drug-resistant TB and HIV

Clinical description

Drug-resistant TB is often associated with higher mortality in PLHIV. Early diagnosis of drug-resistant TB and HIV, prompt initiation of appropriate second-line anti-TB drugs and antiretroviral treatment (ART), are all vital for optimal treatment outcomes.

General considerations in the management of DR-TB/HIV co-infection

• HIV testing is an essential component in the management all presumptive DR-TB

patients.

• Prompt initiation of both DR-TB and antiretroviral therapy (ART) is crucial to successful

treatment; close clinical monitoring is required for DR-TB/HIV co-infected patients due to overlapping toxicities and drug-drug interactions (Table 10.46). It is important to aggressively diagnose and manage adverse events.

• Patients who are not on ART, but are HIV positive, at the time of DR-TB diagnosis

should start DR-TB treatment prior to ART initiation. ART should be initiated for all DR-TB/HIV co-infected patients regardless of CD4 count. ART should be started approximately two weeks after DR-TB treatment initiation, or within 2-8 weeks and as soon as the patient is tolerating DR-TB treatment.

• If the patient is already on ART, request a CD4 and viral load for early detection of ART

failure. If the patient is failing they need to be switched to second line ART without delays.

• Be aware of opportunistic infections, especially at lower CD4 counts, and immune

reconstitution inflammatory syndrome (IRIS, both unmasking IRIS and paradoxical National Tuberculosis Control Programme 89 IRIS) when starting ART in ART-naïve HIV positive patients.

• Provide additional nutritional support and assess functional status for co-infected

patients.

• For patients who are not eligible for the shorter regimen, Delamanid is the preferred

new drug for individualized regimens, since there are no significant drug-drug interactions between Delamanid and antiretroviral therapy (ART). If Delamanid is not available, then Bedaquilline can be used.

• Since Delamanid is metabolized by albumin, patients with low BMIs and/or a low

serum albumin should be provided with high protein dietary foods.

• Bedaquilline and ART:

 Bdq should not be used with any dose of efavirenz (400 mg or 600 mg), as efavirenz (EFV) reduces Bdq levels.

 Nevirapine (NVP) can be used safely with Bdq in HIV-infected patients as there are no drug-drug interactions between the two drugs.

 Lopinavir/ritonavir (LPV/r) has been shown to increase Bdq plasma concentrations hence should be used with caution and frequent monitoring of ECGs and liver function tests; if integrase inhibitors are available (e.g. dolutegravir or raltegravir)

they can be used instead of protease inhibitors.

HIV positive patients not on ART at the time of DR-TB diagnosis

• ART naïve patients on a Bedaquilline containing regimen should start on an NVP based

regimen (with a loading dose for the first 14 days) within 2-8 weeks of starting DR-TB treatment; use caution when initiating ART with NVP at higher CD4 counts, as there is increased risk of liver toxicity.

• If there are concerns starting NVP, especially if the baseline ALT is elevated, the patient

should be initiated on a PI regimen with LPV/r.

• After completion of Bedaquilline patients may be switched from an NVP ART regimen

to an EFV regimen.

• ART naïve patients on a Delamanid containing regimen may initiate ART with an EFV

containing fixed dose combination.

HIV positive patients already on ART at the time of DR-TB diagnosis

• If the patient is already on ART with EFV for ≥ 6 months and there are no viral load

results within 3 months, assess the viral load:

o If the viral load is undetectable, the patient can be switched from EFV to NVP (without the initial loading dose) while he or she is on Bdq and then put back on EFV as soon as Bdq is completed;

o If the viral load is detectable (defined as a VL ≥ 1000), the patient should undergo adherence counseling and be switched from EFV to lopinavir/ritonavir with careful monitoring of ECGs/liver function tests.

90 National Tuberculosis Control Programme

• If the patient is already on second line ART for ≥ 6 months containing lopinavir/

ritonavir, then a viral load should be assessed:

o If the viral load is undetectable, continue with lopinavir/ritonavir with close monitoring;

o If the viral load is detectable, the patient should undergo adherence counseling and be evaluated for third line ART per HIV guidelines.

Table 10.4-6 Overlapping drug toxicities in the treatment of DR-TB and HIV co-infection ANTIRETROVIRAL TOXICITY DR-TB DRUG COMMENTS AGENT Gastrointestinal Eto/Pto, PAS, Cfz, H, Stavudine, didanosine, If diarrhea is chronic, consider (nausea, Z, Bdq, Dlm nevirapine, ritonavir opportunistic infections, especially with vomiting) low CD4 counts Persistent vomiting may be due to other causes (hepatitis, lactic acidosis, meningitis, or pregnancy)

Abdominal pain Eto/Pto, PAS, Cfz, All antiretroviral therapy Abdominal pain may be an early symptom Lzd of severe side effects such as hepatitis, pancreatitis or lactic acidosis Dermatologic H, R, E, Z, FQ, Eto/ Abacavir, nevirapine, Do not re-challenge abacavir if thought to Pto, Cfz efavirenz be the cause of rash, as it can result in life threatening anaphylaxis (skin rash)

Do not re-challenge with any agent that may have caused Stevens Johnson Syndrome Also consider cotrimoxazole as cause of skin rash CNS toxicity Cs, HHD, FQ, Eto/ efavirenz (EFV) EFV CNS side effects often resolve after and/or Pto, imipenem, the first 2 - 4 weeks of treatment, thus psychiatric meropenem other causes need to be ruled out adverse event (depression, psychosis)

Headache Cs, Bdq Zidovudine, EFV Rule out more serious causes of headache as meningitis, toxoplasma, etc.

Peripheral HHD, Lzd Stavudine (d4T), Patient receiving HHD, Cs and/or neuropathy didanosine (ddI) Lzd should receive prophylaxis with pyridoxine (B6)

(less frequent: FQ, SLI, Cs, Eto/Pto, E)

Avoid use of d4t and ddI with Cs and Lzd.

If Lzd is the cause and is grade ≥ 2 stop and do not re-introduce Renal SLI (Am, Km, Cm) Tenofovir (TDF) Avoid concomitant use of TDF and SLI if insufficiency possible. Even without the concomitant use of TDF, PLHIV have an increased risk of renal toxicity secondary to SLI.

hypokalemia Frequent creatinine and electrolytes monitoring is recommended. Adjust doses if clearance <30 ml/min National Tuberculosis Control Programme 91 Hematological Lzd Zidovudine (AZT) Monitor full blood count monthly when (bone marrow using Lzd. All patient with Lzd should toxicity) receive pyridoxine (Vit B 6) 100 mg.

Consider other causes such as cotrimoxazole, HIV infection, opportunistic infections Hepatotoxicity PZA, Hhd, Eto/Pto, NVP, EFV, all NRTIs, all If ALT/LFTs elevated > 5 times stop both PAS, Bdq PIs ART and DR-TB drugs, then restart the DR-TB drugs first (see Chapter 9)

Rule out other causes such as viral hepatitis (A, B, C and CMV)

Pancreatitis Lzd d4T, ddI Avoid the use of these agents together If an agent caused pancreatitis, suspend it permanently Also consider other causes as gallstones or excessive alcohol use Lactic acidosis Lzd d4T, ddI, AZT If an agent has caused high lactate or lactic acidosis replace it Optic Neuritis E, Lzd ddI Permanently suspend the agent that caused optic neuritis and replace it Hypothyroidism Eto/Pto, PAS d4T Monitor thyroid stimulating hormone (TSH) and replace with levothyroxine when necessary Dysglycaemia Gfx, Eto/Pto Protease inhibitors (PI) Eto/Pto can make insulin control in diabetic patients more difficult (hypoglycemia and poor glucose regulation)

PI’s can cause insulin resistance and hyperglycemia Arthralgia Z, Bdq Protease inhibitors (PI) Arthralgia is very common with Z, also reported with Bdq and PI’s QT Prolongation Bdq, Dlm, Mfx, Gfx, ART has been associated Unknown data on additive effects of Cfz (less frequent with QT prolongation combining ART with prolonging QTc Lfx) second line anti-TB drugs. If the QTcF is prolonged > 500ms stop DR-TB QTcF prolonging drugs but do not stop ART