13. DRUG-RESISTANT TB AND HIV

13.1. Introduction

HIV co-infection is a significant challenge for the prevention, diagnosis, and treatment of MDR- and XDR-TB. Provider-initiated HIV counselling and testing should be routinely offered to all TB patients.

HIV is a powerful risk factor for development of all forms of TB including DR-TB. DR-TB is often associated with higher mortality rates in HIV infected when compared with the non-infected.

Diagnosis of DR-TB in HIV positive persons is difficult and all high risk HIV patients with TB should be screened for drug-resistance with DST. ART in addition to treatment of DR-TB has been reported to improve outcomes of DR-TB in HIV-infected.

The national guidelines on the use of ART should be considered in conjunction with the content of this chapter.

13.2. Clinical Features and Diagnosis of DR-TB in HIV-infected Patients

As with drug sensitive TB, the clinical presentation is influenced by the degree of underlying immunodeficiency. In the earlier stages of HIV infection, the pathology of DR-TB is similar to that seen in HIV negative people with smear positive pulmonary TB being the most commonly seen. As immunodeficiency progresses, extra-pulmonary TB disease becomes more common. Furthermore, clinical presentation may be masked by the existence of other opportunistic infections.

The diagnosis of DR-TB in HIV-positive persons is more difficult and may be confused with other pulmonary or systemic infections. Increasingly, the clinical presentation in advanced HIV is extra-pulmonary. This can result in misdiagnosis or delayed diagnosis of DR-TB, which may lead to advanced or complicated drug resistant TB disease and death.

Protocols for the diagnosis of DR-TB in HIV follow the same principles as for HIV-negative patients. Sputum culture and DST should be done on all high risk groups ( i.e., non-converters, all re-treatment patients, contacts of drug resistant TB). Every effort should be made to obtain a specimen in, even if extra-pulmonary TB is suspected.  Common sites of HIV-related extra- pulmonary DR-TB are the pleura, the lymph nodes and the pericardium. Blood cultures for tubercle bacilli sometimes yield positive results.

13.3. Management of Co-Infected Patients

DR-TB treatment is the same for HIV-positive and HIV-negative patients. However, MDR-TB and XDR-TB treatment is much more difficult and ADRs are much more common in HIV-positive patients. Mortality is high during treatment particularly in the advanced stages of immunodeficiency mainly due to advanced MDR- or XDR-TB disease and other HIV-related opportunistic infections. Patients already on ART when MDR- or XDR-TB is diagnosed should immediately be started on appropriate treatment.

The current scope of knowledge has not provided enough evidence to respond to all concerns related to treatment of patients co-infected with MDR- and XDR-TB and HIV. The main issues include:

• Timing of initiation of ART in MDR- and XDR-TB patients (i.e., the appropriate time to initiate ART in MDR-TB patients is not known and depends on a careful calculation of risks and benefits).
• Drug-drug interactions.
• Overlapping toxicities.
• Adherence to complicated treatment regimens.
• Clinical management of co-infected patients.
• The primary goal of ART is to decrease HIV-related morbidity and mortality:
• The patient should experience fewer HIV-related illnesses.
• The patient’s CD4 count should rise and remain above the baseline count.
• The patient’s viral load should become undetectable (<50 copies/ml) and remain undetectable on ART.

13.3.1. Timing of Initiation of ART in Adult DR-TB Patients

All HIV-positive TB, MDR- and XDR-TB patients are eligible to start ART irrespective of CD4 cell count. Furthermore, these patients must be fast-tracked (ART initiation within 2 weeks of being eligible) for the initiation of ART.

Advantages of Starting ART Early

1. Reduced HIV related morbidity and mortality.

2. Increased survival of co-infected DR-TB patients

3. Slower progression to AIDS.

Issues to Consider when Initiating ART

1. Overlapping ADRs from ART and second-line drugs.

2. Complex drug-drug interactions.

3. Occurrence of immune reconstitution syndrome.

4. Treatment non-compliance associated with high pill burden.

The simultaneous initiation of ART and second-line drugs is associated with ADRs that may lead to the interruption of both DR-TB and/or ART. Deferred initiation of ART may help the clinician identify the potential cause of ADRs without neglecting the possibility of concurrent illness.

Two scenarios exist with regard to DR-TB and ART, depending on which condition manifests first:

1.Patient develops DR-TB while on ART

• Start DR-TB treatment immediately.
• Antiretroviral therapy should be continued throughout DR-TB treatment.
• Monitor patient for ADRs, drug-drug interactions and combined toxicities; avoid using tenofovir and aminoglycosides because they are nephrotoxic.

Development of DR-TB is not indicative of ART failure. It is not a reason to stop either DR-TB or

ART or to change any of the regimens.

2.Patient presents with DR-TB before commencing ART

• All patients must be started on ART irrespective of CD4 cell count. Moreover the initiation of ART must be fast tracked as soon the DR-TB treatment is tolerated.

In children  abacavir, lamivudine  and efavirenz  at appropriate dosage constitute the first-line regimen. Lopinavir/rotonavir will replace efavirenz in children younger than 3 years. Dosages are available in the national HIV guidelines.

13.4. Prophylaxis for Opportunistic Infections

Cotrimoxazole is highly effective in preventing:

• Pneumocystis jirovecii pneumonia
• Toxoplasmosis
• Pneumococcus
• Salmonella
• Nocardia
• Malaria

The provision of cotrimoxazole to HIV-infected individuals has resulted in a decrease in hospital admissions as well as mortality in TB patients. Current WHO policies require that all HIV-infected symptomatic (stage 2, 3 & 4) adults and children be given cotrimoxazole prophylaxis as part of a minimum package of care. HIV-infected DR-TB patients are usually in WHO stage 3 or 4 and therefore qualify for cotrimoxazole prophylaxis. Ideally cotrimoxazole should be initiated prior to ART on first adherence visit.

Given the higher likelihood of sulfa-related ADRs in HIV-positive patients (6-8 times greater than in the general population) sulfa-based prophylaxis should be started at least two weeks apart from MDR- or XDR-TB treatment and/or ART. This will allow differentiation between side effects from second-line drugs and cotrimoxazole.

Recommended dosages of cotrimoxazole

In Adults:

Cotrimoxazole 960 mg (two tablets single strength) daily

or

Trimethoprim 5 mg/kg plus sulphamethoxazole 25 mg/kg daily

In Children:

Patients on cotrimoxazole prophylaxis as well as antiretroviral drugs should continue the cotrimoxazole until their CD4 count increases to 350 or above and remains at this level for 3-6 months and then stop.  Patients with known hypersensitivity to cotrimoxazole could be given dapsone instead.

13.5. Immune Reconstitution Syndrome

The immune reconstitution syndrome occurs when the improving immune function unmasks a previously occult opportunistic infection (an infection that was present in the patient’s body, but was not clinically evident). Reactions usually occur within a median of 15 days after initiation of ART. They do not appear to be related to any particular regimen but are usually found in patients with advanced HIV. TB is a common immune reconstitution illness and MDR-TB or XDR-TB patients should be pre-emptively counselled about immune reconstitution syndrome.

Patients with advanced HIV, particularly those with a CD4 count < 50 cells/mm³ may become ill with an immune reconstitution illness during the first few weeks of ART, with symptoms of persistent fever, sweats, loss of weight, cough, shortness of breath, worsening pulmonary infiltrates, and decreasing visual acuity (to name but a few).

Opportunistic infections may present in atypical ways during the phase of immune reconstitution. Management includes high doses of corticosteroids to contain symptoms: prednisolone or methylprednisolone 1 mg/kg for one to two weeks gradually reduced thereafter. It is not unusual to prolong the use of steroids or to restart if symptoms re-occur. Clinicians need to be cautious and attentive to the development of complications due to prolonged use of steroids (e.g. Cytomegalovirus infections).

Non-steroidal agents tend not to be helpful.

13.6. Patient Monitoring

The co-infected DR-TB/HIV patient poses a great challenge and requires intensive monitoring of drug interactions and additive toxicities. The complexity of ART and second-line drugs each with its own toxicity profiles (which may be potentiated during dual therapy) demands even more rigorous monitoring in co-infected patients. In addition, other opportunistic infections have to be prevented, monitored and treated.

Patients with DR-TB and HIV may require special socio-economic support. The treatment regimens are particularly hard to administer, the stigma of both diseases can result in serious discrimination, and the risk of mortality is very high.

The monitoring with chest x-rays, smear microscopy and cultures of patients is the same as for HIV-negative DR-TB patients. In patients receiving ART, CD4 counts should be measured at the time of diagnosis and every six months thereafter. A significant decrease in CD4 count is a decrease from baseline of 30% or more.

Viral load should be measured at baseline and at six-monthly intervals, provided that patients have reached virological goal (defined as a one-log/ 10-fold decrease). If this has not been achieved, an appropriate evaluation of virological failure should be done (assessment of adherence, potency, absorption, and viral resistance). A significant change in plasma viral load is a three-fold or 0.5 log increase or decrease.

ART also requires additional monitoring of tests not usually done in DR-TB treatment. For example, hematocrit and white blood cell count testing in patients on zidovudine, periodic monitoring of liver serum enzymes in patients on nevirapine, and testing of pancreatic enzymes in patients with abdominal pain taking stavudine or didanosine, are required.

13.7. Management of Adverse Drug Reactions

In general, HIV-positive patients have a higher rate of ADRs to both TB and non-TB medications and the risk of these increases with the degree of immunosuppression. Many of the medications used to treat DR-TB and HIV have overlapping, or in some cases additive, toxicity. Identifying the source of ADRs in patients taking treatment for both DR-TB and HIV is difficult.

When possible, avoid the use of agents with shared adverse effect profile. However, benefit of using drugs that have overlying toxicity outweighs the risk but there is a need to increase monitoring of ADRs in HIV infected DR-TB patients.

Some of the common overlying toxicities are:

• Peripheral neuropathy
• Central Nervous System toxicity
• Depression
• Gastro-intestinal intolerance
• Hepatotoxicity
• Skin rash
• Renal toxicity
• Electrolyte disturbances
• Hypothyroidism etc.

13.7.1. Hepatotoxicity

This is a common and potentially serious ADR. It is defined as:

• An AST and ALT serum level of more than three times the upper limit with accompanying symptoms, or
• An AST and ALT serum level of greater than five times the upper limit without accompanying symptoms.

If hepatitis develops, all potentially hepatotoxic drugs must be stopped, including pyrazinamide, antiretrovirals and cotrimoxazole. Serological tests for hepatitis A, B and C should be performed and the patient should be asked about exposure to alcohol and other hepatotoxins.  While the hepatitis is resolving it would be advisable to provide non-hepatotoxic drugs to continue the MDR-TB treatment, such as ethambutol and streptomycin. Treatment may be restarted when the AST, ALT and bilirubin levels have dropped below two times the upper limit of normal levels with significant improvement of symptoms.

13.7.2. Peripheral Neuropathy

Neuropathy may be caused by nucleoside analogues (ddI, d4T) and additive toxicity of ethionamide, cycloserine, terizidone and pyrazinamide when given with stavudine and/or didanosine has also been demonstrated. Pyridoxine 150 mg daily should be used in all HIV-infected patients receiving cycloserine/terizidone.