Management of Treatment Failure

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Monitoring people on ART is important to ensure successful treatment, identify adherence problems and determine whether ART regimens should be switched in case of treatment failure. Compared with clinical or immunological monitoring, viral load testing provides an early and more accurate indication of treatment failure and the need to switch from first line to second-line drugs, reducing the accumulation of drug resistance mutations and improving clinical outcomes. Measuring viral load also helps to discriminate between treatment failure and non-adherence, following enhanced adherence support. Further, viral load testing gives clients a measure of understanding, control and motivation to adhere to treatment and understand their HIV infection. Viral load testing has been strongly recommended as the preferred approach to monitor treatment among people living with HIV.

Table 109: Different Types of Treatment Failure (WHO Definitions)

Failure	Definition	Comments
Clinical failure	Adults and adolescents New or recurrent clinical event indicating severe immunodeficiency (WHO clinical stage 4 condition) after six months of effective Treatment Children New or recurrent clinical event indicating advanced or severe immunodeficiency (WHO clinical stage 3 and 4 clinical conditions except for TB) after six months of effective treatment	The condition must be differentiated from immune reconstitution inflammatory syndrome occurring after initiating ART. For adults, certain WHO clinical stage 3 conditions (pulmonary TB and severe bacterial infections) may also indicate treatment failure

 

Failure	Definition	Comments
Immunologic failure	Adults and adolescents CD4 count at 250 cells/mm3 following clinical failure or Persistent CD4 count < 100 cells/mm3	Without concomitant or recent infection to cause a transient decline in the CD4 count Current WHO clinical and immunologic criteria have low sensitivity and positive predictive value for identifying individuals with virologic failure. There is currently no proposed alternative definition of treatment failure and no validated alternative definition of immunologic failure
	Children Younger than 5 years Persistent CD4 count < 200 cells/mm3 Older than five years Persistent CD4 count < 100 cells/mm3
Virologic failure	Viral load > 1,000 cp/mL based on two consecutive viral load measurements three months apart, with adherence support following the first viral load test. ART switch after first viral load > 1,000 cp/mL for those receiving NNRTI-based regimens	An individual must be taking ART for six months before it can be determined that a regimen has failed   Individuals with viral load > 20 to < 1,000 cp/mL, maintain ARV regimen, EAC may be considered and repeat viral load testing after three months

Table 110: Recommended Second-Line ART Regimens by Specific Populations

Specific populations	Description	1st line ART used	Preferred 2nd line ART	Alternative 2nd line ART
Children (0 – 4 weeks)	All	AZT + 3TC + NVP
Children (≥ 4 weeks), Adolescents and Adults	3 – 24.9kg	ABC + 3TC + DTG	AZT + 3TC + LPV-r	Consult Expert Opinion or call 7040
		ABC + 3TC + LPV-r	AZT + 3TC + DTG
	≥ 25kg	TAF + FTC + DTG2	AZT + 3TC + LPV-r
	≥ 30kg	TDF + 3TC + DTG	AZT + 3TC + DRV-r3	AZT + 3TC + LPV-r TDF + XTC + DRV-r3
		TAF + FTC + DTG2
		TDF + XTC + EFV	TDF + 3TC + DTG1	AZT + 3TC + DRV-r3 AZT + 3TC + DTG AZT + 3TC + LPV-r TDF + XTC + DRV-r3
			TAF + FTC + DTG2

• Emerging evidence indicates the backbone of TDF + XTC can be maintained or recycled even if used in First-Line
• Note that evidence not sufficient/conclusive for use of TAF in patients co-infected with TB on Rifampicin-based ATT, therefore avoid use in such patients.
• DRV-r 400/50mg should be used in those who are ≥ 12 years and ≥ 40kg, otherwise consult Expert opinion or call 7040. Avoid if on Rifampicin-based ATT

Table 111: Summary of Preferred Second-Line ART Regimens for Adults and Adolescents with TB and Hepatitis B Co-Infection

Specific Conditions	Description	1st line ART used	Preferred 2nd line ART	Alternative 2nd line ART
HIV and HBV Co-infection in Adolescents and Adults	All	TDF + XTC + EFV	TDF + 3TC + DTG	Consult expert opinion
		TDF + 3TC + DTG	AZT + 3TC + LPV-r + TDF*
		TAF + FTC + DTG
Children, Adolescents, and Adults Co-infected with TB	3 – 29.9kg	ABC + 3TC + DTG	AZT + 3TC + LPV-r
	≥ 30kg	TDF + 3TC + DTG

TDF + XTC should always be part of the combination in HBV/HIV co-infections. Since stand-alone TDF is currently not available, use TDF + XTC in consultation with expert or call 7040.

People re-engaging with care after treatment interruption or treatment failure

People re-engaging with care after treatment interruption should be provided with positive messages or welcome and should be offered comprehensive clinical assessment for AHD. The package should be given to people who are re-engaging with care after a period of ART interruption or when ART fails, and they have developed AHD. Such people are likely to benefit from the same set of interventions as ART-naive people with AHD.

People interrupting treatment on a NNRTI–containing regimen are at risk of drug resistance and may require more intensive virological monitoring, and consideration should be given to restarting ART using DTG- containing regimen with a goal of re-establishing viral suppression. 

For people presenting with diagnosis consistent with clinical failure (defined as a new or recurrent clinical event indicating severe immunodeficiency), WHO recommends viral load testing. CD4 count testing is no longer recommended for ART monitoring for people receiving ART who are clinically stable where viral load monitoring is available. However, CD4 count testing should be specifically prompted for people with a viral load exceeding 1,000 copies/mL and for everyone whose clinical presentation suggests AHD regardless of ART exposure. For people with suspected treatment failure and AHD, CD4 count, and viral load should be carried out in parallel.

People presenting with AHD because of treatment failure should also benefit from the advanced HIV disease package. If they are severely ill, an expedited switch to a more efficacious regimen should be considered.

When to consider stopping ART

Recipients of Care may choose to postpone or stop therapy, and providers on a case-by-case basis, may select to defer or stop therapy on the basis of clinical and/or psychosocial factors.

The following are indications for stopping ART:

• Patient’s inability to tolerate all available ARV medications
• Patient’s request to stop after appropriate counselling
• Non-adherence despite repeated counselling: treatment should be stopped to avoid continued toxicity, continued evolution of drug resistance, and transmitting drug resistant HIV
• Unreliable caregiver
• For children, the caregiver is instrumental in ART Any factors that affect the capability for the caregiver to give medications consistently may be an indication to stop ART in an HIV-infected child
• Serious drug toxicity or interactions
• Intervening illness or surgery that precludes oral intake
• ARV non-availability

Treatment Failure with No Further Treatment Options

Continue the failing ART regimen unless there are intolerable toxicities or drug interactions. Even with treatment failure, the regimen is likely to have some residual antiviral activity. Stopping therapy in the setting of virologic failure can be associated with rapid falls in CD4 counts and development of OIs.

Referral Criteria

When to Consult or Refer to the Next Level

The following criteria are indications to consult or refer to the next level:

• Suspected hepatotoxicity not responding to standard management (e.g., TB/HIV co-infection treatment, ALT/AST > 3-fold of upper limit of normal with symptoms and > 5-fold upper limit of normal without symptoms)
• Second-Line treatment failure or inability to tolerate Second-Line therapy
• Complications on PI-based regimen
• Severe or life-threatening adverse reactions
• Inability to tolerate therapy despite change in regimen
• HIV-HBV co-infection with renal insufficiency