17.1. Recommendations
A boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs) are recommended for second-line ART.
(Strong recommendation, moderate quality of evidence)
ATV/r and LPV/r are the preferred bPIs for second-line ART.
(Strong recommendation, moderate quality of evidence)
Simplification of second NRTI options is recommended.
If d4T or AZT has been used in first-line therapy, use TDF + (3TC or FTC) as the NRTI backbone in second- line therapy.
If TDF has been used in first-line therapy, use AZT + 3TC as the NRTI backbone in second- line theapy.
(Strong recommendation, moderate quality of evidence)
In making these recommendations, the panel placed high value on using simpler second-line regimens and the availability of heat-stable formulations and fixed-dose combinations.
17.2. Evidence
A systematic review was conducted with the objective of assessing the optimum second-line ART regimen in PLHIV failing first-line therapy in resource-limited settings. Standard Cochrane systematic review methodology was employed. Outcomes of interest in order of priority were mortality, morbidity (combined disease progression and serious adverse events), viral load response, CD4 response and development of antiretroviral resistance.
17.3. Summary of findings
Second-line NRTIs
Despite a comprehensive search, few studies of relevance were identified. One study reported no difference in virological outcomes among those maintaining 3TC in second-line regimens compared to those who did not (low quality of evidence).(157) Observational data supported this finding.(158)
Boosted PI comparisons
bPIs provide most of the antiviral activity in second-line regimens. There is insufficient evidence on critical patient outcomes to distinguish between bPIs in the context of second-line therapy. Randomized trials comparing LPV/r with DRV/r, ATV/r or FPV/r in ART-naive patients showed non-inferiority at 48 weeks of all three bPIs (evidence of low to moderate quality).159–163) DRV/r was superior to LPV/r at 96 weeks.161) There is evidence of moderate quality that ATV/r is non-inferior to LPV/r (in combination with TDF and an optimized second NRTI) in treatment-experienced patients.164) Non-serious adverse events varied by boosted PI and there were no significant differences in serious adverse events.165,166). All unboosted PIs are considered inferior to bPIs.
PI monotherapy
On the question of whether PI monotherapy could be used as second-line ART, there is a moderate quality of evidence from a targeted review (as opposed to a formal systematic review) of nine RCTs and individual study reports showing less virological suppression and higher rates of viral rebound for PI monotherapy compared to standard triple ART regimens.167–173) There were no other significant differences in the critical outcomes of mortality, disease progression or serious adverse events, or the important outcomes of immunological response and drug resistance (both very low to moderate quality evidence). Non-critical outcomes, such as non-serious adverse events and lipoatrophy, were not captured in the GRADE evidence profile. The panel concluded that an NRTI backbone should be maintained in a second-line bPI-containing regimen.
17.4. Benefits and risks
Benefits
These recommendations will facilitate the simplification of therapeutic options and drug procurement as the NRTIs recommended in second-line therapy are also used in first-line therapy (in different combinations), and should be purchased by all programmes. There is a potential for simplified drug regimens.
Risks
There may be confusion because AZT, TDF and 3TC, the only NRTIs recommended in second-line regimens, also are recommended in first-line regimens. Some countries have already chosen alternative bPIs (IDV/r, SQV/r, FPV/r) in preference to the recommended ones (ATV/r, LPV/r).
17.5. Acceptability and feasibility
PLHIV want better second-line options with fewer side-effects. The preferred bPIs are available in most countries. Generic heat-stable LPV/r is on the market already. A generic heat-stable FDC of ATV/r (co-blister packed with TDF/3TC) is in development. Alternative bPIs (SQV, IDV, FPV and DRV) are not available as FDCs and are more expensive than the preferred options. Saquinavir has a high pill-burden, IDV has a high risk of toxicity and FPV is expensive. Clinicians may not be comfortable with not replacing both first-line NRTIs with two new NRTIs in the second-line regimen.
17.6. Clinical considerations
Table 13Preferred second-line ART options
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| Target population | Preferred options | Comments |
|---|
| Adults and adolescents (including pregnant women) | If d4T or AZT used in first-line therapy | TDF + 3TC or FTC + ATV/r or LPVr | NRTI sequencing based on availability of FDCs and potential for retained antiviral activity, considering early and late switch scenarios
ATV/r and LPVr are comparable and available as heat-stable FDCs or co-package formulations |
| If TDF used in first-line therapy | AZT + 3TC + ATV/r or LPVr |
| TB/HIV coinfection | If rifabutin available | Same regimens as recommended above for adults and adolescents | No difference in efficacy between rifabutin and rifampicin
Rifabutin has significantly less drug interaction with bPIs, permitting standard bPI dosing |
| If rifabutin not available | Same NRTI backbones as recommended for adults and adolescents plus LPVr or SQV/r with superboosted dosing of RTV
(LPV/r 400 mg/400 mg twice daily or
LPV/r 800 mg/200 mg twice daily or
SQV/r 400 mg/400 mg twice daily) | Rifampicin significantly reduces the levels of bPIs, limiting the effective options. Use of extra doses of ritonavir with selected bPIs (LPV and SQV) can overcome this effect but with increased rates of toxicity |
| Hepatitis B coinfection | AZT + TDF + 3TC or FTC + ATV/r or LPVr | In case of ART failure, TDF + 3TC or FTC should be maintained for anti-HBV activity and the second-line regimen should include other drugs with anti-HIV activity |
17.7. Selection of second-line NRTIs
The rationale for the selection of the NRTIs in second-line therapy is to choose the most logical combination depending on what was used in the first-line regimen. Residual activity of first-line NRTIs (with the possible exception of 3TC and FTC) is more likely the earlier failure is detected and switching is implemented. Conversely, any new NRTIs may be compromised in the second-line regimen if there is late detection of failure and late switching. The recommended NRTI sequencing is based on likely resistance mutations and the potential for retained antiviral activity.
There are two clinical scenarios:
early switching based on sensitive monitoring for failure, using viral load;
late switching based on insensitive monitoring, using clinical or immunological criteria for defining failure.
If AZT + 3TC are used in the first-line regimen with sensitive monitoring and early switching, the NRTIs with most likely activity are TDF and ddI. In the scenario of insensitive monitoring and late switching, TDF and ddI activity are less likely.
If TDF + 3TC are use in first-line therapy, with early or late switching, the NRTIs with remaining activity are AZT and d4T (both very likely). Retained activity of 3TC is likely in the early switching scenario and less likely in the case of late switching.174)
ABC and ddI are no longer recommended as preffered options in second-line regimens. The panel concluded that there was no specific advantage in using ABC or ddI and their use added complexity and cost, but new data will be generated from ongoing trials.175) One study in the review reported no difference in viral suppression following mainly d4T-based first-line ART, with and without a ddI-containing NRTI backbone in an LPV/r-based second-line regimen.176) Another study reported similar virological outcomes in individuals with and without the M184V mutation and taking a second-line regimen with or without ddI.158) No studies reporting failure following a first-line ABC-containing (or TDF-containing) regimen were identified.
17.8. Maintaining 3TC in the second-line regimen
There is uncertainty about whether 3TC should be added as a fourth drug in the NRTI component of second-line regimens if ddI or ABC are used as the backbone NRTIs. Only one RCT has been conducted to examine this issue; it found no significant difference in the reduction of HIVRNA in individuals who maintained 3TC in their second-line regimen compared to those who did not. 157) One observational study reported similar virological response among individuals with the M184V mutation (indicating resistance to 3TC and FTC) who subsequently took 3TC- or FTC-containing regimen compared to those who took a 3TC- or FTC-sparing regimen.177)
17.9. NRTIs for HIV/HBV coinfection
In individuals with HIV/HBV coinfection who require treatment for their HBV infection and in whom TDF + (3TC or FTC) fail in the first-line regimen, these NRTIs should be continued in the second-line regimen for anti-HBV activity and to reduce the risk of hepatic flares, irrespective of the selected second-line regimen, which should be AZT + TDF + (3TC or FTC) + bPI.
17.10. Selection of boosted protease inhibitor
The recommend bPIs are equivalent in terms of efficacy. In studies of populations with PI resistance, there is growing support for the use of once-daily bPI regimens in which the ritonavir component is only 100 mg per day. Such regimens have fewer gastrointestinal side-effects and less metabolic toxicity than regimens that use ritonavir boosting at a dose of 200 mg per day. 178,179) Large head-to-head trials have demonstrated non-inferiority or superiority of ATV/r compared with LPV/r, with less gastrointestinal and lipid toxicity.159)
