These guidelines are intended as an update to those published in the Southern African Journal of HIV Medicine in 2014 and the update on when to initiate antiretroviral therapy in 2015. Since the release of the previous guidelines, the scale-up of antiretroviral therapy (ART) in southern Africa has continued. New antiretroviral drugs have become available with improved efficacy, safety and robustness. The guidelines are intended for countries in the southern African region, which vary between lower and middle income.

Key principles

While many antiretroviral therapy (ART) guidelines are available internationally, the current guidelines have been written to address issues relevant to southern Africa. The following general principles underpinned the writing process:

Goals of antiretroviral therapy

These goals are achieved by suppressing viral replication completely for as long as possible, by using well tolerated and sustainable treatment taken with good adherence. With prolonged viral suppression, the CD4+ lymphocyte count usually increases, which is accompanied by a restoration of pathogen-specific immune function. For most patients, this results in a dramatic reduction in the risk of HIV-associated morbidity and mortality. For patients who start ART with preserved CD4+ counts, ART is able to prevent the decline in CD4+ count which has been observed in untreated patients and prevent clinical complications of HIV infection. It is still unclear whether immune function ever returns to full normality. Long-term cohorts show that patients who adhere well to ART have a near-normal life expectancy.¹

Standard of care

Maximally suppressive ART regimens should be used in the treatment of HIV-infected individuals to obtain the best results and to prevent resistance.

Antiretroviral drugs: Classes and mechanisms of action

There are currently five classes of ART drugs available in southern Africa (Table 1). The most commonly used drugs inhibit one of three key HIV enzymes required by the virus for intracellular replication:

Antiretroviral drugs currently available in southern Africa

The antiretroviral (ARV) drugs currently available in southern Africa are summarised in Table 2. A number of two-drug and three-drug fixed dose combinations (FDCs) are available in the region. These FDCs reduce the burden of multiple pills and may improve treatment adherence.

Indications for initiating antiretroviral therapy

We now advise starting ART in all individuals diagnosed with HIV. In general, delays to starting ART should be minimised. In particular, patients with profound immunosuppression (CD4+ count < 200 cells/μL) are at significant risk of opportunistic infections (OIs) and associated mortality, and should be assessed rapidly and initiated on ART within one week once adherence counselling has been initiated. An exception to this is patients presenting with cryptococcal meningitis (CM) or tuberculous meningitis (TBM) – see below.

Rationale for these guidelines

In 2015, two seminal randomised controlled trials (RCTs) that addressed the optimal timing of ART in HIV-infected patients with high CD4+ counts were published: strategic timing of antiretroviral therapy (START) and TEMPRANO ANRS 12136 (early antiretroviral treatment and early isoniazid prophylaxis against tuberculosis in HIV-infected adults).^3,4 The findings of these two trials were consistent: there was significant individual clinical benefit from starting ART immediately in patients with CD4+ counts higher than 500 cells/μL rather than deferring until a certain lower CD4+ threshold or clinical indication was met.

Benefits of antiretroviral therapy in reducing transmission

There is evidence that starting ART when HIV-positive people have higher CD4+ counts reduces HIV transmission within couples where one partner is HIV-negative (HPTN 052). This trial showed that treating the HIV-positive partner in a serodiscordant relationship with ART was associated with a 93% reduction in transmission risk to the uninfected partner.^5,6 Wider ART coverage appears to reduce the risk of HIV transmission at a community level. Therefore, early ART initiation has the public health benefits of potentially reducing both HIV incidence and morbidity. This led the Southern African HIV Clinicians Society to update its guidelines on starting ART in 2015 to advise starting ART in all patients diagnosed with HIV infection regardless of CD4+ count or symptoms.

Commencing antiretroviral therapy in patients with tuberculosis

Decisions regarding the timing of ART in patients with TB should be made on the basis of the CD4+ count.

CD4+ count ≤ 50 cells/µL

Antiretroviral therapy should be regarded as urgent, with the aim to start therapy two weeks following the commencement of TB treatment. A meta-analysis of RCTs has demonstrated that this approach reduces mortality.⁷ It is advised to commence ART after it is clear that the patient’s TB symptoms are improving and that TB therapy is tolerated. The exception to this is in the case of CM (see the section ‘Starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses’) or TBM.

CD4+ count > 50 cells/µL

Antiretroviral therapy can be delayed until eight weeks after starting TB treatment, but no later. However, if the patient has other WHO stage 4 conditions, ART should also be initiated two weeks after TB treatment is started. The exception to this is in the case of CM (see the section ‘Starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses’) or TBM. The longer delay before commencing ART in this group is anticipated to reduce the risk of shared toxicity (as the patient will then be receiving fewer TB drugs) and to reduce the risk of immune reconstitution inflammatory syndrome (IRIS) (see the section ‘Immune reconstitution inflammatory syndrome’). The aforementioned meta-analysis of RCTs did not show a higher risk of AIDS progression or mortality in this group when ART initiation was delayed until approximately eight weeks after starting TB treatment.⁷

Tuberculous meningitis

In patients with TBM, starting ART immediately or at two months following diagnosis was shown to have similar high mortality, with more complications in the immediate group.⁸ We recommend starting ART 4–8 weeks after TBM diagnosis.

There are important drug interactions and shared side effects when ART is co-administered with TB therapy (see the section ‘Tuberculosis’). When ART is commenced, patients should be warned that TB symptoms or signs may temporarily worsen and new features may occur in the first three months as a result of TB-IRIS (see the section ‘Immune reconstitution inflammatory syndrome’).

Starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses

With most OIs and acute illnesses (e.g. pneumocystis or bacterial pneumonia), the clinician should aim to start ART within two weeks of commencing treatment for that infection.⁹ In patients with severe Kaposi’s sarcoma and lymphoma, ART counselling should be expedited and ART should be initiated as soon as possible. In a patient diagnosed with an OI in hospital, it is important to ensure referral and linkage to outpatient services for ART initiation without delay. For patients with CM, the optimal time to start ART is 4–6 weeks from the time of starting CM treatment. The COAT (Cryptococcal Optimal ART Timing) trial demonstrated a significantly higher mortality in patients who started ART in hospital 1–2 weeks after CM diagnosis than in those starting 5–6 weeks after diagnosis.²

In HIV-infected patients admitted to the intensive care unit (ICU), if the patient is receiving ART, then this should be continued (through nasogastric tube [NGT], if necessary) and only interrupted if the gastrointestinal tract is not functional (e.g. ileus). If the patient is not yet receiving ART, then it should not be commenced if the reason for admission is an acute critical illness or injury. There are several potential problems associated with commencing ART in this setting: lack of adequate counselling, gastrointestinal dysfunction, malabsorption and possible development of resistance. There are no intravenous options for an ART regimen. In patients admitted to the ICU for prolonged periods, ART initiation in the unit should be considered after multi-organ failure has resolved. Certain ART preparations should not be administered via NGT. In general, paediatric syrups can be administered via NGT. A pharmacist should always be consulted regarding which ART drugs can be administered via NGT and how to do this.

Patient readiness for antiretroviral therapy

Preparing patients for lifelong ART with good adherence is a critical component of achieving long-term efficacy and preventing resistance:

Commencing antiretroviral therapy at the first antiretroviral clinic visit

Several studies have demonstrated that it is possible to initiate ART safely on the same day as HIV diagnosis or receipt of CD4+ count result.^10,11,12 These studies have demonstrated less overall loss to follow-up when ART is initiated immediately in selected patients. Now that treatment is recommended irrespective of CD4+ count this same-day strategy should be considered as a means to improve retention in care.

More experience is needed to make firm recommendations, and this approach is being tested in different programmes. Until then, the following should be considered for patients newly diagnosed or returning for CD4+ or other test results, when deciding about initiating ART on the same day:

Antiretroviral therapy in primary HIV infection

For patients who are diagnosed with HIV during acute seroconversion, we advise that those patients be counselled and initiated on ART as soon as possible. This should preferably be expedited ART initiation as there is evidence that this may limit the size of the HIV reservoir.¹³ Previously, we suggested that these patients could have ART interrupted. Rather, once ART is started in this situation, this should be lifelong ART, and this should be discussed with the patient. Additional counselling once the patient is established on ART may be required for patients who start ART in this acute situation because there is limited time for extensive counselling pre-ART, and there is often considerable psychological distress around this time. Diagnosing seroconversion is facilitated by having a recent negative HIV test that then becomes positive on a subsequent test. Otherwise, the following are suggestive: the compatible clinical syndrome, an indeterminate enzyme-linked immunosorbent assay (ELISA) test result that then becomes positive on a subsequent test, and a very high VL.

Antiretroviral therapy initiation in ‘elite controllers’

A minority of patients (< 1%) have very effective immune control of HIV infection and are able to control HIV viraemia at undetectable levels in the absence of ART – termed ‘elite controllers’. An argument could be made that such individuals do not require ART if their CD4+ count is > 500 cells/μL. The START and TEMPRANO trials did not specifically address the question of whether early ART was beneficial in such patients, and it is highly unlikely that any sufficiently powered RCT could ever be conducted focused on these individuals. In the absence of such data, we rely on indirect evidence. Firstly, elite controllers still have evidence of chronic immune activation and inflammation that may drive non-infectious morbidities.¹⁴

Secondly, elite controllers have been shown to have a higher rate of hospitalisation than patients who are virologically controlled by ART.¹⁵ For these reasons, we do advise starting ART in elite controllers too, with the same caveats regarding the patient being prepared.

One important consideration in such patients is that careful attention should be paid to confirming the diagnosis of HIV before starting ART. They are typically patients who have a positive HIV ELISA test, undetectable HIV VL, CD4+ count in the normal range and are clinically well. The possibility of a false-positive HIV ELISA test should be excluded either by performing a qualitative HIV DNA polymerase chain reaction assay or a Western blot assay. If the patient at some point previously had a detectable HIV VL, this would also serve as confirmation. Such patients should be discussed with a laboratory virologist to assist with confirmation of HIV infection status.

Investigations prior to starting antiretroviral therapy

If HIV diagnosis has been made by using two rapid tests performed outside of a laboratory setting, then we advise confirming the positive serostatus by using a laboratory test prior to commencing lifelong ART. A detectable VL result would be sufficient (note that it may be undetectable in < 1% of patients not receiving ART, i.e. ‘elite controllers’), but if unaffordable or unavailable, then an ELISA should be performed.

We advise a symptom screen for TB (cough, weight loss, fever, night sweats). If any are present then send sputum for Xpert and TB culture, and if CD4+ < 100 cells/μL then send urine for lipoarabinomannan (LAM) assay.

Initial antiretroviral therapy regimens for the previously untreated patient

Rilpivirine cannot be used with rifampicin, and dolutegravir requires dose adjustment with rifampicin.

Nucleoside reverse transcriptase inhibitor component of first-line regimen

The recommended NRTI drugs are TDF with FTC (emtricitabine) or 3TC. FTC and 3TC are both co-formulated in two-drug FDCs with TDF, and in three-drug FDCs with TDF and EFV.

We favour regimens that include FDCs and allow once-daily dosing. TDF is the favoured NRTI to use with 3TC or FTC, as it aligns with public sector programmes, is widely available as an FDC and is very well tolerated. However, patients with a CrCl < 50 mL/min should not start TDF and should rather start ABC. A meta-analysis showed that virological suppression is equivalent with ABC- and TDF-containing first-line regimens regardless of baseline VL.¹⁶ ABC has been associated with an increased risk of myocardial infarction in some but not other cohort studies,^17,18 but the association was not confirmed in a meta-analysis of RCTs.¹⁹ Nevertheless, caution is recommended when considering ABC for patients at significant risk of, or with established ischaemic heart disease. ABC, which does not require dose adjustment in renal failure, is specifically recommended for use during chronic renal failure, as TDF is nephrotoxic and AZT could aggravate the anaemia of renal failure. We now recommend that AZT or short-term stavudine (d4T) is only used in special circumstances in first-line therapy. If both TDF and ABC are unavailable or contraindicated, then AZT should be used, provided that the Hb level is > 8 g/dL. As it is considerably more toxic than other NRTIs, d4T is no longer recommended. Nonetheless, there is still a role for d4T in selected patients, when it is used in the short-term in patients with contraindications to other NRTIs. A common example is a patient with renal dysfunction and anaemia at baseline, who could be initiated on d4T for three months if ABC is unavailable, and then switched to AZT or TDF depending on resolution of the anaemia or renal dysfunction. Patients usually tolerate short-term d4T (≤ 3 months) well. Severe d4T side effects, such as hyperlactataemia, lipoatrophy and other mitochondrial toxicities, typically occur after six months, although peripheral neuropathy can develop earlier.

If there is a need for concomitant nephrotoxic medications, e.g. aminoglycosides to treat multidrug-resistant (MDR)-TB, then ABC or AZT is preferable to TDF during the period of exposure to the other nephrotoxic medication.

The third drug in the regimen: Efavirenz, dolutegravir or rilpivirine

The WHO guidelines currently recommend efavirenz-based first-line ART, with EFV 600 mg as the preferred option and EFV 400 mg as an alternative option. EFV 600 mg is available in public sector programmes in most countries in southern Africa. Efavirenz is thus very widely used in first-line regimens in the region. Although EFV 400 mg demonstrated non-inferior efficacy with moderately improved tolerability in ENCORE1,²⁰ this reduced dose has not been studied in pregnant women or patients who are receiving rifampicin-based TB treatment. EFV 400 mg is currently also not available in FDCs, and for these reasons, we do not recommend the routine use of EFV 400 mg in first-line ART. Dolutegravir is now available as an alternative for first-line ART in the private sector, is included in the first-line regimen in the public sector in Botswana and is likely to be accessible in public sectors in other countries in the region when affordable generic options become available at scale.

Dolutegravir has been shown to be superior to efavirenz-based ART in the SINGLE trial and also has a higher barrier to resistance. The SINGLE trial compared DTG/ABC/3TC versus EFV/TDF/FTC in ART-naïve adults in North America, Europe and Australia (n = 833). At week 48, the proportion of participants with a VL < 50 copies/mL was 88% in the DTG arm versus 81% in the EFV arm (p = 0.003). This difference was largely driven by the superior tolerability of the DTG arm: 2% vs 10% on the EFV arm had an adverse event leading to discontinuation of study drug.²¹ In the 144-week results of this trial the DTG arm remained superior: 71% vs 63% maintained VL suppression < 50 copies/mL (p = 0.01). A striking result was that no participants in the DTG/ABC/3TC arm developed treatment-emergent integrase or NRTI resistance mutations over three years, demonstrating the high barrier to resistance of a DTG-containing first-line regimen.²²

Dolutegravir may cause a small increase in serum creatinine because of interference with tubular secretion. This does not represent renal damage and is not an indication for switching off the drug. There are currently limited data on the use of DTG in patients being treated for TB and during pregnancy, but trial data on these groups are expected soon.

Dolutegravir is preferred to the other integrase inhibitor available in southern Africa, raltegravir (RAL), the major reason being that it has a higher barrier to resistance. In the SPRING-2 trial, DTG- and RAL-containing first-line regimens were compared: DTG was found to be non-inferior.²³ At week 48, 88% of patients on DTG achieved virological suppression (VL < 50 copies/mL) vs 85% on RAL (difference not significant). Adverse events were similar between treatment groups. No patients in the DTG arm were found to have developed resistance, whereas, in patients in the RAL arm, one developed integrase resistance and four developed NRTI resistance. The high barrier to resistance of DTG-containing ART regimens has been replicated in other first-line studies and in a study of ART-experienced patients in which DTG was compared to RAL.^22,24,25 In a meta-analysis that included clinical trials and observational studies, the emergence of integrase resistance was more common with RAL than with DTG (3.9% vs 0.1%).²⁶ In addition, the emergence of integrase resistance on RAL compromises second-generation InSTIs (which otherwise have a very high barrier to resistance) in a proportion of cases.

Another option in first-line regimens is RPV, a second-generation NNRTI. RPV is inexpensive, but drawbacks are that it cannot be used with rifampicin-based TB treatment (subtherapeutic concentrations because of rifampicin induction of its metabolism), and it should not be started in a patient with a VL > 100 000 copies/mL (it is inferior to EFV in such patients).²⁷ It is also not yet available in an FDC in the region.

We no longer recommend NVP use for new patients starting ART because of the severe toxicity that may be associated with its use. In patients currently tolerating NVP, there is no reason to switch for toxicity, which characteristically occurs in the first three months of taking NVP and not later. However, switch for simplification to a once-daily regimen, providing that there is virological suppression, should be considered.

For patients transitioning from the private sector on DTG first-line to the public sector and requiring a switch because DTG is unavailable, we recommend doing a VL and switching to EFV. If VL < 50 copies/mL then repeat VL in one year. If VL is not suppressed then switch to EFV, counsel regarding adherence and repeat VL in 2–3 months.

Baseline resistance test

We recommend a baseline resistance test to guide first-line regimen choice only in the following situations:

Laboratory monitoring for antiretroviral therapy efficacy and safety

Viral load

Timing of viral load monitoring

If the VL is > 50 copies/mL, then the patient should receive counselling, and interventions should be implemented to improve adherence. A repeat measurement of VL should then be done in 2–3 months.

Interpreting viral load results

A VL > 50 copies/mL while receiving ART should be an indication for urgent action to improve adherence. A subsequent ART change must be considered if the patient meets the criteria for a switch to a second-line ART regimen at the subsequent 2–3-month follow-up VL measurement (see the section ‘Indications for changing antiretroviral therapy’).

VL monitoring is key to the success of ART. Decisions to change ART made on the basis of virological failure, rather than on clinical or immunological failure alone, have been shown to result in better patient outcomes.²⁸ If the VL is undetectable, then the virus cannot mutate and develop resistance. A sustained VL of < 50 copies/mL is associated with the most durable benefit.

Isolated, detectable HIV VLs that are < 1000 copies/mL, which are followed by an undetectable VL, are termed ‘viral blips’ and alone are not a reason to change ART regimen.

CD4+ counts

CD4+ counts should be performed every six months. In patients being monitored with VL measurements, if the CD4+ count at baseline was > 200 cells/μL or it increases above this threshold on ART, routine CD4+ testing can be stopped once the VL is suppressed and provided it remains suppressed, as it adds little to management. Data to support this have been summarised.²⁹ However, if virological or clinical failure occurs, then a CD4+ count should be repeated, as cotrimoxazole (CTX) prophylaxis should be commenced if the count falls to < 200 cells/μL while receiving ART.

Laboratory monitoring of antiretroviral therapy safety

Table 5 lists the blood tests and their frequency that we advise for monitoring of ART safety. The section ‘Antiretroviral therapy toxicity monitoring and management’ provides more details regarding the toxicities of ART and their management.

Defining antiretroviral therapy failure

In resource-limited settings where VLs are unavailable, the WHO has devised criteria for defining ART failure on the basis of CD4+ count responses or clinical disease progression. Studies have shown that switching ART regimens using these criteria results in a significant proportion of patients switching very late (with progressive accumulation of resistance mutations) and switching inappropriately (as the CD4+ count response may be poor in some patients, despite optimal virological suppression).³⁰ We therefore advocate using the VL for making decisions regarding ART failure and the need to switch.

Virological criteria for treatment success

Treatment success is defined by a decline in VL to < 50 copies/mL within six months of commencing ART, and sustained thereafter.

Virological criteria for treatment failure

Treatment failure is defined by a confirmed VL of > 1000 copies/mL on two measurements taken 2–3 months apart. Several factors can influence the measurement of the VL. The decision to alter ART should, therefore, be based on the results of repeat testing after 2–3 months, following intensive adherence counselling. Inadequate patient adherence to the prescribed regimen remains the most common reason for treatment failure. Other important causes include: prior use of single-dose NVP for PMTCT; drug interactions that decrease ART concentrations; and transmitted drug resistance, which is currently increasing in the region (estimated to be around 5– 15%).^31,32

CD4+ response

Typically, the CD4+ count increases rapidly in the first month of ART, by approximately 75–100 cells/μL, with a more gradual rise thereafter (50–100 cells/μL/year).³³ Most, but not all, patients achieve a CD4+ count > 500 cells/μL after several years of ART, provided that the VL remains suppressed.^34,35,36 However, CD4+ responses are highly variable and may fail to increase despite virological suppression in about 10–20% of patients.^37,38 Such patients have a delayed or absent CD4+ response to ART despite viral suppression, which is termed an ‘immunological discordant response to ART’. Certain studies suggest that older patients are at higher risk. There is no evidence that such patients benefit from a change in ART regimen; therefore, the same regimen should be continued. CTX prophylaxis should be continued if the CD4+ count remains < 200 cells/μL. There is evidence that the prognosis of such patients is worse than in those who have a CD4+ response, but better than that of patients experiencing both virological and immunological failure.³⁸ If patients with an immunological discordant response to ART are clinically unwell, then TB or lymphoma should be considered as the cause of persistent CD4+ lymphopenia.

CD4+ counts may remain stable in the presence of incomplete viral suppression in patients receiving ART until the VL is high (approximately ≥ 10 000 copies/mL).³⁹

Indications for changing antiretroviral therapy

Individual ART drugs may be substituted in the event of toxicity (see the section ‘Antiretroviral therapy toxicity monitoring and management’), provided that the VL is suppressed or ART is initiated within the preceding six months. Changing the first-line ART regimen to a second-line regimen is a major step. The drugs used in second-line regimens are often not as well tolerated and are more expensive and generally require twice-daily dosing. For this reason, clinicians tend to switch to second-line ART after a prolonged period of virological failure, causing a progressive increase in the accumulation of resistance mutations. If the VL is detectable, it is essential to step up adherence interventions, as discussed above. If the patient is on an NNRTI-based first-line regimen, we advise a switch to a second-line regimen without undue delay when two VL measurements have been > 1000 copies/mL, preferably with the measurements taken 2–3 months apart, with at least four weeks of an intensified adherence intervention in between. In patients with low CD4+ counts (< 100 cells/μL), this process should be expedited. Some patients have persistently detectable VLs at low levels (200–1000 copies/mL). If patients have low-level viraemia (i.e. VL detectable but < 1000 copies/mL) for a prolonged period (> 1 year), or persistently low CD4+ counts (< 100 cells/μL) together with low-level viraemia despite adherence interventions, then they should be switched to second-line ART.

In patients who fulfil the criteria for virological failure on a dolutegravir-based regimen, there is currently an evidence gap with respect to data that inform the approach to switching to second-line ART. Because of the high barrier to resistance of DTG, it is likely that many such patients will not have resistance and will merely require improved adherence on the same first-line regimen. For that reason, we only recommend switching from first-line dolutegravir-based ART to second-line if a resistance test shows resistance. This advice may change as more data on the risks of resistance to dolutegravir-based ART in a programmatic setting become available. A similar approach should be applied for patients on a boosted PI first-line regimen.

Second-line regimens

Resistance testing for selecting second-line antiretroviral therapy

We do not recommend routinely performing a resistance test at first-line failure of NNRTI-based regimens. The EARNEST (Europe-Africa Research Network for Evaluation of Second-line Therapy) and SELECT (second-line ART in resource-limited settings) trials showed that without the use of a resistance test to decide which NRTIs to use in second-line therapy, virological outcomes were good and equivalent to a boosted PI + RAL regimen. In addition, in these trials those patients with more extensive NRTI resistance at first-line failure were those more likely to achieve virological suppression on second-line.^40,41

A potential benefit of a resistance test is that it may be able to differentiate whether failure is because of complete or near complete non-adherence (when the resistance test shows no resistance mutations) and whether there is already established resistance (usually a consequence of sub-optimal adherence). Also, if the resistance test at first-line failure shows that there is no TDF resistance mutation, then TDF could be used to accompany 3TC (or FTC) and a ritonavir (RTV)-boosted PI in second-line.

When DTG is used in first-line ART, reports to date suggest that it is very unlikely that ART resistance will develop. There are inadequate data available for making a recommendation on resistance testing at DTG first-line failure, but similar recommendations as for second-line failure should be used until more data are available: patients with unsuppressed VL on a DTG-based first-line regimen should receive intensive adherence counselling and repeated VL measurements. Only if the VL remains detectable on several occasions despite this, should resistance testing be considered.

Recommended second-line antiretroviral therapy regimen

We recommend a regimen of two NRTIs and a RTV-boosted (/r) PI. Boosting of PIs involves the addition of low-dose RTV, which inhibits PI metabolism, thereby boosting PI plasma concentration and prolonging half-life. We recommend against the use of unboosted PIs.

For patients who failed a first-line NNRTI + 2 NRTI regimen, we do not recommend the use of DTG with 2 NRTIs in second-line as there is currently insufficient evidence to support such a regimen. We await results of the DAWNING trial which will compare such a DTG-based versus LPV/r-based second-line regimen (https://clinicaltrials.gov/ct2/show/NCT02227238).

Ritonavir-boosted protease inhibitor in the second-line regimen

Based on clinical trials demonstrating superior tolerability, we suggest that the preferred PI in second-line therapy should be ritonavir-boosted atazanavir (ATV) 300 mg/RTV 100 mg daily.^42,43 The benefits of ATV/r over lopinavir (LPV)/r include that it is better tolerated in terms of gastrointestinal side effects, has a more favourable lipid profile and is taken once-daily. Drawbacks of ATV/r are: it cannot be used with rifampicin (RIF)-based TB treatment; and there are important drug interactions with drugs that reduce stomach acidity such as proton pump inhibitors. An alternative RTV-boosted PI rather than ATV/r should be used in the following situations:

Other RTV-boosted PI options in second-line therapy are LPV/r and darunavir (DRV)/r. LPV is co-formulated with RTV in a heat-stable tablet (Aluvia). LPV/r is also an option with rifampicin when double-dosed. Darunavir/ritonavir (DRV/r) is taken twice-daily, currently, and is more costly. When the appropriate dose tablet becomes available, the 800/100 mg daily dose will be a feasible option in second-line ART, with fewer side effects than the twice-daily dosing. DRV/r cannot be co-prescribed with rifampicin.

Ritonavir capsules are no longer available and have been replaced with RTV heat-stable tablets.

Selecting second-line dual nucleoside reverse transcriptase inhibitors

Because boosted PIs are robust drugs (i.e. resistance develops slowly) in PI-naive patients, it is very likely that virological suppression will be achieved with good adherence, even if the two NRTIs used in second-line therapy are partially compromised by NRTI resistance mutations (Tables 6 and 7). This is supported by findings of the EARNEST and SELECT trials, which showed good virological suppression rates of second-line LPV/r and NRTI regimens, even in patients with significant NRTI resistance.^40,41 Certain NRTI combinations are contraindicated for toxicity reasons (e.g. d4T + didanosine [ddI], or TDF + ddI). A TDF + ABC combination is not recommended for second-line ART, as these agents share resistance mutations. NRTI combinations advised for second-line regimens include either AZT + 3TC, or TDF + 3TC (FTC can be substituted for 3TC), depending on the likely mutational profile selected during the patient’s first-line NRTI combination.

Even if 3TC (or FTC) was used in a failed first-line regimen and may, therefore, have selected for the M184V mutation, which confers resistance to the agent, 3TC (or FTC) should be reused in second-line therapy because of the capacity of the M184V mutation to partially restore susceptibility to AZT, d4T and TDF in the presence of thymidine analogue mutations (TAMs), and to partially restore susceptibility to TDF in the presence of the K65R mutation. The M184V mutation also reduces the replicative capacity of the virus.

In patients with baseline anaemia or who develop anaemia on second-line ART, AZT should be switched to ABC or TDF. In a minority of patients a second-line regimen of DTG plus a boosted PI may be considered (e.g. broad NRTI intolerance).

Selecting second-line antiretroviral therapy in patients who received a first-line PI-regimen

If a patient was receiving a first-line combination of two NRTIs and a PI (boosted or unboosted), it is best to discuss the choice of second-line regimen with an experienced HIV clinician, and to perform a genotype resistance test. Second-line NNRTI + NRTI regimens are often not effective in such patients because of NRTI resistance mutations. The regimen choice is, therefore, best guided by resistance testing and DTG may have a role in such regimens.

Third-line antiretroviral therapy regimens

Third-line ART is used when a patient has experienced virological failure on drugs from the NRTI, NNRTI and PI classes, and has documented PI resistance. Before considering third-line therapy, adherence interventions should be intensified, and then adherence checked (e.g. check that pharmacy refills are all collected over a 6-month period). If there is still no viral suppression, then a resistance test should be performed to confirm the presence of resistance to the PI being used in second-line therapy. We advise doing this only after patients have been on a PI-based second-line regimen for a period of longer than one year, as the development of resistance earlier than this is very uncommon, unless there has been a medication error (e.g. giving standard dose LPV/r with rifampicin). The resistance test is expensive and the patient must be receiving the failing ART at the time, as ‘wild-type’ HIV is more fit and outgrows the resistant mutant population which therefore cannot be detected within some weeks after cessation of ART. However, third-line regimens are also expensive and are not justified if the patient does not have resistance necessitating such a switch. Currently, data show that most patients failing second-line regimens in the SA public sector have no PI mutations. In these patients, improved adherence is required rather than third-line regimens. See Figure 1.⁴⁴

The decisions regarding treatment choices in third-line therapy are complex and need to be guided by resistance patterns found on resistance testing. It is essential that resistance tests are interpreted by an expert in conjunction with a full ART history.

A number of drugs are available for use in third-line ART: InSTIs (DTG and RAL), the newer PI DRV and newer NNRTIs (ETR and RPV)). These provide an opportunity for effective viral suppression with third-line therapy in the majority of patients, provided that adherence is optimal.^45,46 Regimen choice should be individualised and an expert treater should always be consulted. A few guidelines regarding third-line ART regimens are:

An algorithm approach to third-line ART can be used. Once a genotype resistance test has been performed, Stanford scores are used to determine which combination of ARVs is most appropriate for third-line regimen for the specific patient. Patients are eligible for third-line ART if they have demonstrated genotypic resistance to the PI which they are taking, as evidenced by a Stanford score ≥ 15, and should receive a DRV/r-based third-line regimen. In addition to DRV/r, all patients on a third-line regimen should receive two NRTIs, 3TC/FTC with either TDF or AZT, determined by which of TDF or AZT has the lower Stanford score. If there is resistance to DRV/r (score ≥ 15), or if there is intermediate-level or high-level resistance (score > 29) to the selected NRTI (TDF or AZT), add DTG to the regimen. If there is both DRV/r resistance and intermediate or high (score > 29) level resistance to the selected NRTI, then add ETR or RPV (whichever score is lower) in addition to DTG, unless both ETR and RPV score > 29. See Figure 2.⁴⁹

The SAILING trial compared RAL versus DTG in ART-experienced patients with at least two class resistance who were integrase inhibitor-naïve. At week 48, DTG was superior to RAL (71% vs 64% achieved VL suppression < 50 copies/mL; p = 0.03). Significantly fewer patients developed treatment-emergent integrase inhibitor resistance in the DTG arm. We therefore no longer recommend the use of RAL in third-line unless DTG is not tolerated or there is a contraindication to using DTG. We also recommend that patients currently using RAL in third-line be switched to DTG, because of its higher barrier to resistance.²⁵ If such patients have a suppressed VL then they can be switched to standard dose DTG (50 mg daily), but if they are not virologically suppressed we suggest a resistance test with integrase sequencing before switching. If there are InSTI mutations present that are associated with reduced susceptibility to DTG then the DTG dose should be 50 mg bd.

Stopping antiretroviral therapy

Structured treatment interruptions are not advised as they have been shown to increase mortality (SMART study).⁵⁰ Sometimes, patients need to stop therapy for reasons beyond the control of the patient and clinician. If life-threatening toxicity occurs (e.g. hepatitis with liver failure), all drugs should be stopped at once, but in most cases of toxicity, a continuation of ART should be attempted while switching the culprit drug(s) to an alternative. If stock-outs occur, it may also be necessary to stop ART. With PI and InSTI regimens, it is possible to stop all drugs simultaneously. With an NNRTI regimen, it is necessary to cover the tail with 5–7 days of two NRTIs (not needed if TDF/FTC are the NRTIs because of the long half-life of TDF and FTC).

We strongly advise against 3TC monotherapy ‘holding regimens’ in patients who have virological failure. Such regimens can be associated with a rapid fall in CD4+ count. The objective when prescribing ART should always be to provide a regimen that is most likely to achieve virological suppression.

Patients who return after defaulting therapy

We recommend restarting the same regimen if patients return to care after defaulting therapy. A VL should preferably be performed before restarting. We then recommend that the VL is measured three months after restarting ART; switching to a second-line regimen should be considered if the VL is not < 1000 copies/mL at this point. In patients with multiple episodes of interruption, particularly beyond the first year of ART, many clinicians would consider switching to a second-line regimen, making the assumption that the multiple interruptions resulted in first-line resistance. Reasons for defaulting should be addressed and adherence support increased.

Hospitalisation with an AIDS-defining condition and a CD4+ count < 50 cells/μL represents another scenario in which a patient may be restarted immediately on second-line ART when returning to care after defaulting; the reason being that the patient is considered to be at high risk of mortality if restarted on a first-line therapy to which their virus may be resistant, and that they require a guaranteed effective ART regimen immediately. This decision should usually be taken by the clinicians at a hospital level.

Performing a resistance test after the patient has been off ART for longer than four weeks is of limited value, as many resistance mutations are overtaken by wild-type virus when ART is stopped.

Drug interactions

There are many important drug interactions between ARV drugs and other medications, as well as between certain ARV drugs themselves. These interactions occur because of the metabolism of ARV drugs by cytochrome P450 in the liver and intestine, and the induction or inhibition by ARV drugs of this and other enzyme systems and drug transporters. Some of these drug interactions are discussed in these guidelines (e.g. the interaction between rifampicin and NNRTIs, PIs and InSTIs). The list of all potential drug interactions is, however, very long and beyond the scope of this document. Knowledge of drug interactions is constantly evolving. Clinicians are advised to consult package inserts of ARV drugs and concomitant medications to assess for drug interactions, in addition to the following websites, which provide up-to-date information on drug interactions and the actions required to account for them:

We advise that clinicians assess for potential drug interactions whenever patients start or switch to new ARV drugs or start new concomitant medications. This includes contraception. In addition, herbal medications may also have interactions with ARV drugs.

Antiretroviral therapy in special populations

Tuberculosis

The ARV regimen should be modified if necessary for compatibility with rifampicin. Rifampicin is a critical component of the TB regimen that substantially reduces the risk of relapse after completing TB treatment. EFV is the preferred NNRTI for use with rifampicin. NVP is an alternative in patients with contraindications for EFV (e.g. psychosis), but it carries a higher risk of hepatitis and virological failure when used with rifampicin. RPV and ETR cannot be used with rifampicin. DTG can also be used in patients on rifampicin, but a dose adjustment is required (Table 8).

The plasma concentrations of all boosted PIs are reduced to subtherapeutic ranges with rifampicin. Dose adjustment of LPV/r can overcome this induction (Table 8), but there is a risk of hepatotoxicity: patients require counselling and ALT should be monitored frequently.

An alternative approach is to replace rifampicin with rifabutin. However, rifabutin is not currently widely available at public sector TB clinics. Also, rifabutin is not co-formulated with other TB drugs, and the evidence base for rifabutin in the treatment of TB is much less substantial than that for rifampicin.⁵² There is also uncertainty regarding the optimal dose of rifabutin with boosted PIs; these guidelines recommend 150 mg daily (Table 9) for efficacy reasons but careful monitoring for toxicity is required (ALT, neutrophil count and visual symptoms at least monthly).⁵³ Rifabutin may be considered in patients who are not tolerating co-treatment with LPV/r and rifampicin-based antitubercular therapy (patients unable to tolerate the increased LPV/r dose because of hepatotoxicity or gastrointestinal side effects) or in ART-experienced patients on an ART regimen that is not compatible with rifampicin (e.g. third-line ART with DRV/r). If rifabutin is unavailable and adjusted doses of LPV/r are poorly tolerated in patients receiving second-line ART, then DTG (50 mg 12-hourly) may be substituted for the PI. However, there is not good evidence regarding the robustness of DTG in second-line with compromised NRTIs, as there is for boosted PIs. Nevertheless, short-term use over six months is probably preferable to treating TB without rifampicin, which has a high risk of failure or relapse. ART and TB medication share many side effects (Table 10).

Pregnancy

The aim of ART in pregnancy is both to prevent clinical complications of HIV in the mother and to decrease transmission to the child during pregnancy, delivery and breastfeeding.

Antiretroviral drugs in pregnancy

We recommend standard first-line, second-line and third-line regimens be used in pregnancy. Based on the accumulated evidence, we endorse the WHO guidance that EFV can be used in pregnancy and in women who intend to fall pregnant.⁵⁴ Their guidance was based on a meta-analysis which found that the incidence of neural tube defects and all congenital abnormalities among women exposed to EFV in the first trimester was similar to that of the general population.⁵⁵ The FDA category D classification of EFV should be discussed with women, explaining that this was based on animal studies; human cohort studies have not demonstrated an increased risk of congenital abnormalities, but that there is a background low risk of congenital abnormalities in all pregnancies, unrelated to drugs.

Studies have shown that total LPV concentrations are significantly reduced in pregnancy, but unbound LPV concentrations are not affected.⁵⁶ Therefore, dose adjustment of LPV/r is not recommended in pregnancy. However, once-daily dosing of LPV/r should not be used in pregnancy. Similarly, concentrations of boosted ATV are reduced in pregnancy, but trough concentrations are adequate and dose adjustments are not recommended in pregnancy.⁵⁷ An exception is in patients who are also receiving TDF, as TDF may reduce ATV concentrations: ATV/r dose should be increased to 400 mg/100 mg daily in such patients during the second and third trimester of pregnancy. Unboosted ATV is not recommended in pregnancy.

Recommendations for antiretroviral-naïve pregnant patients

It is beyond the scope of these adult ART guidelines to provide comprehensive guidance for the management of pregnant women. Key recommendations are included but providers are encouraged to refer to the complete PMTCT guidelines should a woman living with HIV be confirmed pregnant in order to optimise management.

All HIV-negative or status unknown pregnant women should be offered an HIV test at confirmation of pregnancy. If the test result is negative, regular retesting should be performed every three months throughout pregnancy and breastfeeding to detect any new infection. Seroconversion during pregnancy or breastfeeding is associated with a substantial risk of MTCT because of the very high maternal VL during acute infection.

Recommendations for antiretroviral-experienced pregnant patients

In women currently taking ART, check VL on the day of pregnancy confirmation, regardless of when it was last performed. If the VL is suppressed then continue the current regimen and reinforce adherence messaging. If the VL is not suppressed, then provide intensive adherence counselling and repeat the VL in one month. If there has not been > 1 log drop in VL then switch patients on first-line to second-line ART. In patients on second-line regimen, if the VL is not suppressed, request an HIV drug resistance test to assess the need for a third-line regimen and continue with adherence support. In women who have previously stopped ART and returned to care when pregnant but not on ART, check the VL and restart the regimen they were taking previously with intensive adherence counselling. Then repeat the VL test in two months. If there has not been > 1 log drop in VL, then switch patients on first-line to second-line ART. In patients on second-line regimen, request a resistance test to assess their need for third-line ART.

If a woman presents in pregnancy and the history suggests previous evidence of virological failure on first-line ART or high likelihood thereof before they stopped ART, the provider should start the woman on second-line ART from the outset to maximise the chances of rapid viral suppression and avoiding the possibility of MTCT with resistant virus. Refer to PMTCT guidelines for recommended prophylaxis regimens for the baby.

Breastfeeding

Late MTCT during breastfeeding remains a considerable problem. All HIV-positive mothers who are breastfeeding should be maintained on triple ART with VL monitoring conducted every six months (if previously virally suppressed) throughout the breastfeeding period.

Women should be provided with breastfeeding support, where available, including counselling about the importance of exclusive breastfeeding during the first six months of life, followed by the addition of complementary foods up to 24 months of life, in combination with ongoing high levels of adherence to ART and regular VL monitoring.

HIV-negative women should also seek to breastfeed for 24 months and should access retesting regularly, at least 3-monthly, throughout this time. If an HIV-negative woman tests HIV-positive, or an HIV-positive woman is found to have a high VL (> 1000 copies/mL) during breastfeeding, then a discussion should be undertaken to assess the risks and benefits of continuing breastfeeding in relation to the nutritional benefits versus the increased risk of mother- to-child-transmission of HIV. In this situation, the baby should be tested immediately for HIV, as an HIV-positive infant requires urgent treatment and should continue breastfeeding.

If breastfeeding is to be discontinued, ensure that a safe, adequate alternative is available.

Postnatal period

Retention in care and ART adherence often decline in the postnatal period. Women who do not attend for their ART supply should be tracked, traced and re-engaged in care. If a woman is found to have low adherence or a treatment interruption is suspected or confirmed then a VL should be repeated, regardless of when last done, and the woman should be provided with support. She should be assessed for post-natal depression, gender-based violence, substance abuse and other reasons for low adherence.

Partner engagement

Renal failure

Antiretroviral drug dosages

Renal function is estimated either by the modified Cockgraft–Gault equation (Table 11) or the modification of diet in renal disease (MDRD) method, which most laboratories report as eGFR. The results of these formulae differ slightly, but either can be used for clinical management. For peritoneal dialysis, the dose given with a CrCl < 10 mL/min should be given daily. For haemodialysis, the dose given with a CrCl < 10 mL/min should be given daily.

Antiretroviral drug choice and dosing in patients on chronic haemodialysis

Patients with HIV may develop end-stage renal failure requiring chronic haemodialysis owing to HIV-associated nephropathy or an HIV-unrelated cause. In patients on chronic haemodialysis, there are a number of important ART issues that arise. The NRTI class is eliminated through the kidneys, and thus doses of most NRTI drugs need to be adjusted in patients on dialysis (Table 11). Although TDF can be used in patients on chronic haemodialysis, dosing is once weekly, which can be difficult for patients to remember. AZT is generally avoided because of anaemia associated with renal failure. NNRTI drugs do not require dose adjustment.

We recommend the following first-line options for patients on chronic haemodialysis:

Atazanavir concentrations are reduced in patients on haemodialysis to a greater degree than LPV, and thus ATV is preferably not used in treatment-experienced patients. LPV/r should be used with twice-daily dosing in patients on haemodialysis. In patients on haemodialysis, we recommend an LPV/r-based second-line regimen with two NRTIs in the regimen (selected after consideration of issues related to NRTIs discussed above). DRV/r and InSTIs may be used at standard dosages. It is suggested that patients on chronic haemodialysis (who generally receive ongoing medical care in a dialysis unit) are reviewed by a clinician experienced in ART management at least 6-monthly, to monitor treatment efficacy and side effects and to adjust the regimen when needed.

Daily dosages or the evening doses of a twice-daily ART regimen on the day of haemodialysis should be given after the haemodialysis session to prevent the drug from being dialysed out.

Antiretroviral therapy in patients with acute kidney injury

In patients with acute kidney injury (AKI), dosages of NRTI drugs should be adjusted based on estimated CrCl calculation (Table 11).^58,59,60 TDF should be interrupted even if it is not thought to be the cause of the AKI. Once there is clear evidence that renal function is improving (creatinine on downward trend), NRTI dosages should be readjusted to standard dosages to avoid underdosing. In patients with AKI who are not yet receiving ART, initiation is preferably deferred until AKI has resolved. See the section ‘Nephrotoxicity’ for discussion of ART nephrotoxicity.

Antiretroviral therapy dosages in liver impairment

Unlike in renal impairment, there is no blood test that can accurately quantify liver impairment. Child-Pugh class C may require dose adjustment for the relevant ART drugs listed in Table 12. In general, the combination of TDF with 3TC (or FTC) and DTG or RAL (or EFV, which can be hepatotoxic) is regarded as the least hepatotoxic.

Hepatitis B co-infection

Hepatitis B is a common co-infection with HIV in southern Africa, with significant implications for progression to cirrhosis, as well as for treatment options. Clinicians are encouraged to support current efforts in the region to vaccinate all children for hepatitis B, and to extend coverage to eligible adults. Access to vaccination, laboratory resources and treatment options are limited to some extent in southern African countries, and the recommendations below should each be considered in the light of the local context.

All HIV-infected patients should be screened for active hepatitis B (limiting screening to those with liver function abnormalities will miss many cases, as liver enzymes are often normal in hepatitis B infection). HBsAg is an appropriate screening test. Hepatitis B VL correlates with disease progression and may be used to monitor antihepatitis B therapy, but it is expensive and availability is limited.

Drugs directed against hepatitis B that have no or minimal anti-HIV activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in our region. For practical purposes, the only available therapy is to use ART drugs that also have antihepatitis B activity (TDF + 3TC/FTC). As with HIV, these drugs suppress hepatitis B, but do not eradicate it. Effective treatment prevents or slows progression to cirrhosis. For all HIV-infected HBsAg-positive patients the ART regimen should include TDF and 3TC (or FTC). Using 3TC without including TDF leads to hepatitis B resistance in 80–90% of patients after five years of treatment. If a patient meets the criteria for switching to a second-line ART regimen (to treat HIV), this combination (TDF + 3TC/FTC) should be continued to suppress hepatitis B infection, as interruption of TDF or FTC/3TC has been associated with flares of life-threatening hepatitis. The second-line ART regimen should be shaped around these two drugs. NVP should be avoided in patients with hepatitis B co-infection.

In patients with hepatitis B and renal dysfunction, the use of TDF may be considered with dosing frequency adjustment based on CrCl (see package insert) and more frequent creatinine monitoring. If renal dysfunction is severe or renal function deteriorates with TDF, then 3TC monotherapy (with or without pegylated interferon-alpha, which is very costly) or other drugs with antihepatitis B activity should be considered.

Malaria

There are several drug interactions between antimalarials and ART drugs: Artemether-lumefantrine (Coartem) can safely be administered with NVP. EFV significantly lowers the concentrations of artemether (and its active metabolite) and lumefantrine, which is likely to increase the risk of failure of antimalarial therapy. There is no clear guideline on how to overcome this interaction, but some experts recommend repeating the 3-day course of artemether-lumefantrine (i.e. treat for six days). Boosted PIs dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. Close monitoring for toxicity is recommended when coadministering artemether-lumefantrine with ART.

Quinine concentrations are significantly decreased by LPV/r, probably owing to induction of metabolism by RTV. It is likely that quinine concentrations will also be reduced by EFV and NVP; therefore, quinine should be avoided in patients receiving PIs or NNRTIs. Patients with severe malaria should receive artesunate, if this is available, and those with milder malaria should be treated with artemether-lumefantrine.

Among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between ARVs and mefloquine or doxycycline. However, mefloquine and EFV both cause frequent neuropsychiatric side effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving EFV.

There are several interactions with atovaquone-proguanil (Malanil). Atovaquone concentrations are reduced by PIs and EFV. It is also likely that NVP decreases atovaquone concentrations. Proguanil concentrations are also reduced by PIs and EFV. Use of atovaquone-proguanil is, therefore, best avoided in patients receiving PIs or NNRTIs.

No significant drug interactions are predicted between InSTIs and antimalarial drugs.

Antiretroviral therapy toxicity monitoring and management

Currently recommended ART is generally well tolerated. Many adverse drug reactions are mild and occur only in the first few weeks of therapy. If toxicity does not resolve or is severe, then the offending drug should be substituted as indicated below. It is important to ensure that the VL is suppressed before substituting a single drug for toxicity; otherwise, resistance may develop to the new drug, consequently compromising future regimens. However, single drug substitutions can be done in the first few months of ART without measuring the VL, as the VL may take up to six months to suppress.

It is rarely necessary to stop the entire ART regimen because of toxicity. It is advised to switch only the culprit drug(s) and continue the rest of the ART regimen. In certain life-threatening situations (e.g. hepatitis with liver failure), it may be necessary to cease use of all ARVs.

Haematological toxicity

Cytopenias occur commonly in HIV infection without exposure to ART. Patients receiving AZT, d4T or CTX may experience abnormalities in their FBCs. Significant bone marrow toxicity from CTX generally only occurs with high doses used for treating OIs. Patients receiving prophylactic CTX rarely develop isolated neutropenia. Hb and neutrophil monitoring is necessary with AZT; this should be performed monthly for three months, then after six months of therapy and thereafter if clinically indicated (it is unusual to see haematological toxicity developing after six months). The main problem arising from AZT use is anaemia and neutropenia; platelet counts generally rise with use of the drug. Management guidelines are provided in Table 13. Macrocytosis is usual with d4T and AZT therapy; there is no need to measure vitamin B12 and folate concentrations unless there are other indications that these may be deficient.

Pure red cell aplasia, which presents with severe anaemia and low reticulocyte production index, has rarely been associated with 3TC and FTC. A bone marrow examination should be performed to confirm the condition. Parvovirus B19 infection should be excluded (a polymerase chain reaction [PCR] test should be requested on blood sent in an ethylenediaminetetra-acetic acid [EDTA] tube).

Hepatotoxicity

Alanine transaminase should be performed at ART initiation and repeat ALT testing is indicated in patients who develop symptoms or signs suggestive of hepatitis. All ART classes have been associated with hepatotoxicity – most commonly NNRTIs. NRTIs very rarely present with acute hepatitis. Mild ALT elevations occur very commonly and usually transiently with many drugs in general. ALT elevations > 5× the upper limit of normal (ULN) are significant in the absence of symptoms. In the presence of symptoms of hepatitis, ALT elevations > 2.5× ULN are significant. Management guidelines are provided in Table 14.

Nevirapine is the ARV drug most frequently associated with drug-induced liver injury (DILI) and most cases occur in the first three months of starting the drug. Ideally, in patients starting NVP, ALT should be monitored at 2, 4, 8 and 12 weeks after initiation. If monitoring is performed, a system should be in place to obtain the result and contact the patient. Routine ALT monitoring makes little sense in settings where the result will only be available when the patient is seen in 2–4 weeks, or where the patient cannot be contacted. It is essential to educate all patients starting NVP about the symptoms of hepatitis (nausea, vomiting, anorexia, malaise, jaundice and right-upper-quadrant pain) and drug rash, which is frequently associated with hepatitis. Hepatitis often follows the rash after about 10 days. If such symptoms develop, ALT should be determined urgently.

Hepatotoxic drugs should be discontinued at high levels of LFT abnormality or at lower levels if any symptoms of hepatitis appear and an alternative ARV drug substituted. Rechallenge may be considered in selected cases; a specialist should be consulted. If hepatitis occurs together with a rash or fever, or with other systemic involvement, then rechallenge with NNRTIs, ABC or CTX should not be attempted.

Prolonged use of NRTIs, especially d4T and ddI, may cause fatty liver. Typically, ALT concentration is more significantly elevated than AST, and the concentrations of canalicular enzymes (gamma-glutamyl transferase [GGT] and alkaline phosphatase [ALP]) are more elevated than those of the transaminases. Non-tender hepatomegaly may be present. Ultrasound or computed tomography (CT) imaging may show decreased hepatic density. The condition is not benign and fibrosis has been reported with long-term ddI use. Patients should be advised to avoid alcohol and switched to alternative dugs with lower potential for causing fatty liver.

In patients with severe hepatitis or jaundice, the international normalised ratio (INR) and serum glucose should be assessed, as well as features of hepatic encephalopathy (i.e. features of hepatic failure).

If the concentration of canalicular enzymes is more significantly elevated than that of ALT, or if conjugated bilirubin is elevated, an ultrasound of the liver should be conducted to exclude biliary obstruction.

Isolated unconjugated hyperbilirubinaemia (drug-induced Gilbert’s syndrome) is associated with ATV. In this case, all other LFTs are normal and the patient has no other symptoms of hepatitis. Although this is a benign condition (it does not reflect liver injury, but isolated competitive inhibition of the enzyme in the liver which conjugates bilirubin), it is often cosmetically unacceptable to patients requiring a switch from ATV to an alternative.

While EFV has been recognised to be an infrequent cause of DILI since it first became available, recently a novel pattern of DILI associated with EFV has been recognised.⁶¹ Among these patients, many were found to have a particularly severe pattern of liver injury at liver biopsy (termed ‘submassive necrosis’, and associated with severe jaundice and raised INR) and overall mortality was 11%. While severe EFV-related DILI is likely to be uncommon, clinicians should be aware of the features observed:

We do not advise routine liver function test monitoring in patients on EFV, as there is no evidence that this would lead to earlier detection of this DILI or improve outcomes. However, those managing patients on EFV should monitor for symptoms and signs of hepatitis (nausea, vomiting, right-sided abdominal pain or jaundice). If these occur, an ALT should be requested and the patient examined for jaundice. EFV should be switched to an alternative (e.g. DTG) and the patient managed appropriately for DILI if there are hepatitis symptoms with ALT > 120, or there is jaundice.

Many other drugs can cause hepatotoxicity, notably antituberculous agents (including prophylactic isoniazid) and azoles. CTX is an uncommon cause of hepatitis, often as part of a systemic hypersensitivity reaction.

Recommendations for the management of DILI in patients receiving TB treatment have been published by the Society in 2013.⁶²

Hyperlactataemia and lactic acidosis

The management of symptomatic hyperlactataemia depends on lactate and bicarbonate concentrations:

Dyslipidaemia

PIs can cause hypertriglyceridaemia and elevated low-density lipoprotein (LDL) cholesterol. Boosted ATV and once-daily boosted DRV (800 mg DRV/100 mg RTV once-daily) are associated with less severe dyslipidaemia than other boosted PIs; d4T and AZT can cause mild hypertriglyceridaemia, and EFV can cause elevated total cholesterol and mild hypertriglyceridaemia.

We suggest routinely assessing lipids after three months on a PI-regimen. If normal at this stage, reassessment should be performed only in those with cardiovascular (CVS) risk factors.

Diet and lifestyle modification should always be advised. Diet is more effective for controlling hypertriglyceridaemia than hypercholesterolaemia. Other CVS risk factors should be addressed. Clinicians should consider and investigate secondary causes of hypertriglyceridaemia and hypercholesterolaemia (e.g. diabetes, nephrotic syndrome, alcohol abuse and hypothyroidism).

If patients on LPV/r develop significant dyslipidaemia, then they should be switched to ATV/r, if possible, rather than adding lipid-lowering therapy. However, lipid-lowering therapy is indicated in patients with persistent elevations despite switching to ATV/r. Switching the PI to DTG is another option, because DTG has a more favourable lipid profile than PIs. However, DTG should only be used in a regimen in which at least one other ARV drug is known to be fully active. In patients with hyperlipidaemia on EFV, switch EFV to RPV.

Marked hypertriglyceridaemia (> 10 mmol/L) can cause pancreatitis and requires urgent treatment with diet modification (restrict total triglyceride intake to < 30 g/day), fibrates and switching LPV/r to ATV/r or DTG (fibrates can be stopped after one month, followed by reassessment within 4–6 weeks).

Indications for statin therapy in HIV-positive patients should be the same as in HIV-negative patients, using the Framingham heart disease risk score. As a general rule, in young patients with isolated elevated cholesterol but no other CVS risk factors, a threshold of total cholesterol > 7.5 mmol/L (or LDL cholesterol > 5.0 mmol/L) should be used for initiating statin therapy, and the patient should be referred to a lipid clinic for investigation if feasible. In patients with CVS risk factors (e.g. smoking, diabetes, hypertension) decisions should be made using the Framingham heart disease risk score (https://www.mdcalc.com/framingham-coronary-heart-disease-risk-score). All patients with established atherosclerotic disease (coronary, cerebral or peripheral), all patients with familial hypercholesterolaemia and all patients with type 2 diabetes aged > 40 years should be started on statin treatment.

Many statins have interactions with PIs that can lead to potentially toxic statin concentrations, with the exception of pravastatin and fluvastatin. Atorvastatin concentrations are significantly raised by PIs, but low doses (maximum 10 mg daily) can be used with monitoring for symptoms of myalgia. Lovastatin and simvastatin should not be coadministered with PIs, as their concentrations are dramatically increased and severe rhabdomyolysis has been reported. We also advise against the use of rosuvastatin with PIs because of a complex drug–drug interaction: PIs increase the plasma concentrations of rosuvastatin while reducing their efficacy in the liver.

Lipodystrophy

Lipodystrophy can present with fat accumulation (visceral obesity, breast enlargement, ‘buffalo hump’ or lipomata) or subcutaneous fat loss (lipoatrophy, most noticeable in the face, limbs and buttocks), or with both forms of lipodystrophy.

The thymidine analogue NRTIs (AZT and especially d4T) are associated with fat loss. Lipoatrophy improves when d4T/AZT are substituted with TDF or ABC, but resolution is very slow and often incomplete; therefore, it is important to recognise lipoatrophy early or, better still, to use NRTIs that are not associated with the condition.

Previously, PIs were thought to be the cause of lipohypertrophy. However, more recent studies have shown that all ART classes are associated with fat gain to the same extent. Furthermore, longitudinal studies comparing HIV-negative people with HIV-positive people on long-term ART have demonstrated that the extent and distribution of fat gain are similar. A systematic review of RCTs concerning switching ART for fat accumulation failed to show any benefit.⁶³ These data indicate that fat gain is a consequence of treating HIV rather than a drug-specific side effect. Telling the patient that the ART drugs are causing fat gain is not only incorrect, but may result in the patient discontinuing ART. The appearance of the fat gain is particularly unsightly when accompanied by lipoatrophy in the face, limbs and buttock.

There is no evidence to support the switching of ART drugs in patients with fat accumulation. Healthy diet and exercise should be advocated, as in the HIV-negative population. Surgery should be considered in selected cases with focal fat gain (e.g. those with prominent ‘buffalo humps’). Metformin modestly reduces weight and improves insulin resistance in patients with the metabolic syndrome or isolated dysglycaemia.

Visceral fat accumulation is associated with insulin resistance and dyslipidaemia. Other CVS risk factors should be addressed.

Hypersensitivity

Rash with NNRTIs is common (more severe and frequent with NVP) in the first six weeks of therapy. If the rash is accompanied by systemic features (e.g. fever, elevated ALT or hepatitis), mucosal involvement or blistering, then the NNRTI should be discontinued immediately and rechallenge must not be performed as these are features of life-threatening reactions. If the rash is mild and occurs without these features, then the NNRTI can be continued and the rash can be treated symptomatically with antihistamines, and possibly topical steroids. Systemic steroids should not be used.

Nephrotoxicity

In a minority of patients, TDF may cause a tubular wasting syndrome (including wasting of phosphate and potassium). If patients receiving TDF develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. TDF can also cause acute renal failure, but this is uncommon. TDF should be switched to ABC (or an alternative NRTI) immediately in patients with acute renal failure as it may exacerbate injury even if it is not the primary cause. Consider recommencing TDF with careful monitoring when the creatinine is normal only if an alternative cause of renal failure is established and TDF was considered not to have contributed.

We recommend that the CrCl should be estimated before commencing TDF, which should not be used if the eGFR or CrCl is < 50 mL/min. For patients receiving TDF, creatinine should be monitored at three months, six months and then 6-monthly thereafter. In high risk patients (particularly those with coexistent hypertension or diabetes), creatinine should also be checked at one and two months. Long-term use of TDF together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents [NSAIDs]) should be avoided. Where TDF is avoided because CrCl is < 50 mL/min at baseline, it may be possible to switch to TDF at a later point if renal function improves. This is often the case where patients had diarrhoea or other OIs at the time of ART initiation.

Neuropsychiatric toxicity

Zidovudine and raltegravir frequently cause headaches when started, but this usually resolves. EFV frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. Both dysphoria and euphoria may occur. Fortunately, these features subside in the majority of patients within the first 4–6 weeks. Psychosis may occasionally occur. If the neuropsychiatric effects of EFV are not tolerated, then the patient should be switched to RPV, DTG, lower-dose EFV or NVP (if the CD4+ count is < 250 cells/μL in women or < 400 cells/μL in men; if virologically suppressed, then EFV can be switched to NVP at higher CD4+ counts as this is not associated with increased risk of rash-associated hepatitis), 400 mg daily. Patients starting EFV should be warned about these symptoms, and reassured that they resolve in most patients continuing the drug, but if not, that an alternative can be substituted. DTG may also cause insomnia, headache and neuropsychiatric side effects. RAL has been associated with similar CNS side effects.

Dysglycaemia

The older PIs, notably IDV, may cause diabetes. However, the newer PIs (ATV, DRV and LPV) do not. EFV, AZT and d4T are associated with small increased risks of dysglycaemia. Visceral fat gain, which occurs to a similar extent with all ART classes, is associated with insulin resistance. Blood glucose should be assessed serially in these patients as part of a CVS risk assessment.

Gynaecomastia

Gynaecomastia, which is a benign glandular breast tissue proliferation seen in males, has most consistently been associated with the use of EFV, although d4T and ddI have also been implicated.^64,65 This is not related to lipodystrophy. The onset occurs several months after initiation of ART and it may be bilateral or unilateral. The mechanism appears to be related to oestrogen receptor activation in breast tissues by EFV.⁶⁶

It is important to exclude other common causes of gynaecomastia, such as other medications (including spironolactone, calcium channel blockers, metoclopramide). A serum testosterone is useful in excluding hypogonadism as a cause. If the serum testosterone is low, other appropriate investigations should be performed to identify the cause and manage accordingly. If the serum testosterone level is normal, then EFV should be substituted, bearing in mind the general principles of single drug substitutions (patients who are virologically suppressed should be switched to DTG or RPV).

Resolution of gynaecomastia is generally slow, taking months and may be incomplete in a small percentage.⁶⁷ It is, therefore, important to manage the expectations of the patient in this regard.

Immune reconstitution inflammatory syndrome

Approximately 10%–20% of patients who start ART with advanced immunosuppression experience clinical deterioration during the first months because of IRIS. Two forms are recognised:

Immune reconstitution inflammatory syndrome is most frequently described in association with TB and CM. Skin conditions such as molluscum contagiosum and Kaposi’s sarcoma may also worsen because of IRIS. The diagnosis of IRIS can be difficult, mainly because there is no confirmatory diagnostic test. Diagnosis relies on recognition of the characteristic clinical presentation, ensuring that OIs are correctly diagnosed, and excluding alternative causes for deterioration, such as drug resistance (e.g. MDR-TB). Case definitions for TB and cryptococcal IRIS have been published.^68,69 It is important to ensure that the underlying OI is treated appropriately. ART should be continued, unless IRIS is life-threatening (e.g. neurological involvement in TB-IRIS with depressed level of consciousness). Corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical TB-IRIS,⁷⁰ and can be used in mycobacterial and fungal forms of IRIS when other causes for deterioration have been excluded, and particularly when IRIS features are severe. For paradoxical TB-IRIS, prednisone can be commenced at a dose of 1.5 mg/kg/day and weaned over four weeks, but a longer course may be required if symptoms recur on weaning.⁷¹ Steroids should not be used in patients with Kaposi’s sarcoma.

Support and counselling

The patient should be informed about the benefits of ART and that side effects are usually minor and transient, or manageable. The patient should be given a treatment plan, specifying the drugs to be used (with names and details including the appearance of each drug, when and how they are to be taken and a brief indication of anticipated side effects and toxicity).

Poor adherence results in the development of drug resistance. There is a bell-shaped relationship between adherence and resistance: patients with very poor resistance may not acquire resistance to certain drugs because of insufficient drug pressure to select for resistance. The patient should be encouraged to discuss drug-related issues with his or her clinician.

Prophylaxis in patients receiving antiretroviral therapy

Opportunistic infections

The use of appropriate prophylaxis (primary or secondary) is essential in patients initiating ART. In general, prophylaxis can be discontinued once the CD4+ count has increased to 200 cells/μL (but certain minimal durations of prophylaxis apply for secondary prophylaxis – local and international guidelines should be consulted).

Isoniazid preventive therapy

Clinical trials conducted in SA and Cote d’Ivoire have shown that isoniazid preventive therapy (IPT) has an additive effect with ART in preventing incident TB in HIV-infected patients.^4,72 In the SA trial, there was a 37% reduction in incident TB when patients receiving ART were prescribed IPT (vs placebo) for 12 months. This benefit applied irrespective of tuberculin skin test (TST) status, and the trial included patients established on ART. All patients receiving ART should be considered for IPT and screened for active TB by using a symptom screen⁷³ – defer IPT and investigate for active TB if any of the four symptoms (current cough, fever, night sweats or weight loss) are present. Consider sputum TB culture in all patients with a CD4+ count < 200 cells/μL before IPT initiation where feasible. In patients receiving IPT, monitor for neuropathy and hepatitis symptoms. Routine ALT monitoring is not indicated, but request ALT if hepatitis symptoms occur. The duration of IPT depends on TST and ART status as outlined in Table 15.

Acknowledgements

This work is supported and funded by the Southern African HIV Clinicians Society. G.M. has received honoraria for speaking engagements from Sanofi Aventis and Janssen Pharmaceuticals, serves as a consultant for Aid for AIDS and TB Alliance and is on the Gilead Antifungal Advisory Board. M.M. is part of the OPTIMIZE consortium that includes drug donations from Gilead and ViiV and also includes Mylan as part of the consortium. She has received speaker fees and honoraria from SA HIV Clinicians Society, Gilead Sciences, AbbVie and Janssen; has received conference sponsorship from BD, Gilead, Merck, Cipla and Mylan; has acted as a consultant to AbbVie, GSK, ViiV and Gilead; and is a member of the Johnson and Johnson Global Public Health HIV Therapeutic Area Steering Committee. S.D. has received honoraria for speaking engagements from MSD and Pfizer. C.v.V. has received honoraria for speaking engagements from Pfizer and MSD and has received support to attend conferences from Pfizer and MSD. T.M. has received support from Gilead to attend a conference. M.M. has received support from Cipla and Aspen to attend conferences and honoraria from Johnson & Johnson for the development of educational presentations. Y.M. has received honoraria for speaking engagements from Mylan, MSD, Abbott Laboratories, Aspen and Gilead and support from Gilead to attend conferences. J.N. has received honoraria for speaking engagements from Cipla and Mylan. F.C. is a board member of the SAMRC, HIV consultant for Discovery Medical Aid and is employed by Clinical HIV Research Unit; has received support from Mylan, Aspen and Merck to attend conferences; honoraria for speaking engagements from SA HIV Clinicians Society, Mylan, Cipla and Janssen; and acted as a consultant to AbbVie, Mylan and ViiV. F.V. is part of the OPTIMIZE Consortium that includes drug donations from Gilead and ViiV and also includes Mylan as part of the consortium. He has given talks and participated on advisory boards (all < $1000) for these companies, as well as J&J, Roche, Merck, Aspen, Abbott and Adcock-Ingram in the last 10 years.

The authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article.

All expert panel members have completed and submitted conflict of interest disclosure forms. Disclosure information represents the previous 3 years (updated 5 May 2017) and includes relationships with pharmaceutical companies and medical aids. S.C., Y.P., J.W., G.V.Z., J.N. and N.D. report no conflicts of interest.

References

Johnson LF, Mossong J, Dorrington RE, et al. Life expectancies of South African adults starting antiretroviral treatment: Collaborative analysis of cohort studies. PLoS Med. 2013;10:e1001418. https://doi.org/10.1371/journal.pmed.1001418
Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370:2487–2498. https://doi.org/10.1056/NEJMoa1312884
INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807. https://doi.org/10.1056/NEJMoa1506816
Group TAS, Danel C, Moh R, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373:808–822. https://doi.org/10.1056/NEJMoa1507198
Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med. 2016;375:830–839. https://doi.org/10.1056/NEJMoa1600693
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493–505. https://doi.org/10.1056/NEJMoa1105243
Uthman OA, Okwundu C, Gbenga K, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: A systematic review and meta-analysis. Ann Intern Med. 2015;163:32–39. https://doi.org/10.7326/M14-2979
Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)-associated tuberculous meningitis. Clin Infect Dis. 2011;52:1374–1383. https://doi.org/10.1093/cid/cir230
Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: A multicenter randomized strategy trial. PLoS One. 2009;4:e5575. https://doi.org/10.1371/journal.pone.0005575
Amanyire G, Semitala FC, Namusobya J, et al. Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: A stepped-wedge cluster-randomised trial. Lancet HIV. 2016;3:e539–e548. https://doi.org/10.1016/S2352-3018(16)30090-X
Pilcher CD, Ospina-Norvell C, Dasgupta A, et al. The effect of same-day observed initiation of antiretroviral therapy on HIV viral load and treatment outcomes in a US public health setting. J Acquir Immune Defic Syndr. 2017;74:44–51. https://doi.org/10.1097/QAI.0000000000001134
Rosen S, Maskew M, Fox MP, et al. Initiating antiretroviral therapy for HIV at a patient’s first clinic visit: The RapIT randomized controlled trial. PLoS Med. 2016;13:e1002015. https://doi.org/10.1371/journal.pmed.1002015
O’Brien M, Markowitz M. Should we treat acute HIV infection? Curr HIV/AIDS Rep. 2012;9:101–110. https://doi.org/10.1007/s11904-012-0113-0
Krishnan S, Wilson EM, Sheikh V, et al. Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis. 2014;209:931–939. https://doi.org/10.1093/infdis/jit581
Crowell TA, Gebo KA, Blankson JN, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2015;211:1692–1702. https://doi.org/10.1093/infdis/jiu809
Cruciani M, Mengoli C, Malena M, et al. Virological efficacy of abacavir: Systematic review and meta-analysis. J Antimicrob Chemother. 2014;69:3169–3180. https://doi.org/10.1093/jac/dku279
Sabin CA, Worm SW, Weber R, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: A multi-cohort collaboration. Lancet. 2008;371:1417–1426. https://doi.org/10.1016/S0140-6736(08)60423-7
Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: Short and long-term results from ACTG A5001/ALLRT. Clin Infect Dis. 2011;52:929–940. https://doi.org/10.1093/cid/ciq244
Cruciani M, Zanichelli V, Serpelloni G, et al. Abacavir use and cardiovascular disease events: A meta-analysis of published and unpublished data. AIDS. 2011;25:1993–2004. https://doi.org/10.1097/QAD.0b013e328349c6ee
Group ES, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): A randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383:1474–1482. https://doi.org/10.1016/S0140-6736(13)62187-X
Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection. N Engl J Med. 2013;369:1807–1818. https://doi.org/10.1056/NEJMoa1215541
Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: Week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70:515–519. https://doi.org/10.1097/QAI.0000000000000790
Raffi F, Rachlis A, Stellbrink HJ, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet. 2013;381:735–743. https://doi.org/10.1016/S0140-6736(12)61853-4
Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015;2:e127–e136. https://doi.org/10.1016/S2352-3018(15)00027-2
Cahn P, Pozniak AL, Mingrone H, et al. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: Week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382:700–708. https://doi.org/10.1016/S0140-6736(13)61221-0
You J, Wang H, Huang X, et al. Therapy-emergent drug resistance to integrase strand transfer inhibitors in HIV-1 patients: A subgroup meta-analysis of clinical trials. PLoS One. 2016;11:e0160087. https://doi.org/10.1371/journal.pone.0160087
Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27:939–950. https://doi.org/10.1097/QAD.0b013e32835cee6e
Tucker JD, Bien CH, Easterbrook PJ, et al. Optimal strategies for monitoring response to antiretroviral therapy in HIV-infected adults, adolescents, children and pregnant women: A systematic review. AIDS. 2014;28(Suppl 2):S151–S160.
Ford N, Meintjes G, Pozniak A, et al. The future role of CD4 cell count for monitoring antiretroviral therapy. Lancet Infect Dis. 2015;15:241–247. https://doi.org/10.1016/S1473-3099(14)70896-5
Rawizza HE, Chaplin B, Meloni ST, et al. Immunologic criteria are poor predictors of virologic outcome: Implications for HIV treatment monitoring in resource-limited settings. Clin Infect Dis. 2011;53:1283–1290. https://doi.org/10.1093/cid/cir729
Manasa J, Katzenstein D, Cassol S, Newell ML, de Oliveira T. Primary drug resistance in South Africa: Data from 10 years of surveys. AIDS Res Hum Retrovir. 2012;28:558–565. https://doi.org/10.1089/aid.2011.0284
Hunt GM, Ledwaba J, Basson AE, et al. Surveillance of transmitted HIV-1 drug resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005–2009. Clin Infect Dis. 2012;54(Suppl 4):S334–S338. https://doi.org/10.1093/cid/cir1017
Smith CJ, Sabin CA, Lampe FC, et al. The potential for CD4 cell increases in HIV-positive individuals who control viraemia with highly active antiretroviral therapy. AIDS. 2003;17:963–969. https://doi.org/10.1097/00002030-200305020-00004
Guihot A, Tubiana R, Breton G, et al. Immune and virological benefits of 10 years of permanent viral control with antiretroviral therapy. AIDS. 2010;24:614–617. https://doi.org/10.1097/QAD.0b013e32833556f3
Kaufmann GR, Furrer H, Ledergerber B, et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to < 500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis. 2005;41:361–372. https://doi.org/10.1086/431484
Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: An observational cohort study. Lancet. 2007;370:407–413. https://doi.org/10.1016/S0140-6736(07)60948-9
Loutfy MR, Genebat M, Moore D, et al. A CD4+ cell count < 200 cells per cubic millimeter at 2 years after initiation of combination antiretroviral therapy is associated with increased mortality in HIV-infected individuals with viral suppression. J Acquir Immune Defic Syndr. 2010;55:451–459. https://doi.org/10.1097/QAI.0b013e3181ec28ff
Tuboi SH, Pacheco AG, Harrison LH, et al. Mortality associated with discordant responses to antiretroviral therapy in resource-constrained settings. J Acquir Immune Defic Syndr. 2010;53:70–77. https://doi.org/10.1097/QAI.0b013e3181c22d19
Ledergerber B, Lundgren JD, Walker AS, et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet. 2004;364:51–62. https://doi.org/10.1016/S0140-6736(04)16589-6
Paton NI, Kityo C, Hoppe A, et al. Assessment of second-line antiretroviral regimens for HIV therapy in Africa. N Engl J Med. 2014;371:234–247. https://doi.org/10.1056/NEJMoa1311274
La Rosa AM, Harrison LJ, Taiwo B, et al. Raltegravir in second-line antiretroviral therapy in resource-limited settings (SELECT): A randomised, phase 3, non-inferiority study. Lancet HIV. 2016;3:e247–e258. https://doi.org/10.1016/S2352-3018(16)30011-X
Johnson M, Grinsztejn B, Rodriguez C, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS. 2006;20:711–718. https://doi.org/10.1097/01.aids.0000216371.76689.63
Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323–332. https://doi.org/10.1097/QAI.0b013e3181c990bf
Department of Health. 2015. National consolidated guidelines for the prevention of mother-to-child transmission of HIV (PMTCT) and the management of HIV in children, adolescents and adults. Department of Health, South Africa.
Yazdanpanah Y, Fagard C, Descamps D, et al. High rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant HIV: Results of the ANRS 139 TRIO trial. Clin Infect Dis. 2009;49:1441–1449. https://doi.org/10.1086/630210
Meintjes G, Dunn L, Coetsee M, et al. Third-line antiretroviral therapy in Africa: Effectiveness in a Southern African retrospective cohort study. AIDS Res Ther. 2015;12:39. https://doi.org/10.1186/s12981-015-0081-8
Stevens WS, Wallis CL, Sanne I, Venter F. Will etravirine work in patients failing nonnucleoside reverse transcriptase inhibitor-based treatment in southern Africa? J Acquir Immune Defic Syndr. 2009;52:655–656. https://doi.org/10.1097/QAI.0b013e3181ba1b00
Petersen ML, Wang Y, van der Laan MJ, Rhee SY, Shafer RW, Fessel WJ. Virologic efficacy of boosted double versus boosted single protease inhibitor therapy. AIDS. 2007;21:1547–1554. https://doi.org/10.1097/QAD.0b013e32825a69a8
Conradie F, Fox M, Moorhouse MA, et al. South Africa’s national third-line art cohort: Descriptive analysis. Conference on Retroviruses and Opportunistic Infections (CROI); 2017 February 13–16; Johannesburg, South Africa. University of the Witwatersrand; 2017. http://www.croiconference.org/sessions/south-africa%E2%80%99s-national-third-line-art-cohort-descriptive-analysis
Strategies for Management of Antiretroviral Therapy Study Group, El-Sadr WM, Lundgren J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283–2296.
Grinsztejn B, De Castro N, Arnold V, et al. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): A multicentre, phase 2, non-comparative, open-label, randomised trial. Lancet Infect Dis. 2014;14:459–467. https://doi.org/10.1016/S1473-3099(14)70711-X
Davies G, Cerri S, Richeldi L. Rifabutin for treating pulmonary tuberculosis. Cochrane Database Syst Rev. 2007;(4):CD005159. https://doi.org/10.1002/14651858.cd005159.pub2
Hennig S, Svensson EM, Niebecker R, et al. Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs. J Antimicrob Chemother. 2016;71:1330–1340. https://doi.org/10.1093/jac/dkv470
World Health Organization. Technical update on treatment optimization. Use of efavirenz during pregnancy: A public health perspective. Switzerland: WHO Press; 2012.
Ford N, Calmy A, Mofenson L. Safety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis. AIDS. 2011;25:2301–2304. https://doi.org/10.1097/QAD.0b013e32834cdb71
Patterson KB, Dumond JB, Prince HA, et al. Protein binding of lopinavir and ritonavir during 4 phases of pregnancy: Implications for treatment guidelines. J Acquir Immune Defic Syndr. 2013;63:51–58. https://doi.org/10.1097/QAI.0b013e31827fd47e
Eley T, Bertz R, Hardy H, Burger D. Atazanavir pharmacokinetics, efficacy and safety in pregnancy: A systematic review. Antivir Ther. 2013;18:361–375. https://doi.org/10.3851/IMP2473
Bartlett JG. Medical care of patients with HIV Infection. Philadelphia, PA: Lippincott Williams and Wilkins; 2010.
Gilbert DN, Moellering Jr., RC (Editor), Eliopoulos GM, editors. The Sanford Guide to Antimicrobial Therapy. Sperryville, VA: Antimicrobial Therapy Inc; 2012.
Lucas GM, Ross MJ, Stock PG, et al. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update. Clin Infect Dis. 2014;59(9):e96–e138. https://doi.org/10.1093/cid/ciu617
Sonderup MW, Maughan D, Gogela N, et al. Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa. AIDS. 2016;30:1483–1485. https://doi.org/10.1097/QAD.0000000000001084
Jong E, Conradie F, Berhanu R, et al. Consensus statement: Management of DILI in HIV-positive patients treated for TB. S Afr J HIV Med 2013;14(3):113–119. https://doi.org/10.4102/sajhivmed.v14i3.63
de Waal R, Cohen K, Maartens G. Systematic review of antiretroviral-associated lipodystrophy: Lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PLoS One. 2013;8:e63623. https://doi.org/10.1371/journal.pone.0063623
Manfredi R, Calza L, Chiodo F. Another emerging event occurring during HIV infection treated with any antiretroviral therapy: Frequency and role of gynecomastia. Infez Med. 2004;12:51–59.
Mira JA, Lozano F, Santos J, et al. Gynaecomastia in HIV-infected men on highly active antiretroviral therapy: Association with efavirenz and didanosine treatment. Antivir Ther. 2004;9:511–517.
Sikora MJ, Rae JM, Johnson MD, Desta Z. Efavirenz directly modulates the oestrogen receptor and induces breast cancer cell growth. HIV Med. 2010;11:603–607. https://doi.org/10.1111/j.1468-1293.2010.00831.x
Njuguna C, Swart A, Blockman M, et al. Cases of antiretroviral-associated gynaecomastia reported to the National HIV & Tuberculosis Health Care Worker Hotline in South Africa. AIDS Res Ther. 2016;13:40. https://doi.org/10.1186/s12981-016-0121-z
Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: Proposed clinical case definitions. Lancet Infect Dis. 2010;10:791–802. https://doi.org/10.1016/S1473-3099(10)70170-5
Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: Case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–523. https://doi.org/10.1016/S1473-3099(08)70184-1
Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24:2381–2390. https://doi.org/10.1097/qad.0b013e32833dfc68
Meintjes G, Sonderup MW. A practical approach to the diagnosis and management of paradoxical tuberculosis immune reconstitution inflammatory syndrome. Contin Med Educ. 2011;29(10):410–417.
Rangaka MX, Wilkinson RJ, Boulle A, et al. Isoniazid plus antiretroviral therapy to prevent tuberculosis: A randomised double-blind, placebo-controlled trial. Lancet. 2014;384:682–690. https://doi.org/10.1016/S0140-6736(14)60162-8
Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: Individual participant data meta-analysis of observational studies. PLoS Med. 2011;8:e1000391. https://doi.org/10.1371/journal.pmed.1000391

Guidelines

Adult antiretroviral therapy guidelines 2017

Graeme Meintjes, Michelle A. Moorhouse, Sergio Carmona, Natasha Davies, Sipho Dlamini, Cloete van Vuuren, Thandekile Manzini, Moeketsi Mathe, Yunus Moosa, Jennifer Nash, Jeremy Nel, Yoliswa Pakade, Joana Woods, Gert Van Zyl, Francesca Conradie, Francois Venter

Abstract

Key principles

Goals of antiretroviral therapy

Standard of care

Antiretroviral drugs: Classes and mechanisms of action

Antiretroviral drugs currently available in southern Africa

Indications for initiating antiretroviral therapy

Rationale for these guidelines

Benefits of antiretroviral therapy in reducing transmission

Commencing antiretroviral therapy in patients with tuberculosis

CD4+ count ≤ 50 cells/µL

CD4+ count > 50 cells/µL

Tuberculous meningitis

Starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses

Patient readiness for antiretroviral therapy

Commencing antiretroviral therapy at the first antiretroviral clinic visit

Antiretroviral therapy in primary HIV infection

Antiretroviral therapy initiation in ‘elite controllers’

Investigations prior to starting antiretroviral therapy

Initial antiretroviral therapy regimens for the previously untreated patient

Nucleoside reverse transcriptase inhibitor component of first-line regimen

The third drug in the regimen: Efavirenz, dolutegravir or rilpivirine

Baseline resistance test

Laboratory monitoring for antiretroviral therapy efficacy and safety

Viral load

Timing of viral load monitoring

Interpreting viral load results

CD4+ counts

Laboratory monitoring of antiretroviral therapy safety

Defining antiretroviral therapy failure

Virological criteria for treatment success

Virological criteria for treatment failure

CD4+ response

Indications for changing antiretroviral therapy

Second-line regimens

Resistance testing for selecting second-line antiretroviral therapy

Recommended second-line antiretroviral therapy regimen

Ritonavir-boosted protease inhibitor in the second-line regimen

Selecting second-line dual nucleoside reverse transcriptase inhibitors

Selecting second-line antiretroviral therapy in patients who received a first-line PI-regimen

Third-line antiretroviral therapy regimens

Stopping antiretroviral therapy

Patients who return after defaulting therapy

Drug interactions

Antiretroviral therapy in special populations

Tuberculosis

Pregnancy

Antiretroviral drugs in pregnancy

Recommendations for antiretroviral-naïve pregnant patients

Recommendations for antiretroviral-experienced pregnant patients

Breastfeeding

Postnatal period

Partner engagement

Renal failure

Antiretroviral drug dosages

Antiretroviral drug choice and dosing in patients on chronic haemodialysis

Antiretroviral therapy in patients with acute kidney injury

Antiretroviral therapy dosages in liver impairment

Hepatitis B co-infection

Malaria

Antiretroviral therapy toxicity monitoring and management

Haematological toxicity

Hepatotoxicity

Hyperlactataemia and lactic acidosis

Dyslipidaemia

Lipodystrophy

Hypersensitivity

Nephrotoxicity

Neuropsychiatric toxicity

Dysglycaemia

Gynaecomastia

Immune reconstitution inflammatory syndrome

Support and counselling

Prophylaxis in patients receiving antiretroviral therapy

Opportunistic infections

Isoniazid preventive therapy

Acknowledgements