Antiretrovial Therapy - Adults & Adolescents

The aims of antiretroviral therapy (ART) are:

• Maximal and durable suppression of replication of HIV,
• Restoration and/or preservation of immune function,
• Reduction of HIV-related morbidity and mortality,
• Improvement of quality of life,
• Prevention of parent-to-child transmission of HIV (vertical transmission)
• Reduction of transmission of HIV from infected to uninfected individuals through use of ARVs by the infected individual now commonly known as 'Treatment as prevention'
• Reduction of transmission through provision of pre-exposure (PrEP) prophylaxis to high risk

Prior to starting ART, patients should be assessed for readiness to take ARVs; the ARV regimen; dosage and scheduling; the likely potential adverse effects; and the required monitoring. Both medical and psychosocial issues need to be addressed before initiating ART. Patients should be adequately counseled about adopting appropriate life style measures such as safer sexual practices (including appropriate use of condoms), and any other psychosocial problems that may interfere with adherence (e.g., alcohol, psychiatric disorders) should be addressed. At each clinic visit always screen for tuberculosis using a TB symptom checklist, advise patients about adequate nutrition, the importance of medicine adherence and regular follow up care. People taking ARVs should also be regularly asked whether they are taking other medicines including herbal remedies as they may interfere with the efficacy of ARVs.

Early treatment is associated with clinical and HIV prevention benefits, improved survival and reduced incidence of HIV infection at the community level. Increasing evidence also indicates that untreated HIV may be associated with the development of severe non-AIDS defining conditions including cardiovascular disease, kidney disease, liver disease and neurocognitive disorders.

Medical Criteria for initiating ART in adolescents/ adults

All individuals with a confirmed HIV diagnosis are eligible for anti-retroviral therapy (ART) irrespective of WHO clinical stage and CD4 count level i.e. TREAT ALL. Health workers should retest all people newly and previously diagnosed with HIV before they initiate ART. As a priority , initiate ART in all individuals with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) or CD4 count less than or equal to 350 cells/ mm3. It is also recommended to initiate ART, as a priority, in the following categories of patients regardless of CD4 cell count:

1. Active TB disease
2. Pregnant and breast-feeding women with HIV
3. Individuals with HIV in sero-discordant relationships
4. HBV co-infection with severe chronic liver disease

Once an individual is confirmed to be HIV positive; health workers should provide adequate counselling and start ART within a week. However, for those patients who are not yet ready to start ART, they should receive on-going counselling and support.

Patients with CD4 <100

Patients with low CD4 below 100 should be fast-tracked for treatment initiation. They should be screened for symptomatic TB, cryptococcal disease (CrAg screening), visual changes and direct retina exam. They should receive Cotrimoxazole prophylaxis and TB Preventive Therapy (TPT) and should be closely monitored for 3 months as this is their highest risk period for bacterial infections and TB or crypto IRIS. Health workers should educate them and their families to report immediately to a health facility if they are unwell whilst their CD4 is < 100.

Psychosocial criteria for initiating ART

Consider the following psychosocial criteria when initiating ART:

• Has the patient been adequately counselled and informed about ARVs?
• Is a treatment partner available and/or has disclosure been made to that treatment partner (strongly encouraged)?
• Is there an easy method of following up on the patient?
• Is the patient ready to take medication indefinitely?

Situations where it may be necessary to defer ART initiation

A patient may be deferred (delayed) from starting therapy if the patient

• has cryptococcal meningitis,
• needs further psychosocial support (e. for alcohol problems),
• has TB (defer starting ART for at least 2 weeks),
• needs further information on HIV and AIDS,
• very ill patient and unable to swallow oral medication (palliative care is then offered to such a patient).

SUCH PATIENTS SHOULD BE OFFERED CONTINUED MONITORING ANO CLOSE FOLLOW-UP AS WELL AS COUNSELLING SO THAT ART CAN BE COMMENCED AT AN APPROPRIATE TIME.

WHO defines treatment adherence as 'the extent to which a person's behaviour- taking medications, following a diet and/or executes lifestyle changes' corresponds with agreed recommendations from a health care provider.

Efforts to support adherence should start before ART initiation and should include basic information about HIV, the ARV medicines, expected adverse events, preparations for long-term ART. Effective adherence support interventions include client-centred behavioural counselling and support, support from peer educators trained as "expert patients," community treatment supporters and mobile text messaging. Other interventions involve encouraging people to disclose their HIV status and providing them with adherence tools such as pill boxes, diaries, and patient reminder aids. During follow-up, patients should be assessed for adherence to whatever treatment plan has been agreed upon (Integrated HIV training curriculum, MoHCC).

The choice of medicine regimen is based on the "essential medicine" concept and the rational use of medicine. To maximise adherence, use of fixed-dose combinations (FDC) medicines is strongly encouraged.

The choice of ARVs has been based on evidence of efficacy and safety, on availability and cost of medications, as well as on the side effects profile and the potential for development of resistance. The national ART programme will use the following FDCs in the first line regimens:

First Line ART

1. Adults and adolescents including women of child-bearing potential

*TAF (tenofovir alafenamide) can be used as a substitute for TDF (tenofovir disoproxil fumarate)

**TB patients on Rifampicin to receive DTG 50mg twice a day

***ABC/3TC/DTG 50mg can be administered to patients weighing at least 20 kg

AZT/3TC backbone may be used in special circumstances

• DTG is one of the preferred antiretroviral medicines for first- and second­ line regimens for everyone living with HIV including adults, pregnant women, women and adolescent girls of childbearing potential, children and people co-infected with TB.
• Dolutegravir (DTG) is a safe and efficacious medicine with a rapid viral suppression, low potential for drug-drug interactions and a high genetic barrier to developing ARV drug resistance. It should be included in the preferred first line regimen for all populations unless where contraindicated
• Exposure to DTG at the time of conception may be associated with an increased risk of neural tube defects (NTDs) among infants although NTD risk has been further reduced compared to when first reported.
• DTG use has been associated with weight gain especially when co­ administered with TAF/3TC. Prior to initiating DTG containing regimens; clinicians should advise patients on this potential side effect and advise on the importance of adopting healthy life-styles including exercising, taking healthy diets and avoidance of smoking.
• Effective contraception should be offered to adult women and adolescent girls of childbearing age or potential.
• DTG can be prescribed for adult women and adolescent girls of childbearing age or potential who wish to become pregnant or who are not otherwise using or accessing consistent and effective contraception if they have been fully informed of the potential increase in the risk of neural tube defects (at conception and until the end of the first trimester).
• Pregnancy test should be made available at health facilities to ascertain pregnancy status among women in order to support patient management. However, non-availability of pregnancy test kits should not be a barrier for administering DTG based regimens. If a woman's first realization of pregnancy is after the first trimester, DTG should be initiated or continued for the duration of the pregnancy.
• ART experienced patients should be transitioned to a DTG-containing regimen after confirming a suppressed HIV viral load of <1,000 copies/ml in the past twelve months:
  • If VL is suppressed, substitute the NNRTI with DTG
  • If VL is unsuppressed, manage as treatment failure. Provide 3 enhanced adherence counselling (EAC) sessions over 3 months to allow for good adherence followed by a repeat VL test. If the patient remains unsuppressed , switch patients to a DTG-based second line regimen.
• In PLHIV with TB using rifampicin , the dose of DTG should be increased to 50 mg twice daily.
• Tenofovir alafenamide (TAF) a derivative of TDF has less renal and bone toxicity compared to TDF. TAF may be used as a substitute for TDF for adults and adolescents . When available, TAF should be considered in elderly patients above 50 years, patients with Creatinine Clearance of 30- 60mL/min and HBV co-infected. However, TAF should NOT be used in: HIV/TB co-treatment or HIV infected pregnant women and patients with renal impairment with CrCl below 30mL/min.
• In order to facilitate effective management of patients on ART; it is critical to make the distinction between patients on first line versus those taking second line ART. The program will use TLD1 to refer to patients taking first line DTG-based regimens while TLD2 will refer to those on second line DTG-based regimens. 
• Use of Nevirapine (NVP) and Efavirenz (EFV) 600mg (NNRTI) in adults and adolescents is being phased out and health providers are advised to limit its use. Due to high levels of pretreatment HIV drug resistance in Zimbabwe (>10%), NNRTls are less preferred.

• Efavirenz 400mg is safe for use among pregnant women. Pharmacokinetic and pharmacodynamics studies suggest that the drug concentrations decline slightly during pregnancy; however, remain within therapeutic range and unlikely to reduce the drug efficacy.
• Efavirenz 400 mg can be co-administered with rifampicin containing anti-TB treatment; is well tolerated and plasma concentrations were maintained above the levels considered to be effective. 
• When available, tenofovir alafenamide (TAF) may be considered for elderly patients above 50 years; patients with impaired kidney function, established osteoporosis and among HBV co-infected patients.

Caution: Tenofovir (TDF)

TDF may be associated with acute kidney injury or chronic kidney disease as well as reduced bone mineral density in pregnant women.

Clinical considerations when using TDF:

• Patients should be initiated on TDF even in the absence of laboratory monitoring capacity for U&Es. However, efforts should be made to strengthen laboratory monitoring of patients,
• Routine blood pressure monitoring,
• Urine dipsticks may be used to detect glycosuria or severe TDF nephrotoxicity in individuals without diabetes using TDF-containing regimens
• If the creatinine test is routinely available, use the estimated glomerular filtration rate at baseline before initiating TDF regimens.

Do not initiate TDF when the estimated glomerular filtration rate is <50 ml/min, or in long term diabetes, uncontrolled hypertension and renal failure.

If the patient has suspected adverse medicine events, therapy should be altered as follows (change of a single medicine in a multi-medicine regimen is permitted-that is, the offending medicine may be replaced, preferably with an alternative medicine of the same class):

• Given Zidovudine toxicity such as anaemia or neutropenia, Zidovudine will be replaced by Tenofovir
• In the event of lactic acidosis, the current ARVs should be discontinued and ART restarted after checking for normalization of the lactate
• In case of severe psychiatric reaction on EFV give NVP
• In case creatinine clearance is known and < 50ml/min give AZT

An alternative to lamivudine (3TC) is emtricitabine (FTC); these medicines are considered pharmacologically equivalent. In the event that you come across a patient on Tenofovir/Emtricitabine/Efavirenz, you may substitute Emtricitabine with Lamivudine.

For patients presenting with renal impairment, consult/refer for specialist opinion.

Ideally, patients who fail to respond to first-line treatment should be treated with a different regimen containing medicines that were not included in the first regimen. The second-line regimen will consist of two NRTls but with a Pl if the initial regimen contained DTG. The second-line regimen should be initiated only after assessing treatment adherence and failure and in consultation with a specialist in HIV and AIDS treatment or the clinical mentorship team at the OI/ART clinic, as the recommendation will be based on what the patient is already taking or has taken in the past. Clinical mentors should be consulted where there is doubt about what to do. More adherence counselling will be required in preparation for the planned new therapy.

 Preferred second line regimens for adults and adolescents including pregnant and breastfeeding women

Tenofovir 300mg {TDF (or TAF)} + Lamivudine 300mg (3TC) + Dolutegravir 50mg (DTG) or ABC + 3TC + DTG

Preferred second line Regimen

TDF (or TAF) + 3TC (or FTC)+ ATV/r or TDF (or TAF) + 3TC + EFV

Preferred Second Line Regimen

AZT + 3TC + EFV

Preferred Second Line Regimen

**TB patients on Rifampicin to receive DTG 50mg twice a day

If TDF + 3TC or ABC + 3TC (or FTC) was used in the failing first-line regimen, AZT+ 3TC should be used in second-line ART and vice versa

For HIV/TB coinfection on rifampicin-based regimen, use LPV/R (super booster) instead of ATV/r and DTG twice daily instead of DTG once daily Maintain TDF in the second line for patients with chronic HBV coinfection.

Main Considerations:

• Patients failing first line (ref to ART Guidelines) should be switched to an effective second line regimen.
• Precautions in the use of DTG also apply for second- and third-line ARV regimens

In adolescents older than 12 years and adults; the preferred 3^rd line ART can include Dolutegravir (50mg), Darunavir (600mg)/Ritonavir (100mg) and 2NRTls.

Main Considerations:

• GENOTYPING TESTING IS RECOMMENDED PRIOR TO SWITCHING PATIENTS FAILING SECOND LINE ART with clinicians required to actively rule out poor adherence before genotypic testing.
• In Pl experienced patients; Darunavir (600mg)/Ritonavir (100mg) should be given twice daily

3rd line patients with a history of integrase strand transfer inhibitor (INSTI) use e.g. DTG or Raltegravir, DTG should be given twice daily.

Mother to child transmission is responsible for more than 90% of HIV infection in children and at least two thirds of such infections occur during pregnancy and delivery whilst the remainder occur during breastfeeding. It is therefore critical to identify HIV positive pregnant and lactating women and manage them appropriately.  

When to start ART in HIV positive pregnant and breastfeeding women

• All HIV infected pregnant and breastfeeding women should be initiated on lifelong antiretroviral treatment (ART) irrespective of their CD4 count or WHO clinical stage (Option B+) 
• Women who are not yet ready for lifelong ART should be initiated on triple ARVs (ART), which should be continued at least for the duration of breastfeeding to prevent further risk of mother to child transmission of HIV through breast milk. 

Being on lifelong ART will necessitate ongoing counselling of HIV positive pregnant and breastfeeding women to support retention and adherence and to minimize loss to follow up. 

• Emphasise modes of HIV transmission and prevention, PMTCT, and access to care and treatment. 
• Encourage partner HIV testing and counselling
• Encourage the importance of skilled birth attendance, clean and safe delivery, and newborn care
• Counsel on infant and young child feeding and maternal nutrition
• Counsel on sexual and reproductive health including family planning and the need for dual contraception (reliable hormonal contraceptive plus barrier method like male or female condoms) 
• Make an appointment for family planning at six weeks post partum. 
• Stress the need for condom use for prevention of STIs and HIV during pregnancy and in the post partum period. 
• Retest previously negative women: during 3rd trimester of pregnancy and/or at delivery, 6 weeks postnatally and 6 monthly thereafter.  
• Stress the importance of follow up for the HIV exposed infant 
  • Commence on cotrimoxazole prophylaxis from 6 weeks of age
  • Collect Dried Blood Spot (DBS) for HIV DNA PCR test at 6 weeks of age i.e. Early Infant Diagnosis (EID)
  • Infants should be re-tested at the end of the breast feeding period. 

When using ARVs in pregnant women, certain precautions should be kept in mind: 

Dolutegravir (DTG)

Exposure to DTG at the time of conception may be associated with an increased risk of neural tube defects (NTDs) among infants although NTD risk has been further reduced compared to when first reported. 

Efavirenz (EFV)

Previously there was a recommendation not to use efavirenz during the first trimester and in women at risk of becoming pregnant. However, WHO issued evidence based update on efavirenz safety in pregnancy in 2011 which recommends it to be safe for use even in the first trimester. 

Efavirenz 400mg is safe for use among pregnant women. Pharmacokinetic and pharmacodynamic studies suggest that the drug concentrations decline slightly during pregnancy; however, remain within therapeutic range and unlikely to reduce drug efficacy. 

(Refer to the latest national TB guidelines or TB/HIV guidelines)

TB is the most common OI encountered among people with HIV infection in Zimbabwe. Since the advent of the pandemic of HIV infection, TB has remained a serious public-health problem. Studies have shown that up to 50% of people with HIV infection develop TB and that up to 85% of patients with TB have HIV infection. In addition, TB accounts for a third of HIV-related deaths. There is a need to integrate the HIV and TB services, as TB and HIV coinfection is common. All patients living with HIV should be screened for TB at every visit using the standard TB screening tools. Rifampicin interacts adversely with some antiretroviral agents such as PIs therefore,

• TB patients on rifampicin should receive DTG 50mg twice a day
• Efavirenz 400mg can be co-administered with rifampicin containing anti­ TB treatment; is well tolerated and plasma concentrations were maintained above the levels considered to be effective.
• For HIV/TB coinfection on rifampicin-based regimen, use LPV/R (super booster) instead of ATV/r

Patients with TB who are not yet on ART

In patients who have HIV-related TB but are not yet on ART, treatment of TB takes priority. ART should be started at least two weeks after the start of TB therapy i.e. during the intensive phase when the patient has stabilised on TB treatment regardless of their CD4 count status. Cotrimoxazole prophylaxis should be provided with the commencement of the TB therapy if the patient is not on it already.

Patients who develop TB when already on ART

Treat TB as per national TB guidelines.

Prevention of Cryptococcal Disease

Patients initiating ART with undiagnosed cryptococcal disease are at higher risk of early mortality than patients who are pre-emptively diagnosed and treated for cryptococcal disease. All patients initiating ART should be clinically screened for evidence of symptomatic cryptococcal disease - headache, neck stiffness, fever, focal neurologic signs, confusion, and altered mental status. All those who screen positive should be referred for further diagnostic work up for meningitis. Screening of asymptomatic ART narve individuals with CD4 count <100cells/mm3 is recommended and should be done with a Cryptococcal neoformans antigen test (CrAg) using latex agglutination tests (LA) or lateral flow assays (LFA) on serum, plasma or CSF. A lumbar puncture should be offered to individuals who screen positive for cryptococcal antigen, as a positive cryptococcal antigen may precede the onset of clinical cryptococcal meningitis by many weeks.

Individuals who are screened for cryptococcal disease should be managed as indicated in the table below. 

Treatment decisions for asymptomatic cryptococcal disease

Timing of ART for individuals with asymptomatic cryptococcal antigenemia is unknown. We recommend initiation of ART 2-4 weeks after initiation of antifungal therapy in individuals who screen positive for serum CrAg without any evidence of disseminated cryptococcal meningitis.

Timing of ART in cryptococcal meningitis

The timing of the initiation of ART in patients with cryptococcal meningitis is still uncertain. Early initiation of ART is recommended for all Ols except for intracranial Ols such as TB meningitis and cryptococcal meningitis. In cryptococcal meningitis ART can be initiated 4- 6 weeks after initiation of antifungal therapy with amphotericin B based regimens. In patients who are predominately treated with fluconazole monotherapy ART should be initiated at least 4 weeks after initiation of antifungal therapy.

ART should not be commenced at the same time that amphotericin B and/or fluconazole therapy is commenced for cryptococcal meningitis.