Antiretroviral Therapy (ART) Dr S Ntshalintshali Ngwelezana hospital November 2016

HIV prevalence in RSA The national estimate for HIV prevalence among South Africans in 2012 was 12.2% (95% CI: 11.4–13.1). This estimate is statistically significantly different (p<0.001), from the 2008 national estimate of 10.6% (95% CI: 9.8–11.6). In absolute numbers, there has been a significant increase of almost 1.2 million more people living with HIV in South Africa, an increase from 5,253,493 PLHIV in the 2008 to 6,422,179 PLHIV in 2012.

HIV virion

HIV replication 1. Binding and Fusion 2. Reverse Transcription and Integration 3. Transcription and Translation 4. Assembly, Budding and Maturation

Objectives of ART - Reduce HIV-related morbidity and prolong survival - Improve quality of life - Restore and preserve immunologic function - Maximally and durably suppress viral load - Prevent vertical HIV transmission

ART classes 2. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Block RT before HIV genetic code combines with infected cell’s genetic code Mimic building blocks used by RT to copy HIV genetic material, so disrupt copying of HIV genetic code 2. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Physically prevent RT from working. 3. Protease Inhibitors (PIs) Block protease enzyme that cuts long protein strands into small functional proteins and enzymes needed to assemble mature virus Prevent maturation of new viral particles

ART classes cont… 4. Fusion Inhibitors (FIs) 5. CCR5 Antagonists Block fusion of HIV with cell membrane preventing HIV ‘s ability to infect cells 5. CCR5 Antagonists Bind to and block the CCR5 co-receptor of the immune cell, thereby preventing HIV from entering and infecting the cell 6. Integrase inhibitors Prevent integration of HIV DNA into the nucleus of infected cells

ART classes in clinical trials - Gene therapies- block HIV genes. - Maturation inhibitors- inhibit development of HIV’s internal structures in new virions. - Zinc finger inhibitors- break apart structures holding HIV inner core together. - Antisense drugs- mirror HIV genetic code, lock onto virus and block replication.

Current ART NRTI: Abacavir, Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zidovudine. NNRTI: Delavirdine, Efavirenz, Etravirine, Nevirapine. PI: Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir. Fusion inhibitor: Enfuvirtide Receptor antagonist: Maraviroc Integrase inhibitor: Raltegravir

Factors to Consider in Selecting Initial ART Regimen - Comorbidity : Renal, psychiatric, and liver impairment. - Patient adherence potential - Convenience :pill burden, dosing frequency, and food and fluid considerations. - Potential adverse drug effects and drug interactions with other medications: TB treatment (avoid NVP). - Pregnancy potential: Favours NVP instead of EFV

Eligibility criteria – RSA guidelines 2015 When to start ART? Eligibility criteria – RSA guidelines 2015 - CD4 count ≤ 500 cells/μL OR WHO stage 3 or 4 - Irrespective of CD4 count or clinical staging: All types of active TB disease, all pregnant and breastfeeding women, & Hepatitis B virus (HBV) co-infection. Fast track: - Immediate initiation: Pregnant or breastfeeding patients, once TB excluded - Within 7 days: Patients with CD4 < 200 cells/μL or Stage 4, irrespective of CD4 count. Delay initiation: Patients with cryptococcal meningitis (CM) or TB meningitis (TBM) : delay initiation of ART for 4 – 6 weeks. Patients with TB: If CD4 < 50 cells/μL, start ART at approximately 2 weeks, or If CD4 > 50 cells/μL, start ART at approximately 8 weeks

ART Regimens (RSA 2015 adult guidelines) All NEW PATIENTS eligible for ART, including: pregnant and breastfeeding women HBV or TB co- infection, adolescents > 15 years AND > 40 kg AND CrCl* > 80 mL/min > TDF + FTC (or 3TC) + EFV Provided as fixed dose combination (FDC) ------- Adults on d4T-based regimen: Change d4T to TDF if virally suppressed and eGFR**/CrCl > 50mL/min. If viral load (VL) > 1000, do NOT change, manage as potential treatment failure. Adolescents on (ABC or d4T) + 3TC + EFV: switch to FDC if > 15 years, weigh > 40 kg, CrCl > 80 mL/min, no proteinuria and virally suppressed (VL done within the last 8 weeks).

ART Regimen cont… Adolescent < 40 kg and < 15 years > ABC+3TC+EFV (Dose according to paediatric dosing chart). ------- Contraindications to EFV: Signicant psychiatric co-morbidities OR Intolerance to EFV OR EFV may impair daily functioning e.g. shift workers. > TDF + FTC (or 3TC) + NVP Contraindication to EFV and NVP: Baseline CD4 ≥ 250 for females, Baseline CD4 ≥ 400 in male patients. > TDF + FTC (or 3TC) + LPV/r

ART Regimen cont… Contraindication to TDF: Renal disease (eGFR/CrCl < 50 mL/min) or the use of other nephrotoxic drugs e.g. aminoglycosides (kanamycin, amikacin) > ABC + 3TC + EFV (or NVP) ------- Regimen 2 Failing on a TDF-based 1st line regimen: > Hepatitis B surface antigen (HBsAg) negative: AZT + 3TC + LPV/r > HBsAg positive: TDF + AZT + 3TC + LPV/r Failing on a d4T- or AZT-based 1st line regimen: > TDF + 3TC (or FTC) + LPV/r

ART Regimen cont… Patients with anaemia and renal failure: > ABC + 3TC + LPV/r ------- Dyslipidaemia (Total Cholesterol > 6 mmol/L) or intractable diarrhoea associated with LPV/r > Switch LPV/r to ATV/r Failing any 2nd line regimen: > Specialist referral – Regimen should be chosen according to genotype resistance testing, managed by an expert panel. Third line drugs will be managed centrally

Thank you…