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Guidelines for the treatment of opportunistic infections in adults and adolescents with HIV

Introduction

The institution of highly activate antiretroviral therapy (HAART) has witnessed a major impact on immune reconstitution: sustained increased in numbers of circulating CD4 T cells associated with a rapid drop in plasma viral RNA levels. The mechanisms proposed to explain the increase in numbers of CD4 T cells include cellular redistribution from lymphoid tissue, cellular proliferation of peripheral T cell pool, new T cell synthesis from a thymic source and reduced levels of apoptosis. However, despite the efficacy of these medications, treatment-limiting adverse events are frequent.

The following are treatment strategies currently being used against HIV infection.

Inhibit reverse transcriptase: (some reverse transcriptase inhibitors are known). One way to do this is to  use nucleotides which lack OH attachment site (AZT, DDI, DDC). A problem is that every cell has to duplicate its genome and needs DNA building blocks. Viral transcriptase come about that also are able to discriminate the OH nucleotides.

Nucleoside analog reverse-transcriptase inhibitors (NRTIS):

Nucleoside reverse transcriptase inhibitors (NRTIs) prevent HIV from replicating by blocking an enzyme called reverse transcriptase. This reduces the viral load of HIV in a person’s body.

Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were the first class of drugs to be approved by the FDA. They are adminsitered as prodrugs, whihch require host cell entry and phosphorylation. Lack of a 3’hydroxyl group at the sugar (2′-deoxyribosyl) moeity of the NRTIs prevents the formation of a 3′-5′ phosphodiester bond between the NRTIs and incoming 5’nucleoside triphosphates, resulting in temrination of the growing viral DNA chain. Cahin temrination can occur during RNA-dependent DNA or DNA-dependent DNA synthesis, inhibiting prouction of either the (-) or (+) strands of the HIV-1 proviral DNA. (Hazuda “HIV-1 antiretroviral drug therpay” 2012).

Zidovudine (INN) or azidothymidine (AZT) (also called ZDV) is a nucleoside analog reverse-transcriptase inhibitor (NRTI). AZT inhibits the enzyme (reverse transcriptase) that HIV uses to synthesize DNA, thus preventing viral DNA from forming.

Efavirenz (EFV, brand names Sustiva, Stocrin, Efavir etc.) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) discovered at Merck Research Laboratories.

Tenofovir (marked as Viread by Gilead Sciences): Tenofovir is also available in a fixed-dose combination tablet called  Truvad which contains 300 mg tenofovir and 200 mg FTC (emtricitabine, Emtriva) and approved in the US August 2004.

–Integrase strand transfer inhibitor (INSTI )+Nucleoside reverse transcriptase inhibitor (NRTI):

Dolutegravir + Lamivudine: (Dovato) is a once-daily, single-pill, 2-drug regimen (2DR) that combines the integrase strand transfer inhibitor (INSTI) dolutegravir (Tivicay, 50 mg) with the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine. Like a traditional 3-drug regimen, Dovato uses two medicines to inhibit the viral cycle at two different sites. INSTIs, like dolutegravir, inhibit HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. Lamivudine is an NRTI that works by interfering with the conversion of viral ribonucleic acid (RNA) into deoxyribonucleic acid (DNA) which in turn stops the virus from multiplying. (Epivir, 300 mg). See GSK

Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) prevent HIV from replicating by binding to and altering reverse transcriptase, which HIV uses to replicate. This reduces the viral load of HIV in the person’s body.

NNRTIs inhibit HIV-1 RT by binding and inducing the formation of a hydrophobic pocket proximal to, but not overalpping the activate site. The binding of NNRTIs changes the sptial conformation of the substrate binding site and reduces polyemrase activity. (Hazuda “HIV-1 antiretroviral drug therpay” 2012)

Currently, there are four apporved NNRTIs; etravirine, delarirdine, efavirenz, and nevirapine. Others are in development. (Hazuda “HIV-1 antiretroviral drug therpay” 2012)

NNRTI resistance generally results form amino acid substitutions such as L100 in the NNRTI binding pocket of RT. (Hazuda “HIV-1 antiretroviral drug therpay” 2012)

  Combination Therapies:

Atripla,Virady: Efavirenz was combined with Truvada, which consists of tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications was approved by the  FDA in July 2006 under the brand name Atripla and provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients. Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

Stribild: contains a combination of cobicistat, elvitegravir, emtricitabine and tenofovir: Cobicistat reduces the action of enzymes in the liver that break down antiviral medicines which allows such medicines to be used more safely and effectively at lower doses.

Complera: combines emtricitabine/rilpivirine/tenofovir disoproxil fumarate for use in certain virologically suppressed (HIV RNA,50 copies/mL) adult patients on a stable antiretroviral regimen. Complera was first approved in 2011 for patients new to therapy and is now one of the most widely prescribed HIV regimens in the US. The products contains Gilead’s Truvada, which itself is a fixed dose combination of two HIV medicines and Janssen R&D Ireland’s rilpivirine (marketed as Edurat).

Protease inhibitors: 

HIV protease inhibitors act during the late stage of the HIV-1 viral cycle by inactivating the HIV-1-encoded aspartyl protease and preventing the cleavage of Gag and Gag-Pol proteins, thereby inhibiting the production of mature infectious HIV-1 virions. (Indinavir, Lamivudine,nelphinavir, ritonavir, saquinirir, stavudine) Although not a cure, these drugs have shown reduction of viral RNA. Protease inhibitors cause substantial increases in CD4+ T-cell counts (both naive and memory cells) in HIV-infected patients.

Because of its vital role in the life cycle of HIV-1 and relatively small size, it was initially expected that resistance to protease inhibitors would be rare. However, the protease gene ahs great plasticity, with polymorphisms observed in 49 of the 99 condons, and more than 20 substituitons known to be associated with resistance. (Hazuda “HIV-1 antiretroviral drug therpay” 2012)

Atazanavir sulfate, marketed as Reyataz, has been used since 2003. Bristol-Myers Squibb Company has filed an NDA for a fixed dose combination of Reyatax® and a pharmacokinetic enhancer called cobicistat which is being developed by Gilead Sciences, Inc., on April 4, 2014. It would offer a single tablet that would elminate the need to take a boosting agent in a separate tablet.

Pre-exposure Prophylaxis (Prep):

Descovy: tenofovir alafenamide and emtricitabine. Descovy comes as a tablet in one strength: 200 mg of emtricitabine/25 mg of tenofovir alafenamide. One tablet is taken daily for either HIV treatment or HIV PrEP. Descovy (emtricitabine and tenofovir alafenamide) is also used for Pre-Exposure Prophylaxis and treatment for HIV-positive individuals.

Descovy is approved by th FDA for a pre-exposure prophylaxis (“PrEP”) indication to reduce the risk of sexually aquired HIV-1 infection in certain at-risk patients.

Truvada: emtricitabine and tenofovir disoproxil fumarate. Truvada (emtricitabine/ tenofovir disoproxil fumarate) is a medication used for Post-Exposure Prophylaxis, Pre-Exposure Prophylaxis and treatment for HIV-positive individuals.

Post exposure Prophylaxis

PEP (Truvada plus Raltegravir) is prescribed for 28 days.  A ‘stat pack’ for 3-7 days is given in the emergency department and prescriptions are given for the remainder of the days.

Pre-exposure prophylaxis (PrEP):

People who took HIV pre-exposure prophylaxis (PrEP) “on demand” — that is, before and after sex — were just as likely to prevent HIV infection as people who took PrEP once a day according to a new study.

On-demand PrEP has been endorsed by the World Health Organization, the British HIV Association, the European AIDS Clinical Society and the International AIDS Society-USA. This regimen is not yet approved by the US Food and Drug Administration or recommended by the US Centers for Disease Prevention and Control, but some American providers are already offering it as an option in addition to daily PrEP. See Aidsmap